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FOURTH EDITION

KHAN’S

Treatment Planning in Radiation


Oncology
EDITORS

Faiz M. Khan, PhD


Professor Emeritus
Department of Radiation Oncology
University of Minnesota Medical School
Minneapolis, Minnesota

John P. Gibbons, PhD


Chief Medical Physicist
Department of Radiation Oncology
Ochsner Health System
New Orleans, Louisiana

Paul W. Sperduto, MD, MPP, FASTRO


Radiation Oncologist
Minneapolis Radiation Oncology
Minneapolis, Minnesota

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4th edition

Copyright © 2016 Wolters Kluwer

Copyright © 2012 Lippincott Williams & Wilkins, a Wolters Kluwer business. Copyright © 2006
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Library of Congress Cataloging-in-Publication Data


Names: Khan, Faiz M., editor. | Gibbons, John P., Jr., editor. | Sperduto,
Paul W., editor.
Title: Khan’s treatment planning in radiation oncology / editors, Faiz M. Khan,
John P. Gibbons, Paul W. Sperduto.
Other titles: Treatment planning in radiation oncology.
Description: Fourth edition. | Philadelphia : Wolters Kluwer [2016] |
Preceded by Treatment planning in radiation oncology / editors, Faiz M. Khan,
Bruce J. Gerbi. 3rd ed. c2012. | Includes bibliographical references and
index.
Identifiers: LCCN 2016004611 | ISBN 9781469889979
Subjects: | MESH: Neoplasms—radiotherapy | Radiotherapy Planning,
Computer-Assisted | Radiation Oncology—methods
Classification: LCC RC271.R3 | NLM QZ 269 | DDC 616.99/40642—dc23
LC record available at http://lccn.loc.gov/2016004611

This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied,
including any warranties as to accuracy, comprehensiveness, or currency of the content of this work.

This work is no substitute for individual patient assessment based upon healthcare professionals’
examination of each patient and consideration of, among other things, age, weight, gender, current
or prior medical conditions, medication history, laboratory data and other factors unique to the

4
patient. The publisher does not provide medical advice or guidance and this work is merely a
reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of
this work including all medical judgments and for any resulting diagnosis and treatments.

Given continuous, rapid advances in medical science and health information, independent
professional verification of medical diagnoses, indications, appropriate pharmaceutical selections
and dosages, and treatment options should be made and healthcare professionals should consult a
variety of sources. When prescribing medication, healthcare professionals are advised to consult the
product information sheet (the manufacturer’s package insert) accompanying each drug to verify,
among other things, conditions of use, warnings and side effects and identify any changes in dosage
schedule or contraindications, particularly if the medication to be administered is new, infrequently
used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no
responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a
matter of products liability, negligence law or otherwise, or from any reference to or use by any
person of this work.

LWW.com

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To Kathy, my wife and companion of fifty years:
Happy Anniversary, My Love.
—Faiz M. Khan

To my wife Nicole, for her continued patience and support


—John P. Gibbons

To Jody, Luke, Maria, and Will for their love and laughter and my patients who
provide me the privilege of caring for them in times of greatest need.
—Paul W. Sperduto

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Contributors

Judy A. Adams, CMD


Director of Dosimetry
Department of Radiation Oncology
Massachusetts General Hospital Cancer Center
Boston, Massachusetts

Fiori Alite, MD
Department of Radiation Oncology
Stritch School of Medicine
Loyola University
Maywood, Illinois

John A. Antolak, PhD


Associate Professor & Consultant
Department of Radiation Oncology
Mayo Clinic
Rochester, Minnesota

James M. Balter, PhD


Professor
Radiation Oncology Department
University of Michigan
Ann Arbor, Michigan

Christopher Beltran, PhD


Mayo Clinic
Department of Radiation Oncology
Rochester, Minnesota

Rachel C. Blitzblau, MD, PhD


Assistant Professor
Department of Radiation Oncology
Duke University School of Medicine
Attending Physician, Radiation Oncology
Duke University Medical Center
Durham, North Carolina

Stefan Both, PhD


Associate Attending
Medical Physics Department
Memorial Sloan Kettering Cancer Center
New York, New York

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Frank J. Bova, PhD, FACR, FAAPM, FAAPM
Albert E. and Birdie W. Professor of Computer-Assisted Stereotactic Neurosurgery
University of Florida College of Medicine
Gainesville, Florida

Jason Chan, MD
Resident in Training
Department of Radiation Oncology
University of California San Francisco
San Francisco, California

Albert Chang, MD, PhD


Assistant Professor in Residence
Departments of Radiation Oncology and Urology
University of California, San Francisco
San Francisco, California

George T. Y. Chen, PhD


Department of Radiation Oncology
Massachusetts General Hospital and Harvard Medical School
Boston, Massachusetts

Zhe (Jay) Chen, PhD


Professor
Department of Therapeutic Radiology
Yale University School of Medicine
Yale-New Haven Hospital
New Haven, Connecticut

Yen-Lin Evelyn Chen, MD


Instructor
Radiation Oncology
Massachusetts General Hospital
Boston, Massachusetts

James C. L. Chow, PhD


Assistant Professor
Department of Radiation Oncology
University of Toronto
Radiation Physicist
Radiation Medicine Program
Princess Margaret Cancer Center
Toronto, Ontario, Canada

Benjamin M. Clasie, MD
Resident Physician
Radiation Oncology
Rush University Medical Center

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Chicago, Illinois

Brian G. Czito, MD
Gary Hock and Lyn Proctor Associate Professor
Department of Radiation Oncology
Duke University Medical Center
Durham, North Carolina

Thomas F. DeLaney, MD, FASTRO


Andres Soriano Professor of Radiation Oncology
Harvard Medical School
Radiation Oncologist
Department of Radiation Oncology
Medical Director, Francis H. Burr Proton Therapy Center
Co-Director, Center for Sarcoma and Connective Tissue Oncology
Massachusetts General Hospital
Boston, Massachusetts

Lei Dong, PhD


Director, Chief of Medical Physics
Scripps Proton Therapy Center
Professor, Department of Radiation Medicine and Applied Sciences
University of California—San Diego
San Diego, California

Bahman Emami, MD, FACR, FASTRO


Professor
Department of Radiation Oncology
Loyola University Medical Center
Chicago, Illinois

Robert L. Foote, MD, FASTRO


Professor of Radiation Oncology
Mayo Medical School
Chair
Department of Radiation Oncology
Mayo Clinic
Rochester, Minnesota

Ryan D. Foster, PhD


Medical Physicist
Department of Radiation Oncology
Carolinas HealthCare System/Levine Cancer Institute
Concord, North Carolina

William A. Friedman, MD
Professor and Chair
Department of Neurosurgery

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University of Florida College of Medicine
Gainesville, Florida

Yolanda I. Garces, MD, MS


Consultant
Assistant Professor of Radiation Oncology
Mayo Clinic
Rochester, Minnesota

John P. Gibbons Jr, PhD


Chief Medical Physicist
Department of Radiation Oncology
Ochsner Health System
New Orleans, Louisiana

Eli Glatstein, MD, FASTRO


Emeritus Professor
Department of Radiation Oncology
University of Pennsylvania
Philadelphia, Pennsylvania

Vinai Gondi, MD
Co-Director, Brain & Spine Tumor Center
Northwestern Medicine Cancer Center, Warrenville
Warrenville, Illinois

Aditya N. Halthore, MD
Resident
Department of Radiation Medicine
Hofstra North Shore-LIJ School of Medicine
North Shore-LIJ Health System
Lake Success, New York

Andrew Jackson, PhD


Associate Attending Physicist
Medical Physics Computer Service
Memorial Sloan-Kettering Cancer Center
New York, New York

Julian Johnson, MD
Resident in Training
Department of Radiation Oncology
University of California San Francisco
San Francisco, California

James A. Kavanaugh, MS
Department of Radiation Oncology
Washington University in St. Louis
Director of Satellite Services

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Siteman Cancer Center
St. Louis, Missouri

Paul J. Keall, PhD


Professor and NHMRC Australian FellowDirector, Radiation Physics Laboratory
Central Clinical School
Sydney Medical School
The University of Sydney
New South Wales, Australia

Faiz M. Khan, PhD


Professor Emeritus
Department of Radiation Oncology
University of Minnesota Medical School
Minneapolis, Minnesota

Eric E. Klein, PhD


Professor
Department of Radiation Medicine
Northwell Health
Lake Success, New York

Jonathan P. S. Knisely, MD
Associate Professor
Department of Radiation Medicine
Northwell Health
Hofstra University School of Medicine
Lake Success, New York

Hanne M. Kooy, PhD


Associate Professor
Department of Radiation Oncology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts

Rupesh Kotecha, MD
Resident
Department of Radiation Oncology
Taussig Cancer Institute
Cleveland Clinic
Cleveland, Ohio

Gerald Kutcher, PhD


Professor
History Department
Binghamton University
State University of New York

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Binghamton, New York

Guang Li, PhD, DABR


Associate Member and Associate Attending Physicist
Department of Medical Physics
Memorial Sloan Kettering Cancer Center
New York, New York

Tony Lomax, PhD


Professor
Centre for Proton Therapy
Paul Scherrer Institute
Switzerland

Shannon M. MacDonald, MD
Associate Professor of Radiation Oncology
Massachusetts General Hospital/Harvard Medical School
Francis H. Burr Proton Therapy Center
Boston, Massachusetts

Gig S. Mageras, PhD


Member, Memorial Hospital
Memorial Sloan Kettering Cancer Center
Attending Physicist
Department of Medical Physics
Memorial Hospital
New York, New York

Amit Maity, MD, PhD


Professor
Department of Radiation Oncology
University of Pennsylvania
Philadelphia, Pennsylvania

Charles Mayo, PhD


Department of Radiation Oncology
University of Michigan
Ann Arbor, Michigan

Minesh P. Mehta, MD, FASTRO


Professor
Department of Radiation Oncology
University of Maryland School of Medicine
Baltimore, Maryland

Loren K. Mell, MD
Associate Professor
Department of Radiation Medicine and Applied Sciences
University of California San Diego

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La Jolla, California

Dimitris N. Mihailidis, PhD, FAAPM, FACMP, CAMC


Chief Medical Physicist
Cancer Center-Alliance Oncology
West Virginia University School of Medicine
Clinical Professor
Radiation Oncology
Charleston, West Virginia

Radhe Mohan, PhD


Professor
Department of Radiation Physics
University of Texas MD Anderson Cancer Center
Houston, Texas

Yvonne M. Mowery, MD, PhD


Resident Physician
Department of Radiation Oncology
Duke University School of Medicine
Resident Physician
Radiation Oncology
Duke University Medical Center
Durham, North Carolina

Arno J. Mundt, MD, FACRO, FASTRO


Professor and Chair
Department of Radiation Medicine & Applied Sciences
University of California San Diego
President, Radiating Hope Society Chair
American College of Radiation Oncology
San Diego, California

Sasa Mutic, PhD, FAAPM


Professor and Director of Medical Physics
Department of Radiation Oncology
Washington University School of Medicine
St. Louis, Missouri

Colin G. Orton, PhD


Professor Emeritus
Wayne State University
Detroit, Michigan

Manisha Palta, MD
Assistant Professor
Duke Cancer Institute
Department of Radiation Oncology

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Duke University Medical Center
Durham, North Carolina

Niko Papanikolaou, PhD


Professor and Chief
Division of Medical Physics
University of Texas Health Science Center at San Antonio
San Antonio, Texas

Anthony Paravati, MD, MBA


Resident in Radiation Oncology
Department of Radiation Medicine and Applied Sciences
Moores Cancer Center
University of California, San Diego
La Jolla, California

Charles A. Pelizzari, PhD


Associate Professor
Department of Radiation and Cellular Oncology
The University of Chicago Medical Center
Chicago, Illinois

Bradford A. Perez, MD
Resident
Duke Cancer Institute
Department of Radiation Oncology
Duke University Medical Center
Durham, North Carolina

John P. Plastaras, MD, PhD


Associate Professor
Department of Radiation Oncology
University of Pennsylvania
Philadelphia, Pennsylvania

Ezequiel Ramirez, MSRS, CMD, RT(R)(T)


Department of Radiation Oncology
University of Texas Southwestern Medical Center
Dallas, Texas

Mark J. Rivard, PhD, FAAPM


Professor of Radiation Oncology
Tufts University School of Medicine
Boston, Massachusetts

Gregory C. Sharp, PhD


Assistant Professor
Department of Radiation Oncology
Massachusetts General Hospital

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Boston, Massachusetts

Daniel R. Simpson, MD
Assistant Professor
Department of Radiation Medicine and Applied Sciences
Moores Cancer Center
UCSD School of Medicine
La Jolla, California

Chang W. Song, PhD


Professor Emeritus
Department of Radiation Oncology
University of Minnesota Medical School
Minneapolis, Minnesota

Paul W. Sperduto, MD, MPP, FASTRO


Medical Director, Minneapolis Radiation Oncology
Co-Director, University of Minnesota Gamma Knife Center
Minneapolis, Minnesota

Kevin L. Stephans, MD
Assistant Professor
Taussig Cancer Institute
Department of Radiation Oncology
Cleveland Clinic
Cleveland, Ohio

Kenneth R. Stevens Jr, MD


Professor Emeritus and Former Department Chair
Radiation Medicine Department
Oregon Health & Sciences University
Portland, Oregon

Alexander Sun, MD, FRCPC


Associate Professor
Department of Radiation Oncology
University of Toronto
Staff Radiation Oncologist
Princess Margaret Cancer Centre
Toronto, Canada

Nancy J. Tarbell, MD, FASTRO


CC Wang Professor of Radiation Oncology
Dean for Academic and Clinical Affairs
Harvard Medical School
Boston, Massachusetts

Bruce R. Thomadsen, PhD


Professor

15
Medical Physics
University of Wisconsin
Madison, Wisconsin

Robert Timmerman, MD
Professor, Vice Chair
Department of Radiation Oncology
University of Texas Southwestern Medical Center
Dallas, Texas

Wolfgang A. Tomé, PhD, FAAPM


Professor and Director of Medical Physics
Institute for Onco-Physics
Department of Radiation Oncology
Albert Einstein College of Medicine
Professor and Director
Division of Therapeutic Medical Physics
Department of Radiation Oncology
Montefiore Medical Center
Bronx, New York

Jordan A. Torok, MD
Resident Physician
Department of Radiation Oncology
Duke University School of Medicine
Duke Cancer Institute
Durham, North Carolina

Jan Unkelbach, PhD


Assistant Professor of Radiation Oncology
Harvard Medical School
Assistant Radiation Physicist
Department of Radiation Oncology
Massachusetts General Hospital
Boston, Massachusetts

Jacob (Jake) Van Dyk, BSc, MSc, FCCPM, FAAPM, FCOMP, DSc(hon)
Professor Emeritus
Oncology and Medical Biophysics
Western University
Former Manager/Head
Physics and Engineering
London Regional Cancer Program
London Health Sciences Centre
London, Ontario, Canada

Gregory M. M. Videtic, MD, CM, FRPC


Professor of Medicine

16
Cleveland Clinic Lerner College of Medicine
Staff Physician
Department of Radiation Oncology
Taussig Cancer Center
Cleveland Clinic
Cleveland, Ohio

Yi Wang, PhD
Instructor
Department of Radiation Oncology
Harvard Medical School
Medical Physicist
Radiation Oncology
Massachusetts General Hospital
Boston, Massachusetts

Kenneth J. Weeks, PhD


Medical Physicist
Federal Medical Center
Butner, North Carolina

Christopher G. Willett, MD, FASTRO


Professor and Chairman
Department of Radiation Oncology
Duke University
Durham, North Carolina

John A. Wolfgang, PhD


Physicist
Department of Radiation Oncology
Harvard Medical School
Massachusetts General Hospital
Boston, Massachusetts

Neil M. Woody, MD, MS


Resident
Department of Radiation Oncology
Taussig Cancer Institute
Cleveland Clinic
Cleveland, Ohio

Catheryn M. Yashar, MD, FACRO


Professor
Department of Radiation Medicine and Applied Sciences
University of California San Diego
San Diego, California

Fang-Fang Yin, PhD

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Professor
Department of Radiation Oncology
Duke Clinics
Durham, North Carolina

Darwin Yip, MD
Clinical Fellow
Department of Radiation Oncology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts

Sua Yoo, PhD


Associate Professor
Department of Radiation Oncology
Duke University Medical Center
Durham, North Carolina

Ellen D. Yorke, PhD


Attending Physicist and Member
Memorial Sloan Kettering Cancer Center
Department of Medical Physics
New York, New York

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Preface

The field of radiation oncology has advanced considerably since the advent of Intensity-
Modulated Radiation Therapy (IMRT) and related technologies such as Image-Guided
Radiation Therapy (IGRT), Volumetric-Modulated Arc Therapy (VMAT), and Stereotactic
Body Radiotherapy (SBRT). As a result of maturation of these techniques in the past
decade or so, their application in the treatment of various cancers has accelerated at a
rapid pace. Also, parallel to these developments, proton beam therapy has gained
widespread acceptance as an effective modality, especially in the treatment of pediatric
tumors and other malignancies where greater conformity of dose distribution is required
than possible with photons. Consequently, we invited some leading experts to write
about these latest developments in the field. It is our hope that the fourth edition will
bring our readers up-to-date with the state of the art in the physics, biology, and clinical
practice of radiation oncology.
This book provides a comprehensive discussion of the physical, biologic, and clinical
aspects of treatment planning. Because of its primary focus on treatment planning, it
covers this subject at a much greater depth than is the case with other books on medical
physics or radiation oncology. Like the previous editions, it is written for the benefit of
the entire treatment planning team—namely the radiation oncologist, medical physicist,
dosimetrist, and radiation therapist. A distinctive feature of this edition is the inclusion
of Key Points and Study Questions at the end of each chapter. This is intended to make
the book useful not only for the practitioners but also residents preparing for their
board examinations.
We acknowledge Julie Goolsby, Acquisitions Editor, Emilie Moyer, Senior Product
Development Editor, and other editorial staff of Wolters Kluwer for their support in the
development and production of this book.
Last but not the least, we wish to acknowledge the contributing authors whose
expertise and efforts are greatly appreciated. Their valuable contributions have made
this publication possible.

Faiz M. Khan
John P. Gibbons
Paul W. Sperduto

19
Preface to First Edition

Traditionally, treatment planning has been thought of as a way of devising beam


arrangements that will result in an acceptable isodose pattern within a patient’s
external contour. With the advent of computer technology and medical imaging,
treatment planning has developed into a sophisticated process whereby imaging
scanners are used to define target volume, simulators are used to outline treatment
volume, and computers are used to select optimal beam arrangements for treatment.
The results are displayed as isodose curves overlaid on multiple body cross-sections or
as isodose surfaces in three dimensions. The intent of the book is to review these
methodologies and present a modern version of the treatment planning process. The
emphasis is not on what is new and glamorous, but rather on techniques and
procedures that are considered to be the state of the art in providing the best possible
care for cancer patients.
Treatment Planning in Radiation Oncology provides a comprehensive discussion of the
clinical, physical, and technical aspects of treatment planning. We focus on the
application of physical and clinical concepts of treatment planning to solve treatment
planning problems routinely encountered in the clinic. Since basic physics and basic
radiation oncology are covered adequately in other textbooks, they are not included in
this book.
This book is written for radiation oncologists, physicists, and dosimetrists and will be
useful to both the novice and those experienced in the practice of radiation oncology.
Ample references are provided for those who would like to explore the subject in greater
detail.
We greatly appreciate the assistance of Sally Humphreys in managing this lengthy
project. She has been responsible for keeping the communication channels open among
the editors, the contributors, and the publisher.

Faiz M. Khan
Roger A. Potish

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Contents

Contributors
Preface
Preface to First Edition

SECTION I
Physics and Biology of Treatment Planning
CHAPTER 1 Introduction: Process, Equipment, and Personnel
Faiz M. Khan
CHAPTER 2 Imaging in Radiotherapy
George T.Y. Chen, Gregory C. Sharp, John A. Wolfgang, and Charles A.
Pelizzari
CHAPTER 3 Treatment Simulation
Dimitris N. Mihailidis and Niko Papanikolaou
CHAPTER 4 Treatment Planning Algorithms: Photon Dose Calculations
John P. Gibbons
CHAPTER 5 Treatment Planning Algorithms: Brachytherapy
Kenneth J. Weeks
CHAPTER 6 Treatment Planning Algorithms: Electron Beams
Faiz M. Khan
CHAPTER 7 Treatment Planning Algorithms: Proton Therapy
Hanne M. Kooy and Benjamin M. Clasie
CHAPTER 8 Commissioning and Quality Assurance
James A. Kavanaugh, Eric E. Klein, Sasa Mutic, and Jacob (Jake) Van Dyk
CHAPTER 9 Intensity-Modulated Radiation Therapy: Photons
Jan Unkelbach
CHAPTER 10 Intensity-Modulated Proton Therapy
Tony Lomax
CHAPTER 11 Patient and Organ Movement
Paul J. Keall and James M. Balter
CHAPTER 12 Image-Guided Radiation Therapy
Guang Li, Gig S. Mageras, Lei Dong, and Radhe Mohan
CHAPTER 13 Linac Radiosurgery: System Requirements, Procedures, and Testing
Frank J. Bova and William A. Friedman
CHAPTER 14 Stereotactic Ablative Radiotherapy

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Ryan D. Foster, Ezequiel Ramirez, and Robert D. Timmerman
CHAPTER 15 Low Dose-Rate Brachytherapy
Mark J. Rivard
CHAPTER 16 High Dose-Rate Brachytherapy Treatment Planning
Bruce R. Thomadsen
CHAPTER 17 Electron Beam Treatment Planning
John A. Antolak
CHAPTER 18 Proton Beam Therapy
Hanne M. Kooy and Judy A. Adams
CHAPTER 19 Role of Protons Versus Photons in Modern Radiotherapy: Clinical
Perspective
Darwin Yip, Yi Wang, and Thomas F. DeLaney
CHAPTER 20 Fractionation: Radiobiologic Principles and Clinical Practice
Colin G. Orton
CHAPTER 21 Radiobiology of Stereotactic Radiosurgery and Stereotactic Ablative
Radiotherapy
Paul W. Sperduto and Chang W. Song
CHAPTER 22 Tolerance of Normal Tissue to Therapeutic Radiation
Bahman Emami and Fiori Alite
CHAPTER 23 Treatment Plan Evaluation
Ellen D. Yorke, Andrew Jackson, and Gerald J. Kutcher

SECTION II

Treatment Planning for Specific Cancers


CHAPTER 24 Cancers of the Gastrointestinal Tract
Jordan A. Torok, Bradford A. Perez, Brian G. Czito, Christopher G. Willett,
Fang-Fang Yin, and Manisha Palta
CHAPTER 25 Gynecologic Malignancies
Anthony Paravati, Daniel R. Simpson, Loren K. Mell, Catheryn M. Yashar,
and Arno J. Mundt
CHAPTER 26A Cancer of the Genitourinary Tract: Prostate Cancer
Jason Chan and Albert Chang
CHAPTER 26B Genitourinary Cancers: Bladder Cancer
Julian Johnson and Albert Chang
CHAPTER 26C Cancers of the Genitourinary Tract: Testis
Julian Johnson and Albert Chang
CHAPTER 27 The Lymphomas
John P. Plastaras, Stefan Both, Amit Maity, and Eli Glatstein

22
CHAPTER 28 Cancers of the Head and Neck
Yolanda I. Garces, Charles Mayo, Christopher Beltran, and Robert L. Foote
CHAPTER 29 Cancers of the Skin, Including Mycosis Fungoides
Aditya N. Halthore, Kenneth R. Stevens Jr., James C. L. Chow, Zhe (Jay)
Chen, Alexander Sun, and Jonathan P. S. Knisely
CHAPTER 30 Breast Cancer
Yvonne M. Mowery, Sua Yoo, and Rachel C. Blitzblau
CHAPTER 31 Cancers of the Central Nervous System
Vinai Gondi, Wolfgang A. Tome, and Minesh P. Mehta
CHAPTER 32 Pediatric Malignancies
Shannon M. MacDonald and Nancy J. Tarbell
CHAPTER 33 Cancers of the Thorax/Lung
Gregory M. M. Videtic, Rupesh Kotecha, Neil M. Woody, and Kevin L.
Stephans
CHAPTER 34 Soft Tissue and Bone Sarcomas
Yen-Lin Chen and Thomas F. DeLaney

Index

23
SECTION I
Physics and Biology of Treatment
Planning

24
1 Introduction: Process, Equipment, and
Personnel

Faiz M. Khan

Every patient with cancer must have access to the best possible care regardless of constraints
such as geographic separation from adequate facilities and professional competence, economic
restrictions, cultural barriers, or methods of healthcare delivery. Suboptimal care is likely to
result in an unfavorable outcome for the patient, at greater expense for the patient and for
society.
—Blue Book (1)

INTRODUCTION
Radiotherapy procedure in itself does not guarantee any favorable outcome. It is
through meticulous planning and careful implementation of the needed treatment that
the potential benefits of radiotherapy can be realized. The ideas presented in this book
pertain to the clinical, physical, and technical aspects of procedures used in
radiotherapy treatment planning. Optimal planning and attention to details will make it
possible to fulfill the goal of the Blue Book, namely, to provide the best possible care for
every patient with cancer.

TREATMENT PLANNING PROCESS


Treatment planning is a process that involves the determination of treatment
parameters considered optimal in the management of a patient’s disease. In
radiotherapy, these parameters include target volume, dose-limiting structures,
treatment volume, dose prescription, dose fractionation, dose distribution, patient
positioning, treatment machine settings, online patient monitoring, and adjuvant
therapies. The final product of this activity is a blueprint for the treatment, to be
followed meticulously and precisely over several weeks.

TARGET VOLUME ASSESSMENT


Treatment planning starts right after the therapy decision is made and radiotherapy is
chosen as the treatment modality. The first step is to determine the tumor location and
its extent. The target volume, as it is called, consists of a volume that includes the tumor
(demonstrated through imaging or other means) and its occult spread to the
surrounding tissues or lymphatics. The determination of this volume and its precise
location is of paramount importance. Considering that radiotherapy is basically an
agent for local or regional tumor control, it is logical to believe that errors in target
volume assessment or its localization will cause radiotherapy failures.
Modern imaging modalities such as computed tomography (CT), magnetic resonance
imaging (MRI), ultrasound, single photon emission computed tomography (SPECT), and

25
positron emission tomography (PET) assist the radiation oncologist in the localization of
target volume. However, what is discernible in an image may not be the entire extent of
the tumor. Sufficient margins must be added to the demonstrable tumor to allow for
uncertainty in the imaging as well as microscopic spread, depending upon the invasive
characteristics of the tumor.
Next in importance to localization of the target volume is the localization of critical
structures. Again, modern imaging is greatly helpful in providing detailed anatomic
information. Although such information is available from standard anatomy atlases, its
extrapolation to a given patient is fraught with errors that are unacceptable in precision
radiotherapy.
Assessment of the target volume for radiotherapy is not as easy as it may sound. The
first and foremost difficulty is the fact that no imaging modality at the present time is
capable of revealing the entire extent of the tumor with its microscopic spread. The
visible tumor, usually seen through imaging, represents only a part of the tumor, called
the gross tumor volume (GTV). The volume that includes the entire tumor, namely, GTV,
and the invisible microscopic disease can be estimated only clinically and is therefore
called the clinical target volume (CTV).
The estimate of CTV is usually made by giving a suitable margin around the GTV to
include the occult disease. This process of assessing CTV is not precise because it is
subjective and depends entirely on one’s clinical judgment. Because it is an educated
guess at best, one should not be overly tight in assigning these margins around the GTV.
The assigned margins must be wide enough to ensure that the CTV thus designed
includes the entire tumor, including both the gross and the microscopic disease. If in
doubt, it is better to be more generous than too tight because missing a part of the
disease, however tiny, would certainly result in treatment failure.
Added to the inherent uncertainty of CTV are the uncertainties of target volume
localization in space and time. An image-based GTV, or the inferred CTV, does not have
static boundaries or shape. Its extent and location can change as a function of time
because of variations in patient setup, physiologic motion of internal organs, patient
breathing, and positioning instability. A planning target volume (PTV) is therefore
required, which should include the CTV plus suitable margins to account for the above
uncertainties. PTV, therefore, is the ultimate target volume—the primary focus of the
treatment planning and delivery. Adequate dose delivered to PTV at each treatment
session presumably assures adequate treatment of the entire disease-bearing volume, the
CTV.
Because of the importance of accurate determination of PTV and its localization, the
International Commission on Radiation Units and Measurements (ICRU) has come up
with a systematic approach to the whole process, as illustrated in Figures 1.1 and 1.2.
The reader is referred to ICRU Reports 50, 62, and 71 for the underlying concepts and
details of the system (2–4).

26
FIGURE 1.1 Schematic illustration of ICRU volumes. (From ICRU. Prescribing, Recording, and Reporting
Photon Beam Therapy. ICRU Report 50. Bethesda, MD: International Commission of Radiation Units and
Measurements; 1993.)

FIGURE 1.2 Schematic representation of ICRU volumes and margins. (From ICRU. Prescribing, Recording, and
Reporting Photon Beam Therapy [Supplement to ICRU Report 50]. ICRU Report 62. Bethesda, MD: International

27
Commission on Radiation Units and Measurements; 1999.)

Although sophisticated treatment techniques such as intensity-modulated radiation


therapy (IMRT) and image-guided radiation therapy (IGRT) are now available, which
account for organ motion and positional uncertainties as a function of time, the basic
problem still remains: How accurate is the CTV? Unless the CTV can be relied upon with
a high degree of certainty, various protocols to design PTV from it and the technical
advances to localize it precisely in space and time would seem rather arbitrary, illusory,
or even make-believe. Therefore, the need for technologic sophistication (with its added
cost and complexity) must be balanced with the inherent uncertainty of CTV for a given
disease.
However, the above, seemingly pessimistic view of the process should not discourage
the development or the use of these technologies. It should rather be taken as a
cautionary note for those who may pursue such technologies with a blind eye to their
limitations. Technologic advances must ultimately be evaluated in the context of
biologic advances. “Smart bombs” are not smart if they miss the target or, worse yet,
produce unacceptable collateral damage.
Treating the right target volume conformally with the right dose distribution and
fractionation is the primary goal of radiotherapy. It does not matter if this objective is
achieved with open beams or uniform-intensity wedged beams, compensators, IMRT, or
IGRT. As will be discussed in the following chapters, various technologies and
methodologies are currently available, which should be selected on the basis of their
ability to achieve the above radiotherapy goal for the given disease to be treated. In
some cases, simple arrangements such as a single beam, parallel-opposed beams, or
multiple beams, with or without wedges, are adequate, while in others IMRT or IGRT is
the treatment of choice.

EQUIPMENT
Treatment planning is a process essentially of optimization of therapeutic choices and
treatment techniques. This is all done in the context of available equipment. In the
absence of adequate or versatile equipment, optimization of treatment plans is difficult,
if not impossible. For example, if the best equipment in an institution is a cobalt unit or
a traditional low-energy (4 to 6 MV) linear accelerator, the choice of beam energy for
different patients and tumor sites cannot be optimized. If a good-quality simulator
(conventional or CT) is not available, accurate design of treatment fields, beam
positioning, and portal localization are not possible. Without modern imaging
equipment, high accuracy is not possible in the determination of target volumes and
critical structures, so that techniques that require conformal dose distributions in three
dimensions cannot be optimized. Accessibility to a reasonably sophisticated
computerized treatment planning system is essential to plan isodose distributions for
different techniques so as to select the one that is best suited for a given patient.
Therefore, the quality of treatment planning and the treatment itself depend on how
well equipped the facility is with regard to treatment units, imaging equipment, and
treatment planning computers.

External Beam Units

Low-Energy Megavoltage X-ray Beams


Low-energy megavoltage beams without IMRT capability (e.g., cobalt-60 and/or 4–6-MV

28
x-rays) are principally used for relatively shallow or moderately deep tumors such as in
the head and neck, breast, and extremities. For treatments using parallel-opposed
beams, the body thickness in the path of these beams should not exceed approximately
17 cm. This is dictated by the ratio of maximum peripheral dose to the midline dose (5).
In addition to the beam energy, it is also important to have machine specifications
that improve beam characteristics as well as accuracy of treatment delivery. Some of the
major specifications, for example, are isocentric capability with source-to-axis distance
of 100 cm (not less than 80 cm for cobalt-60), field size of at least 40 × 40 cm,
versatile and rigid treatment couch, asymmetrical collimators, MLCs, and other features
that allow optimization of treatment techniques.
For IMRT or IGRT techniques, a 6-MV x-ray beam is sufficient so far as the energy is
concerned. However, the unit must be equipped with a special collimator having
dynamic MLC or apertures suitable for these techniques. Its operation must be computer
controlled to allow for intensity-modulated beam delivery in accordance with the IMRT
or IGRT treatment plans.

Medium- or High-Energy Megavoltage X-ray Beams


X-ray beams in the energy range of 10 to 25 MV allow treatment techniques for deep-
seated tumors in the thorax, abdomen, or pelvis. For parallel-opposed beam techniques,
the deeper the tumor, the higher the energy required to maximize the dose to the tumor,
relative to the normal tissue. Again, the ratio of the maximum peripheral dose to the
midline dose is an important consideration (5). In addition, the dose buildup
characteristics of these beams allow substantial sparing of normal subcutaneous tissue
in the path of the beams.
One may argue that the degree of normal tissue sparing achieved by x-ray beams of
10 MV energy can also be achieved by lower megavoltage beams using more than two
beam directions, as in multiple isocentric fields, rotation therapy, or IMRT. However,
for deep-seated tumors, high-energy beams offer greater tissue sparing for all
techniques, including IMRT.

Charged-Particle Beams
1. Electrons. Electron beams in the range of 6 to 20 MeV are useful for treating
superficial tumors at depths of 5 cm. They are often used in conjunction with x-ray
beams, either as a boost or a mixed-beam treatment, to provide a particular isodose
distribution. The principal clinical applications include the treatment of skin and lip
cancers, chest wall irradiation, boost therapy for lymph nodes, and the treatment of
head and neck cancers.
Depth–dose characteristics of electron beams have unique features that allow effective
irradiation of relatively superficial cancers and almost complete sparing of normal
tissues beyond them. The availability of this modality is essential for optimizing
treatments of approximately 10% to 15% of cancers managed with radiotherapy.

2. Protons. Proton beam therapy has been used to treat almost all cancers that are
traditionally treated with x-rays and electrons (e.g., tumors of the brain, spine, head
and neck, breast, lung, gastrointestinal malignancies, prostate, and gynecologic
cancers). Because of the ability to obtain a high degree of conformity of dose
distribution to the target volume with practically no exit dose to the normal tissues, the
proton radiotherapy is an excellent option for tumors in close proximity of critical
structures such as tumors of the brain, eye, and spine. Also, protons give significantly
less integral dose than photons and, therefore, should be a preferred modality in the

29
treatment of pediatric tumors where there is always a concern for a possible
development of secondary malignancies during the lifetime of the patient.

3. Carbon ions. Efficacy of charged particles heavier than protons such as nuclei of
helium, carbon, nitrogen, neon, silicon, and argon has also been explored. Although
carbon ions or heavier charged particles have the potential to be just as good as
protons, if not better, it is debatable whether the benefits justify the high cost of such
machines. As it stands, for most institutions, even the acquisition of protons is hard to
justify over the far less expensive but very versatile megavoltage x-ray and electron
accelerators.
Protons and heavier charged particles no doubt have unique biologic and physical
properties, but “Are they clinically superior to x-rays and electrons with IMRT and IGRT
capabilities?” The answer awaits more experience. Clinical superiority of heavy charged
particles needs to be demonstrated by carefully conducted clinical trials.

Patient Load Versus Treatment Units


The number of patients treated on a given unit can be an important determinant of the
quality of care. Overloaded machines and overworked staff often give rise to suboptimal
techniques, inadequate care in patient setup, and a greater possibility of treatment
errors. As in any other human activity, rushed jobs do not yield the best results. In
radiotherapy, in which the name of the game is accuracy and precision, there is simply
no room for sloppiness, which can easily creep in if the technologist’s primary concern
is to keep up with the treatment schedule. An assembly line type of atmosphere should
never be allowed in a radiotherapy facility because it deprives the patients of their right
to receive the best possible care that radiotherapy has to offer.
A report like the Blue Book is the best forum for setting up guidelines for equipment
use. The recommendation of this document is that the load for a given megavoltage unit
should not exceed 6,000 standard treatments (single patient visit equivalent) per year.
Depending upon the complexity of procedures performed on a machine, its calibration
checks, and quality assurance, the patient load per megavoltage machine for full use
can vary from 20 to 30 patients treated per day. Details of calculating realistic load for
a megavoltage unit and criteria for replacing or acquiring additional equipment are
given in the Blue Book (1).

Brachytherapy Equipment
Brachytherapy is an important integral part of a radiotherapy program. Some tumors
are best treated with brachytherapy, alone or in conjunction with an external beam. It is
therefore important to have this modality available if optimal treatment planning is the
goal. Although electrons are sometimes used as an alternative, brachytherapy continues
to have an important role in treating certain tumors such as gynecologic malignancies,
oral cancers, sarcomas, prostate cancer, and brain tumors.
Currently, the sources most often being used are cesium-137 tubes, iridium-192 seeds
contained in ribbons, iodine-125 seeds, and palladium-103 seeds. These isotopes can be
used in after-loading techniques for interstitial as well as intracavitary implantation.
Numerous applicators and templates have been designed for conventional LDR
brachytherapy. The institution must follow a particular system consistently with all its
hardware, rules of implantation, and dose specification schemes. Remote after-loading
units, LDR as well as HDR, are becoming increasingly popular, especially among
institutions with large patient loads for brachytherapy. Brachytherapy hardware,

30
software, and techniques are discussed in later chapters.

Imaging Equipment
Modern treatment planning is intimately tied to imaging. Although all diagnostic
imaging equipments have some role in defining and localizing target volumes, the most
useful modalities currently are the CT, MRI, and PET.
Most radiotherapy institutions have access to these machines through diagnostic
departments. The only problem with this kind of arrangement is that the fidelity of
imaging data obtained under diagnostic conditions is quite poor when used for
treatment planning. This is caused primarily by the lack of reproducibility in patient
positioning. Besides appropriate modifications in the scanner equipment (e.g., flat
tabletop, patient positioning aids), the patient setup should be supervised by a member
of the treatment planning staff. With the growing demand for CT, 4-dimensional (4D)
CT (respiration-correlated), and MRI in radiotherapy and the large number of scans that
3-dimensional (3D) treatment planning requires, dedicated scanners in radiotherapy
departments are becoming the norm.

Simulator
There is still a role for conventional simulators in a radiation therapy department
although their presence is becoming less common. It is important that the simulator has
the same geometric accuracy as the treatment machine. In addition, it should allow the
simulation of various treatment techniques that is possible with modern treatment
machines.
With the advent of 3D treatment planning, conformal field shaping, MLCs, 4D CTs,
and electronic portal imaging, it is logical to move into CT simulation. A conventional
simulator may be useful for final verification of the field placement, but with the
availability of good-quality DRRs and special software for CT simulation, this need no
longer exists. Final field verification before treatment can be obtained with the portal
imaging system available on modern linacs.
CT scanners have been used for treatment planning for many years because of their
ability to image patient anatomy and gross tumor, slice by slice. These data can be
processed to view images in any plane or in three dimensions. In addition, CT numbers
can be correlated with tissue density, pixel by pixel, thereby allowing heterogeneity
corrections in treatment planning. The only drawback of diagnostic CT scans is that of
geometric accuracy of localization needed in radiotherapy. Diagnostic CT units, with
typically narrow apertures and curved tabletops, cannot reproduce patient positions
that would be used for treatment. Although variations due to positioning can be
minimized by using flat tabletops and units with wide aperture (e.g., 70 cm or larger
diameter), the personnel operating diagnostic equipment are not trained to set up
patients accurately to reproduce radiation therapy conditions. In addition, diagnostic
simulation units are usually too busy to allow sufficient time for therapy simulations.
Because of these technical and logistic problems, a dedicated CT scanner for radiation
therapy has gained wide acceptance.
A dedicated radiation therapy CT scanner, with accessories (e.g., flat table identical
with those of the treatment units, lasers for positioning, immobilization, and image
registration devices, etc.) to accurately reproduce treatment conditions, is called a CT-
simulator. Many types of such units are commercially available. Some of them are
designed specifically for radiation therapy with wide apertures (e.g., 85 cm diameter) to
provide flexibility in patient positioning for a variety of treatment setups. The CT image
data set thereby obtained, with precise localization of patient anatomy and tissue

31
density information, is useful not only in generating an accurate treatment plan, but
also in providing a reference for setting up treatment plan parameters. This process is
sometimes called virtual simulation.

Positron Emission Tomography/Computed Tomography


The physics of PET is based on the positron–electron annihilation into photons. For
example, a radiolabeled compound such as fluorodeoxyglucose (FDG) incorporates 18F
as the positron-emitting isotope. FDG is an analog of glucose that accumulates in
metabolically active cells. Because tumor cells are generally more active metabolically
than normal cells, an increased uptake of FDG is positively correlated with the presence
of tumor cells and their metabolic activity. When the positron is emitted by 18F, it
annihilates a nearby electron, with the emission of two 0.511-MeV photons in opposite
directions. These photons are detected by ring detectors placed in a circular gantry
surrounding the patient. From the detection of these photons, computer software (e.g.,
filtered back projection algorithm) reconstructs the site of the annihilation events and
the intervening anatomy. The site of increased FDG accumulation, with the surrounding
anatomy, is thereby imaged with a resolution of about 4 mm.
Combining PET with CT scanning has several advantages:
1. Superior quality CT images with their geometric accuracy in defining anatomy and
tissue density differences are combined with PET images to provide physiologic
imaging, thereby differentiating malignant tumors from the normal tissue on the basis
of their metabolic differences.
2. PET images may allow differentiation between benign and malignant lesions well
enough in some cases to permit tumor staging.
3. PET scanning may be used to follow changes in tumors that occur over time and with
therapy.
4. By using the same treatment table for a PET/CT scan, the patient is scanned by both
modalities without moving (only the table is moved between scanners). This
minimizes positioning errors in the scanned data sets from both units.
5. By fusing PET and CT images, the two modalities become complementary.
Although PET provides physiologic information about the tumor, it lacks correlative
anatomy and is inherently limited in resolution. CT, on the other hand, lacks
physiologic information but provides superior images of anatomy and localization.
Therefore, PET/CT provides combined images that are superior to either PET or CT
images alone.

Accelerator-Mounted Imaging Systems


After the treatment planning and simulation comes the critical step of accurate
treatment delivery of the planned treatment. Traditionally, patients are set up on the
treatment couch with the help of localization lasers and various identification marks on
the patient, for example, ink marks, tattoos, or palpable bony landmarks. Sometimes
identification marks are drawn on the body casts worn by the patient for
immobilization. These procedures would be considered reasonable, if only the patient
would not move within the cast and the ink or tattoo marks did not shift with the
stretch of the skin. Bony landmarks are relatively more reliable, but their location by
palpitation cannot be pinpointed to better than a few millimeters. Good immobilization
devices are critical in minimizing setup variations and are discussed later in the book.
With the introduction of 3D conformal radiation therapy (CRT), including IMRT and

32
IGRT, it has become increasingly apparent that the benefit of these technologies cannot
be fully realized if the patient setup and anatomy do not match the precision of the
treatment plan within acceptable limits at every treatment session. As the treatment
fields are made more conformal, the accuracy requirements of patient setup and the
PTV coverage during each treatment accordingly have to be made more stringent. These
requirements have propelled advances in the area of patient immobilization and
dynamic targeting of PTV through imaging systems mounted on the accelerators
themselves. Thus began the era of IGRT.
Each of the three major linear accelerator manufacturers, Varian, Elekta, and
Siemens, provide accelerator-mounted imaging systems allowing online treatment plan
verification and correction (adaptive radiation therapy) and dynamic targeting,
synchronized with the patient’s respiratory cycles (gating). The commercial names for
the systems are Trilogy (www.varian.com), Synergy (www.elekta.com), and ONCOR
(www.siemens.com). These products come with various options, some of which may be
works in progress or currently not FDA approved. The reader can get the updated
information by visiting the corresponding Web sites.
The important consideration in acquiring any of these systems is dictated by the
desire to provide state-of-the-art radiation therapy. Such a system is expected to have
the following capabilities:

1. 3D CRT with linac-based megavoltage photon beam(s) of appropriate energy (e.g., 6


to 18 MV)
2. Electron beam therapy with five or six different energies in the range of 6 to 20 MeV
3. IMRT, IGRT, and gated radiation therapy capabilities
4. Accelerator-mounted imaging equipment to allow the treatment techniques mentioned
earlier (such as IMRT and IGRT)
Typically, such a system consists of an electronic portal imaging device (EPID), a kVp
source for radiographic verification of setup, an online fluoroscopic mode to permit
overlaying of treatment field aperture on to the fluoroscopy image, and cone-beam CT
capability for treatment plan verification. Many of these devices and their use in
modern radiotherapy such as IGRT are discussed in the following chapters.

Treatment Planning Computers


Commercial treatment planning computers became available in the early 1970s. Some of
the early ones such as the Spear PC, the Artronix PC-12, Rad-8, Theratronics Theraplan,
and ADAC were instant hits and provided a quantum jump from manual to
computerized treatment planning. They served their purpose well in providing fast and
reasonably accurate 2-dimensional (2D) treatment plans. Typically, they allowed the
input (through the digitizer) of external patient contours, anatomic landmarks, and
outlines of the target volume and of the critical structures in a specified plane (usually
central). Beams were modeled semiempirically from the stored beam data obtained in a
water phantom. Various corrections were used to apply the water phantom data to the
patient situation, presenting irregular surfaces, tissue inhomogeneities, and multiple
beam angles. However, from today’s standards, the old systems would be considered
very limited in capability and rudimentary in the context of modern 3D treatment
planning.
With the explosion of computer and imaging technologies in the last 20 years or so,
the treatment planning computers and their algorithms have accordingly become more
powerful and sophisticated. Systems that are currently available allow 3D treatment

33
planning in which patient data obtained from CT scanning, MRI, PET, and so on, are to
be input electronically. Beams are modeled with sophisticated computational
algorithms, for example, pencil beam, convolution–superposition, semi Monte Carlo, or
full Monte Carlo. These algorithms for photons, electrons, and brachytherapy sources
are discussed in later chapters.
Besides major improvements in dose computational methods, there have been
revolutionary advances in software, which allow planning of complex treatments such
as 3D CRT, IMRT, IGRT, and HDR brachytherapy. One of the most powerful treatment
planning algorithms is called inverse planning, which allows the planner to specify the
desired dose distribution and let the computer generate a plan as close to the input
specifications as possible. Again, these techniques and algorithms are topics of
discussion later in the book.
Major 3D treatment planning systems that are commercially available are Pinnacle
(www.medical.philips.com), Eclipse (www.varian.com), and Computerized Medical
Systems (CMS; www.cms.stl.com). As these systems are constantly evolving and
undergoing revisions, the reader should be mindful of the fact that an older version of
any given system may not carry much resemblance to the newest version. Therefore,
anyone in the market for such a system needs to do some researching and check out
each system with its most current version. Also, because these systems and their
software are frequently revised and updated, the user is advised to carry a service
contract for maintenance as well as the option of receiving future updates as they come
along.

Staffing
The 1991 Blue Book has been updated by ASTRO to a new document, entitled Safety Is
No Accident: A Framework for Quality Radiation Oncology and Care (6). This book was
published in 2012 and is available online at https://www.astro.org/Clinical-
Practice/Patient-Safety/Blue-Book/bfp/index.html#/60. The new document
provides a blueprint for modern radiation oncology facilities in terms of structure,
process, and personnel requirements.
The basis for these recommendations is the fundamental principle that radiation
oncology practice requires a team of personnel with appropriate educational and
training background. Besides the physician specialists, the radiation oncologists,
radiotherapy requires the services of medical physicists, dosimetrists, therapists, and
nurses. The minimum level of staffing recommended is shown in Table 1.1. In the
specific areas of treatment planning, the key personnel are radiation oncologists,
medical physicists, and dosimetrists. The quality of treatment planning largely depends
on the strength of this team.

TABLE 1.1 Minimum Personnel Requirements for Clinical Radiation Therapya

34
Radiation Oncologist
The radiation oncologist, who has the ultimate responsibility for the care of the patient,
heads the treatment planning team. It is his or her responsibility to formulate the
overall plan for the treatment, including dose prescription to tumor-bearing sites of the
body. Details of the actual treatment technique, beam energies, beam directions, and
other specific details of the treatment are finalized after a number of isodose plans have
been calculated and an optimal plan has been selected. The final plan must meet the
approval of the radiation oncologist in charge of the patient.
The ACR standards require that the radiation oncologist be board-certified to practice
radiation oncology. In addition, the number of radiation oncologists in a given
institution must be in proportion to the patient load (Table 1.1). No more than 25 to 30
patients should be treated by a single physician. It is important to ensure that each
patient receives adequate care and attention from the physician and that the treatments
are not compromised because of the physician’s lack of time.

Medical Physicist
No other medical specialty draws as much from physics as radiation oncology. The
science of ionizing radiation is the province of physics, and its application to medicine

35
requires the services of a physics specialist, the medical physicist. It is the collaboration
between the radiation oncologist and the medical physicist that makes radiotherapy an
effective treatment modality for cancer. Ralston Paterson (7), emphasizing this
relationship, stated in 1963: “In radiotherapy the physicist who has given special study
to this field is full partner with the therapist, not only in the development of the
science, but in the day-to-day treatment of patients. The unit team, therefore, even for
the smallest department, consists of a radiotherapist and a physicist.”
The unit team of radiation oncologist and medical physicist must have a supporting
cast to provide radiotherapy service effectively to all patients referred to the
department. Dosimetrists, radiation therapists (previously called technologists), nurses,
and service engineers are the other members of the team. It must be recognized by all
concerned that without this infrastructure and adequate staffing in each area of
responsibility, radiotherapy is reduced to an ineffective, if not unsafe, modality of
treatment.
Adequacy of the support of physics has been spelled out in the ASTRO document (6).
The number of physicists required in a radiotherapy institution depends not only on the
number of patients treated per year but also on the complexity of the radiotherapy
services offered. For example, special procedures such as stereotactic radiotherapy,
HDR brachytherapy, total-body irradiation for bone marrow transplantation, 3D CRT,
IMRT, IGRT, SBRT, respiratory gating, TomoTherapy, CyberKnife treatments, and
intraoperative radiotherapy are all physics-intensive procedures and therefore require
more physicists as recommended by ASTRO.
According to the American Association of Physicists in Medicine (AAPM), a medical
physicist involved with clinical services must have a PhD or MS degree and be board
certified in the relevant specialty; in this case, radiation oncology physics. Also, most
physicists in an academic setting teach and do research, and therefore a doctorate
degree is more desirable for them. Such research plays a key role in the development of
new techniques and in bringing about new advances to radiation oncology. Paterson (7)
emphasized this role by stating “While the physicist has a day-to-day routine task in this
working out or checking of cases, it is important that he has time for study of special
problems. These may include the development of new x-ray techniques, the devising of
special applicators to simplify or assist treatment, the critical analysis of existing
techniques, or research work of a more fundamental nature.”
TABLE 1.2 Roles and Responsibilities of Physicists

A medical physicist’s role in radiotherapy is summarized in Table 1.2. Specifically in


treatment planning, the physicist has the overall responsibility of ensuring that the

36
treatment plan is accurate and scientifically valid. That means that the physicist is
responsible for testing the computer software and commissioning it for clinical use. He
or she is also responsible for proper interpretation of the treatment plan as it relates to
the dose distribution and calculation of treatment duration or monitor units.
One important role of a medical physicist that is often overlooked is that of a
consultant to radiation oncologists in the design of the treatment plan. Physicians
working directly with dosimetrists to generate a treatment plan without any significant
input from the physicist can often be seen. This process may be operationally smooth
and less costly but can be risky if serious errors go undetected and the final plan is not
optimal. It must be recognized that a qualified medical physicist, by virtue of education
and training, is the only professional on the radiotherapy team who is familiar with the
treatment planning algorithm and can authenticate the scientific validity of a computer
treatment plan. It is important that he or she be actively involved with the treatment
planning process and that the final plan receives his or her careful review. Because of
the tendency of some physicians to bypass the physicist, some institutions have
developed the policy of having the physicist present during simulation and doing the
treatment planning either personally or closely working with the dosimetrist in the
generation and optimization of the treatment plan.

Dosimetrist
Historically, dosimetrists were classified as physics personnel with a Bachelor of Science
degree in the physical sciences. They assisted physicists in routine clinical work such as
treatment planning, exposure time calculations, dosimetry, and quality assurance. They
could be called a physicist assistant, analogous to physician assistant.
Today the dosimetrist’s role is not much different, but the educational requirements
have been formalized to include certification by the Medical Dosimetrist Certification
Board (MDCB), in addition to a Bachelor’s Degree and graduation from an accredited
Medical Dosimetry training program.
As discussed earlier, the role of a dosimetrist is traditionally to assist the physicist in
all aspects of physics service. However, in some institutions, dosimetrists substitute for
physicists, and/or the treatment planning procedure is made the sole responsibility of
the dosimetrist with no supervision from the physicist. Whether it is done for economic
or practical reasons, leaving out the physicist from the treatment planning process is
not appropriate and definitely not in the best interest of the patient. The dosimetrist’s
role is to assist the physicist, not to replace him or her. The radiation oncologist must
understand that a computer treatment plan necessitates the physicist’s input and review
just as much as it necessitates consultation of other medical specialists in the diagnosis
and treatment of a patient.

REFERENCES
1. ISCRO. Radiation Oncology in Integrated Cancer Management: Report of the Inter-Society
Council for Radiation Oncology (Blue book). Reston, VA: American College of
Radiology; 1991.
2. ICRU. Prescribing, Recording, and Reporting Photon Beam Therapy. ICRU Report 50.
Bethesda, MD: International Commission on Radiation Units and Measurements;
1993.
3. ICRU. Prescribing, Recording, and Reporting Photon Beam Therapy (Supplement to ICRU
Report 50). ICRU Report 62. Bethesda, MD: International Commission on Radiation

37
Units and Measurements; 1999.
4. ICRU. Prescribing, Recording, and Reporting Electron Beam Therapy. ICRU Report 71.
Bethesda, MD: International Commission on Radiation Units and Measurements;
2004.
5. Khan FM, Gibbons JP. The Physics of Radiation Therapy. 5th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2014:179–180.
6. American Society for Radiation Oncology (ASTRO). Safety is No Accident: A
Framework for Quality Radiation Oncology and Care. Fairfax, VA: American Society
for Radiation Oncology; 2012. https://www.astro.org/clinical-practice/patient-
safety/safety-book/safety-is-no-accident.aspx
7. Paterson R. The Treatment of Malignant Disease by Radiotherapy. 2nd ed. Baltimore,
MD: Williams & Wilkins; 1963:527.

38
2 Imaging in Radiotherapy

George T.Y. Chen, Gregory C. Sharp, John A. Wolfgang, and Charles A. Pelizzari

INTRODUCTION
Imaging is the basis of modern radiotherapy; it plays a major role in disease
localization, treatment planning, guiding radiation delivery, and monitoring response.
While projection radiography was the backbone of medical imaging in the first 75 years
of its existence, transformative imaging advances in the 1970s led to visualizing patient
anatomy through computer assisted tomography. Soft tissue tumors can alter the spatial
relationships of normal organs, and with transverse 3-dimensional (3D) maps radiation
oncologists could assess target extent and proximity to sensitive organs at risk for
collateral damage. Shortly after the introduction of computed tomography (CT)
scanning in diagnostic radiology departments, radiation oncologists explored its
potential use in therapeutic radiology. Initial studies found tumor coverage was
marginal or inadequate in nearly one-half of patients studied (1). Advances in
volumetric imaging have continued to evolve, and today multimodality imaging
provides insight into tumor biochemistry and microenvironment normal organ function
as well as structure.
In parallel, advances in radiation delivery such as intensity modulated, charged-
particle-beam, and stereotactic body radiotherapy provided the capability to deliver
highly conformal doses to the 3D target using personalized anatomical maps (2–4).
Such delivery advances in turn increased the interest in the development of more
accurate methods to image and treat moving targets. Advances in treatment-room
imaging have further provided the capability of image-guided radiotherapy, where
images obtained on a daily basis before or during treatment can be used to correct for
variations in setup and organ motion. With advances in imaging and radiation
treatment, dose conformation has provided an opportunity to safely increase tumor
dose, thereby increasing the probability of tumor control, while minimizing dose to
normal radiation sensitive organs below thresholds of serious complications.
The general principles of medical image formation and clinical oncologic imaging are
described elsewhere (5,6). Observance of the centennial anniversary of the discovery of
x-rays has resulted in historical reviews (7,8). This chapter provides an overview of the
imaging modalities and image processing relevant to conformal external beam
radiotherapy.

IMAGE ACQUISITION
Volumetric Imaging
Imaging in radiotherapy is broadly categorized into acquired and processed images.
Figure 2.1 diagrammatically summarizes imaging modalities used in radiotherapy.
Imaging in radiotherapy is dominated by volumetric data sets from multiple modalities.
The modalities probe the body noninvasively, utilizing different physical interactions of
tissues and the probe modality. Each modality has its strengths and applications, and

39
complements the strengths of other imaging techniques. Volumetric image acquisition is
emphasized, although projection radiography has an important role in the clinic. Use of
advanced imaging technologies was surveyed and reported in 2009 (9).

Computed Tomography
CT is the primary imaging modality used in radiation oncology. The history and basic
principles of CT image formation are discussed elsewhere (5,10). Briefly, CT measures
the linear attenuation coefficient of each pixel in the transverse imaging plane. A fan
beam of diagnostic energy x-rays passes through the patient, and the transmitted
radiation is measured. Multiple projection views are acquired as the x-ray source rotates
around the patient. From these projections, image reconstruction algorithms generate a
transverse digital image. Each pixel value is a measurement of μx, the linear attenuation
coefficient (relative to water μw) at an effective diagnostic x-ray energy. At diagnostic
energies, the dominant photon/tissue interactions are the photoelectric and Compton
effects. Pixel values are quantified in Hounsfield units (HU):

For a single energy scan, the HUs associated with various body components are: air,
-1,000 HU; water, 0 HU; fat, ∼-80 HU; muscle, ∼30 HU, and bone variable up to or
greater than 1,000 HU. HUs of different tissues at diagnostic energies can be
approximately extrapolated to electron density values used for dose calculations (11).
Tissue characterization to separately unfold the atomic composition and electron
density per pixel can be performed with dual energy scanning (12), although most
radiotherapy planning scans are performed at a single x-ray potential. A possible need
for dual energy scanning is the calculation of charged particle stopping powers used in
proton and heavy ion radiotherapy.

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FIGURE 2.1 A: Imaging modalities acquired in radiation therapy; B: Image processing performed on acquired
images to extract and integrate information needed for treatment.

Figure 2.2 shows a human abdominal cadaver section compared to the corresponding
CT image (13). While delineation of an organ on CT will not exactly correspond to
photographic ground truth (14,15), CT can be geometrically very accurate. Early CT
scanners produced a single transaxial slice; 3D volumes were constructed by stacking
images. Multiplanar reconstruction of CT data provides the user with sagittal, coronal,
and oblique views.
Volumetric CT studies are acquired on CT-simulators within the department. These
devices are essentially diagnostic quality scanners with a slightly larger gantry opening
to accommodate treatment accessories. The resulting images are nearly the same quality
as those used in diagnosis, and provide images usually more than adequate for
radiation therapy planning.

CT Scan Acquisition for Treatment Planning


The volumetric CT scans are input into treatment planning, with the goal of calculating

41
the dose delivered at treatment. Thus, care is taken to position the patient as he/she will
be treated on the linear accelerator. Flat treatment couches are used rather than the
diagnostic scanner curved table-tops to ensure that internal organs closely approximate
their shape and location at treatment. Treatment immobilization devices are used
during the scan. High-speed scanning reduces motion artifacts and can capture a bolus
of contrast before dissipation.

FIGURE 2.2 A: Photographic transaxial section of a human abdomen from a cadaver. B: Corresponding CT
scan (courtesy Visible Human Project).

Three-dimensional CT acquisition modes include (a) axial and (b) helical mode. In
axial mode, the patient support assembly is static an image slice is acquired, the x-ray
source is then gated off, and the couch is advanced to the next longitudinal position.
The procedure is repeated to build a 3D image volume. In helical mode, the couch is
continuously advanced while the x-ray tube continuously rotates, leading to faster
volumetric scan acquisitions. The time to complete one rotation is ∼0.5 seconds.
Tagging the x-ray longitudinal coordinate with the image projection data and resorting
as the patient advances into the gantry provides the information needed for helical scan
image reconstruction.
A scan field of view (FOV) is selected to permit visualization of the external skin
contour, data needed for dose calculations. For sites such as head and neck, often two
FOVs are used: a smaller FOV for the neck, and a larger FOV to fully image the
shoulders. Longitudinal scan limits are chosen to capture both the tumor extent and
longitudinal extent of organs at risk. Slice thickness of 3 mm and a total of 200 slices
per scanning study are typical in planning scans.
Convention dictates that cross-sectional images are displayed as viewed from below;
for a patient in the supine position on the table, head first into the scanner gantry, the
image left is the patient’s right side. Icons and alphanumeric information imprinted on
the scan image provide details of pixel size, slice thickness, and radiographic
parameters used during imaging.

CT Artifacts
Artifacts can degrade CT planning studies (16). Artifacts may originate within the
patient. Beam hardening results in streaks when the photon beam crosses particularly
opaque regions, such as the bone in the posterior fossa of the brain, or metallic fillings
in teeth. Physiologic motion can also cause streak artifacts. Intravenous or oral contract
can artificially elevate HUs. These artifacts can perturb the calculation of radiographic
path length leading to inaccurate dose calculations. Artifacts can also originate within
the scanner hardware or by choice of imaging parameters. Partial volume sampling is
an artifact resulting from choice of slice thickness; too thick a slice influences the

42
detectability of small lesions. Other artifacts are introduced in helical or cone-beam
reconstructions.

Limitations of 3D Imaging of Moving Anatomy


Imaging organ motion is essential in conformally irradiating moving targets.
Quantifying motion can ensure adequate tumor coverage and unnecessary irradiation of
adjacent normal tissues. Conventional 3D imaging of moving anatomy may result in an
inaccurate depiction of organ shape and location. A motion artifact can frequently be
seen in a thoracic CT scan of a patient breathing lightly during a scan (17). Figure 2.3
is an example of such an artifact, where the lung/diaphragm interface is distorted.
Phantom studies under controlled conditions illustrate this temporal aliasing artifact
(18). The first column in Figure 2.4 is a photograph of test objects embedded in a foam
block. An initial scan is taken with the phantom stationary. Surface rendering of the
scan shows life-like realism, as seen in the second column. The phantom is then set into
motion simulating respiration, and scans are acquired in standard scan mode. The
resulting images of test objects are strikingly distorted, as shown in the next three
columns. For scale, the largest ball is 6 cm in diameter. With a motion amplitude of 1
cm (2 cm peak to peak), this sphere may be imaged with an inaccurate longitudinal axis
dimension as small as 4 cm. The distortion visualized is dependent on both scan and
object motion parameters as well as the respiratory phase at the instant the imaging
planes intersect the test object, which explains why distortions vary.

FIGURE 2.3 Temporal aliasing artifacts when scanning a patient during respiration. Note distortion at the
lung/diaphragm interface, indicated by yellow.

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FIGURE 2.4 Imaging test objects in a phantom. The objects are surface rendered when the phantom is static
and undergoing respiration simulated motion. Note the geometric distortions of the pear and balls.

4D CT Scanning
Four-dimensional (4D) CT scanning here is defined as CT acquisition at a respiratory
time scale. The objective of 4D CT scanning is to capture the shape and trajectory of
moving organs during breathing. The motion data can then be used to design an
aperture to encompass the observed motion, or to apply motion mitigation strategies
such as beam gating. Proof of principle of 4D scanning was initially prototyped on
single-slice scanners in 2003 (19–21). A multislice 4D CT simulator system became
commercially available shortly thereafter and rapidly became the scanner of choice for
radiation therapy (22).

FIGURE 2.5 Coronal MPRs of 4D liver tumor scan. Organs move craniocaudally (yellow reference line) at exhale
(A); at inhale (B); residual artifacts due to irregular breathing (C).

Respiration-correlated CT uses the motion of the abdominal surface, volume of air


measured by spirometry, or other respiratory surrogate signal to correlate the
respiratory state during CT acquisition of each slice. The signals are used to re-sort the
approximately 1,500 slices of reconstructed image data to a set of coherent
spatiotemporal CT data set corresponding to specific time points of the respiratory
cycle. A 4D CT acquisition requires a few minutes, and produces 10 static CT volumes,
each with a temporal separation of ∼one-tenth of the respiratory period (∼0.4
seconds). Details of the 4D CT acquisition methods and applications are described
elsewhere (22–24). Dose during a 4D CT scan is approximately five times that of a

44
conventional treatment planning scan, although studies have shown that this may be
reduced by altering the radiographic technique without significant reduction of motion
information (25).
Figure 2.5 displays coronal images of a 4D CT scanned for a liver tumor. The first two
images represent anatomy at exhale and inhale, showing a caudal movement of the
dome of the liver by several centimeters.
A 4D capable CT-simulator is suited for assessing organ motion at ∼1 second time
scale, but has insufficient temporal resolution to image cardiac motion. Ultrahigh-speed
cardiac scanners have shown that vessels and tumors near the heart can move by >1
cm (26) due to cardiac pulsation.
While an important advance, 4D CT acquisition can still have residual artifacts. Phase
resorting neglects variability of lung tidal volume during free breathing. Figure 2.5C
shows an example of an artifact from phase-based 4D CT resorting where breathing
amplitude was irregular. Respiratory variations in amplitude, periodicity, and trajectory
can perturb 4D scans. Strategies to coach breathing during 4D scanning have included
voice prompts and visual feedback but with variable success. Physical breathing control
has been attempted through abdominal compression or active breathing control, where
the patient breathes through a regulated valve and is forced to hold his breath at a
specific respiratory phase. This interventional approach reduces the 4D problem to a
static scenario, where both imaging and treatment are performed with minimal motion
(27,28).

Volumetric Imaging in the Treatment Room


The interest in precision radiotherapy spurred x-ray volumetric image acquisition in the
treatment room. As this topic is covered in detail in the chapter on Image Guided
Radiotherapy, we briefly cover selected highlights of image-guided therapy.
CT scanning in the treatment room was extensively used to study prostate and
seminal vesicle volume over a protracted treatment regimen (29). The study acquired
over 360 CT scans in 15 patients at a 3-scan-per-week rate. The patient is initially set
up on the treatment couch and CT scanned in room (with the scanner advancing along
the patient’s longitudinal axis by translating on rails). After tumor localization, the
patient support assembly is rotated into treatment position. This solution provided a
stopgap volumetric imaging capability in the treatment room while other imaging
solutions were developed and refined.
The most common implementation in use today involves adding tomographic imaging
capability to the treatment machine. Much of the interest was spurred by investigators
at William Beaumont Hospital (30). An x-ray tube and flat panel detector are mounted
orthogonal to the treatment axis. The imaging approach is known as cone-beam
computed tomography (CBCT) because the imaging beam is divergent along the
longitudinal axis. Projection images for volumetric reconstruction are acquired at
multiple angles as the gantry is rotated around the patient in ∼1 minute.
Reconstruction algorithms optimized for CBCT are used to generate volumetric
anatomical maps. While diagnostic CT scanners still set the image quality standard,
CBCT images provide clinically useful information even in the presence of motion
during acquisition, radiation scatter, and mechanical isocenter wobble during scans. An
advance in in-room CBCT imaging was the development of 4D CBCT (31). Time-resolved
data can be obtained by sorting the acquired projection data into different temporal
bins according to respiratory motion phase in an approach similar to standard 4D CT.
A third approach to treatment room tomographic imaging is to use the MV treatment
beam itself. The therapeutic beam serves as the radiation source and a flat panel

45
radiation detector to acquire image projections (32). Although soft tissue contrast is
reduced in the megavoltage CBCT images, there is adequate information for patient
positioning. MV CT is less susceptible to imaging artifacts due to high-density objects
such as metallic hip implants or dental fillings. As with other tomography imaging,
CBCT is affected by motion during data acquisition.
Innovative integrated imaging/treatment hardware has also been developed.
Tomotherapy (33) incorporates fundamental principles of CT imaging into a
megavoltage treatment system. IMRT is delivered slice by slice as radiation intensity
across the slice is modulated by shutters. Rotation around the patient similar to CT
acquisition produces highly conformal MV dose distributions. An unmodulated fan
beam can generate an MVCT image before treatment for image guidance. The
Cyberknife (34) is another approach; a compact linear accelerator is mounted on an
industrial robotic arm. The robotic arm covers more patient solid angle than a
conventional linac, and enables irradiation from noncoplanar angles. Image guidance is
provided by room-mounted x-ray tubes and digital image receptors, providing real-time
2D fluoroscopic imaging. The system has been used to “track” motion of tumors in the
lung and abdomen by following radio-opaque markers.

Magnetic Resonance Imaging


Magnetic resonance imaging probes the body with magnetic and RF radiation, providing
a spatial map of the bulk magnetization of a voxel. Acquisition sequences can be
tailored to vary image contrast and content. The most commonly acquired MRI scans
are proton density, T1- and T2-weighted images. T1, T2 notation refers to spin–lattice
and spin–spin relaxation times, time constant associated with nuclear magnetic moment
reorientation after excitation to an elevated energy state. Factors that influence image
appearance include the proton density within the voxel, relaxation times, blood flow,
and magnetic susceptibility (5,6). Spin density and relaxation times of soft tissues vary
considerably depending on microenvironment, leading to images with superior contrast
resolution in comparison to CT. Figure 2.6 shows CT and MRI scans of an abdominal
scan of a patient at the same anatomical level.
MRI contrast agents are paramagnetic materials that have unpaired electrons,
resulting in magnetic susceptibility. These materials alter the T1 and T2 relaxation
rates. Gadolinium chelates are used as contrast media for brain imaging when a
breakdown of the blood–brain barrier is suspected.

FIGURE 2.6 CT and proton density weighted MRI scan of patient with liver tumor, at approximately the

46
same anatomical level. Lesion is well visualized in the MRI due to superior soft tissue contrast. Bone in CT
(white) appears dark on MRI. Fat, due to its high hydrogen content, appears brighter on MRI.

MRI Artifacts
Magnetic field inhomogeneity, RF field spatial distribution, and effects associated with
rapidly changing magnetic field gradients can cause artifacts in MRI images. Artifacts
due to magnetic field inhomogeneity can result in geometric distortion, which leads to
slight differences in geometric scale along image axes. Foreign materials also result in a
local geometric distortion. On MRI, surgical clip artifacts result in loss of signal and
spatial distortion, even when the metallic fragments are small. With patient motion,
multiple ghosts in the image may appear. Treatment planning scans using MRI must
therefore pay particular attention to geometric distortions (35,36). Phantoms may be
useful to calibrate MR scanners, but in vivo variations are difficult to correct. Often, a
CT scan is also available, and direct comparison provides a measure of determining
geometric integrity.

Target Delineation with MRI


MRI is useful in delineation of tumors and normal structures of the brain (35,37). In
comparing CT and MRI with stereotactic biopsies, investigations found that both CT and
MRI defined gross tumor by their contrast enhanced ring, but T2-weighted MRI detected
a larger edematous region containing infiltrating tumor.
Isotropic margins for high-grade gliomas (1 to 2 cm) are commonly used. Diffusion
tensor imaging (DTI) is an MR technique sensitive to disruptions of white matter tracts
resulting from tumor infiltration. A current hypothesis is that such data can predict
areas of potential tumor involvement along structural pathways (37,38), increasing CTV
delineation accuracy.
Cine MRI has been used to study organ motion (39–41). Patients are scanned every
few seconds in the selected anatomical plane for up to 1 hour, during which physiologic
motion in them is visualized. Advantages of MRI over CT in studying motion include no
radiation dose and direct imaging in the plane of interest. These studies revealed
information on the range of organ motion and distortion possible over a treatment time
interval.

Functional Magnetic Resonance Imaging


Functional MRI (fMRI) reveals physiologic and neurologic activity in contrast to
structural information (42). When a task is performed, oxygen demand in the region of
the brain controlling the activity rises, resulting in a net increase in oxyhemoglobin.
Since deoxyhemoglobin is paramagnetic, changes from increased blood flow result in
changes in the signal. Functional imaging of the brain has been used to map the human
visual system during visual stimulation, language processing areas, and sensory and
motor cortex (43,44).
If the neuropsychologic activation sites of a specific patient are localized before
treatment planning, it may be possible to avoid irradiating these eloquent areas during
focal radiotherapy. Figure 2.7A shows an image of a patient with an astrocytoma in the
left parietal region. fMRI was used to identify an area during silent word generation,
finger movement, tactile stimulation, and other motor functions. Dose calculations
performed showed dose to certain functional areas could be reduced (45) by shifting
dose to another less critical area.

Magnetic Resonance Spectroscopic Imaging

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The dominant MR signals result from the 1H nuclei of water. Suppression of water
signals permits the measurement and analysis of other compounds. Spectroscopy was
initially limited to small regions of interest but technology has evolved in imaging
multiple voxels. For each voxel, the MR spectrum then reveals the chemical
composition. Differences in metabolite concentrations—either observed by peak heights
or peak ratios of different peaks—can be used to characterize the tissue. Application of
MRSI imaging in radiation therapy includes applications to characterize brain and
prostate tumors (46,47).

FIGURE 2.7 A: fMRI scan showing proximity of brain tumor to eloquent areas of the brain. The functional
areas (silent word generation, motor cortex controlling finger/hand) were labeled OAR areas and dose was
optimized to spare regions. B: Metastatic lymph nodes (yellow) are mapped on to pelvic vessels using a
lymphotropic iron nanoparticle contrast agent. The prostate (green) and seminal vesicles (gold) are also shown.
Left – AP view; Right – LPO view.

An example of combining functional and spectroscopic imaging in the treatment of


brain tumors has been reported (48). This feasibility study involved patients whose
target volume was defined in part by MRSI (by detecting voxels with a choline:creatine
ratio associated with tumors) and functional areas of the brain. This general approach
was proposed by Ling et al. (49) decades ago when the technology for studies were
evolving. The authors reported that the combination of these special imaging
procedures complemented conventional CT and MRI studies with the potential of dose
painting.

Lymph Node Visualization in the Pelvis


Nodal metastases from prostate cancer are primarily located along the major pelvic
vasculature. Defining nodal irradiation treatment portals based on vascular rather than
bony anatomy could decrease the irradiation of normal pelvic tissues, thereby reducing
toxicity.
An experimental MRI imaging technique is visualization of lymph nodes with iron
nanoparticles. Lymphotropic nanoparticle-enhanced magnetic resonance imaging has
been shown to identify the location and extent of the lymphatic system involved with
cancer. Nanoparticles increase contrast of the lymphatic system during optimized MRI
pulse sequences. Figure 2.7B shows lymph node distributions for prostate cancer (50).

MRI Imaging in the Treatment Room


With MRI’s superior soft tissue imaging, it is natural to explore its integration with
treatment machines. Two devices under development have been reported. The ViewRay
System (51) employs a low field strength MRI imaging system to provide volumetric
images. Treatment is delivered via a cobalt 60 triple headed system, capable of IMRT.

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Co-60 provides a nonferrous solution to avoid complexities associated with operating a
linear accelerator near a magnetic field. An alternative approach is the union of a
diagnostic MRI unit and a linear accelerator (52).

Emission Tomography
Emission tomography probes tumor biochemistry by measuring the biodistribution of
biologically active radiolabeled pharmaceuticals. Specific tracers can probe tumors for
hypoxia, the degree of cell proliferation, angiogenesis, apoptosis, and response to
therapy. These data complement anatomical and structural information from CT and
MRI, and may provide the data needed to identify tumor sub-volumes for dose painting.
The current status of functional and molecular imaging for radiotherapy is described in
a 2014 review (53).
Emission imaging is based on the detection of gamma rays emitted by intravenously
injected radiopharmaceuticals. Scintillators detect the γ-rays emitted and the resulting
visible light is amplified by photomultiplier tubes. Reconstruction of these signals
provides volumetric information on the 3D and 4D biodistribution of the administered
radiopharmaceutical. In SPECT imaging, single γ-emitting isotopes are administered,
while for PET, positron emitters are used. The positrons annihilate nearby electrons
with emission of opposed γ-rays. PET scanners include a ring of detectors to allow
simultaneous detection of the emitted γ-rays in the transverse plane. Volumetric data
sets are acquired at several couch positions, requiring several minutes at each position.

PET in Radiation Planning


PET is useful in staging disease and in defining the target volume. Its use in target
volume delineation in non-small cell lung cancer (54) has been prospectively studied.
Target volumes were drawn with and without the use of PET. The most common tracer
used is 18F-FDG, which identifies regions of high glucose metabolism, often associated
with tumors. In this study, use of PET altered the treatment volume in ∼60% of cases.
PET distinguished tumor from atelectasis (CT cannot), identified nodal disease in one-
third of patients, and identified additional tumor foci. Applications of PET in treatment
planning have been studied (55,56).
Cu-ATSM is a radiopharmaceutical labeled with a positron-emitting isotope of copper,
that has been shown to identify areas of tumor hypoxia. Identifying such regions could
be used to focus an additional boost radiation dose to control these historically radio-
resistant cells. Chao et al. (57) reported the feasibility of using Cu-ATSM in treatment
planning for head and neck tumors. By simulating hypoxic regions with a distribution
of the radiopharmaceutical localized by PET, they showed that additional dose could be
delivered by IMRT accurately after fusing the PET data with a planning CT.

PET/CT
The role of PET in radiation oncology has increased with the development of PET/CT
scanners. A PET/CT scanner is a mechanical union of a multislice CT scanner with a
PET scanner (58). By mechanical integration, technical image registration issues are
minimized, although data acquisition periods for the modalities differ. This significant
difference can result in ambiguities in bio-distributions that arise from different patient
positioning during scanning.
As with other tomographic imaging modalities, respiratory motion poses a challenge
to PET imaging. During the ∼20 minutes of data acquisition, periodic motion leads to
blurring of the reconstructed isotope distributions. Four-dimensional PET acquisition

49
has been reported (59,60). Data acquisition is performed in temporal correlation to
respiratory motion by labeling each detected event with the actual motion state.
Following encoded temporal data acquisition, reconstructions are performed using
temporal bins of detected events.

Imaging Response
The importance of imaging response to therapy is clear. For the individual patient, early
evidence of treatment ineffectiveness can prompt adjustments in treatment. In clinical
trials, evidence of the effectiveness of a new agent or technique can speed its approval
by regulatory agencies. Because overall survival from a therapeutic modality may
require decades to quantify, biomarkers that indicate response can indicate which
therapeutic approaches are most promising. Imaging both anatomical and biologic
response to treatment provides a noninvasive method to measure response. A current
standard for quantifying response is Response Evaluation Criteria in Solid Tumors
(RECIST) (61), which has been refined since its introduction 15 years ago. RECIST
applies unidimensional measurements to objectify response. Newer quantitative methods
for response evaluation (61,62) (PET, volumetric measurements) are considered to have
promise, but await standardization and validation before widespread adoption.

Other Imaging Techniques

Projection Imaging
Thus far, the focus has been on volumetric 3D/4D image acquisition. Two-dimensional
projection imaging still has an important role in radiotherapy. While limited in
visualizing soft tissues and 3D localization, it is useful in patient setup and quality
assurance.

Simulation Images
Conventional radiographic simulators generate 2D projection images and fluoroscopic
sequences. Historically, radiation oncologists outlined the region to be irradiated on
radiographs; cerrobend blocks were fabricated to shield uninvolved tissues. Today, with
3D simulation, 2D simulation workload has been reduced, and limited to simple setups
(e.g., palliative cases). A right lateral simulation radiograph for a metastatic brain lesion
is shown in Figure 2.8A. Bony anatomy and low-density areas, for example, airways, are
well visualized in projection radiography. Typically AP and lateral images are acquired
for field placement and treatment. If more complex oblique or noncoplanar beam angles
are used, reference films still provide data useful for confirming isocenter placement.
Fluoroscopic imaging on a digital simulator produces dynamic planar images that can
be used to estimate lung tumor motion in 2D. Conventional simulators also are used to
simulate the first treatment setup, known as a verification sim, to free linear
accelerators of lengthy first day setup.

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FIGURE 2.8 A: simulator radiograph of left lateral treatment field. B: Corresponding MV port film.

FIGURE 2.9 A: Ultrasound image to align prostate to isocenter. Contours from the planning scan are projected
onto daily ultrasound image. B: Surface imaging is used to align breast. The region of interest (purple) on
treatment day is aligned to the reference surface (acquired on first day or from simulation). The system
computes couch translation and rotation moves required to bring surface du jour to reference surface.

Quality Assurance Images


Treatment verification images are required once per week to verify setup. Historically, a
majority of verification films were acquired through MV planar imaging. Figure 2.8B is
such an image for verification of the port shown in the simulator film in Figure 2.8A.
Today, linacs have the flexibility to acquire verification images by 2D kV or MV imaging
or by CBCT. Critical setup verification (IMRT, SRS, SRT) is often performed using CBCT
scans on the treatment machine. Choice of modality for QA images primarily depends
on the Department’s preference.

Ultrasound
Ultrasound imaging has been used in prostate localization for image-guided therapy.
High-frequency sound waves, in the range of 1 to 10 MHz, are generated by a
piezoelectric crystal. A handheld ultrasound probe is positioned manually over the
suprapubic region. The US waves are reflected at tissue interfaces and used to generate
an anatomic image (63). Since the position of US probe is known in the machine
coordinate system, the required correction of the target to isocenter can be determined.
A typical radiotherapy ultrasound image for prostate alignment during external beam

51
conformal therapy is shown in Figure 2.9A. Use of ultrasound to image the prostate
prior to IMRT was a milestone in the utilization of routine IGRT. The technique was an
improvement over laser setup and bony landmark imaging. However, as other IGRT
approaches matured, studies showed systematic differences between US-guided setup
compared to radio-opaque implanted markers (64), leading to a shift away from its use.
The skill level needed to reproducibly identify and localize the prostate with US was
also a factor. In a 2009 study of image-guided therapy (65), approximately 20% of
radiation oncologists reported use of US in IGRT, although use over the years has fallen.

Surface Imaging
Video imaging to aid patient repositioning was proposed as early as 1970s (66). With
digital video imaging, a 3D map of the patient surface topology at simulation can be
captured. A corresponding 3D surface image is acquired on the treatment machine. In
3D video-guided setup, the patient surface du jour is brought into congruence with the
3D reference image in real time to provide setup correction. The key assumption in
surface-guided target setup is that reproducible repositioning of external surface leads
to precise subsurface target alignment.
A 3D video generated image is shown in Figure 2.9B. In this technology, stereo
cameras view the patient during a flash exposure of a projected speckle pattern. The
system reconstructs the surface topology to an accuracy of <1 mm (67). The surface at
treatment is fitted to a reference surface to determine the transformation needed to
bring the two surfaces into congruence. The system has been applied to the setup of
partial breast irradiation (68,69). Video also provides a nonionizing means of patient
position surveillance.

Image Processing
Acquired tomographic images undergo extensive processing to generate new
information. The data extracted from the acquired studies are utilized to determine the
size, shape, location, and motion of the target volume relative to adjacent normal
tissues. One of the most critical tasks of image processing is image segmentation.

Segmentation Nomenclature
Image segmentation involves the process of classifying regions by defining their
boundaries. The boundaries define organs or volumes associated with treatment
planning objectives. Nomenclature is important to ensure clear communication between
members of the treatment planning team within a department, and to facilitate
interinstitutional comparison and collaboration in clinical trials. Nomenclature
continues to evolve as more precise documentation of delivered dose is sought (70–74).
Table 2.1 lists basic abbreviations of target and organs at risk originating from ICRU
reports. The Gross Target Volume (GTV) localizes the visible tumor. The Clinical Target
Volume (CTV) includes a margin around the GTV to encompass microscopic tumor
extension. Planning Target Volumes (PTV) include geometric margins to account for
setup error, tumor motion, physiologic variability (e.g., variable bladder filling), and
other uncertainties. Organs at Risk (OARs) identify radiation sensitive structures to
which dose should be minimized to avoid collateral radiation injury. The Planning
Volume at Risk (PRV) is to be protected in dose optimization.
In an effort to more completely define volumes and sub-volumes, groups have
proposed additional nomenclature for radiation planning (75,76). One proposal
recommends additional descriptors to basic nomenclature to simultaneously identify

52
target and dose. For example, PTVp1_5000 would be used to identify the planning
target volume associated with primary tumor p1, to be treated to 5000 cGy. A Level 2
node clinical target volume treated to 4,000 cGy would be denoted as CTVn2_4000. For
OARs with additional geometric expansion margins (in case of setup uncertainty),
planning organs at risk volumes (PRVs) could be defined. For example, a left kidney
could be identified as: Kidney_L_10, denoting a 10-mm safety margin.
TABLE 2.1 Target and Normal Organ Volume Definitions

Segmentation
Volumes of interest can be segmented manually or automatically. In manual
segmentation, points are digitized by mouse on each transaxial CT scan and connected
by a closed contour. A 3D surface is created by tessellation. When a steep HU gradient
clearly identifies a boundary, simple threshold edge detection is used; the skin and
lung/chest wall interface are typically outlined by this method. However, threshold
edge detection fails when organ boundaries are fuzzy and indistinct, or when an organ
abuts another soft tissue. Since image segmentation is important to many medical
specialties, algorithms to perform accurate automated segmentation have been an area
of continued development in radiology and radiation oncology as well as in computer
science (77).
Newer algorithms apply more sophisticated approaches to image segmentation.
Information from anatomical atlases and databases has been used as well as methods
that apply statistical models of shape and appearance. Studies have evaluated machine
learning to teach computers to segment. Multimodality imaging combined with image
registration can sometimes be used to enhance the performance of automated
segmentation schemes. In evaluating the efficacy and accuracy of various automated
schemes, metrics have been proposed to compare performance with “ground truth”
(78).
Segmentation variability can also be traced to the radiation oncologist, who uses his
personal experience, clinical knowledge, findings documented in surgical notes, and
other sources in addition to the digital image data set to define the target. A study (79)
involving 12 physicians were asked to delineate a tumor and target volume on five
brain tumor cases; all were given the same image data. Variations of factors of 2 in
volume and 2 to 3 cm in location were observed.

Beam’s Eye View and Digitally Reconstructed Radiographs


The segmented target and normal tissues are used to build an interactive 3D model of

53
the patient’s anatomy. The concept of an interactive BEV was initially proposed by
McShan (80), who used planar tomography to extract skin, lung, and internal contours.
By adjusting the beam angle, it is often possible to geometrically avoid irradiation of a
critical organ. Goitein (81) advanced the concept to contiguous volumetric CT-based
treatment planning and further proposed using digitally reconstructed radiographs
(DRRs). A DRR is generated by 3D ray tracing from the radiation source through the
volume of CT data, projecting the resulting image onto a plane. Like a radiograph, the
DRR shows bony anatomy and low-density anatomy (airways, lung), providing an
internal anatomy backdrop for segmented organ contours. The DRR is the reference
image against which the IGRT radiograph is compared to make final adjustments in
treatment setup. A BEV of a thoracic tumor is shown in Figure 2.10.

FIGURE 2.10 BEV image of a thoracic tumor. Structure contours are segmented from a CT scan. Red: primary
tumor; violet: nodal areas. OARs include spinal cord (green), esophagus (yellow) and heart (light blue). Isocenter:
green crosshairs. Multileaf collimator vanes are step stair lines within the rectangular primary jaw opening. The
DRR shows bony structures and lung.

Image Registration
Image registration is the process that aligns different image data sets into a common
coordinate system. Reviews of medical image registration have been published (82,83).
We describe common approaches to image registration and their application to
radiation oncology.
Registration can be performed manually, semi-automatically, or fully automatically.
In manual registration, the user visually inspects and adjusts images interactively, by
sliding images over each other, or using a landmark tool to define matching points.
Interactive alignment in its basic form provides image alignment with three degrees of
freedom (translation). Semi-automatic tools allow for a limited degree of feedback from
the user, such as a starting guess or an incomplete set of matching points. Fully
automated methods can generate a transformation matrix without operator feedback,
but still require inspection of the final alignment to validate its correctness. Ideally,
image registration defines a one-to-one mapping between the coordinates of points in
one space with a corresponding point in the second space.
An important use of image registration is in multimodality imaging for target
delineation. Tumor extent may be more visible on MRI, but needs to be accurately
mapped into the CT coordinate system for treatment planning. Anatomic and fMRI or
PET volumes can also be defined and mapped onto CT scans for planning. Strategies for

54
daily IGRT also rely on image registration to bring the planned treatment and daily
setup into alignment. Correlation of multiple serial scans of a patient provides data on
movement of internal organs needed to determine appropriate portal margins. The
variation of prostate and seminal vesicle position during the course of fractionated
external beam therapy (84–86) through serial CT data sets first requires the serial CT
coordinate systems to be aligned relative to each other.

Automated Image Registration


In fully automatic image registration approaches, the user does not digitize landmarks
or contours, or interact with data. The images themselves provide the necessary
information. Automatic image registration methods are characterized by a transform and
cost function. The transform defines the nature of the mapping between spaces, and is
either linear (i.e., pure translation, rigid, and affine), or nonlinear (B-spline or free-
form). The cost function is a score that defines the relative quality of a match. The best
transform for a given cost function is selected using an optimizer that searches for the
best match.
Automated image registration in radiation oncology often utilizes maximization of
mutual information (or the converse—minimization of entropy). The utility of mutual
information is based on the intuitive assumption that while corresponding anatomical
regions may have different distributions of intensities in different imaging modalities,
the relationship between those intensities is predictable and consistent. For example,
bony anatomy is bright in a CT scan but dark in MRI; therefore one could map very
bright regions in a CT scan onto very dark regions in MRI. Mutual information
implicitly extends this idea to every location in the image through its mathematical
definition in terms of the joint probability density function of the matched images.
To illustrate how the joint probability distribution can characterize image matching,
consider the simplified illustration shown in Figure 2.11A, where a volumetric CT scan
and MRI scan of the same patient’s brain are to be matched. In this example, we assume
there are only four tissue types: air, bone, brain, and fat. Air is dark on both MRI and
CT; bone is bright on CT scan and dark on MRI; brain and fat are of intermediate
intensity in both modalities but their relative intensities are reversed. Brain is brighter
on CT and fat is brighter in MRI. Assume further that there is only one intensity value
associated with each tissue type. If the entire 3D image volumes were perfectly
registered, then every bone CT voxel would map onto a bone MR voxel, brain onto
brain, and so forth. We construct a joint histogram of the CT and MR intensities in
Figure 2.11B, where each point on the plane represents a single combination of CT and
MR intensity. The histogram would contain zeros everywhere except at the four points
corresponding to (CT bone, MR bone); (CT brain, MR brain); (CT air, MR air); and (CT
fat, MR fat).
If the image volumes were to become slightly misaligned, some CT bone voxels would
map onto MR brain voxels, introducing another peak in the joint histogram. Some MR
bone voxels would likewise map onto CT brain voxels, introducing yet another peak. In
fact, some voxels from each of the four CT tissue classes could map onto all four MR
voxel classes, leading to potentially 16 different peaks. Thus the effect of misalignment
is to reduce the sharpness of the joint histogram. The sharpness of such a distribution
can be expressed in terms of its entropy. The details of the mathematics are covered
elsewhere (87–89). Here we state that when the images are perfectly registered,
knowing that a voxel has the bone value in the CT scan means that the corresponding
voxel in the MR scan will have the MR bone value, with no uncertainty. In this case, the
entropy would be low and the mutual information would be high. The search for the

55
optimal transformation involves minimizing this score. Mutual information and its
variants have been used to register CT, MRI, PET, SPECT, and various 2D images
(anatomic and functional, radiographic, and photographic) with themselves and with
each other.

FIGURE 2.11 A: CT and MRI brain scan to be automatically registered. B: Joint intensity histogram of
simplified CT and MRI volumes when perfectly registered. Image intensities for four tissues considered: air,
bone, fat, brain. Misregistration of the scans broadens peaks in histogram.

Deformable Image Registration


An advance of image registration is the development of deformable image registration
(DIR). Applications of DIR include registration of interfractional patient scans (where
scans on different days may show organ shift and deformation), intrafractional
registration (at respiratory time scale), and multimodality image registration. An
overview of DIR for radiotherapy applications can be found elsewhere (90). Recently a
test data set representing ground truth was used to evaluate and validate the accuracy
of various approaches to DIR (91). The best performing algorithms mapped landmarks
to within a few millimeters of ground truth.
A useful application of DIR is the segmentation of organs in 4D CT data, which is
impractical without significant computer assistance. With DIR, it is feasible to
propagate contours of organs from one respiratory phase to another. Figure 2.12 shows
such an example. In this example, the liver was segmented by the physician on the T30

56
respiratory phase. To study organ deformation and perform 4D dose calculations, it is
necessary to contour the liver on all 10 phases, a tedious task if manually performed.
With DIR, the vector mapping of each voxel from one phase to all other phases is
calculated. This transformation may then be applied to the voxels that define the
contour, to map the organ outline to other phases. There are some small discrepancies,
but most contours are acceptable. Editing can be performed to the propagated contours
as needed. A full set of 3D contours at each phase permits calculation and quantitative
assessment of organ trajectories.

FIGURE 2.12 Four-dimensional liver segmented by deformable registration. The liver was manually contoured
in 3D at T30 respiratory phase; deformable registration was applied to map at the segmented contours to all
other respiratory phases. Accuracy is best near T30, with a few millimeter inaccuracies at phases farther from
reference phase.

Volume Visualization
An alternative to ring-stack or surface display of anatomy is volume visualization,
initially described in the computer science literature (92). In volume rendering, the
opacity and hue of a voxel of the 3D image data set can be interactively set to be a
function of its CT number. Volume-rendered displays have been used in treatment
planning for radiotherapy (93) and in radiology (94).
Figure 2.13 is a volume rendering of CT data. The image is of a patient with a lung
tumor, and the data rendered are from a high-quality treatment planning scan (0.5-mm
slice thickness, 256 slice scanner). Low-density lung parenchyma is rendered
transparent, and the tracheobronchial tree is visualized along with bony anatomy. The
visualization software used displays regions of high gradients in HU that essentially
display interfaces. Therefore, the contents of organs (e.g., heart) are not visible.

57
An advantage of volumetric visualization in radiotherapy planning is that this
technique can display anatomic detail not normally segmented. Nerves, vessels, and
lymph nodes are difficult to identify and laborious to segment on axial cuts. Yet these
structures often may be directly seen in a volumetric rendering from a selected BEV. The
hypothesis is that visualization of these structures may help in aperture design of the
clinical target volume.

FIGURE 2.13 Volume visualization of a lung tumor: Lung parenchyma is rendered transparent. The
tracheobronchial tree is visible as are surface interfaces of bony anatomy and mediastinum. Scan: 1-mm slice
thickness performed on a 256 slice CT scanner.

FIGURE 2.14 Prototype visualization combines 4D volume rendered CT data with additional quantitative
parameters overlaid. Key: Brown-longer RPL; Green-shorter RPL. (A) The skin surface with overlayed
radiological path length color map from skin to distal PTV. The skin surface/air interface is selected for display
in grey level. The image can be animated to show RPL variation during breathing. B: Left anterior oblique view
indicates internal RPL between the chest wall/lung interface and the proximal surface of the PTV. The brown
region indicates the beam grazes heart, leading to an undesirable steep compensator gradient. C: Changing to a
more oblique angle avoids this, resulting in more uniform compensator geometry. D: Overshoot image, the
amount by which each ray at chosen beam angle overshoots the distal PTV during respiration. Green indicates
overshoot is <3 mm. Dark brown areas indicate greater overshoot (>1 cm) as the tumor moves during respiration.
PTV includes upper airways, which also move during respiration, resulting in beam overshoot. Visualizations
help quantify variation of beam penetration in dynamic situations.

The difficulty of volume visualization is that so much anatomy, including overlying


tissues, is visualized, and some are not relevant to the planning task. Methods to display
only the relevant anatomy from a given beam perspective are needed. Interactive tools
capable of selectively peeling away tissues obscuring the volume of interest must be

58
incorporated into these techniques to reveal the volumes of interest.

Scientific Visualization Challenges


We can be easily overwhelmed with the gigabytes of multimodality image data
generated by 4D volumetric images. Additional data arise from dosimetric and imaging
data in the course of treatment planning 4D dose, image-guided treatment, and follow-
up. The challenge we face is articulated by Johnson (95), who addressed the major
unsolved problems in scientific visualization. Several of the unsolved problems are
relevant to visualization of radiotherapy image data, including (a) visualization of
uncertainty, (b) displaying time dependent data sets, (c) visualizing multidimensional
data (beyond 4D anatomy, dose, etc.), and (d) quantitatively establishing the value of
scientific visualization to decision making.
We provide an example of how advanced visualization techniques might be used in
radiation oncology. One possibility is interactive display of 4D anatomy overlaid with
quantitative data. Because charged particle beam therapy is particularly sensitive to
inhomogenities, we use a 4D CT data set to illustrate features of a quantitative n-
dimensional visualization problem (96). Figure 2.14 shows a series of images to extract
hidden information and display it in an intuitive way. Consider the need to understand
the radiological pathlength (RPL) associated with proton irradiation of a lung tumor. As
detailed in the caption, we use volume rendering on the fly to quantify the RPL changes
during 4D motion of a lung tumor, and explore how graphics and visualization can aid
in extending the BEV concept beyond geometric relationships. The quantities we wish to
ultimately display not only include RPL as a function of BEV, but treatment uncertainty.

KEY POINTS
• Multimodality volumetric imaging is the basis of modern radiotherapy. Imaging modalities
provide not only geometric/anatomic information for treatment planning and delivery, but
important information on organ function and tumor physiology that may be useful in
designing the target and avoiding critical structures.
• Data sets undergo extensive image processing, including segmentation, building 3D/4D
models of the patient. The anatomical representations provide insight into beam portal design
to optimize dose delivery.
• Images are becoming an integral part of target alignment, especially for conformal treatments
that promise high conformality of dose (IMRT, charged particle therapy, stereotactic
radiosurgery). Daily target confirmation is becoming more common.
• With vast amounts of image data available to the radiation oncologist, new approaches to
segmentation and display are needed. Some possibilities include volume rendering in real
time and powerful graphics for scientific visualization.

QUESTIONS
1. Which of the below provides information to estimate the electron density of each

59
voxel needed for dose calculations?
A. MRI
B. Ultrasound
C. CT
D. SPECT
E. None of the above.
2. Functional MRI is used to locate cognitive and eloquent areas of the brain. The
detection mechanism involves measuring which of the following?
A. Proton density
B. Reflectivity of RF from interfaces
C. Attenuation coefficient
D. Oxygen in hemoglobin
E. SUV
3. PET has been used to determine tumor hypoxic regions through which of the
following?
A. Measurement of SUV
B. Using 18F-FDG
C. Cu-ATSM
D. Electron spin resonance.
4. Organ motion over an 1-hour interval is best measured through which of the
below types of imaging?
A. MRI
B. CT
C. PET/CT
D. Cone-beam CT
E. Fluoroscopy
5. Which of the following best completes this statement: Image registration by
maximization of mutual information
A. involves defining corresponding points and surfaces to be matched.
B. involves interactive image alignment.
C. minimizes entropy.
D. is only applicable to deformed organs.
E. is not clinically used.

ANSWERS
1. C
2. D
3. C
4. A
5. C

60
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3 Treatment Simulation

Dimitris N. Mihailidis and Niko Papanikolaou

INTRODUCTION
Treatment planning is one of the most crucial processes of radiotherapy, through which
the most appropriate way to irradiate the patient is determined. The process is
composed of several important steps, such as:

1. Reproducible patient positioning and immobilization;


2. Accurate identification of the location and shape of the tumor and neighboring
critical organs;
3. Selecting the most appropriate beam arrangement;
4. Computing the doses to be delivered and evaluation of resulting dose distributions;
5. Transfer of the treatment planning information to the treatment delivery system;
In today’s radiotherapy, 3-dimensional (3D) patient anatomy visualization and target
definition enables planning to conform the dose to the target volume, delivering as high
doses as possible, while avoiding the critical organs. In order to achieve this, a process
called treatment simulation is necessary to be performed. In essence, treatment simulation
is a combination of, or requires that steps 1 to 3 (mentioned above) have been
performed successfully. There are several ways to perform a simulation, each with a
different level of complexity. The most common ones are:
1. When clinical treatment volume can be determined via simple radiographic and
fluoroscopic images from a traditional radiotherapy simulator (1), sometimes called
the anatomical approach (clinical setup).
2. When only a limited number of transverse computed tomography (CT) images are
used for the target delineation along with radiographic planar images (as above) in
order to complete the treatment planning, sometimes called the traditional approach.
3. When simulation can be performed on a CT scanner via a special computer software
that provides a full 3D patient representation in the treatment planning position, a
process called CT-simulation. Then, a complete treatment planning strategy can be
designed, a process referred to as virtual simulation (1,2).

Radiotherapy simulation is a very important process on which treatment planning


and treatment delivery depend and are based on. The accuracy of the entire
radiotherapy treatment can be influenced by the quality of treatment simulation on a
patient-per-patient basis.

SIMULATION METHODS
Treatment simulation can also be thought of as a “feasibility study” of the patient
treatment strategy. Technologic advances of medical imaging and computing have
brought great improvement to the simulation process and limitless capabilities.
We will describe the three most common methods of radiotherapy simulation today,

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which strongly depend on the treatment strategy that will be followed for the patient.

Simple Simulation—Anatomical and Traditional Approach


When the patient is necessary to be prepared for treatment in a short amount of time, or
there is a simple treatment to be delivered, a conventional simulation can be performed.
In this case, a radiographic simulator, which actually operates in both the radiographic
and fluoroscopic mode, is used (Fig. 3.1A,B). It is an apparatus that uses a diagnostic x-
ray tube with an image intensifier (Fig. 3.1C) but duplicates the radiotherapy treatment
unit in terms of its geometric, mechanical, and optical properties (3–5).
The patient is set up and immobilized on the simulator the same way that she will be
treated in the treatment unit. The clinical borders of the treatment area are marked on
the patient skin by the physician and radio-opaque markers are placed on skin on these
borders. The selection of the treatment isocenter is done via fluoroscopic imaging of the
area, typically with two orthogonal reference views, anterior (AP) and lateral (LAT) (Fig.
3.2). Upon selection of the isocenter, two orthogonal radiographic films (or digital
images) are produced for further use and comparison with the treatment setup, and
documentation purposes. Then, the beams that will be used for treatment are simulated
in order to be geographically optimized, depending on the treatment site, by selecting
gantry and collimator angles, treatment field sizes, and so forth; all in relationship to
externally placed markers and internal bony landmarks. A crucial step is the proper
marking of the patient, like the isocenter (as a “3-point” marking) and alignment skin
marks using the simulator laser system in all planes. At the same time, other necessary
information is collected to be used for setup and dosimetry, such as source-to-surface
distances of the simulated treatment fields, patient thickness, determination of the time-
set or monitor unit calculation point relative to the isocenter (if half-blocked or heavily
blocked fields are used, as in Figure 3.2), simple contours of the patient surface (with
contour-makers) through points of dosimetric interest, and evaluation data for bolus or
compensator.

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FIGURE 3.1 Typical radiotherapy simulator. Patient setup represented by a phantom (A), room view (B), and
geometric diagram (C).

Some simulators have a tomographic attachment (simulator-CT) that analyzes and


reconstructs the images from the image intensifier using either analog or digital
processing (6). The quality of the reconstructed image is inferior to the CT-based
simulation. However, it is adequate for acquiring patient contours and identifying bony
landmarks. The simulator-CT does provide a volumetric reconstruction of the patient’s
anatomy and as such could be used as a basic image data set in treatment planning. The
reduced spatial resolution of such volumetric imaging renders this technique unsuitable
for high precision conformal radiotherapy planning where a series of many thin slices is

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required for detailed volume reconstruction (7,8).

FIGURE 3.2 Typical simulation portal, lateral view for a head and neck treatment. The blocking is represented
by the black marker outlines on the film and the prescription point is denoted as “Calc Point,” which is off-axis
related to the half-blocked central-axis.

Interestingly, the concept of simulator-CT has recently re-emerged and is referred to


as cone beam CT (CBCT). Cone beam imaging is currently used in the context of image-
guided radiotherapy (IGRT) for daily patient localization and setup verification prior to
treatment. Those images could also be used for patient re-planning in the context of
adaptive radiotherapy, although for the time being this is only a research application.
However, it is expected that once the image quality, imaging dose to the patient, and
the speed of re-planning improve, the CBCT adaptive radiotherapy will become an
integral part of advanced radiotherapy.
CBCT imaging can be obtained using the kV imaging system of a linac (Varian, Elekta)
or the MV beam itself (Tomotherapy, Siemens). Regardless of the implementation, CBCT
is similar to and suffers from the same characteristics as the simulator CT.

Verification Simulation
This is a simulation approach “positioned” between the previously described approach
and the virtual simulation that will be described next. This process starts by
immobilizing the patient in the treatment planning position with all the necessary
devices, this time on the CT scanner flat table-top. In this case, there is no laser
localization system available in the CT room. A standard treatment planning study of
the patient will be obtained throughout the clinical area, after radio-opaque markers are
placed by the physician on the patient’s skin. The simulation team will need to place “3-
point” tattoos or another type of long-lasting markers on the patient’s skin. For CT
purposes, the “3-point” locations and the treatment area borders will be visible on the
CT images. Patient scans are typically obtained in an axial mode, 3 to 5 mm slice
thickness. Smaller slice thickness can be used for small areas, when higher resolution
and accuracy are necessary.
The CT images are reviewed and then imported to a treatment planning system where
a computer simulation will be done off-line. The physician will define the volumes of
interest and the isocenter might be adjusted to accommodate the target volume
extensions. The coordinates of the treatment isocenter can be referenced to the original
“3-point” location marked in the CT room. Next, the remaining treatment planning
process is completed and the plan gets finalized. Two orthogonal (AP & LAT) digitally

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reconstructed radiographs (DRRs) (9,10) will be produced at the original CT point and
the new isocenter (Fig. 3.3). DRRs of the treatment fields will also be produced.
A verification simulation is scheduled in the conventional simulator, where the
patient is immobilized and set up again in the treatment planning position. The patient
is then simulated according to the approved treatment plan. A sample simulation form
is shown in Figure 3.4, where all the appropriate shifts from the original CT marks to
the final isocenter are implemented. An orthogonal set of setup ports, first at the
original CT point (“3-point” mark) and then at the treatment isocenter, will assure the
proper localization when compared to the DRRs at the same locations. The patient will
be marked appropriately to insure reproducibility of setup during treatment. Further
on, additional ports of the treatment fields can be obtained to increase the accuracy of
the simulation setup and for documentation purposes. The orthogonal and treatment
ports will be compared to portal images or portal films in the treatment room, especially
on the first day of treatment. A diagram of the verification simulation process is shown
in Figure 3.5A.

CT-Simulator and Virtual Simulation


This is an exciting development in the area of simulation because it converts a CT (or
other scanning modality) scanner into a simulator (1,2,11–13). Both patient and
treatment unit are virtual, the patient being represented by CT images and the
treatment unit by model beam geometry and expected dose distributions. The simulation
film is replaced by the DRRs. The DDRs are generated from the CT scan data by
mapping average CT values computed along lines drawn from a “virtual source” to the
location of the “virtual film.” A DRR is essentially a calculated port film that serves as a
simulator film, which contains all the useful anatomical information of the patient (Fig.
3.6). A dedicated radiation therapy CT scanner, with the above described virtual
simulation software and simulation accessories (e.g., flat table-top, immobilization
devices, etc.), is called a CT-simulator (Fig. 3.7A). In addition, CT-simulators are
equipped with high-precision movable laser systems to mark the isocenter location on
the patient during the virtual simulation process. The laser system is mounted on fixed
pedestals on the floor and ceiling as shown in Figure 3.7B.

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FIGURE 3.3 Breast patient CT image with two orthogonal reference fields on the treatment isocenter-GREEN
point (A), 3D reconstruction of the patient imaged area with the reference field (B), LAT-reference field to the
treatment isocenter (C), AP-reference filed to the isocenter (D). The RED-point is the original CT point.

Modern radiotherapy CT-simulators are based on the most recent CT scanner


technology with multislice (multidetector) detector technology, axial and helical
scanning mode capabilities, rapid CT acquisition time, and high-image quality
performance and wide bore (>75 cm diameter) to accommodate the patient
immobilization devices. Further on, an option called gating allows the scanner to
perform “motion-correlated” scanning, a process called 4-dimensional (4D) CT (the
fourth being the time information), useful for accurate treatment planning on moving
anatomy (e.g., respiratory motion in lung). The standard linear accelerator (linac)
requirements for large weight capability (up to 450 to 600 lb load), small sag (<2 mm),
and hard table-top apply for CT-simulators, too.
A diagram that describes the CT-simulation and virtual simulation processes is shown
in Figure 3.5B.

CT-Simulation Process
The patient is immobilized on the CT table and in the treatment planning position. At
this initial stage, all special immobilization devices (e.g., head and neck masks, pelvic
shells, breast boards, etc.) are required to be constructed and/or utilized, in order to be
included in the CT image study of the patient. These devices can be indexed on the CT
table top, the same way that later on will be indexed on the linac treatment table (Fig.
3.8A–C). Additional planning modifiers, such as skin bolus are also required to be

72
included. The borders of the clinical area marked by the physician on the patient can be
outlined with CT radio-opaque markers (Fig. 3.8C). Sometimes, initial reference skin
marks are placed in the middle of the clinical treatment area. The CT movable lasers are
used to define and mark the CT reference point on the patient.

FIGURE 3.4 Sample in-house simulation form for breast setup. Note the setup instructions and appropriate
shift information from the “3-point” computed tomography (CT) mark to the treatment isocenter. Detailed
information on the treatment fields are entered in the table below. This form can also be used for verification

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simulation.

A set of anterior and lateral topograms (“scout views”) will assist the patient
alignment on the CT table. The patient will be scanned based on a preset protocol
according to the disease site and the images will be stored for virtual simulation, while
the patient remains on the CT table.

FIGURE 3.5 Verification simulation process diagram (A) and computed tomography (CT) simulation process
(B).

FIGURE 3.6 Virtual simulation as part of computed tomography (CT) simulation for a lung patient. The user
can visualize the anatomical information that will assist appropriate placement of points, such as the treatment
isocenter and the fields. In addition, tumor and other critical volumes can be outlined at this stage. This
information will be eventually transferred to the treatment planning system.

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FIGURE 3.7 A: A large (wide) bore CT-simulator accommodates the majority of immobilization devices to be
included in patient setup. B: A room view of a CT-simulator with the localization laser system.

FIGURE 3.8 Patient immobilization devices as integral part of computed tomography (CT) simulation process
for radiotherapy. A head and neck head holder and mask (A), indexing grooves for the immobilization devices on
the table top (B) and a breast patient on a breast board with reference CT radio-opaque markers ready to be
CT-simulated (C).

Virtual Simulation Process


There are three tasks that pertain to virtual simulation. First is the treatment isocenter
localization, which is typically placed at the geometric center of the treatment volume;
the second is the target and critical structures volumes delineation; and the third is to
determine the treatment beam parameters via beam’s-eye-view (BEVs) (14) using DRRs,

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including gantry, collimator and couch angles, field sizes, shielding block, and so forth.
This last part can also be performed at a later time during the treatment planning and
isodose computation process.
The CT images will be utilized to render a 3D view of the patient which will allow the
more precise localization of the isocenter and later on, more efficient placement of the
treatment fields (Fig. 3.9). The isocenter will be marked on the reconstructed patient
anatomy and two reference fields (typically an AP and a LAT) will be assigned at that
point. The DRRs (Fig. 3.10) of the reference fields will be compared with the equivalent
port films later on, the same way simulator films have been used at the past. Having
determined the isocenter, the patient is marked with the assistance of the movable
lasers, one anterior and two lateral marks on each side of the “3-point.” Shifts between
the original CT reference marks and the isocenter marks should be logged in the
patient’s chart.
At this stage, the patient can be removed from the CT table. The rest of the virtual
simulation process can be performed off-line via the special simulation software or the
treatment planning system software. Connectivity between the CT scanner’s computer
system and the treatment planning computer is essential to be evaluated and tested by
the physicist on a frequent basis (13). Image format standards such as DICOM (15) and
DICOM-RT (16) (developed especially for radiation therapy) transfer protocols between
imaging devices, and the treatment planning computer are the industry standard. One
needs to keep in mind that DICOM-RT transfer protocol can be highly complex to
implement and vary in interpretation from one manufacturer to another.
In the treatment planning system, the patient’s CT study and CT-simulation
information (reference marks, points, reference fields, etc.) should be available for
potential registration or fusion with other imaging modalities (other CT studies, MRI,
PET, etc.) that the patient might have gone through (Fig. 3.11). The information
provided by the multiimaging studies will allow the physician to outline target and
other volumes more accurately.
Starting from the reference marks and setup ports, the treatment isocenter is typically
selected at the center of the treatment area. Relative shifts of the isocenter from the
reference CT marks are monitored for subsequent patient setup, as described above, and
shown in Figure 3.12. The physician will outline the target areas and other critical
structures in a slice-by-slice process and will review the 3D representation of these
volumes in three major views (axial, sagittal, and coronal). Delineation of target and
critical organs is an extremely time-consuming process, in most clinical cases. Progress
has been made toward computer-assisted automatic contouring, pattern recognition,
and auto segmentation (17). Figure 3.13 compares manually outlined and auto-
segmented heart volumes. However, the basic problem remains that target delineation is
inherently a manual process, since the extend of target depends on tumor grade, stage,
and patterns of spread to adjacent structures. Clinical evaluation of the contouring
results by a radiation oncologist provides the final judgment in defining the target
volume.

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FIGURE 3.9 Virtual simulation based on 3D reconstruction allows accurate placement of treatment fields (top-
right). In this brain treatment, for example, two lateral (top-left and bottom-right) and a vertex (bottom-left)
treatment field shaped by multi-leaf collimators (MLCs) are shown.

FIGURE 3.10 Isocenter placement during virtual simulation, based on reconstructed planes (top) and
orthogonal digitally reconstructed radiographs (DRRs) (bottom) for a head and neck treatment.

With all the volumes (targets and critical structures) approved by the physician, the
treatment planning team can initiate the selection of the appropriate treatment fields

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via BEVs and 3D reconstruction of internal geometry of the patient (Fig. 3.9). Keeping
in mind the clinical and setup margins to the tumor volume, as defined by the ICRU
(International Commission on Radiation Units and Measurements) (18,19), appropriate
blocks with multileaf collimators (MLCs) can be used for 3D conformal treatment
planning. It is important to remember that each beam has physical penumbra where the
dose varies rapidly and that the dose at the edge of the field is approximately 50% of
the center dose. For this reason, to achieve adequate dose coverage of the target volume,
the field penumbra should lie sufficiently beyond the target volume to offset any
uncertainties in PTV. Beam apertures can be designed automatically or manually
depending on the proximity of the critical structures and the uncertainty involved in
the allowed margins to the target volume (Fig. 3.14). Clinical judgment is frequently
required between sparing of critical structures and target coverage.

FIGURE 3.11 Multiimage registration for a brain patient. MRI and CT are aligned and fused in all three
major views: axial, sagittal, and coronal. This allows the user to outline volumes that are visualized in MR images
onto the CT images and proceed with treatment planning.

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FIGURE 3.12 A diagram showing the relative shifts from the reference computed tomography (CT) marks to
the treatment isocenter. Visualization of internal body structures are essential in this process.

All possible gantry, collimator, and couch angles can be evaluated based on target
coverage and avoidance of critical structures. Some commercial planning systems
provide software-assisted beam geometry parameter optimization (20,21) which is
important for highly conformal treatment plans. Beam directions that create greater
separation between the target and critical structures are generally preferred unless
other constraints such as obstructions in the beam path or gantry collisions with the
treatment couch or patient preclude those choices. Alternatively, dose–volume
objectives for the target volume and critical structures can be employed to produce an
inversely optimized plan, with the majority of commercial planning systems being
capable of providing inverse planning optimization algorithms (22). Final dose
computations take full advantage of CT-electron density information in order to account
for tissue inhomogeneities (23). The virtual simulation process smoothly makes a
transition into treatment planning and the treatment evaluation stage, which is beyond
the purpose of this chapter.

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FIGURE 3.13 Subsequent CT axial images. Compare the heart volume that has been manually outlined
(BLUE-line) and the result of auto-segmentation (GREEN-line).

FIGURE 3.14 A field shaped around the prostate with specific margins using multi-leaf collimators (MLCs).
The BEV view (left) and the axial view (right).

A few points of precaution are in order when virtual simulation is performed.

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• Due to precise visualization of internal organ and target volumes, one might be misled
to use arbitrary small margins to the target volume in a feeling of false confidence.
Thus, other important effects such as patient setup and target motion might not be
taken into account in a proper way, since patient and organ motion is not well
visualized by traditional 3D virtual simulation. In the absence of 4D CT imaging, an
additional fluoroscopic study, in a traditional simulator, might be of great benefit to
treatment planning, especially for moving targets such as lung.
• The spatial resolution is generally limited by the spacing of the axial images. Thus,
within the target area it is required that smaller scanning spacing (typically 2 to 3
mm) is used while a larger spacing (typically 1 to 2 cm) can be used further from the
area of interest. One needs to keep in mind that this will affect the quality of the
reconstructed DRRs.
• Limitation of CT imaging in visualizing all treatment sites can influence the clinical
target volume (CTV) design; in other words, CT imaging do not always provide the
best method to visualize microscopic disease. Most commonly, in the case of brain
tumors, CT imaging cannot provide clear borders of the disease. The clinician needs to
keep in mind that combination (image registration process) of the treatment planning
CT with other modalities, such as MR or PET, will allow a more accurate delineation of
the target volume. It is important to remember that the ability to precisely conform to
a target volume has limited value if the target is not determined accurately.

4D CT-Simulation Process
Modern CT scanners are capable of providing a high-resolution volumetric
reconstruction of the patient’s anatomy. Each image voxel has a characteristic CT
number that is uniquely related to the electron (or mass) density of that voxel. The
density information is used in the computation of dose and accounts for the effects of
tissue inhomogeneity in treatment planning. When the anatomy that is imaged is mobile
(tumor and organs move during the imaging study due to cardiac or respiratory
motion), the image data are subject to motion artifacts. Consequently, the resulting
volumetric reconstruction of the patient is a blurred representation of the true patient
anatomy. In addition, motion artifacts will result in erroneous CT numbers and electron
density values in the vicinity of the mobile anatomy. It is therefore important to
minimize any motion artifact as it impacts not only the image quality and the specificity
by which we can resolve anatomical changes, but also the accuracy of the calculated
dose in treatment planning.
There are three different types of motion artifacts that we can observe during a CT
acquisition (24):

• If the CT scanning speed in the superior–inferior direction is much less than the tumor
motion speed, then we observe a smeared image of the tumor.
• If the CT scanning speed is much faster than the tumor motion speed, then the tumor
position and shape are captured on the image at an arbitrary phase of the breathing
cycle.
• If the CT scanning speed is similar to the tumor motion speed, then the tumor position
and shape can be significantly distorted.

It is evident that patient motion can cause significant artifacts during 3D CT imaging
(25,26), which not only degrade the image quality and our ability to delineate

81
anatomical structures (27), but sometimes can even simulate the presence of disease
(28). Figure 3.15 illustrates image artifacts that are caused by superior–inferior motion
during conventional CT imaging of a test sphere (29).

FIGURE 3.15 Illustration of image artifacts that are caused by superior–inferior (SI) motion during 3D CT
imaging. A: CT coronal section of a static sphere. B: CT coronal section of the same sphere in oscillatory motion
(range, 2 cm; period, 4 seconds) (29).

Ritchie (30) proposed a high speed (fast) scan to avoid motion artifacts that was of
limited success with the third-generation CT scanners. The use of multislice technology
(31) has significantly reduced motion artifacts in CT images when acquired in fast
scanning mode. However, fast scans, although less susceptible to motion artifacts, do
not portray the full extent of motion of the tumor and are therefore not of clinical use in
treatment planning of mobile tumors. Multislice helical scanning, on the other hand,
can be used with a 4D CT scanning protocol and reduces the overall scanning time
while achieving the goal of capturing the temporal position of the tumor in the imaging
study.
When we consider the organ motion, we have to choose an imaging technique that
will minimize motion artifacts during the CT simulation. Several methods have been
proposed to address this problem, including:

• A breathhold CT simulation, where the patient is instructed to voluntarily hold his


breath while the scanning beam is turned on. A similar result can be achieved using
the active breathing control technique (ABC) proposed by Wong et al. (32).
• A slow CT scan where axial images are acquired at a speed of 4 seconds or slower per
slice. A slow scan will ensure that the envelope of motion of any moving organ subject
to respiratory motion will be captured in the image (typical respiratory period is 4 to 6
seconds).
• A gated CT scan where the beam is turned on only when the patient’s breathing is at a
certain window of the respiratory cycle (typically 30% to 35% of duty cycle). The
respiratory-related motion is usually monitored using an external marker. In one of the
commercially available implementations, this is accomplished by correlating the
respiration-related tumor motion to the displacement of an external marker placed on
the patient’s chest as measured using an infrared camera. The user can specify which
portion of the sinusoidal-shaped signal obtained from the infrared camera is used to
trigger the CT scanner using the cardiac gating port. This method of imaging is also
known as prospective gated image acquisition.
• A 4D CT scan where multiple scans are obtained for each location (oversampling)

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whereby the organ motion is captured at different sampled phases of the respiratory
cycle. At the end of the scan a very large set of 3D images is produced corresponding
to each of the phases in which the breathing cycle was sampled (Fig. 3.16). The
collection of those 3D CT scans constitutes the 4D CT study for this patient. This
method is also known as retrospective image reconstruction.

FIGURE 3.16 The 4D CT phase-sorting process: the CT images, breathing tracking signal, and “X-ray ON”
signal form the input data stream. The breathing cycle is divided into distinct bins (e.g., peak exhale, mid
inhale, peak inhale, mid exhale). Images are sorted into those image bins depending on the phase of the
breathing cycle in which they were acquired (29).

Of all the imaging methods that aim to minimize respiration-related motion artifacts,
the 4D CT technique is the most comprehensive way to perform the task because it not
only reduces motion artifacts but also captures the changing topography of the tumor
during the respiratory cycle. This information can be used during treatment planning to
optimally delineate treatment volumes and margins under the assumption that the
patient will be breathing the same way during treatment as they did during the 4D CT
simulation. Irregular breathing (during imaging or treatment) is not desirable and we
often coach the patient to breath regularly and reproducibly. Coaching can be auditory,
where a computerized voice instructs the patient to breath in and out, or visual, where
for example the patient looks at the superposition of their baseline breathing curve and
their real-time breathing curve and tries to match them as they control and pace their
breathing.
Ultimately, the goal of simulation is to uniquely and reliably identify, in the patient’s
treatment position anatomy, the exact target shape and location that can be
reproducibly localized and treated during the daily treatments. Four-dimensional CT
simulation allows us to segment the target and organ volumes with high specificity
resulting in more educated decisions on margin selection but also improved dose
calculation during treatment planning.

ACCEPTANCE TESTING AND QUALITY ASSURANCE


When it comes to conventional simulators and CT-simulators, the initial acceptance
testing is performed to verify that the unit is operating as specified by the manufacturer

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and to serve as a baseline data pool for future comparisons with periodic quality
assurance (QA) testing.

Conventional Simulator
Acceptance testing of a simulator may be divided into two parts: (a) geometric and
spatial accuracies verification and (b) performance evaluation of the x-ray generator
and the associated imaging system. The first part is similar to the acceptance testing
and evaluation of a linear accelerator for mechanical performance. Because the
simulators are designed to mimic the treatment accelerators, their geometric accuracies
should be comparable with those of the accelerators. To minimize differences between
the simulator and the accelerator it is desired to use the same table design and
accessory holders as those on the treatment machine.
The second part is a performance evaluation of a diagnostic radiographic and
fluoroscopic unit.
Several authors have discussed the technical specifications of treatment simulators
and the required testing procedures and have presented comprehensive reviews on this
subject (3,4,33–35). The quality assurance for the x-ray generator and the imaging
system has been discussed by various groups (36,37). The most recent recommendations
on QA for conventional simulators are from AAPM Task Group #40 (Table III in the
report) (38). Of course a well-established QA program requires daily and annual testing
for simulators, in addition to the monthly testing.

CT-Simulator
Acceptance testing for a CT-simulator requires the acceptance testing of the CT scanner
as an imaging device to be done first. This process is described in detail by AAPM
Report No. 39 (39). For the purpose of CT-simulation, additional literature needs to be
employed to cover the needs of radiotherapy (see McGee and Das in Ref. 11). Due to the
complexity of the new technology scanners, the manufacturer’s acceptance testing
procedure (acceptance testing procedure (ATP) manual) provides a great guide to
suggested recommendations for testing tolerances for the particular scanner. We
recommend that the AAPM Task Group #66 report is followed for all the QA needs of a
CT-simulator as it applies to radiotherapy procedures (13). Table I in Ref. 13 outlines
the electromechanical components testing (e.g., lasers, table, gantry, and scan
localization). Table II outlines test specifications for image performance evaluation (e.g.,
CT number vs. electron density, image noise, contrast and spatial resolution). A
simplified set of tests are shown in Figure 3.17. Keep in mind that the CT-simulation
process QA should be performed along with the treatment planning process QA where
information and data are transferred between the CT scanner and the treatment
planning computers.
When 4D CT scans are used for simulation, the quality assurance is for the most part
the same as that for the CT simulator. In addition to the tests described previously, one
could include scans of test phantoms that are placed on a moving platform. Such
motorized platforms can be programmed to a user-defined moving cycle that is typically
1-dimensional (1D) or 2-dimensional (2D), which is adequate for QA purposes. Since the
physical size of the phantom and any objects embedded inside it are known, a 4D CT
scan would test the ability of the scanner and the accompanying software to build the
4D model of the phantom and to reproduce the true dimensions of the imaged objects.
Although there is currently not much information on QA for 4D CT, such protocols can

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easily be developed and incorporated in routine quality assurance programs for CT
simulation.

RECENT DEVELOPMENTS IN RADIOTHERAPY SIMULATION


During the last decade, positron emission tomography (PET) in combination with CT in
hybrid, cross-modality imaging systems (PET/CT) has gained more and more importance
as a part of the treatment planning procedure in radiotherapy. The fusion of PET with
CT adds anatomical information to the physiologic information of PET, allowing for
improvement in spatial resolution. The high sensitivity and specificity of PET/CT in
identifying the areas of tumor involvement in various disease sites (40,41) attracted
great interest in integrating functional imaging with PET/CT into the radiotherapy
planning process. The aim is to better define and delineate the tumor’s extent and its
relationship to the surrounding radiosensitive vital structures and to improve the
therapeutic index (Fig. 3.18).

85
FIGURE 3.17 Set of monthly QA tests for CT-simulator. This set of tests is based on AAPM TG-66 (13).

86
FIGURE 3.18 PET/CT fusion of a patient with nasopharyngeal cancer with an upper left lobe lung nodule
(white arrow).

Magnetic resonance imaging (MRI) is becoming an increasingly important tool in


radiation oncology, as it can provide anatomical and functional information regarding
the tumor and normal tissues, which may be complimentary to information from CT
alone. For more than a decade MRI has been successfully used in stereotactic
radiosurgery procedures. Thus, MRI has already been integrated into a CT-based RT
workflow, using image registration tools. Such tools are already an inherent part of the
RT workflow, for multimodality and multiphasic image registration for radiation
treatment planning (for MRI, PET, and other imaging) and for image guidance at the
treatment unit (42).

CONCLUSIONS
Treatment simulation is a crucial component of the entire treatment planning process
and guarantees successful radiotherapy practice. The advancements of today’s
technology, both in hardware and software, allow more accurate patient setup and
representation with customization of the treatment plans to the specific patient and site.
However, stringent QA procedures are necessary to maintain optimum and safe use of
such technologies. The introduction of multimodality imaging for RT introduces the
need for deformable image registration early in the RT simulation process, which, as a
whole, is an exciting topic to investigate.

KEY POINTS
• Treatment planning requires accurate patient data to be acquired through the process of
treatment simulation.

87
• Radiographic, CT, PET/CT, ultrasound, and MRI simulators are essential in modern
radiotherapy treatment planning.
• Image fusion between different simulation modalities is necessary for complex modern
radiotherapy techniques for mapping out structural or functional anatomy of the targeted
areas.
• Important components of CT-simulations and virtual simulation are 3D representation of
the patient, DRRs, image registration and segmentation, and tumor motion management.
• Treatment volume delineation, treatment portal placements, and their directional
optimization can be performed as part of the virtual simulation process based on 3D
visualization of the patient model.
• Process quality assurance and periodic testing of the radiotherapy simulation equipment
should be an integral part of the modern radiotherapy simulation process in order to secure
optimal and safe implementation of all aspects of the simulation process.

QUESTIONS
1. What is the most common imaging modality used in radiotherapy simulation?
A. MRI
B. Planar imaging
C. Ultrasound
D. CT
E. PET
2. When compared with CT, MRI provides better
A. spatial resolution
B. contrast resolution
C. patient setup
D. tissue density information
E. geometrical accuracy
3. When compared with MRI, PET provides better
A. spatial resolution
B. patient setup
C. tissue density information
D. malignancy differentiation from normal tissue
E. geometric accuracy
4. During a 4D CT process,
A. the CT beam is turned on only when the patient’s breathing is at a certain
window of the respiratory cycle.
B. a slow CT scan of axial slices is acquired.
C. multiple scans for each location are obtained and are shorted via

88
retrospective image reconstruction.
D. a breathhold technique is used during the image acquisition.

ANSWERS
1. D
2. B
3. D
4. C

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4 Treatment Planning Algorithms: Photon
Dose Calculations

John P. Gibbons

INTRODUCTION
Computerized treatment planning systems have been utilized in radiotherapy planning
since the 1950s. The first computer algorithm used has been attributed to Tsien (1) who
used punch cards to store isodose distributions to allow for the addition of multiple
beams. Since that time, advancements in computer speeds and algorithm development
have vastly improved our capability to predict photon dose distributions in patients.
In an early attempt to classify computer planning algorithms, ICRU Report 42 (2)
divided photon dose calculation methods into two categories: empirical and model-
based algorithms. Early empirical algorithms such as Bentley–Milan were developed
using clinical beam data measured on a flat water phantom as input. Corrections were
then made to incorporate various effects, such as changes in patient external contour,
blocking or physical wedges, and so forth. Eventually, patient heterogeneity correction
factors became incorporated, but these were applied afterward, that is, after water-
based calculations were performed assuming a homogenous patient geometry. Most of
this development occurred prior to the advent of CT, or at least before the incorporation
of CT-images into the radiotherapy planning process.
However, eventually the commercial utilization of empirical algorithms faded. In the
early 1990s, 3-dimensional (3D) conformal radiation therapy (3D CRT) began to use
patient-specific CT-image data in the planning process. Initially this was limited to
virtual simulation. At that time computer-based algorithms which could incorporate the
newly available volumetric density information and compute true 3D dose distributions
in a reasonable amount of time were not yet available. In order to fully utilize this new
information, it was necessary to develop new algorithms which could more accurately
incorporate variations in individual patient anatomy. As a result, most, if not all,
commercial treatment planning systems have moved to model-based photon calculation
methods.
In this chapter, we will describe three photon calculation models currently in use in
radiotherapy clinics. Photon calculation models are an area of continuous development
and it is likely that each commercial vendor’s implementation of one or more of these
models will differ in many respects. Nevertheless, the intent is to provide a basic
understanding of the principles behind these algorithms.
This work represents an update of the chapter of Mackie, Liu, and McCullough from
the previous edition (3). Their work contained thorough coverage of the subject and
much of their description and analyses have been reproduced here. In particular, their
expertise regarding the convolution/superposition algorithm is without equal, and the
reader is encouraged to review their work for greater details.

THE REPRESENTATION OF THE PATIENT FOR DOSE

92
PLANNING
Patient representation has evolved dramatically over the past 40 years. Initially,
patients were considered as a flat water phantom of a specific SSD and depth for use in
simple dose or monitor unit calculations. Development of external contour tools aided
the treatment planner in determining patient-specific dose distributions. Such
procedures resulted in the patient being represented as a homogeneous composition
(i.e., water) but did allow for the application of surface corrections to the calculation.
Patient heterogeneities could be represented in simple ways, such as using internal
contours with assigned densities. The electron density to assign to the region could be
inferred from CT atlases or, if available, the mean patient-specific CT number within the
contoured structure (4). The problem with this approach was that tissues such as lung
and bone are not themselves homogeneous, and their density variations would not be
taken into account using this approach.
All modern radiotherapy systems use volumetric imaging data to characterize the
patient in a 3D voxel-by-voxel description. The most common imaging dataset used for
radiotherapy treatment planning is a treatment-planning CT scan, obtained using a
conventional CT-simulator. A CT dataset of the treatment region constitutes the most
accurate representation of the patient applicable for dose computation, primarily
because of the one-to-one relationship between CT number and physical and/or electron
density (4). Dose algorithms that can use the density representation on a point-by-point
basis are easier for heterogeneous calculations because contouring of the heterogeneities
is typically not required. An exception to this occurs when data is present within the CT
scan which will not be present for the treatment. One obvious example is the CT-
simulator couch, which is either manually or automatically removed and, in some cases,
replaced with a treatment couch by the planning system. Also relevant are temporary
contrast agents that can produce a CT number that mimic a higher density material
within the body. Usually, the contrast agent is used to aid in the tissue segmentation,
and so only the additional step of providing a more realistic CT number in the
segmented region is required to correct for the presence of the contrast agent. The
spatial reliability of CT scanners is typically within 2%, which leads to dose
uncertainties of ∼1% (4).
Other imaging modalities provide information which will aid in the location and
delineation of structures, but is of less value in the calculation of dose. For example, the
advent of cone-beam CT within the treatment room provides invaluable information
regarding patient alignment. However, the scatter contained within the images makes
accurate determination of density difficult. Although MRI is often able to provide
superior tissue contrast, the information in MRI is not strongly related to electron
density. Furthermore, MRI images are more prone to artifacts during image formation,
which will degrade the quality of the calculated dose distributions.
In addition to electron density, it is also necessary to determine the tissue composition
for more modern calculation algorithms. In convolution/superposition algorithms,
fluence attenuation tables are typically computed using mass-attenuation coefficient
data, which are somewhat weakly dependent on material. Often these coefficients are
determined for each voxel by linearly interpolating between published results of two
different materials (e.g., water and bone) based on the density assigned to the voxel. For
both Monte Carlo (MC) and Boltzmann transport calculations, a full material
assignment must be made to allow for accurate cross-section determination for both
photon and electron transport throughout the patient volume.
Ideally, the size of the voxels in the treatment planning CT should be close to the dose

93
grid resolution used for calculation. A CT volume set typically consists of 50 to 200
images with a voxel matrix dimension of 512 × 512 for each image. For a 50-cm field
of view, this corresponds to a voxel size of ∼1 mm in the transverse direction. The
longitudinal voxel size depends on the slice thickness, but is typically from 2 to 5 mm.
In many planning systems, the CT slice thickness is chosen as the voxel size of the dose
grid. For these systems, it may be appropriate to downsample the CT image set to 256
× 256. This makes the transverse resolution more closely matched to that of the
longitudinal direction, with only a minor degradation in the image. Degrading the
resolution further from 256 × 256 may result in an unacceptable loss of detail.

BASIC RADIATION PHYSICS FOR PHOTON BEAM DOSE


CALCULATION
Here we present an introduction to the important aspects of x-ray production and
interaction to understand the capabilities and limitations of model-based photon
treatment planning algorithms.

Megavoltage Photon Production


Figure 4.1 displays a cross-sectional view of a linear accelerator treatment head, which
consists of a high-density shielding material such as lead, tungsten, or lead-tungsten
alloy. It consists of an x-ray target, flattening filter, ion chamber, and a primary and
movable collimator. High-energy electrons are accelerated in the linac’s accelerating
structure and impinge on the x-ray target.
The production of Bremsstrahlung, or braking radiation, occurs when the high-energy
electrons strike a tungsten target located in the head of the accelerator. The size of the
focal spot of the electrons on the target is small, typically on the order of a few
millimeters (5). This finite size contributes to the penumbra, or the blurring of the beam
near the edges of the field.
A first, or primary collimator, fabricated from a tungsten alloy, defines the maximum
field diameter that can be used for treatment.
At megavoltage energies, Bremsstrahlung is produced mainly in the forward direction.
In most conventional C-arm accelerators, to make the beam intensity more uniform, a
conical filter positioned in the beam preferentially absorbs the photon fluence along the
central axis. The presence of the field-flattening filter alters the energy spectrum, since
the beam passing through the thicker central part of the filter has a higher proportion
of low-energy photons absorbed by the filter. This may not be necessary for modern
treatment deliveries where modulation is used to vary the intensity of the beam. Indeed,
many treatment units now have the option of removing the filter for these treatments
(e.g., Varian TrueBeam, Palo Alto, CA; Elekta Versa HD, Atlanta, GA), or have removed
the flattening filter entirely (e.g., TomoTherapy, Inc. Hi-Art, Madison, WI) when a
uniform field is not needed.

Compton Scatter
Photons can inelastically scatter via three main processes: photoelectric absorption,
incoherent (Compton) scattering with atomic electrons, and pair production in the
nuclear or electron electromagnetic field. In the energy range used for radiation
therapy, most interactions are Compton scattering events, which are discussed in more
detail here.

94
FIGURE 4.1 Components of the treatment head of a linear accelerator. A: A cross-sectional view of the
treatment head operating in x-ray therapy mode. B: A cut-away diagram of the linac. (From Varian Medical
Systems: www.varian.com, with permission.)

Compton scattered photons may originate in either the accelerator treatment head or
the patient (or phantom). Most of the scatter dose generated by the accelerator head is
produced within the primary collimator and the field-flattening filter. These scattered
photons and electrons are sometimes referred to as “extrafocal radiation” which may be
added to the primary photon beam emitted from the source. As the collimator jaws
open, more scattered radiation is allowed to leave the treatment head, which results in
an increase in the machine output with field size. This effect is known as collimator
scatter (6), although the collimator jaws themselves contribute little forward scatter. The
photons scattered in the primary collimator and field-flattening filter also add to the
fluence just outside the geometrical field boundary.
Like accelerator-produced scatter, phantom scatter primarily occurs in the forward
direction and increases with the size of the field. However, for phantom-generated
scatter, the penetration characteristics of the beam are also altered. As the field size
increases, the phantom scatter causes the beam to be significantly more penetrating
with depth. This effect is significant enough that this energy difference must be
included in the dose computations.
The behavior of scatter from beam modifiers such as wedges must also be considered
within the photon model. When the field size is small, a beam modifier mainly alters the
transmission and does not contribute much scatter that arrives at the patient. However,
when the field is large, beam modifiers begin to alter the penetration characteristics of
the beam, much as phantom scatter does. This effect is exemplified by the increase in
the wedge transmission factor with increasing field size and depth (7,8).

Electron Transport

95
Photons are indirectly ionizing radiation. The dose is deposited by charged particles
(electrons and positrons) set in motion from the site of the photon interaction. At
megavoltage energies, the range of charged particles can be several centimeters. The
charged particles are mainly set in forward motion but are scattered considerably as
they slow down and come to rest. Electrons lose energy by two processes: inelastic
collisions within the media (primarily with target electrons), and radiative interactions
(primarily with target nucleus). Inelastic collisions which ionize the target atom can
lead to secondary electrons, known as delta rays. Radiative interactions occur via
Bremsstrahlung, which effectively transfers the energy back to a photon. Equations
which model these coupled electron–photon interactions are described later on.
The indirect nature of photon dose deposition results in several features in photon
dose distributions. Initially, the superficial dose increases, or “builds up” from the
surface of the patient because of the increased number of charged particles being set in
motion. This results in a low skin dose, the magnitude of which is inversely proportional
to the path length of the charged particles. The dose builds up to a maximum at a
depth, dmax, characteristic of the photon beam energy. At a point in the patient with a
depth equal to the penetration distance of charged particles, charged particles coming
to rest are being replenished by charged particles set in motion, and charged particle
equilibrium (CPE) is said to be reached. In this case, the dose at a point is proportional
to the energy fluence of photons at the same point. The main criterion for CPE is that
the energy fluence of photons must be constant out to the range of electrons set in
motion in all directions. This does not occur in general in heterogeneous media, near the
beam boundary, or for intensity-modulated beams.
Electrons produced in the head of the accelerator and in air between the accelerator
and the patient are called contamination electrons. The interaction of these electrons in
and just beyond the buildup region contributes significantly to the dose, especially if the
field is large.
Perturbation in electron transport can be exaggerated near heterogeneities. For
example, the range of electrons is three to five times as long in lung as in water, and so
beam boundaries passing through lung have much larger penumbral regions. Bone is the
only tissue with an atomic composition significantly different from that of water. This
can lead to perturbations in dose of only a few percent (9), and so perturbations in
electron scattering or stopping power are rarely taken into account. Bone can therefore
be treated as “high-density water.”

SUPERPOSITION/CONVOLUTION ALGORITHM
The most common photon dose calculation in use for radiotherapy planning today is the
Superposition/Convolution algorithm (9–19). This method incorporates a model-based
approach in describing the underlying physics of the interactions, while still being able
to calculate dose in a reasonable time.
The convolution–superposition method begins by modeling the indirect nature of dose
deposition from photon beams. Primary photon interactions are dealt with separately
from the transport of scattered photons and electrons set in motion.

Dose Calculation under Conditions of Charged Particle Equilibrium


To begin, we consider the special case of dose determination under conditions of CPE.
In this case, the total energy absorbed by charged particles at position r is the same as
the total energy which escapes due to photon interactions at the same location. Thus,

96
the primary dose Dp and the first-scattered dose from a parallel beam of monoenergetic
photons can be computed as (3):

where YP(r) and (Kc(r))P are the primary energy fluence and collision kerma,

respectively, at point r is the mass energy absorption coefficient, øP(r = 0) is

the primary photon fluence at the surface of the phantom, hnP is the primary photon
energy, and μ is the attenuation coefficient of primary photons. The total dose is the
sum of the primary and scatter components

where dPscat(q,r′)/dV is the probability per unit volume of a primary photon being
scattered into a solid angle centered about angle q.
These equations are complicated enough, but they do not take into account any
secondary or higher-order photon scatter. They also neglect beam divergence and do not
take into account tissue heterogeneities. They are valid only for CPE situations, so that
the dose computation is not valid in the buildup region or near the field boundaries,
and the scatter dose is perturbed by heterogeneities lying between the scatter site at r′
and the point r, where the total dose is being computed.

Convolution/Superposition Method
Unfortunately, Equation (4.1) is simplistic because it does not take into account the
finite range of charged particles. In other words, the energy fluence that was present at
the point the charged particles were set in motion upstream should replace the energy
fluence in Equation (4.1). We may think of this energy fluence as that originating
upstream (i.e., assuming that the charged particles all moved linearly downstream), but
in reality, the particles may originate from any location around the calculation point, as
long as it is within the particles’ range. Thus, rather than a single effective photon
interaction site, this expression for dose becomes a convolution integral about r:

where Ac(r−r′) describes the contribution of charged particle energy that gets absorbed
per unit volume at r from interactions at r′ and the integration is over all values of r′
that make up volume dr′. The charged particle energy absorption kernel has a finite

97
extent because the range of charged particles set in motion is finite.
Equation (4.3) requires knowledge of the energy fluence due to both primary and
scattered photons at all points. Time-consuming transport methods, such as the method
of discrete ordinates or the MC method would be needed to compute the scattered
component accurately. A simpler solution is to utilize a scatter kernel that includes the
scattered photon component along with the contribution from charged particles. The
kernel is no longer finite because photon scatter (which has no range) is included. Now
only primary photons are explicitly transported. A convolution equation that separates
primary photon transport and a kernel that accounts for the scattered photon and
electrons set in motion away from the primary photon interaction site is as follows:

where is the mass attenuation coefficient, ΨP(r′) is the primary energy fluence, and

A(r − r′) includes the contribution of scatter. The product of the mass attenuation
coefficient and the primary energy fluence is the primary terma (total energy released
per unit mass) TP(r′). Terma, first defined by Ahnesjo, Andreo, and Brahme (20), is
analogous to kerma, and has the same units as dose.
The convolution kernels can, in principle, be obtained by analytic computation,
deconvolution from dose distributions, or even by direct measurement. Most often, the
kernels are computed with the MC method by interacting a large number of primary
photons at one location and determining from where energy is absorbed, that is, from
primary-generated charged particles, charged particles subsequently set in motion from
scattered photons, or both (12,13,20,21). Figure 4.2 illustrates isovalue lines for a 1.25-
MeV kernel in water. As is evident from the figure, the kernel is forward directed even
at this low energy. As the energy increases, the kernel becomes even more forward
peaked.

Modeling Primary Photons Incident on the Phantom


The convolution equation is restricted to describing monoenergetic parallel beams of
primary photons interacting with homogeneous phantoms. To model a clinical
radiotherapy beam, the contribution for each energy bin of the photon spectrum must
be summed. At present, the spectral information is derived from MC simulations
benchmarked by measurement. Using the EGS4 MC method, Mohan and Chui (22) first
quantified the spectrum of clinical accelerators using the MC method. Since that time,
several other authors have performed simulations to calculate photon energy spectrum
(18,23,24).

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FIGURE 4.2 Cobalt-60 (more precisely, 1.25-MeV primary photons) kernels for water computed using Monte
Carlo simulation (MCS). The isovalue lines are in units of cGy MeV−1 photon−1. A: The contribution due to
electrons set in motion from primary photons (i.e., the primary contribution). B: The first scatter contribution.
C: The sum of the primary and all scatter contributions. (Reprinted from Mackie TR, Bielajew AF, Rogers
DW, et al. Generation of photon energy deposition kernels using the EGS4 Monte Carlo code. Phys Med Biol.
1988;33:1–20, with permission.)

The spectrum will also vary with off-axis position if a field-flattening filter is used.
Figure 4.3 shows that the mean energy of primary radiation (directly from the target)
for a Varian 2100C (flattened) 10-MV photon beam decreases off-axis, but the
extrafocal photons (primary collimator and flattening filter) do not (18). This off-axis
decrease is due to differential hardening of the beam by the field-flattening filter. Since
the direct photon component dominates, the model must take into account the change
in the energy spectrum across the field.

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FIGURE 4.3 The photon mean energy distribution in an open 40 × 40-cm field from a 10-MV photon beam
target, primary collimator, and field-flattening filter. Values are for in-air photons arriving at the plane of the
isocenter. (Reprinted from Liu HH, Mackie TR, McCullough EC. A dual source photon beam model used in
convolution/superposition dose calculations for clinical megavoltage x-ray beams. Med Phys. 1997;24:1960–
1974, with permission.)

Collimators and block field outlines are usually modeled with a mathematical mask
function, which consists of the fraction of the incident fluence transmitted through the
modifier. For a collimator, the mask function inside the field is unity, and underneath
the collimator it is equal to the primary collimator transmission. For a block, the mask
function inside the field is the primary transmission through the block tray, and
underneath the block it is equal to the primary block transmission. The mask function
alone would not be able to model the penumbral blurring of the field boundary. This has
been modeled by an aperture function. The mask function is convolved by a 2-
dimensional (2D) blurring kernel that represents the finite size of the source. The
blurring kernel is usually assumed to be a normal function with a standard deviation
equal to the projection of the source spot’s width through the collimation system
(thereby accounting for magnification of the source at large distances from the
collimator system). Finally, the mask function is multiplied by the energy fluence
distribution for the largest open field.
The energy fluence outside the field is greater than that which can be accounted for
by collimator transmission of the primary photons generated in the target. It can be
modeled by adding short, broad normal distribution to the energy fluence. The source of
this component is mainly the extrafocal radiation produced from Compton scattering in
the field-flattening filter. The magnitude of the extrafocal radiation source can also be
used to account for the variation in the machine-generated output factor, because the
scatter outside the field and the increase in machine-generated output are both due to
scatter from the accelerator head (18,25).
Conventional wedges and compensators cannot be accurately modeled with primary
attenuation only. These components produce scatter and cause differential hardening of
the beam. The hardening of the primary beam can be accounted for according to the
material of the wedge and the beam spectrum as a function of radial position. Scatter
from the wedge is more difficult to account for. The increased scatter results in the
wedge factor increasing by a few percent as a function of field size. This can be
adequately modeled by a field size-dependent factor that duplicates the effect.
Alternatively, the wedge or compensator can be included as part of the patient
representation. This extended phantom has a large heterogeneity in it, namely, the air

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gap between the device and the patient. This method can predict the variation in the
wedge factor as a function of field size.

Ray-Tracing the Incident Energy Fluence Through the Phantom


The incident 2D energy fluence distribution is ray-traced through the patient to create a
3D distribution of energy fluence (Fig. 4.4). The density of the rays followed and the
sampling of the rays along their path must be sufficient to represent the attenuation
behavior of the phantom. Sufficient sampling density is especially important for head,
neck, and breast tangential fields. In general, the sampling density required is higher
than the dose resolution desired, so several rays are traversing each calculation voxel.

FIGURE 4.4 The ray-tracing of a two-dimensional (2D) energy fluence distribution through the patient to
create a three-dimensional (3D) energy fluence distribution in the patient. SSD, source-to-surface distance.

Terma is computed within the calculation matrix by multiplying the primary fluence
by the mass attenuation coefficient. The primary ray attenuation coefficient, weighted
to the appropriate beam spectrum, is based on the voxel properties. The energy fluence
at a sample point is reduced from the previous sample along the ray. Hardening of the
primary energy fluence spectrum with depth and off-axis position is accounted for by
changing the attenuation coefficient with position. The speed of the ray-tracing
operation can be improved significantly by the use of lookup tables to store
precomputed results.

Electron Contamination
The electron contamination of the beam is not accounted for in the conventional
convolution method, so an additional independent component must be added to
account for this dose. The surface dose from megavoltage photon beams is almost
entirely due to the electron contamination component. Studies in which the electron
contamination has been removed by magnetically sweeping electrons from the field
reveal that dose from the contaminating electrons resembles an electron beam with a
practical range somewhat greater than the depth of maximum dose. A reasonable

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agreement with measured depth–dose curves can be obtained by scaling the
contamination electron depth–dose curve with the surface dose and adding this
component to the convolution-computed dose distribution.

Kernel Spatial Variance and Phantom Heterogeneities


The convolution equation assumes that the kernel is spatially invariant in that the
kernel value depends only on the relative geometrical relationship between the
interaction and dose deposition sites and not on their absolute position in the phantom.
When this is true, the convolution calculation can be done in Fourier space, saving
much time. Unfortunately, this is not the case as the kernel varies with position.
The effects of hardening and divergence of the beam are small and can be calculated
in a number of ways. A multiplicative correction to the terma in the patient can be used
to correct for hardening of the kernel (17,26). Alternatively, several kernels valid for
different depths in the phantom can be used as a basis for interpolation to a specific
depth (17,19). Liu et al. showed that the correction as a function of depth is nearly
linear, and not employing any correction results in ∼4% discrepancy at 30-cm depth.
Tilting the kernel to match the beam divergence results in only a minor improvement in
accuracy for the worst-case examples (19).
Phantom heterogeneities are a more serious problem. Modeling the transport of
electrons and scattered photons through a heterogeneous phantom would require a
unique kernel at each location. Each kernel would be superimposed on the dose grid
and weighted with respect to the primary terma. What is required to make the
calculation tractable is to modify a kernel, computed in a homogeneous medium, to be
reasonably representative in a heterogeneous situation. If most of the energy between
the primary interaction site and the dose deposition site is transported on the direct
path between these sites, it is possible to have a relatively simple correction to the
convolution equation based on ray-tracing between the interaction and dose deposition
sites, and on scaling the path length by density to get the radiologic path length
between these sites. The convolution equation modified for radiologic path length is
called the superposition equation:

where ρr−r′ · (r - r′) is the radiologic distance from the dose deposition site to the
primary photon interaction site and ρr · r′ is the radiologic distance from the source to
the photon interaction site.
Woo and Cunningham (15) compared the modified kernel using range scaling for a
complex heterogeneous phantom with a kernel computed de novo for a particular
interaction site inside the phantom. The results shown in Figure 4.5 indicate that
agreement is not perfect, but the computational trends are clearly in evidence in that
isovalue lines contract in high-density regions and expand in low-density regions.

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FIGURE 4.5 Comparison of Monte Carlo–generated 6-MeV primary photon kernel in a water phantom
containing a ring of air. The dashed line is a kernel modified for the heterogeneous situation using range scaling
from one derived in a homogeneous phantom. The continuous line is a kernel computed expressly for the
heterogeneous situation. It is impractical to compute kernels for every possible heterogeneous situation, and there
is sufficient similarity to warrant the range scaling approximation. (Reprinted from Woo MK, Cunningham JR.
The validity of the density scaling method in primary electron transport for photon and electron beams. Med
Phys. 1990;17:187–194, with permission.)

MONTE CARLO
The Monte Carlo (MC) technique of radiation transport consists of using well-
established probability distributions governing the individual interactions of electrons
and photons to simulate their transport through matter. MC methods are used to
perform calculations in all areas of physics and math for any problems which involve a
probabilistic nature. Several excellent reviews of MC calculations in radiation therapy
exist (27–31), as well as an AAPM Task Group Report which discusses its clinical
implementation (32).
Although the MC method had been proposed for some time, it was not capable of
being fully utilized until the development of the digital computer in the 1940s.
Radiation transport was one of the first uses for this methodology at that time, and
public codes, such as Monte Carlo N-Particle Transport code (MCNP) began appearing
as early as the 1950s. In photon transport calculations, the Electron Transport (ETRAN)
code, developed by the National Bureau of Standards in the 1970s, was based on the
condensed history technique (discussed below) first introduced by Berger in 1963. The
Electron Gamma Shower (EGS4) code was originally developed at the Stanford Linear
Accelerator in the 1980s, and is now maintained (as the modified EGSnrc) by the
National Research Council of Canada (33).

Analog Simulations
As pointed out by TG 105, an analog simulation is the random propagation of a particle
through the following four steps: (1) determining the distance to the next interaction,

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(2) transporting the particle to the interaction site, (3) selecting which interaction will
take place, and (4) simulating this interaction (32). The initial step is performed based
on the probability that the particle will interact within the medium in question. For
example, if the probability of interaction is represented by an attenuation coefficient m,
a random interaction distance r can be determined from a random number e (between 0
and 1) by the following (30,32):

The second step is relatively straightforward, but knowledge of the mass density (and
the corresponding changes in μ) is required for heterogeneous materials. Another
random choice will be made for step 3, weighted proportionally to the relative
probabilities of interaction choices (e.g., Compton scatter vs. photoelectric absorption
vs. pair production). Finally the results of the interaction must be randomly simulated,
including the particles of new energy (if not absorbed) and trajectory.

Condensed Histories
While analog simulations work well for photon interactions, a practical problem arises
for the transport of electrons. The mean free path for electrons in the therapeutic
energy range is of the order of 10−5 g/cm2. This means that a single electron of energy
>1 MeV will have more than 105 interactions before stopping. To perform an analog
simulation of this event is impractical.
The condensed history electron transport technique was first introduced by Berger in
1963. Berger noted that most electron inelastic interactions did not lose a great deal of
energy or have a significant directional change. These “soft” interactions could be
separated by more significant “catastrophic” events, where the electron had a
significant energy loss (e.g., delta ray production, Bremsstrahlung event). The soft
interactions could be separately simulated by combining these into single virtual large-
effect interactions, while the catastrophic events can be analog simulated as described
above (30). For electrons with energies above an energy threshold, the mean free path
for catastrophic interactions is of several orders of magnitude higher.
While this approach allows for faster computations, the step size choice for the
condensed histories has been shown to produce artifacts in the results (34). However,
these issues have led to improved, high-accuracy condensed history methods (34–36).

Variance Reduction Techniques


Instead of simulating individual events as in an analog simulation, one may employ
techniques to improve the MC calculation efficiency in obtaining a particular result.
Variance reduction techniques are used to reduce the variance of a given calculation
result for a given number of histories. For example, an analog simulation of a
Bremsstrahlung event would randomly select an energy and direction (proportional to
their respective probabilities) for the resulting photon emission. Alternatively, one could
simulate the emission of a large number of photons with lower weights to better mimic
the random directional emission of these events. This particular technique is termed
Bremsstrahlung splitting (37) and is one of many different techniques which may be
employed within a particular MC code. These techniques are important in keeping
calculation times practical for most situations. However, care must be taken that the

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underlying physics is not biased by the results.

Monte Carlo Radiotherapy Dose Calculations


In principle it is possible to simulate histories for the entire radiation therapy delivery,
that is, from the initial accelerated electron’s impact onto the target to the delivery
dose. However, this would be a tremendously inefficient process, as few of these
histories would make it beyond the accelerator head to the patient. Alternatively, it is
possible to transport the particles through the patient-independent structures (e.g.,
target, primary collimator, ion chamber), and store this information for future use. This
information is known as a phase-space file, and it contains information including the
position, energy, and direction of the photons and electrons emitted from the
accelerator.

FIGURE 4.6 Illustration of the components of a typical Varian linear accelerator treatment head in photon
beam mode. Phase space planes for simulating patient-dependent and patient-independent structures are also
represented. (Reprinted from Chetty IJ, Curran B, Cygler JE, et al. Report of the AAPM Task Group No. 105:
Issues associated with clinical implementation of Monte Carlo-based photon and electron external beam
treatment planning. Med Phys. 2007;34:4818–4853, with permission.)

Figure 4.6 shows a cross-sectional view of a Varian linac which demonstrates a


possible location of a phase-space plane located distal to all the patient-independent
components of the accelerator head. Once initially computed, this information may be
continually used to calculate the dose to individual patients. It may also be
advantageous to create phase-space planes further down the beam path (c.f., phase-
space plane 2 in Fig. 4.6), particularly for standard collimator settings and/or beam
modifiers. Otherwise, these data can be projected directly onto the patient for dose
calculation.

DISCRETE ORDINATES METHOD

105
More recently several authors have reported on a direct numerical solution of the
Boltzmann transport equations (BTEs). The approach has been commercialized in the
Varian Eclipse Treatment Planning System, under the name Acuros. In particular, this
methodology has been proposed as an alternative to MC calculations, in order to
produce accurate dose distributions with a substantially reduced calculation time.

Derivation of the Transport Equations


The linear Boltzmann Transport Equation can be derived by assuming particle
conservation within a small volume element of phase space (38–40). We define a
quantity called the angular density of electrons, Ne(r,Ω,E,t), which represents the
probable number of electrons at location r and direction W with energy E at time t per
unit volume per unit solid angle per unit energy. Ω represents the unit director in the
direction of motion, that is, parallel to v. Thus, Ne(r,Ω,E,t) dV dΩ dE represents the
number of electrons at time t in a volume element dV about r, in a narrow beam of solid
angle dΩ about Ω, and energy range dE about E.
After a time Δt, these electrons have moved to position r + v Δt, and have been
reduced due to collisions within the medium by an amount e−av∆t. Here σ is the
macroscopic cross-section for electrons, and represents 1/λ, where λ is the mean free
path. Although not strictly a cross-section, σ is analogous to the photon attenuation
coefficient and has units of 1/length. For very short times Δt, the number of electrons
from this packet which have reached r + v Δt is ≈ Ne (1 – σ v Δt) dV dΩ dE.
At the same time scattered electrons from elsewhere in the medium may reach the
same position (r + v Δt). This quantity may be determined by integrating the angular
density over phase space multiplied by the probability for these interactions:

where represents the doubly differential cross-section for electron

scatter from energy E′ and direction W′ to energy E and direction W.


In addition, any additional sources of electrons produced during time Δt may also
reach position r + v Δt. In this case, the number of additional electrons at r + v Δt
becomes Q(r,W,E,t) Δt, where Q(r,W,E,t) represents the rate of electron production from
other sources. The total number of electrons at position r + v Δt is now given by the
following equation:

Dividing the equation by Δt, and taking the limit Δt → 0, we obtain

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The limit term represents the total time derivative of Ne for an observer moving with the
packet of electrons (i.e., from r to r + vΔt). It may be rewritten to simplify the equation:

The first term in Equation (4.10) represents the velocity times the directional derivative
of Ne in the direction of W. It is known as the streaming term, as it represents the
difference in the time derivative between the moving and rest frames, the latter of
which also includes the effects of electrons moving past r without any collisions.
Upon inserting (4.10) into (4.9), the resulting equation becomes:

where we have removed the arguments for simplicity. This is the basic form of the
transport equation, which is often called the Boltzmann equation because of its
similarity to the expression derived by Boltzmann involving the kinetic theory of gasses
(39). It is more often written in terms of the angular flux, Ye, where Ye(r,W,E,t) =
νNe(r,W,E,t):

Use of the Transport Equations for Photon Beam Calculations


In external beam radiotherapy, the time-independent form of Equation (4.12) is used,
since steady state is achieved in a much shorter time than that when the beam is on
(41). Equation (4.12) is an integro-partial–differential equation which can be solved
numerically using either stochastic or deterministic methods. Most reports have utilized
the latter, employing some form of grid-based numerical method in which phase space is
discretized in spatial, angular, and energy coordinates (40,42,43), although there are
some differences in the literature about which techniques are used. Finite difference and

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finite element methods are used for spatial discretization, and Boman et al. reported
using the finite-element method for all variables (40). Alternatively, the method of
discrete-ordinates has been employed for angular discretization in the Attila solver
(44,45), and in the subsequent Acuros XB algorithm currently available in the Varian
Eclipse treatment planning system (Varian Assoc, Palo Alto, CA). Energy-dependent
coupled photon–electron cross-section data are available through CEPXS, which uses
the multigroup method to discretize the particle energy domain into energy intervals or
groups (46). This class of solvers is commonly known as the discrete ordinates method,
although technically the name only refers to the method for numerically discretizing in
angle.
Up to now, we have only discussed electron angular density (or angular flux).
However, in external beam calculations, collisions involve photons, electrons, and
positrons. In principle, Equation (4.12) then becomes a set of coupled equations. For
example, excluding positron interactions, we have the following:

where represents the differential cross-section for the creation of

particle 2 with energy E, direction Ω, from particle 1 of energy E′, direction W′.

Acuros XB Implementation of the Linear Boltzmann Transport Equations


Currently the only commercial implementation of the linear BTE is the Acuros XB dose
calculation algorithm available on the Varian Eclipse treatment planning system. Acuros
XB was developed using many of the methods employed with a prototype BTE solver
developed at Los Alamos National Laboratories called Attila, which was co-authored by
the founders of Transpire, Inc. (Gig Harbor, WA) (47). Transpire, Inc., established a
licensing agreement to commercialize Attila, for a broad range of applications. Acuros
XB has adapted and optimized the methods within Attila for external photon beam
calculations (48).
Within the Acuros algorithm, both charged pair-production particles are assumed to
be electrons, and the contribution of electron-produced Bremsstrahlung within the
patient is assumed to be deposited locally.
As already mentioned, energy discretization is performed using a multigroup
representation of the cross-section. However, this is difficult for electrons where the
inelastic cross-section increases rapidly when energy losses become small. These “soft”
interactions would require a very large number of energy bins to accurately describe,
which is impractical for an efficient solution. As a result, electron interactions are
separated into large and small energy losses, the latter of which are described by a
continuous slowing-down (CSD) approximation. In this case, the angular electron
fluence is described by the Boltzmann–Fokker–Planck transport equation:

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FIGURE 4.7 Comparison of EGS4/PRESTA with Attila for a percent depth–dose calculation in a
heterogeneous phantom. (Reprinted from Gifford KA, Horton JL, Wareing TA, et al. Comparison of a finite-
element multigroup discrete-ordinates code with Monte Carlo for radiotherapy calculations. Phys Med Biol.
2006;51:2253–2265, with permission.)

In this case σee represents larger, “catastrophic” interactions that are represented by
standard Boltzmann scattering (48).
Gifford et al. (44) first performed an evaluation of the prototype solver Attila for
radiation therapy dose calculations. Dose calculations performed by Attila were directly
compared with those calculated using MC codes MCNPX for a brachytherapy
calculation, and EGS4 for an external photon beam calculation. Differences in doses
were compared, along with relative calculation speeds.
The photon dose calculation comparison was made comparing Attila versus EGS4 for
an 18-MV photon beam from a Varian 2100 accelerator. A narrow beam geometry was
used to highlight any differences in regions of electron disequilibrium. In addition, a
heterogeneous multislab phantom was used, which consisted of water, lung, and
aluminum. The Attila calculation was divided into 24 and 36 photon and electron
energy groups, respectively. A comparison of depth doses between these two
calculations is shown in Figure 4.7. The agreements here was also good, with an RMS
difference of 0.7% of the maximum dose.
Vassiliev et al. (45) extended these comparisons to include external beam calculations
of heterogeneous patient geometries. In their work, Attila was compared with EGSnrc
MC simulations for a 6-MV photon beam from a Varian 2100 for a prostate and a head
and neck case previously treated within their department. For both the BTE and MC
calculations, CT datasets were converted into a material map of four materials with
fixed densities: air, adipose tissue, soft tissue, and bone. In their comparison,
calculations were performed with the same beam geometries as those used clinically,
with the exception of beam modulation which was removed for this comparison. Dose

109
calculation differences were investigated along with the resolution of various
discretization variables required for accurate Attila calculations.
Figure 4.8 displays the material map for an axial slice through the center of the PTV
for the head and neck case. Also displayed is the resulting dose distribution performed
using the Attila dose calculation engine. The black areas on each image are regions
where the difference between the MC and BTE calculations exceeded 5% of the
maximum dose. A more quantitative comparison can be seen by looking at a dose profile
through the center of the PTV (Line “L1” on Fig. 4.8) and off-axis (Line “L2”). The dose
profiles for both the Attila and EGSnrc codes for these lines are displayed in Figure 4.9.
The overall agreement between these two methods was good, with over 98% of the
calculation points within a ±3%/±3 mm criterion.
Since the release of Acuros XB, there have been a number of planning studies
investigating the efficiency and accuracy of the discrete ordinates method. Comparisons
are made either with other planning algorithms or with measured results for a variety of
treatment sites including lung (49,50), breast (51), and nasopharynx (52). Evaluations
of Acuros for calculations within heterogeneous media (53) or for radiosurgery
treatments (54) have also been reported. The interested reader is referred to these works
for additional information.

FIGURE 4.8 A: Dose field calculated by Attila for a head-and-neck case on the axial plane through isocenter.
Pixels, where the dose difference between Attila and Monte Carlo (EGS) exceeds 3%/3 mm, are shown in black
on A and B. B: Material map through the axial plane containing the isocenter for the dose distribution
calculated in A. (Reprinted from Vassiliev ON, Wareing TA, Davis IM, et al. Feasibility of a multigroup
deterministic solution method for three-dimensional radiotherapy dose calculations. Int J Radiat Oncol Biol Phys.
2008;72:220–227, with permission.)

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FIGURE 4.9 Dose line plot comparisons between EGSnrc (red) and Attila (blue) along line L1 A and L2 B in
Figure 4.8. Sharp peaks and dips in the Attila solution correspond to material heterogeneities, which are revolved
at the CT image pixel level by Attila. (Reprinted from Vassiliev, Wareing TA, Davis IM, et al. Feasibility of a
multigroup deterministic solution method for three-dimensional radiotherapy dose calculations. Int J Rad Onc
Biol Phys. 2008;72:220–227, with permission.)

KEY POINTS
• Modern radiation therapy planning systems have evolved tremendously over the past few
decades. A number of complex model-based photon dose algorithms exist which calculate
dose to a 3D representation of the patient. These algorithms have been developed in response
to improvements in algorithm development, computing power, and greater availability of
volumetric imaging data.
• Today, most commercial photon dose algorithms are a variation of the
convolution/superposition method. As algorithm development and computing power

111
improve, the use of MC and discrete-ordinates methods which better incorporate
nonequilibrium dosimetry will likely increase.
• A convolution/superposition model should account for the following characteristics:
• Off-axis energy variations
• Finite source size
• Extrafocal radiation
• Scatter and attenuation from beam modifying devices

• MC algorithms track histories of individual photons and electrons that undergo hard
(“catastrophic”) collisions. Soft electron collisions are dealt with using condensed history
methods.
• The discrete ordinates method represents a numerical solution to the coupled Boltzmann
transport equations. In this method, the energy, position, and direction of the radiation
quanta are discretized for the numerical solution of the integro-differential equations.
• Photon beam optimization presents additional challenges within the planning process. The
need to calculate dose rapidly under conditions of changing incident fluence is necessary in a
modern radiotherapy clinic.

QUESTIONS
1. Which of the following algorithms is/are measurement based?
A. Bentley–Milan
B. Convolution/Superposition
C. Monte Carlo
D. Discrete ordinates
2. Which of the following is/are used to speed up a Monte Carlo dose calculation?
Choose all that apply.
A. Variance reduction technique
B. Condensed history method
C. Kernel tilting
D. Density scaling
3. Which of the following algorithms account for nonequilibrium conditions (e.g., at
tissue interfaces)? Choose all that apply.
A. Bentley–Milan
B. Convolution/Superposition
C. Monte Carlo
D. Discrete ordinates
4. For a typical 6-MV beam, an error in CT number of 2% leads to an error in dose
of around:

112
A. 0.1%
B. 1%
C. 5%
D. 10%
5. The inelastic photon scattering processes which must be accounted for include
A. Rayleigh scattering
B. Moller scattering
C. Photoelectric absorption
D. Bremsstrahlung interactions
6. The convolution dose equation cannot be solved using Fourier analysis primarily
because
A. Scatter kernels are depth dependent
B. Patient heterogeneities
C. Beam hardening within the patient
D. Step-size artifacts

ANSWERS
1. A
2. A and B
3. C and D
4. B
5. C
6. B

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5 Treatment
Brachytherapy
Planning Algorithms:

Kenneth J. Weeks

INTRODUCTION
Brachytherapy involves the treatment of cancer using photon, electron, and positron
emissions from radioisotopes. Brachytherapy was developed using naturally occurring
radioisotopes such as radium 226. The history, applications, and emission details of
radioisotopes are described elsewhere (1–5). It is the goal of brachytherapy treatment
planning to determine the number of sources, their individual strengths, and the
location of each source relative to the treatment volume, so as to treat a localized
volume to a given minimum dose while respecting tolerances of normal tissues. It is
important to note that the original brachytherapy clinical applications were developed
realizing that brachytherapy demanded 3-dimensional (3D) planning because the
sources were distributed in three dimensions. Because of this fact and the absence of
computers, these original treatment systems were all inclusive. They were systems with
rules for distributing the sources, rules for picking and arranging source strengths, and
given the latter, precalculated dose-rate tables for determining the dose to a point. The
Manchester, Paris, Stockholm, Memorial, and Quimby systems (1–5) all specified in
alternate ways how to do this for interstitial and intracavitary implants. See Chapter 15
for discussion of these systems. From this history we can obtain knowledge of the range
of the radioactive source applications, which is important in devising dose calculation
algorithms. Thus, we summarize guidelines, which include the following: When
distributing lines of sources, attempt to keep them spaced no closer than 8 mm (smaller
volumes) and no farther than 2 cm (larger volumes) apart. The periphery of the
treatment volume is generally not much farther than 5 cm from the center of gravity of
the source distribution. The very high doses close (less than 5 mm) to the sources are
not prescribed or evaluated as to clinical significance. At distances greater than 10 cm
from the center of the implant, the dose delivered is low and the precise dose is not
considered a treatment objective. Therefore, we conclude that dose calculation
algorithms that are very accurate from 5 mm to 5 cm and generally accurate to 10 cm
are required. The availability of computers and advanced imaging capabilities means
precalculated dose tables for predetermined patterns of multiple sources are no longer
required. Calculation of the dose distribution for the individual patient’s source
distribution is possible.
Radioisotopes decay randomly with a time independent probability (1,3,5,6). If there
are N0 radioactive atoms at time t = 0, then at a later time t we have N(t) atoms given
by

where l (0.693/T1/2) is the radioisotope’s decay constant and T1/2 is the half-life (time
it takes for half of the sample to decay). The activity (A) at time = t, is proportional to

117
the number of radioactive atoms present and is defined by

where A0 is the initial activity. Throughout the following we will consider the
calculation of the dose-rate, (in cGy/h). The total dose D delivered during an implant
which lasts for time t, is found from the initial dose-rate, , at the start of the implant
from

for the case t >> T1/2, for example, a permanent implant, the total dose (D) is simply
whereas if t << T1/2, D = t . Throughout the following, we will
calculate the dose-rate at the start of the implant . The total dose delivered in time t
is then found from Equation 5.3.
The isotope emits energy (in the form of photons, electrons, and sometimes positrons)
in all directions and that energy is absorbed in the mass (tissue) around the isotope,
giving rise to absorbed dose (absorbed energy/mass). The calculation of dose-rate
depends on the number of radioactive atoms, the types and energies of the emitted
particles, the time rate of emission of those particles, and finally the energy absorption
and scattering properties of the surrounding media and the radioactive material itself.
In this chapter, we will begin with the simplest case of a point source. From there we
will use the point source result to determine the dose-rate for an ideal line source and
then a real clinical cylindrical source. Finally, we will obtain the dose-rate distribution
for a 3D source/shield/applicator via numerical integration of the point source result.
Various intermediate parameterized calculation methods are discussed. This inevitably
leads to systems which explicitly model the flow of energy from the radioactive sources.
These include Monte Carlo and Boltzmann transport theory. These latter techniques owe
their existence to the extensive computation power now available. The advantages and
disadvantages of these methods will be discussed.

CALCULATION OF DOSE-RATES AROUND A POINT SOURCE


A point source is the simplest situation to calculate. The first approximation, used in
radiation oncology, is to ignore the charged particle emissions and consider only the
photons. The significance of this approximation is best understood by reviewing the
basic nuclear decay data (7). Consider the well-known 192Ir which has a half-life of
73.8 days and decays via β decay (95% of the decays) or electron capture (5%). The
decay of a single 192Ir nucleus produces on average 2.38 photons (there are 44 possible
photon energies ranging from 7.8 to 1,378 keV which can be emitted in a single decay
event) and 0.95 β-decay electrons (with the β decay continuous energy spectrum
ranging from 0 to 669 keV). In addition, atomic electrons can be emitted with various
discrete energies ranging from 11 to 1,378 keV. In a single decay, the average total
energy output from photons is 813 keV (note the average energy of the photons is
therefore 341 keV from 813 keV/2.38) and the average electron energy output is 216
keV (7). Therefore, the total average energy output per decay is 1,029 keV. Our decision
to ignore the emitted electrons means we are going to ignore around 21% of the total
energy output from the source in our dose-rate calculations. Why is this justified? The
reason is that practical commercial sources used for Radiation Oncology will be
encapsulated radionuclides and that encapsulation will scatter and slow down the

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electrons such that most do not leave the source capsule itself, and for those that do
escape, their range in tissue outside the source is much smaller than 5 mm and thus will
not contribute dose at a clinical prescription distance. This encapsulation of the source
is essential for the clinical use of most isotopes used in radiation oncology. Historically,
in the early days of radiotherapy, in the United States, a clever technique to enclose
radon gas in glass capsules was developed. The high energy of the β particles and the
light filtration led to unfavorable clinical results (4). We end this discussion with the
observation that there can be a major clinical dose distribution difference between an
encapsulated and an insufficiently encapsulated radionuclide.
Consider a sample of radioactive material whose largest dimension is much smaller
than 0.1 mm. This will be small enough so that all atoms can be approximately
considered as located at a single point. Restricting ourselves to the photon emissions
from the point source, we will first think about the dose-rate produced in a small
volume (dV) of tissue located at a distance (r) from the source. For simplicity, consider
the source in vacuum (so no scatter) and that in each decay it emits exactly one photon
with energy E. The situation is shown in Figure 5.1. The dose-rate in dV must be equal
to the product of the following: time rate of emission of the photons, that is, activity A,
the probability of the photon hitting dV (we will abbreviate that as P(r,dV)), the
probability that the photon of energy E which hits dV actually interacts with dV as
opposed to just passing through (P(E,dV)), and the average amount of energy (dEabs)
that is absorbed in dV whenever a photon interacts with it, all divided by the mass (m)
of dV. The units are energy/mass/time, which is dose-rate. Explicitly,

FIGURE 5.1 Point source (S) emission of photons (wavy lines) in vacuum. Direction is random. Only the
photon emitted straight at dV can deposit energy in dV and only if it randomly interacts with the material in dV.

FIGURE 5.2 Point source (S) emission of photon radiation in vacuum. Cross-sectional area (da) of small
material volume dV faces the source. dV is moved from radius r to radius R causing a reduced probability of
being hit by the photons by the factor r2/R2.

The first question is, what happens to the dose-rate in dV if we simply change its
distance from r to R (Fig. 5.2)? The two things that do not change, at all, are the

119
activity of the source and the mass of the tissue that we move around. P(E,dV) and dEabs
should not change if the angles with which the photons hit the volume are similar, that
is, the solid angle subtended by dV is small. So we are left to focus on the probability of
a photon hitting dV. When a nucleus decays and gives off a photon, that photon is
emitted isotropically, which means the photon is equally likely to go in any direction.
Let the cross-sectional entrance area of the mass m be denoted as da (Fig. 5.2). Of
course, the total surface area at a distance r is 4pr2. So the probability of a photon
emitted in a random direction hitting da after it has traveled a distance r is

If we move dV to a larger distance R, the probability of hitting da now equals da/(4pR2).


Therefore the probability of hitting da has been reduced by a factor of r2/R2 in moving
from r to R. This suggests that we can try and approximate Equation 5.4 as simply

where we have defined c = P(E,dV)dEabs/m and we are hoping that c is constant, under
the assumption that the factors in c do not change much as we move the small volume
around in vacuum.
In Equation 5.6, it is understood that we should not move the little volume of tissue
someplace where it makes no sense to assume that c remains constant. A
counterexample best illustrates why it is not true that c is a constant. Suppose that we
had moved the volume dV and centered it on r = 0, so that it completely surrounded
the radioisotope. The factor P(r,dV), where we got r2 from in the first place, is now P(r
= 0, dV) = 1, that is, every photon emitted from the radioisotope hits the volume. One
can easily see from Equation 5.4 that the dose-rate does not become infinite at r = 0 (as
Equation 5.6 implies); in fact, depending on the photon energy (E) and the size of dV,
the dose-rate (from the photons emitted) could be extremely small. This example clearly
shows that the algorithms we devise to calculate dose-rate have their regions of validity.
Historically, radioisotope emissions were first measured in air. In particular, the
concept of exposure (1,3,5,6) (amount of ionization of air per unit mass) was used
extensively because charge collection in air-filled cavities are the easiest measurements
to make. The process was: first, measurement of exposure rate in air; second, conversion
of that exposure rate in air to dose-rate to a small amount of tissue in air; and finally,
conversion to dose-rate to a point in the patient. The result of this process (1,3) led one
to define a dose-rate to a small amount of water at a distance r surrounded by air as

where the single constant c in Equation 5.6 is split into two constants. Γ is the exposure
rate constant (1,3,5) (in units of R cm2/mCi/h) which represented the conversion of
photon energy to ionization of air for the given isotope and fmed (in units of cGy/R) is
the conversion constant from exposure in air to dose to medium (water) at the average
photon energy given off by the radioisotope. Normally, people choose to express dose to
water since its radiation properties are similar to tissue and measurements were/are
made in water. Values of fmed (range 0.88–0.97 cGy/R) and Γ (range 1.45–13 R

120
cm2/mCi/h) for various radioisotopes are summarized in the literature (1,3,5).

FIGURE 5.3 Point source (S) emission of photon radiation in homogeneous water medium. Wavy lines are
photons, straight lines are electrons, and crosses (x) mark photon interaction points. Three photons are followed.
Photon a: Compton scatters above dV, the electron produced misses dV, the Compton photon scatters again (just
above dV). The Compton electron after slowing down deposits its remaining energy in dV. Photon b: It was
aimed right at dV coming out of S but halfway there was scattered. Both the Compton photon and electron miss
dV. Photon c: Compton scatters below dV and the scattered photon heads right for dV and is photoelectrically
captured inside dV, its photoelectron (not shown) is absorbed in dV.

In Equation 5.7, we have the dose-rate to water in air, but what we ultimately want is
the dose-rate in water (i.e., to the patient). Let us look again at a source radiating
photons toward dV but this time in a full water medium. Figure 5.3 shows three
examples of photon histories. First, a photon that was going to miss dV (a in Fig. 5.3) is
scattered several times; eventually, a secondarily scattered electron deposits a fraction
of the original energy into dV. Second, a photon (b) which is emitted from the source
aimed right at dV interacts on the way there and no part of its energy reaches dV.
Finally, a photon (c) which was going to miss dV interacts and the scattered photon
from that interaction is completely absorbed in dV.
One thing we might guess is that inverse square is not going to be valid anymore
because how dV absorbs energy is much more complicated. However, we remember that,
inverse square was not a law anyway, and what we want is an approximation in a
restricted region of interest. In any event, we could start by describing the dose-rate to a
point r in water as

In this equation the major effect of attenuation is represented in the first term where we
exponentially attenuate the in-air dose-rate of Equation 5.7 with the linear attenuation
coefficient (μ) for water for the average energy E emitted by the radionuclide (roughly
0.1 cm–1) (1,3,5). The exponential attenuation factor takes care of one of these effects
above (photon [b] in Figure 5.3), scatter out of the path from the radionuclide to dV.
Dscat now represents the result of all the various scatter possibilities and is far more
complicated. Equation 5.8 has merely organized the calculation into a primary part and
a secondary scatter part. Now we note in Figure 5.3 that the attenuation scattering
events [b] reduce the dose-rate in dV but the scatter events [a and c] increase the dose-
rate relative to the (Fig. 5.1) in-vacuum case. Maybe, if we get lucky, these will cancel
out. It turns out that scatter and attenuation effects do not cancel out at all distances
from the source, but close to the source they almost do and their change with distance

121
farther away can be simply parameterized. Meisberger et al. (8) showed that the
measured variation in dose-rate in water as r changed from 1 to 10 cm was such as to
establish Equations 5.9 and 5.10 as a good approximation for the dose-rate to water

Application of this algorithm (Equation 5.9) has, in the past, been a popular choice in
commercial computerized treatment-planning systems. Technically, fmed should now be
a function of r to account for the lower energy of the scattered photons with greater
distance in water (9,10); however, that detail is usually ignored. Comparing the in-air
Equation 5.7 with the in-phantom Equation 5.9, the difference is simply the inclusion of
the parameterized factor T(r). T(r), the attenuation and build up factor, is a polynomial
in r (Equation 5.10) which Meisberger et al. (8) used to represent the ratio of the
exposure in water to the exposure in air. The free parameters A,B,C, and D are
determined by least squares fit to the experimental data for each isotope. One notes
(1,3,5,8) that A is close to 1.0 and that B,C,D are on the order of 10–3 or less. Because
of this, the value of T(r) is very close to 1.0 up to a certain distance. Attenuation and in-
scatter are balanced at a distance rA where T(rA) = 1.0. Hale (11) pointed out that in-
scatter cancels out the attenuation loss, which was not obvious. For instance, if we
consider 137Cs (E = 662 keV), the distance is around 3 cm. If we estimate the reduction
in dose from attenuation of 3 cm of water (using μ = 0.086 cm–1) we would expect a
23% drop off. Clinically, the fact that a simple dose calculation such as in Equation 5.9
can be used, instead of something as in Equation 5.8, makes calculations easy both by
hand and by early computers and has been extremely useful. The mathematical form,
Equation 5.10, which was chosen by Meisberger et al. (8) for T(r) is not a unique
parameterization of the attenuation and scatter effects. One could use the form
proposed by Evans with equal ease (12)

Kornelson and Young (13) fit the coefficients ka and kb to Monte Carlo results (14).
Venselaar et al. (15) extended the range of the fitted data to 60 cm. Other mathematical
expressions (16–18) have been utilized; there is little difference of clinical significance
between them or Equations 5.9 and 5.11. The reader should note that Equations 5.9 or
5.11 can be used to perform quick hand check verifications of clinical implant plans. If
one looks at a dose-rate at a point 10 cm from the implant center, all the implanted
sources can be considered approximately as one point source located at the center of
gravity of the implant. Add all the activities together and calculate the cGy/h value
expected and compare it to your treatment planning system isodose line. One cannot
use this method to determine a small error in the computer plan result but one can use
it to uncover the presence of a major error.
Comparing Equations 5.8 and 5.11, the first term is identical and is the attenuated
primary in-air dose-rate. Comparing the second terms, one can see that Equation 5.11
assumes that is proportional to the attenuated primary dose-rate. This is physically
reasonable since scatter comes from the attenuation that occurs in the out-of-path
directions and this should be similar to the in-path attenuation. To the extent that this

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is not true, we make up for that by letting ka and kb be completely free parameters for
each different isotope. Fitting the parameters can be done in two ways: fitting the free
parameters to match measured data, or fitting (13–15) to match a better calculation
such as Monte Carlo. All the parameters (A,B,C,D, and ki) have no direct physical
meaning, they are chosen to allow us to describe the dose-rate as accurately as possible.
Because of that, it is required to keep track over what range of data the parameters
were determined. For example, the best-fit value of D just happens to be negative
(1,3,5,8) for 192Ir, 198Au, and 137Cs. Hence, at large distances (r > 25 cm), where the
r3 term in Equation 5.10 dominates T(r), T(25 cm) is negative, and therefore Equation
5.9 predicts negative dose-rate for those isotopes at large distances. This negative dose
result arises because we have applied Equation 5.9 outside the range of the fitted
parameters and have obtained a nonphysical (wrong) result.

CALCULATION OF DOSE-RATES AROUND A LINE SOURCE


In Equation 5.9, we now have an expression for the dose-rate in water due to a simple
point source. We can now apply this result (we could have just as easily used Equation
5.11 instead) to help us calculate the dose-rate from different source geometries. The
next simplest case is a line (length L) of radioactive material (Fig. 5.4). In the point
source case, we had spherical symmetry, which meant that the direction from the source
did not change the dose, only the distance (r) did. With a line source we need to
consider direction and distance relative to the center of the line. There is still symmetry
remaining, specifically rotational and reflection symmetry, so if we can calculate the
dose-rate to every point in the shaded region of Figure 5.4, the dose-rate anywhere else
in the patient volume is determined without calculating. For example, the dose-rate at P
in Figure 5.4 is the same as at point B (reflection of P with respect to Y–Z plane), C
(reflection of P with respect to X–Y plane), or D (reflection of B with respect to X–Y
plane). Moreover, any point off the plane (y ≠ 0) of Figure 5.4 that can be mapped to a
point in the plane of Figure 5.4 by a rotation about the z-axis will have the same dose-
rate as that point in the plane.

FIGURE 5.4 Line source geometry. Dose-rate calculation to point P depends on distance and direction (r, q) of
P from the source center. The active length (L) defines angles (q1 and q2) from the endpoints of the line source
to point P. β = q2 − q1 is the angle from P to the endpoints of the active source. Results need only be calculated
for the shaded quadrant, dose to points B, C, and D will be identical to point P by symmetry, likewise for all
points in 3D space obtained by rotation of the source about the z-axis.

123
The solution can be found in an analytic form by defining an activity per unit length
(A/L) of source and integrating the point source expression of Equation 5.9 along the
line of the source (dl) to obtain the dose-rate at any point P(r, q) in the plane (19). The
final result

L is the active length of source and β = q2 − q1 is the angle subtended by the line
source when viewed from point P.

CALCULATION OF DOSE-RATES AROUND AN ENCAPSULATED


CYLINDRICAL SOURCE
Most applications in radiation oncology entail the use of encapsulated (e.g., stainless
steel) cylindrical sources. Consider a cylindrical source S (radioactive source radius rS,
active length L) and enclose it (Fig. 5.5) inside a cylinder of encapsulation material
(radial wall thickness t and end cap thickness te). Again, we will consider the active
source region to be divided up into many small point sources and determine the
contribution from each point source separately using Equation 5.9 and add the results.
Clearly the first-order effect of the encapsulation will be to reduce the dose-rate by an
amount that depends on the path lengths through the encapsulation. As the path length
through the encapsulation from every small point source to a given dose point is
different, the reduction will be different in different directions. The solution to an
encapsulated line source was given by Sievert (20). He presented the equivalent (T(r)
was ignored in those days) of the following expression for the dose-rate at a point P
located at planar coordinates r and q (measured from the radioactive source center, Fig.
5.5)

FIGURE 5.5 Cylindrical encapsulated source geometry, thickness of encapsulation is t, radius of source is rS,
and the end cap thickness is te. Radioactive material in the source region is subdivided into N tiny regions.
Photons from each of the regions are attenuated by their path length through source material and encapsulation.
Dose-rate at P (located at r, q from center of source) involves repeated application of point source calculation for
all N cubes. For the ith cube, its distance to P is ri, the path through the source material is dSi, and through the

124
encapsulation is dei.

where μe is the attenuation coefficient for the radioisotope’s photons through the
encapsulation material, t is the perpendicular wall thickness of the encapsulation, and
q1 and q2 are the angles from the point P to the ends of the active length of the source.
The integral expression in Equation 5.13 is the Sievert integral, which can be numerically
evaluated with a computer. Young and Batho (21) later provided expressions for an
effective wall thickness accounting for source radius. As an aside, Γ would be the
unfiltered exposure rate constant in Equation 5.13 because the attenuation of the
source’s photons by encapsulation is explicitly calculated. The differences between
filtered and unfiltered exposure rate constants are discussed in detail elsewhere
(1,3,5,6,22,23).
Equation 5.13 is valid for points (such as P in Fig. 5.5) in the patient where path
lengths do not go through the ends of the source. Expressions (19,20) that give the
dose-rate in the other geometrically distinct regions (through ends of the source
capsule) will not be presented here, as calculations involving numerical integration (21)
can be obtained with computers. We can present a single equation for calculation
anywhere in the region by numerical integration. We subdivide the source volume into
N equal parts. Each little source volume element i contributes independently to the dose-
rate at P. The dose-rate at a point P located at r, q, from the center of the source is given
by adding all N exponentially attenuated point source contributions

where dsi (dei) (Fig. 5.5) are the individual path length distances through the source
(encapsulation) material from tiny source region i to point P. For a clinical 137Cs source
N = 100 is a fine enough subdivision. The effects of the attenuation coefficient of the
source (μs) and its path length (dSi) are included. The numerical integration method in
one form or another has been used often in the past (21,24–28). In Equation 5.14, the
coefficients μ are either chosen to give the best fit of Equation 5.14 to experimental
measurements or directly measured. If the coefficients are directly measured, one sees
that measurements (28) of attenuation produced by materials relative to attenuation by
water work better than linear attenuation coefficients in Equation 5.14 because the
material is a perturbation of the water medium and not a perturbation of air medium.

ENCAPSULATION AND THE LOW ENERGY PROBLEM


In our discussion up to now, we have avoided details such as where we get the activity
(A) of a given source, what is the correct way of calculating the exposure rate constant,
how does one calibrate a source and the relationship of the latter procedures to the final
step, and calculation of dose-rate. To get an idea of the ambiguities, consider a
hypothetical encapsulated source where a manufacturer makes the encapsulation
container from lead and the radioactive material emits a photon of energy 30 keV in
half of the nuclear decays and a photon of energy 1 MeV in the other half. If we were to
measure the output of this encapsulated source we would never detect the decays
wherein photons of 30 keV are produced because the lead would absorb them. The
activity we would infer from measurement would then be less than what it really is
because we would only be aware of half the decays. We would be in a dilemma to call

125
that measured activity the activity, because the activity is essentially a measure of the
actual number of radioactive atoms (Equation 5.2). This example illustrates why there
arose a need for “apparent activity.” In short, the source manufacturer would tell you
the “apparent activity” under the assumption that you would use the same value of Γ
that he used to derive his apparent activity. Then when you multiply A and Γ together,
you will get the correct result. Look at Equations 5.9 to 5.14; notice that what you need
to calculate the dose correctly is the value of AΓ. You do not need the true activity A
and the theoretical Γ. We emphasize that you have to check that the value of Γ that the
source manufacturer quotes it uses matches the value in your treatment planning
system in order to use the source manufacturer’s reported activity. As an aside, it is no
wonder that the use of mg Ra eq (1,2,3,5) for quantifying activity lasted so long after
the abandonment of radium implants because everyone agreed that the value of Γ =
8.25 (R cm2/mg Ra eq hour) for radium filtered by 0.5 mm of Pt would be the value you
would use for all isotopes.
The second problem (opposite in nature to the first) comes from the details of
calibration of the sources. It is easier to measure the emission output of a radioisotope
in air than in water. Suppose a low energy photon is given off by the source and it gets
out of the capsule or is scattered from the capsule, giving rise to a photon even lower in
energy, and such a photon travels through air and its ionization is measured by the
detector. By everything said above, for determining the activity, that seems like a good
thing (a nucleus decayed and its effect was registered). However, suppose that photon is
so low in energy that it would be absorbed very quickly by tissue (within an mm or so).
Its effect is included in the calibration of the source in air but clinically it is of no
significance in delivering a dose at a distance in a patient (29). Therefore its effects
should be excluded.

TWO-DIMENSIONAL DOSE CALCULATION FORMALISM


It should be noted that both these problems were present even from the earliest days of
brachytherapy using radium (1–3). The problems were not a great enough danger to
warrant rethinking the dose-rate calculation formalism till low-energy sources such as
125I and 103Pd came into clinical use. It has been recently decided to define a more
consistent method. Task Group 43 (TG43) of the American Association of Physicists in
Medicine (AAPM) recommended the adoption of a new system (30–34) for calculating
the dose-rate to water for low-energy sources. This system is designed to be consistent
from calibration of the source by the accredited calibration laboratories to the final
clinical calculation for the patient. The 2-dimensional (2D) dose-rate equation for
cylindrically symmetric encapsulated sources in the TG43 formalism (30) is given by

This dose-rate equation is a 2D calculation as points in the plane with coordinates r and
q are calculated and all other points in 3D space are then found by rotation about the z-
axis. Equation 5.15 is really a choice between two equations, where X = P signifies that
you will use a point source geometry factor and X = L indicates a line source is used.
All quantities in Equation 5.15 are referenced to a single reference position, usually ro
= 1 cm and qo = 90o (i.e., 1 cm from the source center in a direction perpendicular to
the symmetry axis of the source, e.g., 1 cm along the x-axis in Figure 5.5). The product

126
SK is the dose-rate in water at the reference position, ro, qo.
Two new quantities are defined in Equation 5.15. First, the air kerma strength
(1,30,33), SK, gives a measure of the absolute amount of radionuclide available. Its
source calibration unit U equals cGy cm2/h by definition. The air kerma strength is the
air kerma rate in vacuum times d2 (due to photons of energy greater than a cutoff
energy, >5 keV, measured with a free air chamber centered at a distance d); d is
usually 1 m. This energy cutoff (5 keV) is chosen so that the calibration effects of low-
energy photons (which ultimately would not contribute to tissue dose at distances
greater than 1 mm from the source) are subtracted from the calibration result. Source
manufacturers now provide both the air kerma strength (referenced to the reference
position) as well as apparent activity (for historical comparison). Typical conversions
from air kerma strengths to “apparent activity” values (U/mCi) for isotopes used
clinically are 1.27, 1.29, 2.86, and 4.12 for 125I, 103Pd, 137Cs, and 192Ir, respectively.
The second new quantity in Equation 5.15 is the radionuclide’s dose-rate constant,
(units = μGy/h/U at 1 m). The dose-rate constant is the ratio of a reference dose-rate
(ro,qo) in water to SK. The dose-rate constant is determined once and for all for each
manufacturer’s source via Monte Carlo modeling plus experimental measurements
usually with thermoluminescent dosimeters (TLDs) (30,31,35–38). There are errors in
both methods, so results are averaged to produce a “consensus” value for (31,35).
G(r, θ) is a new symbol for the simple geometry dependence already seen in Equations
5.9 and 5.12, namely, point (P) source and line (L) source (30,31,39). G accounts for
the main effects of distance and direction of source from point of measurement. TG43
defines GP and GL,

The ratio of G(r,q) to the reference value G(ro,qo) is explicitly indicated in Equation
5.15.
In Equation 5.15, the radial dose function g(r) redefines the traditional attenuation
and scatter build-up factor. It accounts for photon attenuation and scatter in water in
the radial direction to the source symmetry axis (qo = 90o). The radial dose function is
essentially fmed(r)T(r) renormalized so that g(ro) = 1.0. Since we know that the
parameters of Equation 5.10 can be fitted accurately, it is not surprising that a
polynomial expansion can be used to accurately represent g(r)

where X = P or L means that one compares their dose-rate data (at varying positions r
with qo = 90o) to their calculations using Equation 5.15, and determines the six
coefficients ai in Equation 5.18 using point or line source formula Equations 5.16 or
5.17 for the geometry factor. The dose-rate data required to determine the radial dose
functions come from Monte Carlo calculations and are verified by measurements. Each
radioisotope has its own set of ai determined (5,30,31,40,41).

127
The anisotropy of source distribution function F(r,q) is introduced to account for
differences in dose-rate as a function of angle from the symmetry axis due to the
specific geometry of the encapsulation of the radionuclide source. In other words, it
takes into account the different path lengths through the source and encapsulation at
various angles. If we have information on the dose-rate in all directions (such as from
Monte Carlo modeling or numerical integration or the Sievert integral) then the
anisotropy function can be determined (5,30,42–44) from Equation 5.15. The
normalization for F is, F(r, qo = 90o) = 1.0.
In high dose-rate afterloader applications using 192Ir (Chapter 16), there is a single
high activity cylindrical source. Optimization techniques (Chapter 16) are used to vary
source dwell times at various positions in fixed implanted catheters. Because you must
localize the catheters to plan the patient, you have the orientation of the source
symmetry axis in the patient at all possible dwell positions and therefore you can
determine the angle q in Figure 5.4 for any position P. Therefore one uses the 2D dose
calculation (X = L) of Equation 5.15. Similarly 125I seed sources loaded into a fixed
geometry eye plaque for ocular melanoma treatment can use the line source form.
There is a practical problem in using Equation 5.15 for cylindrical sources that are
not constrained to be in a definitive geometric orientation by the applicator which holds
them. Namely, it is not always easy to determine orientation. Consider permanent
prostate implants which use 125I seed sources. Computed tomography (CT) scans
and/or radiographs cannot easily provide the necessary resolution to determine the line
direction in 3D space for all the sources, (though methods are being developed to do
that (45,46)). So we definitely have line sources but we cannot determine each angle q
(from each and every source to each and every point P). Thus we are forced to use the
point source geometry factor. In this event, one can use a better approximation (31).
Although the anisotropy function is a function of r and q, one can average F over the 4p
geometry and F can be approximated by a simple radial function, fan(r), called the 1-
dimensional (1–D) anisotropy function, e.g. this results in a roughly a 5% reduction for
192Ir (5,31). Where a 2D calculation cannot be used for cylindrical sources, the revised
TG43 protocol (31) recommends the use of

Compare Equation 5.19 to Equation 5.15 (with X = L) with respect to the geometry
function. In Equation 5.19, the line source geometry formula is used but regardless of
what the angle q is on the left side of the equation, we evaluate the right-hand side
using q = qo = 90o. The advantage of Equation 5.19 is that it is more accurate for
cylindrical sources at distances less than 1 cm than if we use Equation 5.15 with the
point source approximation (X = P).
It is important to understand the methodology behind the 2D dose calculation
algorithm provided by Equation 5.15. A point or line source approximation for the
geometry function is chosen (this choice is determined by practical realities in most
cases as almost all clinical sources are cylinders). Experimental measurements and/or
Monte Carlo calculations provide the desired 3D dose distribution answer. The radial
dose-rate function in point source geometry is then determined by choosing the
parameters of Equation 5.18 so that multiplying all the factors together at points where
q = qo = 90o yields the correct dose-rate (which you already know from the full 3D
Monte Carlo result) at those points. Once you have that, you can determine the

128
anisotropy factor, in the same way using the already known correct dose distribution.
One can either store a table of results (5,30,31) or create a fitting function to reproduce
the results. Furhang and Anderson (47) proposed the functional form:

where a, b, c, and d are polynomials in r with a total of 12 free parameters. Sloboda and
Menon (48) fit those parameters to the results of Monte Carlo calculations. Ling et al.
(49) had also used a similar parameterization to fit the dose-rate results for an 125I
source.
Equations 5.9, 5.11, 5.12, and 5.14 can be converted to the more modern formalism
by substituting SKg(r) for fmed AΓT(r). For example, Equation 5.14 for the dose-rate
about a cylindrical encapsulated source would be

where SK would have been determined for the encapsulated source; hence already
accounting for source size and encapsulation, we subtract the source radius, rS, and the
encapsulation wall thickness, t, from the path differences.
Finally, let us review the rationale of the change in Equation 5.15. In the old system,
calibration in air, calculation in air, and then conversion to dose in medium was the
calculation process. The new TG43 system is more akin to external beam calculations. In
Equation 5.15, SK is the cGy/h calibration in water at a reference position (the analog
of linear accelerator calibration at dmax). The product of G(r,qo) and g(r) is like a depth
dose correction along the x-axis in Figure 5.4 normalized at ro. Finally, F(r,q) is like
external beam off axis ratios. Looked at in this way, the new formalism does not look so
foreign.

THREE-DIMENSIONAL DOSE CALCULATIONS—ASYMMETRIC


DOSE DISTRIBUTIONS REQUIRED BY APPLICATORS AND
SHIELDS
Some treatments involve the use of asymmetric metal applicators to introduce the
radioactive sources into the body. In treatment of carcinoma of the uterine cervix (1,2)
some of the applicators have tungsten shields attached, which provide a severe
asymmetry in the measured dose-rate distribution. The measurement (27,28,50,51) of
dose-rate in the presence of these asymmetries shows that the effects are to reduce dose-
rate in particular directions (geometric shadow of the shields) by up to 40%. These
applicators clearly have an effect on the dose-rate distribution that is different in
different directions; hence the dose-rate algorithm must calculate dose-rate over the
entire 3D grid centered on the source (25,27,28,52–54). Now because clinical use
involves a source loaded into the same applicator with shields every single time, the
calculation can be done once for the source/applicator/shield and the result for that
dose distribution stored on the computer. Figure 5.6 shows that the dose point P has
paths from the various source volume elements that miss or go through the shield.
Numerical integration can be extended to this case quite easily, thereby accounting for
primary attenuation for path length through source (S), encapsulation (e), shield (Sh),
and applicator housing (A). The expression is the following:

129
FIGURE 5.6 Asymmetrical source/applicator/shield geometry. Radioactive material in source region is
subdivided into N tiny regions, photons from each of the regions are attenuated by their path length through
source material, encapsulation, shield material, and applicator material. Dose-rate at P (located at r, q from
center of source) involves repeated application of point source calculation for all N regions. For the ith cube, its
distance to P is ri, the path through the source material is dSi, through the encapsulation is dei (the latter two are
not shown here, see Fig. 5.5), the path through the shield material is dShi, and the path through the applicator
material is dA i. For the jth cube, its distance to P is rj, its path misses the shield and the path through the
applicator material is dA j.

The path length intersection differences (d) have to be evaluated for every direction and
the μ are free parameters. The strength of Equation 5.22 is that it is simple and the 3D
results can be obtained clinically fast. The 3D calculation for a point P in Equation 5.22
involves numerous ray line (the radial direction from each source subvolume piece to
the point P) calculations. The attenuation produced by the metal structure along each
path is accounted for, which is the greatest effect. However, the metal structure off the
ray line path to point P (secondary effect) is ignored in Equation 5.22. For example, in
Figure 5.6 the evaluation of the contribution to dose at P from source subvolume j is the
same whether there is a tungsten shield present in the applicator or not. In Equation
5.22, it is g(r) which represents scatter, determined from the case of a homogeneous
water medium. We are assuming in Equation 5.22 that g(r) is the same when a nonwater
material is lateral to the ray line. Equation 5.22 is a very fast calculation method and
comparison to Monte Carlo calculations (53) show it works very well for 137Cs. Lower
photon energies require a method to deal with scatter.
Reasonably fast 3D methods having a scattering component, have been developed by
Williamson (52) and Russell and Ahnesjo (55). Monte Carlo calculations of dose results
for source/applicator and just source are each separated into primary and scattered
components. Monte Carlo calculations are used to create precalculated distance-
dependent scatter ratios that are a function of distance and mean free path in the
patient. Surprisingly, scatter is shown to be fairly isotropic about each applicator, so
scatter dose can be treated as a distance-dependent but angle-independent term. This
approximation speeds up the calculations. As Williamson (52) points out, this
demonstration of the simple angle-independent nature of the scatter also explains why
formalisms such as Equation 5.22 work very well for the high-energy photons of 137Cs.

130
At larger distances from the implant or for lower-energy isotopes such as 125I, the
scatter separation method remains accurate.
Generalization of the TG43 2D dose calculation formalism Equation 5.15 to a form
suitable for 3D dose calculation would look something like this:

F(r,q,φ) is extended to explicitly include the angle φ dependence, 0 < φ < 2p and
includes all angular variations. F could be described by a function such as Equation
5.20 with the 12 free parameters themselves a function of φ. This would then involve
hundreds of parameters.
At this point, historical review helps us understand that simple equations such as
Equations 5.9 or 5.11, among others, arose because the developers needed some simple
equation to calculate or check treatments by hand. Today, many parameter fits (such as
Equation 5.23 would require) can easily be done on a computer. However, it is also true
that characterizing the dose-rate calculation directly using Monte Carlo over a full 3D
volume 20 × 20 × 20 cm3 and storing such a 3D matrix would not be a problem
either. So one could follow the historical development and precalculate the Monte Carlo
result, then fit the parameters of Equation 5.23 to the Monte Carlo, throw away the
Monte Carlo result and use Equation 5.23 with the large number of parameters to
calculate the dose distribution. Alternatively, one could just store and use the Monte
Carlo results directly (after smoothing to minimize statistical errors). Therefore it is
unlikely that the description of the results of 3D dose calculations will follow TG43 in
describing the dose-rate as a product of several fitted functions whose parameters were
found by comparing to Monte Carlo results. Instead “consensus” 3D Monte Carlo
generated dose-rate matrices normalized to the dose at a reference position could be
provided.

THREE-DIMENSIONAL TREATMENT PLANNING WITH 3D


DOSE DISTRIBUTIONS
If we have a precalculated 3D dose-rate distribution, how do we use it clinically? It is
necessary to determine the position and orientation of each source’s 3D dose
distribution in the patient. Figure 5.7 shows a single source, which is arbitrarily angled
in the patient. The patient coordinate system (x, y, z) is defined by a 3D imaging device
such as a CT scanner. The 3D dose-rate distribution of the source/applicator would
have been (pre-)calculated in a coordinate system (x′, y′, z′) centered on the source. This
is the intrinsic coordinate system of the source/applicator system. If there was
cylindrical symmetry about the intrinsic z′-axis, there would be no need to determine in
what direction the x′ and y′ axes are oriented in the CT scan coordinate system, but here
we are assuming there is no symmetry whatsoever. We define as the calculated
dose-rate distribution in its own intrinsic coordinate system for a unit air kerma
strength source. So in Figure 5.7, the dose-rate at point P (located at in the CT scan)
produced by the source (located at implies looking up the value for from the
precalculated 3D matrix. We therefore need to determine the vector (distance and
direction) In practice, this requires that we determine which way the x′,y′,z′ axes
point in the CT scanner. Now , the vector from S to P, is the same vector as only
expressed in the coordinates of the CT scanner. These are shown in Figure 5.7 and

131
related via

FIGURE 5.7 Relationship between patient coordinate system (as defined by a computed tomography [CT]
scan) and the internal dose-rate calculation coordinate system of a precalculated 3D source, which is rotated
relative to the CT system. The center of the source is at rS (relative to the CT scan). Point P in the patient is
located at rP in the CT scan but at r′p relative to the internal source coordinate system. rPS and r′p are physically
the same vector, expressed in CT and intrinsic coordinates, respectively.

where E(α,β,g) is the rotation matrix (56) for a solid body and α,β,g are the Euler
rotation angles, which rotate the intrinsic coordinate system of the source in
correspondence with the CT coordinate system. Our problem is to find the three degrees
of rotational freedom, the Euler angles. Finding both ends of the source defines a line in
space and decides the z′-axis orientation (equivalent to two degrees of freedom). The
last degree of freedom (rotation about that line) is found by identifying a landmark in
the CT scan not on the z′-axis. Methods and equations for calculating the Euler angles
based on this information have been given for particular 3D source/shield/applicators
(57). One last problem is that CT scans do not determine absolute position with a
precision better than one-half the scan spacing. Three-dimensional graphic positioning
of the entire applicator can make the determination more precise (57).
Continuing on to the case of multiple sources, in Figure 5.8, the dose at point P from
two sources requires that the orientations of both sources be determined. In order to
look up the value for and , we have to determine and . So the Euler
angles for two coordinate systems must be found. For N sources we use Equation 5.24,
and the total dose-rate in the patient’s 3D coordinate system for N sources is
given by

where SKi is the source strength and is the inverse of the Euler rotation matrix for
the ith source. The Euler angles (αi,βi,gi) for each source must be determined. It is the
latter task, which is the additional work needed to implement 3D dose distributions in a
clinical real-time setting (57).
Once a dose-rate calculation algorithm has been implemented there are two choices in
calculating the total 3D dose-rate distribution in the patient from a multitude of sources
(enclosed in applicators with or without metal shields). They are (a) dose superposition,
that is, addition of individual source/applicator dose distributions independent of the
presence of the other sources (Equation 5.25 is dose superposition), or (b) direct dose

132
calculation, that is, using the calculation algorithm with all the sources and applicators
accounted for in the calculation. The first is the least computationally taxing because
the dose-rate matrices ( ) may be precalculated. The second method is what would be
used in real time clinical Monte Carlo or GBBS applications using CT data.

FIGURE 5.8 Superposition approximation. The dose-rate at P is found by adding the contribution from source
1 (assuming source 2 is not present), to the contribution from source 2 (assuming source 1 is not present). The
internal coordinate system for each source is shown. Only two out of three axes are shown.

Commercial treatment-planning systems currently use dose superposition. How


important is it to correct for interapplicator shielding effects, and patient
inhomogeneities? The answer depends on the number of sources, shields, or applicators
and their positions relative to one another. At this time, it is not clear how important
these effects are to clinical applications. Let us try and estimate this for one particular
example where we have a significant amount of metal in the form of tungsten shields in
an applicator. Consider Figure 5.9, which shows just two sources. Let the point P be at a
distance of 2 cm from the center of source 2 and 4 cm from source 1 on the left. It is
reasonable to assume that the perturbation of having source/applicator 1 to the left of
source/applicator 2 cannot affect the contribution that source 2 makes to the dose at P
very much. Therefore, that part of the total dose stays the same for dose superposition
or direct dose calculation. However, it is obvious that having source/applicator 2 in
between point P and source 1 changes the dose contribution of source 1 to the dose at
P. Crudely, we will estimate the error using inverse square considerations alone. In dose
superposition, the contribution of source/applicator 1 is roughly (2/4)2 = 1/4 of the
contribution that source/applicator 2 makes to the dose-rate at point P. So if
source/applicator 1’s contribution is reduced by 33% (which would only be for points
fully in the shadow of the shield), the error in the dose-rate (caused by forgetting about
interapplicator effects, as you do for dose superposition) would be roughly 1/12 or 8%
of the total dose. In treatment of carcinoma of the uterine cervix (2) (Figure 5.9 is an
example in a plane through the ovoids to a point lateral to the ovoids) this 8%
difference would be reduced even more by the dose-rate contributions from the tandem
sources, whose contribution to P would be about the same in superposition or direct
calculation.

133
FIGURE 5.9 Direct calculation of dose from multiple sources. Two radioactive source calculation including
attenuation effect of all regions. Sources 1 and 2 are subdivided into N regions each. Dose-rate at P involves
repeated application of point source calculation for all 2N regions and calculation of path lengths through each
region from both sources. For the ith cube in source 1, its distance to P is rS1i, the path goes through source 1’s
source material, encapsulation and applicator material, it then enters and leaves source 2 on the way to point P.
It passes through source 2, shield 2 and through the second applicator (entering and leaving). For the jth cube in
source 2, its distance to P is rS2j and the path does not pass through source 1 and only intersects its own
materials.

In low dose-rate permanent implants of the prostate, one may have up to 100 125I
stainless steel clad sources in a 40 cc volume. Potentially, the overall inhomogeneity
effect caused by seed-to-seed attenuations might be severe especially since the photon
energy is low. Burns and Raeside (58) in a Monte Carlo study of a model two plane
implant showed that the shadowing effect reduces the dose in the interior of the
implant, but this reduction was not enough to drop the dose below the reference
prescription dose. So, the significance is that very high doses here and there inside the
implant region are not really as high as one thought. Meigooni et al. (59) also studied
interseed effects for 125I and found through measurements that variations were not only
dependent on direction but that overall, the dose at the periphery of the implant is
reduced by 6%. Chibani et al. (60) used Monte Carlo simulation and found similar
results for 125I and 103Pd. Based on these studies it is not easy to see the need for any
correction other than possibly a 5% reduction of predicted overall dose to the
periphery. We emphasize that these studies justify a dose documentation correction, not
a 5% boost of the seed activity/strength. The latter is a completely different question
which is beyond the scope of this chapter. At the present time, it is unclear (61) whether
these corrections are needed in permanent seed implants.
Finally, as regards patient heterogeneities, this problem is harder still to evaluate
since the variations can be endless. Das et al. (62) found that the dose beyond bone is
most affected and that the perturbations of the dose distribution are too complex to be
modeled by simple dose calculation algorithms, so Monte Carlo calculations must be
used. Meigooni and Nath (63) used measurements plus Monte Carlo simulation and
found in their model that lower-energy sources such as 125I and 103Pd have significant
changes in dose due to patient heterogeneity whereas 192Ir does not. Calculation
methods to produce simple corrections have been proposed by Williamson et al. (64).
They used Monte Carlo generated primary and scatter components and incorporated
empiric parameters into a scatter subtraction method to gain the advantages of Monte
Carlo computation but with a large saving in computation time. Agreement with full

134
Monte Carlo simulations was within a few percent in most examples considered.
Furstoss et al. (65) studied both interseed and breast tissue heterogeneity effects for 125I
and 103Pd seed permanent breast implants using Monte Carlo simulation. At these low
energies, they found that breast tissue can change D90 by 10% relative to the
homogeneous water case, interseed attenuation is not important.

THREE-DIMENSIONAL DOSE CALCULATIONS—MONTE


CARLO AND BOLTZMANN TRANSPORT TECHNIQUES
In this section, we move away from macroscopically parameterized calculations and
calculate the dose distribution using microscopically parameterized functions. These
calculations can handle all inhomogeneities as straightforwardly as the homogeneous
case. The techniques require significant computer power which are now available. The
techniques are feasible for brachytherapy applications because the distances and
volumes of interest are small. The method of Monte Carlo (66–69) involves the concepts
figuratively expressed in Equation 5.4 at the start of this chapter. Namely, a photon
leaves a radioisotope in a random direction and when it hits something, there is a
chance of something happening, or not. In Monte Carlo, a photon is randomly created,
starts off in a random direction, and each step of the way has a probability (cross-
section) of photoelectric interaction, Compton interaction, pair production, or coherent
scattering. If it spits off an electron at a certain location headed in a certain direction
determined by a “roll of the dice,” that electron loses energy (6) as it moves through the
medium. The medium is split into small volume regions (cells), as electrons lose energy
in those cells; that energy loss is tallied as being deposited into that cell. So after the
one photon has left and all its scattered photon and electron descendants have ended
up as too low in energy to escape any more cells and are absorbed, you say that one
history has been completed. After that first history, almost every cell volume around the
source has zero dose because most cells were either not geometrically hit by anything or,
if hit, no interaction event occurred within them. In order to get useful results we will
have to rerun this “rolling of the dice” process over and over again. The computer is
tailor made to handle this task, many millions of times or more to finally get smooth
continuous results close to the source. We note that Monte Carlo simulation tries to
mimic what is happening in the patient. Monte Carlo is sometimes thought (67) of as a
simulated measurement process carried out on the computer.
The errors in Monte Carlo are of two types, systematic and statistical. The systematic
errors arise from the fact that the scattering cross-sections are themselves parameterized
approximations to the real atomic scattering. When Monte Carlo is used in Radiation
Oncology to predict average macroscopic properties such as dose distributions, these
errors are insignificant. The random statistical errors arise because of the need to stop
the calculation in some finite time, before statistical variation in each and every volume
element of the patient is rendered insignificant. The details can be misleading. Suppose
we use 50 million histories in a Monte Carlo modeling of a prostate HDR treatment, this
seems like an enormous number. In that case a 10 Ci source can expose the patient for
300 seconds and therefore, the actual treatment involves around 1014 photon histories.
So the seemingly huge Monte Carlo computation models 2 million times less decays than
the real treatment. Looked at the other way, the 50 million history Monte Carlo
calculation represents what we would expect from a less than millisecond HDR
treatment. In Monte Carlo, the statistical uncertainty in the dose varies in the patient.
The uncertainty is larger the farther away from the source distribution which one

135
considers. Near the source distribution, the 50 million histories modeling are usually
acceptable. If not, run more histories.
Monte Carlo for brachytherapy investigations has a long history starting with Berger’s
work (66), which provided analysis and insight into Meisberger et al. results (8). The
encapsulated radioactive source can be modeled and the relationship between
calibration, measurement, and calculation of 3D distributions determined. An
unequaled advantage of Monte Carlo is in handling any case regardless of complexity.
All that is required is to determine the radionuclide spatial distribution and the
positions of the inhomogeneities, subdivide each into regions, subdivide the entire
patient region of interest into small regions, and let the Monte Carlo program run until
the results stop changing significantly. This advantage cannot be too highly praised.
Consider that the Monte Carlo N-Particle (MCNP) (67) input used for full 3D
calculations of a source/shield/applicator (53) required typing only 100 lines of text.
Meanwhile experimental measurements of 3D dose-rate distribution for the same and
similar applications (28,50,51) involved machining of positioning devices to allow
rotation of applicators with high precision in water tanks. Measurements are made in
different orientations and the results have to be merged together. It is obvious which is
easier.
Monte Carlo is also useful even when you are not going to use it explicitly. All the
approximations for dose-rate calculation in this chapter involve parameters. If one fits
the values of the parameters of your algorithm to best match the results of Monte Carlo
simulations (53), then one obtains a parameterization which one can have more
confidence in than from the traditional method of fitting to experimental results (28).
The reasons for this were pointed out by Boyer (70) regarding the limitations of
brachytherapy measurement, for example, finite size of detectors, energy response
changes of detector with distance, and so on. Monte Carlo does not have these
limitations. Monte Carlo does have the limitation or more precisely the requirement that
the source emission spectrum (7) must be precisely known and that the exact
specifications of source/applicator construction are defined correctly. Because of that,
there is still a need for measurement but only to spot check the results at a few points
for confidence that the above requirements are correct. In summary, Monte Carlo
simulation is some part of every brachytherapy dose calculation.
Recently a new method (71–73) has been proposed for brachytherapy dose
calculation. Suppose we return to our 50 million history Monte Carlo example and
rerun it again on the computer. We would obtain a different (albeit similar) dose
distribution result. If we could (we cannot) run the actual 1014 histories, get the results,
and then rerun that simulation once more and compare, we expect that we would have
no significant difference in results. Therefore there is an expectation that an exact
solution exists, that is, an infinite history solution. To find that solution we turn to
methods for solving the linear Boltzmann transport equation (74) that were developed
at Los Alamos National Laboratory (75,76). The Boltzmann transport equation governs
the motion of a particle in a fluid subject to random collisions. It has no analytic
solution. To make the problem computationally feasible, the scattering energies and
angles are discretized and the equations are solved on a grid of discrete points. The
technique is called lattice or grid-based Boltzmann solvers (GBBS) (77). We can
understand this method applied to radiation as having the radioactive source creating
the driving flux of photons (Fig. 5.10). This photon flux flows out, suffers random
collisions, and is both modified and creates electron flux. The solution which GBBS finds
is the resulting photon and electron final total flux at every grid position throughout
the patient. These fluxes are also determined approximately in the Monte Carlo method

136
but far faster in GBBS, thousands of times faster. Error in GBBS is systematic not
statistical. It is said that the solution is exact (77). However, the solutions of the
differential equations can be affected by the aforementioned discretization
approximations. Hence there is a danger that the solution could be incorrect. As in
Monte Carlo, this is a technique wherein more and more computer processing power
makes the calculations more and more reliable in shorter times.

FIGURE 5.10 Point source S of single energy photons, photon flux ΨS in homogeneous medium. Resulting
identical photon flux Ψ at positions 1 to 3 and lower energy flux at position 4. Monte Carlo or GBBS can do no
better than equal the accuracy of simple parameterized point source dose calculations.

FIGURE 5.11 Source distribution S and dose at five positions in the presence of bone (grey) and air (blue). Only
Monte Carlo or GBBS can accurately predict dose at all positions.

In Figure 5.10, we show the photon flux in the homogeneous case, assuming a single
energy point source emitter. As one goes away from the source the intensity of the
orange photons drops (line gets shorter), other lower-energy photons (shades of blue)
appear at different angles. Electron flux is not shown. The assumption with GBBS is that
the resulting flux at positions 1 to 4 cannot be random and must be definite and related
to each other via the transport equations. Let us compare the use of Equation 5.15 with
Monte Carlo and GBBS to illustrate the advantages and disadvantages. In Figure 5.10, if
we used Equation 5.15, the dose which we would calculate at equally distant positions
1 to 3 would be exactly equal and correct. Assuming position 4 is 10 cm away, the dose
would be roughly accurate. In contrast, with Monte Carlo the dose would be very close
to correct for positions 1 to 3 but the doses would not be exactly equal because of
statistical error. With GBBS, the dose would be exactly equal and correct for positions 1
to 3. Both Monte Carlo and GBBS would be more accurate for position 4 especially if it
were much greater than 10 cm away. Therefore, for the homogeneous case, really
nothing is to be gained over any of the historical methods of dose calculation by using
Monte Carlo or GBBS. In Figure 5.11, we show a source distribution S, and dose points
in the presence of inhomogeneities, grey is bone, blue is air. If we use Equation 5.15

137
(assume we can ignore intersource attenuation effects), the calculated doses at a
prescription point such as D5 or D1 are very accurate, while the dose at D2 is fairly
accurate (unless position 2 is very close to the bone), the dose at D3 is underestimated,
and D4 is overestimated. On the other hand, for Monte Carlo and GBBS, all doses are
accurately predicted; moreover, intersource attenuation effects need not be ignored.
There is no question, that if inhomogeneity is present, the Monte Carlo and GBBS are
superior in dose calculation accuracy throughout the patient.

FUTURE DIRECTIONS IN 3D DOSE-RATE CALCULATION


ALGORITHMS
At the present time, commercial treatment planning systems do not provide 3D
calculation of dose and do not allow precalculated 3D dose matrices to be used for
planning. TG43 formalism is supported for all sources. It is clear that only Monte Carlo
and GBBS can handle all difficulties in brachytherapy dose calculation. One reason is
that heterogeneities do not hamper the accuracy of these methods. If the Monte Carlo
calculation is deciding whether a photon will randomly scatter as it goes through bone
or if it is going through water, it is all the same for the computation procedure. A
similar statement applies to GBBS. There is not much extra computation power needed
for the interapplicator/patient heterogeneity calculation relative to a homogeneous
calculation. Of course, the calculation time plus time for identification and accurate
orientation of all sources, and applicators in the CT scan and definition in the Monte
Carlo or GBBS calculation framework is still not a real-time clinical reality except in
special cases. However, all these problems will eventually be addressed using increased
processing power both for calculations and image analysis. In the future, we expect to
be able to take all inhomogeneity effects into account using full clinical Monte Carlo or
GBBS calculations.
Recently, BrachyVision (Varian Medical Systems, Palo Alto, CA) has introduced a
GBBS option for their HDR treatment planning system. The user generates an optimized
plan using Equation 5.15 to calculate dose and thereby determine all dwell times. After
completion, he or she have the option to run a GBBS calculation. This documents the
dose distribution in the patient accounting for all inhomogeneities. This calculation
takes less than 10 minutes. What the user does with that information is not clear. That
the information is now available is noteworthy. However, it would be a mistake to think
that the fact that the inhomogeneity corrected dose is different than the homogeneous
dose, justifies changing the integral dose (1) to the patient. That is a more complicated
question.
The last paragraph indicates that (unexpectedly) GBBS has leap-frogged Monte Carlo
in regard to individual patient-specific clinical utilization. A problem with commercial
implementation of Monte Carlo is when do you stop the calculation, that is, how many
histories? That can be a function of the geometry of the case itself. Since even the
homogeneous case takes too long, to design a software system to run more histories than
you ever expect to need is not feasible today. So the reasons for GBBS success are
increased speed and that GBBS provides an “exact” solution. The former is easy to
understand, the latter should be accepted with caution. Since the solution is exact (and
hence when it completes, you are finished) it is a huge software design advantage.
There is one potential problem. Namely, what happens to the “exact” solution when you
have artifact in the CT scan, or misinterpretation of the size or density of metal objects
or calcifications. Since in GBBS the dose results in all areas of the patient are linked by

138
the differential equations, this could result in the prescription dose result being made
inaccurate by other less important regions of the patient being incorrectly specified.
This could mean that the “exact” solution is “exactly” wrong. Whether it is possible to
be clinically significant wrong is unclear at this time. Having said all that, one has to be
excited by this new development as much will be learned from it, and in the current
GBBS implementation for HDR, Equation 5.15 still determines the actual clinical
treatment.

SUMMARY
The history of algorithm development was that extensive use of measurements led to
simple calculation algorithms based on a point source. Using numerical integration
these were extended to cylindrical geometries of varying complexity. These
developments were then improved by comparison to specialized Monte Carlo studies.
The rise in computer power made available more extensive Monte Carlo investigations.
These Monte Carlo studies more precisely determined the best parameters of the
calculation algorithms to give a better agreement with experiment and later permitted a
unification of source calibration and clinical calculation of dose. The ease of these
investigations has made extensive 3D measurement projects a thing of the past. In fact,
the GBBS literature bypasses experimental measurements and compares to Monte Carlo
for justification. The GBBS will have a greater utilization in clinical practice as it is
faster than Monte Carlo and gives definite results. As computer power increases in the
future, the power and dominance of these two techniques in providing detailed dose
distribution results will increase. It will then seem as if all the simple equations are no
longer needed as advanced computer modeling has superseded them. One notes that
none of the governing equations for Monte Carlo or GBBS were given in this chapter.
There is no need as no one is going to use them to check the dose in a patient. The vast
computational labor of these methods is such that only the computer can produce the
results. It is then that the historical methods reappear as the only way to check that the
computer results can be believed. One is advised to always do exactly that.

ACKNOWLEDGMENTS
The author gratefully thanks Glenn Glasgow, Ph. D. for useful discussions, Vania Arora, MS,
for a careful reading of the manuscript and Mr. Paul Weeks for producing the figures.

KEY POINTS
• Historical calculations for a source calibrated to specify its activity use Equations 5.9 or 5.11.
• Modern TG43 calculations for a source calibrated to specify its dose-rate in water at a
reference position use Equation 5.15.
• Dose at a point near a cylindrical source should be calculated using a line source
approximation.
• Monte Carlo simulation has been essential to accurately determine the basic parameters
needed for Equations 5.9, 5.11, or 5.15.
• Increasing computer power, will eventually lead to using Monte Carlo and GBBS approaches

139
for individual patient treatment planning.

QUESTIONS
1. If the air kerma strength (SK) doubles and the distance doubles, the dose-rate at a
given point most nearly
A. Decreases by 50%
B. Doubles
C. Remains the same
D. Decreases by 25%
2. If a 0.5 mCi 192Ir source (Г = 4.6 Rcm2/mCi h) is replaced by a 0.5 mCi 125I
source (Г = 1.45 Rcm2/mCi h), the initial dose rate at 1-cm most nearly
A. Increases by a factor of 2
B. Decreases by a factor of 2
C. Remains the same
D. Decreases by a factor of 3
3. If a SK = 2.0 U, 192Ir (^ = 1.12 cGy/hU) source is replaced by a SK = 2.0 U,
125I source (^ = 1.036 cGy/hU), the dose rate at 1-cm most nearly
A. Increases by a factor of 2
B. Decreases by a factor of 2
C. Remains the same
D. Decrease by a factor of 3
4. Consider a 192Ir source and an ion chamber separated by 10 cm and fixated at
the same height in an empty tank. As water is poured into the tank, the
ionization reading from the ion chamber is observed in three regions. First
region, water level getting closer to the source–chamber height; second region,
water level covers the source–chamber; and third region water level rising
higher in the tank above the source and ion chamber. Observation of the signal
from the ion chamber as the tank fills would show that the signal:
A. Remains the same, increases, increases
B. Increases, decreases, increases
C. Increases, stays the same, increases
D. Increases, decreases, decreases
5. Consider a 125I seed source with an air kerma strength of 0.6 U, use TG43
formalism to calculate the dose rate at r = 2-cm and q = 30° in Fig. 5.4. (Use
the line source geometry factor, L = 4-mm, gL(2) = 0.819, ^ = 0.965 cGy/hU
and F(2,30) = 0.842)
A. 0.02 cGy/h
B. 0.1 cGy/h
C. 0.2 cGy/h

140
D. 0.4 cGy/h

ANSWERS
1. A From Equation 5.15, air kerma strength change increases dose by factor
2, distance change decreases dose by factor 4. Dose drops by a factor of 2.
2. d Exposure rate constant for 125I is more than three times smaller than that
for 192Ir.
3. c Dose rate constants for the two isotopes differ by less than 10%.
4. B In the first region, increasing scatter from rising water increases the dose-
rate; in region 2 as water covers the path from source to the chamber,
attenuation decreases the dose-rate; in third region, increasing scatter
from rising water above the source increases the dose-rate.
5. B Note when you calculate the line source geometry ratio in Equation 5.15,
when L << r the result is very close (in this case, within 2%) to simply
using the point source approximation. Far enough away, all source
distributions look like point sources.

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6 Treatment Planning Algorithms: Electron
Beams

Faiz M. Khan

Most commercial treatment planning systems incorporate electron beam planning


programs. However, not all programs have comparable accuracy or limitations. In
general, the electron beam algorithms are more complex than those of the photon beams
and require more careful testing and commissioning for clinical use.
Early methods of computing dose distribution were based on empiric data or
functions that used ray line geometries assuming broad beam depth dose distribution in
homogeneous media. Inhomogeneity corrections were determined with transmission
data measured with large slabs of heterogeneities. These earlier methods have been
reviewed by Sternick (1).
The major problem with the use of broad-beam distributions and slab geometries is
that this approach is inadequate in predicting the effects of narrow beams, sudden
changes in surface contours, small inhomogeneities, oblique beam incidence, and so
forth.
An improvement over the empiric methods came about with the development of
algorithms based on age–diffusion equation by Kawachi (2) and others in the late
1970s. These models have been reviewed by Andreo (3). A semiempiric pencil beam
model developed by Ayyangar and Suntharalingam (4) and based on age–diffusion
equation was adopted for the Theraplan treatment planning system (Theratronics,
Kanata, Ontario). This semiempiric algorithm, if properly implemented for a given
electron accelerator, allowed reasonably accurate calculation of dose distribution in a
homogeneous medium. Contour irregularity and inhomogeneities were considered only
in the plane of calculation, as for example, a computed tomography (CT) slice, without
regard to the effects of the third dimension, such as adjacent CT slices. Whereas pencil
beams placed along the surface contour can predict effects of contour irregularity and
beam obliquity, inhomogeneity corrections were still based on effective path length
between the virtual source and the point of calculations. In these cases, bulk density of
the inhomogeneity in the given CT slices was used to determine effective depth. The
main limitation of such algorithms was that the effects of the anatomy in three
dimensions were not fully accounted for, although empirically derived correction
factors could be used in simple geometric situations (5).

PENCIL BEAM MODELS BASED ON MULTIPLE SCATTERING


THEORY
In the early 1980s, there was a significant surge in the development of electron beam
treatment planning algorithms (6–9). These models were based on gaussian pencil beam
distributions obtained with the application of Fermi–Eyges multiple scattering theory
(10). For a review of these algorithms, see Brahme (11) and Hogstrom (12). A brief
discussion of these algorithms is presented here to familiarize the users of these
programs with the basic theory involved.

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Assuming small-angle approximation for multiple scattering of electrons, the spatial
distribution of electron fluence or dose from an elementary pencil beam penetrating a
scattering medium is very nearly gaussian at all depths. Large-angle scattering events
could cause deviations from a pure gaussian distribution, but their overall effect is
considered to be small. The spatial dose distribution for the gaussian pencil beam can be
represented thus:

where dp(r,z) is the depth dose contributed by the pencil beam at a point at a radial
distance r from its central axis and depth z, dp(o,z) is the axial dose, and is the
mean square radial displacement of electrons as a result of multiple Coulomb scattering.
It can be shown that , where and are the mean square lateral
displacements projected into the X, Z and Y, Z planes. The exponential function in
Equation 6.1 represents the off-axis ratio for the pencil beam, normalized to unity at r
= o.
This is another useful form of Equation 6.1.

where D∞(o,z) is the dose at depth z in an infinitely broad field with the same incident
fluence at the surface as the pencil beam. The gaussian distribution function in
Equation 6.2 is normalized so that the area integral of this function over a transverse
plane at depth z is unity.

FIGURE 6.1 A pencil beam coordinate system. Dose at point P is calculated by integrating contributions from
individual pencil beams.

In Cartesian coordinates, Equation 6.2 can be written thus:

where dp(x,y,z) is the dose contributed to point (x,y,z) from a pencil beam whose central
axis passes through (x′,y′,z′) (Fig. 6.1).

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The total dose distribution in a field of any shape can be calculated by summing all
the pencil beams:

The integration of a gaussian function within finite limits cannot be performed


analytically. To evaluate it, this function necessitates use of the error function. Thus,
convolution calculus shows that for an electron beam of a rectangular cross-section (2a
× 2b), the spatial dose distribution is given thus:

where the error function is defined thus:

The error function is normalized so that erf(∞) = 1. (It is known that the integral
.) Error function values for o < x < ∞ can be obtained from tables

published in mathematic handbooks (13). Although, D∞(o,o,z) in Equation 6.5 is given


by the area integral of the dose from pencil beams over an infinite transverse plane at
depth z, this term is usually determined from measured central axis depth dose data of
a broad electron field (e.g., 20 cm × 20 cm).

Pencil Beam Characterization

Lateral Spread σ
As discussed earlier, the spatial dose distribution of an elementary pencil electron beam
can be represented by a gaussian function. This function is characterized by its lateral
spread parameter σ, which is similar to the standard deviation parameter of the familiar
normal frequency distribution function:

Figure 6.2 is a plot of the normal distribution function given by Equation 6.7 for σ = 1.
The function is normalized so that its integral between the limits −∞ < x < +∞ is
unity.
As a pencil electron beam is incident on a uniform phantom, its isodose distribution
looks like a teardrop or onion (Fig. 6.3). The lateral spread (or σ) increases with depth
until a maximum spread is achieved. Beyond this depth there is a precipitous loss of
electrons as their large lateral excursion causes them to run out of energy.
The lateral spread parameter σ was theoretically predicted by Eyges (10), who

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extended the small-angle multiple scattering theory of Fermi to the slab geometry of any
composition. Considering σx (z) in the X–Z plane,

where q2/ρl is the mass angular scattering power and ρ is the density of the slab
phantom.

FIGURE 6.2 Plot of a normal distribution function given by Equation 6.7 for σ = 1. The function is
normalized to unity for limits −∞ < x < +∞.

FIGURE 6.3 Pencil beam isodose distribution measured with a narrow electron beam of 22-MeV energy
incident on water phantom. (Reprinted with permission from ICRU Report 35. Radiation Dosimetry: Electron
Beams with Energies Between 1 and 50 MeV. Bethesda, MD: International Commission on Radiation Units and
Measurements. 1984:36.)

There are limitations to the Eyges’ equation. As pointed out by Werner et al. (8), σ,
given by Equation 6.8, increases with depth indefinitely, which is contrary to what is
observed experimentally in narrow-beam dose distributions. The theory does not take
into account the loss of electrons when lateral excursions exceed the range of the
electrons. Also, Equation 6.8 is based on small-angle multiple Coulomb scattering;
hence, it underestimates the probability of large-angle scatter. This gives rise to an

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underestimation of σ. Correction factors have been proposed to counteract these
problems (8,14,15).
Hogstrom et al. (7) correlated electron collision linear stopping power and linear
angular scattering power relative to that of water with CT numbers so that effective
depth and σ could be calculated for inhomogeneous media using CT data. Effective
depth calculation using CT numbers also allows pixel-by-pixel calculation of
heterogeneity correction.
Experimental measurement of σ(z) is possible with the use of narrow beams (1-mm to
2-mm diameter). The transverse dose distribution in a narrow beam has a gaussian
shape at each depth. The root mean square (rms) radial displacement, σr(z), can be
obtained from the profiles by a mathematic deconvolution of the gaussian distributions.
Several investigators (15–17) used a narrow-beam depth dose distribution to
determine σr. Some (6) used the edge method, in which a wide beam is blocked off at the
center by a lead block; σ is evaluated from the excursion of electrons into the block
penumbra.
Werner et al. (8) used strip beams 2-mm wide to obtain transverse profiles in
homogeneous phantoms of various compositions. The strip beam profiles were then
fitted by gaussian distributions at various depths. Figure 6.4 shows the results,
comparing σs calculated by Eyges’ equation, with and without correction for the loss of
electrons.

FIGURE 6.4 Spatial spread parameter, σx, plotted as a function of depth in water for a 13-MeV electron beam.
Comparison is shown between σx’s calculated by Eyges’ equation (dashed line) and Eyges’ equation modified for
loss of electrons (solid lines) with measured data. (Reprinted with permission from Werner BL, Khan FM,
Deibel FC. A model for calculating electron beam scattering in treatment planning. Med Phys. 1982;9:180–
187.)

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Central Axis Distribution
As seen in Equation 6.5, the central axis depth dose for a rectangular field of size (2a ×
2b) can be derived from the measured broad-beam central axis distribution. It is given
thus:

The normalization of the dose distribution function against D∞(o,o,z) is useful because
the central axis dose distribution for a broad beam can be readily measured and
includes Bremsstrahlung as well as the inverse square law effect. Multiplication with the
error functions provides the required field size dependence factor due to lateral scatter.

SUCCESS AND LIMITATIONS OF PENCIL BEAM ALGORITHMS


Algorithms based on gaussian pencil beam distribution have solved many of the
problems that plagued the previous methods, which used measured broad-beam
distributions or empirically derived best fit functions with separate correction factors
for contour irregularity and tissue heterogeneity. Analytic representation of pencil beam
allows for calculation of dose distribution for fields of any shape and size, irregular or
sloping surface contours, and tissue heterogeneities in three dimensions. However, there
are limitations to pencil beam algorithms, and they have been discussed by several
investigators (12,18–20). Most of the inaccuracies occur at interfaces of different
density tissues such as tissue–lung, tissue–bone, and bone edges. Within the
homogenous media of any density, the algorithm has an accuracy of approximately 5%
in the central regions of the field and approximately 2-mm spatial accuracy in the
penumbra.

Central Axis Distribution


One of the essential requirements of a treatment planning algorithm is that it calculates
the central axis depth dose distribution in water with acceptable accuracy. For broad
beams, there is no problem because measured data are input as part of the formalism
(Equation 6.9). So, the critical test of the algorithm is to reproduce depth dose
distribution for small and irregularly shaped fields. Figure 6.5 shows such a test of the
Hogstrom algorithm.

Isodose Distribution
The next step is to check isodose distributions, especially in the penumbra region. Figure
6.6 from Hogstrom et al. (7), shows a reasonably good agreement. The success of the
pencil beam algorithm in this case is in part attributable to the measured broad-beam
central axis data, measured off-axis profiles at the surface to provide weighting factors
for the pencil beams, and an empirically derived multiplication factor (1 to 1.3) to
modify calculated values of σx(z) for a best agreement in the penumbra region. This is
true of most algorithms—that some empiric factors are required to obtain a best fit of
the algorithm with measured data.

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FIGURE 6.5 Comparison of measured depth dose distributions with those calculated from 10 cm × 10 cm field
size data. Electron energy, 17 MeV. (Reprinted with permission from Hogstrom KR, Mills MD, Almond PR.
Electron beam dose calculations. Phys Med Biol. 1981;26:445–459.)

FIGURE 6.6 Comparison of calculated and measured isodose distribution. (Reprinted with permission from
Hogstrom KR, Mills, MD, Almond PR. Electron beam dose calculations. Phys Med Biol. 1981;26:445–459.)

Contour Irregularity
A pencil beam algorithm is ideally suited, at least in principle, to calculate dose
distribution in patients with irregular or sloping contour. Pencil beams can be placed
along rays emanating from the virtual source, thus entering the patient at points
defined by the surface contours. The dose distribution in the X–Z plane from the
individual pencil beams depends on the gaussian spread parameter, σx(z), which is
properly computed as a function of depth along the ray line. The composite dose profile
therefore reflects the effect of the surface contour shape by virtue of the individual
pencil beams entering the contour along ray lines, spreading in accordance with
individual depths, and the contributing dose laterally. Figure 6.7 shows a schematic
representation of the pencil beam algorithm used to calculate dose distribution in a
patient correction.

Tissue Heterogeneities
As discussed earlier, the Fermi–Eyges theory is strictly valid for slab geometry. That is, a
pencil beam traversing a slab of material is scattered with a gaussian profile, and the

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spread, σ, of the transmitted beam depends on the thickness of the slab and its linear
angular scattering power (Equation 6.8). Application of this theory to the human body
with inhomogeneities of different sizes and shapes becomes tenuous. Not only do many
different pencil beams pass through tissues of different composition, but also each
pencil with its increasing spread with depth may not stay confined to one kind of tissue.
Thus, the algorithm is bound to fail where the cross-section of the inhomogeneity is
smaller than the pencil beam spread or at interfaces where parts of the pencil beam pass
through different inhomogeneities. Research in this area continues, but no practical
solution to this problem has yet been found.

FIGURE 6.7 Schematic representation of the Hogstrom algorithm for the calculation of dose distribution in a
patient cross-section. SSD, source-to-surface distance, SCD, source-to-collimator distance. (Reprinted with
permission from Hogstrom KR, Mills MD, Almond PR. Electron beam dose calculations. Phys Med Biol.
1981;26:445–459.)

Figure 6.8 shows an example of how CT-based inhomogeneity corrections have been
applied with a pencil beam algorithm. A tissue substitute phantom simulating a nose
was irradiated with a 13-MeV electron beam and a detailed thermoluminescent
dosimetry was done. The agreement between the measured and calculated distribution
was approximately 13%. This is not an acid test for the algorithm, since many sources
of uncertainties can compound the errors in this case. However, if the user understands
its limitations of accuracy in complex clinical situations, the pencil beam algorithm is
capable of providing clinically useful information about overall dose distribution. These
limitations must be considered in making therapeutic decisions in the use of electrons

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when the target or critical structures are encountered in the path of the beam.

FIGURE 6.8 Experimental verification of the Hogstrom algorithm. Calculated isodose contours are compared
with measured data using TLD in a tissue substitute phantom. Electron energy 13 MeV; field size, 8 cm × 8
cm; source-to-source distance (SSD), 100 cm. (Reprinted with permission from Hogstrom KR, Almond PR.
Comparison of experimental and calculated dose distributions. Acta Radiol. 1983;364:89–99.)

COMPUTER ALGORITHM
Implementation of a pencil beam algorithm requires dose distribution equations to be set
up so that the dose to a point (x, y, z) in a given field can be calculated as an integral of
the doses contributed by gaussian pencil beams. The points of calculation constitute a
beam grid, usually defined by the intersection of fan lines diverging from the virtual
point source and equally spaced depth planes perpendicular to the central axis of the
beam (X–Y planes). An irregularly shaped field is projected at the depth plane of
calculation and is divided into strip beams of width ∆X and length extending from Ymax
to Ymin (Fig. 6.9). The strip is also divided into segments so that σ of the pencil beams
and effective depths can be calculated in three dimensions and integration can be
carried out over all strips and segments.
Starkschall et al. (18) evaluated the Hogstrom algorithm (7) for one-, two-, and three-
dimensional heterogeneity corrections. The general equation that they set up for three-
dimensional (3D) dose computation is reproduced here to illustrate the mathematical
formulation of the pencil beam algorithm:

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FIGURE 6.9 Schematic representation of an irregularly shaped field divided into strips projected at the plane of
calculation (z). (Reprinted with permission from Starkschall G, Shiu AS, Bujnowski SW, et al. Effect of
dimensionality of heterogeneity corrections on the implementation of a three-dimensional electron pencil beam
algorithms. Phys Med Biol. 1991;36:207–227.)

155
where De(x,y,z) is the electron dose at point (x,y,z); N is the number of strips; M is the
number of segments; W(xk,y1) is the beam weight along the fan line at point (xk,y1); α2
is the pencil beam spread in the medium at depth z (obtained by integrating linear
angular scattering power along a fan line from the surface of the patient to the plane of
calculation); σair is the pencil beam spread in air at the plane of final collimation and
projected to the plane of calculation in the absence of the medium; is
the measured broad-beam central axis depth dose; SSD is the effective source-to-surface
distance; is the maximum limit of the jth segment of the ith strip; is the
minimum limit of the jth segment of the ith strip.
Equation 6.10 does not include the Bremsstrahlung dose. Assuming that the dose
beyond the practical range, Rp, is all due to photons, one can back-calculate the photon
dose by using attenuation and inverse square law corrections.

MONTE CARLO METHODS


There is active interest in adopting Monte Carlo (MC) methods for treatment planning
of photon and electron beams. The MC technique consists of simulating transport of

156
millions of particles through matter. It uses the fundamental laws of physics to
determine probability distributions of individual particle interactions. Each particle is
followed as it travels through the medium and gives rise to energy deposition by
interaction with the atoms of the medium. The larger the number of simulated particles
(histories), the greater is the statistical accuracy of predicting their distribution. As the
number of simulated particles is increased, the accuracy gets better but the
computational time becomes prohibitively long. So, the challenge lies in using a
relatively small sample of randomly selected particles to predict the average behavior of
the particles in the beam. The dose distribution is calculated by accumulating (scoring)
ionizing events in bins (voxels) that give rise to energy deposition in the medium. It is
estimated that the transport of a few hundred million to a billion histories will be
required for radiation therapy treatment planning with adequate precision.
In order to improve computational efficiency and decrease calculation time, a number
of fast MC codes have been developed in the past 15 years or so. Examples include
Voxel-based MC (VMC, VMC++) (21–23), Dose Planning Method (DPM) (24), and
MCDOSE (25). Some of these codes have been implemented commercially, for example,
Nucletron OMTPS, Varian Eclipse, and CMS Xio eMC. Before clinical implementation,
the user is advised to build an appropriate program for commissioning and routine
quality assurance of the MC-based treatment planning system. Report of the AAPM Task
Group No. 105 (26) would be helpful in this regard.
With the continuing advancement in computer technology and computation
algorithms, it now seems probable that full-fledged MC code will be implemented for
routine treatment planning in the not too distant future.

KEY POINTS
• The most commonly used methods of electron beam dose calculation include pencil beam
(PB) algorithms and Monte Carlo (MC)-based algorithms.
• The premise of a pencil beam algorithm is that the lateral spread of an elementary pencil
beam of electrons penetrating a scattering medium can be represented approximately by a
gaussian distribution function.
• The lateral spread parameter, σ, can be theoretically predicted by Fermi–Eyges multiple
scattering theory.
• Practical implementation of pencil beam algorithm, based on Fermi–Eyges theory, was
carried out by Hogstrom et al. in 1981 and has been adopted by several commercial treatment
planning systems.
• PB algorithms have acceptable accuracy in homogeneous media of any density (e.g., a dose
accuracy of ∼ 5% in the central regions of the field and a spatial accuracy of ∼ 2 mm in the
penumbra).
• PB algorithms are not accurate at interfaces of different density tissues such as tissue–lung,
tissue–bone, and bone edges.
• MC methods consist of simulating transport of millions of particles and statistically
determining probability distributions of individual particle interactions.

157
• Full-fledged MC codes for treatment planning require inordinate amount of computational
times but they are the most accurate methods of calculating dose distribution.
• Fast MC codes have been developed to improve efficiency and reduce computational time.
Examples include Voxel-based Monte Carlo (VMC, VMC++), Dose Planning Method
(DPM), and MCDOSE.

QUESTIONS
1. Spatial spread of a pencil beam of electrons traversing a medium:
A. Is caused predominantly by knock on collisions
B. Increases with increase in energy
C. Is mostly due to secondary electrons ejected laterally
D. Can be represented approximately by a gaussian distribution function
2. Pencil beam algorithms for electron beam treatment planning:
A. Usually require input of measured depth dose data as well as lateral beam
profiles for broad fields as a function of beam energy
B. Can accurately predict surface dose
C. Are useful in predicting hot and cold spots occurring at bone–tissue interfaces
D. Are especially useful at tissue–lung interfaces
3. Fast Monte Carlo codes for electron beam treatment planning simulate transport
of:
A. Electron beam as energy kernels
B. Electrons using age-diffusion model
C. Millions of individual electrons and their interaction probabilities in a
medium
D. A single electron per pixel in a calculation grid

ANSWERS
1. D Lateral spread of an electron pencil beam is caused predominantly by
random small-angle Coulomb scattering and can be represented by a
gaussian normal distribution.
2. A Existing electron pencil beam algorithms cannot accurately take into
account the effect of beam collimation on depth dose or surface dose.
Input of measured central axis depth data and lateral beam profiles takes
those effects into account and assures better accuracy.
3. C Monte Carlo is not a model-based algorithm. It simulates individual
electron interactions and statistically measures interaction probabilities.
Greater the number of electrons simulated, better the statistical accuracy.

158
REFERENCES
1. Sternick E. Algorithms for computerized treatment planning. In: Orton CG, Bagne F,
eds. Practical Aspects of Electron Beam Treatment Planning. New York, NY: American
Institute of Physics; 1978:52.
2. Kawachi K. Calculation of electron dose distribution for radiotherapy treatment
planning. Phys Med Biol. 1975;20:571–577.
3. Andreo P. Broad beam approaches to dose computation and their limitations. In:
Nahum AE, ed. The Computation of Dose Distributions in Electron Beam Radiotherapy.
Kungalv, Sweden: Miniab/gotab; 1985:128.
4. Ayyangar K, Suntharalingam N. Electron beam treatment planning incorporating CT
data. Med Phys. 1983;10:525 (abstract).
5. Pohlit W, Manegold KH. Electron beam dose distribution in homogeneous media. In:
Kramer S, Suntharalingam N, Zinniger GF, eds. High Energy Photons and Electrons.
New York, NY: Wiley; 1976:343.
6. Perry DJ, Holt JG. A model for calculating the effects of small inhomogeneities on
electron beam dose distributions. Med Phys. 1980;7:207–215.
7. Hogstrom KR, Mills MD, Almond PR. Electron beam dose calculations. Phys Med
Biol. 1981;26:445–459.
8. Werner BL, Khan FM, Deibel FC. A model for calculating electron beam scattering in
treatment planning. Med Phys. 1982;9:180–187.
9. Jette D, Pagnamenta A, Lanzl LH, et al. The application of multiple scattering
theory to therapeutic electron dosimetry. Med Phys. 1983;10:141–146.
10. Eyges L. Multiple scattering with energy loss. Phys Rev. 1948;74:1534.
11. Brahme A. Brief review of current algorithms for electron beam dose planning. In:
Nahum AE, ed. The Computation of Dose Distributions in Electron Beam Radiotherapy.
Kungalv, Sweden: Miniab/gotab; 1985:271.
12. Hogstrom KR, Starkschall G, Shiu AS. Dose calculation algorithms for electron
beams. In: Purdy JA, ed. Advances in Radiation Oncology Physics. American Institute of
Physics Monograph 19. New York, NY: American Institute of Physics; 1992:900.
13. Beyer WH. Standard Mathematical Tables. 25th ed. Boca Raton, FL: CRC Press;
1978:524.
14. Lax I, Brahme A. Collimation of high energy electron beams. Acta Radiol Oncol.
1980;19:199–207.
15. Lax I, Brahme A, Andreo P. Electron beam dose planning using Gaussian beams.
Acta Radiol. 1983;364:49–59.
16. Brahme A. Physics of electron beam penetration: fluence and absorbed dose. In:
Paliwal B, ed. Proceedings of the Symposium on Electron Dosimetry and Arc Therapy.
New York, NY: American Institute of Physics; 1982:45.
17. Mandour MA, Nusslin F, Harder D. Characteristic function of point
monodirectional electron beams. Acta Radiol. 1983;364:43–48.
18. Starkschall G, Shiu AS, Buynowski SW, et al. Effect of dimensionality of
heterogeneity corrections on the implementation of a three-dimensional electron
pencil-beam algorithm. Phys Med Biol. 1991;36:207–227.
19. Hogstrom KR, Steadham RE. Electron beam dose computation. In: Paltra JR,
Mackie TR, eds. Teletherapy: Present and Future. Madison, WI: Advanced Medical
Publishing; 1996:137–174.
20. Hogstrom KR. Electron-beam therapy: dosimetry, planning and techniques. In:
Perez C, Brady L, Halperin E, Schmidt-Ullrich RK, eds. Principles and Practice of
Radiation Oncology. Baltimore, MD: Lippincott Williams & Wilkins; 2003:252–282.
21. Neuenschwander H, Mackie TR, Reckwerdt PJ. MMC-a high performance Monte

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Carlo code for electron beam treatment planning. Phys Med Biol. 1995;40:543–574.
22. Kawrakow I, Fippel M, Friedrich K. 3D Electron Dose Calculation using a Voxel
based Monte Carlo Algorithm. Med Phys. 1996;23:445–457.
23. Kawrakow I, Fippel M. Investigation of variance reduction techniques for Monte
Carlo photon dose calculation using XVMC. Phys Med Biol. 2000;45:2163–2184.
24. Sempau J, Wilderman SJ, Bielajew AF. DPM, a fast, accurate Monte Carlo code
optimized for photon and electron radiotherapy treatment planning dose
calculations. Phys Med Biol. 2000;45:2263–2291.
25. Ma C, Li JS, Pawlicki T, et al. MCDOSE- A Monte Carlo dose calculation tool for
radiation therapy treatment planning. Phys Med Biol. 2002;47:1671–1689.
26. Chetty IJ, Curran B, Cygler JE, et al. Report of the AAPM Task Group No. 105:
issues associated with clinical implementation of Monte Carlo-based photon and
electron external beam treatment planning. Med Phys. 2007;34:4818–4853.

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7 Treatment Planning Algorithms: Proton
Therapy

Hanne M. Kooy and Benjamin M. Clasie

INTRODUCTION
A clinical dose computation algorithm, a “dose algorithm,” must satisfy requirements
such as clinical accuracy in the patient, computational performance, representations of
patient devices and delivery equipment, and specification of the treatment field in terms
of equipment input parameters. A dose algorithm has been invariably imbedded within
a larger treatment planning system (TPS) whose requirements and behavior often affect
the dose algorithm itself. Current clinical emphasis on the patient workflow and
advanced delivery technologies such as adaptive radiotherapy will lead to different dose
algorithm implementations and deployments depending on the context. For example, a
treatment planner needs highly interactive dose computations in a patient to allow
rapid evaluation of a clinical treatment plan. A quality assurance physicist, on the other
hand, needs an accurate dose algorithm whose requirements could be simplified
considering that QA measurements are typically done in simple homogeneous
phantoms.
A dose algorithm has two components: a geometry modeler and a physics modeler. In
practice, the choice of a physics model drives the specification of the geometry modeler
because the geometry modeler must present the physics modeler with local geometry
information to model the local effect on the physics-model calculation. Physics models
come in two forms: Monte Carlo and phenomenologic. The latter models the transport of
radiation in medium with analytical forms and has been the standard in the clinic
because of the generally higher computational performance compared to Monte Carlo.
Monte Carlo, in general, models the trajectories of a large number of individual
radiation particles and scores their randomly generated interactions in medium to yield
energy deposited in the medium. Monte Carlo is considered an absolute benchmark and
much effort is expanded to produce high-performance implementations. The accuracy of
a Monte Carlo model is inversely related to the extent and complexity of the modeled
interactions and improved performance can be achieved by limiting the model to meet a
particular clinical requirement. We describe, as an example, a basic Monte Carlo, which
outperforms a phenomenologic implementation because of its simple model and
implementation on a graphics processor unit (GPU).
The geometry modeler creates a representation of the patient, which is invariably
derived from a CT volumetric data set and the CT voxel coordinates are sometimes
chosen as the coordinates for the points for which to compute the dose. Dose points are
typically associated to individual organ volumes after the dose calculation proper for
the computation of, for example, dose-volume histograms. A more general
implementation allows the user to select arbitrary point distributions. The geometry
modeler also provides the physical characteristics of the patient including, for example,
electron density derived from CT Hounsfield Units and, for protons, the stopping power
ratio relative to water (also derived from CT Hounsfield Units, albeit indirectly). The

161
geometry modeler also implements a model of the treatment field. For a Monte Carlo
implementation this is a two-step procedure. First, the treatment field geometry and
equipment parameters are used to create a representative phase-space; that is, the
distribution of particles in terms of position and energy, and perhaps other parameters,
of the radiation particles that impinge on the patient. Second, the particles are
transported individually through the patient until they are absorbed in or exit the
patient volume. For a phenomenologic implementation, the treatment field geometry
forms a template whose geometric extents are projected through the patient volume.
This projection is typically implemented by a ray tracer where individual rays populate
the treatment field to sufficiently sample the features within the patient and where the
physics model becomes a function of distance along the ray. Figure 7.1 shows the
various computational approaches.
Proton transport in medium has been exhaustively studied and the references in this
chapter are but a minimum.

PHYSICS OF PROTON TRANSPORT IN MEDIUM


Interactions
The physics of proton interactions for clinical energies, that is, between 50 and 350
MeV, is well understood. The publication “Passive Beam Spreading in Proton Radiation
Therapy” by Bernard Gottschalk (1) provides an in-depth, theoretical, and practical,
elaboration of this physics and this section relies significantly on that material.

FIGURE 7.1 The left panel shows a Monte Carlo schematic while the right panel shows a phenomenologic
schematic. The beam includes an aperture and a range-compensator. The beam for both is assumed subdivided
in individual pencil-beam “spots.” These spots are physical in the case of pencil-beam scanning (see text) while
for a scattered field they are a means for subdividing the field for computational purposes. The initial spot is
characterized by a spread σ′, an intensity G, and an energy R. In the Monte Carlo, the spot properties can be
used as a generator of individual protons. Thus, there will be more “red” protons than “blue” protons than
“green” protons. The total number of protons is on the order of 10 6 or more. Each proton is transported through
the patient and its energy loss is scored in individual voxels (a “yellow” one is shown). In the phenomenologic
model, the spot defines one or more pencil-beams that are traced through the patient. Each ray-trace models the
broadening of the protons in the pencil-beam as a continuous function of density ρ along the ray-trace. Dose is
scored to points P, where the deposited dose depends on the geometric location of P with respect to the ray-trace
axis and the proton range R and pencil-beam spread σ. The latter may include the initial spot spread σ′ if the
ray-trace axis represents all the protons G in the spot. Otherwise, the spot can be subdivided into multiple sub-

162
spots such that the superposition of those spots equal the initial spot.

Protons lose energy in medium through interactions with orbital electrons, scatter
predominantly through electromagnetic Coulomb interactions with the nuclear electric
field, and have inelastic interactions with the nucleus itself. Proton–electron
interactions produce delta electrons that deposit dose in proximity to the proton
geometric track. The mass of the proton is about 2,000 times that of the electron, hence
the collision is equivalent to a blue whale moving at near-relativistic speed toward you:
the proton emerges unscattered. Proton–nucleus Coulomb interactions result in small
angular deviations in the proton direction and produce, to a very good approximation,
a gaussian diffusion profile in a narrow parallel beam of protons. The gaussian form of
this profile is a consequence of the very large number of random scattering events,
which, as described by the central limit theorem, is approximate to a continuous
gaussian function to describe the underlying discrete random events.
Protons also have inelastic interactions with the nucleus and produce secondary
particles including secondary protons, neutrons, and heavier fragments. The secondary
protons contribute up to 10% of the dose within a proton depth-dose (2). The secondary
neutron production is of specific concern because of their long-range effect. These
neutrons deposit dose to healthy tissues throughout the patient, far from the target
region, and impact on the shielding requirements of a proton therapy facility. The
neutron contribution to the dose distribution is only considered implicitly through their
contribution in the physics parameters such as a depth-dose distribution. The effect of
heavier secondary particles is small and can be ignored for dose calculation purposes.

Relative Biologic Effectiveness


Dose deposited by protons is considered to be biologically equivalent to Co60 dose. That
is, cellular response to proton and photon interactions are considered equivalent.
Clinically, though, the proton physical dose (in Gy) is scaled by an RBE factor of 1.1 to
yield the proton biologic dose with units of Gy (RBE) (3). Thus, a photon fraction
prescription of 1.8 Gy (which implicitly has an RBE of 1 as Co60 is the “standard” dose
reference) can be delivered with a proton fraction of 1.8 Gy (RBE), which corresponds
to 1.64 Gy physical proton dose. The latter is the value one would measure in a
radiation detector and to which one would calibrate the field to deliver 1.8 Gy (RBE).
Clinically, the RBE is assumed 1.1 throughout. Of special consideration is the change
in RBE at the distal drop-off of the Bragg peak. In this region, the change in RBE has the
effect of differentially shifting the distal edge deeper by about 1 mm compared to
measurements. That is, the biologic dose fall-off is shifted 1 mm deeper compared to the
physical dose fall-off. This inherent uncertainty in the distal edge is one reason why the
sharp distal edge is not used to achieve, for example, a dose gradient between a target
and a critical structure. The other reason (see below) is the uncertainty in the relative
stopping power, which is estimated on the order of 2% to 3%. These uncertainties could
result in overdose to the critical structure or underdose to the target (Fig. 7.2).

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FIGURE 7.2 An SOBP depth-dose distribution with its constituent pristine Bragg peak depth-dose
distributions scaled relative to their contribution. The deepest pristine peak is at 160 mm, which results in a
lower SOBP range of 158.4 mm because of the other peak contributions. The 90–90 modulation width is
100.2 mm while the 90–98 is 83.1 mm. The range uncertainties create a band of uncertainty both distally and
proximally (see dashed distal fall-offs). The effect is most pronounced at the distal fall-off and the error must be
considered to ensure that the target coverage is respected. The 80% depth, R80, of a pristine peak correlates
accurately with the proton energy in MeV. The clinical historical range is in reference to the 90% depth, which
also depends on the energy spread. The difference in practice is on the order of 1 mm. Care should be practiced
especially considering calibration and reference conditions.

The RBE, in general, depends on other factors such as dose fraction size, number of
fractions, clinical end point, and so on. These factors can be ignored for proton
radiation computations but are significant for higher LET charged particles such as
carbon. Computation algorithms for such particles are, therefore, much more
complicated and must implement a model for the LET distributions in the patient to
resolve such dependencies.

Stopping Power
The various electromagnetic interactions transfer energy to electrons in the medium and
the proton energy is reduced as a consequence. The proton energy loss, transferred to
the medium, is quantified as the rate of energy loss per unit length, dE/dx, where E
(MeV) is the energy and x (cm) is the distance along the proton path. The stopping
power S is defined in combination with the local material density ρ (g/cm3):

and is called the mass stopping power.


The mass stopping power in a given medium is a function of the proton energy E and
increases significantly when the proton has lost nearly most of its energy. The proton
mass stopping power in a given material can be calculated using the Bethe–Bloch
equation (4) or directly from tables (5). For example, the mass stopping power values
for protons of energies 100, 10, and 1 MeV in water are 7.3, 45.7, and 261.1 MeV

164
cm2/g, respectively. Thus, a proton of 1 MeV energy cannot travel more than 0.004 cm
in water. It is this rapid increase in energy loss per unit length, and the very localized
energy deposition, that leads to the characteristic Bragg peak of the proton depth-dose
distribution (Fig. 7.2). Note that a Bragg peak is a characteristic feature of all charged
particles, including electrons, of the energy loss along the particle track. The feature
disappears for electrons traversing a medium due to their large scattering angle. In
effect, the track becomes “tangled up” and the Bragg peak becomes averaged out over
all the entwined tracks. Thus, a monoenergetic electron depth-dose distribution has a
broad and flat high-dose region followed by the distal fall-off.

FIGURE 7.3 Conversion from CT Hounsfeld units of the volume to relative stopping power, SWV, for biologic
tissues. Figure is adapted from Schneider et al. (7).

Water-Equivalent Depth and Proton Range, R


In a photon algorithm, the computational quantity is the radiologic path length,
that gives the density (ρ in units of g/cm3 or relative to water) corrected
depth along the ray up to the physical depth z in cm. For a proton algorithm, the
appropriate quantity is the water-equivalent thickness, τwet in g/cm2, which is the
thickness in water that produces the same final proton energy as the given thickness in
the medium. It is calculated from relative stopping power, SWV, defined as the ratio of
the stopping power of protons in the medium over that in water. In practice, SWV is
known for the materials such as polyethylene used in range-compensators or derived
empirically from CT numbers (Fig. 7.3). The proton water-equivalent thickness1 along a
ray trace is given as

where ρw is the density of water.


The mass stopping power ratio, is almost independent of therapeutic proton

energies for biologic materials (6). If this ratio is unity, the radiologic path length and
water-equivalent thickness are mathematically equivalent. However, in treatment
planning, the differences between τRPL and τWET can be clinically significant.
Range, R, which is often called the mean proton range, is the average water-
equivalent depth where protons stop in the medium. This is a very close approximation
of the range in the continuous slowing down approximation, RCSDA, and the depth at

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distal 80% of maximum dose, R80, of a pristine proton Bragg peak (Fig. 7.2). These
definitions of range are often used interchangeably in proton therapy.

Dose to Medium
The dose to a volume element, of thickness t along and area A perpendicular to the
proton direction, is given by the energy lost in the voxel divided by the mass of the
voxel

where f = N/A is the proton fluence in (cm−2). Consider a fluence of 109 (1 Gigaproton
[Gp]) per cm2 of 100 MeV protons in water where s/ρ = 7.3 MeV cm2/g. The dose is

at the entrance of the water (where the proton energy is 100 MeV) and where we used
the factor 10−3 to convert from gram to kilogram and the conversion factor is 0.1602
× 10−12 J/MeV. Equation 7.4 shows that the number of protons to deliver a clinical
dose is of the order of gigaprotons, a number less than 10−15 of the number of protons
in a gram of water. A convenient rule of thumb is that 1 Gp delivers about 1 cGy to a 1
L (i.e., 10 × 10 × 10 cm3) volume.
The mass stopping power only measures the energy loss from electromagnetic
interactions and does not include the energy deposited from secondary particles. In
practice, a measured depth-dose is a surrogate for the mass stopping power and thus
effectively includes all primary and other interactions in calculational models.
A CT data representation of the patient does not provide the necessary stopping
power information; it only provides the electron density on a voxel level. The conversion
from this electron density to relative stopping power is empirical and is based on an
average for particular organs over all patients (7). Thus, the conversion has inherent
uncertainties due to (1) the nonspecificity for a particular patient, and (2) the lack of
knowledge of precise stopping powers for particular organs. One, therefore, assumes a
3% uncertainty in the relative stopping power in patients (Fig. 7.2). This 3%
uncertainty must be considered by the treatment planner as is described elsewhere.
A dose algorithm may use longitudinal depth-dose distributions in water for all
available proton energies. Dose distributions in the patient are calculated from the dose
in water using the local density and relative stopping power, both of which come from
CT data. In the presence of heterogeneities, the depth-dose distribution in the medium,
TM(E, τWET), is obtained from that in water by (following from Equation 7.3 and
assuming constant fluence)

where E is the incident proton energy, z is the geometric depth in centimeters, and the
superscript ∞ indicates that broad beam depth-dose distributions are at infinite source-

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to-axis distance (SAD). The effect of inhomogeneities is twofold. First, the physical
depth of the Bragg peak is shifted relative to a water phantom based on the water-
equivalent depth in the patient. The shift for material M with geometric thickness zM
and water-equivalent thickness τWET,M is

Second, the dose in the heterogeneity is scaled by the relative mass stopping powers.
The latter ratio of relative mass stopping powers is close to 1 and the scaling of the dose
is typically ignored in dose algorithm implementations. These effects are illustrated in
Figure 7.4.
It was well recognized early on that protons could be used instead of x-rays for
tomography and thus measure the stopping power for a patient directly (8). Such an
image measures the energy loss, which is a function of the integrated stopping power,
along a particular proton ray instead of an attenuation measurement along an x-ray,
which is a function of the integrated electron density. The resultant reconstructed
tomographic image is thus a stopping power distribution rather than an electron density
distribution. There is considerable interest in this technology to achieve further
precision in proton beam dosimetry and to achieve accurate volumetric imaging at very
low doses.

FIGURE 7.4 TW is the depth-dose distribution in a homogenous water phantom and TW+B is the depth-dose

distribution in a water phantom with bone at 5 cm depth. The relative mass stopping power, of bone to

water gives the ratio of the dose deposited in bone to water in the shaded region. Bone has larger relative
stopping power, , compared to water and, for 2.9 cm geometric thickness of bone with 1.72 relative
stopping power, the Δ z is −2.1 cm by Equation (7.5b).

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FIGURE 7.5 Monte Carlo (GEANT4) generated proton and electron tracks in water with comparable
penetration range. Protons maintain near constant direction of motion while continuously slowing down by
losing energy in collisions with electrons. An electron track becomes “tangled” up with its collision electron
partner and undergoes many wide-angle scattering events. The minimal scatter of the proton makes the dose
distribution accurately described by the gaussian pencil-beam model.

Proton Lateral Spread


The numerous multiple elastic scattering events produce, for an initial parallel and
infinitesimally narrow beam of protons, a gaussian lateral distribution profile. The
characteristic spread of this gaussian profile in the Bragg peak region is about 2% of the
range (in centimeters). Thus, a proton beam of 20 cm penetration range in water has a
spread of 4 mm in the Bragg peak region. In comparison, an electron beam has a spread
of about 20% of its range (Fig. 7.5).
The scattering angle that underlies the widening gaussian profile was originally
described by Molière (9), who investigated single scattering in the Coulomb field of the
nucleus and multiple scattering as a consequence of numerous interactions. A complete
description of scattering theory is beyond the scope of this chapter. In practice, the
Highland approximation (10,11), or similar readily computable variants, are used to
compute the lateral beam spread in matter. For dose calculations in thick,
heterogeneous matter, the volume is divided into N homogeneous slabs that represent
the material along the particle track. The standard deviation of the gaussian spread σP,i
at radiologic depth L due to the ith slab is

where pv is the product of the proton momentum and speed (in MeV), LR is the
radiation length (in g/cm2), and the ith slab extends from radiologic depth Li − 1 to Li.
The total gaussian spread, σP, is the quadrature sum of the individual gaussian spreads

168
from each slab

Solving Equation 7.6a at each dose calculation point is not feasible due to computation
time and two simplifications are made: the radiation length in the patient is set to the
radiation length of water (36.1 g/cm2) and the density ρ is set to the density of water (1
g/cm3) in the integration. The simplified equation for the gaussian spread

is only a function of the radiologic depth L in the media. The simplifications are
acceptable for most cases. Consider protons with 100 MeV energy incident on a
homogeneous water phantom, then σP at the maximum water-equivalent depth is 0.179
mm. If the same beam passes through 1 g/cm of compact bone (LR = 16.6 g/cm2 and ρ
= 1.85 g/cm3) followed by water, then σP at the maximum water-equivalent depth is
0.169 mm, an acceptable difference compared to the homogeneous phantom. However,
in general, one should give special attention to treatment plans that have materials with
properties significantly different from water.
Treatment planning algorithms use tables or parameterizations of σP in water to
improve the computation time. Numerical solutions of Equation 7.6c are described by
Hong et al. (6) and Lee et al. (12). Figure 7.6 shows a similar calculation in water where
the momentum and velocity of protons at radiologic depth, L, and range, R, are
calculated through range-energy tables from J. Janni (5).

FIGURE 7.6 Left: The normalized gaussian spread σP(L)/σP(R) versus normalized radiologic depth, L/R. This
relation is essentially independent of R; the width of the line gives the variation from 0.1 g/cm2 < R < 40 g/cm2.
Right: The gaussian spread at the end of range of the pristine proton beam as a function of range.

MODELS OF DOSE DISTRIBUTIONS

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Phenomenologic Models
A phenomenologic model uses analytical forms to describe the physical processes and,
typically, represents the passage of the radiation through the medium as geometric rays
or pencil beams. Ray tracing, as applied in radiotherapy algorithms, derives primarily
from computer graphics techniques to create images of three-dimensional (3D) objects
as a consequence of light rays interacting with those objects as described by their
physical properties. Monte Carlo methods in radiotherapy, in essence, also implement
ray tracing methods where individual rays are the particles and their path is, in
general, distorted as a consequence of local interactions. We will refer to this technique
as particle tracing in distinction from ray tracing.
The performance of ray tracing algorithms through rectilinear volume
representations, such as a CT volume, is high and the computation time for this part of
an algorithm tends to be small compared to the computation time needed for the
physics model calculations. The ray trace along a particular line, typically a line from
the radiation source through a point in the isocentric plane, is used to accumulate the
volume physical information along the trace.
The main computational burden in a ray-trace algorithm implementation is the
association of dose to points surrounding the ray (Fig. 7.1). In general, at a given depth
z, one has to find the points that will receive a relevant contribution from the
“particles” modeled by the ray. In the case of a proton algorithm, this means that at a
depth z, one has to search an area of radius 3σ as this, for a gaussian distribution,
contains 99% of the laterally distributed profile. To efficiently find these points, as
opposed to explicitly checking each point at each depth for the distance from that point
to the ray axis, one can resort to sorting and indexing algorithms before commencing
the ray-trace calculation. Original implementations of dose calculation algorithms used
fan-beam grids where the points on the calculation grid fan out along rays from the
source. Such methodologies are impractical when considering requirements such as
noncoplanar beams and arbitrary distributions of points. A more general
implementation relies on indexing and sorting the dose points, in the beam coordinate
system, in the isocentric plane, and along the axis of the beam or ray (Fig. 7.7).

GAUSSIAN PROTON PENCIL-BEAM MODEL


The gaussian behavior of charged particle spread in medium was first used in an
electron pencil-beam algorithm described by Hogstrom et al. (13). The use of gaussian
functions has the convenient mathematical property of yielding well-behaved
integration and summation results to describe the field profile and lateral penumbrae.
In a pencil-beam model, the radiation field is subdivided into narrow subfields, that is,
pencil beams. The central axis of the pencil beam, the “ray,” is traced through the
medium and only density variations along the axis are considered in the calculation of
the lateral spread of particles with respect to the pencil-beam axis. The density
distribution lateral to the pencil-beam axis is considered to be that encountered on the
axis and the calculation is thus insensitive to heterogeneity variations comparable to the
width of the pencil beam. The gaussian description for electron beams works well in
homogeneous medium but less so in heterogeneous media as a consequence of the large
scattering angle of electrons (Fig. 7.5). The gaussian model is a good mathematical and
physical representation if the spread is much smaller such as is the case for proton
beams.

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FIGURE 7.7 A pencil-beam traced through the volume needs to find the points that are within its extent.
Consider all dose calculation points Z projected on the isocentric plane (“dots”), binned in rectangles (the grid
shown above) in that plane, and sorted along the central axis of the overall field. At a particular depth at Z(d)
the pencil-beam has the extent shown above (blue ellipse) which is projected on the isocentric plane (red). The
pencil-beam only needs to consider the points in those bins within its extent and only those points Z for which
Z(d) − Δ < Z < Z(d) + Δ (i.e., those within the thickness of the ray trace step (2Δ)). Such an algorithm can
improve performance well over 10× compared to a brute force approach.

The gaussian pencil-beam model was used by Hong et al. (6) to describe a scattered
proton field produced by a general delivery device. Such a device contains beam
scatterers, an aperture, a range-compensator, an air-gap between the range-
compensator and the patient, and the patient itself (Fig. 7.8). A physical narrow pencil
beam of protons can be mathematically modeled even in the presence of heterogeneities
while retaining good resolution. For example, a pure pencil beam of 15-cm range still
has better than 4-mm resolution at depth.
The dose D to a point (x,y,z) from a pencil-beam field is

where the sum is over all pencil beam i (each of range Ri) whose central axis at a depth
at the coordinate z is at (xi,yi), Y(xi, yi) is the number of protons at (xi,yi), σT is the total
spread of the pencil beam, and T W• Ri, τWET are broad-field depth-dose distributions in
water with infinite SAD. TW• Ri, and τWET are determined from measured depth-dose
distributions with finite SAD by correcting for inverse square.

where z is the longitudinal geometric coordinate of the measurement with axis at z = 0.


Equation 7.7 is a general description of proton diffusion through medium as a
function of depth. Its basic form is used for describing a scattered proton field, where a
proton beam is passively scattered in the lateral dimension and modulated in depth,
and a pencil-beam scanning field, where a narrow beam of proton pencils is scanned
magnetically in the lateral dimension and modulated in depth.

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Scattered Field Implementation
A scattered proton field is not dissimilar from an electron scattered field. The scattered
field is characterized by a virtual source from which the protons appear to emanate and
diverge and which has a spread σS. The source position and size can be determined by
measuring the field width and the penumbral width of an aperture as a function of
distance from the aperture. The field width projects back to the source position, while
the penumbral width is given by the back-projection of the measured penumbra through
the aperture, where the penumbra is 0, to that position (as described, e.g., in 13). The
resultant “virtual” source size of the proton beam is large with σS between 5 and 10 cm
as a consequence of the proton scatter in the scattering system (Fig. 7.8). This large
source size can only be mitigated by placing the aperture as close to the patient as
possible (as is the practice for an electron aperture) and to move the source position as
far as possible from the patient. The latter is one reason for the size of proton gantries;
the other being the bending radius necessary to bend the proton beam toward the
patient. The effective source size (the projection of the source to Z = 0 through a
pinhole at the aperture) thus becomes

which for a typical beamline, with an SAD of 300 and an aperture distance ZA to the
patient of 10 cm, reduces the source size by a factor of (300 − 10)/10 = 29 and the
contribution of the virtual source is reduced to 3 mm or less.
The proton beam passes through the aperture and subsequently is modified by a
range-compensator, which locally shifts the proton range such that the distal surface of
the field is beyond the distal target volume surface (with respect to the beam axis).
Passage through the range-compensator introduces compensator thickness-dependent
scatter, which introduces a penumbral spread component in the patient at depth z given
by

172
FIGURE 7.8 A schematic double-scattering nozzle (top) with a range-modulator wheel (RM, insert) and
scatterer (SS), ionization chamber IC, and a snout that holds the aperture and range-compensator (insert). The
fixed scatterer (FS) inserts thin layers of lead and ensures that the overall mean scattering angle remains constant
as a function of energy, thus maintaining a flat lateral profile. The protons in the model are assumed to spread as
a consequence from the effective source (green profile and eq. 7.9), from the range-compensator thickness
(yellow and eq. 7.10) and the scatter in patient (red profile and eq. 7.6c). The bottom shows a scanning nozzle
with a pair of scanning magnets (SM). The absence (in general) of an aperture and range-compensator requires
that the incoming pencil-beam be as narrow as possible to minimize its contribution (green) to the in-patient
spread. The SAD is defined by the bending points in the X and Y magnets (shown here in the center of the
magnets). The SAD defines the origin of the proton pencil-beam axis. The relative widths of the pencil-beam
are for illustration purposes and do not imply that a scanning beam is, by definition, narrower. The schematics
represent the core features of the IBA nozzle (IBA LTD, Louvain la Neuve).

where q0(t) is the scattering angle produced by the protons passing through the local
thickness t at (x,y) of the range-compensator at position ZR.
The protons in the patient further scatter and introduce a third spread factor, σP, to
the total spread of the proton pencil beam. The derivation of σP is computed, for
example, from the Highland formula (Equation 7.6c). The total spread of the pencil
beam is the quadratic sum of the three spread factors in Equations 7.9, 7.10, and 7.6b
(Fig. 7.8).
The complete algorithm thus subdivides the scattered field extent circumscribed by
the aperture into many small pencil beams, typically spaced in a rectangular grid of 2-
mm resolution. This high resolution ensures that heterogeneities within the patient are
sufficiently sampled in the lateral extent. Each pencil beam axis is traced through the

173
CT volume from the virtual source through a grid point and through the CT. The
calculation points (x,y,z) are transformed to the beam coordinate system and are sorted
in z (Fig. 7.7). The ray trace evaluates the water-equivalent depth (Equation 7.5) for the
point whose z is first in this sorted list and whose that is, those
points are close enough to the pencil-beam axis to receive sufficient dose. For those
points, the evaluation of Equation 7.7 yields the dose. The ray trace continues and
repeats the procedure for the next point z in the list.

Scattered Proton Field Composition


The general framework for the algorithm for scattered fields is the evolution of the
proton field in medium described by Equation 7.7 as a composition of individual pencil
beams i. The pencil beams for this application should be considered mathematical
constructs for the decomposition of the field; the physical field is a laterally uniform
flux of protons at different energies. The mathematical decomposition in depth is the
weighted superposition of single Bragg peak proton fields, typically uniform in the
lateral dimension or weighted according to a measured off-axis ratio profile, to produce
a spread-out Bragg peak (SOBP) field. The SOBP is thus a weighted sum of pristine
Bragg peaks Pi.

The superposition of Bragg peaks is achieved by mechanically inserting range-shifting


material in the monoenergetic proton beam with the insertion time proportional to the
required contribution of a peak to the SOBP (Fig. 7.8). The common method is to use a
rotating wheel with increasing step thicknesses and where the angular extent of the step
is proportional to the weight. A rotating wheel can produce SOBPs of varying
modulation by turning the beam off before a full rotation has been completed.
The modulation width traditionally is specified as the distance between the distal and
proximal 90%. However, this definition leads to modulation values larger than the
range value for some fields and becomes hard to measure in the shallow entrance dose
region. Thus, in our practice at least, we specify the modulation width between the
distal 90% and the proximal 98% (Fig. 7.2).
Absolute dose calculations for SOBP models have, in general, not been implemented
and output calculations rely on empirical models (14). The complexity, specific
construction details, and large number of mechanical components in a “modern”
scattering nozzle make such a description very difficult. This complexity increases the
burden on the physicist to establish a practical quality assurance protocol for output
calibrations (15).

Pencil-Beam Scanning Field Implementation


For pencil-beam scanning fields, we have physical beams of narrow protons whose
lateral position, quantified in the isocentric plane, is controlled by the scanning magnets
(SMs) and whose penetration depth is quantified by the energy. This energy is nearly
uniform with an energy spread dE/E on the order of 0.5% or less. The effect of the
energy spread is a broadening of the Bragg peak width.
In principal, one could use the physical pencil beam directly as a representation for
the gaussian form in Equation 7.7. However, this will lead to an implementation that is
insensitive to patient heterogeneities. The physical pencil beam typically has a spread of
4 to 15 mm at the entrance as a consequence of the beam transport system and scatter

174
in air and windows. Thus, considering Equation 7.7, the dose algorithm implementation
would be unable to discern inhomogeneities smaller than that spread. Schaffner et al.
(16) describe various techniques of modeling dose distributions near lateral
heterogeneities and one such model is the Fluence-dose model. The physical pencil beam
(PPB) is decomposed at the entrance into constituent mathematical pencil beams (MPB)
to retain sufficient resolution of the proton transport inside the patient. This can be
represented by considering the spot spread σ0 separately from the in-patient spread σP
in the gaussian function and modifying Equation 7.7 to the mathematically equivalent
form

where the first term (Equation 7.12a) is the number of protons GS (in units of billions or
Gigaprotons) in a PPB in the set S, the second term (Equation 7.12b) is the
apportionment of these GS protons, given the intrinsic lateral spread (RS, z) of the
PPB, over the set of MPB’s K. This set of MPB’s K in Equation 7.12c is defined at the
highest resolution (∼2 mm) necessary to accurately represent the dose in the patient.
Equation 7.12c models the diffusion of the number of protons, given by the product of
Equations 7.12a and 7.12b, in the patient given the scatter spread σP(RS,τWET) in the
patient due to multiple Coulomb scattering. The intrinsic lateral spread (RS,z) in
Equation 7.12b is determined by the scatter in air, magnetic steering, and focusing
properties of the PBS system (Fig. 7.8), and is a function of the spot range RS and
position z along the pencil-beam spot axis. The parameter ΔS, K denotes the position of a
point in the computational pencil beam area AK with respect to the spot coordinate
system. The final term (Equation 7.12c) follows Pedroni et al. (17), where TW•(RS,τWET)
(in units of Gy cm2 Gp−1) is the absolute measured depth-dose per Gigaproton (Fig.
7.9) integrated over an infinite plane at water-equivalent depth τWET, τWET σp(RS,τWET)
is the total pencil-beam spread at τWET caused by multiple Coulomb scatter in the
patient (6), and is the displacement from the calculation point to the K pencil-
beam axis. Equation 7.12 is a phenomenologic description of the distribution in the
patient of protons delivered by the set of spots S.

A Monte Carlo for Proton Transport in the Patient


The limitation of the gaussian pencil-beam model is well known: insensitivity to lateral
inhomogeneities as only variations along the pencil-beam axis is sampled (Equation
7.2). For clinical purposes, the gaussian pencil-beam model is a very good
representation (18), given the relatively small dispersion of the MPB (Fig. 7.5). Thus, if
lateral scatter were accurately modeled, there would be little further improvement
necessary. We describe a simple Monte Carlo that only models lateral scatter and is
implemented on a GPU, generally available on any personal computer.

175
FIGURE 7.9 A set of pristine peaks in absolute dose (Gy cm2) per gigaproton. Note the change in peak width
and height as a function of range.

The physics of proton transport is well described by considering multiple Coulomb


scatter using Molière’s theory and energy loss S along the track. Individual protons are
transported through a volume represented by a rectangular 3D grid of voxels of
dimension (dx, dy, dz) and localized by their index (i,j,k). Each voxel has the relative (to
water) stopping power SWV. The dose to a voxel is the sum of energy depositions along
the individual proton tracks that traverse the voxel and divided by the voxel mass.

FIGURE 7.10 Pseudocode for transporting a single proton through a voxel. The proton enters with energy Eo
and scatters by a mean polar angle q, a random azimuthal (around the proton direction) angle φ (green line). The
energy loss (Ei − Eo) depends on the energy only and is computed as a function of energy for a mean path length
·λÒ. The dose d deposited is the deposited energy divided by the mass of the voxel.

A proton, of energy ES, enters a voxel on one of its faces and exits on another. We
compute the (unscattered) exit point along the incoming proton direction (u,v,w) and
the distance λ between the entrance and this projected exit point. We compute the
mean polar scatter angle in the voxel as and the azimuthal angle randomly
uniform between 0 and 2p. The mean scatter angle q0(Es) is derived and quantified by
Gottschalk (10), analogous to the Highland formula (Equation 7.6c) but more

176
appropriate to traversal through thin layers. The azimuthal angle is the only random
variable. The proton direction is adjusted to (u,v,w), given the scattering angles and the
actual exit point are computed.
The energy loss of the proton along the mean voxel geometric track length λ is
derived from either the measured depth-dose distribution, TW• (R, τWET), or from range-
stopping power tables as in Fippel and Soukup (19). The energy loss in a voxel in the
former model is.

In either model, the depth-dose in the Monte Carlo is tuned to match the measured
depth-dose by adjusting the energy spread at the entrance to the phantom. The use of a
mean track length ·λÒ solely serves to reduce computational overhead. Figure 7.10
shows the pseudocode for this simple algorithm and Figure 7.11 shows the ability of the
algorithm to model traversal through heterogeneous medium.
This algorithm is implemented on a GPU, which contains numerous processors and
where each processor can execute multiple threads of the code in Figure 7.10. The
implementation can transport on the order of 600,000 protons/s on an off-the-shelf
graphics card. Such speed is competitive to a “conventional” pencil-beam application
and we, therefore, expect that such implementations will replace the conventional
implementations.

FIGURE 7.11 Energy loss distribution of 2 physical pencil-beams traversing water with inhomogeneous blocks
(gray for “bone” and open for “air.” Note the differential lateral scatter as expected).

The clinical proton field is defined by a set of numerous protons (∼106 or 107) with a
mean energy E, spread ΔE/E, entry point (x, y, z) on the surface of the voxel volume,
and direction (u, v, w). This computational set is derived from the properties of the
decomposed pencil beams as they are for either scattered or PBS field as described
above.

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KEY POINTS
• Pencil-beam dose algorithms rely on the decomposition of the radiation field into numerous
smaller, pencil-beam, fields that in aggregate represent the transport of the whole field
through the patient. Note that the term pencil-beam in proton pencil-beam algorithm refers
to the decomposition of the field—not the physical delivery! Each decomposed pencil-beam
is transported through the patient where the local energy (dose) is considered as a function of
the radiologic depth along the pencil-beam axis and a function of the convolution of the
energy at the radiologic depth to surrounding volume.
• The accuracy of a gaussian pencil-beam algorithm is limited by the width of the gaussian at
the calculation depth. The algorithm assumes that all volume contained by the gaussian
experiences the “same” physics and thus becomes insensitive to lateral heterogeneities on the
order of the width of the gaussian. Thus, for protons, this limits the algorithm to about 5 mm
at depth.
• Monte Carlo dose calculations calculate dose based on the energy losses of individual particles
in a computational (voxel) volume, which is often the smallest geometric representation of the
patient. Thus, Monte Carlo dose calculations are accurate up to the size of a voxel.
• The definition of dose–response is based on the empirical experience gained (primarily) from
photon irradiation and as referenced to Cobalt-60. For photon irradiation, physical dose is
therefore equated to biologic dose and its radiobiologic effectiveness (essentially in
comparison to itself) is 1. Ions exhibit different energy deposition along their tracks compared
to electrons, which in turn may create a difference between physical dose and biologic dose.
For example, clinical proton fields are assumed to have an RBE = 1.1 which means that 2 Gy
of Cobalt-60 dose can be delivered by 1.8 Gy of proton dose.

QUESTIONS
1. Given a prescription dose of 2 Gy (RBE) per fraction, what is the physical dose to
be delivered by the proton field?
A. 1.82 Gy
B. 2.20 Gy
C. 2.00 Gy
2. What is the thickness of a Lucite range shifter (ρ = 1.15 g/cm3) to shift a proton
beam range of 10 cm to 8 cm?
A. 2.30 cm
B. 2.00 cm
C. 2.00 g/cm2
3. What is the gaussian spread of an infinitesimal parallel proton pencil-beam of
range = 20 cm at 10 cm in water?
A. 4.5 mm
B. 1.5 mm

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C. 3.0 mm
4. In a scattered proton field, the virtual source size is (typically) very large and on
the order of σ = 5 cm. A large SAD (say 300 cm) and a short aperture-to-
isocenter distance (say 20) reduce this source size to:
A. 3.3 mm
B. 3.6 mm
C. 5.3 mm

ANSWERS
1. A 1.82 Gy [2 Gy (RBE)/1.1 (RBE)]
2. B 2.00 g/cm2 [thickness expressed in “water” thickness]
3. B (from Figure 7.6) 4.8 mm × 0.3 = 1.5 mm
4. B 20/(300 − 20) × 50 mm = 3.6 mm

REFERENCES
1. Gottschalk B. Passive beam spreading in proton radiation therapy.
http://huhepl.harvard.edu/∼gottschalk/.
2. Paganetti H. Nuclear interactions in proton therapy: dose and relative biological
effect distributions originating from primary and secondary particles. Phys Med Biol.
2002;47:747–764.
3. International Commission on Radiation Units and Measurements. Prescribing,
recording, and reporting proton-beam therapy (ICRU Report 78). J ICRU.
2007;7(2):NP.
4. Amsler C, Doser M, Antonelli M, et al. (Particle Data Group). Phys Lett. B667
2008;1.
5. Janni J. Proton range-energy tables, 1 keV–10 GeV. At Data Nucl Data Tab.
1982;27:147–339.
6. Hong L, Goitein M, Bucciolini M, et al. A pencil beam algorithm for proton dose
calculations. Phys Med Biol. 1996;41:1305–1330.
7. Schneider U, Pedroni E, Lomax A. The calibration of CT Hounsfield units for
radiotherapy treatment planning. Phys Med Biol. 1996;41:111–124.
8. Cormack AM, Koehler AM. Quantitative proton tomography: preliminary
experiments. Phys Med Biol. 1976;21:560–569.
9. Molière G. Theorie der Streuung schneller geladener Teilchen II Mehrfach—und
Vielfachstreuung-streuung. Z Naturforsch B. 1948; 3A:78–97.
10. Gottschalk B. On the scattering power of radiotherapy protons. Med Phys.
2010;37:352–367. arXiv:0908.1413v1 (physics.med-ph).
11. Lynch GR, Dahl OI. Approximations to multiple Coulomb scattering. Nucl Instrum
Meth. 1991;B58:6–10.
12. Lee M, Nahum A, Webb S. An empirical method to build up a model of proton dose
distribution for a radiotherapy treatment-planning package. Phys Med Biol.
1993;38:989–998.
13. Hogstrom KR, Mills MD, Almond PR. Electron beam dose calculations. Phys Med
Biol. 1981;26:445–459.

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14. Kooy HM, Schaefer M, Rosenthal S, et al. Monitor unit calculations for range
modulated spread-out Bragg peak fields. Phys Med Biol. 2003;48:2797–2808.
15. Engelsman M, Lu HM, Herrup D, et al. Commissioning a passive scattering proton
therapy nozzle for accurate SOBP delivery. Med Phys. 2009;36:2172–2180.
16. Schaffner B, Pedroni E, Lomax A. Dose calculation models for proton treatment
planning using a dynamic beam delivery system: and attempt to include density
heterogeneity effects in the analytical dose calculation. Phys Med Biol. 1999;44:27–
41.
17. Pedroni E, Scheib1 S, Bohringer T, et al. Experimental characterization and
physical modelling of the dose distribution of scanned proton pencil beams. Phys
Med Biol. 2005;50:541–561.
18. Jiang H, Paganetti H. Adaptation of GEANT4 to Monte Carlo dose calculations
based on CT data. Med Phys. 2004;31:2811–2818.
19. Fippel M, Soukup M. A Monte Carlo dose calculation algorithm for proton therapy.
Med Phys. 2004;31:2263–2273.

1Proton path length is the thickness of material summed over the track of the proton.
Protons at clinical energies, however, undergo little deviation from straight paths and
path length and thickness can be used interchangeably in proton therapy. Depth is the
thickness of material summed along a ray from the entrance of the phantom to a given
endpoint.

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8 Commissioning and Quality Assurance

James A. Kavanaugh, Eric E. Klein, Sasa Mutic, and Jacob Van Dyk

INTRODUCTION
Modern radiation therapy requires increasingly sophisticated technologies to accurately
deliver high doses of radiation to very specific anatomic targets. The successful
administration of a patient’s radiation treatment is the final step of a complex process,
an overview of which is illustrated in Figure 8.1. Errors at any one of these steps can
produce deviations between the delivered radiation treatment and the intended
prescription with such deviations having the potential for markedly inferior clinical
outcomes compared with those whose treatment was initially protocol compliant (1). On
rare occasions, these deviations can have catastrophic consequences to the patient’s
health (2,3). To ensure accuracy of the prescription and the fulfillment of treatment
intent, a rigorous quality assurance (QA) program is required at all stages of the
radiation treatment process. The purpose of a QA program is to provide systematic
evaluations and necessary corrective actions to maintain the quality and safety of a
radiation therapy program. These evaluations, or quality controls (QC), measure a
specific quality metric, compare it to an existing standard baseline, and adjust the
metric to conform to the baseline as necessary. The baselines used within a QA program
are typically defined during the initial commissioning process (4). Commissioning is the
preparation of a new device, technique, or procedure for clinical use.
The more darkly shaded region of Figure 8.1 highlights the stages that relate
specifically to treatment planning. Virtual simulation combined with the use of a
computerized treatment planning system (TPS) for dose computation and technique
optimization is standard practice in the modern radiation therapy department.
Developments in automated optimization (5), beam intensity modulation (6), the use of
a variety of imaging modalities (7), and the inclusion of biologic parameters (8) to
calculate tumor control probabilities (TCPs) and normal tissue complication
probabilities (NTCPs) have added dramatically to the complexity of the modern TPS.
More recently, developments in auto segmentation contouring algorithms,
automated/knowledge-based planning (KBP) techniques (9), and adaptive radiation
therapy (ART) (10) have further compounded this complexity.
The continually expanding complexity of the modern TPS has made the
commissioning process one of the most challenging and error-prone steps in modern
radiation therapy (11,12). Historically, measurements and modeling of the basic
radiation dataset needed to accurately commission a TPS have been the responsibility of
the local medical physicist. Despite comprehensive guidance documents (13–16), the
variation of skill and experience of the local physicist has produced drastic variations in
the accuracy of the calculated dose distributions across institutions utilizing the same
linear accelerator technology (12). As modern linear accelerator technology has been
shown to be consistently stable and uniform, there has been increased discussion
regarding the use of a vendor specified standardized basic radiation dataset for
commissioning a TPS (17,18). The standardized dataset for a specific vendor (Varian
Medical Systems), known as golden beam data (GBD), would minimize the variation in

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TPS commissioning and would still require local verification measurements to ensure it
matches the dose delivery data. Utilizing GBD instead of locally measured data is quite
controversial and is mentioned here to inform the reader of the current disagreement in
the field (19).
The overall need for QA in radiation therapy is well defined (20–22). As mentioned
previously, comprehensive reports on treatment planning QA have been developed by
the AAPM (13) and, more recently, by the International Atomic Energy Agency (IAEA)
(14–16). This chapter addresses issues related to the use of treatment planning
computers in the context of acceptance testing, commissioning, and routine clinical
application. Although the emphasis is on commissioning and QC, there is also some
discussion on QA of the total treatment planning process. The intent of this chapter is to
be as generic as possible so that it applies to both conventional and more sophisticated
radiation treatment techniques; however, because of page limitations, details for
specialized techniques are confined to references where indicated.

Historical Perspective, Current Status, and Future Possibilities


Publications on computer applications in radiation therapy date back to 1951, when
Wheatley (23) produced an analog computer to perform “dosage estimation of fields of
any size and any shape.” The primary purpose was to relieve the tedium associated with
dosage calculations (24). It appears that computers were used in radiation therapy as
early as in any other field of medicine. Tsien (25) has been credited with being the first
in the application of “automatic computing machines to radiation treatment planning.”
During the past 60 years, there has been an enormous technologic evolution of
computer technology, including microcomputers, large time-sharing systems,
minicomputers, graphics workstations, and desktop personal computers, as well as
laptops, handhelds, and tablets. During each phase of computational development,
computers provided treatment planners with faster and more sophisticated capabilities
for dosage calculations, better image and graphical displays, and improved automated
optimization capabilities (26). The evolution of these sophisticated technologic
developments can be readily followed by reviewing the proceedings of a series of
international meetings on the use of computers in radiation therapy, the first and last of
which occurred in 1966 and 2013 (27,28).

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FIGURE 8.1 Schematic flowchart of the steps in the total radiation therapy process. The shaded region
emphasizes those steps specifically associated with treatment planning and the use of the TPS. (Adapted from
Van Dyk J, Rosenwald J-C, Fraass B, et al. Commissioning and quality assurance of computerized planning

183
systems for radiation treatment of cancer. Figure 1 of IAEA TRS-430 (14), reproduced with permission.)

The advances in computer technology led to a revolution of diagnostic imaging


during the 1970s that provided a further breakthrough for radiation therapy planning.
Until then, it was difficult both to localize the tumor with any kind of accuracy and to
provide accurate dose calculations accounting for patient-specific tissue densities. With
the advent of computed tomography (CT) it became possible for the first time to derive
in vivo density information that could be incorporated into the dose calculation process.
The combination of developments in computers and in diagnostic imaging resulted in
much research, improving dose calculation procedures that accounted for the actual
tissue composition of the patient.
Over the past two decades, the utilization of multiple imaging modalities and the
ever-increasing computational demands has necessitated changes in the TPS hardware
and storage capabilities. Modern fluence optimization and dose calculations require
significantly more computational power, resulting in a migration from local desktop PCs
to large local server farms. Storing the vast amount of on-treatment and historical
treatment planning data often requires utilizing picture archiving and communications
systems (PACS). While the installation of these systems is often completed by industry
experts, it is typically the responsibility of the local physics or information technology
(IT) staff to provide management for routine data backup/restoration,
software/hardware issues, and future upgrades. While larger institutions may have the
necessary resources to fully support all components of a modern local server-based TPS,
the increased hardware/software components may be beyond the means and expertise
available for smaller clinics.
One possible solution currently being explored is the utilization of cloud-computing
(29). The ubiquity of modern high-speed fiber optic communications may allow clinics
to outsource the dose computation, data archiving, and other TPS functionalities to
professionally managed server farms. Cloud-computing would allow all radiation
oncology clinics to install modern TPS functions without extensively investing in
hardware or specialized staff. Implementing cloud-computing could provide several
other advantages, including easy sharing of plan data and a standardization of TPS
parameters between institutions with matched machines. Before being adopted
clinically, several issues, including data security/privacy and data transfer integrity,
would need to be fully resolved.
The topic of QA for TPSs has only recently received extensive attention from national
and international radiation oncology groups, as demonstrated by the development of
several reports formalizing TPS QA (13–16,30–33). This is partly due to the nature of
QA, which has not historically been considered a major area for high-powered research
and partly in response to the increased complexity and sophistication of technology
used in the modern radiation oncology clinic. This chapter summarizes recent
developments and recommendations associated with QA issues in radiation treatment
planning, especially the implementation and clinical use of computerized radiation
TPSs.

Treatment Planning Process


In its broader sense, treatment planning includes all the steps from therapeutic decision
making to target volume and normal tissue delineation, selection of treatment
technique, determination of the direction of radiation beams, simulation, fabrication of
ancillary devices and treatment aids, monitor unit (MU)–time calculations, treatment

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verification, and finally, first treatment (Fig. 8.1). In its narrower sense, treatment
planning includes the outlining of target and critical volumes (34); the determination of
the number, directions, and modality/energy of radiation beams; and the corresponding
MU calculations. In this narrower definition, treatment planning involves the use of
image information and the computer to perform the appropriate virtual simulation and
dose calculations. The QA considered in this chapter primarily addresses the use of the
TPS to generate appropriate beam arrangements and dose calculations. The following
specific issues are associated with that part of the QA process.

Patient Data
Patient data can be derived in various ways, including simple methods of external
contour determination and various imaging modalities, most commonly CT. Image
registration techniques (rigid and deformable) are used to accurately overlay the
patient’s anatomy from various imaging modalities so that each can be fully used during
contour delineation. The important issue at this stage of planning is to ensure that the
patient is positioned identically to the eventual treatment position and that the derived
data represents this position (35). It is important that the data be transferred accurately
to the TPS. Also, any conversions of digitized data, such as the conversion of CT
numbers to electron densities, must be handled accurately by the system.

Display of Patient and Beam-Related Information


Once the data have been transferred to the TPS, the treatment planner can manipulate
the information, look at the data on various slices or in 3-dimensional (3D), and allow
the system to perform reconstructions of images. With the patient data on the computer,
the radiation oncologist is able to outline target volumes and critical organs-at-risk
(OAR) on the appropriate slices (34). The correctness of the display of patient data is
not only important for target/OAR delineation but also for the treatment planner to
accurately design the placement and optimization of radiation beams. Beam placement
is often performed by entering parameters such as field size, beam direction, and
collimator rotation. At this stage, various options can be used for the definition of the
field shape. In each case, the beam edges can be displayed either on a beam’s-eye-view
perspective or as perspectives of the beam edges intersecting any specified plane.
Associated with the beam edge display, information demonstrating gantry angle,
collimator angle, beam energy, and collimator size should also be displayed on the
screen.

Dose Calculation and Display


Once the beam geometry has been determined, the dose distribution can be calculated
and displayed. Displays vary from simple colored isodose lines to color washes to
individual point doses. The accuracy of the geometric correctness of isodose lines on the
display is very difficult to assess, although very specific phantom geometries, whereby
one can assess the position of a specific isodose line, can help with this process. Doses
calculated at individual points can be correlated to the isodose lines as well as measured
data.

Development and Implementation of Treatment Planning Algorithms


The clinical implementation of treatment planning programs involves a number of steps.
Some are under the control of the user, and some are not, because they depend on
software developed by others. The typical clinical implementation of treatment planning

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programs usually takes the following steps.

Development of Calculation Algorithms


Dose calculation algorithms are based on the physics of radiation interactions within
tissue. Because of the complexity of the physics of these types of interactions, the
algorithms usually involve simplifications allowing the calculations to be completed fast
enough to be useful to the treatment planner. These simplifications result in
approximations to the complicated physics, and therefore, the algorithms have inherent
uncertainties and generally work well only over a limited range of conditions. Usually,
the more complex algorithms handle the physics in more detail, but also require longer
calculation times. The extreme example of this is Monte Carlo calculations, which can
take hours to days, depending on the mode of treatment and the complexity of the plan,
although recent commercial clinical versions for electron beams can be calculated in
minutes (36) and photon beams from minutes to hours (37). To be practical, a clinical
algorithm should generate dose distributions nearly in real time, but usually in seconds.
The details of the algorithm implemented on a given commercial TPS are not in the
control of the user.

Development of the Computer Programs Implementing the Algorithms


Once a developer of a TPS has determined the nature of the algorithm, the algorithm
must be coded into software. This software must include appropriate input–output
routines, image display, and manipulation routines, options that allow the user to
define the treatment technique, and plan optimization and evaluation routines. The
development of the software is not under the control of the user. It is the responsibility
of the developer of the software to ensure that the algorithms are properly coded.
It is important for the user to have some knowledge of the nature of the dose
calculation algorithms to help understand their capabilities and limitations.
Furthermore, a basic knowledge will also help the user diagnose specific TPS problems
and can be of some help in developing a QA process. A detailed description of different
dose calculation algorithms can be found in the preceding chapters. A detailed report
on external beam tissue inhomogeneity corrections for photon beams has been produced
by AAPM Task Group 65 (38). In recognizing that the thorough description of
algorithms was also beyond the scope of the IAEA TRS-430 (14), the report provides a
series of questions that users may want to address either as part of the search process
for a new TPS or in attempting to understand the calculation algorithm(s) currently
available on their TPS. This information is provided in 14 tables addressing different
issues related to TPSs. To give an idea as to the subjects covered, the titles of these
tables are summarized in Table 8.1. Table 8.2 is an example of one of the tables in IAEA
TRS-430 (14) and shows questions related to external beam dose calculation algorithms
in a water-like medium without any beam modifiers.
For brachytherapy, an interesting review of the evolution of treatment planning has
been provided by Rivard et al. (39).

Determination of the Radiation Database Required by the Algorithms


All algorithms, even sophisticated Monte Carlo procedures, require a basic radiation
dataset as input. As discussed earlier in this chapter, the data used to create a basic
radiation dataset originates from two possible sources. Traditionally, the data are
independently measured for each energy on each therapy machine in every radiation
therapy department. The quality and accuracy of such data depend on the individuals
commissioning the TPS. Alternatively, one can commission the TPS using GBD supplied

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by the system manufacturer and validate the supplied data against a subset of beam
measurements from the local radiation therapy machines.
TABLE 8.1 Titles of Tables in IAEA TRS-430 (15). Addressing Questions Associated with
TPS Algorithms

Such data are always determined over a limited range of conditions. Thus,
calculations that extend beyond the range of the original measurements may be subject
to question, depending on the extrapolation procedures used by the calculation
algorithms. Furthermore, measured data have their own inherent uncertainties and
depend on the type and size of detectors used and the care taken by the experimentalist
(18). The accuracy of the measured data also depends on the stability of the radiation
therapy machine and its ability to yield the same kind of radiation characteristics from
day to day and hour to hour.
The input data required by TPSs at minimum are relative, in the form of dose ratios,
with the denominator being the dose under some reference condition. Any TPS capable
of calculating MU or treatment times also requires absolute information in the form of
MUs per gray or grays per minute. These are all part of the input dataset required by
the TPS.

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TABLE 8.2 External Beam Dose Calculation Algorithm: Dose in Water-Like Medium
without Beam Modifier

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Clinical Application
Finally, the clinical use of the TPS requires patient-specific information in the form of
patient contours, usually generated with the aid of CT, PET, and/or MRI. Appropriate
parameters must be entered to determine the treatment configuration. Dose calculations
are usually performed for each beam independently, with the summed doses displayed
on a monitor. This clinical application of treatment planning depends entirely on the
user and his or her knowledge of the capabilities and limitations of the TPS. Admittedly,
the newer inverse planning optimization routines (5) used for IMRT are automated and
leave little in the control of the user other than entering the dose-volume constraints as
required by the objective function for the optimization.

TREATMENT PLANNING SYSTEM COMMISSIONING AND


QUALITY ASSURANCE
Terminology Associated with QA
Four major topics that are associated with the installation of any major piece of
apparatus are specifications, acceptance testing, commissioning, and QC. In the context of
TPS, the distinction between some of these terms is not entirely clear, and therefore they
warrant special discussion.

System Specifications
In the context of treatment planning computers, specifications define the detailed
functionality criteria of how the TPS will be utilized within the clinical workflow. Until
relatively recently, there have been numerous commercial and home-grown TPSs with
each offering unique functionality. This broad selection made it extremely important for
an end user to carefully match system specifications to their current/future clinical
workflow. Currently there are only a few commercially available systems, each offering
a standard range of functions that facilitate all applications used within most clinical
workflows. Manufacturers of these modern TPSs provide specifications that define the
capabilities of their equipment. For TPSs, the specifications tend to include necessary
hardware, system administration software, networking software, and dose planning
software. Software specifications include detailed descriptions of what the software is
capable of doing and how accurate the dose calculations can be made. Networking
software specifications should detail the ability for the TPS to be fully integrated with
the electronic medical record, information management, and record and verify software
systems.

Acceptance Testing
Upon the installation of any new device, the user should assess the device to ensure that
it behaves according to its vendor-defined specifications. For a TPS, this takes at least
two forms: assessment of the hardware and the software. The latter can also be divided
into several components, including assessment of the integrity of the operating system,
dose calculations, image transfer, and image display. Acceptance testing is typically
conducted by the vendor’s installation engineers, who must show the accuracy of all
specifications, are within preagreed upon standards. Successful completion of
acceptance testing represents the final stage of the installation contract.

Commissioning
Commissioning is the process of putting the system into active clinical service. This

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includes the production of a basic radiation database, which is entered into the TPS,
after which the user tests the system over a range of clinically relevant conditions.
Quality evaluations of the programs’ outputs are then made. Such a process cannot test
all the system’s pathways or subroutines; however, it does provide the user with a level
of confidence over a wide variety of often-used treatment conditions. In addition, it
helps the user understand the degree of uncertainty associated with these specific
calculations. Finally, during commissioning the user produces a baseline of performance
standards to be utilized for future QC (4).

Quality Control
As indicated earlier, QA and QC are closely related. QA is the total process required to
ensure that a certain level of quality is maintained for a defined product or service. QC
consists of systematic actions necessary to ensure that the product or process performs
according to specification. QC contains three components: (a) the measurement of the
performance, (b) the comparison of this performance with existing baselines or
specifications defined during commissioning, and (c) the appropriate actions necessary
to keep or regain agreement with the baseline.
In summary, QA and QC first necessitate defining a series of specifications.
Acceptance tests ensure that the system meets the basic requirements as defined by the
specifications. Commissioning makes the computer ready for clinical use and provides a
series of baselines that can be used for ongoing QC to ensure that the system is
maintaining the required standards. Ongoing QC must be performed at intervals to
confirm that there have been no changes in the basic radiation and machine parameter
data files, in the input–output hardware, in the CT, MRI, or other imaging-related
software or hardware, or with the transfer of data between clinical systems. Each of
these four sections will be described in detail throughout the remainder of the chapter.

System Specifications

Sources of Uncertainties
Specifications take various forms. One form is simply a statement of whether the TPS is
capable of doing a particular function or not. Another form is quantitative, for example,
calculation speed, number of images it can hold, and so on. A third form is a statement
of accuracy. This is particularly relevant for dose calculations. To assess the accuracy of
a TPS and to define realistic accuracy specifications, it is necessary to understand the
sources of uncertainties.
The determination of uncertainties in dose calculations is complex because dose
calculation algorithms depend on input information, which is usually generated by
measurement. Thus, the uncertainty in the calculation output depends on the
uncertainties associated with the measurements as well as the limitations of the
calculation algorithms. Measurements are of various types, including relative doses in
water phantoms, absolute dose calibrations for MU calculations, patient anatomy using
imaging techniques or contouring devices, and thickness profiles of compensators or
bolus.

Suggested Tolerances
Criteria of acceptability for dose calculations have been described by various authors
(21,40–42). Task Group 53 of the AAPM (13) and IAEA TRS-430 (14) also include
discussions on criteria of acceptability and tolerances generally considered achievable.
All tolerance values vary dependent on the region of calculation. Greater accuracy can

190
be achieved on the central ray in a homogeneous phantom than in the penumbra region
at the beam edge. Generally, four regions can be considered: (a) regions of low-dose
gradients in the central portion of the beam, (b) regions of large-dose gradients such as
those occurring in the penumbra or in the fall-off region for electron beams, (c) regions
of low-dose gradients in low-dose areas such as those occurring outside the beam or
under large shielded areas, and (d) doses in the buildup or build-down regions at the
entrance and exit surfaces of the patient. Criteria of acceptability are generally quoted
as a percent of the reference dose except in regions of high-dose gradients, where a
spatial agreement in millimeters is a better descriptor, since the dose uncertainties in
such regions can be very large.
Criteria of acceptability should include a statement of confidence. For example, we
may state the criterion of acceptability is an accuracy of 2% of the dose calculated on
the central ray of the beam for a homogeneous phantom. However, it is not clear if this
statement expects all calculated doses to be less than the criterion or if it expects only a
certain percentage, such as one standard deviation (68%) to be within the 2% of the
measured values. This is an important consideration, since ambiguities in these criteria
can generate tremendous frustration from the user’s perspective as well as some
troublesome legal interactions with manufacturers of TPSs. By way of example, Van Dyk
et al. (41) produced some tables of criteria of acceptability clearly outlining the system’s
general capabilities. Tables 8.3 and 8.4 are similar to the Van Dyk data, but some
adjustments have been made in the numerical values to indicate a slightly tighter range
of acceptability reflecting improvements in dose calculation algorithms available with
modern TPSs. These criteria of acceptability represent one standard deviation about the
mean. Venselaar et al. (42) have used a somewhat more complex, but more rigorous,
definition of a “confidence limit” and this has been discussed in IAEA TRS-430 (14). It
should also be noted that calculation accuracies depend not only on the input data and
the limitations of the algorithms, but also on the user’s performance of the calculation,
which includes issues such as the choice of grid spacing. Grid spacing can have a large
impact on the accuracy of dose calculations, especially in regions of high-dose gradient.
TABLE 8.3 Sample Criteria of Acceptability for Photon and Electron Dose Calculations

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TABLE 8.4 Sample Criteria of Acceptability for Brachytherapy Calculations

192
For brachytherapy calculations, uncertainty estimates are more difficult to determine
because of the very short treatment distances and the corresponding large-dose
gradients. Furthermore, brachytherapy calculations usually include absolute dose
estimates, which require a detailed understanding of absolute source output
specifications. A recent AAPM report suggests that when all uncertainties are combined,
the two standard deviation (or two sigma uncertainty, k = 2 in the report) of dose rates
used in treatment planning are approximately 9% and 7% for low-energy and high-
energy photon-emitting brachytherapy sources, respectively (43). These stated
uncertainties are for a single location, 1 cm from the source along the transverse plane.
It should be noted that the one standard deviations (or one sigma uncertainty, k = 1 in
the report) are less than 5% for both low-energy and high-energy sources. These
findings keep in agreement with the suggested criteria of acceptability for
brachytherapy calculations with a confidence of one standard deviation given in Table
8.4.
These criteria of acceptability are based on what may be realistically achievable.
Ideally, the recommendations of ICRU 42 (40) should be used as a goal for developers
of treatment planning computer software. For external beam therapy, ICRU 42
recommends 2% accuracy in low-dose gradients and 2 mm accuracy in high-dose
gradients. For brachytherapy, 5% to 10% accuracy (two-sigma uncertainty) at distances
of 0.5 cm or more has been suggested (43).

Acceptance Testing
The system specifications determine the acceptance tests that have to be performed. As
a first step upon completion of the installation of a new system, the user should
determine that all the components have been delivered and are consistent with the
specifications. This includes a review of each component of the hardware. With rapidly
changing technologies, manufacturers often switch one piece of hardware with an
updated version or with a device from another manufacturer. It is up to the user to
ensure that the new hardware equals or surpasses the specifications set out in the
purchase document.
The next step is to ensure that each component of the hardware functions at a simple
level, that is, make an assessment of the monitor, mouse, printer, scanner, storage
media, network connection, and other hardware items. A check that all the relevant
manuals and schematics have been delivered is also important. The next level of
hardware testing is to use the diagnostic programs provided with the system to ensure
that all the hardware components assessed by the diagnostic routines are functioning

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properly. This provides both a test of the system and a baseline for the user to
understand any changes that may be observed in the follow-up QA tests.
The next step is to run the system software and to ensure that each component of the
software listed in the specifications is actually installed and functional. This includes
third-party software (commercial software purchased by the vendor and included in the
TPS) in addition to the treatment planning software.
The TPS software acceptance is very complex, primarily because the testing of the
software requires input data specific to the therapy machines to allow direct
comparisons of calculations with measurements. A practical approach is to test the
system’s input–output hardware to ensure that the system is capable of providing the
options as defined in the specifications and then to assess the accuracy of the
calculations as part of the commissioning process. In the signing of the acceptance
document, the purchaser should indicate that the software acceptance will be completed
as part of the commissioning process.
It should be noted that acceptance testing for IMRT requires a special emphasis on
the system’s capability of handling the penumbra region of small radiation fields as well
as the leakage radiation outside the field. Small differences between measured and
calculated dose in these regions can yield relatively large dose differences when many of
these small fields are summed together. Due to the difficulty of small field dosimetric
measurements, extreme care should be taken to ensure that the input data accurately
represent the radiation delivery system.
A major component of potential error relates to maintaining the spatial integrity of
imaging datasets during input–output with the TPS. Analysis of the spatial integrity
during input–output should include validating the consistency of size, shape, distance,
and orientation of the dataset, and the uncertainty should be <1 mm. All contours,
target volumes, normal tissue structures, CT images, beam outlines, ancillary devices
such as wedges and blocks, and isodose lines should be accurate and consistent between
screen display and hard-copy output. Scales, distance calipers, and any other
measurement routines should be assessed for both function and accuracy. This includes
autocontouring, automatic contour expansion for target volume margins, density
assessments, automatic field shaping, and other features used by the planning software.
A more comprehensive process for acceptance testing has been proposed by the IAEA
(15). The IAEA process is based on an earlier document specifically made for vendors of
TPSs by the International Electrotechnical Commission (IEC) (32), which developed a
series of requirements for manufacturers in the design and construction of a TPS. The
consultants group for the IAEA has proposed that vendors should perform a series of
“type” tests for their system, the results of which should be provided by the vendor to
the user as part of the purchase documentation (15). Type tests refer to those tests that
are to be done by the manufacturer, normally at the factory, to establish compliance
with specified criteria. The type tests proposed by the IAEA are based on an
intercomparison of photon dose calculation data (44). In addition to the 6, 10, and 18
MV data in the Venselaar and Welleweerd report, cobalt-60 data have also been added
to the IAEA dataset. These data are provided by the IAEA to all vendors. The vendors
enter the basic radiation beam data as though they were commissioning those beams for
their dose calculation algorithms. Then, the vendors should perform all the tests as
described in the IAEA document. Once the TPS is installed at the user’s site, a select
subset of tests should be performed to demonstrate consistency with the vendor’s type
tests. The vendors should update the type test results, if necessary, whenever software
changes or upgrades are made, and again these should be documented and provided to
all purchasers of that software. At the time of software updates by the user, another

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select subset of tests can be made to ensure consistency of results between the vendor’s
calculations in the factory and the user’s calculations in the clinic.

Commissioning
As discussed in the introduction, there is an ongoing debate on the utilization of GBD
for commissioning a TPS (19). Supporters of the historical customized method of using
institution specific beam data contend that manufacturing and installation variations
between linear accelerators require unique beam models developed from the beam data
produced by extensive commissioning measurements (18). In this approach, it is the
responsibility of the physicist, guided by numerous formalized documents, to correctly
commission the TPS and develop ongoing QA processes (13,18). Proponents of using
GBD contend that variations between machines from the same vendor/series are
minimal (17) and reference of several studies indicating measurement and modeling
errors during TPS commissioning and QA produce more extensive dose calculation
inaccuracies (11,12). Furthermore, prepackaged TPSs modeled on extensively validated
GBD have the potential to drastically reduce gross systematic errors and standardize
delivery quality across the entire radiation oncology industry (19). Several vendors of
both generalized and specialized commercial TPSs install units using manufactured
measured GBD (45–47). Validation of GBD to the measurements made on the local
linear accelerator is still needed to ensure an accurate match between the planned and
delivered dose. Regardless of which set of beam data is used during TPS commissioning,
the same general measurement and comparison methodology should be followed,
including comprehensive end-to-end testing for the entire treatment planning and
delivery process. The commissioning process should also incorporate the development of
treatment planning procedures, training for staff, and designating expert users who will
be responsible for the continually TPS QA program. The remainder of this section
provides examples and highlights of tests that should be conducted during TPS
commissioning.

Photon Beams
The clinical implementation of the TPS can be divided into several components. These
include entry of basic radiation data, entry of machine-specific parameters, entry of
data related to ancillary devices such as wedges, assessment of image transfer
capabilities, assessment of the accuracy of the electron density conversion formula, and
the validation of data transfer between all systems in the clinical workflow. Each of
these components involves data entry and then tests of the software. For each
component it is important for the user to understand the capabilities and limitations of
the software.
For TPS commissioning using unique local beam data, the data entry for dose
calculations can have various forms, including a direct entry from data stored in the
water phantom computer. The software of both the water phantom systems and TPSs
evolves with time and therefore comes in various versions. To ensure version
compatibility, it is always important to assess that the data have been read properly by
the data entry programs.
Basic radiation data can be entered in various forms, including tissue–air ratios,
tissue–phantom ratios, tissue–maximum ratios, percentage depth doses (PDD), and
cross-beam profiles. Cross-beam profiles may also have to be measured under a variety
of conditions, including profiles for the machine collimators, shielding blocks, wedges,
and multileaf collimators. The quality and accuracy of the measured basic radiation

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data should be evaluated prior to implementation in the TPS. A standard set of
procedures for acquiring radiation beam data, along with examples of commonly
identified errors, are provided by the AAPM (18). Limitations of physical measurements,
specifically for small fields, high gradients such as the penumbra and buildup regions,
and peripheral dose regions should be carefully evaluated. In all situations it is
imperative that the user ensures the accuracy of the entered data by looking at the
numerical values on the screen or by plotting out the data and comparing directly with
what has been entered. An independent verification of the beam data using either
Monte Carlo generated data or GBD should be considered.
Should GBD be used during commissioning to create dose calculation models, the
validation measurements taken on the linear accelerator should be directly compared to
the GDB values. Any discrepancies should be evaluated and, if necessary, modifications
can be made to the delivery system.
The types of tests that should be used to assess the quality of the algorithms are
summarized through working group reports as seen in references 13, 14, and 31. Table
8.5 provides a summary of the relevant parameters and variables that should be
included in the testing process. This is a guide to the kinds of issues that should be
considered when assessing the calculation capabilities of the TPS.

Examples of Photon Commissioning Tests


Several examples of the types of tests that can be performed, possible methods of
evaluation, and some additional issues to consider are provided for non-IMRT photon
beam commissioning. These examples do not represent extensive commissioning testing
and primarily serve to illustrate possible methods for completing the commissioning
process. Figure 8.2 illustrates an example of simple central axis PDD data for a range of
field sizes. A comparison is made between the calculated data (lines) and the measured
data (points). Figure 8.3 shows how the data of Figure 8.2 can be analyzed more
critically by taking the absolute difference between the entered and the calculated data
for a 10 cm × 10 cm field size. It is clear that beyond the buildup depth (40 mm) the
differences are minimal (<0.2%), but in the buildup region differences can be as large
as 9%. The reason for these differences is not clear, but the trends are similar for all
field sizes. Figure 8.4 shows a difference comparison for cross-beam profiles and
includes two different calculation algorithms, one being a table look-up algorithm and
the other a convolution calculation. In these graphs, it is clear that there are sizable
differences in dose in the penumbra region, although spatially these differences are
quite small (1 to 2 mm).
TABLE 8.5 Initial Dose Calculation Tests: Variables to Consider

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FIGURE 8.2 Central ray percentage depth doses (PDD) for fields of dimensions 4 × 4 cm, 10 × 10 cm, 25 ×
25 cm, and 40 × 40 cm. The data points entered into the treatment planning system are labeled Meas and the
calculated data are shown by the lines. The data are for the 25 MV beam from a linear accelerator and are
normalized to 100% at a depth of 4 cm.

Figure 8.5 shows a comparison of measured and calculated dose profiles with the
gantry angle at 40 degrees incident on a flat water phantom. This comparison tests the
integrity of the TPS to correct for nonnormal incidence of the primary beam. Figure 8.6
is a demonstration of the accuracy of the wedge calculations for a motorized wedge (a
physical wedge that is inserted by motor in the beam for a fraction of the treatment and
withdrawn for the remainder). This is a severe test of the algorithms, since the wedge is
very thick, with a wedge factor of about 0.25. Figure 8.7 shows the difference between
calculated and measured dose for central ray PDD data under the motorized wedge for
a number of field sizes.

FIGURE 8.3 The absolute difference between calculated and entered (or measured) percentage depth dose
(PDD) data for a 10 × 10 cm field for the 25 MV photon beam from a linear accelerator.

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FIGURE 8.4 Absolute differences in relative doses comparing measurements with calculations for cross-beam
dose profiles for two dose calculation algorithms. The beam profiles were measured at a depth of 4 cm for the 25
MV beam of a linear accelerator. The pencil beam (convolution) algorithm shows the largest difference, about
10% in the penumbra region, although this difference represents a spatial uncertainty of only 2 mm (not shown
in figure).

Figure 8.8 shows cross-beam dose profiles calculated for a multileaf collimator with
the three 1-cm leaves covering the central portion of the beam to yield a central beam
block. Note that one of the leaves is on one side of the central ray and the other two are
on the opposite side. At depths of 4, 10, and 25 cm, the dose profiles agree reasonably
well except in the centrally blocked region. A more detailed comparison of this is shown
in Figure 8.9, where calculated central ray depth doses are shown first for an open
beam and then with the three central leaves covering the beam. Also shown are
measured central ray data under the leaves. The differences between calculated and
measured data under the leaves are about 5% to 7% except in what is normally the
buildup region, where the differences are as large as 28%. These differences may be due
to this program’s inability to handle electron contamination under the leaves or shields.
This is a physics problem that occurs in older algorithms but has been improved in most
new commercial treatment planning programs (48,49). Differences could also be
originating from the limitations of physical measurements within these regions.

FIGURE 8.5 Calculated and measured dose profiles with a gantry angle of 40 degrees incident on a flat water
phantom for a 10 cm × 10 cm field at depths of 4 and 10 cm for the 25 MV beam of a linear accelerator.

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FIGURE 8.6 Calculated and measured dose profiles under a motorized wedge. Profiles are shown for the 25 cm
× 25 cm at depths of 4 and 15 cm, as well as a 30 cm × 30 cm field at a depth of 4 cm for a 25 MV beam.

FIGURE 8.7 Difference profiles comparing measurements with calculations for central ray doses measured
under a motorized wedge for 6, 10, 25, and 30 cm square fields for a 25 MV beam. Most differences are within
0.5% except in the buildup region, where differences are as large as 3.5%.

FIGURE 8.8 Comparison of measured and calculated cross-beam profiles under a multileaf collimator. Three
leaves are in the center of the beam, with one leaf on the left side of the central ray and the other two on the
right. The largest differences occur under the centrally shielded region of the multileaf collimator.

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FIGURE 8.9 Doses along the central ray for the same geometry as Figure 9.9. The upper curve is calculated
with no multileaves in the center of the beam. The lower curve is calculated under the leaves, and the individual
data points are the measured data under the leaves. The differences between measured and calculated doses in
the buildup region under the leaves are due to the inadequacies of the algorithm to handle electron scatter
(contamination) under shields.

IMRT
There are some unique aspects to commissioning IMRT compared to 3D conformal
radiation therapy (CRT). IMRT uses automated inverse planning routines, which use
iterative algorithms to yield acceptable plans based on specified dose–volume
constraints. The resulting dose distribution can have steep gradients between the target
and the organs at risk and the commissioning tests need to reflect this added
consideration. Because IMRT could involve the summation of very many small fields or
multiple field edges, it is extremely important to ensure that the modeling of the
penumbra and the low-dose region outside the beam is handled accurately.
Furthermore, the accurate calculation of the leakage radiation through the body, side,
and end of the leaves, especially those with curved ends, is very important to yield an
accurate penumbra (50,51). Because of these small field considerations, ICRU Report 83
(52) points out that the Van Dyk criteria of acceptability (41) of 3% in the high-dose
region and 4% in low-dose regions for 3D CRT may be too restrictive for IMRT in the
high-dose region and insufficiently restrictive in the low-dose region.
It should also be noted that the delivered dose distribution is dependent on the leaf
sequencing algorithm that is used to convert the TPS-derived intensity maps to a
deliverable set of MLC sequences. The results are dependent on leaf width, leaf-travel
distance, interdigitization of leaves, and maximum field size. Using smaller MLC steps
and a larger number of intensity levels can result in many segments with small field
sizes again compounding the need for accuracy in MLC positioning and penumbra
modeling. Furthermore, there may be accelerator constraints on the delivery of many
segments each with a small number of MUs.
Because of the difficulty in measuring doses in small fields and potential accelerator
constraints, the ICRU Report 83 (52) suggests that the use of end-to-end testing is
integral to the beam commissioning process. End-to-end testing validates the entire
treatment planning process including data collection, beam modeling, treatment
planning and delivery, data transfer from the TPS to the record-and-verify system, and
QA of the delivered absorbed dose. A typical end-to-end test involves scanning a QA
phantom, creating an IMRT plan on the image dataset, measuring the delivered dose
within the phantom, and comparing the measurements to the calculated dose

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distribution (33). The AAPM Task Group 119 provides an end-to-end testing suite for
IMRT planning (33).

Automated and Knowledge-based Planning


Automated and KBP techniques have recently been developed to improve both treatment
planning efficiency and plan quality (53–57). Automated techniques replace repetitive
steps of the manual workflow typically completed by a planner by automatically
applying predefined site-specific parameters (structure names, beam angles, weighted
optimization objectives) to a new patient dataset. These predefined parameters provide
a standardized basis to begin the optimization process and help minimize the variations
introduced by planner. KBP is an additional method that aims to reduce the variation in
IMRT plan quality and improve efficiency by providing achievable, patient-specific
optimization objectives derived from a model trained with a cohort of previously treated
site-specific plans (57–60). This database of existing treatment plans is used to create a
dose prediction model that correlates patient-specific anatomic relationships (contours)
with prior dose distributions and can be applied to future patients being treated to a
similar anatomic site. Recent research for automated, knowledge-based contour
validation has also shown promise (61).
Commissioning automated treatment planning software requires a thorough
understanding of how the program takes input data and creates treatment plans.
Ideally, predefined planning parameters as discussed above are evaluated to ensure
they correlate to an institution’s treatment planning practice. To ensure acceptable
quality is achieved, plans generated using the automated software should be evaluated
at specific dosimetric endpoints against manually generated plans for several patients
across all treatment sites for which the software will be clinically used. If acceptable
plan quality is not achieved, the predefined planning parameters should be adjusted
until the necessary quality is met.
Additional considerations are necessary when commissioning KBP software. Users
have the option to commission their own local KBP model or to utilize existing global
models created by another institution. KBP models are intrinsically dependent on the
anatomic relationships (contours), clinical trade-offs, and dosimetric endpoints of the
initial IMRT plans selected to train the model. Global models are sometimes provided by
the vendor with a detailed description of the parameters associated with these
dependencies and each should be carefully compared to the clinical practice before
being considered for implementation. When creating a local model, the quality and
diversity of the plans included should reflect the intended scope for which the model
will be clinically applied. Both local and global models should be extensively validated
against an independent validation cohort of manually created clinical plans to ensure
the model will meet or exceed expected target and OAR dosimetric goals (9). If plans
created with the model are not consistently comparable or superior to manually created
plans, the model should not be selected for use within the clinical workflow.

Image Registration
The utilization of multimodality imaging in the definition of anatomic OARs and targets
has become increasingly common in the modern radiation therapy clinical workflow
(62,63). While CT imaging still remains the primary modality for radiation treatment
planning, it is often inadequate when attempting to accurately delineate the tumor (64).
Tumors located in the central nervous system, abdomen, pelvis, breast, or head and
neck may require MRI/ultrasounds to provide high contrast between soft tissues (65).
Other sites in the thorax, abdomen, pelvis, and head and neck benefit from metabolic

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information provided from PET and SPECT imaging (7,66,67). In addition, specialized
CT scans (4D CT) may be necessary to assist in the management of tumor motion in the
thorax or abdomen (68). In order for the physician to accurately and efficiently use the
information provided by all imaging modalities, it is necessary for all imaging datasets
to be geometrically associated via a process called image registration.
Image registration creates a vector transformation that maps specific anatomic
structures in the secondary imaging dataset to the corresponding anatomic structures in
the primary imaging dataset (typically the planning CT). This transformation may be a
rigid (consisting of a global shift/rotation) or deformable (incorporating relative local
modifications of the secondary dataset). Once the image datasets are registered, it is
possible to map information such as soft tissue contrast, metabolic uptake, tissue
boundaries, or previously delivered dose from the secondary datasets onto the primary
CT dataset. This combination of information from various imaging modalities is known
as image fusion. Many modern TPSs have developed integrated image registration and
fusion software. Due to their role in delineating radiation targets and healthy tissue, the
accuracy and reliability of the registration and fusion software necessitates a thorough
commissioning process.
The process of validating image registration and fusion software is relatively new. To
thoroughly evaluate the accuracy and uncertainties of any registration software, it is
necessary to quantitatively compare the generated coordinate system changes to known
true changes within baseline image datasets. These tests should be completed across all
imaging modalities using virtual geometric and anatomic phantoms and include both
rigid and deformable registration techniques (69). Virtual phantoms allow for
predetermined changes to an imaging set against which registration algorithms can be
evaluated (52). AAPM Task Group 132 describes a series of virtual phantoms and
related tests to be used during commissioning and proposes making this standard set of
virtual phantoms available via download in order to standardize the commission
process (70). Additional end-to-end tests using physical phantoms, such as those
supplied by the Imaging and Radiation Oncology Core (IROC) in Houston, should also
be conducted. A series of typical clinical images should also be evaluated qualitatively
and an ongoing patient specific QA process should be developed to efficiently evaluate
image registration within the treatment planning workflow. While no formalized
guidance documents currently exist, the AAPM is in the process of developing
acceptance, commissioning, and QA guidelines (70).

Autosegmentation
Clinical autosegmentation algorithms significantly improve the efficiency of the
contouring process but can produce contours with small to moderate errors (71,72).
Commissioning tests for autosegmentation algorithms should identify the frequency and
magnitude of consistently occurring deviations from the clinically accepted manual
contours for each structure and all treatment planning staff should be familiar with
these deviations. Continuing patient-specific contour QA should be incorporated into
the clinical treatment planning workflow.

Adaptive Radiation Therapy


ART seeks to account for the dosimetric impact of daily anatomical variations that occur
during treatment to ensure the initial planned dose distribution matches the final
delivered dose distribution. Online ART requires the rapid implementation of many of
the typical treatment planning steps, including image acquisition, image registration,
anatomic contouring, dose optimization, daily/cumulative plan evaluation, and patient-

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specific QA (10). While each of the hardware and software components for the ART
process may have been independently commissioned in the normal TPS, their specific
application in the ART workflow should be evaluated (73). In order to minimize the
time needed for online ART, many of the planning steps are automated. The accuracy
and functionality of any automated tools, such as DVH evaluation scripts, cumulative
dose analysis, and OAR/target assessment, should be validated for all treatment sites.
Finally, due to the time sensitivity of online ART, each member of the staff should be
extensively trained in each of their roles. End-to-end tests of both the system and
workflow should be conducted with the staff to ensure the online ART can be accurately
and efficiently completed under the necessary time constraints (73). A thorough
evaluation of the integrated ART workflow using modern process improvement tools has
been shown to be useful in identifying potential sources of error and should be
conducted for each unique ART workflow during the commissioning process (74).

Electron Beams
Good examples of specific tests for electron beams can be found in recent working group
reports (13,14,21). Tests of specific concern to electrons relate to changes in source-to-
skin distance (SSD), output factor calculations, oblique beam incidence, and variations
in output for shaped fields. Additional tests to validate the accuracy of the calculated
dose in heterogeneous medium, such as bone, fat, and lung, should also be conducted.

Brachytherapy
Verification of brachytherapy dose calculation should be approached similarly to the
external beam tests. In this situation, however, it becomes much more difficult to
compare measurements with calculations because of the difficulty in performing
measurements over the short distances involved in brachytherapy. The user may have to
resort to comparing calculations with previously published source data. Relevant
information can be found in various reports (13,14,75,76,77). One unique test for
brachytherapy is the assessment of anisotropy calculations if these are provided by the
system. A recent report by Rivard et al. (78) provides enhancements to commissioning
techniques and QA of brachytherapy TPS that use model-based dose calculation
algorithms. Additional information regarding model-based dose calculation algorithms
has been included in a recent AAPM Task Group 186 (79). As previously noted, a recent
joint AAPM-ESTRO Working Group addressed the uncertainty in dose calculation
accuracy for brachytherapy TPSs (43).

Proton Therapy
Commissioning proton beam models within a TPS is often accomplished through a
combination of simulated Monte Carlo data and measured beam data (80).
Requirements for specific commissioning tests depend on the type of proton system
(dual passive scatter vs. active spot scanning) and examples of each have been
described thoroughly (81–84). For dual passive scattering systems, validation will
typically include measuring longitudinal fluence, virtual source position, effective
source position, source size, Bragg peaks, and lateral beam profiles. Active spot
scanning may require validation of spot size, in air lateral profiles, and integral depth
dose data. During commissioning, the lateral and range uncertainties associated with
the accuracy of the model for the full range of treatment conditions should be carefully
evaluated and accounted for within the clinical treatment planning process (85,86).
Consideration needs to be given to accurately correlate proton stopping power ratios to
CT numbers within a patient and difference between phantom stopping powers and

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patient tissue stopping power should be evaluated (87).

Commissioning of Other Components


Modern TPSs contain many other commissioning aspects than those related to dose
calculations. Examples of other types of issues that must be considered and verified are
shown in Table 8.6. The ability of the TPS to accurately handle tissue heterogeneities
when calculating dose is of particular importance and validation requires the use of a
specialized phantom (16). Other nondosimetric parameters, such as image transfer and
contouring validation, can also be evaluated using specialized phantoms to specifically
address some commissioning and QA issues (16,88).
TABLE 8.6 Commissioning of Other Components

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TABLE 8.7 Techniques Requiring Special Workup

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Special Techniques
Special and individualized techniques require their own unique evaluation. Examples of
special techniques that require additional workup and commissioning are summarized
in Table 8.7. In addition, there are now a number of new technologies that have
specialized TPS specifically made for that technology. Examples include helical
tomotherapy (45), robotic radiation therapy (89), onboard MRI-guided radiation
therapy (46), and multiple cobalt source, small field radiation therapy, used mostly for
neurologic sites (47).

Quality Assurance and Quality Control


QC of a product or process involves three steps: (a) the measurement of the
performance, (b) the comparison of the performance with a given standard, and (c) the
actions necessary to keep or regain the standard. The commissioning process of the TPS
provides the standard for comparison. Once the TPS is fully commissioned, a QA
program should be implemented to ensure the system is able to remain within the
standards determined during commissioning. However, the problems associated with
maintaining consistency and quality within a TPS are quite different from the problems
associated with QA of a CT simulator or accelerator, which have electrical and
mechanical components that can wear and change with time.
Closely associated with QA is risk management. Risk management consists of four
components: (a) identifying the possible sources of risk of failure or malfunction, (b)
analyzing the frequency of incidents of failure or malfunction, (c) taking corrective
action to minimize such failure, and (d) monitoring the outcome of such changes. Thus,
to develop an appropriate QA program for treatment planning computers, an
assessment of the likelihood of failure helps focus on the issues of concern. IAEA TRS-
430 (14) provides a good summary of reported errors associated with radiation
treatment planning. For the “accidents” (major clinically significant errors) associated
with TPSs, they determined that the key contributory factors include the following:
a. A lack of understanding of the TPS
b. A lack of appropriate commissioning (no comprehensive tests)
c. A lack of independent calculation checks
The major issues related to treatment planning errors were summarized by four key

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words: (a) education, (b) verification, (c) documentation, and (d) communication.
The development of a thorough QA program is a compromise between cost and
benefit. An appropriate program has specific QCs to identify and mitigate high
probability and high impact errors without being excessively burdensome on a facility’s
resources. However, as new technology is implemented in the clinic, it can be
challenging to identify the appropriate QC tests that provide the necessary balance. A
careful evaluation of a new process should be conducted before determining changes
and additions to any QA program.
AAPM Task Group 100 (90) is attempting to deal with the issue of ever-increasing QA
activity as new and more complex technologies evolve. The central idea of TG-100 is to
transition from traditional device-centered QA to a more comprehensive risk-based,
process-centered approach. To implement a process-centered QA program, the task
group describes three techniques that have been historically used in engineering circles:
process tree mapping, failure mode and effects analysis (FMEA), and fault tree analysis
(FTA). Process tree mapping is a visual illustration of all the relationships of each step
for a specific process. It tracks the physical and temporal flow of each step, from start
to finish, and is useful in easily identifying and tracking weaknesses and error
migration. FMEA is a prospective approach to QA. When used in conjunction with a
process tree map, it assesses the potential risks (failure modes), likelihood of errors, and
impact of such errors for each step defined within the process. For each step, there may
be many potential failure modes, and each one may have several potential causes and
outcomes. For each potential cause of failure, values are assigned in three categories: O,
the probability that a specific cause will result in a failure mode; D, the probability that
the failure mode resulting from the specific cause will go undetected; and S, the severity
of the effects resulting from a specific failure mode should it go undetected throughout
treatment. Convention uses numbers between 1 and 10. Category O ranges from 1
(unlikely failure, <1 in 104) to 10 (highly likely, >5% of the time). Category D ranges
from 1 (undetected only <0.01% of the time) to 10 (undetected >20% of the time).
Category S ranges from 1 (no appreciable danger) to 10 (catastrophic if persisting
through treatment). The product of these three indices forms the risk probability
number (RPN = O × S × D). A complete FMEA applied to an entire process helps
develop a fault tree analysis, which is a visualization of all errors at each step and
associated root causes for each error. By applying a FTA, it is possible to determine
appropriate QC measures that can be implemented at the necessary steps to accurately
mitigate identified root causes of failure. The prospective approach described by TG-100
provides guidelines to determine an efficient application of resources within a QA
program that accurately minimize all major sources of error. Examples of FMEA
analyses have been published for the external beam radiation therapy process (91),
dynamic MLC tracking systems (92), and intraoperative radiation therapy (93).
A necessary element in developing a prospective QA program is the inclusion of an
electronic incident event reporting system (94,95). A department level reporting system
provides a platform for all employees to voluntarily and anonymously report events, the
severity of which range from minor miscommunication to near-miss to severe treatment
error. Submitted events can be analyzed and previously unidentified patterns can be
systematically addressed prior to the occurrence of serious errors (96). Several major
groups have recently begun development of national/international reporting systems
(ASTRO’s RO-ILS and IAEA’s SAFRON), which will provide the possibility of shared
learning across all participating institutions.

Program and System Documentation and Training

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At the most basic level of QA, the user must be aware of what the computer programs
are doing when any specific option is requested. Even if the programs are perfectly
accurate, any error in data entry results in an error in the output. Thus, the user must
have adequate information in terms of manuals and online help to aid in the
commissioning and operational process of the TPS. The types of documentation that
should be available are listed by Van Dyk et al. (41) and in Table A1-1 of AAPM TG53
(13).
A significant amount of documentation occurs during the commissioning process and
encompasses all systems and software that were tested. Appropriate documentation
should include detailed descriptions of all tests run, origin of data used in the TPS, and
baselines for the QA program. Documentation detailing with the treatment planning
procedures should also be developed during the commissioning process and all
appropriate staff should be provided training to fulfill their roles.

User Training
Closely associated with proper manuals and information is user training. The user must
be clearly aware of normalization procedures, dose calculation algorithms, image
display and reconstruction procedures, and program calculation capabilities and
limitations. This training can be carried out at at least three levels: (a) vendor training
courses, (b) in-house staff training, and (c) special training courses set up by user
groups or third-party software vendors.
TPS training has traditionally been formatted for dosimetrists and physicists and
often only limited training is available to physicians. Physicians should be able to
effectively operate the simple tools of any planning system (setting beams parameters,
defining field sizes, contour tools). Beyond the basic functionality, in order to accurately
evaluate a treatment plan, physicians need to be aware of inaccuracies and limitations
of the planning system. This includes the inherent inaccuracies of the dose calculation
algorithms (central axis, buildup region, penumbra, heterogeneities) and clinical
situations in which these inaccuracies are a common factor. In addition, physicians
should be aware of the capabilities and limitations of IMRT optimization algorithms to
achieve organ/target specific dosimetric planning goals and the common clinical trade-
offs. Finally, physicians should be able to evaluate the quality of image
registration/fusion and understand the processes of rigid and deformable image
registration.

Reproducibility Tests
A normally functioning computer is unlikely to generate small changes in output.
Computer system hardware malfunctions are likely to be obvious. A more probable issue
of concern is inadvertent access by treatment planners to the basic radiation or machine
data files. This can result in changes to accuracy of calculations without the user being
aware that changes have taken place.
For inadvertent software or hardware changes, a binary comparison of all the
software and data files can test whether any changes have occurred. If changes are
found, the details of the changes must be assessed and a partial system recommissioning
may have to be implemented. Alternatively, as described in the IAEA report (15), a
select subset of the vendor type tests should be performed to demonstrate consistency
with previous results.
From a risk management perspective, other possible sources of error include intended
or unintended changes in software or data files. These can occur within the TPS or in
the computers associated with data generation, such as CT scanners and water phantom

209
systems. Software upgrades in these external computer systems can result in changes to
the data entered into the TPS.
To aid in the assessment of any software changes, a series of reproducibility tests of
the dose calculation algorithms, the image display algorithms, and the plan evaluation
tools should be undertaken on a regular basis. Examples of such reproducibility tests
can be found in Van Dyk et al. (41) and in the reports from the AAPM (13) and the
IAEA (14). Users should develop their own tests based on their particular TPS and what
components of the hardware, software, and data files have any likelihood of being
changed.

Patient-Specific Tests
Since no system of computer programs is error-free, nor are users of such programs
perfect, routine inspection of each treatment plan is a requirement for proper QA.
Calculation of the external beam dose usually consists of two components: (a)
calculation of a relative dose distribution, and (b) calculation of the machine output in
terms of MUs. Both of these components require a check by a participant independent of
the first calculation. For relative dose distributions, secondary checks, either conducted
manually or with a third-party software, can be performed by choosing a specific point,
usually on the central ray, and calculating a dose estimate for each of the beams using
simplified tables to generate the results. These checks should agree to about 2% to 3%
of the computer-calculated values in regions of uniform dose delivery and relatively
simple inhomogeneity corrections (97). More complicated plans have to be evaluated on
an individual basis to assess the trends of the numerical values. Similarly, the machine
setting calculation should be checked independently of the first calculation.
With the advent of more complex segmented or dynamic conformal therapy and
IMRT, such manual checks become very difficult if not impossible. In these situations,
the absolute dose is determined as part of the planning process, with the MUs being
defined for each component of the treatment. QC checks must be developed for each
individual technique. Georg et al. (98) suggested action levels between ±3% and ±5%
dependent on the treatment site and treatment technique. They also conclude that
independent calculations may be used to replace experimental dose verification once the
IMRT program is mature (99). Similarly, ICRU Report 83 (52) describes the use of one
or more of the following methods for patient-specific QA:

• Measurement of the intensity pattern from individual beams for a specific patient
• Measurement of absorbed dose in phantom of the beam-intensity pattern planned for a
specific patient
• Independent absorbed dose calculations for the patient-specific beam intensity pattern
• In vivo dosimetry

For brachytherapy, manual single-point calculations are more difficult, and therefore
a check can be performed with one of the conventional systems of dosage calculations,
such as the Manchester system. This approach can be used to make crude checks to an
accuracy of about 10%. Again, assessing trends is crucial in evaluating the quality of
the calculation.

In vitro and in vivo Dosimetry Checks


As a final check of the quality of the overall treatment planning process, it is useful to
perform measurements using special-purpose or anthropomorphic phantoms (in vitro

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dosimetry) or to perform measurements on or in the patient with the patient in
treatment position (in vivo dosimetry). In vitro dosimetry is an important component of
the implementation of any new treatment technique or clinical procedure. Generally, it
is performed with thermoluminescent dosimetry (TLD) in a phantom containing human-
like tissue densities and composition, such as an anthropomorphic phantom. More
recently, optically stimulated luminescence (OSL) is being used in place of TLD (100).
Diodes and metal-oxide semiconductor field-effect transistor (MOSFET) (101) dosimetry
systems are now readily available and provide instant readout capability. This type of
dosimetry ensures that the basic procedures associated with a new treatment technique
are in agreement within a predetermined range of accuracy. A report by Dunscombe et
al. (102) gives a good overview of the use of an anthropomorphic phantom to evaluate
the quality of treatment planning computer systems. While providing a good indication
of the accuracy of the dose delivery process near the center of the target volume,
differences between measurements and calculations away from the central region were
difficult to interpret as to whether the calculations were off, the measurements were off,
or the beam placement was inaccurate. Thus, in vitro dosimetry must be established in
such a manner that differences between measurements and calculations can be readily
interpreted.
Similar concerns of interpretation also apply to in vivo dosimetry (103). There is a
tendency by radiation oncologists to request in vivo measurements to give them an
assurance that the dose delivery process is accurate, especially in regions where there is
concern about critical structures such as the eyes, gonads, or a fetus. Sometimes, these
regions are close to the edge of the radiation beams. Under such circumstances, small
changes in beam alignment can generate large changes in measured dose, leaving
ambiguity in the interpretation of the results. These interpretation difficulties should be
clearly explained to the radiation oncologist requesting the measurements. Better
comparisons of calculations and measurements can be made in regions where doses are
not changing as rapidly—either on the entrance or exit surfaces or, if possible, by
placing dosimeters in body cavities such as the mouth, trachea, esophagus, vagina,
uterus, or rectum. In vivo dosimetry is a recommended check under some treatment
conditions and it may provide an opportunity to mitigate treatment errors (104), but it
should not replace pretreatment in vitro phantom measurements for more complex
treatment techniques, such as IMRT. AAPM Task Group 158 has been charged with
assessing the current status of in vivo dosimetry for nontarget, out-of-field exposures
and to formulate recommendations for methods to improve measurements and
calculations for doses outside the treatment volume (105). The IAEA has also produced
a recent review on in vivo dosimetry (106).

Quality Audits
It is always useful to review the QA activities of individual institutions. Recent years
have seen the public reporting of various errors or “accidents” in radiation therapy.
While such errors can have a devastating effect on individual patients, the actual error
rate in radiation therapy is very low. However, it is the responsibility of members of the
radiation therapy team to ensure that proper procedures are in place to minimize such
errors. As a first approach, an institutional self-auditing process is beneficial. This is
best done in the context of a QA committee that should exist in every radiation therapy
department (107). External audits have proven to be extremely beneficial for finding
inadvertent deviations from acceptable practice. The IROC in Houston, Texas, has done
this for years for institutions participating in clinical trials involved with the Radiation
Therapy Oncology Group (RTOG) (12,108). Dosimetry intercomparisons are also useful

211
especially in the development of new techniques such as IMRT and provide a means to
standardized the quality of radiation treatment facilities (12,109).
The IAEA has developed an external audit process, which involves a review of the
total treatment process (110). They do this through the use of a QA team in radiation
oncology (QUATRO), which consists of a radiation oncologist, medical physicist,
radiation therapist, and sometimes a specialist in radiation protection. A similar
external quality audit has been incorporated into the ASTRO Apex and ACR radiation
therapy accreditation process (111). Dosimetric intercomparisions and external audits
provide a substantial benefit to improve the overall quality of radiation therapy across
all facilities.

QA of Total Radiation Therapy Planning Process


As indicated earlier, the total radiation therapy planning process consists of many steps,
of which computerized treatment planning is only one component. For the computer
plan to be implemented accurately, it is important that the basic patient data and image
information be derived accurately. This requires QC of the imagers generating the data
(87). It also requires assurance that the patient is positioned precisely in a manner that
will be readily reproducible on subsequent simulation and treatment setups.
Geometric accuracy, before planning, begins with proper immobilization and
localization of the patient in treatment position. Accuracy during planning includes
assessing uncertainties associated with image transfer, image registration, target volume
and normal tissue localization, beam placement, and dose calculations. To ensure that
the plan can be implemented on the therapy unit, the planner must verify the correct
transfer of plan data to the electronic medical record system and that geometric
arrangements are physically achievable. QA after planning may include the comparison
of the radiographs with DRRs to verify that the field shapes are correct, as well as
confirmation that the internal anatomy is located accurately within the fields. Finally,
accuracy can be ensured at treatment by verifying that the setup parameters such as
source-to-surface distances for each field are consistent with the planned parameters. In
addition, daily online imaging, including kV CBCT, MVCT, and kV 2D imaging, can be
used to assure geometric accuracy of the beam positioning and provide a confirmation
of the location of the internal anatomy of the patient, immediately before each dose
fraction is delivered.

QA Administration
An important component of any QA program is its effective organization and
administration. Any QA program should be carried out according to a predetermined
schedule and ongoing records of the activities and the results should be maintained.
Proper administration requires that one person, usually a qualified medical physicist, be
responsible for the QA program. Although this individual does not necessarily have to
carry out all the tests and their evaluations, he or she must ensure that there is written
documentation on the QA process, that the tests are carried out according to their
specified frequency, and that appropriate actions are taken as needed.
As TPSs become networked into clusters with various planning and target volume
delineation stations, servers, and peripheral devices, system management becomes an
integral component of the entire QA of the TPS. This management includes maintaining
an adequate check on system security and limiting user access not only to the system,
but also to specific software and data file modifications. It is important that the
radiation data files not be inadvertently changed and that patient confidentiality be
fully maintained.

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To avoid the possibility of any undesired loss of information, a regular schedule for
system backup is essential (13). This may include daily backups of the most recent
patient additions and changes, weekly backups of all patient information, and monthly
backups of the entire TPS. Backups are also warranted immediately after any major
changes to the software of the system.
In addition to standard backups, it may also be desirable to archive specific patient
information, especially if patients are to be grouped for study purposes. In some cases,
patient data may have to be forwarded to clinical trial groups such as the RTOG, which
accepts such information through the internet. However, patient data must also be
archived in case the patient comes back for retreatment.
Proper QA of the modern 3D TPS is a time-consuming process. Adequate staff
resources must be allocated to ensure that the QA is completed in an appropriate
manner.

SUMMARY
QA programs for radiation therapy machines, especially with the clinical
implementation of high-energy accelerators have been well defined for many years.
Formalized (CT) simulator QA is a more recent phenomenon (88). While redundant
checks for MU and time calculations have also been standard practice, the formalization
of a QA program for treatment planning computers occurred more recently. This is
partly due to the tremendous variation in TPSs and their algorithms and partly to the
complexity of treatment planning QA, since it involves multiple facets and is inherently
centered on the entire process and not specific equipment. Because of these
complexities, it is clear that a comprehensive program depends on institutional
procedures, the type of planning system in use, and the entire treatment planning
workflow.
Treatment planning errors can be minimized with a good QA program. As indicated
earlier in this chapter, the major issues that relate to treatment planning errors can be
summarized by four key words: (a) education, (b) verification, (c) documentation, and
(d) communication (14). Education is required not only at the technical and
professional level in terms of the use of the TPS, but also at the organizational level with
respect to institutional policies and procedures. A very important component of
education relates to understanding the software capabilities and limitations. Secondary
dose verification of TPS produced plans are also important as many reported errors
involved a lack of an appropriate independent secondary check of the treatment plan or
dose calculation. Clear documentation is required both of each patient’s individual
treatment plan and of departmental policies and procedures. Finally, communication
among staff members is essential for all aspects of treatment, since various individuals
at various professional levels are involved in the treatment process. Poor
communication was a key factor in a number of the errors reported that relate to
treatment planning.
A carefully executed program of treatment planning computer commissioning and
ongoing QA assessment provides users with confidence that their work is being carried
out accurately. Furthermore, it gives the user a clear understanding of the TPS’s
capabilities and limitations. Finally, the quality of the delivered radiation dose to the
patient depends on the quality of all the steps in the treatment planning process,
including patient imaging, simulation, target volume delineation, treatment planning,
treatment verification, and quality factors associated with dose delivery and related to
the radiation therapy machine. Thus, it is imperative that the medical physicist, as well

213
as all other staff associated with the radiation therapy process, be actively involved in
the QA process at all stages. This provides both full awareness of the capabilities and
limitations of each step of the process and a mechanism for decision making about any
corrective action deemed to be necessary.

ACKNOWLEDGMENTS
Contributions of Dr. Jacob Van Dyk to previous editions of this chapter are still prevalent
throughout the content in current edition, as his expertise in TPS commissioning and QA is
unparalleled. Editorial guidance provided by Dr. Sasa Mutic and Dr. Eric Klein greatly aided in
shaping the addition of new content and the update of existing material. I would also like to
thank my wife, Kate Kavanaugh, my eternal ghost proof reader, for providing suggestions of
structural changes that make this chapter infinitely more readable.

KEY POINTS
• Key contributing factors for major treatment planning system (TPS) accidents typically
involve at least one of the following:
• Lack of understanding of the TPS.
• Lack of a appropriate commissioning.
• Lack of independent calculation checks.

• A rigorous quality assurance (QA) program for TPS is necessary to ensure an accurate
delivery of the treatment intent. Such a QA program consists of the following components:
• System specifications: definitions of the capabilities of the software and the accuracy of the
dose calculations.
• Acceptance testing: assessment of the hardware and software to ensure the accuracy of all
system specifications.
• Commissioning: acquisition of all data needed to bring the system into clinical service.
■ Radiation beam data can be acquired onsite for each individual radiation producing
device or be a validated universal set of golden beam data (GBD).
■ Baselines of performance standards used for quality controls are determined during
commissioning.
• Quality controls: systematic actions to ensure specific performance standards are
maintained.

• The uncertainty of the calculated dose depends on the accuracy of the beam data used during
commissioning and the limitations of the calculation algorithms.
• For external photon beam calculations in a homogenous phantom, this uncertainty is
typically smallest on the central axis and largest in the buildup region.
• Criteria of acceptability should be based on what is realistically achievable and include
statements of confidence.
• Commissioning of a TPS typically requires basic radiation data, which may include tissue–
air ratios, tissue–phantom ratios, percentage depth doses, cross-beam profiles, and output

214
factors.
• Additional measurements are needed for any ancillary devices such as wedges, blocks, and
MLCs.
• End-to-end validation of the TPS and treatment workflow should be conducted for each
unique treatment modality. End-to-end tests typically include:
• Acquiring a CT simulation of a QA phantom.
• Creating a treatment plan on the image dataset.
• Validating the calculated dose to the measured dose.

• Modern TPSs include new functionalities such as image registration, autosegmentation,


automated planning/KBP, and adaptive radiation therapy. While specific commissioning and
quality assurance tasks differ for each functionality, end-to-end tests and validations against
the existing manual workflow should be included prior to clinical implementation.

• Quality assurance for the total radiation therapy planning process incorporates all steps from
the initial simulation to the treatment delivery. Quality controls need to be developed for each
aspect of the treatment planning workflow. Several tools that can aid in developing a strong
QA program include:
• An FMEA analysis provides the framework to identify key steps in the treatment
planning workflow at which implementing quality controls will provide the greatest
utility.
• Reproducibility tests of the dose calculation, image display, and plan evaluation tools are
useful quality controls that easily determine no significant changes have occurred to the
planning system hardware/ software.
• In vivo and in vitro patient specific checks provide a useful final validation of the dose
distribution and can identify gross errors that may result in harm to the patient.
• Quality audits of treatment planning process, either conducted internally or by an
external third party, can identify weaknesses prior to implementing a new planning
system, treatment modality, or treatment technique. Such quality audits can incorporate
end-to-end tests to validate the entire treatment planning workflow.
• A proper training program for all staff should be developed or re-evaluated during the
commissioning process. Annual credentialing should be considered to ensure everyone is
up-to-date on any new changes that may have been implemented.

QUESTIONS
1. Dose calculations for an enface photon beam in a homogenous phantom exhibit
the highest absolute uncertainty in which region?
A. Central axis after a depth of maximum dose
B. Lateral penumbra
C. Buildup
D. Out of field

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2. When upgrading a TPS, it is important to complete the following tests except:
A. End-to-end tests
B. In-phantom patient-specific dose measurements
C. Third-party linear accelerator output audits
D. Reproducibility tests of basic dose calculations
3. Implementation of effective quality controls with the treatment planning process
is aided by a prospective quantitative technique that assesses potential risks,
likelihood of errors, and impact of such errors. This technique is known as:
A. Process Tree Mapping
B. Fault Tree Analysis
C. Risk Management
D. Failure Modes and Effects Analysis
4. The advantages of using golden beam data when commissioning a treatment
planning system include all of the following except:
A. GBD accounts for the inherent differences that exist between individual linear
accelerators.
B. GBD allows for much of the TPS commissioning process to be “pre-packaged”
and minimizes the chance of gross systematic errors arising from the input of
incorrect data.
C. GBD standardizes the delivery quality of all linear accelerators from a specific
vendor.
D. GBD eliminates the possibility of poor quality commissioning measurements
being used for the basic radiation data needed to define beam models.

ANSWERS
1. C Uncertainties in the dose calculation are dependent on the accuracy of
the measured data used to create the beam model and the inherent
accuracy of the dose calculation algorithm. Both exhibit the lowest
uncertainty on the central axis. Measurements in the buildup region are
inherently challenging and vary greatly with detectors typically available
to the physicist acquiring the basic radiation data. In addition, many dose
calculation algorithms do not handle the physics of electron
contamination very well.
2. C End-to-end tests, patient specific QA, and reproducibility tests all validate
either the integrity of the dose calculation algorithms or the planning
workflow. As a TPS system upgrade does not impact the linear accelerator
output and reproducibility tests will confirm minimal changes to the basic
beam data, third party output audits are unnecessary.
3. D While process tree mapping and fault tree analysis can be useful in
determining effective quality controls, FMEA provides the quantitative
framework to examine the balance between risks, probability of
occurrence, and impact.
4. A Golden beam data is intended to standardize the delivery basic radiation
data used during commissioning, thus it does not account for small local

216
variations that may exist between linear accelerators. Validation
measurements of the basic radiation data should be conducted and
compared to the GBD to determine if any differences exist.

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9 Intensity-Modulated Radiation Therapy:
Photons

Jan Unkelbach

INTRODUCTION
The Rationale for IMRT: Concave Target Volumes
The development of intensity-modulated radiation therapy (IMRT) was preceded by two
important technologic developments: computed tomography (CT) and multi-leaf
collimators (MLCs). Before the widespread availability of CT scanners, radiotherapy
planning was based on 2D x-ray images. In these images, the projection of the target
volume could be delineated, which lead to the design of 2D treatment fields. With the
development of CT imaging, a 3D model of the patient became available. The target
volume as well as organs at risk could be delineated in three dimensions and their
spatial relation became known. This led to the development of 3D conformal
radiotherapy. Conforming the radiation dose to the target volume required improved
ways of collimating the radiation field. The solution to this problem was the MLC. 3D
conformal radiotherapy is still the standard for many treatment sites today. However,
conforming the dose distribution to the tumor is limited to round or convex shapes of
the target volume. In 3D conformal radiotherapy, the tumor is treated with one
radiation field from each incident beam direction, where the shape of the radiation field
is the projection of the target volume in beam’s eye view. The incident fluence is
homogeneous over the field. This makes it impossible to carve out concavities in the
target volume. The problem is illustrated in Figure 9.1, which shows a patient treated
for a spinal metastasis. The target volume shown in red includes the entire vertebral
body, which surrounds the spinal cord. An emerging treatment paradigm for such cases
consists in delivering a single fraction dose of 18 to 24 Gy to the target volume. This
treatment approach requires that the dose to the spinal cord is limited to approximately
10 Gy. With 3D conformal radiotherapy, it is impossible to spare the spinal cord. As a
first approach, the projection of the spinal cord in beam’s eye view could be removed
from the treatment field, and the area to the right and to the left would be treated as
two separate fields. However, this strategy would yield an inhomogeneous dose
distribution to the target volume and would underdose the target volume near the
spinal cord. More specifically, in order to deliver the prescribed dose to the target, the
fluence at the edge of the spinal cord has to be increased. Anders Brahme has studied
this phenomenon for a stylized geometry in his 1982 paper (1). The work can be
considered as one of the first papers illustrating the need for inhomogeneous fluence
distributions across the treatment field when treating concave target volumes. This
eventually led to the development of IMRT.

Typical Applications of IMRT


The treatment of spinal metastasis in hypofractionated regimens is a recent application
of IMRT. However, over the past years, IMRT has become the standard of care for a

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variety of treatment sites. Two of the established applications are prostate cancer and
head-and-neck tumors, which are illustrated in Figures 9.2 and 9.3. The prostate lies in
the mid-sagittal plane between the bladder and the rectum. In radiotherapy treatments
of prostate cancer, the target volume contains the entire prostate gland. The main dose-
limiting normal tissue is the anterior rectal wall. In many patients, the lateral lobes of
the prostate partially wrap around the rectum, as illustrated in Figure 9.2. Only
millimeters separate the prostate gland from the radiosensitive lining of the rectal wall.
Historically, the prescription dose was therefore limited by rectal toxicity as the anterior
rectal wall received the full prescription dose. Today, in the era of IMRT, a commonly
used prescription dose is 79 Gy using standard fractionation, which is among the
highest prescriptions throughout radiotherapy. This necessitates that the high-dose
region carves out the concavity formed by the rectum, which became possible with
IMRT.
Tumors in the head-and-neck region represent a third example in which IMRT has
replaced 3D conformal techniques for the most part. This includes tumors arising in the
oral cavity, the nasopharynx, and the oropharynx. These tumors are often inoperable
and are close to a variety of radiosensitive structures. These include the saliva secreting
glands as well as structures related to swallowing and speech. Thus, radiotherapy to
cancers of the head and neck is associated with acute und long-term side effects that
seriously impact quality of life. Examples of these side effects are mouth dryness, dental
decay, and swallowing dysfunction. IMRT allows for sparing of the parotid glands and
carefully distributing dose in normal tissues. Furthermore, IMRT allows for complex
dose prescriptions that are standard of care today. Nowadays, treatment protocols often
use three dose levels, in which 70 Gy is delivered to the gross tumor volume (GTV), 60
Gy to high-risk lymph nodes, and 54 Gy to low-risk nodal stations. This type of dose
painting approach would be very difficult to mimic using forward planning techniques
and 3D conformal radiotherapy.

FIGURE 9.1 A: Geometry of a spinal metastasis treated with IMRT. The target volume (red) entirely
surrounds the spinal cord (dark green), which is to be spared. Additional organs at risk are the kidneys (orange).
B: IMRT provides the means to spare the spinal cord while delivering a high dose to the target volume, as shown
in the dose distribution.

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FIGURE 9.2 A: Prostate cancer represents a typical application of IMRT. The prostate (red) abuts the rectum
(orange) and the bladder (yellow). B: IMRT has the ability to conform the high dose to the prostate while
carving out the concavity formed by the rectum.

FIGURE 9.3 A: A head-and-neck cancer patient treated with IMRT. The target consists of multiple volumes
prescribed to different doses: GTV (brown), high-risk clinical target volume (CTV) (purple), and low-risk CTV
(red). Radiosensitive structures including the parotid glands (blue), the submandibular glands (yellow), and the
spinal cord (light blue) are near the target volume. B: IMRT allows for conformal dose distribution to complex-
shaped target volumes.

The examples above illustrate problems in oncology in which the technical


development of IMRT had profound impact on the way patients are treated. In the case
of prostate cancer, the widespread availability of IMRT causes a shift from radical
prostatectomy toward radiotherapy as the mainstay of therapy. In the case of spinal
metastasis, IMRT offers the option of high single fraction doses with the intent of local
control, where the role of radiotherapy was limited to palliative treatments before.

Scope and Organization of This Chapter


This chapter focuses on the concepts of IMRT, the treatment planning process, and the
mathematical methods used. It discusses steps in the planning process and the user

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interface between treatment planner and planning software, and it provides an
understanding of the algorithms used behind the scenes by modern treatment planning
systems (TPS). For a review of the history of IMRT, the reader is referred to the paper by
Bortfeld (2) and references therein. For a comprehensive review of IMRT including the
physics and technology aspects, we recommend the book by Webb (3). The remainder of
this chapter is organized as follows:

• The section IMRT–concepts and planning process introduces the main concepts in IMRT
and illustrates the planning process step-by-step using a head-and-neck cancer
example.
• The section Fluence map optimization discusses fluence map optimization (FMO) in more
detail, which represents the most important concept in IMRT planning. In that
context, the formulation of IMRT treatment planning as a mathematical optimization
problem is discussed.
• The section Leaf sequencing describes the leaf sequencing problem, that is, the method
to deliver intensity-modulated radiation fields using MLCs.

The above-mentioned sections reflect the historical development of IMRT, and thereby
the functionality and algorithmic foundation of the first-generation IMRT planning
systems. In recent years, IMRT TPS have evolved to more advanced planning algorithms
and support more complex delivery techniques. To that end, the remaining sections
describe recent developments in IMRT planning.

• The section Direct aperture optimization describes methods for direct aperture
optimization (DAO), which aims to overcome problems of the traditional two-step
approach of FMO plus leaf sequencing.
• The section Arc therapy describes treatment planning for volumetric-modulated arc
therapy (VMAT), that is, a delivery technique where the gantry continuously rotates
around the patient while radiation is delivered.
• The section Specialized topics in IMRT planning addresses current areas of research and
development in IMRT including new approaches to deal with inherent tradeoffs
between conflicting planning goals. Pareto-surface navigation methods are introduced
as a means for interactive planning, which provide the treatment planning with a
graphical user interface to navigate in a database of treatment plans to determine the
treatment plan with the most desirable tradeoff.

IMRT—CONCEPTS AND PLANNING PROCESS


This section demonstrates the concepts of IMRT planning step-by-step for an example
case. We consider the head-and-neck cancer patient shown in Figure 9.3, which
represents a typical application of IMRT. The target consists of multiple volumes, the
GTV and adjacent lymph nodes, which are prescribed to different dose levels. In
addition, several radiosensitive structures are located in proximity of the tumor. This
includes the saliva-producing parotid glands, the spinal cord, and the larynx.
Radiotherapy in the head-and-neck region is typically related to acute and long-term
side effects, such as swallowing dysfunction. Reducing dose to all normal tissues is of
great importance.

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The Fluence Map
IMRT refers to radiotherapy delivery methods for which the fluence distribution in the
plane perpendicular to the incident beam direction is modulated. To that end, the
radiation beam is divided into small beam segments, which are in principle deliverable
by an MLC, as further described in the leaf sequencing section. The lateral fluence
distribution of the beam is thereby discretized into small elements, which are commonly
referred to as beamlets or bixels. For an MLC with 1-cm leaf width, the fluence
distribution is represented by the intensities of 1 × 1-cm beamlets. Nowadays, modern
MLCs with a smaller leaf width often allow for a finer discretization into 5 × 5-mm
beamlets. The discrete representation of the fluence is commonly referred to as the
fluence map. In IMRT planning, the goal is to find the fluence maps of all incident beam
directions that yield the best possible dose distribution in the patient. This problem is
referred to as FMO and is the topic of this section and the following one.
The definition of the fluence map is illustrated in Figure 9.4. Similar to 3D conformal
therapy, this starts with the definition of the isocenter. For IMRT planning, we
subsequently determine the set of all beamlets that are potentially helpful in finding the
most desirable treatment plan. Loosely speaking, this corresponds to all beamlets that
contribute a significant dose to the target volume. A common method for initializing the
fluence map consists in including all beamlets for which the central axis of the
corresponding beam segment intersects the target volume.

FIGURE 9.4 Illustration of the fluence map definition for IMRT planning for a head-and-neck cancer patient.
The figure shows the digitally reconstructed radiograph (DRR) for one of the incident beam directions. The
contours show the projections of the three target volumes in beam’s-eye-view. The fluence map consists of all

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beamlets that cover the projection of the target volume.

The Dose-Deposition Matrix


The quality of a treatment plan is primarily judged based on the dose distribution in the
patient. Thus, we would like to determine the fluence maps of the incident beams as to
best approximate a desired dose distribution. To that end, we have to relate the incident
fluence to the dose distribution in the patient. The dose-deposition matrix concept, which
is frequently used in IMRT planning, provides this link.
For dose calculation, the patient is discretized into small volume elements referred to
as voxels. A dose calculation algorithm is used to calculate the dose distribution of every
beamlet in the fluence map in the patient. Let us denote the dose that beamlet j
contributes to voxel i in the patient as Dij, and let us denote the intensity of beamlet j as
xj. The total dose di delivered to voxel i is then simply given by the superposition of all
beamlet contributions:

Here, the matrix of dose contributions Dij of beamlets j to voxel i is referred to as the
dose-deposition matrix. In practice, the fluence is commonly quantified in monitor units
(MU). In this case, the natural unit of the dose influence matrix is Gy/MU, such that the
resulting dose distribution in the patient is obtained in Gy. The dose-deposition matrix
concept is convenient since it allows for a separation of the mathematical optimization
of beamlet intensities xj from the dose calculation algorithm. In IMRT planning, the
dose-deposition matrix is often calculated up front and held in memory. Subsequently,
the dose distribution is obtained by a simple matrix multiplication d = Dx.

Formulation of IMRT Planning as an Optimization Problem


In order to determine the optimal fluence map for every incident beam direction, we
have to specify the desired dose distribution. In other words, we have to characterize
what a good treatment plan is. In the example case in Figure 9.3, treatment planning
aims at different goals including:

1. A prescribed dose dpres should be delivered to all parts of the target volume. In this
case, the target volume consists of multiple parts. The GTV is often prescribed to 70
Gy; adjacent lymph nodes which are likely to contain microscopic tumor and are
prescribed to an intermediate dose of 60 Gy; and more distant lymph nodes that may
contain tumor cells but are less likely to do so are prescribed to 54 Gy. The lymph
node targets essentially consist of normal tissue such that treatment planning aims at
a homogeneous dose in the target, avoiding both under- and overdosing.
2. The dose distribution should conform to the target volume. Outside the target
volume, a steep dose falloff is desired and unnecessary dose to all healthy tissues
should be avoided.
3. The dose delivered to the parotid glands is to be minimized to avoid or reduce side
effects such as xerostomia (mouth dryness).
4. The dose to the spinal cord has to be limited. The maximum dose delivered to any
part of the spinal cord has to stay below a maximum tolerance dose dmax.

For IMRT planning, these goals have to be translated into mathematical terms. This is

229
done by defining functions, which represent measures for how good a treatment plan is,
and whether it is acceptable at all. In this context, we distinguish objectives and
constraints:

Constraints are conditions that are to be satisfied in any case. Every treatment plan
that does not satisfy the constraint would be unacceptable.
Objectives are functions that measure the quality of a treatment plan. They may
represent measures to quantify how close a treatment plan is to the ideal or desired
treatment plan.

In the above example, the first three goals can be formulated as objectives; the fourth
goal of enforcing a strict maximum on the spinal cord dose represents a constraint. The
goal of delivering a homogeneous dose to the target volume can be formulated via a
quadratic objective function:

Ideally, every voxel that belongs to the target volume receives the prescribed dose
dpres,which corresponds to a value of zero for the function fT . Otherwise, fT yields the
averaged quadratic deviation from the prescribed dose. The larger the objective value is,
the more the dose deviates from the prescription dose, corresponding to a worse
treatment plan.
Similarly, the goal of minimizing the dose to the parotid glands can be formulated as
an objective function. For example, we can define the objective fP as

which aims at minimizing the mean dose to the parotid glands. The goal of conforming
the dose distribution to the target volume can for example be described via a piecewise
quadratic penalty function

where the + operator is defined through (di − dimax)+ = di − dimax if di ≥ dimax, and
zero otherwise. Thus dimax is a maximum dose that is accepted in voxel i; dose values
exceeding dimax are penalized quadratically. Clearly, in normal tissue voxels directly
adjacent to the target volume, high doses are unavoidable, whereas at large distance
from the target volume, treatment planning should aim at avoiding unnecessary dose.
Therefore, dimax can be chosen based on the distance of voxel i to the target volume. For
example, dimax is set equal to the prescribed dose in voxels directly adjacent to the
target volume, and to half the prescription at 1 cm distance.
Finally, we would like to ensure that the dose in all voxels that belong to the spinal
cord does not exceed a maximum tolerance dose dsmax. If we do not accept any
treatment plan that exceeds the maximum dose, this can be implemented as a
constraint, not an objective. In this case we can formulate the constraint as

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where S is the set of all voxels belonging to the spinal cord.
Treatment planning simultaneously aims at minimizing all of the above objective
functions, that is, ideally we would like each tumor voxel receive the prescribed dose
while no dose is delivered to the normal tissues. It is clear that the objectives associated
with different structures are inherently conflicting. Thus, the treatment planner will
have to weight these conflicting objectives relative to each other and accept a
compromise. The traditional approach in IMRT planning consists in manually assigning
importance weights w to each objective, using a high weight for the most important
objective, and a smaller weight for less important goals. The best treatment plan is then
defined as the one that minimizes the weighed sum of objectives

IMRT planning uses mathematical optimization algorithms in order to determine the


fluence map x, corresponding to the dose distribution d = Dx, which minimizes the
weighted sum of objectives, subject the all constraints on the dose distribution, and
under the condition that all beamlet weights have to be positive. We will further discuss
optimization algorithms in the section Fluence map optimization. Below, we first look at
the result of such an optimization for a specific choice of optimization parameters.

Solution to the IMRT Problem: The Optimal Treatment Plan


Figure 9.5 illustrates an IMRT treatment plan using 11 incident beam directions. It
shows the dose distribution overlaid on a coronal slice of the patient’s CT. Also shown
are the 11 beams together with the effective fluence that is incident from each direction.
One of the radiation fields is illustrated in more detail in Figure 9.6, in which the
fluence is overlaid on the digitally reconstructed radiograph (DRR). The figure
illustrates the modulation of the intensity over the radiation field.
The resulting dose distribution of the IMRT plan is shown in Figure 9.7. The middle
panel shows the cumulative dose distribution of all beams. IMRT allows for dose
distributions that conform to complex-shaped, concave target volumes. A single IMRT
plan allows for different dose levels in high- and low-risk lymph node targets, as well as
a simultaneous integrated boost (SIB) to the GTV. The peripheral images in Figure 9.7
show the dose contributions of 6 of the 11 incident beams.

Controlling Tradeoffs
Different objectives in IMRT planning are inherently conflicting. Clearly, there is a
tradeoff between delivering dose to the tumor and reducing dose to healthy tissues. In
the above example, the target volume is directly adjacent to the parotid glands. Sparing
the parotid glands from radiation will lead to a dose reduction in the adjacent part of
the target volume. Ensuring coverage of the target will in turn lead to higher doses to
the parotid glands. In addition, there are tradeoffs between different normal tissues. In
order to deliver the prescribed dose to the target volume, some dose to the normal
tissues is unavoidable. However, using intensity modulation and enough beam
directions, the dose distribution in the normal tissue can be shaped according to the
physician’s preference.

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FIGURE 9.5 Illustration of an IMRT plan for the head-and-neck cancer patient generated in the RayStation
planning system, version 4.0. The dose distribution is shown on a coronal slice of the patient’s CT scan. The
blue circle indicates the isocenter. The 11 beam directions are displayed with their respective fluence. Red color
indicates a low fluence, white a high fluence.

FIGURE 9.6 Illustration of a single intensity-modulated field, overlaid on the DRR. The figure shows the
effective fluence that is incident on the patient surface for the final treatment plan. This includes modification

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of the optimized fluence map through leaf sequencing (Leaf sequencing section) and refinement of MLC leaf
positions (Direct aperture optimization section). The same applies to Figure 9.5.

In most TPS that are in use today, treatment planners control the tradeoffs between
different planning goals manually by manipulating the relative weights w of objective
functions. This can lead to a time-consuming trial-and-error process. Different
approaches have been suggested to improve the interaction of the treatment planner
with the TPS, including interactive Pareto-surface navigation methods, which are
discussed in the section Specialized topics in IMRT planning.

Delivery of Intensity-Modulated Fields


In order to deliver an intensity-modulated field, the fluence map is decomposed into a
number of smaller radiation fields that can be delivered using an MLC. This process is
called sequencing and is described in more detail in the Leaf sequencing section. As an
outlook to subsequent sections, Figure 9.8 illustrates how the fluence shown in Figure
9.6 is delivered as a sequence of three MLC openings.

FLUENCE MAP OPTIMIZATION*


The previous section illustrated the main concepts in IMRT planning for an example
case. In this section we take a more formal look at IMRT planning as a mathematical
optimization problem. We first discuss some of the frequently used objective and
constraint functions, in particular the handling of dose–volume effects (section on Dose–
volume effects). The subsequent section briefly outlines the use of outcome models in
IMRT planning and their limitations. Finally, the section on Optimization algorithms
introduces basic mathematical optimization algorithms used in IMRT planning to solve
IMRT problems.

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FIGURE 9.7 IMRT dose distribution for the head-and-neck case example, demonstrating the ability of IMRT
to conform the dose distribution to complex target volumes (middle panel). Also shown are the dose
contributions of 6 (out of 11) beam directions (surrounding images).

In mathematical terms, a general FMO problem can be formulated as the following


mathematical optimization problem:

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FIGURE 9.8 Delivery of an intensity-modulated field through a sequence of MLC openings. Each figure
shows the incident total fluence overlaid on the DRR, together with the leaf positions of the multi-leaf
collimator that define the field opening. Also shown are the positions of the Y-jaws that reduce transmission
through closed MLC leaves (blue).

Treatment planning involves balancing different clinical objectives. Therefore, the


objective function f is a weighted sum of individual objectives:

Here, wn are positive weighting factors, which are used to control the relative
importance of different terms in the composite objective function.
The objective function that may be the most commonly used in current TPS is a piece-
wise quadratic penalty function:

Here, dmax is a maximum tolerance dose for an organ, which is usually specified by
the treatment planner through the graphical user interface in the TPS. Similarly, for
target volumes dmin is a minimum dose that is to be delivered to the target volume.
The functions gs(d) correspond to hard constraints on the dose distribution. Common

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constraints are maximum dose values in organs at risk and minimum doses in target
volumes. In this case, cs is the maximum dose in a structure, s is an index over all voxels
in the structure, and gs(d) is simply the dose in voxel s. In the subsection Dose-Volume
effects, additional commonly used objectives and constraints are discussed.

Dose–Volume Effects
An organ at risk will typically receive an inhomogeneous dose distribution. The question
arises whether it is better to irradiate a small part of the organ to a large dose while
sparing the remaining parts to a large extent; or whether it is better to spread out the
dose and avoid large doses in all parts of the organ. In that context, one distinguishes
parallel organs and serial organs. For organs with a serial structure, the function of the
whole organ will fail if one part of the organ is damaged. One prominent example for a
serial organ is the spinal cord. For serial organs it is therefore crucial to limit the
maximum dose delivered to the organ, rather than the mean dose. For a parallel organ,
the function of the organ as a whole is preserved even if a part of the organ is damaged.
The lungs are an example of a parallel organ. The dependence of a clinical outcome on
the irradiated volume of an organ is commonly referred to as a volume effect or dose–
volume effect. For IMRT planning, clinical knowledge on dose–volume effects are to be
translated into appropriate objective functions. Today, mainly two types of
objective/constraint function are being applied: dose–volume histogram (DVH)
constraints and the concept of equivalent uniform dose (EUD).

Equivalent Uniform Dose


One approach to quantifying dose–volume effects consists of using generalized mean
values of the dose distribution:

where the exponent α is larger than 1 for OARs. For the special case α = 1, EUD(d) is
equivalent to the mean dose in the organ. In the limit of large α values, the value of
EUD(d) approaches the maximum dose in the organ. Thus, parallel organs are described
via a small value of α close to 1, whereas serial organs are described via large values of
α (approximately 10). The generalized mean value is commonly referred to as EUD. The
generalized mean value can also be applied to target volumes by using negative
exponents. For a large negative value of α, the EUD approaches the minimum dose in
the target volume. In practice, exponents in the range of α = –10 … –20 are
considered. The EUD can be used as both an objective function and a constraint
function.

DVH Objectives and Constraints


The clinical evaluation of treatment plans often uses the DVH. A typical evaluation
criterion for the target volume is: at least 95% of the target volume should receive a
dose equal to or higher than the prescription dose. Similarly, a criterion for an OAR
could be: at most 20% of the organ should receive more than 30 Gy. From an
optimization perspective, it is not straightforward to handle DVH constraints in a
rigorous way. In practice, DVH constraints are therefore handled approximately using a
quadratic penalty function. We consider the example that no more than 20% of an

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organ should receive a dose higher than dmax. Given an initial dose distribution, one can
identify the fraction of voxels that exceed the dose level dmax. If this fraction is smaller
than 20%, the DVH constraint is fulfilled. Otherwise, a quadratic penalty function is
introduced that aims at reducing the dose to those voxels that exceed dmax by the least
amount. For example, if 30% of the organ receives a higher dose, the 20% of voxels
receiving the highest dose are ignored. For the 10% of voxels a quadratic penalty term
as in Equation 9.2 is added to the objective function.

The Use of Clinical Outcome Models in IMRT Optimization


Since the beginning of the IMRT era, the question regarding the adequate objective
function has persisted. Intuitively, we would like to translate the notion of “maximizing
the tumor control probability (TCP)” while “minimizing the normal tissue complication
probability (NTCP)” more directly into mathematical terms.
One of the most common methods for relating treatment outcome to the dose
distribution consists in performing logistic regression. As an example, we consider NTCP
models, however, the same methodology can be applied to TCP models. The severity of a
radiation side effect is clinically assessed in discrete stages. Typically, one is interested
in avoiding severe complications. For example, in the treatment of lung cancer,
treatment planning may aim at minimizing the probability for radiation pneumonitis of
grade 2 or higher. This converts the observed clinical outcome into a binary outcome
label. NTCP modeling can thus be considered as a classification problem, which aims at
estimating the probability of a complication given features of the dose distribution.
Standard statistical classification methods, such as logistic regression, can be applied to
this problem. In logistic regression, the NTCP model is given by:

Here, f is a function of the dose distribution d and the model parameters q. The
central problem in statistical analysis and modeling of patient outcome consist in
determining the function f, that is, selecting features of the dose distribution that are
correlated with outcome. One of the most commonly used representations of f is given
by:

In this case, f is a linear function of a single feature of the dose distribution, namely
the EUD. For EUD(d) = TD50, the value of NTCP evaluates to 0.5, that is, TD50
corresponds to the effective dose that leads to a complication probability of 50%. The
parameter γ determines the slope of the dose-response relation. The NTCP model has
three parameters (TD50, γ, and the EUD exponent α) which can be fitted to outcome
data, for example, through maximum likelihood methods. This NTCP model is
equivalent to the Lyman–Kutcher–Burman (LKB) model, except that the LKB model
traditionally uses a different functional form of the sigmoid.
Although phenomenologic outcome models play an increasing role in treatment plan
evaluation, their capabilities from a treatment plan optimization perspective have
remained limited so far. One reason for that is the uncertainty in outcome models. A
second reason is that currently used models are not more powerful than dose-based

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objective functions. In particular, the NTCP model above represents an increasing
function of the EUD, that is, independent of the parameters TD50 and γ, higher EUD
always leads to higher NTCP. As a consequence, the dose distribution that minimizes
EUD is the same as the dose distribution that minimizes NTCP. Hence, from an IMRT
optimization perspective, minimizing EUD and NTCP is equivalent (5).

Optimization Algorithms
Our goal in this chapter is to provide the reader with an understanding of the most
basic optimization algorithms, which do not require advanced knowledge of
optimization theory. We start with a geometric visualization of the IMRT optimization
problem. Subsequent, the gradient descent algorithm is described, which is in principle
sufficient to optimize fluence maps. Afterward, extensions of gradient descent methods
toward quasi-Newton algorithms are outlined. Certainly, the field of IMRT optimization
has advanced significantly, and increasingly complex algorithms for constrained
optimization are being applied. These algorithms require knowledge of optimization
theory, which is beyond the scope of this chapter. The interested reader is referred to
the optimization literature (6,7). Ehrgott et al. (8) provide a review of radiotherapy
planning from a mathematical optimization perspective.

Visualization of The Fluence Map Optimization Problem


Due to the large number of beamlets (optimization variables) it is not possible to directly
visualize the objective and constraint functions for a full IMRT planning problem.
Nevertheless, it is helpful to understand the structure of the IMRT optimization
problem. To that end, we consider a simplified version of an IMRT planning problem in
which only 2 beamlets and 4 voxels are considered. We consider the following dose-
deposition matrix:

where the first two columns correspond to the tumor voxels, and columns 3 and 4
correspond to OAR voxels. We further assume that we aim to deliver a dose of 2 to both
of the tumor voxels, and we impose a maximum dose constraint on OAR voxel of 0.8
and 1.0, respectively.
The goal of delivering the prescribed dose to the tumor voxels is expressed via a
quadratic objective function. The optimization problem for this illustrative example can
be formulated as:

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Since we only have two optimization variables, the objective and constraint functions
can be visualized explicitly. This is done in Figure 9.9. The objective function is
illustrated via isolines. Since we consider a quadratic objective function, it represents a
two-dimensional parabola. The minimum of the objective function is located at beamlet
intensities x1 = 1 and x2 = 1. At this point, both tumor voxels receive the prescribed
dose and the objective function is zero.
We now consider the constraints on the OAR voxels. Since the dose in each voxel is a
linear function of the beamlet intensities, the constraints represent hyperplanes in
beamlet intensity space, that is, lines in two dimensions. In Figure 9.9 we show the lines
where the constraints d3 = 0.8 and d4 = 1.0 are met exactly. For all beamlet intensity
beyond these lines, the maximum dose to an OAR voxel is exceeded. All beamlet
intensity combinations below the lines form the feasible region. Thus, the optimal
solution to the IMRT planning problem is given by the point within the feasible region
that has the smallest value of the objective function. In this example, this is given by x1
= 0.7 and x2 = 1.2 and is indicated by the red dot in Figure 9.9. By multiplying this
solution with the dose-deposition matrix, we obtain the corresponding optimal dose
distribution.
In this case, the constraint for OAR voxel 3 is binding, that is, the OAR voxel receives
the maximum dose we allow for. We further note that the minimum of the objective
function is outside of the feasible region, which means that, in order to fulfill the
maximum OAR dose constraint, we have to accept a compromise regarding target dose
homogeneity.

FIGURE 9.9 Visualization of the IMRT optimization problem for two beamlets. The quadratic objective

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function is shown via isolines; the linear maximum dose constraints of OAR voxels are shown as thick black lines
(with permission reproduced from (4)).

FIGURE 9.10 Visualization of the composite objective function containing quadratic penalty functions to
approximate maximum dose constraints. For increasing weights w for the penalty function, the minimum of the
composite objective function moves closer to the optimal solution of the constrained problem (with permission
reproduced from (4)).

Approximate Handling of Constraints Via Penalty Functions


In IMRT planning, maximum dose constraints in OARs are often approximated via
penalty functions. More specifically, we can consider the composite objective function
where a quadratic penalty function, multiplied with a weight w is added to the original
objective for target dose homogeneity:

Adding the penalty function does not change the objective function within the
feasible region, only the objective function values outside of the feasible region are
increased. This is shown in Figure 9.10 for penalty weights of w = 5 and w = 20.
While w is increased, the unconstrained minimum of the function f moves closer to the
optimal solution of the constrained problem.

The Basic Gradient Descent Method


In this section we introduce the most generic optimization algorithm, which can in
principle be used to generate an IMRT treatment plan. To that end, we assume that we
want to minimize an objective function f, subject to the constraint that all beamlet
intensities are positive. We do not consider additional constraints g on the dose
distribution, that is, all treatment goals are included in the objective function.
The gradient of the objective function is the vector of partial derivatives of f with
respect to the beamlet intensities xj:

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The gradient vector is oriented perpendicular to the isolines of the objective function;
it points in the direction of maximum slope in the objective function landscape. Thus,
taking a small step into the direction of the negative gradient yields a fluence map x
that corresponds to a lower value of the objective function, that is, an improved plan.
This gives rise to the most basic nonlinear optimization algorithm: In each iteration k,
the current fluence map xk is updated according to:

where α is a step size parameter, which has to be sufficiently small in order for the
algorithm to converge.

Gradient Calculation. The gradient of the objective function with respect to the
beamlet intensities can be calculated by using the chain rule in multiple dimensions:
Given that the objective is a function of the dose distribution we have

The partial derivative of the voxel dose di with respect to the beamlet weight xj is
simply given by the corresponding element of the dose-deposition matrix:

The partial derivative of the objective function with respect to dose in voxel i
describes by how much the objective function changes by varying the dose in voxel i.
For the quadratic objective function

the components of the gradient vector are given by

which has an intuitive interpretation. The total change in the objective function value
due to changing the intensity of beamlet j is obtained by summing over the
contributions of all voxels. The contribution of a voxel is given by the dose error (di −

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dpress) multiplied by the influence Dij of beamlet j onto the voxel i. If the dose di exceeds
the prescribed dose, the voxel’s contribution is positive; voxels that are underdosed
yield a negative contribution to the gradient component. If the gradient component is
negative after summing over the contributions of all voxels, the impact of the
underdosed voxels dominates. A step in the direction of the negative gradient
corresponds to increasing the beamlet weight xj, thus reducing the extent of
underdosing.

Handling the Nonnegativity Constraint. So far, only the objective function f was
considered, not taking into account the nonnegativity constraint on the beamlet
intensities. Applying the gradient descent algorithm without accounting for the
nonnegativity constraint leads to negative intensities for some of the beamlets, which is
not meaningful. Different extensions of the gradient descent algorithm exist in order to
ensure positive beamlet weights.
One method consists in simply setting all negative beamlet intensities to zero after
each gradient step. Formally, this corresponds to a projection algorithm for handling
bound constraints. An alternative approach is based on a variable transformation. In
this case, a new optimization variable is introduced for every beamlet, which is defined
as the square root of the intensity. Thus, the beamlet intensity, given by the squared
value of the variable, is always positive, while the optimization variable can take any
value. This way, the constrained optimization problem is converted into a fully
unconstrained problem.

Improvements to Gradient Descent


The generic gradient descent algorithm shows slow convergence in practical IMRT
optimization problems. Improvements to the generic gradient descent algorithm can be
made mainly in three aspects:
1. Selecting an appropriate step size using line search algorithms.
2. Improving the descent direction by including second derivative information.
3. Improve the handling of constraints using more advanced algorithms for constrained
optimization.

For the first and third aspects, the reader is referred to the advanced optimization
literature. The second aspect is outlined below.

Including Second Derivatives. The generic gradient descent algorithm considers the
first derivative of the objective function at the current fluence map x. This can be
interpreted as finding a hyperplane that is tangential to the objective function at x. The
convergence properties of iterative optimization algorithms can be improved by
including second derivative (i.e., curvature) information. This can be interpreted as
finding a quadratic function that is tangential to the objective function at x. The
iterative optimization algorithm, known as the Newton method, then performs a step
toward the minimum of the quadratic approximation.
To formalize this concept, we consider a second-order Taylor expansion of the
objective function f at the fluence map x:

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By defining the Hessian H as the matrix of second derivatives, this can be written as:

The idea of the Newton method consists in taking a step Δ x such that we reach the
minimum of the quadratic approximation. For the special case that the original
objective function f is a quadric function, the approximation is exact, and thus the
Newton method finds the optimal solution in a single step. Generally, f will not be a
purely quadratic function. However, it is assumed that a Newton step will approach the
optimum faster than a step along the gradient direction.
To calculate the Newton step Δx*, we set the gradient of f with respect to Δx to zero,
which yields the condition

Thus, the Newton step is given by

This leads to a modified iterative optimization algorithm in which the beamlet


intensities are updated according to

We can further note that the Newton method has a natural step size α = 1.
In practical IMRT optimization, the pure Newton method is not applied. A naïve
computation of the Newton step involves the calculation of the Hessian matrix at point
x, inverting the Hessian matrix, and multiplying the inverse Hessian H(xk)−1 with the
gradient vector. In IMRT optimization, the size of the Hessian matrix is given by the
number of beamlets squared. Therefore, the explicit calculation and inversion of the
Hessian is often computationally prohibitive. Thus, IMRT optimization employs the so-
called quasi-Newton methods, which rely on an approximation of the Newton step. One
of the most popular methods that is applied in IMRT planning is the limited memory L-
BFGS quasi-Newton algorithm. In this algorithm, the descent direction H(xk)−1∇f(xk) is
approximated based on the fluence maps and gradients evaluated during the previous
iterations of the algorithm, which avoids a costly matrix inversion. The comprehensive
description of the L-BFGS algorithm can be found in the textbook by Nocedal and
Wright (6).

Convexity
Many objective functions commonly applied in IMRT planning are convex. This is in
particular the case for the piecewise quadratic objective, linear objectives, and the
generalized EUD for exponents |α| > 1. The convexity property of objective and
constraint functions has important implications for the optimization of fluence maps.
An optimization problem defined through a convex objective function f and convex
constraint functions gs has a unique global minimum, that is, there are no local minima,
which are not the global minimum. Thus, gradient descent–based optimization
algorithms do reliably find the optimal fluence map. The only nonconvex objectives
commonly applied in practice are DVH constraints. However, practical experience
suggests that the nonconvexity of DVH constraints does not cause severe local minima-
related issues in IMRT planning.

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LEAF SEQUENCING
In this section, we discuss ways to deliver intensity-modulated radiation fields. The
section is focused on IMRT delivery using conventional Linacs equipped with an MLC.
This represents, by far, the most widely used IMRT technique, although it is not the only
possible form of IMRT. Historically, IMRT delivery with compensators has been
performed in many centers. In that technique, an intensity-modulated field is created
using an absorber placed in the beam path in the Linac head. The absorber causes an
exponential attenuation of the fluence. By varying the thickness of the absorber across
the beam profile, the desired intensity-modulated field can be created. Compensators
had to be custom made for every patient and every field, and where typically cast in
lead. This required a machine shop connected to the radiotherapy department.
Nowadays, the use of computer-controlled MLCs, which eliminates the need for patient-
specific hardware, has replaced compensator-based IMRT delivery.

FIGURE 9.11 Illustration of beam collimation for IMRT delivery using multi-leaf collimators and jaws.

Beam Shaping and Multi-Leaf Collimators


This section briefly introduces MLCs. We focus on the main aspects of MLCs that are
relevant for IMRT planning and delivery as described in the remainder of this chapter.
For details on the mechanical and technical aspects, the reader is referred to the
literature (3). Figure 9.11 illustrates of the main components used to collimate the
radiation beam: the jaws and the MLC. The MLC is the primary collimation device that
defines the shape of the beam. It consists of thin sheets of tungsten, which are moved in
and out of the beam using computer-controlled electric motors. Each leaf has a
considerable height (measured in beam direction) of approximately 5 to 10 cm in order
to keep the transmission of radiation through closed leaves low. In contrast, each leaf is
only a few mm thick to yield a projected beamlet size of 5 mm or 10 mm at the
isocenter. The jaws represent rectangular field collimators upstream of the MLC. Figure
9.12 illustrates the use of the MLC for beam collimation in beam’s-eye-view. A variety of
terms are used to refer to a radiation field produced by an MLC. In this chapter, we use
the term aperture; other common terms are segment or MLC opening.
Depending on the MLC model, there are a number of constraints on leaf motion and

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leaf positioning. This limits the set of apertures that can be delivered by an MLC. With
the latest generation of MLCs some of these restrictions are eliminated or mediated, but
especially for older models some of the following restrictions may apply:

• Interdigitation: For some MLCs it is not possible for neighboring leaf pairs to cross,
that is, the tip of the left leaf cannot move past the tip of a neighboring right leaf. The
leaf configuration of leaf pairs 7 and 8 in Figure 9.12 would be prohibited. The
interdigitation constraint has been eliminated for most modern MLCs.

FIGURE 9.12 Illustration of beam collimation in beam’s-eye-view using an MLC and jaws. The MLC leaves
(gray bars) are used primarily for beam shaping. The jaws (red and yellow blocks) are typically placed in a post-
processing step to irradiate the smallest rectangular field that covers the MLC aperture. The jaws reduce
transmission through closed MLC leaves. In addition, for MLCs that require a finite gap between the left and
right leaf tip, closed leaf pairs can be hidden behind the jaws, as illustrated in rows 1 and 8.

• Maximum overtravel: Most linear accelerators have a 40 × 40-cm field of view at the
isocenter. However, for some MLCs it is not possible for the left leaf to travel all the
way the right side of the field of view. The maximum distance that the leaf tip can
travel beyond the isocenter projection is called the maximum overtravel. The
constraint implies that the MLC cannot deliver small apertures far away from the
isocenter.
• Minimum leaf gap: For some MLCs a leaf pair cannot fully close, that is, a minimum
gap between the right and left leaf tips has to remain.
• Maximum leaf speed: In addition to restrictions on leaf positioning, MLCs have
dynamic constraints. Leaves cannot move faster than a maximum speed; typical values
are 3 cm/s or 6 cm/s.

Aperture Decomposition of Fluence Maps


It is intuitively clear that the superposition of multiple distinct radiation fields formed
by an MLC may yield an intensity-modulated field. This is schematically illustrated in

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Figure 9.13.
In IMRT planning, the inverse problem needs to be solved, that is, given an optimized
fluence map, we have to determine a set of apertures that closely reproduce the fluence
map. This is called the leaf sequencing problem. We assume for now that the fluence map
is discretized into evenly spaced fluence levels. A closer look at Figure 9.13
demonstrates that the leaf sequencing problem does not have a unique solution, that is,
a given fluence map can be decomposed into a set of apertures in many different ways.
We consider MLC rows 3 and 4 in Figure 9.13, which yield the same fluence, created
with a distinct sequence of leaf openings. MLC row 3 uses a sliding window
decomposition, in which the right and left leaves move unidirectionally from left to
right. In contrast, MLC row 4 uses a close-in technique, in which case the first aperture
corresponds to the largest field opening. Subsequent apertures shrink the field and
deliver additional fluence at the beamlets that have higher intensity. In Figure 9.13 and
throughout this section, we assume that the fluence over an open field is homogeneous,
which is applicable to Linacs with flattening filter. Although not discussed here, leaf
sequencing methods can be extended to flattening filter free (FFF) delivery of IMRT,
which has the advantage of higher dose rates.

FIGURE 9.13 Schematic illustration of the decomposition of a fluence map (right panel) into apertures. The
positions of MLC leaf ends are indicated by the green bars. It is assumed that each aperture delivers one unit of
fluence; the colors yellow, orange, and red indicate one, two, and three units of fluence, respectively.

Sliding Window Sequencing


We consider the sliding window decomposition of fluence maps in more detail (9). To
that end, we consider a single leaf pair. The upper panel in Figure 9.14 shows an
example of one row of a fluence map for a single leaf pair. The bottom panel shows the
sliding window type aperture decomposition. In the example, both leaves move
unidirectionally from left to right.

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FIGURE 9.14 Illustration of sliding window sequencing. The upper panel shows the fluence map (vertical bars)
corresponding to a single leaf pair. The bottom panel shows the set of apertures (horizontal bars) to realize the
fluence map.

It is intuitive that the gradients in the fluence map, that is, changes in the intensity
between neighboring beamlets, determine the leaf positions. In the example, the fluence
increases by 4 units between beamlet 1 and beamlet 2. This determines that, during the
delivery of 4 units of fluence, beamlet 1 has to be blocked by the left leaf while beamlet
2 is exposed. Likewise, the fluence decreases by 1 unit between beamlets 2 and 3, which
determines that during the delivery of 1 unit of fluence, beamlet 3 has to be blocked by
the right leaf while beamlet 2 is exposed. We call an increase in the fluence from one
beamlet to the next higher numbered beamlet a positive gradient, and a decrease a
negative gradient. It is clear that the sum of positive gradients (SPG) equals the sum of
negative gradients. In sliding window sequencing, the positive gradients uniquely
determine the left leaf positions, while the negative gradients uniquely determine the
right leaf positions. In the first aperture, the left leaf is positioned to the left of beamlet
1, the right leaf is positioned where the first negative gradient occurs, which is between
beamlet 2 and 3. For the second aperture, the left leaf stays in the same position while
the right leaf moves to the next negative gradient position, which is between beamlets 3
and 4.
It is intuitive that an irregularly shaped fluence map with several peaks and valleys
requires more apertures to deliver than smooth fluence maps. It can be shown that the
minimum total number of MU to deliver a fluence map is given by the SPG. Sliding
window sequencing is therefore optimal regarding the total number of MU since it

247
always reproduces a fluence map with the shortest possible beam-on time.

Sequencing as an Optimization Problem


As illustrated in Figure 9.13, the leaf sequencing problem does not have a unique
solution. The degeneracy of the problem provides some freedom that can be exploited,
that is, the sequencing step can aim at determining apertures that have desirable
features. Criteria for good aperture sets are:

• The total number of MU to be delivered is small, which corresponds to the total beam-
on time.
• The total number of apertures is small.
• Leaf travel is minimized, that is, the MLC leaves move as little as possible
• Apertures should have regular shapes and very small apertures are avoided.
• The fluence map is reproduced exactly or as closely as possible without prior
discretization.
• All MLC constraints are satisfied.
The sliding window sequencing method is optimal regarding the total number of MU.
However, other sequencing methods can potentially reduce the total number of
apertures needed. To that end, the sequencing problem can be formulated as an
optimization problem. While the FMO problem is a continuous optimization problem for
which gradient-based optimization methods are applied, the sequencing problem is
discrete and requires different optimization techniques. The interested reader is referred
to the literature. For example, the work by Engel (10) describes a sequencing algorithm
that yields the minimum number of MU and simultaneously approximately minimizes
the number of apertures.

Step-and-Shoot Delivery Versus Dynamic Delivery


In IMRT, two types of delivery are distinguished: step-and shoot delivery and dynamic
delivery. In step-and-shoot IMRT, the fluence map is sequenced into a set of apertures
as described above. Each aperture is irradiated individually, that is, the MLC leaves
move to the desired position, and the beam is turned on to deliver the specified number
of MU. Subsequently, the beam is turned off while the MLC leaves are moved to shape
the next aperture. In dynamic delivery, the MLC leaves move while the treatment beam
is on. In this case, the sequencing task consists in determining the trajectories of MLC
leaves, that is, the leaf positions as a function of time.

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FIGURE 9.15 Illustration of dynamic IMRT delivery using a sliding window technique. The red lines in the
upper panel show the positions of the left and right leaf as a function of time. The green line in the bottom panel
shows the corresponding fluence profile.

Dynamic delivery is frequently associated with a sliding window type delivery,


because this gives rise to a constructive method to determine the leaf trajectories (11).
To that end, we consider a generalization of the sliding window aperture decomposition
in Figure 9.14. Figure 9.15 schematically illustrates continuous trajectories of the left
and right leaf in one MLC row. The horizontal axis shows the position of the leaf end,
while the vertical axis shows the time when the leaf end traverses a given position. At
every beamlet position in the MLC row, the effective fluence of the beamlet is given by
the exposure time. Initially, both leaves are positioned on the left side and the right leaf
covers the beamlet. At time t1 the right leaf end traverses the beamlet and opens the
radiation field at that position. At a later time point t2 the left leaf traverses the beamlet
and closes the radiation field. The fluence of the beamlet is proportional to the time
interval t2 – t1 during which the beamlet is exposed. Thus, the distance of right and left
leaf on the vertical axis determines the corresponding fluence profile (green line in the
bottom panel).
In practice, the MLC leaves cannot move arbitrarily fast and have to respect a
maximum leaf speed. In Figure 9.15, the maximum leaf speed constraint corresponds to
a minimum slope of the leaf trajectory. To allow a leaf to move a certain distance on the
horizontal axis, a minimum amount of time has to pass. This is indicated by the black
dashed line in the upper panel.
Dynamic delivery is frequently associated with sliding window type delivery and used
synonymously by some people. However, dynamic delivery is not per se tied to sliding
window trajectories. In principle, other sequencing methods that allow for bidirectional
leaf motion could be developed and used. In fact, delivery of VMAT can be considered

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as dynamic delivery with bidirectional leaf motion.

DIRECT APERTURE OPTIMIZATION


Historically, IMRT planning was developed as the two-step approach of FMO plus
sequencing. However, there are a number of disadvantages related to the two-step
approach. For example, in step-and-shoot IMRT, a large number of apertures may be
required to faithfully reproduce a fluence map. Other problems relate to dose
calculation accuracy during the FMO step. In order to cope with the limitations of the
two-step approach, DAO methods are being developed and integrated into commercial
TPS. In this section, we first summarize some of the limitations of the two-step
approach. Subsequently, approaches to DAO are discussed, which directly determine the
shapes and intensities of apertures.

Limitations of the FMO + Sequencing Approach


Limitations of the two-step approach can broadly be categorized into three types:
1. The fluence map is not accurately reproduced by the set of apertures. This is
primarily a problem in step-and-shoot IMRT if the total number of apertures is kept
small.
2. In step-and-shoot IMRT, the leaf ends are positioned at the boundary between two
beamlets after the sequencing step. Especially for large 1 × 1-cm beamlets, the dose
distribution can be improved by positioning the leaves at intermediate positions.
3. Even if the leaf sequencing step reproduces the fluence map exactly, there will still be
a discrepancy between the FMO dose distribution used during plan optimization and
the dose that is actually delivered by the set of apertures.

While the first two limitations are quite apparent, the third aspect is more complex.
There are multiple reasons for dose discrepancy. Some are inherent to the dose-
deposition matrix concept, which does not take into account higher-order effects on the
incident fluence that the MLC causes. Others are related to compromises being made
between accuracy and computational performance in the FMO stage.
Dose calculation accuracy: The calculation of the dose-deposition matrix often uses
a simplified dose calculation algorithm to speed up the computation. For example, the
dose-deposition matrix may be based on a pencil beam algorithm while the final dose
distribution of the apertures may be calculated with a convolution-superposition
algorithm. In addition, the dose-deposition matrix may not store small scatter dose
contributions far away from the central axis of the beamlet in order to reduce memory
requirements. This leads to dose discrepancy between the sequenced FMO solution and
the final dose distribution. This issue is not an inherent limitation of the two-step
approach, and using accurate dose calculation methods for computing the dose-
deposition matrix could mitigate the problem. However, in practice fast treatment plan
optimization is desired, which requires compromises.
Tongue-and-groove effect: Other dose calculation problems are inherent to the dose-
deposition matrix concept. For mechanical reasons, two neighboring MLC leaves cannot
be arbitrarily close to each other. However, a small gap between MLC leaves would lead
to radiation leaking through. In order to avoid such inter-leaf leakage, many MLCs
adopt a tongue-and-groove design, which is schematically illustrated in Figure 9.16. Let
us consider an aperture consisting of two neighboring beamlets in adjacent leaf pairs.
The dose-deposition matrix concept used in FMO assumes linearity. This means, if both

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beamlets are combined to a single aperture, the resulting dose distribution is predicted
to be the same compared to the situation in which both beamlets are delivered
individually as separate apertures. However, for MLCs with tongue-and-groove design,
this is not true. The regions where both leaves overlap are now blocked as soon as one
of the two leaves is closed. This leads to an underdosage of the region of the beamlet
boundary if both beamlets are delivered as separate apertures.

FIGURE 9.16 Illustration of MLC leaves with tongue-and-groove design.

Leaf transmission: During the FMO step, the fluence of beamlets may be zero if the
beamlet is not beneficial for the treatment plan. Also, the sequencing method typically
assumes that the fluence for closed leaves is zero. In reality this is only approximately
true as there is some transmission of radiation through closed MLC leaves. The effect is
mitigated by the jaws and is small when considering a single aperture. However, the
leaf transmission effect can add up for treatment plans consisting of a large number of
irregularly shaped apertures.
Mitigation of dose discrepancies: There are approaches to mitigate the effects that
lead to discrepancies between the dose distributions at the FMO stage and after
sequencing. One approach consists in adding regularization terms to the FMO problem
to favor smooth fluence maps that require fewer apertures to deliver. In this context,
the L1-norm regularization term is of particular interest, which has edge-preserving
properties and favors piece-wise constant fluence maps (12,13). Furthermore,
enhancements to the sequencing algorithm have been devised, which for example, aim
to reduce tongue-and-groove effects (14).

Direct Aperture Optimization for Step-and-Shoot IMRT


In light of the above-mentioned limitations of the two-step approach of FMO plus
sequencing, it appears desirable to directly optimize the shapes and intensities of
apertures based on the dosimetric objective function f(d). As a modification of the FMO
problem in the section on Fluence map optimization, the DAO problem can be stated as
follows:
Determine the intensities and shapes of K apertures that minimize the objective function f(d)
subject to the constraints gs(d) ≤ cs. Optimizing shapes of the apertures refers to optimizing the
positions of all MLC leaves.
In order to appreciate the inherent difficulties in DAO, we recall the favorable
properties of the FMO problem. For FMO, the optimization variables are the beamlet
intensities, while the objective is a function of the dose distribution. Given the dose-

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deposition matrix elements as fixed parameters, the dose distribution is a linear
function of the beamlet intensities. A small change in the intensity of one beamlet leads
to a small linear change in the dose to a voxel. Thus, the objective function can be
written explicitly as a function of the optimization variable. In addition, if the objective
is a convex function of dose, the overall optimization problem is convex and gradient-
based algorithms can be used to determine the global optimum reliably.
The DAO problem does not have this favorable property. The dose distribution is a
more complex and nonconvex function of the optimization variables (the MLC leaf
positions), which cannot easily be stated in closed form. If we consider the dose in a
voxel as a function of the position of an MLC leaf, the dependence is given by a
smoothed step function. While both leaves are fully open, the leaf pair contributes its
maximum dose to the voxel. While one leaf moves to close the field, the leaf pair’s dose
contribution goes to zero. However, for most parts, a change in the leaf position has
little impact on the dose to a particular voxel. Only in a small region that corresponds
to the projection of the voxel onto the MLC plane, a small change in the leaf position
yields a steep change in the voxel’s dose.
In addition, there is a combinatorial aspect to the DAO problem. An IMRT plan
typically consists of 5 to 11 beam directions. Some beams contribute more dose than
others, and not all beam directions require the same amount of intensity modulation.
Therefore, the best distribution of a limited number of apertures over the incident beam
angles is unclear a priori. Assigning the same number of apertures to every beam may
not yield the best treatment plan.
All approaches to DAO have to cope with these intrinsic difficulties. DAO approaches
can broadly be categorized into three types:
1. Stochastic search methods
2. Aperture generation methods
3. Gradient-based leaf position optimization

Stochastic Search Methods


Stochastic search methods for DAO include simulated annealing (15) and genetic
algorithms (16,17). These approaches typically start with a geometry-based
initialization of aperture shapes, that is, apertures that conform to the target volume,
possibly excluding projections of the OARs. Subsequently, random perturbations of leaf
positions are generated and dose distribution d and objective function f (d) are
evaluated. If the treatment plan improves, the modification of the aperture set is
accepted; otherwise it is rejected with some probability. Stochastic search methods have
a number of advantages. First, random perturbations of leaf positions can be restricted
such that all MLC constraints are fulfilled. In addition, these methods can in principle
escape from local optima of the objective function. Simulated annealing–based DAO has
been commercialized by PROWESS in the Panther TPS for step-and-shoot IMRT.
Furthermore, the method has been adapted to VMAT (section on Arc therapy) and is used
in the RapidArc module in the Eclipse TPS marketed by Varian.

Aperture Generation Methods


The second class of methods refers to techniques that iteratively generate new apertures
that are added to a treatment plan. Such an approach has been suggested by Romeijn et
al. (18) and Carlsson (19). Here, we illustrate the main idea behind the approach. We
assume that the current treatment plan consists of n – 1 apertures and we are interested
in generating the nth aperture that yields a large improvement to the current treatment

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plan. To that end, we consider the partial derivative ∂f/∂xj of the objective function f
with respect to the intensity of a beamlet j. If the derivative is negative, adding the
beamlet with a small positive intensity reduces the objective function, that is, improves
the treatment plan. Furthermore, if |∂f/∂xj | is large, the beamlet promises a large
improvement to the treatment plan. Therefore, a plausible approach to identifying a
valuable new aperture consists in finding a deliverable aperture that contains many
beamlets j for which ∂f/∂xj < 0 and |∂f/∂xj | is large. Romeijn et al. (18) describe an
efficient algorithm to identify the aperture A for which

is minimized. The aperture is added to the treatment plan and the intensities of all n
apertures are optimized. The problem of optimizing the aperture intensities is formally
identical to the FMO problem and can be solved using the algorithms described in the
section on Fluence map optimization. The dose distribution of an aperture Ak in the
patient is obtained by summing the dose-deposition matrix elements over the beamlets
contained in the aperture,

and the dose distribution is simply given by summing the contributions of all apertures,

where yk is the intensity of aperture k. The iterative generation of new apertures can be
stopped once a maximum number of apertures is reached or the plan quality is
sufficiently high.

Local Leaf Position Optimization*


In the remainder of this section, we describe the third approach of gradient-based leaf
position optimization in more detail. The reason is that this approach is implemented in
several of the widely used commercial TPS including Pinnacle (Philips) (20), RayStation
(Raysearch Laboratories), and Monaco (Elekta).
In this approach to DAO, we assume that we are given an initial set of apertures. This
set of apertures can, for example, be obtained by sequencing a fluence map solution, or
from the aperture generation method discussed above. Due to the nonconvex nature of
the problem, the initial set of apertures should represent a good starting point for leaf
position refinement, that is, ideally forms a decent treatment plan already. The set of K
apertures, indexed by k, is characterized by

• aperture intensities yk.


• leaf positions for the left and right leaf edges: Lkn and Rkn where n is the index of the
MLC leaf pair.

The goal of gradient-based leaf refinement is to optimize the objective function f (d)
with respect to the leaf positions and aperture weights. In particular, we allow the leaf

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positions to change continuously, that is, the leaf edge does not have to be positioned at
a beamlet boundary.

Approximate Dose Calculation


We first formulate the dose distribution as a function of the optimization variables, that
is, leaf positions and aperture intensities. The dose in voxel i is given by the sum of the
contributions of the individual apertures, weighted with their intensity yk. Furthermore,
the dose contribution of each aperture is given by the contributions of each MLC leaf
pair:

To proceed, we have to further characterize the function . For that purpose,


we consider a particular MLC row n in aperture k. We first imagine that the left leaf is
located at the left-most position at the edge of the field; and we consider the dose
contribution of the MLC row as a function of the right leaf position, which we denote by
the function . Let us further assume that the voxel i is within the beam’s-eye-view
of the MLC row such that the MLC row contributes a significant dose to voxel i. We
know that the function has the shape of a smooth step function: If the right leaf is
located at the left most position, the MLC row is closed and the dose contribution is
zero. While the right leaf is moving to the right, the dose contribution increases
monotonically. This is illustrated in Figure 9.17.
We now consider the dose-deposition matrix representation of the dose to further
characterize the function . We note that we know the function at discrete
points, namely when the right leaf is positioned at an edge of a beamlet. Let Δx denote
the size of a beamlet, and let j denote the beamlet index in leaf motion direction. At
position jΔ x, the dose contribution is simply given by the sum over the exposed
beamlets, that is,

where we introduce the dose-deposition matrix notation to denote the dose


contribution of beamlet j in MLC row n to voxel i. For a continuous leaf position in
between, we consider a linear interpolation (Figure 9.17). This corresponds to the
assumption that the dose distribution of a beamlet that is half exposed is given by the
beamlet dose distribution with half the intensity. This approximation will break down
for large beamlet size Δx, however, for practical beamlet sizes of 5 mm, the
approximation yields adequate results. Using the function we can express the dose
contribution of an MLC row as

The first term represents the beamlets that are exposed by the right leaf; the second
term subtracts the beamlets that are blocked by the left leaf.

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FIGURE 9.17 Illustration of the function , representing the dose contribution of an MLC row to a
voxel as a function of the right leaf position. The function is known at discrete position where the right leaf is
positioned at a beamlet boundary and the dose contribution can be expressed as a sum of dose-deposition matrix
elements. In between, the dose contribution is interpolated linearly (with permission reproduced from (4)).

Optimizing Leaf Positions


To optimize leaf positions and aperture intensities we can utilize gradient descent–based
algorithms for nonlinear optimization. To apply the generic gradient descent algorithm
described in the section on Fluence map optimization, we have to evaluate the gradient of
the objective function with respect to leaf positions and aperture intensities.
This can be achieved with the help of the function ø. Let us consider the derivative
with respect to one of the right leaves, Rkn:

The calculation of the partial derivatives ∂f/∂di is identical to the case of FMO as
described in the Fluence map optimization section. Using the linear approximation
illustrated in Figure 9.17, the derivative of the dose contribution function only
depends on the beamlet where the leaf edge is currently located. If we further assume
that the leaf position is measured in units of beamlets (i.e., moving a leaf by the width
of one beamlet corresponds to a distance of 1), the derivative of is simply given
by

where jkn is the index of the beamlet where the leaf edge is located. The derivative of the
voxel dose with respect to the aperture intensity is simply given by the dose
contribution of the aperture for unit intensity:

Evaluating the dose gradient of the objective function with respect to the optimization
variables provides the prerequisites for the use of a gradient-based nonlinear

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optimization algorithm. In contrast to FMO, DAO considers two types of optimization
variables simultaneously, that is, leaf positions and aperture intensities. Therefore, the
use of second derivatives in the optimization algorithm is important. In particular, the
quasi-Newton methods like L-BFGS can be used. Variations of gradient-based leaf
position optimization are described by De Gersem et al. (21) and Cassioli and Unkelbach
(22).
DAO provides the opportunity to directly account for restrictions of the MLC. These
can be integrated into the optimization problem in the form of bound constraints and
linear constraints. In addition, DAO provides better ways of mitigating dose calculation
inaccuracies compared to FMO. For example, at an intermediate stage of gradient-based
leaf position optimization, the dose distributions of the current aperture set can be
calculated using a convolution-superposition algorithm. In subsequent iterations,
changes can be approximated by a pencil beam–based dose-deposition matrix. If leaf
position changes remain small, the error in the dose distribution is minor.

ARC THERAPY
In IMRT, the patient is irradiated from discrete beam directions. Typically between 5
and 9 beam directions are used. While the gantry moves from one angle to the next one,
the treatment beam is off. Arc therapy refers to a radiotherapy delivery mode in which
the treatment beam is continuously on while the gantry rotates around the patient.
Conformal arc therapy has long been used as a delivery mode for conformal therapy,
especially for small spherical lesions that do not require intensity modulation. In
conformal arc therapy, the treatment field is fixed during gantry rotation or conforms
to the projection of the target volume. VMAT refers to an extension of IMRT to a
rotational treatment mode, delivered at conventional Linacs equipped with an MLC. The
treatment field does not necessarily conform to the target at every angle. Instead, an
effectively intensity-modulated field is delivered over an arc sector.
The motivation for VMAT has been twofold: First, the patient is irradiated from all
gantry angles rather than a relatively small number of discrete angles. This bears the
potential for better and more conformal treatment plans. Second, VMAT bears the
potential for shorter treatment times because the treatment beam is continuously on.
The idea of delivering intensity-modulated fields through arc therapy was suggested by
Yu as early as 1995 (23). However, a clinical implementation of VMAT was delayed in
part by the lack of TPS that support this technique. In 2008, Varian introduced the
RapidArc planning module in the Eclipse planning system and provided a commercial
VMAT solution. Around the same time, Philips Medical Systems provided the SmartArc
module in the Pinnacle planning system to support VMAT. Today, most treatment
systems including Monaco (Elekta) and RayStation (Raysearch Laboratories) support
VMAT planning.
Before the clinical adaptation of VMAT, specialized hardware to deliver intensity-
modulated fields in a rotational mode was developed. The device has been proposed by
Mackie (24) and was commercialized as Tomotherapy, resulting in the first patient
treatment in 2002. The design of Tomotherapy machines resembles a serial CT scanner
in which the x-ray tube is replaced by a Linac that produces a therapeutic MV treatment
beam. The radiation source continuously rotates while the patient is shifted through the
device. The patient is irradiated slice-by-slice using a fan beam, whose intensity is
modulated using a customized binary MLC. From a treatment planning perspective,
Tomotherapy can build on the FMO concepts described in the Fluence map optimization
section. The leaf sequencing problem is simple compared to MLCs at conventional

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Linacs. In this section, we therefore focus on VMAT, which poses new challenges for
treatment planning. For further details on Tomotherapy, we refer the interested reader
to the review by Mackie (25) and references therein. A more extended review of
treatment plan optimization approaches to VMAT is provided by Unkelbach (26). For
further information on the clinical implementation of VMAT, we suggest the review by
Yu (27).

The VMAT Treatment Planning Problem


VMAT can be thought of as a dynamic MLC technique to deliver IMRT, with the
modification that the gantry does not stand still at discrete angles but continuously
rotates while radiation is delivered. The dose distribution delivered by a VMAT plan is
determined through three types of variables:
1. The MLC leaf trajectories, that is, the positions of the left leaves Ln and the right
leaves Rn as a function of time;
2. The gantry angle φ(t) as a function of time;
3. The dose rate δ(t) as a function of time.
In principle, the jaws, collimator and treatment couch also could move. However,
here we assume that the collimator and couch are at fixed angles, and that the jaws can
be positioned in a post-processing step with minor impact on the treatment plan. For
dose calculation, a VMAT arc is discretized into small arc sectors. For example, a 360-
degree arc is divided into 180 arc sectors of 2-degree length. For treatment planning, a
dose-deposition matrix can be calculated at the center of each arc sector.

FIGURE 9.18 Relation between leaf trajectories and effective fluence in VMAT delivery. The red area
corresponds to the exposure time of the beamlet in arc sector φ and is proportional to the beamlet’s effective
fluence.

Given the trajectories for leaves, gantry, and dose rate, a VMAT plan delivers an
effective fluence at any gantry angle φ. The relation between effective fluence and
leaf trajectories is illustrated in Figure 9.18 for a single leaf pair n. Let us for simplicity
assume that the dose rate is constant over the arc sector φ. Then the effective fluence
is determined by the time that beamlet j is exposed by the MLC leaves. In Figure 9.18,
the red-colored area enclosed by the leaf trajectories and the beamlet boundaries

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corresponds to the effective exposure time. This method to relate leaf positions to
fluence involves the common approximation made in Figure 9.17: If at time t, a beamlet
is partially exposed by the MLC leaves, the time point’s contribution to the beamlet’s
effective fluence is proportional to the exposed fraction of the beamlet. The dose
distribution is obtained by multiplying the effective fluence with the dose-deposition
matrix at each arc sector.
VMAT planning aims at determining short trajectories that lead to high plan quality,
that is, VMAT plans that only take a short amount of time to deliver. Thereby, the
trajectories have to satisfy a number of machine constraints. In particular, the MLC
leaves have to satisfy the maximum leaf speed constraint. In addition, the gantry speed
is limited to one full rotation per minute. Limitations on the dose rate are highly
machine dependent. Some Linacs allow for continuously varying dose rates while others
allow for discrete values only. All machines have a maximum dose rate.

DICOM Specification of a VMAT Plan


VMAT planning approaches differ in the way that the leaf trajectories are
parameterized. The most common representation is driven by the DICOM specification
of a treatment plan, which is used to communicate the plan between the TPS and the
treatment machine control system. Using DICOM standard, the treatment plan is
defined via a sequence of control points. Each control point is defined through a set of
leaf positions, a gantry angle, and the total number of MU that is delivered up to that
control point. Thereby, the DICOM specification gives rise to formulating VMAT
planning as a DAO problem. For example, a prostate patient may be treated with a
single 360-degree arc, which is divided into 90 arc sectors of 4-degree length. For VMAT
planning, one control point (i.e., one aperture) is assigned to the center of each arc
sector. Subsequently, the DAO methods discussed in the Direct aperture optimization
section can be applied for plan optimization.
The DAO algorithm will return the aperture shapes and aperture intensities for each
control point along the arc. It is apparent that a given aperture intensity yφ, which
corresponds to the number of MU delivered over the arc sector, depends on the gantry
speed sφ, the dose rate δφ, and the length of the arc sector Δφ and is given by

Large aperture intensities can be realized by a large dose rate or a slow gantry speed.
Since the motivation for VMAT treatments is in part the reduction in treatment time, the
machine controller should select the largest possible gantry speed.
In principle, a DAO algorithm applied to VMAT planning yields a deliverable plan if
the gantry speed can vary between the maximum and very small values. However,
without modifications, the resulting treatment plan may be inefficient regarding
delivery time. As an example, we assume that we want to deliver a 360-degree arc in 90
seconds at constant gantry speed. Then, the gantry sweeps over each 4-degree arc sector
in 1 second. If the maximum leaf speed of the MLC is 3 cm/s, the MLC leaves can only
move by 3 cm between two neighboring control points. Otherwise, the gantry speed has
to be reduced, leading to longer delivery times. Hence, VMAT planning typically aims at
limiting the leaf travel between adjacent control points—in the interest of treatment
time and also dose calculation accuracy. For gradient-based leaf position optimization
methods, constraints on leaf travel correspond to linear constraints on the leaf

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positions.

Illustration of a VMAT Plan


Figure 9.19 illustrates a VMAT plan for a prostate cancer patient treated with a single
360-degree arc, delivered by moving the gantry counter-clockwise from 180 to –180
degrees. The arc is evenly divided into 90 arc sectors that are assigned one aperture
each. The circle around the patient indicates the coplanar incident beam directions. The
yellow bars depict the number of MU that is delivered over each arc sector. In the
foreground, one of the apertures along the arc is shown.

FIGURE 9.19 Illustration of a VMAT plan for a prostate cancer patient generated in RayStation 4.0. The
treatment plan consists of a single 360-degree arc divided into 90 sectors. The dose distribution is shown on a
coronal slice of the patient’s CT.

Approaches to VMAT Plan Optimization


The VMAT implementations in commercial systems heavily build on the concepts that
were previously developed for IMRT planning. Bzdusek et al. (28) suggest a three-step
approach to VMAT, using all three concepts of IMRT planning.
1. In the first step, FMO is performed at discrete, equi-spaced beam angles. In practice,
15 to 20 beam angles are used.
2. In the second step, the resulting fluence maps are converted into apertures that are
distributed over the corresponding arc sector. Assuming 15 beam angles are
considered in the FMO step, leading to 24-degree arc sectors, each fluence map can
be segmented into six apertures, which results in one control point every 4 degrees.
In this arc sequencing step, it is desired that neighboring apertures are similar. For
that reason, most arc sequencing methods use a sliding window type decomposition,
which leads to a natural ordering of the apertures.
3. In the third step, DAO methods are applied to refine the leaf positions and aperture
intensities. Assuming that the first two steps yield a good starting point, local
gradient-based DAO methods can be used in the third step.
Such a three-step approach is implemented in several commercial systems including
the SmartArc module in Pinnacle (Philips Medical Systems), the RayArc module in
RayStation (Raysearch Laboratories), and in Monaco (Elekta). Planning systems differ in
the exact implementation of each step and not all details are disclosed.

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The work by Otto (29) is the basis for the RapidArc module in the Eclipse planning
system (Varian). This approach primarily depends on DAO using simulated annealing as
described by Shepard et al. (15), and uses a geometry-based initialization of aperture
shapes. Other VMAT optimization approaches proposed in the literature are based on
sliding window delivery of a fluence map over an arc sector (30–32). An overview of
VMAT planning approaches can be found in the review by Unkelbach et al. (26).

SPECIALIZED TOPICS IN IMRT PLANNING


Multi-Criteria Planning Methods
IMRT treatment planning has to find a tradeoff between inherently conflicting clinical
goals. The traditional approach to explore these tradeoffs consists in manually choosing
relative weights for different objectives. This can lead to a time-consuming trial-and-
error process. Several methods have been proposed to improve the planning process in
that regard.

Prioritized Optimization
One approach is referred to as prioritized optimization (33) or lexicographic ordering
(34). It is motivated by the assumption that the clinical objectives can be ranked
according to their priority. For example, in the prostate cancer example shown in Figure
9.2, the main planning goal may be to deliver the prescribed dose to the target volume.
The second planning goal is the sparing of the anterior rectal wall. Additional objectives
are related to bladder dose and conformity, but are considered of lower priority.
A prioritized optimization scheme performs a sequence of IMRT optimizations. In the
first step, we obtain the treatment plan that yields the best possible plan only
considering the highest ranked objective. In the prostate example, we may minimize a
quadratic objective function for the target volume:

where gs(d) ≤ cs represents the hard constraints on the dose distribution. This yields an
optimal value fT* for the quadratic objective function for the target volume. In the next
step, the target objective is turned into a constraint, while minimizing the objective with
the second highest priority, which could be the EUD in the rectal wall:

In this formulation, the EUD in the rectal wall is minimized, subject to the constraint

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that the target dose homogeneity deteriorates by at most ε compared to the optimally
achievable value fT*. Solving this optimization problem yields the optimal rectal wall
EUD fR* that is achievable under the given constraints. In the third step, the objective
function for dose conformity can be minimized as the only objective, subject to the
constraints that the target and rectum objectives only deteriorate by a small ε from their
optimal values fT* and fR*.

Pareto-Optimality
Prioritized optimization schemes rely on a ranking of the objectives, and make the
assumption that higher ranked objectives are not compromised to improve lower ranked
objectives. This is a potential drawback in situations where a large improvement in one
objective can be achieved by only a minor degradation of a higher ranked objective, or
if the ranking is unclear a priori.
For simplicity, we consider only two objectives below, for example, target dose
homogeneity and rectal wall EUD in a prostate case. By varying the tolerance level ε in
the prioritized optimization scheme, one can generate a sequence of treatment plans as
illustrated in Figure 9.20. The plans obtained in this manner define the set of Pareto-
optimal treatment plans that form the Pareto surface. A treatment plan is Pareto-optimal
if it is not possible to improve the plan in one objective without worsening at least one
other objective.

Interactive Pareto-Surface Navigation Methods


For radiotherapy planning, we are interested in choosing a treatment plan from the
Pareto surface. However, it may depend on the patient’s or physician’s preference which
treatment plan to pick. Especially for difficult cases such as the head-and-neck cancer
example in Figure 9.3, the physician or treatment planner may want to explore the
tradeoffs between different planning goals. Both tasks are straightforward in a two-
dimensional tradeoff as illustrated in Figure 9.20. In this case, the Pareto surface can be
approximated with a few treatment plans that are evenly spaced on the one-dimensional
Pareto surface in the clinically relevant range. The treatment planner can then choose
one of these pre-computed treatments plans. However, IMRT planning typically involves
tradeoffs between more than two objectives (say, 5 to 10). It is apparent that in higher
dimensions the approximation of the Pareto surface is more challenging due to the curse
of dimensionality. In addition, exploring the tradeoff space is nontrivial. The
development of a treatment planning framework has to address two problems:
1. Developing methods to efficiently represent the Pareto surface with a small number
of Pareto-optimal treatment plans, which are called database plans. One method to
achieve this is the so-called Sandwich method described by Craft et al. (35).
2. Providing a graphical user interface and the underlying mathematical methods that
allow the treatment planner to interactively explore and visualize the tradeoffs
between conflicting planning goals.

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FIGURE 9.20 Schematic illustration of the Pareto surface for the tradeoff between target dose homogeneity and
rectal wall EUD. All treatment plans below the Pareto surface are impossible to achieve; treatment plans above
the Pareto surface are undesirable because they can be improved in one objective without worsening the second
objective. Points on the Pareto surface can be generated using the constrained method, that is, by minimizing
the rectal wall EUD, subject to different target homogeneity constraints (with permission reproduced from (4)).

One goal of Pareto-surface navigation methods is to allow for a continuous


exploration of treatment plans. To that end, not only the discrete database plans are
considered but also linear combinations of plans. We assume that a treatment plan is
defined through the fluence map x. Given two treatment plans with fluence maps x1
and x2, we can form a convex combination of the two treatment plans by considering
the averaged fluence map

which is obtained by averaging the beamlet intensities beamlet-by-beamlet, using a


mixing parameter q ∊[0,1]. If x1 and x2 are Pareto-optimal treatment plans, the convex
combination of two plans is expected to be also a “good” treatment plan (although not
strictly Pareto-optimal).
In a TPS, the planner has to be provided with tools to navigate in the space of convex
combinations of database plans. In a practical scenario, the planner may have evaluated
a current treatment plan, and would like to improve the treatment plan regarding one
particular objective, say the rectum dose. The TPS has to provide a user interface to
express this request. Figure 9.21 shows the Pareto-surface navigation interface in the
RayStation TPS (version 4.0), distributed by RaySearch Laboratories. Each objective is
associated with a slider. By moving the slider, the user can request an improvement of
the treatment plan with respect to the chosen objective. In the background, the TPS
translates the slider movement into a new convex combination of database plans.

Beam Angle Optimization


IMRT planning primarily refers to determining the fluence maps of incident beam
directions and their delivery with MLCs. In this context it is assumed that the incident
beam directions are given. In practice, treatment planners often use a template of
standardized beam directions for a given treatment site. For example, for prostate
treatments a set of 7 evenly spaced coplanar beam directions is used. For treatment sites
that exhibit relatively little geometric variation across patients, such templates often

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provide satisfying plan quality. However, treatment planning studies suggest that some
treatment sites, for example intracranial lesions may benefit from individualized
noncoplanar beam directions. Despite this benefit, current TPS have very limited
support for automated selection of optimized beam directions. Typically, the treatment
planner selects beam angles manually based on experience and the patient’s geometry.
Approaches to automated beam angle optimization (BAO) in the literature can broadly
be categorized in two types:

• Beam angle selection and FMO are considered jointly. That means, the quality of a
treatment plan is judged by an objective function f (d) as used for FMO. The goal of
BAO is then to simultaneously select a set of beam angles and their associated fluence
maps such that the objective function f is minimized.
• Beam angle selection is separated from the FMO problem. In the first step, beam angles
are selected based on simplified measures to score the quality of a beam direction. This
is done mostly based on geometric features. In the second step, FMO is performed for
the fixed set of beam angles.

Approaches in the first category are typically formulated as a combinatorial


optimization problem. In that setting, BAO aims to select a small subset of n beams from
a larger pool of N candidate beam directions. This yields a very large number of possible
beam ensembles given by the binomial coefficient. No computationally efficient
algorithms exist to determine the optimal beam ensemble, and it is in part this
combinatorial nature of BAO that has prevented a practical implementation in
commercial TPS. Most approaches to combined FMO and beam angle selection amount
to solving a large number of FMO problems for different beam ensembles. This includes
stochastic search methods like simulated annealing (36) as well as integer programming
methods (37). For a review of BAO from a methodology perspective we suggest the
paper by Ehrgott et al. (8). BAO research suffers from the lack of shared patient data
sets. Works that compare different BAO algorithms on a common patient data set using
the same objective functions are scarce. The work by Bangert et al. (38) is an exception
and compares three stochastic search methods and an iterative beam selection heuristic,
observing similar performance of the investigated methods.

FIGURE 9.21 Graphical user interface for multi-criteria IMRT planning in the RayStation treatment planning
system (version 4.0). Each objective is associated with a slider. The user can drag sliders to improve the treatment
plan regarding the corresponding objective. The user request is translated into a new convex combination of
database plans and the corresponding DVH and the dose distribution are displayed. By locking sliders (visible as
the check boxes to the left of each slider) the user has additional control over the navigation process. For
example, by locking the slider for target dose homogeneity, the user can request that the navigation is restricted
to treatment plans for which the target homogeneity is no worse than indicated by the current slider position.

Integrating Uncertainty and Organ Motion in IMRT Planning


Setup uncertainties and organ motion in radiotherapy is traditionally handled via a
safety margin approach. The clinical target volume (CTV) is expanded by a margin to

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form the planning target volume (PTV). Radiotherapy planning aims at delivering the
prescribed dose to the PTV. As long as the CTV stays within the PTV, it can be assumed
that the CTV receives the prescribed dose despite variations of the CTV location. IMRT
planning is formulated as a mathematical optimization problem, which provides the
possibility of incorporating a model of patient motion directly into the IMRT treatment
planning problem. In this case, the manual definition of the PTV becomes obsolete and,
in some cases, better sparing of normal tissues can be achieved.

Accounting for Respiratory Motion


As an example, we consider the handling of respiratory motion in the lung. Tumors
located close to the diaphragm that are not attached to the chest wall may move
approximately 2 cm in superior–inferior direction between exhale and inhale.
Nowadays, the magnitude of motion can be assessed using 4D CT, which provides
snapshots of the patient geometry at 10 phases during the respiratory cycle.
Traditionally, motion is accounted for using the internal target volume (ITV) concept.
The ITV represents the union of the target volume defined on each individual phase.
Treatment planning aims at delivering the prescribed dose to the entire ITV to ensure
that the target volume receives the prescribed dose in any phase of the breathing cycle.
The dose delivered to the surrounding lung tissue can be reduced via a nonuniform
dose distribution within the ITV. Rather than irradiating the ITV homogeneously with
the prescription dose, the dose can be higher in regions that are covered by the tumor
most of the time. Thereby, the dose can be reduced in regions that are occupied by lung
tissue most of the time, and only rarely by the tumor. The dose inhomogeneities are to
be designed such that the tumor eventually receives the prescribed dose while
accumulating dose contributions from different phases in the respiratory cycle. IMRT
optimization provides the means to formalize this idea.
We assume that a 4D CT provides a CT image for each respiratory phase s. Typically,
the exhale phase is used as a reference phase, which is used to define OAR voxels and
tumor voxels. IMRT planning can be based on the cumulative dose that a voxel
accumulates over the breathing cycle, which can be approximated as

Here, dis is the dose received by voxel i in phase s, Dsij is the dose-deposition matrix in
phase s, and ps is the relative amount of time that the patient spends in phase s. The
calculation of the dose-deposition matrices in phase s represents a substantial practical
difficulty. Dsij represents the dose that the anatomical voxel i defined on the reference
phase receives from beamlet j in another phase s. Its calculation requires a dose
calculation on phase s, but also a deformable registration of the dose distribution to the
reference phase.
In the respiratory motion case as described so far, the motion is assumed to be
predictable in the sense that the cumulative dose distribution can be calculated.
Although this involves practical challenges, it does not require conceptual changes in
terms of the optimization method used. IMRT planning can be performed by minimizing
the objective function f that is evaluated for the cumulative dose.

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Handling Uncertainties
The presence of uncertainty is different from the case of predictable motion. For
example, a systematic setup error implies that the dose distribution delivered to the
patient is not predictable and is inherently uncertain. This requires conceptual changes
regarding the formulation of the treatment planning problem.
To illustrate the handling of uncertainty, we consider systematic setup errors. For
example we can consider six patient shifts of ±5 mm in anterior–posterior, superior–
inferior, and left–right direction. For each patient shift a separate dose-deposition
matrix Dsij can be calculated, leading to different dose distributions d s (where s is now
an index for the error scenario). Since we consider a systematic error, only one of the
dose distributions dis can be realized, not an average. Generally, the goal is to obtain a
treatment plan that is good or acceptable for any error scenario that is accounted for.
There are mainly two approaches to translate this notion into mathematical terms for
IMRT planning: the probabilistic approach and the worst-case approach.
In the probabilistic approach, a probability ps is assigned to each scenario s. For
example, a higher probability can be given to the nominal scenario (i.e., no setup error
occurs), and a lower probability is assigned to setup error scenarios. IMRT treatment
plan optimization is performed by minimizing the expected value of the objective
function f:

In words, the composite objective function is a weighted sum of objectives evaluated


for each error scenarios, where a higher weight may be given to likely scenarios, and a
lower weight to less likely scenarios. While the probabilistic approach can be seen as
optimizing the average plan quality, the worst-case approach aims at finding the
treatment plan that is as good as possible for the worst error scenario that is accounted
for. Formally, this can be formulated as

Methods to incorporate motion and uncertainty in IMRT planning have been


investigated in the literature. For example, Trofimov et al. (39) consider respiratory
motion for lung tumors, and Heath et al. (40) extend this work to include uncertainties
in the breathing trajectory. Bohoslavsky et al. (41) consider random and systematic
setup errors for prostate treatments. In recent years, these methods have been applied
to intensity-modulated proton therapy (IMPT) to handle range uncertainties. In IMPT,
the PTV concept is fundamentally limited (42) and cannot generally ensure robust
treatment plans. The need for methods to incorporate uncertainty directly into IMPT
planning has led to the first commercial implementations. The RayStation planning
system (version 4.5) implements a worst-case approach for handling systematic setup
errors (and range errors when applied to IMPT).

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KEY POINTS
• Illustrate the need for intensity-modulation when treating concave target volumes such as
head-and-neck tumors, prostate cancer, or spinal metastasis.

• Discuss fluence map optimization (FMO) and the formulation of IMRT planning as a
mathematical optimization problem.

• Review the traditional two-step approach of IMRT planning, that is, FMO plus leaf
sequencing.

• Understand gradient-based methods for direct aperture optimization (DAO) to optimize


MLC leaf positions.

• Provide an overview of treatment plan optimization approaches for volumetric-modulated arc


therapy (VMAT).

• Provide an introduction to advanced topics in IMRT planning including multi-criteria


optimization (MCO) and the incorporation of uncertainty and organ motion.

QUESTIONS
1. How is a VMAT plan communicated between the treatment planning system
(TPS) and the Linac?
A. The TPS determines the optimal MLC leaf positions as a function of time as
well as the gantry speed and dose rate.
B. The TPS generates a sequence of control points defined through leaf positions,
gantry angle, and cumulative monitor units.
C. The TPS optimizes incident fluence maps and the Linac control system
converts these into MLC apertures.
2. What are advantages of the sliding window leaf sequencing method?
A. The conversion of a fluence map into a sliding window leaf trajectory can be
performed analytically without the need for time-consuming optimization.
B. Sliding window sequencing yields the smallest number of apertures.
C. Sliding window sequencing yields the smallest total number of monitor units.
3. Which statement about direct aperture optimization (DAO) is appropriate?
A. DAO is an important component of many VMAT planning algorithms.
B. DAO has been developed for step-and-shoot IMRT and is therefore not
applicable to dynamic delivery techniques such as VMAT.
C. DAO eliminates the need for mathematical optimization methods in IMRT
planning and hence makes IMRT planning faster and better.
D. DAO can in part overcome the problem of dose degradation that may occur in

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the leaf sequencing step following fluence map optimization.
E. The DAO problem can be solved much more reliably compared to the
traditional fluence map optimization approach and therefore leads to better
treatment plans.
4. What is the motivation for multi-criteria optimization (MCO)?
A. MCO potentially provides better treatment plans because the traditional
planning approach does not yield Pareto-optimal plans.
B. Allowing the treatment planner to assess tradeoffs is one of the main
motivations for MCO.
C. In MCO, direct aperture optimization or VMAT planning can more easily be
integrated compared to the traditional planning approach.
D. MCO is a way to overcome the cumbersome tweaking of objective weights,
which can be time-consuming in traditional planning.

ANSWERS
1. B VMAT plans are communicated via DICOM standard, that is, via a sequence of
control points. Gantry speed, dose rate, and MLC leaf trajectories are
determined by the machine controller based on the sequence of apertures
generated by the TPS.
2. A and C It is the main disadvantage of sliding window sequencing that it may
generate a large number of small apertures.
3. A and D DAO addresses the shortcomings of the traditional fluence map plus
sequencing IMRT planning approach. Although DAO was originally developed
for step-and-shoot IMRT, it is widely used in VMAT algorithms, in parts due to
the DICOM specification of a VMAT plan as a sequence of apertures.
4. B and D The main motivation for MCO is to provide methods for an efficient
and interactive exploration of tradeoffs between planning goals. This may in
turn translate into improved treatment plans. It is a common misconception
that the traditional planning method of assigning importance weights does not
yield Pareto-optimal plans. In fact, the same optimization methods are used in
MCO, except that importance weights are determined by an algorithm rather
than manually. Incorporating DAO or VMAT into an MCO framework is
difficult and subject to ongoing research.

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*This section was in parts adapted from the book chapter Boyer A, Unkelbach J. Intensity-
modulated radiation therapy planning. In: Brahme A, ed. Comprehensive Biomedical Physics,
Vol 9, Chapter 17, Elsevier; 2014.
*This section was in parts adapted from the book chapter Boyer A, Unkelbach J. Intensity-
modulated radiation therapy planning. In: Brahme A, ed. Comprehensive Biomedical Physics,
Vol 9, Chapter 17, Elsevier; 2014.

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10 Intensity-Modulated Proton Therapy

Tony Lomax

INTRODUCTION
Proton therapy is becoming an increasingly relevant modality in radiation therapy. In a
recent review of proton therapy facilities worldwide, it was reported that there are more
than 50 particle therapy facilities now in operation, with at least another 50 being built
or in an advanced stage of planning. Consequently, by the end of 2018, the number of
particle therapy facilities will be quickly approaching 100 or more, with this trend
being very likely to continue. In addition, by the end of 2015, it is also predicted that,
for the first time, the number of treatment rooms having the capability of delivering
pencil-beam scanning (PBS) will overtake those delivering passive scattering (PS) (1,2),
with the number of PBS rooms being predicted to expand exponentially in the next
years. Thus, it is becoming increasingly clear that not only will proton therapy become a
mainstream cancer treatment, but that PBS will be the particle therapy modality of
choice in the future.
There are two main reasons for this paradigm change in proton therapy. First is the
inherent automation of the PBS approach in comparison to PS, and second is the ability
of PBS to deliver the so-called intensity-modulated proton therapy (IMPT). The
treatment planning aspects of PBS and IMPT will be the focus of this chapter.

BASIC PHYSICS OF PROTON INTERACTIONS


Before looking at the treatment planning process for PBS, it is first necessary to briefly
review the physics of proton interactions with matter and the basic characteristics of
the PBS approach.

Energy Loss and Scattering


Typical depth dose curves for quasi monoenergetic proton beams are shown as red
curves in Figure 10.1. As can be seen, in contrast to the depth–dose curve for photons,
this is characterized by a relatively low entrance dose, which gradually increases with
penetration and culminates in the well-known Bragg peak. At the distal (far) end of this
peak, the dose drops off very quickly. This characteristic is determined by the inverse
square relationship of dose deposition as a function of particle velocity, which can be
analytically described by the Bethe–Bloch equation

where dE/dz is the rate of change of energy of the proton (equivalent to the deposited
energy to tissue) and β is the velocity of the particle represented as the fraction of the
speed of light (3). As such, in comparison to photon beams, where the depth dose
characteristics are predominantly determined by photon absorption, the proton curve is

270
characterized by energy loss of the protons, which leads to the well-defined range and
shape of the Bragg peak in tissue. Thus, the higher the initial energy, the deeper the
Bragg peak, while the lower the energy, the shallower its range, at least if both are
applied to the same medium. However, the absolute range of the Bragg peak is also
dependent on the physical characteristics of the medium, and is determined by the
medium’s stopping power to protons. Typically, this is defined relative to water (when it
is then referred to as the relative proton stopping power). Indeed, to a good
approximation, this is a linear relationship, with the geometric range in a medium with
a relative stopping power of two being half that of the range in water.
In reality of course, it is impossible to deliver perfectly monoenergetic proton beams,
with most clinical beams having an energy spectrum (usually referred to as the
momentum band) of about +/–1%. This will tend to broaden the Bragg peak above that
of the pure energy loss curve given by the Bethe–Bloch equation. In addition, as energy
loss is a statistical process, there is an additional broadening of the Bragg peak due to
statistical smearing, an effect referred to as range straggling. Although a complex process,
the amount of range straggling is dependent on the range of the proton beam (and
therefore the energy) and can be approximated as broadening the width of the Bragg
peak by about 1% of its range (4).
In addition to energy loss, protons also undergo scattering processes, mainly due to
multiple Coulomb scattering (MCS) events (electrostatic deflection of the protons as they
pass close to the positively charged nuclei of atoms). For instance, the additional
broadening of a proton pencil beam with an initial energy of 177 MeV (range in water
∼21 cm) due to MCS will be about 4 mm (σ) at the BP. However, due to the resulting
divergence of the beam after such scattering, this broadening can be much larger if the
beam subsequently passes across air gaps (5) or through regions of low density in the
patient (6). This is an important characteristic that needs to be taken into account
during the treatment planning process.

FIGURE 10.1 The concept of the “Spread-Out-Bragg-Peak,” showing how range (energy) shifted Bragg peaks
can be modulated in order to deliver a homogeneous depth–dose profile.

This angular-spatial divergence of a proton beam is generally represented using


Fermi–Eyges transport theory. Although quite involved mathematically, in its simplest
form, the doubled spatial variance of a narrow proton beam can be represented in the
form (5):

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where A′2,x describes the doubled spatial variance of the beam width in the lateral x
direction at position z (beam width in air plus MCS scattering in the medium) and A0,
A1, A2 are the moments of the angular-spatial distribution of the beam in air. The term
in brackets and the integral represent the additional scattering due to MCS in the
medium. From these, the width (σ) of the beam in the medium, at distance z, is then
given by:

A similar equation is used for the y direction. For a detailed description of scattering
theory of protons, the reader is referred to Gottschalk et al. (7) and Safai et al. (5).

NUCLEAR INTERACTIONS
Whereas energy loss and scattering are the primary interactions of protons with matter,
there are also secondary processes that can have a significant effect on calculated and
delivered PBS fields. As protons penetrate tissue, there is a small, but finite probability
that they will interact directly with an atomic nucleus, either in an elastic or inelastic
way. In the first, this will lead to a potentially wider deflection of the proton, whereas
in the second process, the proton will be absorbed from the beam and secondary
particles produced. This loss of proton fluence as a function of depth is small (about 1%
per centimeter of penetration in water (4)), but nevertheless leads to a 20% loss of
proton fluence at the Bragg peak for an initial energy of 177 MeV. In addition, the
secondary particles and their trajectories can lead to an “extension” of the lateral, low-
dose tail of the beams profile, together with a generally forward projected background
of secondary neutrons. For a more detailed description of proton interactions with
matter, the reader is referred to the publications of Gottschalk (3) or Lomax (8).

LET and RBE


Before moving on to the technicalities of PBS, two more, somewhat related properties of
proton beams should be mentioned, namely linear energy transfer (LET) and relative
biological effectiveness (RBE). Let’s first look at RBE.
There is plenty of evidence from in vitro cell experiments, that the biological
effectiveness of protons for the same applied physical dose is somewhat higher than for
photons. The reader is referred to the papers by Paganetti et al. (9,10) for an excellent
review of this. This enhanced biological effect is defined as the RBE, and depending on
the cell line and end point can vary from 0.9 to 1.8 or even higher. It has also been
demonstrated that RBE tends to be highest for the lowest energies (i.e., in the Bragg
peak) and also increases as dose reduces. Despite this, most proton centers still assume
a global RBE of 1.1 to biologically “scale” proton doses to allow for an average RBE
effect.
In contrast to RBE, LET is a physical quantity that is, in principle directly

272
measureable. As such it can be more precisely defined and related back to the
underlying physics. In short, LET is a measure of the local linear energy deposited to
tissue and has the units of keV/μm. In regions where protons are losing (depositing)
energy rapidly, the LET will be higher than where energy deposition is less intense.
Thus, LET is higher in the Bragg peak and distal fall-off region than in the plateau,
mainly due to the inverse relationship of energy deposition with particle energy. In
addition, although the relationship between LET and RBE is complex, there is a clear
correlation between higher LET and increased RBE, and thus LET can be considered a
good surrogate (but not a direct predictor) for RBE.

PENCIL BEAM SCANNING


Pencil-beam scanned (PBS) proton therapy is a conceptually simple technique (11,12),
and is shown schematically in Figure 10.2. As protons (and other particles used for
therapy such as carbon and helium ions) have a charge, they can be easily deflected by
magnetic fields. Thus, if a narrow beam of particles can be produced (a pencil beam),
this can be scanned laterally to the incident field direction such as to paint dose over the
target volume. If this is performed using a near monoenergetic beam, this will deliver
what is called a single energy layer, or a surface of Bragg peaks, all with the same range
in a uniform medium such as water. However, as should be clear from Figure 10.1, the
delivery of a single monoenergetic layer will not necessarily ensure the delivery of a
homogeneous dose throughout the whole tumor. Thus, a full PBS field will typically
consist of a number of such layers, each modulated in energy in order to “fill-in” the
missing dose along the field direction.

FIGURE 10.2 Schematic representation of the pencil-beam scanning approach. Energy modulated Bragg peaks
are scanned across the tumor volume, with the delivered fluence at each BP also being modulated.

In a one-dimensional sense, such a combination of individual, energy-modulated


Bragg peaks, combined in such a way as to deliver a homogeneous dose in depth across
the tumor volume, is called a “Spread-Out-Bragg-Peak” (SOBP) (1), an example of which
is shown as the blue curve in Figure 10.1. Although a key aspect of passive scattered
proton therapy, the SOBP concept actually has little meaning in PBS other than to
indicate that, typically, the Bragg peak weights (fluences) at the distal end of the field
will tend to be higher than those at the proximal end. Instead, it is much more
meaningful to think of a PBS field as a set of three-dimensionally distributed,
individually weighted Bragg peaks, the position and calculation of which are free
variables which can all be manipulated to define PBS treatment fields and plans.
In the rest of this chapter we will use both pencil beam and Bragg peak to describe the
individual elements delivered as part of a PBS proton field. However, Bragg peak (BP)
will be used to specifically refer to the “spot of high dose” in and around the Bragg

273
peak, whereas pencil beam will refer to the whole pencil beam, from the exit of the
nozzle to the Bragg peak.

THE TREATMENT PLANNING PROCESS


In common with other forms of radiotherapy, the goal of the treatment planning process
is to design clinically acceptable treatments by predicting a three-dimensional
distribution of the delivered dose in relation to patient anatomy. As such, the overall
planning process for PBS and IMPT is identical to that of conventional therapy, and will
be briefly outlined here, if only to define the subsequent structure of this chapter.
From the physics point of view, a fundamental basis for any treatment planning
system is a succinct and accurate description of the characteristics of the treatment
system to be modeled (beam model). This will be used as input into a dose calculation
engine, which can then calculate a three-dimensional prediction of the delivered dose to
the patient. In addition, modern treatment planning is unimaginable without a physical
model of the patient in the form of volumetric x-ray CT data. For reasons discussed
below, this is even more important for proton therapy. However, as with conventional
treatments, it is more or less standard of care in proton therapy to also use MRI and, if
available, PET to help with the delineation of the tumor and organs at risk (OAR). As
such, once all relevant imaging data has been imported into the planning system, the
task of target/organ delineation is essentially the same as for conventional approaches,
even if there may be some differences in the definition of the PTV or ITV, as discussed in
more detail below.
Once all structures have been defined, the next task is to define one or (more usually)
multiple fields such as to best “focus” the high-dose volume on the target, while
ensuring that dose constraints to critical organs are likely to be met and that any
physical limitations on field directions are, where possible, observed. Once the fields
have been defined, then each field needs to be shaped and optimized. Finally, when a full
plan has been calculated, the quality of the plan needs to be evaluated, both clinically
and also from the point of view of its robustness to potential delivery uncertainties.
Each of these steps will be discussed in more detail in the following sections.

Beam Modeling
Before any form of predicted dose in a phantom or patient can be calculated, a
parameterization of the characteristics of the delivery machine and radiation modality
must be performed. Typically, this is called beam modeling and can be broken down into
two main components; the definition of a set of energy-dependent depth dose curves
and a corresponding representation of the angular-spatial distribution of the beam for
each energy (see Equation 10.2).
For the dose calculation, the energy-dependent depth dose curves are usually
represented as integral depth dose curves. That is, the dose at any depth is the integral
dose deposited at that depth in an infinite plane perpendicular to the incident direction
of the beam. Although based on measured data, such depth dose curves are generally
converted into a numeric representation (such as a depth-dependent look-up table)
using analytical or empirical fitting algorithms (13,14). In contrast, the beam width is
dependent on two components—a model for MCS in the medium (represented by the
integral part of Equation 10.2) and an analytical representation of the beam width in
air (the A0, A1, A2 parameters in Equation 10.2). Although beam broadening due to
MCS is determined solely by physics considerations, the beam width in air will need to

274
be measured and the A parameters then derived from these measurements using data
fitting techniques. However, in addition to being dependent on energy, for scanning
gantries, beam width in air could well be also dependent on both the beam deflection
and gantry angle.

Dose Calculations

Analytical Calculations—Primary Dose


Although it is likely that Monte Carlo (MC)–based dose calculations will become more
prevalent in the future, most dose calculations for treatment planning of PBS proton
therapy are analytically based. Although such approaches are inherently limited in their
accuracy, they are also inherently fast. Even with today’s computer power, this is still a
big advantage over MC techniques, especially when being used for optimization (see
below).
All analytical dose calculations for the primary dose for PBS proton therapy (we will
return to approaches for incorporating the distribution of secondary particles resulting
from nuclear interactions later) are based on a parameterization of a physical, or
calculational, pencil beam in the following form:

where d(x, y, z) is the dose at calculation point x, y, z, with x and y being the distances
of the dose calculation point away from the central axis of the pencil beam, z is the
coordinate of the dose calculation point along the beam direction, D(WER(0,0,z)) the
integral dose deposited at depth WER(0,0,z), 0, 0, z is the WER at distance z along the
central axis of the pencil beam and σx(z) and σy(z) are the beam widths in the two
directions orthogonal to the beam direction at distance z along the beam direction. σx(z)
and σy(z) can be derived from Equations 10.2 and 10.3. In essence, the first quotient
gives the central axis dose at position z, whereas the two exponents correct for the off-
axis position of the point away from the central axis (x and y), and can therefore be
considered as providing the off-axis ratios for the pencil-beam dose.
Equation 10.4 is all that is really needed for calculating primary dose in water and is
remarkably accurate, as long as the beam model parameters (depth dose curves, in-
phantom MCS and phase space) are correctly parameterized. However, when
calculating in patient geometries, methods of dealing with density heterogeneities also
have to be included.
Perhaps the simplest method of dealing with density heterogeneities is the ray casting
approach described in the paper by Schaffner et al. (15). In this, Equation 10.4 is
slightly modified such that D(WER(0,0,z)) becomes D(WER(x,y,z)), indicating that the
WER of the dose calculation point itself determines the depth at which the integral dose
is extracted from the depth dose curve, rather than that of the central axis of the pencil
beam. Thus, off-central-axis density heterogeneities can be incorporated into the
calculations, allowing for estimations of the distorting effects of density heterogeneities
on the pencil beam. In fact, as this approach neglects the effects of proton scattering
after the density heterogeneities, it actually overestimates the effects of these.
Nevertheless, this algorithm is still the one used clinically at PSI, and all dose
distributions in this chapter (Fig. 10.3) have been calculated using this approach.
A more sophisticated approach (but not necessarily more accurate in all

275
circumstances) is to decompose the physical pencil beam into a set of smaller,
calculational pencil beams and then apply Equation 10.4 to each individual
calculational beam. This approach has been proposed by both Schaffner et al. (15) and
Soukup et al. (16). In the Schaffner approach, the total fluence contribution from the
sum of all pencil beams for a given energy layer is first calculated, with this fluence
envelope then being decomposed into a set of narrow, calculational beams for the
calculation. This approach has the advantage of efficiency, but is not convenient for the
optimization, as the correlation between calculational and physical pencil beams is lost.
Soukup’s approach then, although less efficient, is more appropriate for the
optimization step. In addition, Soukup et al. also proposed the calculation of the
multiple scattering angle on a voxel by voxel basis along the beam direction, rather than
using a precalculated look-up table of beam broadening in water, in order to better
model the effect of the position of density heterogeneities along the beam direction.
Similarly, Szymanowski and Oelfke (17) have proposed to mitigate this problem using a
material-specific lateral scaling factor.

Analytical Calculations—Secondary Dose


As discussed above, a small but clinically relevant component of a proton dose
distribution is due to secondary particles resulting from interactions of the primary
protons with atomic nuclei. As such, a number of corrections to the basic primary dose
algorithms described above have been proposed.

276
FIGURE 10.3 Example cases treated with PBS at PSI. (A) Skull base chordoma. (B) Ependymoma. (C)
Meningioma. (D) Sacral chordoma. Arrows indicate the field directions. Green are coplanar, yellow noncoplanar.

The earliest of these is that of Pedroni et al. (13), who attempted to represent this
secondary component using a two Gaussian model of the following form:

where d(x,y,w) is the dose at point x, y with depth w, D(w) is the integral dose at depth
w, fNI is the fraction of the total integral dose at depth w resulting from secondary
particles, Gp is the Gaussian distribution of the primary beam, σp is the beam width of
the primary beam, GNI is the Gaussian distribution of the secondary particle distribution
and σNI is the width of the secondary distribution. In this work, values for fNI and σNI
were determined experimentally using a series of “frame” fields of different sizes with a
thimble detector in the middle of each frame to measure the resulting peripheral dose.
From these, values for fNI and σNI could be deduced. Soukup et al. (16) proposed a
similar approach, but based on MC simulations of the secondary dose in water, from
which they could then deduce an analytical model of this distribution.
Although the fraction of dose delivered by secondary particles is small, their

277
contribution is nevertheless important for correctly predicting absolute dose (as
reported in the paper by Pedroni et al.), and if neglected, can lead to an overestimation
of the dose at the edge of a homogeneous field or an underestimation of the dose in
“dose-valleys” in highly modulated IMPT fields, as shown in Figure 10.4.

Monte Carlo Dose Calculations


It is undisputed that the most accurate dose calculations available are MC methods. In
short, these model the transport and interactions of individual protons, that are tracked
through the patient geometry (and sometimes the whole-beam line and gantry), using
knowledge about the underlying physics, together with probabilities of the various
interactions that protons can undergo. As they track individual, simulated protons, MC
calculations do not have many of the limitations of analytical calculations, and as such
can be considered to be the gold standard for the calculation of dose for PBS proton
therapy.

FIGURE 10.4 The effects of secondary particles. Primary dose calculation (solid line) and the corrected dose
taking into account secondary particle distributions. Note the reduced dose at the field edges (left) and increased
doses in dose “holes” (right).

There are currently a number of different MC codes available that have been used for
proton therapy calculations, the main ones of which are FLUKA (18), GEANT4 (20),
MCNPX (21), VMCPro (22), and Shield-HIT (23). All have their advantages and
disadvantages, with some having more accurate modeling of various interactions than
others. Nevertheless, none of these codes are necessarily easy to use without
considerable knowledge of the code and underlying physics, and as such, MC
calculations have been slow to get into clinical use, except in departments with

278
specialized staff. This is changing somewhat now with the development of MC tool kits
specifically designed for RT applications and with simplified interfaces for ease of
programing and specification. Perhaps the most widespread of these at the time of
writing is the TOPAS system (24), which is based on GEANT4 and has been widely
validated for proton therapy applications by the group at Massachusetts General
Hospital and elsewhere (25).
The drawback of MC calculations is still the time required for accurate calculations,
with MC calculations typically taking many hours to run. However, methods are being
developed to improve efficiency through the use of, for example, track repeating
algorithms (26) or implementation on graphical processing unit (GPU) hardware. With
such measures, full MC calculations are now being performed in a few seconds with
clinically acceptable statistics (18,27).

Imaging for Treatment Planning


Although MRI, PET, and other imaging modalities can all be of great use for helping to
define target volumes and other anatomical structures for the treatment planning
process, the core dataset for treatment planning for PBS proton therapy is x-ray CT.
This is currently the only imaging modality that can be accurately converted into the
relative proton stopping powers required for accurate dose calculations in the patient.
As such, it is important that the CT data set to be used for dose calculations is as good a
quality as possible. This does not necessarily mean that the CT has to have the best
resolution, but more that the Hounsfield units (HU) of the CT are correct.
X-ray CT gives a three-dimensional model of the patient in terms of x-ray attenuation,
and as such needs to be converted into relative proton stopping power. This is a
nontrivial and nonunique process. Although a number of methods of performing this
calibration have been reported (28–30), the most widely used calibration procedure is
that of Schneider et al. (29), referred to as the stoichiometric calibration. As the name
implies, this approach is based on knowledge of the densities and chemical composition
of the mediums to be calibrated. Unfortunately, there is no unique and one-to-one
relationship between HU and proton SP, with different materials with the same HU
value having different proton SP and vice versa (29). As such, clinically applied
calibration curves are defined based on biologically relevant tissues (29–31) and are
thus, strictly speaking, only valid when applied to patient tissues. Although on first site
this may appear not to be a problem, it can be an issue when treating through
nonbiological materials such as the table couch or metal implants (6,32). In such cases,
it may be necessary to override the HU or SP values in the planning CT in order to
ensure that the correct SP is used for the dose calculations. More details on this issue
can be found in Lomax et al. (6) and Kruse (32).
Thus, planning CTs for proton therapy should be acquired under strict imaging
protocols, such that the acquisition parameters for the images are exactly those used for
the calibration curve to be used in the planning system. Under these conditions, the
HU–SP calibration can be accurate to about 1% in soft tissues and 2% to 2.5% in bones
(31,33). However, allowing for other imperfections in CT data (beam hardening, partial
volume effects, etc.), it is generally recommended that a range uncertainty of 3% to
3.5% be assumed from the CT imaging/calibration process alone.
Such range uncertainties are what can be assumed in the case of high-quality CT data,
that is, CT data that is well calibrated and “clean.” In this context, “clean” refers to CT
datasets that are free of substantial reconstruction artifacts. For CTs in which high-
density implants are present, however (e.g., postsurgical implants, teeth fillings,

279
implanted fiducial markers), reconstruction artifacts can be substantial and thus cannot
be ignored (34,35). Simply put, artifacts resulting from reconstruction problems provide
the wrong HU values for the underlying tissues, and will obviously then provide the
wrong stopping powers for proton range and dose calculations. As such, it is imperative
that the degrading effects of such artifacts are mitigated as much as possible for
treatment fields which pass through them.
There are two main ways of doing this. The first, and the recommended approach, is
to try to reduce such artifacts at the imaging stage. This can be done for instance by
using dual-energy CT, which has been shown to reduce reconstruction artifacts around
metal implants substantially (36,37) or by using artifact reduction methods during the
image reconstruction process (38,39). The second approach is to manually correct the
artifacts in the planning CT, by outlining the most obvious regions of corrupted HU
values and manually setting these regions to average HU or SP values appropriate for
the presumed underlying tissue. Although certainly not optimal, this approach has
recently been shown to significantly improve the agreement between planned and
delivered doses when measured in an anthropomorphic phantom (40) and is considered
as the absolute minimal approach to artifact mitigation for proton therapy. Indeed, as
artifact reduction algorithms and dual energy acquisitions are not perfectly effective, it
may still be necessary to perform manual stopping power corrections to correct for
residual artifacts even when using these techniques.

Structure Definition
The definition of both target and normal tissue structures for PBS proton therapy is an
essential part of the treatment planning process and is, to a large extent, the same
across all external-beam radiotherapy techniques. Certainly, there is no reason why
GTVs or CTVs for a given indication, as well as OAR and other anatomical structures,
should be any different for PBS proton therapy than for conventional therapies.
However, given the potentially different lateral penumbra of proton fields, together
with the additional uncertainty in range, there may be good reasons why PTVs could be
different for PBS proton therapy.
PTV margins should be determined based on the estimated magnitude of random and
systematic errors during the delivery. For proton therapy, these need to be determined
both from positioning errors (which will mainly determine the lateral margin) and range
uncertainties, which should ideally determine the distal margin. Given that these
uncertainties will not necessarily have the same magnitude, and are likely to be of a
different nature (e.g., positioning errors will likely be random, whereas the main sources
of range uncertainty will be systematic (41,33)) it can be argued that PTVs for PBS
should be field rather than target specific, with different margins being defined laterally
to those defined distally and proximally (42,43). In practice, however, this may not be a
practical approach, particularly if field-specific margins are not easily supported in the
treatment planning system. Indeed, at our institute, conventional, isotropic PTV
margins of 4 to 7 mm are routinely used. These have been calculated based on an
analysis of our positioning uncertainties for different sites (44), and using an estimated
uncertainty in range of 3% (see above). As it turns out, this leads to lateral and
distal/proximal margins of similar values, at least for centrally located tumors in the
brain. Nevertheless, field-specific PTVs may become more prevalent in the future as
more sophisticated and automated tools become available.

Beam Selection and Plan Design

280
Due to its ability to deliver a more or less homogeneous distribution to the target from a
single direction (see Fig. 10.1), it is not absolutely necessary to treat with multiple
fields, even if this is highly recommended. This characteristic of proton therapy has a
number of consequences. First, the number of fields for a typical proton plan can be
quite small, and second, there is a lot of flexibility in the choice of these directions as all
can, at least theoretically, deliver a homogeneous dose to the target. In practice,
however, there are a number of issues that should be taken into consideration when
selecting field directions, which will be briefly outlined in this section.
The most obvious consideration is the avoidance of critical structures. Although all
normal tissues in a patient can be considered “critical” in one way or another, some
tissues are more critical than others, and one of the easiest ways of ensuring that
dosimetric constraints are met is to avoid bringing treatment fields through these. This
can be achieved by avoiding the structures with the lateral edge of the field and, given
the stopping characteristics of protons, also by use of the distal dose fall-off. Due to
worries about range uncertainty and increased LET/RBE at the distal end of the field
however, it is currently considered bad practice to directly stop a proton field against
critical structures which may be sensitive to small volumes of large dose, such as the
spinal cord or brainstem. On the other hand, if there is a reasonable distance between
the distal edge of the field and the critical structure (in this context a “reasonable
distance” is difficult to precisely define, but will depend on the estimated range
uncertainty for the field), using the distal field edge to “shield” a critical organ is
perfectly acceptable, and is often the best way of realizing the power of proton therapy.
The second consideration is the avoidance of coarse and complex density
heterogeneities. These should be ideally avoided for the following three reasons;
potential problems with the dose calculation accuracy, limitations with dose
homogeneity and conformity, and sensitivity to potential set-up errors.
The Bragg peaks and SOBP shown in Figure 10.1 are that expected for proton beams
delivered to a perfectly homogenous medium such as water. However, if delivered to a
material that is density inhomogeneous, then these curves can look quite different. For
instance, when a pencil beam partially intersects with a density heterogeneity, then
different portions of the beam will “see” different material densities, thus affecting the
range of those portions of the beam. As such, the beautiful, sharp Bragg peaks shown in
Figure 10.1 becomes degraded and distorted into a broader, more irregular shape with
often a much degraded distal fall-off.

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FIGURE 10.5 Degradation of the distal fall-off for a PBS proton field passing through complex density
heterogeneities.

Such an effect is shown in Figure 10.5. For this field, one can observe that the distal
end of the field does not conform well to the distal end of the target due to the
distorting effect of the density heterogeneities. In addition, as shown by the color bar on
the right side showing the dose banding, the maximum dose in this field is quite high
(138% of the mean dose delivered to the target). This is also a consequence of the
distortion of the Bragg peaks for this field, which the optimization process cannot fully
compensate. Indeed, the dose conformity and homogeneity of this field should be
compared to that of the single field shown in Figure 10.6B. The field in the latter figure
is traversing a particularly homogeneous part of a patient’s anatomy (only skull and
brain), and thus the shape of the Bragg peaks are preserved, leading to a much more
homogeneous (a maximum dose in the field of only 106% of the mean target dose) and
distally conformal distribution. This distorting effect of density heterogeneities on pencil
beams is one reason why they should ideally be avoided.
The second reason is the sensitivity of such field directions to potential positioning
and set-up errors. To explain this, once again consider Figure 10.5. Clearly, the position
of the “tongues” of dose extending beyond the distal edge of the target volume are
correlated with the position of the density heterogeneities and as such, their position in
relation to the patient’s anatomy will change due to any misalignments, particularly
rotational, of the patient in relation to the delivered beam.
In summary then, it is advisable to try to avoid field directions that avoid complex
density heterogeneities, while picking directions that avoid critical structures. In
practice however, following these guideline religiously is simply not possible, and one or
other (if not all) guidelines may have to be compromised depending on the case and
anatomy. Nevertheless, they are worth keeping in mind in plan design wherever
possible.

FIGURE 10.6 Optimization for PBS proton therapy. (A) Optimized Bragg peak positions and fluences
(colours) for a single field planned to an Ependymoma case. (B) The corresponding, optimized dose
distribution.

Field Shaping and Optimization

282
In this section, we will delve a little deeper into the planning process for PBS proton
therapy, by discussing the details of how the individual fields are defined and shaped
such as to efficiently deliver a clinically relevant dose to the target volume. This process
is termed “field shaping,” and has been recently described in detail by Zhu et al. (45).

Bragg Peak Placement


The basic process of field shaping for PBS proton therapy is shown in Figure 10.7. This
shows the stages of shaping a PBS field planned to a central brain ependymoma using
the in-house treatment planning system developed at our institute (46,47). Figure 10.7A
shows the originating planning CT and defined structures for this case, with the PTV
displayed as the green contour, whereas Figure 10.7B shows a three-dimensionally
distributed set of BP positions (the red crosses) for a posterior field applied to this
patient before any field shaping has been applied, with this distribution of BPs
essentially providing the starting conditions for the field-shaping process.
In order to get the distribution of BPs shown in Figure 10.7B, at least two parameters
for the field and/or delivery machine must be known or defined. These are the spot
spacing and energy resolution or spacing. For the case shown in the figure, spot separation
refers to the spacing between BPs/pencil beams in the two directions orthogonal to the
beam direction—so along the horizontal (lateral) axis in this case, as well as in and out
of the plane of the image. The energy resolution then determines Bragg peak separation
along the beam direction. For the case shown, energy resolutions of 3.5 MeV and a spot
spacing of 5 mm have been used. Such a lateral spacing is the standard spot spacing
used for our treatments at PSI and, although a field-specific parameter in our planning
system, is more-or-less a standard for all types of treatment at our institute. This
separation has been determined such that there is a sufficient overlap between the
narrowest spots deliverable by our machine (about 3 mm σ) such as to deliver a
homogeneous (ripple free) lateral profile. Using the definition of spot spacing defined by
Zhu et al. (45), this corresponds to an α of about 0.7 for the narrowest beam dimension
(where the spot spacing, s, is related to the full-width-half-maximum (FWHM) of the
beam by the relationship s = α FWHM, see Zhu et al.)
The next step in field shaping is to define the sub-set of BPs that will deliver useful
dose to the tumor volume, by selecting just those BPs that are within the target volume,
or a short distance outside. This sub-set of BPs is shown in Figure 10.7C, where all BPs
internal to the selected PTV (green contour) have been selected, together with BPs
within 5 mm of the PTV surface. This reduced set of BPs is what can now be referred to
as the shaped field. As a note, the extra, external BPs are required in order to ensure that
the high-dose area of the final dose distribution extends to the target volume surface. In
addition, the sub-set of BPs shown in Figure 10.7C has also been assigned an initial
weight (fluence) as indicated in the figure by the color coding of the BPs and the color
bar on the right-hand side. As we will see in the following section, this initial set of
weights will not typically provide a homogeneous dose to the field, necessitating an
optimization step in the planning process.

Fluence Optimization
The BP fluences shown in Figure 10.7C have been assigned using a precalculated, one-
dimensional weighting scheme based on the SOBP concept (see Fig. 10.1). Such
fluences, if assigned to a PBS field planned to a rectangular box in water, would then
provide a homogeneous dose across the target, and indeed such fields are a way by
which a PBS machine can emulate PS (48). However, when applied to an irregular
target in a nonhomogeneous patient with a nonflat skin surface, then this simple

283
fluence assignment approach is insufficient, as can be seen in Figure 10.7D. This shows
the dose distribution resulting from the set of BP and fluences shown in Figure 10.7C,
calculated using the ray-casting analytical approach (see above). Although the 95%
isodose covers most of the PTV in the slice shown, there are clear areas of under-dosage
(<<95%) at the edge of the PTV. In order to improve this situation, an optimization of
the fluences is required, by which the fluence of each selected BP in the field is
iteratively modified, with the goal of making the resultant dose distribution as
homogeneous as possible across the target volume.

FIGURE 10.7 Field shaping for PBS proton therapy. See main text for details.

The optimization process used for this step is essentially the same as that used for
other applications in radiotherapy (e.g., IMRT) and is based on minimizing the
following function:

where N is the number of dose calculation points and Pi and Di are the prescribed and
calculated doses at point i.
There are numerous ways of going from this simple relationship to the actual update

284
functions applied to each pencil beam per iteration (49), but the one we will show here
is that used in our planning system at PSI and that was originally derived for IMPT
optimization (50). This has the following form:

In this, wj,k and wj,k-1 are the weights of the jth pencil beam at iterations k and k -1
respectively and di,j is the dose delivered by pencil beam j at dose calculation grid point
i. Pi and Di are as in Equation 10.6. As noted by Lomax (50), this formulation has the
advantage that pencil-beam weights can never go negative as part of the optimization
process. For a detailed derivation of Equation 10.7, the reader is referred to Albertini et
al. (51).
The result of applying Equation 10.7 to the case shown in Figure 10.7 is shown in
Figure 10.6. Figure 10.6A shows the fluences, modified as a result of the optimization
process, after 60 iterations, while Figure 10.6B shows the final dose distribution. The
95% dose now almost perfectly encompasses the PTV, and there are no regions with
doses above 106%.
When applied (as in this case) to a single field with the sole constraint of obtaining a
homogeneous dose across the target volume, this approach is called “Single Field,
Uniform Dose” or SFUD. This does not however mean that this approach only ever uses
one field for a plan, but rather that multiple field plans can be designed by combining
one or more such fields, each optimized individually as described above. As an example,
a three-field, SFUD plan for the same case is shown in Figure 10.8. About 60% of all
PBS treatments at our institute are planned and delivered using such an SFUD
approach.
An alternative approach is to perform the optimization for all pencil beams of all
fields simultaneously, a technique called IMPT or multiple field optimization (MFO). In
this case, additional constraints are also typically added to the optimization, such as
dose constraints to one of more critical structures, and Equation 10.6 above is then
expanded a little to the following (see Unkelbach et al. (52)):

Now, WPTV and WOAR are weighting factors defining the relative importance of target
coverage and critical structure sparing, and PPTV and POAR are constraint doses for the
target and critical structures, respectively. Note that in this formulation, the last (OAR
specific) sum is only performed over the dose calculation points where the dose
constraints for the organ are exceeded (so over the sub-set of N′OAR points only). An
update function similar in form to that of Equation 10.7 can then be derived that will
optimize all pencil beams of all fields together, under the constraints of both
maximizing target dose coverage and homogeneity, and reducing doses to critical
structures to below the predefined dose constraints.
An example of a four-field IMPT plan to a skull base chordoma is shown in Figure

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10.9, once again showing the dose distributions for the individual fields, together with
the full plan doses. Note the difference in the form of the individual fields of Figure
10.9 to those in the SFUD example above (Figure 10.8). The “single field, uniform dose”
constraint of SFUD has now been relaxed, with the result that the dose distributions of
the individual fields have become very inhomogeneous and complex, but with the
advantage that the dose can be selectively “carved-out” of neighboring critical
structures such as the brainstem and optic nerves. As examples of the type of SFUD and
IMPT plans that can be achieved using PBS proton therapy, a selection of cases treated
at our institute in the last years are shown in Figure 10.3.

FIGURE 10.8 The individual fields (A-C) and full SFUD plan (C) for an example ependymoma case.

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FIGURE 10.9 The individual fields (A-D) and full IMPT plan (E) for an example skull base chordoma case.

Field-Modifying Devices
In all PBS treatment gantries, there is a lower limit on the transportable beam energy.
This is typically about 70 MeV, but can be as high as 100 MeV on some machines. The
range of 70 MeV protons is roughly 4 cm in water, and thus this determines the
minimum range of BP that can be delivered to a patient without additional modulation
of the beam.
A minimum range of 4 cm is extremely limiting. For instance, for some pediatric cases
(e.g., orbital rhabdomyosarcomas), the maximum required range may only be of the
order of 4 to 5 cm, thus making such tumors untreatable with PBS proton therapy
without measures for reducing the minimal deliverable energy. In addition, in an
analysis of over 3,800 delivered fields at our institute, covering a whole range of
treatment sites and tumor types, it was found that over 30% of all BPs in these fields
were delivered with a range of 5 cm or less. Thus, the delivery of low-energy/low-range
pencil beams is an important issue. And it is for this reason that all PBS proton
treatment facilities have the ability to insert a preabsorber into the beam.
Unfortunately, the use of such a preabsorber is not without its costs. As with any
medium through which protons pass, MCS will occur, broadening the beam as it passes
through the preabsorber. If the preabsorber could be placed directly on the patient
surface, this wouldn’t be a major problem, as the broadening of the beam due to the 4
cm of preabsorber alone is relatively small. However, when the preabsorber is mounted
in the treatment nozzle, it is extremely difficult to get it very close to the patient, and
inevitably there will be a gap of a few centimeters between it and the patient. Indeed,
depending on the geometry of the nozzle, the anatomy of the patient and the type of
fixation devices used (which in the worst case can limit how close the nozzle can be
brought to the patient), gaps of 20 cm or more are not uncommon. As MCS in the
preabsorber doesn’t just broaden the beam, but also adds an angular divergence as well,
the beam geometrically broadens across this gap, and thus, the larger the gap, the
larger the pencil-beam size on entry into the patient. As an example, for the PSI Gantry

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2, the beam width (in air) at iso-center for a 70-MeV proton pencil beam (the lowest
energy that can be transported through the gantry) is about 4.5 mm (σ). However, with
a 4-cm preabsorber and a distance of 31 cm from the exit of the preabsorber to the iso-
center, this increases to over 10 mm (σ) in air. As the lateral penumbra of pure PBS
plans can never be sharper than the lateral fall-off of a single pencil beam, the
consequences on plan quality are hopefully clear. A more detailed discussion on the
problem of treating superficial tumors, and the use of preabsorbers, can be found in Titt
et al. (53), Zhu et al. (45), and Lomax et al. (6).

Advanced Optimization
Up to now, we have looked at two modes of optimization for PBS plans; SFUD and
IMPT. However, given the number of pencil beams available to the optimizer (typically
thousands to tens of thousands of pencil beams per field), the optimization problem is
inherently degenerate. That is, there are many different sets of PBS fluences that could
give quite similar dosimetric results. This aspect of SFUD/IMPT optimization is
discussed in detail elsewhere (51,55) and won’t be elaborated on here. However, the
degenerate nature of the optimization process means that other aspects of field
definition and design may be something that can be exploited.
In Figure 10.6A, one sees that the majority of BPs have generally very low fluences
after the optimization process. Based on this, the question arises whether these BPs are
required, or whether clinically acceptable plans could be delivered with less pencil
beams per field. Indeed, this idea has been proposed very early on in the work of Deasy
et al. (56) and Lomax (50). In the original paper by Deasy et al., the concept of distal
edge tracking (DET) was proposed, in which BPs are only deposited at the distal edge of
the PTV. Although there is no way that such a reduced number of BPs in a field can
deliver a homogeneous dose from one field, the use of multiple DET fields, together with
IMPT type optimization, have been shown to be able to deliver clinically acceptable
plans in which the integral dose to normal tissues can also be somewhat reduced, at
least for centrally located tumors (56,57). An expansion of this work has also been
reported by Albertini et al. (51), in which a so-called “spot-reduction” method was
incorporated into the optimization loop that automatically switches low-weighted pencil
beams off, sequentially reducing the number in the plan as the optimization progresses.
This approach has been shown to be able to reduce the delivered BPs for plans with a
small number of fields (where the pure DET approach has too few degrees of freedom)
while approaching the DET approach (and further) for plans with many fields.
However, due to fears about the robustness of such plans to delivery errors (55,58), at
the time of writing, such “spot-reduction” techniques are not used clinically.
Indeed, robustness itself is a parameter that can also be included into the
optimization process, either indirectly or directly. In the work by Albertini et al.
mentioned above, an indirect approach was taken in which the starting conditions of
the optimization “force” the optimizer to a robust solution. Direct robust optimization
methods, on the other hand, use robustness criteria and measures as additional
constraints in the optimization procedure. More details on this approach can be found
in the literature (52,59–61).
As a last example, it has recently been proposed that LET could also be an interesting
parameter to include in the optimization process (62). In a way, this is also a type of
robust optimization, as the idea is to try to mitigate the potential effects of enhanced
RBE by modulating the LET and thus make the resulting plan more robust to potential
biological effects.
So there are many additional criteria that could be optimized in addition to target

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and critical structure doses, and the optimization process in PBS proton therapy is
clearly a multiple criteria problem. It should be of no surprise, therefore, that one of the
main areas of optimization research in this area is into multiple criteria optimization
(MCO) techniques (60).

Plan Evaluation
The final stage of the treatment planning process is the clinical and physics review of
the plan, before being released for delivery to the patient.
For the most part, the clinical review will be very similar to that for conventional
therapy. Certainly, target coverage and doses to critical structures will need to be
reviewed, through both a visual assessment of the dose distribution in all relevant slices
and DVHs. However, given the potential for increased RBE values in some parts of the
plan, then perhaps an additional clinical assessment of the plan from the point of view
of RBE should be performed. For instance, are highly weighted fields stopping directly
against a critical structure? If so, is this acceptable, or should the dose constraints to
the structure be reduced to allow for this? The differences are somewhat more when
assessing a plan from the physical point of view, however.
One area, which we have not discussed in this chapter up to now, is the effects of
delivery uncertainties on PBS proton plans. This has been an area of considerable
research in recent years, and has recently been reviewed by Mohan and Sahoo (63). We
will not go into details here, other than to outline the two main uncertainties; positional
and range.
Positional uncertainties are of course present in any form of external beam
radiotherapy, but are a particular problem for fractionated treatments. Inevitably, the
accuracy of patient set-up over many days cannot be as accurate as that of a single
treatment, despite image-guided techniques to improve this. In practice, therefore,
positioning inaccuracies of a few millimeters day-to-day have to be expected. Typically,
such uncertainties are managed through the use of a PTV (see above), with estimation of
the potential effects of positional uncertainties being restricted to evaluating dose
coverage of the PTV. However, more sophisticated approaches to this are now being
developed, allowing for more direct visualization of dosimetric uncertainties in three
dimensions and in relation to the patient geometry.
Although some of the first work in analyzing treatment uncertainties was for photon
treatments (64), much of the more recent published work has concentrated on proton
therapy, either as a metric for robust optimization (61,65–67) or for evaluating the
robustness of plans outside of the optimization process (68–71). Many of these provide
uncertainty distributions, estimated by recalculating dose on a number of instances of the
nominal geometry shifted in space to simulate potential treatment set-up errors. The
uncertainty distribution is then calculated at each point by generating dose error bars at
each dose calculation point through the combination of the multiple dose values into a
uncertainty band, typically by displaying the difference in the maximum and minimum
values of all calculated doses at each point (65,66,68,69). Although this approach can
be used for comparing the robustness of two different plans, it is a very conservative
approach which basically assumes that positional errors will be systematic in nature. As
such Lowe et al. (72) have recently modified this approach to also allow for
fractionation under the assumption that set-up errors will generally be random, which
has the effect of reducing the error bars considerably (Fig. 10.10). In the author’s
opinion, this approach provides a more realistic approximation of likely dose
uncertainties resulting from daily set-up uncertainties and thus provides a more

289
clinically relevant tool for evaluating (and optimizing) PBS proton plans from the point
of view of robustness.

FIGURE 10.10 Robustness analysis for positional uncertainties for an IMPT treatment to a sacral chordoma
(A). Robustness analysis without fractionation (B) and for 14 fractions (C). Note the substantial reduction of
uncertainty, particularly in the PTV and around the cauda equina. (Courtesy of Matthew Lowe.)

In additional to positional uncertainties, there are many potential sources of


uncertainty in the proton range in vivo, as reviewed by Lomax et al. (6) and Paganetti
(33). These include inherent uncertainties in the CT calibration, potential extensions to
the Bragg peak range due to RBE enhancement, CT artifacts (e.g., metal implants) and
anatomical changes to the patient anatomy during the course of treatment. In contrast
to positioning errors, all these are systematic in nature and thus have a potentially larger
impact on the quality of the treatment than set-up errors. As such, their incorporation
into the optimization procedure (60), as well as any robustness analysis tools, could be
more important than those of set-up errors. Indeed, IMPT (see Section 8.2) was first
used at our institute in order to make the plan more robust to range uncertainties (73).
It is thus interesting to see that robust optimization can lead to similar results
automatically (60). However, we have found now that our standard optimization
algorithm (i.e., without robustness criteria) anyway leads to range robust results in
many cases, as discussed by Albertini et al. (58,74). A good example of this is also
shown in Figure 10.9. Although each individual field of this complex plan is highly
inhomogeneous, there are no sharp gradients ranging out on the brainstem (the main
constraining organ in this case), with dose sparing of this organ being achieved with
lateral gradients only. In summary, there is much still to be done in the understanding
and quantification of plan robustness for PBS proton therapy.

290
SUMMARY
In this chapter, we have described the main principles of treatment planning for PBS
proton therapy. Given the three-dimensional nature of the delivery system (i.e., that
individual Bragg peaks can be delivered anywhere in the three dimensions from any
single-field direction), PBS is an inherently flexible and automated method which
requires treatment planning tools that can best exploit its potential. The techniques and
examples in this chapter hopefully do justice to its power.
However, it should be remembered that PBS proton therapy is still very much in its
infancy, with only a few thousand patients having been treated worldwide. As such,
much experience still has to be gained into optimizing its planning and delivery, and
many developments, both technical and clinical, remain to be done.
The main areas of such developments in the coming years are likely to be in exploiting
the degeneracy of the optimization problem. The very fact that this is a degenerate
problem implies that the problems we are currently giving the optimizer to solve are
maybe not demanding enough, and thus there is scope for adding more and more
criteria into the optimization step.
A simple approach is to start using PBS proton therapy for “dose painting,” the first
analysis of which has just been published by our group (75). Given the number of
variables available to the optimization process, there is a considerable potential for
IMPT to more precisely form deliberately nonhomogeneous dose distributions. Likewise,
and as we understand more about normal tissue responses, and/or have more access to
functional imaging, it could well be that the concept of “conformal avoidance” becomes
more important. That is, the idea of more precisely “carving-out” dose not from
complete organs but from the main functional parts of the organs. The flexibility and
power of IMPT should have considerable potential for such approaches as well. Finally,
much work still needs to be done in not just optimizing pencil-beam fluences, but in also
optimizing the field-shaping process such as to either more efficiently deliver
treatments, or to use more sophisticated combinations of pencil beams, such as in the
form of, for example, fan-beams or nonregular distributions of pencil beams that
directly follow the contours of the target volume (76).
These are just some of the possibilities of PBS proton therapy that are waiting to be
discovered.

KEY POINTS
• Beam modeling and dose calculations.

• Field shaping and plan design.

• Optimization of single-field uniform dose and intensity-modulated proton therapy plans.

• Plan evaluation and robustness.

QUESTIONS

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1. Please select the answer choice that best completes the sentence. Pencil-beam
scanning (PBS) . . .
A. Relies on collimators and compensators for conforming the dose to the target
B. Delivers individually weighted proton Bragg peaks distributed in three
dimensions throughout the target volume
C. Is dependent on the SOBP concept
D. Is not capable of delivering individually homogeneous field doses across the
target
2. Please select the answer choice that best completes the sentence. Dose
calculations for PBS proton therapy . . .
A. Have to be performed using Monte Carlo techniques
B. Can be analytical, but only for the primary dose component
C. Can be analytical, but only for the secondary dose component
D. Can be analytical, but at the cost of accuracy
3. Please select the answer choice that best completes the sentence. PBS plans…
A. Require many field directions to achieve a high level of conformity
B. Can achieve good dose homogeneity across the target with just a few
treatment fields
C. Are inherently robust to delivery uncertainties
D. Allow for the same amount of normal tissue sparing as IMRT
4. Please select the answer choice that best completes the sentence. Optimization in
PBS treatment planning…
A. Can only be performed using MC dose calculations
B. Is far more complex than for IMRT planning
C. Is a degenerate problem
D. Is not required.
5. Please select the answer choice that best completes the sentence. Accurate dose
calculations for PBS proton therapy…
A. Can only be performed on MRI data
B. Cannot be performed based on CT data, as it provides the wrong information
C. Should be performed on good quality CT data using a scanner-specific
calibration curve
D. Requires PET data for calculating range.

ANSWERS
1. B Pencil-beam scanning magnetically scans individual proton pencil beams
across the target volume in combination with energy changes. As only Bragg
peaks within (or very close to) the target volume are delivered, no collimators
or compensators are needed. In addition, as the fluences of the Bragg peaks
are individually optimized in order to best cover the target with a
homogeneous dose, then the concept of the fixed, one-dimensional SOBP

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required for passive scattering is no longer valid. Finally, as mentioned, in the
so-called SFUD (Single-Field Uniform Dose) mode, the optimization process
ensures that the dose across the target volume is homogeneous. Therefore, the
only correct answer is (B).
2. D All commercial (and noncommercial) treatment planning systems use
analytical calculations for both primary and secondary dose components
rather than Monte Carlo, due to the substantial advantages in computational
speed. Although there is in doubt the Monte Carlo calculations are more
accurate, no proton therapy facility at the moment is using MC calculations
for their routine treatment planning (other than in a few centers as an
independent check of the calculated plan). Therefore, the only correct answer
is (D).
3. B For both passive scattering and PBS, it is possible to achieve homogeneous
doses across the target with a single field, therefore answer (A) is wrong. Due
to the problem of range uncertainties, however, proton plans are not
inherently robust unless specifically designed to be, through careful selection
of beam angles and/or robust optimization. Thus answer (C) is also wrong.
Finally, on average, proton plans reduce the doses to normal tissues by a
factor of 2, and therefore allow for more normal tissue sparing than for IMRT.
Thus, answer (D) is also wrong. This leaves answer (B) as the only correct
answer.
4. C As with Question 3, Monte Carlo calculations are not standard approaches to
proton planning, and may be too slow for the optimization process. Thus,
answer (A) is wrong. Optimization algorithms for proton therapy are the same
as for IMRT, as are the way in which target doses and OAR dose prescriptions
are defined. Therefore, answer (B) is also not correct. Finally, optimization is
essential for PBS proton therapy, thus answer (D) is also incorrect. However,
the optimization problem is highly degenerate (due to the number of free
variables (pencil beams) per field that are available to the optimizer), and thus
answer (C) is the correct one.
5. C CT is the only imaging modality currently from which proton range can be
accurately calculated. Thus, the only correct answer is (C).

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11 Patient and Organ Movement

Paul J. Keall and James M. Balter

INTRODUCTION
The driving tenet of external-beam radiotherapy is the precise delivery of focal radiation
doses to the target, so that an effective dose can be delivered while limiting concomitant
normal tissue irradiation and related toxicity risk. Technical advancements, such as
intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy
(VMAT), and image-guided radiotherapy (IGRT) have provided significant gains in
specifying means to provide such dose distributions. Accurate delivery, so that intended
and actual doses agree, is a more complicated matter.
The problems of patient positioning and motion have been studied extensively.
Although there are currently areas that need further exploration, it is possible to
consider the magnitude of various uncertainties in dose delivery due to patient position
variation and organ movement, and to discuss rational strategies for dealing with these
uncertainties in the context of precision radiotherapy.

DESCRIPTION OF THE PROBLEM OF GEOMETRIC VARIATION


The International Congress on Radiological Units (ICRU) has addressed the relative
problem of geometric variations. In reports 50 (1), 62 (2), and 83 (3), concepts are
evolved to attempt to standardize means of reporting doses. Some of the concepts
presented in these reports have served as the basis for numerous investigations over the
past few years, and have been adopted as standards for clinical trials. A brief discussion
of the key concepts as they apply to geometric variation follows.
The key structures that are delineated are the gross tumor volume (GTV) and organs
at risk (OARs). The GTV is generally defined as the “visible” target, that is, that can be
delineated from imaging or related information. The OARs are tissue structures that are
dose-limiting due to risk of radiation-induced toxicity.
The next volume of interest is the clinical target volume (CTV). This target volume
ideally expands about the GTV to include a reasonable expectation of the true target
extent on a (static) patient model. The CTV expansion includes a reasonable expectation
of the extent of disease below the sensitive range of the imaging modality.
The planning target volume (PTV) adds a margin to the CTV to account for organ
motion or setup error. Margins, allowing for positioning, motion, and anatomical
changes, may also be required for the OAR to arrive at the planning organ-at-risk
volume (PRV). A margin provides a buffer in the delineation of tissues to account for
uncertainties (3). These structures are used for the treatment planning process.
When the patient is imaged to define the CTV and critical structures, the position is
sampled. In general, this sample occurs once, specifically during the computed
tomography (CT) scan for treatment planning. To obtain this sample, the patient is
immobilized and positioned with typical reference marks placed on the skin and/or
immobilization device at the principal axes of the CT scanner for verification of position
and orientation. The sample of the patient serves as the model for treatment planning,

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and all subsequent targeting and density modeling are based on the information
obtained during this session. With the advent of broadly available in-room imaging
modalities, such as cone beam CT (4–7) and the emerging integrated MRI-radiotherapy
systems (8–10), adaptive strategies which can account for inter and potentially
infraction anatomic changes are emerging.
Multiple samples of patient position will form a distribution. If we set the position at
the initial (treatment planning) CT scan as the “true” patient position, then a reasonable
method of describing this distribution of subsequent positioning is by the translation
necessary to make the patient position match that of the treatment planning CT scan.
Conventionally, the average coordinate of this distribution is considered as the
“systematic” error, in that it is the effective transformation that persists throughout the
samples (multiple CT scans in the above example, or multiple patient positions over a
course of treatment). The spread of sampled positions about this average coordinate
represents the random setup variation. It is important to note that the average
coordinate may never be sampled. An excellent overview of margins in radiotherapy is
given by van Herk (11).

MINIMIZING THE IMPACT OF SETUP VARIATIONS ON


TREATMENT
Obviously, these setup variations require margins to create the PTV to ensure proper
coverage of the CTV. Reducing the margins yields a smaller volume of tissue irradiated
to high doses, and can potentially reduce the toxicity to normal tissues. As such,
significant efforts have been made to minimize the range of variations and their
resulting impact on treatment.

Positioning Systems
A significant variety of equipment is in use to aid in repeat setup of patients. This
equipment attempts to address a dual role: immobilization and localization. These dual
roles are not necessarily compatible for any given piece of technology.

Immobilization
Quite simply, the process of immobilization involves limiting or eliminating movement
for the time period of imaging or treatment. The primary objective is to limit target
movement, although critical normal tissue movement also needs to be considered. There
is a large amount of literature on immobilization; however, as the technology is
evolving, it is important to consider a number of key aspects in deciding on a
technology and strategy for use of an immobilization system.
The advantage of a given immobilization method may be compromised by the
complexity of use. If an immobilization system has many degrees of freedom, improper
configuration of the device may lead to systematic errors in patient position or shape at
treatment. Examples of complex systems are multiuse boards for fixation, in which the
angles and positions of arm supports, angle of the upper thorax, shape of neck support,
and other components are adjustable. These devices are very cost-effective, and can be
used effectively, but special care must be taken to properly verify the patient
configuration, including notation of all configuration parameters and documented
photographs of proper setup.
Some systems (e.g., alpha cradle and vacuum loc) form directly to the patient’s shape.
This can be beneficial in positioning, but it is important to separate comfort from

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immobilization. Formed immobilization that extends to distal regions from the target
has been shown to be beneficial in reproducing position (12). However, studies have
shown that simple or no immobilization, when used well, can be as effective as more
complex systems (13). Therefore the training, use, protocols, documentation, and in-
house expertise are as important as the systems themselves and there is no substructure
for qualified expert staff.

Localization Technology
A wealth of technology has been applied to localization in radiation therapy. At present,
the most prevalent technology includes in-room lasers, gantry-mounted kilovoltage x-ray
imaging systems and electronic portal imaging devices (EPIDS) though in-room
localization is a very fast-changing field.
In-room diagnostic radiography is, in fact, a very old concept. Film-based
radiographic systems have existed on linear accelerators for over 30 years (14). Room-
based digital systems have been used for radiographic (15–18) and fluoroscopic (19)
procedures.
A number of different localization technologies have been used to treat radiotherapy
patients. These include dedicated systems such as the real-time tracking radiotherapy
system (20), tomotherapy, (21), CyberKnife (22), and Vero (23) linear accelerators. A
number of additional localization methods have been develop based on markers
including Calypso (24), Navotek (25), and Raypilot (26). Emerging localization
technologies include ultrasound (27) integrated MRI-radiotherapy systems (10, 28–30)
and kilovoltage intrafraction monitoring (KIM) (31,32). Given the reduction in the cost
of camera-based surface imaging for recreational (typically gaming) applications,
surface imaging (33) is anticipated to grow rapidly in use to assist with both setup
reproducibility and intra-treatment patient monitoring.

STRATEGIES FOR POSITION CORRECTION


Online Correction
Generally, online position correction refers to the processes of measuring and correcting
setup error at the start of each treatment fraction. This is the area in which the vast
majority of technical developments have focused recently. The process of online
correction includes three steps: measurement, decision, and adjustment. A fourth step
(verification) may also be used.
Measurement systems include data collection and analysis. Data can be from imaging
(e.g., radiographs, CT scan images, ultrasound, and video) or other markers (e.g.,
electromagnetic and external fiducial). Analysis is the comparison of reference image or
position information to that gathered at treatment.
Decision is the process of choosing to act or not on information from measurements. It
is valuable to consider that the measurement systems as well as correction technology
are not perfect, and therefore the errors in these systems may increase errors in certain
circumstances. The use of thresholds for corrections allows a trade-off between the cost
(frequency of adjustment) and benefit (actual reduction of errors). Figure 11.1 shows
the cost versus threshold for setup adjustment in prostate patients. Of course the
definition of cost in setup adjustment is important here. If integrated, for example, real-
time adaptation, the cost of correction is very low. If the setup adjustment involves a
manual procedure, including treatment pause, reimaging, position shift, and
verification, then the time is long and the cost is high. Automation can substantially

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reduce the cost of radiotherapy. Figure 11.2 shows the impact of positioning strategy on
margins under assumptions of systematic error versus none.

FIGURE 11.1 Cost (frequency of adjustment) versus threshold for online setup adjustment (based on 6-mm σ
for pelvic patients).

Off-Line Correction
One of the earlier forms of position correction was off-line correction. Studies of the
dosimetric impact of setup error (34–37) demonstrate that systematic error has the
largest impact on margin needed to adequately dose a target, and that the geometric
expansion to account for random error is generally small (less than one standard
deviation). Given this observation, it can be seen that, as long as random errors are not
exceedingly large, the most significant patient benefit comes from strategies that rapidly
reduce the magnitude of systematic setup variation.

FIGURE 11.2 Benefit (margin) versus threshold for adjustment (4-mm σ setup, 1.5-mm σ measurement
uncertainty, and 1.0-mm σ setup correction uncertainty).

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A number of strategies have been used to minimize systematic error. Two strategies
are the shrinking action level (SAL) and no action level (NAL) methods (38–40). In the
SAL protocol, setup is verified daily for the first few fractions, and adjustments are
made with tolerances that reduce in magnitude as the fractions progress. This strategy
has shown promising results.
The NAL protocol has also been used. In this method, images from setup are acquired
for n (typically 3 to 5) fractions. These images are analyzed off-line (thereby minimizing
the delay needed to analyze and act on images at the treatment unit), and the best
prediction of the systematic error (typically the average position of the fractions
analyzed) is corrected before the next fraction treated. This protocol has been tested,
and shown to dramatically reduce systematic errors.

ADAPTIVE RADIOTHERAPY STRATEGIES


Adaptive strategies for position adjustment were first proposed by Yan et al. (41). The
adaptive process extends the concept of off-line and online strategies. Essentially, the
patient position variability is assumed to follow a population model before patient-
specific measurements. As information about that patient’s variation is acquired (e.g.,
through multiple CT scans or daily portal images), the model of variation is refined, and
predictions from this refined model can be used to adjust position and margins. The
frequency of further measurement can be similarly adjusted as increased confidence in
the patient variation is gained, and similarly increased frequency of measurement can
be reinstated if, for example, an unexpected outlying measurement occurs during the
treatment course. Such strategies form a basis for plan modification, which is a topic of
active research and development in radiation therapy.

Organ Movement
Internal organ movement is a further, sometimes significant, factor in dose-limiting
geometric uncertainty. The most studied forms of organ movement have been prostate
movement and breathing-induced movement in (primarily) the thorax and abdomen.
Langen and Jones have published an excellent review of the magnitude of organ
movement as studied by several investigators (42). With the availability of real-time
localization systems, rich datasets of tumor position are now available (24,43,44).
Prostate position variability is a combination of pelvic setup variation (mentioned
above) with internal movement of the prostate within the pelvis (45–54). The primary
factors affecting prostate movement are rectal and bladder filling, with differential
influence of these forces in prone versus supine patients. The vast majority of prostate
patients are positioned supine, both for patient comfort and owing to observed
improvements in setup variation of the pelvis. Prone positioning has been reported
advantageous due to a separation of the rectal wall from the prostate, although both
setup variation and (breathing-related) internal movement have been observed to
increase in these patients.

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FIGURE 11.3 Graphic representation of the dominant modes of prostate movement (bladder—yellow, rectum
—brown, prostate—pink, intraprostatic implanted markers—white stars). The major translation axes (black
arrows) about the left–right and anterior–posterior axes have also been significantly attributed as rotation about
the left–right axis (white arrow).

Internal movement of the prostate has generally been observed in the anterior–
posterior (AP) and cranial–caudal (CC) directions. Furthermore, a significant
component of this movement has been correlated to rotations of the prostate about the
left–right (LR) axis, with a pivot at or near the prostatic apex (7) (Fig. 11.3). The
magnitude of this movement (of the prostate relative to the pelvic bones) is typically 1
cm or less in the AP and CC directions, and, 5 mm in the LR direction.
Although most prostate movement studies have examined interfractional position
changes (i.e., on the order of days), some measurements have been made of
intrafractional movement. Breathing has been shown to impact prostate movement,
most notably during deep breathing and in prone patients (55,56). Peristalsis, gas in the
rectum, and bladder filling have a more significant influence on prostate position and
potentially short-term movement. The complexity of prostate motion is shown in Figure
11.4. In most cases, there is little motion, but motion of over 15 mm can be observed
with a variety of motion types.
Prostate movement has been addressed by attempts at reducing motion by diet as well
as immobilization through a rectal balloon. Most common attempts at managing
prostate movement, however, have focused on localization. Radiographic localization
and tracking of implanted markers, studied by several investigators, are routine
practices, with initial localization (before subsequent movement) accuracy of better than
2 mm. Ultrasound and in-room CT scan have also been used for prostate localization
before treatment.

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FIGURE 11.4 Prostate motion exhibits a variety of different motion characteristics. From Ng JA, Booth JT,
Poulsen PR, et al. Kilovoltage intrafraction monitoring for prostate intensity modulated arc therapy: first clinical
results. Int J Radiat Oncol Biol Phys. 2012;84(5):e655–e661.

Vast efforts have recently been focused on the problem of breathing-related movement
in radiation therapy. An AAPM Task Group has been dedicated to this topic (57).
Breathing influences movement and shape change primarily in the thorax and abdomen,
although, as noted above, breathing-related movements can also be seen in pelvic
structures.
Breathing is a complex process. It is controlled both voluntarily and automatically.
Various combinations of thoracic and abdominal muscles (including the diaphragm) can
be used to control breathing, and therefore the shape of a patient can vary for the same
estimated “phase” of breathing when evaluated sequentially.
A few general observations have been made about breathing in population studies. A
typical breathing cycle lasts around 4 seconds for lung cancer patients (58). During
normal breathing, patients tend to spend more time to (or near) exhale than inhale.
Tumors near the apices of the lungs tend to move less than those near the diaphragm.
Although these general observations represent a reasonable population summary,
numerous studies have shown that individual patients may violate any of the above
observations. The need for patient-specific motion assessment has been demonstrated
(59,60). The advent of four-dimensional (4D) CT techniques (61) provides data that
help further elucidate patient-specific movement. 4D CT is now a widely used method in
radiotherapy.

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A very thorough summary of the ventilatory movement patterns of intrathoracic
tumors was published by Seppenwoolde (43). In addition to the above observations, this
study further showed the influence of heartbeat on some tumors, especially those near
the mediastinum. An observation of complex, elliptical movement (“hysteresis”) was also
noted in this study and observed by several other investigators. This elliptical movement
can be attributed to the complex elastic properties of lung tissue, coupled with the
different interactions of muscles and force between the inhale and exhale portions of
the breathing cycle. Lung tumor motion induced by respiration changes with time. The
daily variation of lung tumor motion traces over 4 consecutive treatment days is shown
in Figure 11.5. A large variation in motion within and between fractions is observed,
which challenges the ability to determine suitable treatment margins.
Motion has been studied in breast cancer as well. In general, the breast and chest wall
move <1 cm within a single treatment fraction. Such small movements may not
demand significant intrafraction intervention for motion management. Larger
interfraction variation of chest wall position has been seen in portal imaging studies. Of
note, however, is the potentially significant advantage of deep-inspiration breathhold
(62–67), not only for immobilizing the chest wall temporarily, but also, more
importantly, for reducing lung density and separating the heart from the medial high-
dose region.
The abdomen has demonstrated significant breathing-related movement with typical
amplitudes of 1.5 cm or more. The superior region of the liver moves with strong
correlation to the diaphragm, while more caudal regions of the liver may move
differentially due to deformation (68–71).

Technology to Manage Organ Motion


A number of technologies have been introduced to manage breathing movement. The
most common method currently employed involves using larger margins to account for
the expected inter- and intrafraction motion variation, though as shown in Figure 11.5
this motion is variable and difficult to estimate. Another system involves gating (turning
on and off) the treatment beam. The feedback for gating has generally been from the
monitoring of an externally placed reflective marker on the patient’s abdomen, although
fluoroscopic tracking systems have also been used with tolerance windows for gating
(72). Gating involves a trade-off of residual motion versus efficiency. The narrower the
acceptance range for motion, the less frequently the beam is on. The most significant
concern with external gating is the relationship between the external marker position
and the tumor location. While targets near the skin surface (e.g., breast) may have
significant correlation with external references, other targets, especially those in the
thorax, have been shown to vary in location at the same phase (as estimated from
external motion) over multiple breathing cycles (73–76).

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FIGURE 11.5 Calypso-measured lung tumor motion traces over 4 consecutive days. Note the large changes
within and between fractions. From Shah AP, Kupelian PA, Waghorn BJ, et al. Real-time tumor tracking in
the lung using an electromagnetic tracking system. Int J Radiat Oncol Biol Phys. 2013;86(3):477–483.

FIGURE 11.6 Components of an active breathing control (ABC) system.

Another commonly used technology is active breathing control (ABC) (Fig. 11.6). First
introduced by Wong (77), this concept involves using a system that monitors breathing,
and occludes breath at a given phase of the breathing cycle and/or volume of air
relative to exhalation. Various studies have shown excellent short-term reproducibility
of target position in the thorax and abdomen using this technology (15), (78–82).
Decreased accuracy in long-term reproducibility suggests the advantage of image-guided
localization at the start of a treatment fraction in combination with ABC-aided
ventilatory immobilization.
More complex technology for managing breathing movement involves tracking. In this
process, an estimate of the target’s trajectory is used to adjust the couch, linear
accelerator orientation, or field aperture. The available systems to perform real-time
adaptation, along with the year they were first implemented clinically are shown in
Figure 11.7. Of the four systems shown, the most widely available are the multileaf
collimator (MLC) and couch. The MLC is the lightest and as each leaf can be controlled
individually, higher order corrections such as rotation (83) and deformation (84) can be
performed.
Some breathing management systems rely on the relationship of a surrogate to
estimate tumor position at any given time or patient state. Various surrogates have been
employed, including implanted fiducial markers, external fiducials (usually tracked in
real time by video systems), external surface monitoring, and lung volume and air flow.

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The relationship between surrogate state/position and tumor position may be variable,
and the influence on this variability on geometric accuracy of target position prediction
should determine the extent of additional verification needed or residual error expected.
Two commercial systems, the CyberKnife and Vero, currently employ a hybrid approach
to tracking, in which implanted radiopaque fiducials are periodically localized using
biplanar radiographs, and their position is used to update a correlation with the
constantly monitored external surface of the patient.

FIGURE 11.7 The four systems investigated to realign the radiation beam and tumor due to intrafraction
motion.

SUMMARY
The influence of geometric variations in radiation therapy increases in significance with
the conformality of the planned treatment. Our understanding of motion and its effects
is growing. Interventions to better reduce these movement-related uncertainties are
evolving rapidly. A fundamental understanding of the limitations of any given
monitoring or tracking system, coupled with the impact of uncertainty in target position
on dose, will yield efficient strategies for implementing technology to limit the impact of
patient and organ movement on treatment outcome.

KEY POINTS
• Organ structure nomenclature has been standardized by the ICRU in reports 50, 62, and 83.
The visible gross tumor volume (GTV) may be expanded into a clinical target volume (CTV)
to include microscopic disease, and further expanded into a planning target volume (PTV), to
account for organ motion or setup error. Similarly, the organs at risk (OARs) may be
expanded to planning organs at risk (PRVs) to account for patient position and organ motion.

• Patient positioning systems are designed to immobilize the patient and/or improve the
localization of the treatment site. Immobilization devices should limit target movement, but

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not so complex that systematic setup errors could be introduced. A number of in-room
localization technologies have been introduced in the past few years to assist with setup
reproducibility and intrafractional target monitoring.

• Patient positioning corrections can be made online or off-line. Online corrections include
measurement, decision as to whether to shift, adjustment, and in some cases verification. Off-
line corrections are important in minimizing systematic errors, which have a significant
impact on the margin necessary for adequate treatments. Adaptive strategies can serve to
modify the above corrections, based on the variations observed with individual patients.

• Organ motion within the patient represents another source of positional uncertainty. Several
site-specific studies of interfractional organ motion have been performed, many of which
have focused on the prostate gland. Intrafractional organ motion may also be significant,
especially for diseases within the lung, which has motivated the development of a number of
techniques to manage treatment of this site.

QUESTIONS
1. ICRU 50 first introduced which of the following nomenclature?
A. Gross treatment volume (GTV)
B. Off-axis ratios (OARs)
C. Clinical target volume (CTV)
D. Normal tissue complication probability (NTCP)
2. Which of the following is/are used to immobilize patients?
A. Alpha cradle and/or vacuum loc
B. Calypso
C. Electronic portal imaging systems
D. ABC systems
3. Two strategies for performing off-line corrections to minimize systematic error
are:
A. Inter- and intrafractional motion management
B. Adaptive and non-adaptive margin adjustments
C. System gating and/or tracking
D. Shrinking action level and no action level
4. The magnitude of the interfractional movement of the prostate relative to the
pelvic bones is typically:
A. 1 cm or less in the anterior–posterior direction
B. 1 to 2 cm in the cranial–caudal direction
C. 5 mm or less in the left–right direction
D. <5 mm in any direction.
5. The following technologies was/were developed to help manage breathing
movement:

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A. Ultrasound
B. In-room CT
C. Treatment beam gating
D. Tracking using multileaf collimator

ANSWERS
1. C
2. A
3. D
4. A and C
5. C and D

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12 Image-Guided Radiation Therapy

Guang Li, Gig S. Mageras, Lei Dong, and Radhe Mohan

INTRODUCTION
The aim of external beam radiation therapy (EBRT) of cancer is to target localized
disease noninvasively with radiation that conforms to the target while minimizing dose
to surrounding organs at risk (OAR). Radiation dose is often delivered with inadequate
visualization of the regions being irradiated. Therefore, imaging guidance is crucial at
every step of the process, including cancer diagnosis, staging and delineation; treatment
simulation and planning; patient setup, tumor localization, and motion monitoring; and
treatment response assessment, efficacy evaluation and strategy refinement. In fact,
most of the significant advances in radiation oncology over the last three decades have
been made possible by advances in medical imaging. Using three-dimensional (3D)
images of patient anatomy from computed tomography (CT) and magnetic resonance
imaging (MRI), as well as visualization of viable tumor extent from MR spectroscopic
imaging (MRSI), positron emission tomography (PET), and single photon emission
computed tomography (SPECT), treatment target and OARs can be delineated with
precision, thus reducing the likelihood of marginal misses in tumor and minimizing the
exposure of normal tissues to high radiation dose. Multimodality imaging has become
an integrated component throughout the treatment process, providing the ability to
localize and visualize the tumor in space and time to ensure an accurate delivery of a
highly conformal treatment plan.
Image-guided radiation therapy (IGRT) is composed of a multitude of major
innovations in radiation oncology to address the problems arising from inter- and
intrafractional target variations. IGRT aims to deliver a treatment as it is planned based
on 3D images acquired at treatment simulation. These images establish a 3D reference
frame of patient anatomy (with possible inclusion of motion) for both image-based
treatment planning and image-guided treatment delivery. The former process follows
the exact 3D patient anatomy (the tumor and nearby OARs) for dosimetric planning,
while the latter focuses mostly on tumor alignment between the planning image and
images at the treatment unit prior to and during treatment, thereby aligning to the
radiation fields. The variations of tumor position in the image-guided interfractional
setup (between treatment fractions) and intrafractional (within a treatment fraction)
patient and organ motion can be corrected for more accurate delivery. The variation of
normal tissue positions is often assessed in terms of proximity to the irradiated volume
in the current image-guided approach, but is also a focus of adaptive IGRT research to
assess dosimetric and clinical consequences under various clinical scenarios. Examples
of image guidance in various stages of radiation therapy are illustrated in Figure 12.1.
Increasing evidence has shown that there are substantial inter- and intrafractional
variations, in contrast to the “snapshot” planning anatomy of a patient. The causes of
such variations include voluntary motion (body shift, rotation, and deformation),
involuntary motion (respiratory, cardiac, and digestive), disease-related changes (tumor
growth and weight loss), and radiation-induced changes (tumor shrinkage). The
variation in respiratory-induced tumor motion during treatment may substantially

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deviate from the one-cycle motion extent quantified by 4DCT at simulation, owing to
breathing irregularities. These variations could have a significant impact on the
outcome of treatments, as they may result in underdosing the target or overdosing the
OAR (1–3). In the current practice of treatment planning and delivery, it is assumed
implicitly that patient’s anatomy remains static throughout the course of the radiation
therapy. To account for statistical variations, wide treatment margins derived from
population-based studies are used to ensure coverage of the disease at the expense of
exposing considerable OAR volumes to or near full prescribed radiation dose. A large
margin limits the ability to safely deliver higher tumor doses because of increased risk of
OAR toxicity, especially for hypofractionated stereotactic body radiotherapy (SBRT), in
which the high dose per fraction exceeds the normal tissue’s capacity for sublethal
repair. Furthermore, the margin needed for some patients exhibiting large target
variations may exceed the population-based margin, potentially leading to marginal
misses, especially with the use of highly conformal modalities, such as 3D conformal
radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), volumetric-modulated
arc therapy (VMAT), and proton therapy (4–6). Treatment planning and delivery
techniques that do not correct for such daily volumetric variations adequately may lead
to suboptimal treatments. These factors may, in part, be responsible for the poor
outcome and high toxicity in radiation therapy for some cancers (7). IGRT has the
potential to target gross and microscopic diseases accurately, to individualize
treatments to reduce margins, and to allow dose escalation to higher levels with the
expectation of improving local control and reducing toxicity (8–10). Therefore, IGRT
can help to improve the therapeutic ratio, namely the ratio of tumor control probability
(TCP) and normal tissue complication probability (NTCP) (1,7). The recent efforts to
introduce MRI, PET, and optical surface imaging (OSI) into the treatment room can
further improve the ability to assess the accuracy of treatment delivery by direct
viewing of the target during treatment (11), imaging proton beam path (12), and
visualizing photon Cherenkov scattering (13), respectively.

FIGURE 12.1 Image guidance at various stages of the radiotherapy process.

This chapter focuses on IGRT technologies related to treatment planning and delivery

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of EBRT. The second and third sections introduce various imaging forms of IGRT
technologies and their commercial implementations for inter fractional patient setup
and intrafractional motion monitoring, respectively. The fourth section reviews
requirements and considerations for IGRT, including quality assurance (QA). Various
possible IGRT strategies, margin assessment and reduction, and clinical implications are
described in the fifth section. Finally, the sixth section looks into the future and
speculates on new processes coming into this field.

INTERFRACTIONAL IGRT IMAGING MODALITIES FOR


PATIENT SETUP
In this section, we focus on in-room IGRT imaging modalities for daily patient setup.
Images acquired immediately prior to treatment are used to reposition the patient so as
to align the target or its surrogate (such as implanted radiopaque fiducials in or near
the tumor) with the planned radiation isocenter. Digitally reconstructed radiograph
(DRR) images derived from the planning CT are used as the reference. A couch
positional adjustment is typically used to realign the patient. This is the simplest form
of IGRT without modification of the original treatment plan.

2D Radiographic Imaging
Two-dimensional (2D) radiographic (projection) imaging is typically used in treatment
rooms to align the patient relative to the radiation beams. Megavoltage (MV) imaging
uses therapy x-ray beams and an amorphous-silicon (a-Si) flat-panel imager, known as
electronic portal imaging device (EPID), to verify patient’s setup, defined as the position
of the skeletal anatomy (14). Other uses of MV imaging are to verify treatment beam
apertures prior to treatment and in vivo portal dosimetry during treatment (15,16).
Because imaging uses the therapy beam, it provides direct in-field verification of
treatment delivery, and therefore serves as a “gold standard” for validating new IGRT
techniques. Disadvantages of MV imaging include higher radiation dose to the patient
(typically 1 to 5 cGy) and poorer image quality owing to a large Compton scattering
contribution from the higher x-ray energies and high-energy electrons reaching the
detector.
Two general categories of 2D kilovoltage (kV) x-ray imaging are frequently used for
IGRT. One is a gantry-mounted kV imaging system on a linear accelerator (linac),
orthogonal to the therapy MV x-ray beam. The kV x-ray source and flat-panel imager
are mounted on retractable arms, providing near-diagnostic quality images. The second
category of kV imaging is room-mounted systems: the x-ray source and detector are
mounted on the ceiling or the floor. These systems provide an oblique orthogonal image
pair for stereoscopic imaging at a wide range of treatment couch angles. Most kV x-ray
imaging systems have a companion fluoroscopic imaging mode, which is useful for
observing motion of the internal anatomy or implanted fiducials. Since kV imaging
systems are distinct from the MV beam line, the kV–MV isocenter coincidence must be
established within a clinical tolerance through initial and periodic QA processes.
kV radiographs are often not sufficient for detecting soft tissue targets but are more
successful in aligning skeletal landmarks or implanted radiopaque fiducials as target
surrogates. In-room kV imaging represents a major improvement over MV imaging due
to its superior image quality and its low imaging dose (0.01 to 0.1 cGy), facilitating its
use for daily image-guided patient setup (17). The different appearance of kV and MV
thoracic images is shown in Figure 12.2.

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FIGURE 12.2 The appearance of anatomy kV (top row) and MV (bottom row) radiographs can be quite
different. At kV x-ray energies, the bony structures are enhanced; at the therapeutic (MV) energies, the air
cavity is enhanced.

Tomographic Imaging
CT imaging inside the treatment room provides 3D anatomical information and
improved soft tissue visibility, thus providing advantages over radiographic imaging
with higher imaging dose (18). In-room CT images are the standard for six degrees-of-
freedom (DOF) patient setup and can be used to estimate the delivered dose
distributions based on the anatomy captured at treatment. The planning CT image is
used as the reference for patient alignment on skeletal anatomy, fiducials, or tumors in
some disease sites.

kV Helical CT and kV Cone-Beam CT


Helical multislice CT systems have been widely used in diagnostic imaging and radiation
treatment planning for many years. The first integrated CT-linac clinical system was
designed for noninvasive, frameless stereotactic radiotherapy of brain and lung cancers
with reduced uncertainty between fractions (19). Another integrated system with a rail
system to transport the patient between treatment and CT couches was assembled at the
Memorial Sloan Kettering Cancer Center for treatment of paraspinal lesions and
prostate cancer (20,21).

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FIGURE 12.3 A: An Elekta Synergy unit (Elekta Inc., Sweden). B: A Varian TrueBeam unit (Varian
Oncology Systems, Palo Alto, CA) (Photograph courtesy of Yingli Yang, PhD). Both linear accelerators have a
kV imaging system orthogonal to the therapy beam direction. Both systems provide 2D radiographic,
fluoroscopic, and CBCT modes.

A commercial CT-linac system was introduced in the clinic in 2000 (22). It consists of
a medical linac and a movable CT scanner that slides along a pair of rails (“CT-on-
Rails”). A similar “CT-on-Rails” commercial system (EXaCT, Varian Oncology Systems,
Palo Alto, CA) has the mechanical accuracy of within 0.5 mm (23,24). The biggest
advantage of an in-room CT scanner for IGRT is the similarity of image quality and field
of view (FOV) with planning CT images.
Gantry-mounted kV imaging systems are capable of radiography, fluoroscopy, and
cone-beam CT (CBCT), providing a versatile solution for IGRT applications (25,26).
CBCT imaging involves acquisition of projection images of the patient as the gantry
rotates through an arc of at least 180 degrees plus a so-called cone-beam angle
subtended by the imaging panel (∼200 degrees total). A filtered back-projection
algorithm is used to reconstruct the volumetric images. Geometric calibration of the
CBCT system is needed periodically to maintain image quality and geometric accuracy.
Corrections on the order of 2.0 mm may be required to compensate for the gravity-
induced flex in the support arms of the source, detector, and gantry. Submillimeter
spatial resolution and accuracy have been demonstrated in phantom. The volumetric
image with nearly isotropic spatial resolution is useful in frameless stereotactic
radiosurgery (SRS) (27).
Since 2005, major manufacturers have offered CBCT capabilities (Elekta Synergy and
XVI, Elekta Inc., Sweden; Varian On-board Imager [OBI] and TrueBeam Imaging, Palo
Alto, CA), as shown in Figure 12.3. Elekta’s system uses a slightly larger flat panel
detector (41 × 41 cm), compared to Varian’s detector (40 × 30 cm), which limits the
scan length to 15 cm when using the full-fan scan mode. A half-fan scan method
displaces the detector vertically to capture half projection images and requires 360-
degree rotation to have the axial FOV to at least 40 cm (28).
Limitations of CBCT image quality include elevated x-ray scatter, which reduces
image contrast and introduces cupping artifacts. Scatter can be reduced by using both
anti-scatter grids and post-processing methods (29,30). To further improve the image
quality, Kim et al. have proposed to use orthogonal dual-source and dual-detector “in-
line” with MV beam to produce 2D and 3D images with tetrahedral collimation (31).
Because of regulations on gantry rotation speed (1 rpm), CBCT image quality is
adversely affected by the breathing motion. The IGRT setup process may add 5 minutes
(∼2 minutes acquisition and ∼3 minutes registration/approval) to the regular
treatment schedule.

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MV Helical CT and MV Cone-Beam CT
Tomotherapy (Accuray Inc., Sunnyvale, CA) is an integrated technology that combines a
helical megavoltage CT (MVCT) with a linear accelerator (Fig. 12.4A) as x-ray source,
which is specially designed for delivering intensity-modulated radiation in a slit
geometry (32–34). Low-dose (1 to 2 cGy), pretreatment MVCT images are obtained from
the same treatment beam line but with a nominal energy of 4 MV. The CT detector uses
an array of 738 channel xenon ion chambers and an FOV of 40 cm can be
reconstructed.
MV CBCT uses the therapy MV x-ray and the EPID detector (35,36). With the a-Si flat
panel EPID (37), it has become possible to rapidly acquire multiple, low-dose 2D
projection images with treatment beams, as shown in Figure 12.4B. There is no effective
MV scatter-reduction mechanism for EPID, which limits image quality. The amount of
scatter reaching the detector depends on the photon energy, field size, and thickness of
the imaged object; however, the imaging system can be optimized by calibrating the
system using site-specific phantoms (38).
The MVCT and MV CBCT images provide sufficient contrast to verify patient position
and to delineate many anatomic structures (38,39). It is interesting to note that the
MVCT numbers are linear with respect to the electron density of material imaged,
yielding accurate dose calculations (40). Another advantage is the reduced influence of
implanted metal objects on image quality, in contrast to kV CT, which exhibits strong
artifacts when high-Z material is present (Fig. 12.5).

FIGURE 12.4 A: A picture of tomotherapy unit (TomoTherapy Inc., Madison, WI) (Photograph courtesy of
H. Ning, PhD). Tomotherapy is an integrated IGRT system, which combines a linear accelerator with an
MVCT image guidance system. B: A Siemens MV CBCT imaging system using a conventional linac and a flat-
panel EPID. Reprinted from Morin O, Gillis A, Chen J, et al. Megavoltage cone-beam CT: system description
and clinical applications. Med Dosim. 2006;31:51–61.

Hybrid Cone-Beam CT and Digital Tomosynthesis


A hybrid CBCT can be achieved by combining orthogonal kV and MV x-ray projection
images with a partial arc gantry rotation as little as 90 degrees (41) while maintaining
projection images span an arc of 180 degrees. Acquisition requires only 15 seconds,
making it optimal for breath-hold imaging (42).

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FIGURE 12.5 Images showing the artifacts due to the presence of metal objects in the conventional kV CT
images (left panels). Artifact-free images were obtained with an MV CBCT (right panels). Reprinted from
Morin O, Gillis A, Chen J, et al. Megavoltage cone-beam CT: system description and clinical applications. Med
Dosim. 2006;31:51–61.

Digital tomosynthesis (DTS) is a special situation of tomographic reconstruction with


limited arc (20 to 40 degrees) of projection images (43–45). The DTS scan has short
time (<10 seconds), less radiation, but sacrifices spatial resolution in the direction
perpendicular to the x-ray beam. When necessary, a second DTS can be added quasi-
orthogonal to the first.

Respiration-Correlated (4D) Computed Tomography Imaging


Respiration-induced motion is an important consideration in some disease sites, in
which tumor motion up to 4 cm has been observed (46). CT scans acquired
synchronously with the respiratory signal can be used to reconstruct a set of CT scans,
representing the 3D anatomy typically at 10 respiratory phases. This collection of 3DCT
datasets is called respiration-correlated CT (RCCT), or 4DCT, which describes the
snapshots of patient’s 3D anatomy over one breathing cycle.

Respiration-Correlated 4DCT
Respiration-correlated 4DCT can be acquired in either cine or helical mode. In cine
mode, repeat CT projections are acquired over slightly more than one respiratory cycle
with the couch stationary while recording patient respiration; the couch is then
incremented and the process repeated. Following acquisition, the images are sorted with
respect to the respiratory signal, leading to a set of volume images at different
respiration points in the cycle (47,48). Helical scan uses a low pitch and adjusts the
gantry rotation period such that all voxels are viewed by the CT detectors for at least
one respiratory cycle (49,50). Both techniques have been widely characterized and
applied clinically for estimating the extent of moving tumors in lung and abdomen
(51,52).
The selection of the type of respiratory signal can vary, and commercial systems

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commonly use one of the two types of breathing monitors. One such monitor (Real-time
Position Management, RPM, Varian Oncology Systems, Palo Alto, CA) captures the
anterior–posterior motion of an infrared-reflective block placed on the patient’s
abdomen or chest using an infrared camera. The other is a “pneumo bellows” system
(Philips Medical Systems, Milpitas, CA) that records the digital voltage signal from a
differential pressure sensor wrapped around the patient’s abdomen. Periodic motion is
assumed in the binning approach and breathing irregularity adversely affects the
quality of 4DCT images, leading to anatomical distortions (53,54). Phase-based binning
assumes repeatable breathing cycles and often produces 4DCT images with greater
motion artifacts than amplitude-based binning (55,56). Reduction of motion artifacts in
4DCT is an active area of investigation and numerous methods have been proposed
(57–59).

Respiration-Correlated 4D CBCT
As CBCT is acquired with limited gantry speed at 1 rpm, motion artifacts are different
and more pronounced in CBCT than CT. Respiration-correlated 4D CBCT has been
developed similar to 4DCT (60,61). A slower gantry rotation is required to acquire
sufficient projections in each phase bin, resulting in scan times of 3 to 6 minutes. The
limited number of projections per phase reduces the contrast resolution and introduces
image artifacts; thus, the method is more suited to detecting high-contrast objects such
as tumor in parenchymal lung (60–62). Respiratory-correlated DTS has also been
reported (45). An alternative approach is to process the CBCT images with motion
correction using a patient-specific motion model (63,64). Most of the methods use
deformable image registration (DIR) to deform the images to a common motion state.
Motion-corrected CBCT allows normal scanning time and accurate tumor positioning
(65,66).

Magnetic Resonance Imaging


MRI is well known for its nonionization radiation imaging, high soft tissue contrast,
flexible image orientation, and versatile image appearance. The appearance of the soft
tissue can be manipulated with different pulse sequences, such as T1-weighted or T2-
weighted. The tumor visibility can be further enhanced by administrating a contrast
agent, such as a gadolinium-chelated compound. The magnetic field strength is 0.2
Tesla (T) for open-field MRI and 1.5 T or 3 T for a closed-field whole-body (≤70 cm
bore) MRI scanner.
MRI may suffer from geometric distortion due to nonuniformity of the magnetic field
strength. This scanner-specific factor can be corrected by imaging a large grid phantom
(67). The geometric integrity is also affected by susceptibility differences at tissue
interfaces. MRI yields limited visibility of bone owing to its fast relaxation time.
Recently, MRI-based treatment planning has been studied (68,69); an important area of
investigation is the conversion of MRI voxels to a CT number or electron density for
dosimetric calculation.
MRI-guided treatment delivery systems are an active area of development. An
integrated MRI-cobalt (60) machine (MRIdian System, ViewRay, Inc., Gainesville, FL)
was commissioned at several radiation oncology clinics in the United States in 2014
(70). An integrated MRI-linac system is under development by Philips and Elekta and a
prototype has been installed at the University Medical Center Utrecht in the
Netherlands (71). A third MRI-guided system that has been installed in Princess
Margaret Cancer Center nearing clinical implementation enables a rail-mounted 1.5-T

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MR scanner to operate in three different rooms: MR simulation, MR-guided
brachytherapy, and MR-guided radiotherapy linac (72). Such in-room systems offer
both soft tissue–based 3D target alignment and near real-time 2D tumor motion
monitoring (73). The goals are to provide online treatment guidance, adaptive
replanning, and monitoring of treatment response.

2D, 3D, and 4D MRI


MRI can produce 2D planar, 3D volumetric, and 4D temporal images (74), which are
scanned and reconstructed slice by slice. When a fast scan pulse sequence is applied,
such as TrueFISP (true fast imaging with steady-state precession), cine 2DMR images, or
2D(t), can be acquired at 4 fps without parallel imaging. At this acquisition speed,
respiration-induced tumor motion can be monitored for respiratory gating or real-time
tumor tracking.
A 3D volumetric MR image is potentially useful for MRI-based treatment planning
(68,69,75,76) with high soft tissue contrast without ionizing radiation. It is important
to minimize MRI geometric distortions (77), obtain the electronic density of MRI voxels
for dose calculation (69), and generate pseudo-DRRs as reference images to align with
2D radiographs for patient setup (78).
Four-dimensional MRI imaging provides time-resolved (TR) (79,80) or respiration-
correlated (RC) (76,81) volumetric images during respiration. TR-4DMRI requires
parallel imaging with multi-channel coils and parallel computing to achieve a temporal
resolution of 1 to 2 fps, while RC-4DMRI is achieved based on respiratory correlation.
Hu et al. (80) introduced an amplitude-based triggering system to acquire prospective
T2-weighted 4DMRI for abdominal tumor tracking. Tryggestad et al. (81,82) proposed a
method with two-step reconstruction to produce deblurred 4DMRI images and a method
to track tumor centroid motion using orthogonal cine 2DMRI to achieve local volumetric
information and sufficient patient-specific breathing statistics.

Positron Emission Tomography


PET is used increasingly for tumor delineation in treatment planning and for assessment
of tumor response to radiation treatment. Using a positron-emitting biologic tracer,
tumor metabolic, proliferating, and hypoxic conditions can be probed. A well-
established PET tracer is 18F-fluoro-deoxy-glocose (18F-FDG), a sugar-like molecule,
which accumulates in tumor cells owing to their high metabolic activities. In the event
of positron emission, the positron annihilates with an electron to emit a pair of 511 keV
photons in opposite directions. A PET scanner with a band of scintillation detectors
around the gantry detects the two coincident events and determines the event location
by the times of flight of the two photons. Similarly, SPECT uses gamma-emitting tracers
to image a tumor by detecting independent gamma-decay events.
Hybrid PET/CT, SPECT/CT, and PET/MRI scanners are commercially available, which
provide coregistration of viable lesions in a patient anatomy. Recently, in-room PET and
SPECT have been studied as a direct means for tumor positioning and tracking for IGRT
(12,83–85). For proton therapy, PET has been applied to directly image the by-products
of positron emitters, such as 15O, in the beam path and assess the geometric accuracy of
treatment delivery (84).

Ultrasound Imaging
Ultrasound is useful in soft tissue targeting in the abdomen for radiotherapy.

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Fontanarosa et al. have recently reviewed ultrasound guidance for external beam
radiotherapy (86).
The ultrasound transducer is both a sound source and detector. It transmits brief
pulses that propagate into the tissues and receives the echo that is bounced back at
tissue interfaces where acoustic impedance changes, owing to differences in tissue
density or elasticity. The round-trip time of the pulse-echo wave is used to determine the
transducer-to-object distances. A scan line converter constructs a 3D image of the
patient using 1D (with sweeping) or 2D transducer. Poor ultrasound image quality,
unfamiliar image appearance, and anatomy distortions due to applied pressure have
limited its utility for precise image guidance. The inter- and intrauser variability is large
for ultrasound-guided setup (87) and more pronounced for fiducial alignment (88).

Optical Surface Imaging


Stereoscopic OSI provides real-time imaging, primarily used for aligning superficial
tumors (the breast) or immobile tumors (the brain). A commercial OSI system (AlignRT,
Vision RT, Ltd., London, UK) is composed of two to three ceiling-mounted stereo-camera
pods, each having two cameras and a speckle projector. The triangulation among the
two cameras and a skin point identified by the cameras from the speckle pattern is used
to calculate the location of the point in space. A skin surface image is reconstructed
from all visible surface points with the accuracy within 1.0 mm.
Validated with x-ray imaging, OSI provides a quick and nonradiologic means for
image-guided setup. Early studies of surface imaging in radiotherapy were reported by
Massachusetts General Hospital (89) and Johns Hopkins University (90) in 2005. It has
been applied in breast, lung, brain, and head and neck. Patient setup requires to
register the surface image to a reference region of interest (ROI) defined on the
delineated patient body surface in a simulation CT. The discrepancy between OSI and
CBCT setup in brain cases is usually about 1 to 2 mm (27).
A different type of OSI is Cherenkov video imaging to visualize radiation delivery
relative to patient anatomy, such as the breast (13,91). The optical detection is gated
with the radiation pulse from a linac, providing a direct evidence of radiation delivery.

Patient Position Correction


Rigid body position correction has 6 DOF, including 3 translational (3T) and 3
rotational (3R) adjustments. Usually the alignment correction based on rigid
registration is performed in 3 DOF (3T), 4 DOF (3T + 1R for couch rotation), or 6 DOF
(3T + 3R) if a 6D couch or rotationally adjustable couch extension is used.
Translational correction is essential to align the tumor or tumor surrogate, while
correction for rotation may not be necessary. Deformable/mobile target position may be
corrected using the centroid position and 3 DOF position correction. The centroid of the
visible GTV in the thorax could be used for patient setup alignment (92,93), but may
result in substantial uncertainty in CTV alignment (94). This is still an area of
investigation.

INTRAFRACTIONAL REAL-TIME IMAGING AND MOTION


COMPENSATION
The main goal of real-time tumor tracking is to minimize the effect of target motion not
only at setup, but also during a treatment fraction. Tumor tracking usually requires

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real-time motion monitoring (detection) and motion compensation (execution) with the
minimal time delay. Although implanted markers are primarily used as surrogates for
target position using x-ray fluoroscopy, markerless approaches are emerging, including
MRI (82), EPID (95), fluoroscopy (96), CBCT projection images (97), and OSI (27,98).
In the following sections, we review different approaches for real-time monitoring and
tracking in photon radiotherapy.

Fluoroscopic Imaging with Implant Fiducials


Two commercially available room-mounted systems, as shown in Figure 12.6, are
CyberKnife (Accuray Inc., Sunnyvale, CA) and ExacTrac (BrainLAB AG, Feldkirchen,
Germany). Both are integrated IGRT systems for target localization, setup correction,
and the delivery of high-precision frameless SRS and SBRT. The image guidance uses
two distinct imaging subsystems: kV stereoscopic x-ray imaging and real-time infrared
(IR) marker tracking. CyberKnife provides fluoroscopy for target tracking, external
marker tracking, and can perform adaptive beam gating or real-time target tracking
(99). ExacTrac is designed for intracranial SRS or extracranial SBRT and can acquire x-
ray images at nonzero couch angles for verifying patient position (100). The 6 DOF
patient position adjustment is possible using 2D/3D image registration (section “Image
Registration and Fusion”).

FIGURE 12.6 Two room-mounted kV image-guided IGRT real-time tracking systems. A: CyberKnife system
(Photograph courtesy by Accuray Inc., Sunnyvale, CA). B: ExacTrac system, BrainLAB AG, Feldkirchen,
Germany (Photograph courtesy of BrainLAB AG.)

Gantry-mounted kV imaging systems usually have only one kV x-ray imager and
acquire an orthogonal image pair by rotating the gantry, including Varian’s OBI and
TrueBeam Imaging systems and Elekta’s Synergy and Infinity systems. The kV imaging
beam lines are orthogonal to the MV treatment beam line, sharing the same isocenter of
gantry rotation, as shown in Figure 12.3. The kV–MV configuration provides a
possibility to acquire images during treatment with alternated beam on time (101–103).
Studies have shown that EPID can capture at least one fiducial marker 40% to 95% of
the time in VMAT prostate treatment, while kV imaging can be used as needed for the
rest (104,105). VERO (BrainLAB AG Feldkirchen, Germany) is another gantry-mounted
linac system (Fig. 12.7), equipped with two orthogonal kV imaging and one optical
tracking systems (106). It provides CBCT, simultaneous orthogonal 2DkV imaging and
fluoroscopic imaging. Fast gantry tracking by a gimbal-based gantry system has a
latency less than 50 ms (107). Poels et al. have reported tumor tracking using both

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orthogonal kV and planar MV imaging to achieve 0.3 mm accuracy on phantom (108).
Clinical applications of VERO for SRS and SBRT have been reported (106,108,109).

Optical Fiducial Motion Surrogates


Optical tracking determines the position of an IR-emitting or reflecting marker via
triangulation from two stereoscopic cameras. Owing to its clean stereoscopic marker
images and simple calculation, it is capable of high spatial (0.1 mm) and temporal
(<0.05 s) resolution in marker tracking. Multiple markers can be tracked
simultaneously in real-time allowing continuous correction of patient position during
treatment. Meeks et al. have reviewed this technology in several implementations for
intracranial and extracranial SBRT (110). Markers can also serve as fiducials; but
variation in marker placement between simulation and treatment cause uncertainty.

FIGURE 12.7 A VERO system (BrainLAB AG Feldkirchen, Germany and Mitsubishi Heavy Industries,
Tokyo, Japan) (Photograph courtesy of Dirk Verellen, PhD). The system offers quick gantry movement aiming
to a moving tumor, guided by gantry-mounted stereoscopic x-ray imaging systems. Two rotations of the
radiation beam and 5 DOF couch are available in the system.

Video-Based Optical Surface Imaging


OSI utilizes the same principles as above to determine the position of a surface point,
which is identified with the assistance of a texture image projected onto a patient skin.
High spatial resolution is achievable although temporal resolution is limited by the
substantially increased number of points to track. The speed of 3D surface image
reconstruction depends on the size of the ROI and image resolution: for facial area with
high resolution, 2 to 5 fps is achievable (27). AlignRT (Vision RT, London, UK) is a
commercial optical surface monitoring system (OSMS) that has been integrated with the
Varian Edge system (Fig. 12.8A).
For surface alignment, a ROI should be created with sufficient reliable landscape on a
reference surface, which is either an OSI image acquired at simulation or an external
surface rendered from the planning CT image imported via DICOM-RT. The image
registration algorithm is based on an iterative-closest-point method leading to an
efficient and robust surface alignment of the ROI. Clinical setup time can be less than 2
minutes with high accuracy and reproducibility (27).
The real-time surface matching capability has been applied to head motion

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monitoring during frameless SRS (27,98). Using an OSI image captured at treatment as
reference, systematic errors of the OSI system can be cancelled, yielding 0.2 mm
accuracy for rigid motion detection. For nonrigid anatomy, an OSI-based spirometry has
been reported (111), aiming to utilize all respiration-induced external motion to predict
tumor motion via physical relationships (112).

Real-Time Electromagnetic Localization and Tracking


Tracking of implanted fiducials without ionizing radiation imaging is possible with a
technology that uses radiofrequency (RF) electromagnetic fields to induce and detect
signals from implanted “wireless” transponders (Calypso, Varian Medical Systems).
Electromagnetic tracking is now an integrated component of Varian’s Edge treatment
machine, as shown in Figure 12.8. The system consists of a console, optical tracking
system, and tracking station. The console is situated near the treatment couch with a
magnetic array panel extended above and close to the patient surface. The array panel
contains RF source coils to excite the transponders and sensor coils to detect the
transponder response signals, each at a different resonant frequency for unique
identification at 10 Hz and submillimeter accuracy (113,114). The Calypso system can
be implanted in soft tissue throughout the body except in lung, which is currently under
clinical studies (115).

FIGURE 12.8 Two nonionizing motion-tracking systems equipped for the Edge System (Varian Oncology
Systems, Palo Alto, CA). A: Photograph of the system with the OSMS and Calypso systems. B: A diagram
showing the prototype AC electromagnetic field tracking system with the detector array and the infrared cameras
(Calypso, Varian Oncology Systems, Palo Alto, CA). The Beacon transponder is shown in the inset.

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FIGURE 12.9 Two integrated MRI-guided treatment units. A: A schematic of a prototype MRI-guided real-
time tracking system for IGRT (MRIdian, ViewRay, Inc., Gainesville, FL). The system is designed to have a
low-field open MRI for real-time imaging and three-headed Cobalt source for intensity-modulated gamma ray
irradiation (Photograph courtesy of James Dempsey, PhD). B: A prototype of MRI-Linac system (by Philips
Medical Systems, Milpitas, CA and Elekta Inc., Sweden) with a 1.5T split magnet and a 6MV Linac
(Photograph courtesy of Jan Lagendijk, PhD).

MRI Real-Time Cine Imaging


An integrated MRI-guided cobalt machine (Fig. 12.9A) is commercially available as an
IGRT system (70), which consists of a low-field open MRI system and three cobalt
irradiation sources. Three computerized double-focused multileaf collimator systems
provide intensity-modulated gamma-ray beams, which have lower energy and larger
penumbra than a linac. The technology emphasizes the MRI-guided, near real-time (4
Hz) imaging system, which can track soft tissue targets and OARs without interrupting
treatment delivery.
Integrated MRI-linac systems are an active area of development (71,116,117). It has
a design similar to the MRI-cobalt system in that the radiation beam is perpendicular to
the magnetic field between two split magnets (Fig. 12.9B). The linac waveguide is
shielded from the magnetic field (1.5 T) and RF signal of the MRI unit. However, the
magnetic field interacts with secondary electrons generated in the patient, thereby
affecting the dose distribution (118). The effect is most pronounced at tissue-air
interfaces, where exiting electrons return to the tissue as a result of the Lorentz force
and locally deposit additional dose. On the other hand, the beam modifiers, such as
MLC, can affect the homogeneity of the magnetic field (119).
A fast scan sequence, such as balanced steady-state free precession, is required for
cine 2DMRI (∼4 Hz) and TR 4DMRI (2 Hz) that uses parallel imaging and
approximation in image reconstruction (79,120,121). Respiratory-correlated 4DMRI is
also available (80,81). MRI can sample more respiratory cycles without ionizing
radiation for treatment simulation and planning.

PET Real-time Imaging


In PET/SPECT imaging, the radiation source is the viable tumor, which is also the target
of radiation therapy. In principle, in-room PET/SPECT imaging could provide tumor
position in real time. Fen et al. proposed emission-guided radiotherapy (EGRT) that
combines a PET scanner with a linac (85). In this study, dose delivery was simulated

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using Monte Carlo computation in a digital patient. Yang et al. investigated the
feasibility of using list-mode PET imaging to guide beam tracking of tumor motion in a
phantom study with 1D or 3D motion tracers (122). The current method requires 10
seconds to determine tumor centroid position; thus needs further improvement for
motion tracking. Yan et al. investigated the construction of an in-room SPECT system
for functional image guidance (83). The studies are in early stages of preclinical
research.

Real-Time Tumor Motion Compensation


Real-time tumor tracking refers to continuous adjustment of the radiation beam or
patient position during treatment so as to follow the changing position of the tumor or
its surrogate. In principle, real-time tracking provides a combination of increased
normal tissue sparing relative to motion-encompassing methods by reducing the
treatment margin, and more efficient treatment with near 100% duty cycle relative to
gated treatment. In the following sections, we summarize three strategies in various
stages of development involving motion tracking of a linac system.

Dynamic Multileaf Collimator Approach


Keall et al. have demonstrated motion tracking using dynamic MLC (DMLC) (123). The
Calypso system provides a near real-time motion signal in prostate with better than 2
mm accuracy and 220 ms system latency (114). One concern of this motion
compensation method is the anisotropic tracking resolution owing to MLC
characteristics: Depending on whether target motion is along or perpendicular to the
leaf motion, the spatial resolution for tracking is either <1 mm (the leaf motion) or 2.5
or 5 mm (the leaf width). Different strategies to optimize leaf trajectories have been
studied (124,125). Zimmerman et al. have demonstrated motion tracking with intensity-
modulated arc therapy (126). Motion-tracking radiation delivery has been demonstrated
using cine 2DMRI for image guidance in motion phantom experiments (127). Keall et al.
have reported the first clinical experience on DMLC tracking of Calypso transponder for
a prostate treatment (128).

Mobile Treatment Couch Approach


D’Souza et al. have proposed compensation of the tumor motion using a robotic couch
(129). Unlike the DMLC approach, this method can compensate for 3D tumor motion
with isotropic system responses; however, there may be patient-related physical and
medical concerns. For instance, couch motion could induce a counter-reaction from the
patient, body shift, or tissue deformation when changing motion directions, especially
for obese patients. Varian 6D couch is capable of motion tracking but has not released
for clinical use, while developments on mobile couch/extension have been shown (130).
Menten et al. have illustrated comparable motion compensation between the mobile
couch tracking and DMLC tracking (131).

Movable Gantry Approach


The CyberKnife has a 6D robotic arm to position a light-weighted linac and a 6D robotic
couch to align a patient and provides the first clinical solution for tumor tracking (99).
The robotic arm can move at speeds of several centimeters per second, which makes it
compatible with tracking respiration-induced tumor motion. The VERO system is
designed for image-guided tumor tracking (Fig. 12.7). Based on a gimbaled design, the
beam can rotate transversely (panned) or longitudinally (tilted) to track implanted

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fiducials in or near the tumor with the maximum motion range of 4.4 cm (or 2.5
degrees) at the treatment isocenter and a latency of 50 ms for 4DRT (107,132,133). The
latency effect will be discussed in “Management of Intrafractional Tumor Motion”.

IGRT REQUIREMENTS AND CONSIDERATIONS


IGRT Commissioning and Quality Assurance
Commissioning and QA of IGRT-enabled technologies are essential. The American
Association of Physicists in Medicine (AAPM) has issued several task group (TG) reports,
covering in-room kV x-ray imaging for patient setup/target localization (TG#104)
(134), QA for nonradiographic imaging for patient setup/target localization (TG#147)
(135), QA for CT-based IGRT technologies (TG#179) (136), QA for medical accelerators
(TG#142) (137), SBRT procedures (TG#101) (138), and management of respiratory
motion (TG#76) (46). These reports provide guidelines for clinical use and QA of the
IGRT imaging systems and procedures. In the following, we summarize three important
aspects: geometric accuracy, image quality, and motion detection.

Coincidence of Imaging and Treatment Isocenters


One of most important tasks in commissioning an in-room imaging modality is to
compare the imaging isocenter with the treatment isocenter. Conventionally, it is
paramount to check the alignment of radiation isocenter, mechanical isocenter, and
laser isocenter. When using IGRT, coincidence of imaging and treatment radiation
isocenters must be initially and periodically checked to ensure that discrepancies are
within clinically acceptable tolerances. The MV-EPID is used as the gold standard as it
provides direct reference to the treatment beam. For stereotactic procedures, the
discrepancy must be within 1.0 mm; otherwise, it should be within 2.0 mm (137) for
conventional treatments. A calibration procedure is required to correct mechanical
sagging for kV imaging and EPID detectors (38,139). Customized QA phantoms have
been developed for different IGRT systems, including kV and MV imaging systems of C-
arm linacs (137,140) and MVCT imaging of tomotherapy units (141). To determine the
geometric accuracy of IGRT for SRS/SBRT, an end-to-end (from simulation to delivery)
test is recommended, by comparing the alignment of the center of the delivered MV dose
distribution with the planned isocenter (106,142).

Image Quality
Bissonnette et al. have established a QA program for CBCT image quality with the Elekta
Synergy and Varian OBI systems (29,30,74). The report evaluates flat-panel detector
stability, performance and image quality of 10 linac imaging systems over a 3-year
period. Details for correcting background (dark current) and pixel-by-pixel gain
uniformity (flood-field image) of the plat-panel detector are also described. The CatPhan
500 phantom (The Phantom Laboratory, Salem, NY) is used to quantify image quality
(143). A comprehensive QA program by Yoo and Yin describes safety, functionality,
geometric accuracy, and image quality for the Varian OBI system (144). Image quality
characterization and QA procedures for EPID (145), MV CBCT (146), and MVCT in
helical tomotherapy (141) have also been reported. A stereotactic head phantom (Model
605 Radiosurgery Head Phantom; CIRS, Norfolk, VA) or equivalent is used for imaging
QA of the CyberKnife system (147).

Motion Detection

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Clinical motion management guidelines have been published in AAPM TG#76 (46),
pertaining to respiration-induced motions of the target and normal tissue. For
fluoroscopic imaging, temporal resolution should be 100 ms or less, which produces a
uncertainty of <2 mm for an object moving at speeds up to 2 cm/s. Jiang et al. have
outlined major clinical challenges in respiratory-related procedures, including
respiratory gating, breath hold, and 4DCT (148). As external surrogates are used in
many respiratory gating and breath-hold procedures, the biggest challenge is to ensure
treatment accuracy. Indeed, many have reported the limited reliability of internal–
external correlation using external fiducials. When external monitoring is used,
verification of internal–external correlation using image guidance prior to each
treatment session is needed.

Image Registration and Fusion


In IGRT context, image registration serves to align daily 3D or 2D patient setup images
with the planning CT or DRR images, respectively. Uncertainty in image registration
increases when the underlying anatomy changes, including motion, deformation, or
physical changes. To minimize the uncertainty, image registration often focuses on the
vicinity of the tumor using surrogates, such as the bone and fiducials. Visual
verification with necessary manual adjustment is essential after automatic image
registration. The three orthogonal views of fused 3D images are evaluated using color
blending, checkerboard, or split windows. Direct evaluation of 3D volumetric image
rendered by GPU-based, real-time computation is also possible (149,150). QA of the
image registration and fusion methods should be performed using an appropriate
phantom (151).

Rigid Image Registration


Most image registration tools used for IGRT are rigid registration using a rigid
transformation. In addition to deformation-related uncertainty in rigid image
registration, uncertainty may come from interobserver variation during manual
alignment. Registration accuracy, couch adjustment accuracy, kV–MV isocenter
discrepancy, couch walk for noncoplanar beams, and patient motion after image
acquisition determine the overall setup accuracy for tumor localization.
Rigid image registration in a volume of interest (VOI) is more clinically relevant in the
presence of tissue or patient setup deformation. Zhang et al. (152) and van Kranen et
al. (153) have reported using multiple VOIs for rigid registration to evaluate the local
deformation among the three-to-nine different VOIs in the head-and-neck region. Park et
al. have developed a spatially weighted image registration method to allow users to
define the structure of interest (154). Mencarelli et al. developed an automatic detection
system with multiple VOIs to account for posture variation during head-and-neck setup
(155).
A 3D/3D (CBCT/CT) registration is the standard to achieve 6 DOF. Registration of an
orthogonal pair of 2DkV to CT (2D/3D) can also achieve 6 DOF by using multi-DRRs
with small rotational increments. This technique has been employed in CyberKnife,
BrainLab, and Varian’s OBI with accuracy of 1 mm/1 degree or less in 6 DOF alignment
of bony structure or fiducial markers (100,156).

Deformable Image Registration


DIR may not be suitable for setup correction using couch adjustments, as rigid
transformation cannot effectively compensate for tissue deformation. Nevertheless, DIR

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is essential for contour propagation and delivered-dose estimation: it is a useful tool for
adaptive IGRT. Since 2007, DIR has been intensively studied focusing on deformation
algorithms, physical constraints, self-consistency, and accuracy assessment (157,158).
The uncertainty of DIR is 2 to 3 mm on average. DIR can track deformed anatomy voxel
by voxel between two 3D images, producing a deformation vector field (DVF) useful in
the following three IGRT areas (92,159–161).
First, the DVF provides complete motion transformation matrix between two stages of
motion and useful for motion modeling. To simplify and expedite calculation, Zhang et
al. have shown that the combination of DIR with principal component analysis (PCA)
provides a patient-specific motion model (162). The 4DCT-derived DVF has been applied
to generate motion-compensated CT, CBCT, DTS, and PET with reduced motion artifacts
(58,66,163).
Second, the DVF can be used for contour propagation, which is essential for 4D and
adaptive IGRT, as illustrated in Figure 12.10. Wijesooriya et al. have studied the
accuracy of automated segmentation among different phase CT images in 4DCT by
comparing 692 pairs of automated and physician-drawn contours. The surface
congruence of the GTV and OARs was within 5 mm in >90% cases (161). Wang et al.
have applied DVF to propagate planning contours to daily CBCT in lung and head-and-
neck cancer patients, and found the volume overlap index to be 83% with reference to
physician-drawn contours (164). Physician evaluation of these propagated contours is
highly recommended, especially in the presence of motion and metal artifacts (160).
Third, the DVF can be applied to map a dose distribution. This method has been
applied to 4D planning using 4DCT (123) and for estimating delivered dose using daily
setup CBCT (165), which is essential for adaptive IGRT (166,167). The mapped dose is
only an estimate as tumor shrinkage and weight loss make the mapping unreliable
(168,169). Li et al. compared energy/mass transfer and direct dose mapping in 10 lung
patients and found noticeable dose differences (11% in PTV) (169). Calculation based
on deformed anatomy should provide more accurate dose distribution (170,171).

IGRT Concerns in Simulation and Planning


Although IGRT focus on target alignment in treatment delivery, they are strongly
related to simulation and planning (172,173). As mentioned before, the planning CT
acquired is a snapshot of patient anatomy and may not be representative at treatment.
The variation can be mitigated by preparatory procedures such as hydrogel spacer
placement. Qi et al. (172) have shown an adaptive multi-plan method, in which nine
treatment plans for each patient were produced to cover the most probable prostate
positions relative to the nodes. An alternative method is to perform online (immediately
prior to treatment) reoptimization of the treatment plan (174).

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FIGURE 12.10 Automated image segmentation of multiple repeat CT datasets. In this head-and-neck
example, contours drawn manually on the planning CT were deformed to obtain contours for repeat CT scans
obtained during the course of radiotherapy. Deformations were carried out using transformation matrices based
on deforming planning CT image to match each of the repeat CT images. Such automatic segmentation tools,
once validated by clinical studies, would make adaptive replanning practical.

Information Technology Infrastructure for IGRT


Implementation of IGRT into routine clinical workflow requires tighter integration of
imaging and treatment systems and more efficient information flow. IGRT represents a
shift from a traditionally static treatment planning process to a more dynamic, close-
loop process with multiple feedback check/control points. To meet the technical and
logistical needs, the following infrastructure and software tools are considered
important to IGRT applications:

IGRT Data Management:

• Picture Archival and Communication Systems specifically designed for radiotherapy


(RT-PACS) are needed that integrate IGRT workflows, data management, user
interfaces, and statistical tools among different imaging and treatment procedures.
• The Integrated Health Enterprise in Radiation Oncology (IHE-RO) (175) endeavors to
specify and address specific clinical problems and ambiguities including those for
IGRT. It aims to overcome the shortcomings of the Digital Imaging and
Communications in Medicine (DICOM) in radiotherapy (RT), which is the current
industry standard (176).
• Treatment management systems play a central role in integrating image guidance and
treatment delivery systems. With more frequent use of 2D, 3D, and 4D multimodal
images and possible adaptive replanning during the course of treatment, data storage
requirements can increase one to two orders of magnitude.

IGRT Facilitating Tools:

• Tools for both rigid and DIR are necessary for implementing various IGRT approaches
(92) (159).

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• Automatic treatment planning and optimization are needed to perform plan
adaptation to changing anatomy or altered target volumes (177).
• Cross-platform treatment plan comparison tools are needed for multi-institutional
studies. The computational environment for radiotherapy research (CERR) (178) and
deformable image registration for adaptive radiotherapy research (DIRART) (159)
provide a common platform for treatment plan database and tools for clinical outcome
research and analysis.

Selection of IGRT Technology


The selection of an appropriate image-guidance solution is a complex process that may
involve a compromise among clinical objective, product availability, existing
infrastructure, manpower, and resources (9,179). The implementation of an IGRT
technology in the clinic requires a thorough understanding of the complete clinical
process and the necessary infrastructure to support data collection, analysis, and
intervention. The four considerations: clinical, technical, resource, and administration,
suggested by the AAPM TG#104 report (134), may evolve with industry trend.

IGRT CORRECTION STRATEGIES AND APPLICATIONS


Online Versus Offline Corrections
The establishment of a particular clinical process for correcting patient position based
on the data from various clinical studies is referred to as a correction strategy.
Strategies are broadly divided into online and offline approaches. The online approach
makes adjustment to the current session of treatment based on data acquired. This may
be as simple as couch position adjustment or as complex as a full-plan reoptimization
for adaptation. The offline approach is to intervene treatment at a later time, such as
weekly physician review of portal images and replanning in response to patient changes
(180). The online approach has a greater capacity to increase precision than offline
strategies, but at the cost of a higher workload. A hybrid correction strategy is often
used clinically with different error thresholds and time allowance (9,10,177,179).
In an accuracy-demanding procedure, such as frameless SRS, IGRT patient setup and
motion management can take a large portion of treatment time (27). The overhead
associated with the alignment tools and decision rules can be prohibitive unless
properly integrated. The adaptive radiotherapy program at William Beaumont Hospital
(166,167,181) was made possible only through in-house software integration efforts.
For 4D tumor tracking, additional automatic tools are necessary to support online
correction in the intrafractional intervention.

Correction of Interfractional Setup Error


Various techniques have been developed for pretreatment setup corrections. Without
loss of generality, we consider an in-room CT-guided IGRT system (Fig. 12.11).
Following patient immobilization and alignment of skin marks with room lasers, or
using OSI for alignment, a CBCT is acquired and aligned with the planning CT. The
primary means of intervention is correction of translational deviations, since rotational
corrections are small for single lesions enclosing the isocenter. For multiple lesions with
a single isocenter, rotational deviations may be important and can be corrected using a
6 DOF couch with isocentric rotation. The second level of intervention may be dose

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based. Ideally, the treatment goal would be based on the delivered dose distribution.
The CBCT images of the patient’s treatment anatomy make it possible to estimate the
delivered dose distributions and to calculate accumulated dose. Accumulated dose
deviations can be corrected infrequently using an offline adaptive correction scheme
(177,181).

FIGURE 12.11 An in-room volumetric CT-guided radiotherapy process. CT images of patient’s setup and
anatomy information are acquired and sent to an alignment workstation where the images are compared and
aligned to match with the planning CT. An interventional decision is made based on the magnitude of anatomic
variations to assess the need for an online or off-line correction. If necessary, dose tracking may be enabled and
used for replanning.

Management of Intrafractional Tumor Motion


In the presence of significant intrafractional motion, additional geometric and
dosimetric variations should be taken into account, which will increase treatment
complexity. Not surprisingly, most motion managements are related to the treatment of
lung and abdominal cancers (46,74,177). In patient setup with a mobile tumor,
localization of implanted fiducials using fluoroscopy can be achieved by aligning the
track of the implanted marker with the track discerned from the reference 4DCT. Bony
landmarks may not be used for setup alignment since the tumor motion trajectory
relative to the bony landmark may change (182). Soft tissue imaging with direct target
alignment using 4D CBCT or cine 2DMRI would be more preferable.
Real-time monitoring of implanted fiducials, or of the tumor directly, is needed for
accurate gating of radiation treatments. Respiratory gating used at simulation may be
used to control dose delivery during the quiescent period around end expiration. MLC
motion is intermittent during gated IMRT, thereby reducing possible interplay effects
between MLC and respiratory motions (183). Audiovisual feedback may improve
breathing regularity and breath-hold reproducibility (184,185), and can be used in
respiratory-gated treatment. In voluntary breath-hold, the beam is enabled when the
inspiration level is within tolerance of the planned level (186). Reproducible
involuntary breath hold may be achieved using active breathing control developed by
Wong et al. (187).
There will be a time delay from motion detection to the action of beam hold or motion
tracking, usually 100 to 400 ms (188,189). This latency can cause a targeting error of 1
to 2 mm (104), critical to tumor tracking. A predictive model can be used to anticipate
the tumor position to reduce the latency-caused error to gain submillimeter accuracy
(127,190). Tumor motion can be predicted using external markers based on a motion
correlation model, and such a model needs initially calibration and periodic verification

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and update by frequent imaging measurements (133,191).

Population-Based and Individualized Margins


The relative importance of systematic and random errors in the determination of PTV
margins should be considered in the design of a clinical strategy. Geometric errors in
radiation field placement are typically characterized by distributions of nonzero mean
and variance. The mean represents the systematic discrepancy while the variance
represents the random component. The relative importance of these two categories of
errors may vary in determining appropriate PTV margins (192,193). The reported
margin formula may not completely general, as the number of fractions is not
concerned, especially for SBRT cases with five treatment fractions or less.
A treatment margin depends not only on the imaging modality chosen and tumor
surrogate used, but also on the type of patient immobilization and motion management
technique employed. For respiratory motion, breath hold, abdominal compression,
respiratory gating, or motion tracking manage tumor motion at different levels. As a
consequence, the margin added to form the internal tumor volume (ITV) will be reduced
relative to that for a motion-encompassing ITV (166,194). The overall margin is the sum
of uncertainties from inter- and intrafractional motions.
In lung, patient-breathing irregularities add another level of uncertainty and
complexity for the treatment. Grills et al. proposed a margin formula that contained
components of both population-based and patient-specific systematic and random errors
(195). Such a margin formula was applied to CT-guided setup of lung cancer cases,
resulting in a 65% to 75% margin reduction. To compensate for baseline drift, Pepin et
al. have reported using a dynamic-gating window (196). As the tumor motion is patient
specific and determined using 4DCT, individualized ITV margin is often applied in lung
cancer treatment (195). However, 4DCT-based motion simulation is based on single
respiratory cycles and thus could be statistically unreliable (197). Motion simulation for
ITV derivation based on 4DMRI or cine 2DMRI have been proposed and investigated
(81,82,198).
In prostate cases, IGRT margin reduction is one of the most dramatic examples in all
anatomic sites. With in-room CT guidance, a 3-mm margin was reported adequate for
prostate dose coverage, but may lose some of the seminal vesicles coverage due to daily
variation in rectal and bladder filling that causes local deformation (199). A
comparative study using four different IGRT setup methods, skin marks, 3D bony
landmarks, 3D fiducial markers, and Calypso transponders has shown that the last two
methods can achieve 4 mm and 3 mm margin requirement, respectively (200). Another
study has compared four setup techniques using skin marks, 2D bony registration,
ultrasound guidance, and in-room 3DCT (201). A recent Calypso study has shown that
a margin of 2 mm would produce sufficient CTV dose coverage based on 1,267 tracking
sessions of 35 patients (202). Figure 12.12A demonstrates that the alignment accuracy
increases along with the complexity of the alignment technology: from skin to bone to
ultrasound and to CT (8). The dosimetric result for one patient exhibiting large organ
motion is shown in Figure 12.11B.

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FIGURE 12.12 A: Patient setup accuracy of prostate cancer using different in-room imaging modalities.
Generally, the accuracy increases with imaging frequency, dimension, and use of fiducial. The skin mark and
ultrasound setup have largest variation, as indicated by the error bars. The margin could be reduced from 8 to 2
mm based on this finding. Reprinted with permission from Mageras GS, Mechalakos J. Planning in the IGRT
context: Closing the loop. Semin Radiat Oncol. 2007;17:268–277. B: Target coverage based on various types of
image-guided setups for treatment. In this example, 24 treatment-time CT scans of a prostate cancer patient
were used to compare the effectiveness of four alignment techniques for patient setup using a fixed-margin
IMRT plan. The minimum target dose is lowest (59.3 Gy) for skin marks–based setup and highest (76.0 Gy)
for the CT-guided setup. The day-to-day variations in the minimum dose (represented by the error bars) are
smallest for CT-guided technique and largest for skin-mark and ultrasound-guided techniques.

Anatomic Variations and Dosimetric Consequences

Inter- and Intrafractional Variations in Anatomy


Substantial inter- and intrafractional organ variations and setup uncertainties of lung,
liver, diaphragm, gynecologic, prostate, seminal vesicles, bladder, and rectum have been
reviewed by Langen and Jones (203). Even with careful immobilization and alignment
of the patient, significant changes occur because of the nonrigidity of anatomy, bowel
gas movement, and variable fillings of the bladder (204). Li et al. reported
interfractional anatomic variations for all major sites based on daily CT assessment
(205). Target and OAR variations may follow certain trends, including tumor volume
shrinkage up to 12 months after initial hormone treatment (206), radiation-induced
tumor shrinkage, and disease-related weight loss. Figure 12.13A shows a side-by-side
comparison of a head-and-neck target volume that has shrunk significantly during the
course of treatment. The skin contour no longer matches well with the immobilization
mask. Changes in target volume and OAR position could have significant clinical
consequences (152,153). During a prostate IMRT treatment, changes in bladder filling
can cause prostate and OARs to move away from the planning position, as
demonstrated in Figure 12.14.

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FIGURE 12.13 A: An example of setup error for a patient immobilized with a thermoplastic facemask due to
tumor shrinkage as treatment progresses. Approximately half-way through the treatment course (right panel),
the lower neck was not centered on the headrest, presumably due to the relatively “roomier” mask. B: Dosimetric
impact of interfractional variations in head-and-neck anatomy. The solid lines show the volumes of the parotid
glands (left and right) decreased as the treatment progressed. At the same time, the centers of both parotid glands
also moved medially due to tumor shrinkage and weight loss. As a result, the percent of parotid volume
exceeding 26 Gy increased by least 10% over the course of radiotherapy.

Dosimetric Effects due to Interfractional Motion


The common approach to evaluating a delivered dose is to use the daily setup 3DCT
images and actual dynamic leaf sequence from a treatment log file for dose
reconstruction (207). To generate a cumulative dose distribution over multiple
fractions, dose mapping based on DIR is applied to a reference image for final dose
evaluation (161).
In prostate cases, it is reported that 25% (8/33) of patients would have geometric or
dosimetric miss without daily MVCT guidance to improve prostate localization (208).
Obese patients and patients with large daily rectal motion would be most subject to such
marginal miss. van Herk has pointed out that the systematic uncertainty is more
important and should be minimized (192). Langen et al. have investigated the
dosimetric consequences of prostate motion during helical tomotherapy for 16 patients
with 515 daily MVCT scans (209). The study finds that the mean change in target D95%
is 1 ± 4% and the average cumulative effect is smeared out after five fractions. In
individual fractions, the D95% may be off by up to 20%. For normal tissues such as the

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rectum, Chen et al. have reported that daily dose variation caused by rectal volume
changes is significant and 27% of treatments would benefit from adaptive replanning
(210). Wen et al. have calculated actual accumulated doses with three PTV margins of
10 mm (6 mm at anterior rectum), 5 mm (3 mm) and 3 mm (isotropic) (211). With
calculated TCP and NTCP values in eight early prostate patients, they suggested that
margin reduction resulting from IGRT was an effective means to improve the
therapeutic ratio. Clinically, Sveistrup et al. compared 388 IG-IMRT with 115 non-IG
3DCRT treatments and shown grade 2 or higher toxicity of 5.8% versus 57.3%,
respectively (7). Zelefsky et al. conducted a clinical study with 186 IGRT and 190 non-
IGRT treatments and demonstrated significant improvement in biochemistry control at 3
years among high-risk prostate patients with IGRT versus non-IGRT (97% vs. 77%, p =
0.05) (212).

FIGURE 12.14 Intrafractional variations of anatomy observed in a prostate patient in the span of 20 minutes.
CT images were acquired just prior and immediately after an IMRT treatment fraction. The contours of pelvic
anatomy before treatment (left) are overlaid on the CT image of the patient acquired immediately after the
treatment (right). Prostate target (red) was displaced anteriorly for >5 mm.

In head-and-neck treatments, it is desirable to reduce the dose to the parotid glands


in order to minimize the incidence of late xerostomia (213). Unfortunately, the parotid
glands can decrease in volume and move medially during the course of treatment (214).
As a result, parotid mean dose increased by 10% and exceed 26 Gy (Fig. 12.13B). A
single mid-course correction to adapt the treatment plan to the anatomical change can
help reduce the dose for both parotid glands (215).

Dosimetric Effects of Intrafractional Motion


The dosimetric consequence of intrafractional breathing motion for lung tumors can be

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demonstrated by 4DCT-based planning. Figure 12.15A shows a case study that used a
free-breathing CT image to design a treatment plan with an inadequate 8-mm margin to
cover the CTV (shown in yellow). The actual dose distribution does not cover the entire
target volume in some of the breathing phases due to respiratory motion, which is not
detected in the free-breathing CT. Using DIR, the cumulative dose distribution from the
10 individual phases is calculated and mapped to a free-breathing fast CT scan (near
phase 7). The resultant cumulative dose distribution summed from the entire breathing
cycle shows a dose deficiency in the CTV (red arrow), as illustrated in the bottom row of
Figure 12.15B. In this case, the cumulative dose distribution when using the ITV
derived from the 10-phase 4DCT does not underdose the target but results in treatment
to a larger volume. Wu et al. have compared three delivery techniques, 3DCRT, IMAT,
and IMRT, in five treatment cases in liver, with tumor motions ranging from 0.5 to 1.75
cm. The variation in CTV D95% is largest (−8.3%) for IMRT and smallest (<2%) for
3DCRT, with negligible dose–volume histogram variations for normal tissues (216). Kuo
et al. have found that with an adequate margin for motion, D95% variation is <2% in
the CTV (217). However, the representation of respiratory motion during treatment
using the one-cycle 4DCT simulation has been questioned, and a longer 4DMRI
simulation has been suggested (82,198).

Adaptive Approaches for Correcting Dosimetric Deviations


William Beaumont Hospital has pioneered the adaptive radiotherapy strategy by using a
purpose-built treatment planning system to facilitate offline dosimetric evaluation and
replanning (167,181). Without the support from a more automated planning system,
routine replanning is not feasible. Recently, studies from several groups have focused on
implementing an automated treatment planning system (218,219) and an automatic CT
simulation optimization strategy (220). Predictive treatment planning (221),
incorporating tumor regression model from the start, represents a new approach to
adaptive radiotherapy, which may yield more flexibility in accounting for variations.

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FIGURE 12.15 A: Potential consequence of respiratory motion on target coverage. An IMRT plan, developed
using conventional CT, was applied to the patient’s 4DCT. Dose distributions were calculated in each of the 10
phases of the breathing cycle. A portion of the CTV, shown in thick yellow line, was not covered by the 70 Gy
prescription dose line (red) in phases 1 through 4. B: Comparison of a treatment plan as perceived on a free-
breathing CT (top row) and as realized after accounting for breathing motion in all 10 phases (bottom row). The
latter was obtained by summing dose distributions computed on individual phases of the 4DCT image (A), and
mapped to a reference CT image using deformable image registration (DIR).

Mageras and Mechalakos have discussed treatment planning in the IGRT context and
the various challenges to treatment-plan adaptation strategies in various disease sites
(8). An alternative planning approach to evaluating a PTV is to simulate motion and
other uncertainties directly in the dose calculation, resulting in dose distributions of not
only the CTV but also OARs.
The adaptive concept as applied to radiotherapy practice derives from modern
informatics and control theory. Offline adaptation has been implemented for various
disease sites in various institutions (180,222), and online replanning has been reported,
with computation time within 5 to 8 minutes (174). Oh et al. have reported on a hybrid

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adaptive approach (online MRI guidance and offline replanning) applied to 33 cervical
cancer cases to overcome the substantial organ motion and tumor shrinkage (180). The
knowledge gained from geometric and dosimetric variations via clinical IGRT research
will be useful for guiding the treatment planning in certain clinical scenarios. Four-
dimensional MRI should provide an advantage in this respect.

Future Directions
Image-guided radiotherapy is commonly considered in the context of treatment delivery,
but it is more appropriate to broaden its scope to include imaging at other stages of the
radiotherapy (10). We, therefore, briefly discuss future directions as they apply to this
broader definition.
We believe that further advances in IGRT rely on the innovation and integration of
automated technologies to facilitate evaluation and decision-making processes.
Automation in treatment simulation, planning, and delivery will be active areas of
investigation, allowing standardization of treatment planning based on a planning
library with optimal plans of all anatomical sites and planning techniques. Technologies
such as graphics processing unit (GPU) (97,149) and cloud computing (223,224) allow
online 3D/4D image reconstruction, online plan reoptimization, and real-time tumor
tracking. A new clinical workflow for adaptive IGRT would be implemented with focus
shifting from routine planning process to personalized plan tailoring, plan QA, and
treatment assessment and adaptation.
Further employment of multimodal imaging in both simulation room and treatment
room will be an active area of development. Functional imaging provides viable tumor
volumes for planning and biologic image guidance for treatment. In-room MRI has
visualized a moving tumor and OAR during treatment for the first time and could assist
to minimize the chance of a marginal miss. Treatment verification may be augmented
with in-room PET, SPECT, MRI, or Cherenkov OSI. Cine 2DMRI and 4DMRI with
visualization of tumor and OAR is more clinically desirable for tumor motion assessment
at simulation and tumor motion monitoring during treatment. MRI-based treatment
planning can change the radiotherapy paradigm, especially in conjunction with the
integrated MRI-cobalt or MRI-linac units, realizing adaptive IGRT clinically.
Treatment response evaluation using multimodality imaging will continue to be an
active area of investigation. Due to complexity of radiation response, a multilevel
approach at molecular, cellular, organ, and physiologic levels is more likely to yield
useful information. Different biologic tracers could be designed to probe proper biologic
attributes, such as DNA double-strand breaks or cellular membrane rupture. Ideally,
response assessment within the treatment course would be most beneficial for
individualized treatments, while the reality is lack of an effective assessment index even
after treatment. A response-driven, biologically adaptive radiotherapy is still distant
from clinical practice. The dosimetric feedback loop, which is within reach and will
ensure that the treatment process goes along the intended course, can provide more
reliable clinical data to tune prediction models of treatment outcome.
Radiation therapy has gone through a series of technologic revolutions following
several breakthroughs in imaging in the past three decades. We have witnessed the
growth of IGRT, which has provided improved geometric and dosimetric accuracy in
radiation therapy of localized cancers. We expect that more technologic advances are
forthcoming at all levels of IGRT, and will further close the physical, biologic, and
clinical feedback loop for radiation therapy.

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KEY POINTS
• In the application of IGRT to treatment delivery, we have a better understanding of various
uncertainties, correction strategies, and technical limitations. Geometrically, a large body of
evidence has shown the improved accuracy of IGRT in patient setup and motion
management. Dosimetrically, IGRT improves treatment delivery in treatment plans that
contain sharp dose gradients or mobile targets. Clinically, increasing evidence has revealed
associations of local failure with marginal miss and high-grade toxicity with organ motion.

• In this chapter, we have discussed the importance of image-guided radiation therapy (IGRT)
and many in-room imaging modalities, which serve as visual and quantitative guidance for
3D/4D treatment simulation, accurate treatment planning, and image-guided treatment
delivery. Using 2D radiologic imaging, 3D tomographic imaging, 4D respiration-correlated
imaging, or 4DOSI, the setup image before treatment is aligned to the planning image with
reference to the radiation isocenter, so that the treatment can be delivered as planned. Tumor-
tracking images during treatment serve to align the target with radiation beam so that the
mobile tumor is irradiated continuously or within a gating window.

• Implementation of IGRT requires various tools, QA procedures, and resources to achieve


clinical objectives for radiotherapy. IGRT has been successfully implemented for all major
anatomical sites and has been demonstrated to improve treatment accuracy with reduced
uncertainty and margin requirements.

• In the past three decades, the evolution of IGRT has been punctuated with major technologic
advancements. In the future, IGRT will continue to evolve as emerging technologies and
clinical challenges motivate investigations into new areas.

QUESTIONS
1. On all isocentric linac machines, the kV and MV radiographic imaging are
available commercially. Which of the following statements is incorrect in regard
to kV and MV imaging?
A. The kV and MV images can be used together to produce a hybrid CBCT.
B. The alignment of the kV and MV imaging isocenters should be periodically
checked.
C. The quality of kV imaging is better than that of MV imaging due to a large
component of Compton scatters in the MV beam.
D. The kV image quality can be improved by using metal grid in front of imager
and post-acquisition image processing, the same techniques can be applied to
MV image quality.
E. Both kV and MV CBCT images can be used for evaluating delivered dose,
while MV CBCT has the advantage of less metal artifacts and no need for CT
number conversion.
2. A variety of in-room imaging modalities has been developed for IGRT procedures.
Which of following imaging modalities or nonimaging tools can be used for

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intrafractional real-time motion monitoring as a direct or indirect tumor motion
surrogate?
(1) 4DCT or 4D CBCT imaging
(2) Gantry-mounted orthogonal 2DkV imaging
(3) Room-mounted orthogonal 2DkV imaging
(4) Infrared marker tracking system
(5) Calypso electromagnetic transponder system
A. (1) only
B. (2) + (3)
C. (2) + (4) + (5)
D. (2) + (3) + (4) + (5)
E. All of the above
3. A CBCT scan is acquired during a paraspinal SBRT procedure and ready for
approval. However, the attending physician, who is with another patient,
approves the image alignment 10 minutes later. The physicist on duty requests
that the therapists take a verification orthogonal 2DkV image pair. Is the
physicist’s action correct and why?
(1) No; there is no need for 2DkV verification since 2DkV alignment is inferior to
CBCT.
(2) No; there is no need for 2DkV verification since physician has approved the
CBCT.
(3) No; there is no need for 2DkV verification since the patient is immobilized in
a mask.
(4) Yes; the 2DkV verification is necessary since the patient may have moved
out.
(5) Yes; the orthogonal 2DkV images can provide 6 DOF registration via 2D/3D
registration, so they can be used for verification of CBCT alignment.
A. (1) + (2) + (3)
B. (2) only
C. (3) only
D. (4) only
E. (4) + (5)
4. In a radiation oncology clinic, a frameless SRS (fSRS) procedure is implemented
for clinical use. An end-to-end test is conducted using an anthropomorphic head
phantom with inserted orthogonal films to deliver an fSRS plan and shows a 2-
mm difference between the center of the delivered spherical dose distribution
and the planning isocenter marked on the films. Which of the following factors
could be the major causes to the observed discrepancy?
(1) A misalignment of the isocenter of the gantry-mounted kV and the MV
beamlines.
(2) Couch walk that causes misalignment of the couch isocenter and radiation
isocenter.
(3) Image registration error between the CBCT and planning CT.
(4) Couch sag at the setup position, since a 100-lb object was placed on the

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couch inferior to the phantom to mimic patient body weight.
(5) The film placed inside the head phantom with a small angle relative to the
CT slices.
A. (1) + (2)
B. (1) + (3)
C. (1) + (2) + (3)
D. (1) + (2) + (3) + (5)
E. All of the above
5. When treating SBRT for a mobile tumor such as lung lesions, it is important to
first align the target during patient setup and then to consider intrafractional
motion management. Which of the following methods would introduce the
largest uncertainty in tumor alignment?
(1) Using free-breathing CT for planning with the ITV delineated based on 4DCT
and free-breathing CBCT for setup.
(2) Using respiratory-gated CT at full exhalation for both planning and CBCT
setup.
(3) Using respiratory-gated CT at full inhalation for both planning and CBCT
setup.
(4) Using motion compensated mid-ventilation CT for planning and motion-
compensated mid-ventilation CBCT for setup.
A. (1)
B. (2)
C. (3)
D. (4)
E. (1) and (3)

ANSWERS
1. D The MV image quality cannot be improved using the septa grid, as the MV
photon can be further scattered by the metal grid, causing more scatters.
2. D (1) 4DCT or 4D CBCT are retrospective reconstructed and cannot be used in
real-time; (2) Varian and Elekta linac can only take orthogonal 2DkV one at a
time, but VERO can take orthogonal fluoroscopic imaging simultaneously; (3)
CyberKnife uses fluoroscopy for tumor tracking, (4) and (5) can be used as
external and internal tumor tracking systems.
3. E After CBCT imaging, the alignment approval should be done immediately to
avoid patient motion, even with an immobilization device. The orthogonal
2DkV imaging qualifies as a verification means to conform the correctness of
CBCT alignment.
4. C The kV and MV isocenter discrepancy and couch walk are transparent to
image registration but will affect the setup accuracy. Couch sag and film angle
are minor factors, since they only cause rotational misalignment, which is a
secondary to translational misalignment.
5. C The full-inhalation phase is known to be irreproducible and therefore
unreliable for tumor alignment.

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13 Linac Radiosurgery: System
Requirements, Procedures, and Testing

Frank J. Bova and William A. Friedman

Over the past four decades, the practice of radiosurgery has undergone a broadening in
the underlying algorithms used for localization, planning, and treatment delivery. These
changes have come about for both linear accelerator– and GammaKnife-based
treatments. For planning, geometric solutions have given way to solutions that are more
algorithmically based. For treatment delivery, new approaches have aimed at decreasing
the overall time required to deliver the optimized dose distribution. For immobilization
and localization, approaches aimed at replacing neurosurgical-specific equipment, such
as stereotactic head-frames, with methods familiar across all of radiation oncology, such
as thermoplastic immobilization and orthogonal and cone beam–based localization,
have gained acceptance at some institutions. As always, there are no hard and fast rules
as to when some of these new techniques will provide a clinical advantage or when they
will inadvertently negatively impact safety and efficacy. Target size, location,
prescribed dose, and pathology all contribute to the effect. As these new techniques are
applied to an ever-increasing array of clinical targets, the radiosurgeon must ensure
that each new innovation maintains the accuracy and precision responsible for
Radiosurgery’s established clinical results.
Chapters on radiosurgery traditionally begin by exploring the background of
radiosurgery followed by a discussion of the special parameters that are considered
responsible for the clinical success of this treatment paradigm. We often forget that
these treatments were not derived from a perfectly understood set of interactions. The
relationship between effective doses and complications are reported observations from
carefully controlled clinical trials. While underlying principles are understood the
accurate prediction of clinical effect still lies beyond our understanding. The
radiosurgeon needs to be particularly careful not to accept that therapeutic equivalence
for short-term results, a few months or a year, will be representative of the results’
safety and efficacy when measured in decades. As new techniques are discussed, an
attempt to relate the relevant parameters responsible for radiosurgery’s acceptance as a
valuable clinical tool will be discussed.

HISTORIC DEVELOPMENT OF RADIOSURGICAL PRINCIPLES


In the mid-20th century, the advent of cobalt teletherapy units, and subsequently linear
accelerators, helped radiation therapy play an increasingly important role in cancer
treatment. During this time, external beam radiation therapy relied heavily upon the
fact that normal cells are better than cancer cells at repairing sublethal radiation
damage. Typically, a course of therapy would be divided into small fractions, each
delivering a sublethal dose of radiation to a specified target volume. In the time between
therapeutic fractions, the normal tissues would recover more quickly than the cancerous
cells, and by the end of a course of treatment, the targeted cancer cells would have
amassed significantly more radiation damage (Fig. 13.1).

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This delivery technique was necessary for two reasons. First, in the mid-20th century,
neither computed tomography (CT) nor magnetic resonance imaging (MRI) were yet
available, limiting the clinician’s ability to map out and plan three-dimensional (3D)
conformal radiation distributions. Second, the relative ratio of normal tissue cells to
cancer cells varies considerably through the volume being targeted by the therapeutic
radiation beams. This ratio is lowest at the site of the primary tumor, somewhat larger
at the tumor’s margin, and largest in those regions only suspected of microscopic
disease that are included in the targeted volume. It was necessary to develop a
therapeutic tool that resulted in more cancer cell death relative to normal tissue cell
death for a given course of therapy across this spectrum of tumor burden. Dose
fractionation provided such a tool.
Radiosurgery, defined as a single-fraction stereotactically targeted radiation therapy,
proposed a paradigm shift in the art of radiation delivery. This new approach would
not attempt to leverage differential repair of sublethal cell damage, but instead deliver a
highly concentrated dose of radiation exclusively to the tumor. The normal tissue cells
would be excluded from the target volume as a result of a very steep dose gradient,
significantly reducing the dose to normal tissues. The result of these two changes would
allow an unprecedented escalation in safe and effective radiation delivery.

FIGURE 13.1 Figure shows the effects of a single dose therapy versus that of a fractionated therapy. After each
fraction cell repair sublethal damage before the next fraction is administered.

The term “radiosurgery” was initially conceived by a neurosurgeon, Lars Leksell


(13,14). Leksell’s first attempt at a delivery scheme was to provide a concentrated
radiation dose by attaching an x-ray tube onto an arc-centered stereotactic head-frame
system, allowing a target volume to be placed at the center of two orthogonal arc
systems (Fig. 13.2). For surgical interventions, the normal stereotactic arc allowed a
probe holder to point toward the intersection of the two arcing planes. The probe holder
could then be moved along either arc while maintaining a trajectory that pointed to the
target. Mounting an x-ray tube in place of the probe holder provided a method of
delivering a radiation beam that would remain focused at the targeted tissues. This, in

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turn, provided a means to deliver multiple noncoplanar beams, with separate entrance
and exit pathways that all intersected over the target. This technique was based upon
orthogonal target definitions, which, as will be discussed later, is insufficient to define
irregular 3D structures.

FIGURE 13.2 The two bi-centered arc geometry with the focal point shown at the center of two arcs. The user
can move along each of the arcs maintaining a trajectory that will always go through the focal point.

In the 1950s, teletherapy was still in its infancy, but a transition from delivery with
x-ray tubes and radium systems to cobalt-based units was underway. Leksell
undoubtedly had a thorough knowledge of state-of-the-art radiation delivery devices.
Due to limited specific activity and the resultant self-shielding, tele-radium sources had
a very low-dose rate, leading to extended treatment times, but novel approaches to
increase the dose rate were being developed. One such approach was a device that
could simultaneously focus multiple radium sources at a target (27) (see Fig. 13.3).
These tele-radium beams were focused at a specific depth, converging at a point in
space and then diverging as they left the target volume. This geometric focusing
technique is very similar to the approach Leksell first used in his arc-mounted
orthovoltage x-ray tube design and later in his 179 Cobalt-60 source GammaKnife
design (21,26). Leskell’s primary contribution to radiation delivery was the realization
that the coupling of a multi-focused radiation-beam delivery system to a stereotactic
reference system could enable a highly focused high dose of radiation to be delivered to
a defined target while providing significant sparing of adjacent normal tissues, a
development that preceded isocentric teletherapy designs.

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FIGURE 13.3 Tele-radium device for increasing dose rate over a target volume. Multiple sources are focused at
a distance providing unique entry and exit pathways while only overlapping at the target volume.

FIGURE 13.4 A: Image of Dr. Raymond Kjellberg fitting a stereotactic adapter for proton beam treatment. B:

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Adaption of the Kjellberg’s proton therapy data relating volume to complication demonstrating that as the
treatment volume increases the safe dose must decrease to remain below the 1% probability of radiation necrosis.

Prior to the development of the GammaKnife unit, Leksell and Kjellberg, in separate
efforts, had adapted fixed-port proton beam units for stereotactic radiosurgical
applications (Fig. 13.4). These pioneering systems treated significant numbers of
patients and provided early data on appropriate clinical doses for malignant, as well as
benign, targets. The fact that proton units were retrofitted for patient application and
not readily available to the therapeutic community at large limited their widespread
application. Leksell’s development of the self-contained Co-60–based teletherapy unit,
GammaKnife, provided the first practical commercial unit to offer dose distributions
that rivaled the dose concentration and dose gradient of particle-beam therapy (see Fig.
13.5).
The GammaKnife’s concentration of dose simply relied upon the geometric
convergence of a fixed array of Co-60 sources. With a half-life over 300 times shorter
than Ra-226, Co-60 allowed for the fabrication of a device made up of small pencil-
beam sources with high-dose outputs. A large number of these pencil-beam sources
could be packed into a focused array. Spreading out the sources over approximately a
hemisphere and ensuring a focus accurate to within 0.3 mm at the sphere’s center
created a spherical dose pattern with relative uniform dose across the sphere’s diameter.
The convergence and divergence of the beams caused the dose at the edges of the sphere
to quickly decrease (Fig. 13.6). While Leksell’s initial intent was to provide a means to
produce functional lesion, the anatomic atlases available in the 1950s proved
insufficient as the primary means for image guidance and targeting. CT and MRI, the
tools required for such a target definition, would not be available for several decades.
Techniques for CT-based stereotactic frame localization developed in the 1980s and
the MR-CT image fusion techniques of the 1990s began to provide a novel solution to
the problems of 3D target definition (44). Combining these imaging techniques with a
new dose computation algorithm allowed for a paradigm shift in the treatment of
intracranial targets. For the first time, the ability to deliver a high dose of radiation that
conformed to a 3D target shape and provided an exceedingly steep dose gradient along
the entire target-to-normal tissue interface would become widely available to clinicians.
Over the past two decades, Radiosurgery has gone from a novel treatment approach
limited to a few academic centers to a treatment modality available in most
communities. Systems capable of delivering these precise conformal doses with steep
gradients have been developed on multiple platforms. Joining the isotope-based
GammaKnife is a multitude of linear accelerator-based systems. These include
traditional gantry-based linac approaches as well as robotic arm-mounted systems
(5,31). These newer devices can provide for not only intracranial but extracranial
radiosurgical treatments. While each of these delivery platforms presents unique
challenges, the underlying principles for targeting and the desired characteristics of the
prescribed dose distributions remain the same.

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FIGURE 13.5 GammaKnife with dose distribution for an 18-mm helmet. The distribution and gradient is
relatively symmetric about the vertical axis of the displayed dose distribution.

FIGURE 13.6 The intersection of multiple trajectories on a target point showing the pattern of interesting and
diverging pathways. As can be seen from the blowup in the upper right, the number of interesting beams (1
through 5 are indicated) provides a steep geometric defined dose gradient. The lower-right diagram shows the
resultant dose intensity profile of 36 beams each 1 cm in diameter.

PRIMARY OBJECTIVES OF RADIOSURGICAL LOCALIZATION,


PLANNING AND TREATMENT
The combination of stereotactic localization and the ability to produce a highly focused
dose distribution with exceedingly high gradients provided a radical change from the
existing fractionated treatment paradigm. This new imaging/treatment technique could
successfully address intracranial targets in a single-fraction therapy, eliminating the
dependence upon the rate of radiation repair in normal tissue cells versus cancerous
cells. This paved the way for clinicians to think of radiation as a tool of target
elimination similar to a surgical procedure but in an outpatient setting.
Radiosurgery allowed ionizing radiation to be applied to targets previously resistant
to fractionated therapy. Dose distributions developed with an ever-evolving set of tools

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for high conformality and with steep dose gradients provided new optimization
parameters that were effectively leveraged against both benign and malignant targets.
Radiosurgery treatment of arteriovenous malformations is an example: when differential
repair did not provide a sufficient therapeutic advantage relative to normal tissues,
single-fraction conformal distributions with high-dose gradients provided an effective
therapy.
It is difficult to separate the effects of conformality and gradient on the success of
radiosurgery treatments. The GammaKnife allowed for the treatment of spherical and
irregular targets with a planning/delivery tool commonly referred to as “sphere
packing.” An array of collimators provides a means for the creation of spherical
distributions of varying diameters. For round targets, a sphere is simply fitted to the
target volume. For nonspherical targets, the technique fits the largest possible sphere
inside the target, removes the volume covered by that sphere and repeats the process
with the remaining volume. The result is an alignment of the target-normal tissue
interface with the dose-sphere’s steep gradient.
While eliminating normal tissue from the prescription volume is generally accepted as
a necessary parameter for an effective therapy with few complications, a high-dose
gradient has not been universally recognized as an equally important parameter (6).
When radiosurgery gradients are examined, special attention is paid to the portion of
the distribution where the dose decreases from the prescribed target dose to one-half the
target dose (9,12,20,30). As the volume of treated target increases, the volume
contained in the rim of normal tissue rapidly expands. Therapies for both malignant
and benign disease have shown limitations on the safe maximum target volume of a
single fraction. As the volume of the targets increases, the dose that can be safely
delivered decreases. It is thought that this expansion of the volume of the high-dose rim
is at least partially responsible for the dose–volume limit placed on radiosurgery
treatments.
The importance of gradient can be appreciated by examining the volume enclosed in
the high-dose gradient, a shell defined by the edge of the prescribed isodose volume to
one-half the treatment volume. The first evidence of a volume-limiting normal tissue
threshold was the safe-dose threshold versus target size published for particle beams
(12). This curve demonstrates the relationship between complications and increasing
target volume. Many other reports have provided clinical evidence demonstrating the
correlation between increasing volumes and complications. Several reports have
associated an increase in the 12 Gy volume with an increase in complications. As can be
seen in Figure 13.7, the high-dose shell exposing normal tissue exponentially increases
in volume as the target linearly increases. The lower curve in Figure 13.7 demonstrates
the increase in this shell’s volume if the steep dose gradient, defined as the volume
between the prescribed isodose surface and the isodose surface of one-half the
prescribed dose, is maintained at 3 mm. The upper curve is the volume of this shell if
the gradient is allowed to degrade from 3 to 6 mm. The net effect of the lower-dose
gradient is that the limiting dose volume is reached at smaller target volumes. For
example, assume that it is safe to expose a rim of normal tissue, 2.0 cc in volume, to a
gradient that is decreasing from 20 to 10 Gy. If a plan has a high-dose gradient, 3 mm,
as described above, this volume will not be reached until targets of ∼4 cc (2.0 cm
average diameter) are treated. However, if the high-dose gradient is allowed to degrade
to 6 mm, then the 2.0-cc rim of normal tissue volume is reached when a target of only
0.9 cc (1.2 cm average diameter) is treated. Paying careful attention to the high-dose
gradient is critical to the delivery of a safe and effective therapy.

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FIGURE 13.7 Volume of steep dose shell for 3- and 6-mm gradients. Left: Demonstrates the increase in
volume of the encompasses by the 80% to 40% isodose shells for a 3-mm gradient and a 6-mm gradient. Right:
Shows the effect of this change on a metastatic target.

Early radiosurgery literature was based on particle-beam treatments. For these


treatments, the Bragg peak provided a delivery tool that allowed for both high
conformality and little exit dose. The absence of an exit dose provides for a smaller
integral dose to be delivered. Due to the necessary broadening of the proton’s Bragg
peak, the proximal, upstream dose is approximately equal to that of a photon beam.
When this upstream dose is coupled with the smaller number of beams used in a routine
proton plan, it becomes difficult for protons to outperform photons within the
abovementioned gradient zone.
The literature that established the long-term efficacy and safety of intracranial
radiosurgery, using both GammaKnife and Linac, has several treatment techniques in
common. The first is the optimization of dose through the use of sphere packing. The
second is that in order to create the spherical dose distribution for each intracranial
dose volume, the target was placed at the center of the teletherapy system’s isocenter.
The third is the alignment of the patient through the use of a rigid stereotactic headring
system (10). Placing the treatment’s focus at the isocenter eliminated all but a few of the
delivery machine’s mechanical parameters. Under these conditions, the rotation of the
collimator and gantry only produce a spherical dose distribution, resulting in little to no
effect on the delivered dose. However, if multiple targets are treated simultaneously,
coupled with image-based alignment of the patient’s anatomy through treatment unit-
based imaging, these parameters can affect both accuracy of beam placement and the
distribution’s resultant dose gradient (1,7,38). Take, for example, the treatment of two
targets 8 cm apart. Instead of treating each target separately at isocenter, assume that
the first target is set at the unit’s isocenter and the other is targeted off-axis. If one
assumes a 1-degree resolution in the teletherapy unit’s readouts and 1 degree in image-
based patient alignment accuracy, errors of half a degree (an error below that of the
system’s readouts) can more than double the isocentric error of a linac. It is therefore
recommended that before such “efficient” approaches are applied, the individual

364
clinical situation is carefully evaluated and the potential and consequence for such
inadvertent errors are considered.

IMAGING: BI-PLANAR IMAGE–BASED TARGET DEFINITION


To provide a highly conformal treatment with steep dose gradients, the system must be
able to provide a spatially accurate description of the tissues to be targeted. While
suffering from a lack of true 3D target descriptions, plane film fiducial–based systems
can provide the position of a point within a stereotactic reference frame to within a few
tenths of a millimeter (Fig. 13.8). The overly defined fiducial system and solution, as
described by Siddon (39), not only provides high-precision spatial accuracy but also
removes the previously required orthogonal geometry. As late as the 1980s and early
1990s, images used to define intracranial targets, such as arteriovenous malformations
(AVMs), were obtained on plane film x-rays. These systems utilized flat-imaging planes
that in turn provided the clinician with spatially undistorted projections. The temporal
resolution was limited to the speed at which film changers could shuffle film in and out
of cassettes, approximately two images per views per second. As x-ray film gave way to
higher speed image intensifiers, these unwarped projections were lost. The image
intensifier’s distortions were not only complex in any single orientation but could vary
nonlinearly with the orientation of the image intensifier. With the adoption of solid-
state detectors, these projections are again able to be presented without spatial
distortion.

FIGURE 13.8 Showing stereotactic system for plane films and target localization data. A: Siddon’s description
of the mathematic solution. B: Showing variable phantom that allows for targets to be set throughout the entire

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stereotactic volume. C: Showing data from nine experiments that examine the results along individual axis and in
combinations.

Simple orthogonal image sets are not capable of providing 3D descriptions of such
vascular targets. Figure 13.9 shows a series of objects for which the orthogonal
projections do not provide the information required for true 3D reconstructions. While
such views have been used for decades to reconstruct implanted radiation sources, the
vascular images differ in that unique points in each projection cannot be matched.
Although these solid-state imaging systems provide clinicians with the perception of the
3D nature of the vasculature, the systems have not attempted to format and map this
data relative to a stereotactic reference system.
While angiography remains the gold standard for detection of most vascular targets,
due to the above limitations, computed tomography angiography (CTA) and magnetic
resonance angiography (MRA) became the stereotactic targeting modalities of choice.
This has resulted in many commercial stereotactic systems abandoning radiographic
fiducial frames. Newly introduced imaging platforms capable of rapid rotation during
angiographic image acquisition and cone-beam reconstructions, CBCT-A, have begun to
compete with MRA and CTA as viable stereotactic imaging modalities (18). Currently,
the unavailability of the required fiducial systems make it difficult for CBCT-A to gain a
clinical foothold as a primary stereotactic data source. However, if this 3D dataset can
be mapped and fused to a stereotactic dataset, such as a CT dataset, then cone-beam
computer angiographic targeting can be incorporated into a conformal radiosurgical
planning pathway.

FIGURE 13.9 Series of objects for which a 2D projection are inadequate for an accurate 3D description.

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IMAGING CT
The first significant advance in the ability to define a true 3D intracranial target volume
relative to a rigid reference system was the CT fiducial rod system (Fig. 13.10) (10,16).
The addition of the CT fiducial reference to a stereotactic frame provided a means by
which imaged target tissues could be accurately and precisely mapped to a stereotactic
reference platform (15). The stereotactic frame provided a method of analyzing each CT
slice by mapping CT pixels to stereotactic-based voxels (10,33,35,41). By analyzing the
rods on each image, it also provided a framework for image-by-image quality
assessment. These systems removed scanner-dependent parameters from the required
image analysis and subsequent mapping. No longer was it necessary to obtain an
individual image’s relationship based upon the CT table’s index or the scanner’s
alignment to the stereotactic frame. All such parameters could now be derived from
information contained in each individual CT image.

FIGURE 13.10 A fiducial cage is shown with three transaxial plains. Each image intersects all nine fiducial
rods. The right-most figure shows the fiducial cage attached to a headring with the stereotactic grid mapped
onto the upper projection.

FIGURE 13.11 Image of effects of severe CT gantry tilt (30 degrees).

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Not all scanner misalignments are controllable or easily observed during the scanning
process. As CT tables are made more radio translucent, they begin to lose the rigidity
needed to provide alignment of the patient and reference system to the scan plane. The
patient may be rotated along several axes and the scanner gantry may not remain
perfectly aligned as the scan progresses and the table is extended through the scanner
portal.
While a severe gantry tilt (shown in Fig. 13.11) can be readily identified at the time
of image acquisition, small tilts may be more difficult to detect by casual visual
inspection of the dataset. For example, if a patient’s stereotactic frame is tilted 0.5
degrees relative to the CT gantry, an error of 2.6 mm in the superior–inferior axis across
a 300-mm diameter scan will result. Similar errors will result from misalignments
between the reference system and the scanner’s imaging plane. If the stereotactic
mapping algorithm is not capable of detecting these misalignments, errors of several
millimeters can quickly accumulate. Some systems have approached stereotactic
mapping by simply setting the axial coordinate of a given CT slice to the axial
coordinate at the center of the scan. This procedure can result in millimeters of error as
more anterior and posterior targets are localized. The ability to guarantee such small
misalignments during clinical applications is difficult. It is therefore critical for the
stereotactic localization system to be rigorously tested for accurate identification and
correction of such possibilities.
It is advisable to incorporate detection of misalignment into radiosurgical image-
processing algorithms. This can be done with a high degree of certainty when a fiducial
array is incorporated into the imaging procedure. When, however, such systems are not
present, as is the case in many mask-based procedures, these subtle errors become
difficult to detect and correct. One potential solution is to place a known rigid object in
the imaged volume (24,25,34). Figure 13.12 shows a CT scan for a masked-based
system. Prior to treatment, an algorithm is executed that analyses the reconstructed
geometry of the sphere array and provides an estimate of the error in the volumetric
dataset. If submillimeter precision is to be maintained, the solutions to these potential
problems must be incorporated into the stereotactic image processing—planning–
treatment algorithms.
The ability to perform a local test of stereotactic localization requires assessment of
computed stereotactic coordinates relative to a known standard. It is important not only
for the stereotactic coordinates of the test object to be known, but also that the test
points are distributed through the defined stereotactic volume, not only at the center of
the imaging volume. As with the above example, a small tilt may correctly calculate the
center of the defined stereotactic space. However, as the stereotactic mapping moves
away from the center of the volume to the outer edges, the errors are magnified.
A simple test object has been developed initially for frame-based quality assurance
(29). This object contains spherical targets spaced throughout the frame’s defined
stereotactic volume, allowing a series of tests to be performed by the user that verifies
the correct computation of these known stereotactic coordinates under varying patient–
scanner alignments. Misalignments that can be individually tested or tested in
combination are: (1) gantry tilt, (2) patient frame tilt, and (3) patient frame rotation.

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FIGURE 13.12 Optical target system with a known geometry can be used to detect CT scan error or patient
inter-scan movement. A: Left shows an acceptable scan with the reconstructing of the known fiducial system
predicting errors less than a pixel in dimension at 10 cm from the array and right shows a failed test with the
errors predicting approximately a two pixel error at 10 cm from the array. B: Shows the localization of a
spherical fiducial marker best fitted to a circular template helping to minimize pixelation error.

Figure 13.13 shows two types of phantoms: a fixed absolute phantom and a variable
phantom. Each phantom can be attached to a fixture that allows for the attachment of a
CT localizer as well as to a fixture that allows the system to be mounted onto the
treatment unit. This provides a system that can examine the alignment of the
stereotactic process from imaging through planning and treatment. The fixed phantom
has six targets at known stereotactic positions. Figure 13.14 shows the results of a series
of tests. In these tests the phantom was first aligned as precisely as possible to the CT
scanner. Then tilts, spins, and gantry tilts were introduced. The CT scans were then
processed by the program that automatically found the fiducial rods in each image and

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then processed the image set, mapping the voxels to the stereotactic ring’s reference
coordinate system. The results of this test show that the center of each of the known
targets was correctly mapped to within one pixel, demonstrating the system’s ability to
correct for such misalignments during routine scanning. Figure 13.15 shows the
absolute phantom being used with an optical alignment system. If a ring-based system
and known fiducial device is not available, then a hidden phantom test can be utilized.
The hidden target test provides for a test of the entire imaging–planning–treatment
delivery process. If an error is found then more testing of sub system can be conducted.
The availability of 3D printers makes the manufacture of special phantoms for such
testing within the reach of many clinics. Figure 13.16 shows a skull printed in a 3D
printer within which hidden targets can be placed. This allows the full effect of a
masked-based teletherapy image-based alignment treatment delivery system to be tested
on a realistic anatomic model to better replicate the real-world situation.

FIGURE 13.13 Lower images show variable Winston–Lutz phantom and angiographic with and without
fiducial system, upper images show fixed 6 target absolute phantom with CT with and without localizer attached.

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FIGURE 13.14 Table shows results of scanning the absolute phantom (see Figure 13.11) with CT localization.
Separate runs for phantom spin, tilt and combination spin, and tilt and gantry tilt are shown.

FIGURE 13.15 Absolute phantom and optical positioning system used for end-to-end testing, from image
acquisition through delivery.

One important factor in calculating stereotactic coordinates is the ability to account


for errors inherent in the pixilation of fiducial systems. With a routine CT image matrix
of 512 × 512 pixels and a scan diameter of approximately 350 mm to encompass a
stereotactic fiducial reference system, the in-plane pixels have dimensions of 0.67 ×
0.67 mm. A fiducial rod of 4 mm in diameter that is randomly aligned in the field of
view can demonstrate significant sampling errors. Using prior knowledge that the rod is
straight and that the rod images must therefore fit a straight line, many of the errors
introduced by the pixel dimension can be corrected. For the optical system shown in
Figure 13.15, the knowledge that the passive fiducials are round can also be used to
help correct for these pixilation effects.

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MR IMAGING
Over the past three decades, MRI has become the dominant imaging modality for soft
tissue target definition. A host of sequences have been developed that assist in the
differentiation between normal tissues and target tissues. Most systems rely heavily
upon MRI to provide the target-to-normal tissue contrast necessary for targeting
definition. While the superior contrast of MR scanning for most solid targets is critical
for planning, MRI has limitations in providing pristine spatial uniformity. The
perturbations in the magnetic fields introduced by the patient result in susceptibility
errors that warp the MR image. These errors are most dominant at the interface of
changes in soft tissue and bone, and again at the interface of tissue and air and in the
vicinity of any materials that introduce magnetic perturbations (17). A second set of
errors in direct fiducial-based MR stereotactic imaging are introduced by the positioning
of the fiducial systems at the outer most diameter of the image, an area where magnetic
fields are least uniform. A third issue that arises when direct MR stereotactic imaging is
attempted is that the size of the fiducial system and the stereotactic ring system often
do not fit into head coils that have been optimized to provide the best tissue contrast
and image uniformity.

FIGURE 13.16 Two skulls reproduced using a 3D printer. The use of such devices allows the user to reproduce
anatomic structures providing a means of testing image based time-of-treatment positioning system.

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FIGURE 13.17 Image demonstrating successful CT-MR image fusion. Image alignment is inspected in all
three anatomic planes. Bottom image demonstrating alignment at target location.

Many systems have adopted MR-CT image-registration techniques, also referred to as


“Image Fusion Techniques.” These approaches allow the best MR images to be obtained,
often requiring head coils that cannot accommodate a stereotactic localizer. Image
Fusion Techniques register these images with the spatially more accurate, but often
lower contrast, CT dataset, thereby providing the best of both systems and
compensating for each system’s limitations. Figure 13.17 shows a typical MR-CT dataset
aligned. The structures identified on both scanning systems provide images of common
tissue boundaries, thereby allowing clinicians to judge the acceptability of the fusion-
alignment process.
One other advantage of nonstereotactic MR scanning is that the imaging of the target
tissues can be obtained hours or days before the radiosurgical procedure is to be carried
out. For procedures where stereotactic rings are used, this allows for consultation and
planning without the constraint of a patient waiting on the day of procedure.

DOSE PLANNING
As previously mentioned, the criteria of conformality and gradient have been the
primary focus for plan optimization. For historical sphere packing and target shapes
that are not spherical, planning moves to the procedure of filling the target volume with

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spheres (Fig. 13.18). The resultant hotspots within the target have not been shown to be
associated with increased complications. This is supported by numerous GammaKnife-
based studies in which targets were treated with anywhere from 80% of the maximum
dose to 50% of the maximum dose. These same sphere packing techniques were adopted
by early linear accelerator Radiosurgery systems. Due to the near uniform sensitivity of
intracranial tissues, a uniformly steep gradient is most times considered optimal. A
notable exception is for targets near the optic processes, which are considered more
sensitive for both single and fractionated treatments. In these cases, gradients can be
altered to produce a steeper gradient. For example, gradient alteration is often used in
the optimization of treatments involving pituitary targets. In the case of the pituitary,
the optic chiasm lies just superior. Producing a steeper gradient in the direction of the
optic chiasm, at the sacrifice of more lateral tissues, is often considered beneficial
(Fig. 13.19).

FIGURE 13.18 A hypothetical target being progressively covered, starting in the upper left and progressing to
the lower right, by varying diameter spherical dose projections.

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FIGURE 13.19 Left image shows arcing planes distributed symmetrically the right image shows the most
superior beams eliminated increasing the dose gradient in the anterior–posterior direction, decreasing the dose to
the optic chiasm, while decreasing the gradient in the lateral direction.

Many systems that approach dose planning from other perspectives have been
introduced. Dynamic conformal planning and inverse planning have been applied to
radiosurgical treatment. Dynamic conformal planning, a technique that uses multiple
nonconformal arcs and beam’s eye collimation, has difficulty providing a high degree of
conformality when addressing very small, irregular targets (42,43). The issue of
conformality is better addressed by inverse planning and intensity-modulated
radiotherapy (IMRT), a technique that generally employs a more limited set of beam
paths. While directed gradients against specific adjacent critical tissues can be
accommodated, the gradient over 4 pi provides special IMRT challenges that must be
carefully evaluated. The gradient over the entire surface of the target volume is
particularly critical in most intracranial radiosurgery.
While sphere packing and intensity modulation are often seen as competing
technologies, they are in fact one in the same. Early publications proposing intensity
modulation as a potential approach to dose optimization actually suggested packing the
target volume with spheres of differing intensities (Fig. 13.20) (2). To appreciate the
similarities of these approaches, one needs to examine the relative output of the circular
cones used to create the spheres. Figure 13.21 shows the output for a set of 6 MV
radiosurgical cones. As can be seen, the relative efficiency of monitor unit to dose begins
to fall off toward the smaller cone apertures. Let’s assume that the target volume to be
treated can be covered by two spheres, one 24 mm in diameter and one 10 mm in
diameter. The output of the 24-mm collimator is 0.94 and the 10-mm collimator is 0.84,
relative to that of the reference field. If one is to deliver 15 Gy to the target volume, the
10-mm sphere would require 1.12 times the number of monitor units as the 24-mm
collimator (0.94/0.84 = 1.12). This is easily achieved if the spherical dose distributions
are delivered one at a time, as they are in a sphere packing approach. However, if they
are to be treated on one beam, as with conformal therapy, then there are four options:
(1) under dose the 10-mm spherical volume, (2) overdose the 24-mm spherical volume,
(3) increase the 10-mm sphere to sacrifice conformality for increased output, or (4)
temporally modulate the beam to compensate for the output factors. Figure 13.22 shows
a series of distributions for treating an acoustic neuroma where the degree of
modulation for each of the beams is shown.

FIGURE 13.20 Diagram showing the potential creation of an intensity-modulated plan by packing the target
volume with spheres.

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FIGURE 13.21 Relative output of spherical collimators with three potential scenarios of covering a target
volume. A: Covering the volume with two different spheres allowing for the required monitor units of each
segment to be separately calculated. B and C: The under- and overdose resulting from treating the entire target
with one conformal field allowing for only one monitor unit setting to be selected.

PRESCRIPTION ISODOSE
Because the goal of dose planning is to deliver an effective dose across the target
volume while minimizing the dose to normal tissues, the selection of the prescription
isodose shell has criteria that differ from those used in routine fractionated therapy.
Figure 13.23 shows a dose distribution for a metastatic lesion using a conical collimator
and five noncoplanar arcs. Cross-plots of the dose along the lateral axis are shown in
Figures 13.23A–D. The first plot in Figure 13.23A shows that the distance required for
the dose to decrease from a target isodose shell of 90% of max to 45%, half the target
value, is 5.7 mm. Figure 13.24B–D denotes the distance required if the 80%, 70%, and
60% isodose shells are selected as the target isodose. As shown, the minimum distance,
3.8 mm, along with selecting the 80% isodose shell, provides the lowest integral dose to
normal tissue (36). This essentially selects a prescription point just past the high-dose
shoulder of the dose profile. If a lower prescription isodose shell is selected, then the
high-dose fall-off in normal tissue encounters a lower plateau of the distribution. If
sphere packing is employed, and more than one isocenter is combined over an irregular
target volume, a small hot spot is often produced and the resultant normalization can
shift the optimized prescription shell down to a lower value. Although tools are
available to help dampen the extent of these hotspots, prescription isodose shells of
70% through 50% are commonly encountered. As previously mentioned, the target
volume has no normal tissue, and such hot spots, when confined to the target, have not
been correlated with increased complications.

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FIGURE 13.22 A skull-based tumor that was planned with sphere packing. Table shows the sphere diameters
and relative intensities.

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FIGURE 13.23 Dose cross-plot of a single isocenter, multiple non-coplanar arcing plan. The effect of selecting
the prescription isodose of 95%, 90%, 80%, 70% of maximum dose, demonstrating that the dose falls most
rapidly to one-half the dose when 80% of maximum dose shell is selected. This provides maximum normal tissue
sparing for near target doses.

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FIGURE 13.24 Plans for a simple acoustic neuroma two-isocenter plan for sphere packing and VMAT plan.
Also a more complex plan showing favorable VMAT planning.

Other planning techniques, such as volume modulation arc therapy (VMAT), have
also been applied to intracranial radiosurgery planning. While these systems show
excellent conformality, the ability to maintain exceedingly tight gradients must be
carefully evaluated. Figure 13.24 shows the conformality of a simple two-isocenter
sphere packing plan for an acoustic neuroma and one from several VMAT plans. As has
been observed, the optimal degree of VMAT can be difficult to judge. The number of
noncoplanar VMAT arcs, like the number of noncoplanar arcs in a sphere packing plan,
has been shown to affect the overall, 4 pi, (1,40) dose gradient. While both provide
excellent conformality, VMAT plans have often produced a less steep dose gradient for
small and midsize targets, thereby increasing the volume of tissue exposed to near-
target dose levels. For larger targets, 2.4 to 3.0 cm average diameters, the ability of
sphere packing to rapidly converge and then diverge becomes less effective and
techniques such as intensity modulation begin to compare favorability in the arena of
dose gradient.
Because of the rapid development in treatment planning, the above comparisons are
in a constant state of flux. However, the primary objectives of the planning process
remain the same: a high degree of conformality and exceedingly steep dose gradients.
Many groups have suggested both conformality and gradient as critical planning
parameters (4,28,42). Wagner introduced a conformality gradient index (CGI) for both
conformality (CGIc) and gradient (CGIg) (42). For the gradient score (CGIg), the
formulation converts the volume of the prescription isodose and the volume of the
isodose that encompasses one-half the treatment isodose into effective spherical volumes
and then uses the radii of these effective spheres to compute an average effective
radius. Assigning a score of 100 to an average radius of 3 mm, from prescription to one-
half the prescription isodose, the score is calculated as

Other conformality indexes have also been defined by the ICRU 62 (11) as the volume
of the prescription of the isodose volume to that of the planning target volume (PTV).

Another suggested conformality index utilizes the volume that encompasses 95% of
the PTV divided by the PTV. In yet another conformality index formulation, suggested

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by Paddick, the volume of the treatment isodose that does not include target volume is
not counted in the denominator (28) to ensure that the planning volume counted
overlaps with the target volume.

The goal of radiosurgery is to mimic a surgical resection. The coverage of the PTV is
set equal to the imaging target volume. The goal of the planning process is to ensure
that the full-imaged target is covered. Because of the steep dose gradient, the omission
of any portion of the target volume is analogous to a subtotal surgical resection. It is
therefore common for the prescribed plan to encompass the entire imaged target
volume. The sensitivity of the intracranial tissues requires that safe and effective
treatments result in conformality indexes between 1.0 and 1.3. With average target
volumes in the order of 4 to 5 cc, these plans result in less than 1 cc of normal tissue
being exposed to the prescription dose. The steep dose gradient also minimizes the
exposure of normal tissue adjacent to the target volume. Some typical treatment plans
with conformality indexes and dose gradients are shown in Figure 13.25.

TREATMENT MARGIN, PTV VERSUS GTV


Historically, for both benign as well as malignant targets, the prescription isodose has
been set to coincide with the enhancing volume. This sets the clinical, or imaging, target
volume, CTV, equal to the planning target volume, PTV. As with the discussion of
gradient, increasing target volume ultimately results in the lowering of the safely
administrable, although less effective, dose. With submillimeter localization and
treatment delivery, nearly all centennial studies establishing safety and effectiveness
have adopted setting the PTV equal to the CTV (23,37).

TREATMENT DELIVERY
The above imaging and highly conformal planning with steep dose gradients requires a
highly accurate delivery system. This necessitates that stereotactic targets be aligned
with delivery systems, and that delivery systems be able to deliver multiple noncoplanar
beams while maintaining accurate alignment.
The early GammaKnife units provided the gold standard for stereotactic delivery. The
design of the rigid source alignment with the system’s stereotactic reference provided a
stereotactic target to isocenter alignment of 0.3 mm (19). Early linear accelerator
systems had trouble maintaining such critical alignments (3,8). Winston and Lutz
introduced a system that allowed for the evaluation of stereotactic target alignment to
the delivery system (22). This design provided a means by which noncoplanar delivery
accuracy could be measured. In 1988, Friedman and Bova introduced a system to
correct the linear accelerator’s gantry and patient support “wobble” (9). Redesigned
linear accelerators, capable of maintaining submillimeter delivery alignments, were also
introduced in the mid-1990s. For such systems, the Winston–Lutz delivery testing
procedure remains the standard for certifying accuracy in delivery.
The phantoms shown in Figure 13.13 can be used with the Winston–Lutz test to
provide end-to-end system testing. After evaluation of the CT mapping program, the
computer stereotactic coordinates can be used to “treat” the phantom. This provides a
process by which the entire image-planning–treatment chain can be evaluated.

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Figure 13.26 shows the results of such a test. Again, as with previous evaluations, it is
critical that targets throughout the volume of the definable stereotactic space be
evaluated. Only testing at the center of the defined volume can mask errors in both
image mapping and treatment delivery.
The beams used in radiosurgery treatment are often significantly smaller than those
used in routine radiation therapy. The complement of beams usually does not exceed 40
mm and usually includes beams as small as 5 mm. The measurement of these small
beams poses special problems and requires very small detectors (32). If routine “Farmer
style” chambers are employed for such small beams, then significant errors in both beam
profiles as well as output factors can be made (Fig. 13.27). Figure 13.28 shows beam
profiles using numerous high spatial resolution/small cross-section detectors as well as
the effects of a large volume detector. Figure 13.29 shows first how a set of small beams
behaves when plotted against off-axis distance and again how they agree when plotted
against percent beam diameter. Such cross tests should be carried out to ensure that
detector sizes are not affecting measurement results. Figure 13.30 shows the output
factors for a set of circular beams as well as a set of small square fields. Again, cross
checking using multiple detectors is critical in ensuring that errors can be identified as
these exceedingly small beams are measured.
Services such as those provided by calibration and quality assurance laboratories are
critical in the commissioning of each radiosurgery system to ensure that all such
parameters have been correctly measured and correctly incorporated into the system’s
treatment planning and delivery system services. The ability to localize, plan, and treat
a test phantom and to have an independent laboratory verify the end result in both
accuracy and prescribed dose is critical. Utilizing such services should be part of each
new instillation’s calibration and certification procedure.

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FIGURE 13.25 A: Six isocenter meningiomas, B: single isocenter for acoustic neuroma, C: two isocenter plans
for acoustic neuroma showing gradient (prescription to half prescription) of 2.28 mm, D: two isocenter plans for
meningioma showing gradient of 2.16 mm, one isocenter 24-mm collimator for metastasis showing gradient of

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3.06 mm, and F: five isocenter plans for metastasis showing gradient of 4.9 mm.

FIGURE 13.26 Left: Shows the results of a hidden target test. Targets are CT imaged, planned, and Winston–
Lutz films are taken and analyzed for total vector error. Right: Experiment setup for Floorstand and optical
guidance systems.

SYSTEM CRITERIA
While it is difficult to define absolute accuracy or precision in stereotactic imaging or
treatment delivery, it is possible to examine and provide perspective on the effect of
misalignments and errors. Figure 13.31 shows the addition of treatment errors to
imaging errors and how these added errors can quickly dominate the overall system
accuracy. Accuracy and precision can be affected by (1) incorrect mapping of
stereotactic coordinates during image analysis, (2) planning that does not provide
sufficient conformality or gradient, and (3) delivery systems that do not maintain
sufficient rigidity and precision during noncoplanar beam delivery. These first two
effects have been discussed previously. The third can be simulated in the radiosurgery
planning system.

FIGURE 13.27 Beam profiles using small diode detector and larger ion chamber demonstrating the errors
possible when detectors of large size are used on small radiosurgical beams.

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During treatment planning, a simulated radiation source is maneuvered to deliver
beams from various directions. The mathematic model is designed to point at a specific
stereotactic coordinate without error. This specific error is referred to as the teletherapy
unit’s isocentric accuracy. This accuracy is determined by different design and
manufacturing parameters that vary with each type of delivery system. In every case,
the first critical alignment is the system’s ability to place a specific stereotactic
coordinate at the unit’s nominal isocenter or reference point. In the case of the
GammaKnife, the unit’s delivery accuracy is then determined by how accurately the
collimators are aligned within the treatment head. For a linear accelerator delivery
system, it is the system’s ability to accurately rotate the gantry and patient support unit
about this isocenter. For robotic systems, it is the robot’s ability to maintain alignment
of the beam to a point in space. And for tomographic units, it is the combination of the
isocentric rotation of the source and the system’s ability to accurately translate the
patient through the gantry.

FIGURE 13.28 Beam profile of a 10-mm circular beam data taken with three high spatial resolution detectors.
(AAPM TG 42.)

FIGURE 13.29 Beam cross-plots for absolute distance from central axis and again as percentage of off-axis
distance that can be used to check for effects of detector size.

To help understand how isocentric accuracy can affect dose delivery, one can

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simulate isocentric inaccuracy in the planning system. The resultant dose distributions
can then be compared to those derived from perfectly aligned simulations. For an arcing
linear accelerator delivery system, dividing the arc into several segments and allowing
each segment to aim at a different stereotactic coordinate can accomplish this
simulation. Such a simulation was conducted with the gantry and patient support
rotation maintaining a plus or minus 1-mm isocenter accuracy along each orthogonal
axis. For a typical mid-size target of 18 mm diameter, the effects of this degree of
inaccuracy result in a shrinking of the 80% prescription isodose shell’s volume by 15%
and an 80% to 40% isodose fall off to decrease the sharpness of the gradient by 33%.
While it is difficult to translate these effects into treatment failures or treatment
complications, they do demonstrate the striking effect of small errors in isocentric
accuracy on the delivery of the prescribed dose as well as the maintenance of the steep
dose gradient.

FIGURE 13.30 Output factors for cones and small square fields.

FIGURE 13.31 Demonstrating the effects of treatment errors when added to imaging errors (AAPM report
42).

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FIGURE 13.32 Checklist for time-out prior to initiation of the radiosurgical procedure.

THE TREATMENT PROCEDURE


Unlike routine fractionated radiation delivery, Radiosurgery requires more of a surgical
mindset (1). With a single-fraction therapy, all QA and checking must be completed
prior to the initiation of the first and only treatment. This places special demands on
the radiation oncology department’s teletherapy delivery team, who are more aligned
with an incremental treatment technique.
To assist in the procedure, many departments have adopted a rigid checklist to help
ensure that each critical step is performed and verified by more than one member of the
clinical team. For a ring-based SRS procedure, this checklist would begin when the
clinical team meets the patient and continue until the treatment is complete and the
ring is removed. The procedure would include:

• A “time out”: Prior to ring placement, a “time out” is used to ensure that the team is
focused on the correct radiosurgical target for that individual patient. Figure 13.32
shows a typical “time out” checklist with the accompanying MR image showing the
radiosurgical target.
• Specific written orders to accompany the patient to CT scanning

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• A signoff by the treatment team on the quality of image fusion
• A signoff by the treatment team on the final plan
• The development of a treatment checklist that includes:
• A check of the plan’s transfer to the treatment systems record and verify system
• The pretreatment QA ensuring:
• The correct patient and prescription has been transferred
• The unit’s accuracy is verified prior to each treatment
• A step-by-step procedure to ensure that every step is documented and verified,
including:
• Verification of the stereotactic coordinate
• The cone and/or the collimator settings
• The monitor unit setting for each treatment segment
An example checklist, automatically generated by the treatment planning system, is
shown in Figure 13.33. The use of such a checklist is usually accompanied by a
minimum of one double-check and often with a third “blind check” to ensure that each
parameter is properly set prior to the initiation of each treatment segment.

FIGURE 13.33 Checklist for SRS procedures automatically produced by treatment planning system.

It is also critical to provide an atmosphere that allows the treatment team to


concentrate on delivery and not be distracted by phone calls, scheduling questions or

387
any other unrelated task. While an awareness of the distraction of cell phones during
tasks such as driving a motor vehicle are being realized, similar distractions during
complex procedures, such as radiation delivery, are often not appreciated. Forwarding
the phones at the treatment unit’s console and inside the treatment vault, prohibiting
the use of cell phones, texting and voice, throughout the procedure and minimizing any
discussions that distract the treatment team from the delivery process should be
enacted. Providing the proper environment as well as a thoroughly planned procedure
and post-procedure reviews are critically important to the reduction of human errors
and the identification of general system failures.

KEY POINTS
• Radiosurgery does not depend upon the differential sensitivity between health and diseased
tissue.

• Radiosurgery requires extremely high conformality.

• Radiosurgery requires very steep dose gradients over the entire 4 pi of the target’s surface.

• The radiosurgery process is perhaps the most demanding radiation treatment process and
requires redundancy throughout the process.

• From imaging through planning and delivery it is essential to provide end-to-end testing of
all components and processes.

• Radiosurgery requires 3D targeting. Two-dimensional targeting can lead to either over or


under coverage of target structures.

• Prescription isodose is chosen to provide the maximum gradient at the target to normal tissue
interface.

QUESTIONS
1. Which of the following imaging techniques is not recommended for defining the
3D shape of a vascular intracranial target?
A. Computed tomographic angiography
B. Magnetic resonance angiography
C. Cone-beam angiography
D. Orthogonal angiography
2. Which of the following is usually part of a radiosurgery quality assurance testing
procedure?
A. CT slice–thickness assessment
B. MR uniformity assessment

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C. Hidden target testing
D. Field flatness assessment
3. Which of the following factors limit the application of dynamic conformal dose
optimization?
A. The size of multileaf collimators
B. The rapid change in output factor for small field sizes
C. The isocentric accuracy of teletherapy units
D. The nonlinearity of film dosimetry
4. Which of the following radiation detectors are not used in small field
measurements?
A. Parallel plate buildup detectors
B. Diamond detectors
C. Diode detectors
D. Radiochromic film
5. Why do most radiosurgery treatment units utilize either Co-60 or 6 MV as
opposed to 18 MV photons?
A. 18 MV has lower penetration
B. 18 MV has a greater penumbra
C. 18 MV has a steeper dose fall-off at the edge of the field
D. 18 MV beams are more polychromatic

ANSWERS
1. D
2. C
3. B
4. A
5. B

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14 Stereotactic Ablative Radiotherapy

Ryan D. Foster, Ezequiel Ramirez, and Robert D. Timmerman

INTRODUCTION
Stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SAbR)
has been established over the last few years as a highly effective local therapy for a
wide variety of tumor sites. SAbR requires accurate targeting, effective immobilization,
and tumor motion management to deliver an ablative dose to tumors in a few fractions
(typically less than 5), while sparing surrounding normal tissues via a steep dose
gradient outside the target. SAbR can be performed on a variety of radiation delivery
platforms provided the required mechanical accuracy can be achieved and the system
has the appropriate image guidance for the disease sites that will be treated. SAbR has
become the standard of care for certain patient populations, including inoperable early-
stage lung cancer, inoperable liver metastases, inoperable primary liver cancer and lung
metastases. The goal of SAbR is to deliver a large conformal dose per fraction to the
tumor while using geometric avoidance and an isotropic dose fall-off to spare normal
tissue. SAbR is an extension of cranial stereotactic radiosurgery (SRS) and has many of
the same characteristics, including a heterogeneous dose inside the tumor, sharp dose
gradients outside the tumor, highly effective patient immobilization, and the use of
many beams. Since the seminal publications of Lax and Blomgren (1,2) describing
extracranial stereotactic irradiation using a linear accelerator in the mid-1990s, the
number of publications related to SAbR has increased by more than fivefold based on
PubMed search results, indicating the intense interest in and rapid adoption of this
evolving therapy. While the early SAbR treatments made use of an external stereotactic
coordinate system, which was usually embedded in a body frame, the advancement and
improvement of in-room imaging has made the need for a stereotactic coordinate system
largely unnecessary (Fig. 14.1).

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FIGURE 14.1 Fusion of the planning CT scan to a Cone-Beam CT scan acquired on the treatment machine
allows for accurate repositioning of lung targets.

Since the previous edition of this textbook was published, SAbR has blossomed into a
well-established therapy for localized disease and is considered standard of care for
some disease subsites, thanks to impressive local control results. SAbR is being
investigated as a potential therapy in an increasing number of disease sites and patient
populations and techniques to optimize this therapy are still being explored. This
chapter guides the reader through all aspects of SAbR, including patient simulation,
quality assurance and treatment planning, and recent clinical results for a variety of
disease sites will be summarized.

RATIONALE AND GOALS


Historically, radiation therapy has been fractionated because spreading out a large dose
over many treatments is easier on normal tissue and allows time for damaged cells to
repair. Fractionation was necessary in the early days of radiation therapy because it
was the only way to give tumoricidal doses to deep seated tumors with the available
technology. The disadvantage of fractionation is that tumor cells also can repair and
repopulate over a protracted course of therapy. The underlying reason for the success of
SAbR is still the subject of much debate. Postulations of a “new biology” have taken root
whereas others have made the case for increased cell kill using the linear-quadratic (L-
Q) model due to an increased biologic equivalent dose (BED) (3–6). The hypothesis that
devascularization leads to indirect cell death is well accepted and it has been shown

393
that extensive tumor cell death can lead to an immune response which may promote
further cell death (7). Modifications to the L-Q model have been proposed and shown to
fit clinical data for both conventionally and hypofractionated treatment regimens (8).
The initiation of an antitumor immune response as a result of focal irradiation is
particularly exciting, and SAbR could play a role in therapy for patients with
widespread metastatic disease, with the belief that systemic therapy is unable to
eradicate gross deposits of cancer and local therapy could be of benefit. There is
reported evidence of an abscopal effect in a patients with metastatic melanoma treated
with local radiotherapy (9,10). In the initial case reported in the New England Journal of
Medicine, the patient was treated to a paraspinous lesion to 28.5 Gy in three fractions
while tumors in the hilum and the spleen were not treated with radiation. The patient
also received ipilimumab, a monoclonal antibody. The untreated tumors underwent a
partial response 3 months after radiotherapy and the response was durable out to 9
months postradiation. The combination of SAbR and immunotherapy is a novel
application of this highly focused form of radiation therapy and this application will
certainly be studied extensively in the coming years.
SAbR has been made possible by technologic advances such as 3D treatment planning,
tumor motion assessment and visualization, highly accurate dose calculation algorithms
and in-room image guidance. The goal of delivering an ablative dose to noncranial
lesions while sparing nearby normal tissues was not possible previously. Due to the
technologic advances and impressive clinical results, SAbR has rapidly become an
important tool for clinicians and patients in their fight against cancer.

SIMULATION
The SAbR process starts with patient simulation, which includes several key elements
that will determine the success of the course of therapy. Those elements include patient
immobilization, motion management, and accurate patient imaging. The first aspect of
the patient simulation that must be optimized is patient immobilization. Patients must
be immobilized in an effort to minimize voluntary motion but the method used must be
comfortable and reproducible. Various methods of immobilization have been shown to
be effective. Body frames (11,12), vacuum fixation (13), and alpha-cradles (14) have all
been used successfully for patient immobilization during SAbR. The main goal of patient
immobilization is to ensure that the patient is in a reproducible “state” at the simulation
and, subsequently, in the same state at each treatment. Patient immobilization aids
typically consist of a custom-formed cushion which molds closely to the patient surface
(Fig. 14.2).

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FIGURE 14.2 The vacuum cushion and the stereotactic body frame used for SAbR patient immobilization at
UT Southwestern.

In most cases, the arms are positioned over the patient’s head and must also be
supported by a custom-formed cushion. If possible, the patient should be supported on
three sides, with the molded cushion wrapping up along the sides of the patient.
Patients may become uncomfortable and be unable to remain still for the long treatment
times that accompany SAbR if the immobilization aids are poorly designed. Effective
immobilization can allow smaller PTV margins at the time of planning, thus reducing
the amount of normal tissue receiving a high dose.
At the time of simulation, the tumor motion must be assessed for patients receiving
treatment to the lung or abdomen. For tumors in these locations, motion due to
respiration can be as large as several centimeters and must be minimized or accounted
for. Motion assessment can be in the form of fluoroscopy, 4DCT or cine MRI. Motion
assessment provides the clinician with information about how the tumor moves (period,
amplitude, direction, regularity) and should guide the use of motion management. The
goal of the motion management should be to reduce the motion envelope of the GTV to
no more than 5 mm larger than the GTV itself in any one direction. As with patient
immobilization, there are several strategies available for motion management, including
abdominal compression (11,13), breathhold (15,16), gating (17), and tumor tracking
(18–20). Abdominal compression is the simplest method for motion management in that
it utilizes a compression plate to inhibit diaphragm motion and forces the patient to use
the intercostal muscles for respiration and in the majority of cases, reduces tumor
motion (21). At UT Southwestern, tumor motion is assessed via fluoroscopy before the
CT to determine if compression is necessary. Our current threshold for using
compression is tumor motion more than 1 cm in the superior–inferior direction. The
major disadvantage of compression is patient discomfort. If compression is to be used,
the patient must be simulated with the compression applied.
Breathhold has been used successfully for limiting respiratory motion during the
treatment of lung and liver tumors. Patients take a deep breath and hold it either
voluntarily or are assisted with a device that prevents expiration for a short period of
time. Patients receive training at the time of simulation. The patient is treated only
during the time they are holding their breath and the breathholds typically last for 15

395
to 30 seconds, depending on the patient. Patients with poor lung function are not good
candidates for breathhold techniques because they are unable to hold their breath for a
significant length of time. Another method for motion management is to gate the
delivery of the radiation so that the beam is delivered only during specific parts of the
patient’s respiratory cycle. Gating thresholds are determined during treatment planning
and the beam is on when the tumor (or more typically, its surrogate) is inside the gating
limits. The gating can be performed manually or can be interfaced with the accelerator,
allowing automated gating. The major disadvantage of beam gating is that it has a low
duty cycle and increases treatment times. Another concern is the validity of the
correlation between tumor and surrogate motion. The final method for motion
management, tumor tracking, is technically challenging and is not currently a widely
used technique (22). However, it has advantages over the other techniques in that it is
not uncomfortable for the patient and does not require the beam to turn off during
delivery. Currently available tracking methods track either an external tumor surrogate
or markers implanted in or near the tumor.
Accurate patient imaging is an absolute must for SAbR treatment planning.
Considering the small fields, sharp dose gradients and high doses characteristic of
SAbR, the geometric and density information acquired with the simulation CT must be
highly accurate. Scan length should be sufficient to include any potential organs at risk
and the entrance point of all noncoplanar beams. For accurate contouring of small
lesions, CT slice thickness less than 3 mm is recommended. 4D CT is recommended for
imaging moving tumors and organs in order to account for residual motion after the
motion management techniques, if any, are used. 4D scans can be reconstructed into
minimum, maximum, and average intensity projection datasets. The maximum intensity
projections (MIP) reconstruction is useful for contouring the internal target volume
(ITV) for lung SAbR because it provides the motion envelope for the tumor. The 0% and
50% phase reconstructions represent the limits of respiration and can be used to help
determine the craniocaudal limits of the ITV. The minimum intensity projections
(MinIP) reconstruction should be used when contouring the ITV for liver tumors because
those lesions are typically less dense than the surrounding liver. The average dataset is
used for dose calculation and as the reference for the cone-beam CT (CBCT)
localizations at the time of treatment.
Additional imaging may be required to accurately delineate the tumor for certain
disease sites. For example, tumors in the liver and spine will be easier to contour on
magnetic resonance imaging (MRI) than on CT and MRI allows the spinal cord itself to
be contoured, as opposed to the entire spinal canal. Additional imaging that will be
fused with the treatment planning CT should be acquired in treatment position to allow
for more accurate fusion and contouring. Positron emission tomography (PET) has
limited usefulness during treatment planning for SAbR due to motion artifacts that
obscure the tumor size and location, but is frequently used for evaluation of posttherapy
response. Any registration between a secondary image set and the planning CT must be
evaluated for accuracy before contouring begins.

TREATMENT PLANNING AND DOSIMETRY


One of the most important steps in treatment planning is contouring of targets and
critical structures. In general, any critical structure that is within 10 cm of the target
should be contoured to help obtain accurate dose to these structures from the planning
system. An example of what is contoured for lung cases at UT Southwestern Medical
Center is as follows:

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1. ITV—contoured by the physician using the MIP (or MinIP for liver tumors), 0%, and
50% (when requested). Represents the envelope of motion of the GTV. Isocenter is
placed in the geometric center of the ITV for planning.
2. PTV—5-mm expansion around ITV in all dimensions.
3. Proximal bronchial tree—the most inferior 2 cm of the distal trachea as well as the
bilateral proximal airways.
4. Proximal trachea—contoured beginning 2 cm above the carina and extends 10 cm
superior to the PTV.
5. Spinal cord—contoured based on the bony limits of the spinal canal and extends at
least 10 cm above and below the PTV.
6. Esophagus—contoured at least 10 cm superior and inferior to the PTV.
7. Heart—contoured along with pericardial sac. The superior aspect begins at the
aorta–pulmonary window and extends inferiorly to the apex.
8. Total lung—contoured to include both lungs subtracting out the ITV.
9. PTV + 2 cm—PTV expanded by 2 cm in all dimensions (uniform expansion)
10. Body—contoured as the patient’s body at least 10 cm superior and inferior to the
PTV.
11. Body–PTV + 2 cm—The PTV + 2 cm structure will be subtracted from the body
and the remaining structure is used to evaluate dose fall off 2 cm in every dimension
of the PTV (D2 cm).
12. Brachial plexus—contoured from the spinal nerves exiting from C5–T2. This
contour extends along the subclavian and axillary vessels to the level of the second
rib.
13. Skin ring—contoured to evaluate the skin dose and is a 0.5 cm ring inside body.
14. Ribs—contoured as all ribs in close proximity to PTV.
There are several delivery techniques that can be used in SAbR treatment planning
and the choice of technique often depends on an individual patient’s tumor location and
magnitude of motion, but most often SAbR is delivered using 3D conformal beams. The
use of IMRT or VMAT for SAbR is typically reserved for tumors that exhibit limited
motion and when intensity modulation is necessary for critical structure sparing, such
as spine lesions. The 3D conformal beam arrangement for a right-sided lung lesion is
shown in Figure 14.3 and the gantry and couch angles for right and left lung SAbR
treatments are found in Table 14.1.

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FIGURE 14.3 Reconstructed simulation CT of a lung patient showing the use of noncoplanar beams and the
bellows used for phase binning of the 4DCT.

TABLE 14.1 SAbR Couch and Gantry Angles for Right- and Left-Sided Lung Lesions

SAbR dose distributions are characterized by a highly conformal high-dose volume


and a very compact intermediate dose region which can be achieved by using many
noncoplanar nonoverlapping beams, which insures a rapid isotropic dose fall off outside
the target (23). The intermediate dose is the most challenging aspect of SAbR treatment
planning and achieving this compactness separates a good plan from a bad plan
because the intermediate dose is responsible for normal tissue toxicity. RTOG 0236
specified a max dose at 2 cm outside the PTV(D2 cm) and a ratio of the 50% isodose
volume to the PTV volume (R50%) and on average 10 beams were required to meet these
compactness constraints (24). There was no relationship found between PTV size and
number of beams needed. Due to the large number of beams, SAbR dose distributions

398
are also characterized by a large low-dose region.
In addition to the number and arrangement of the beams, the beam apertures can be
made smaller than the PTV to reduce the volume of normal tissue treated. At our
institution, the MLC aperture is 2 mm smaller in the radial direction and 2 mm larger in
the superior–inferior directions, as shown in Figure 14.4.

FIGURE 14.4 Beams eye view (BEV) for a lung SAbR 3D conformal MLC aperture. The aperture is 2 mm
smaller than the PTV in the radial direction and 2 mm larger in the superior–inferior directions.

The dose distribution within the PTV will be highly heterogeneous and the edges of
the PTV will likely be underdosed if “negative margins” are used. To cover 95% of the
PTV with the prescription isodose line, the plan will be normalized to the 60% to 90%
(usually around 80%) isodose line, resulting in a large hot spot in the tumor. The
planner must balance the need for a conformal dose distribution with the mechanical
limitations of the radiation delivery equipment and treatment delivery efficiency. Beam
weighting is chosen so that dose fall off is isotropic unless an adjacent organ at risk
makes isotropic fall off undesirable. Beam energies used for lung SAbR plans are
typically 6 MV and no higher than 10 MV for beams that must traverse more than 10
cm of tissue. Lower-energy beams have a sharper penumbra, which is especially
important in the low-density lung and for the small fields used for SAbR due to the
lateral electron disequilibrium (25). Higher-energy beams can be used for targets in the
liver and spine, where tumors and the surrounding tissues are of similar density.
Flattening filter free (FFF) beams have been shown to decrease treatment times with the
efficiency improvements most significant for larger doses per fraction, such as those
delivered with SAbR (26–29). By removing the flattening filter, there is much less
attenuation of the beam between the target and the patient and dose rates as high as
2,400 cGy per minute at dmax can be achieved. These beams are also more peaked and
softer (lower beam quality) than their flattened counterparts.
When planning lung SAbR, accurate heterogeneity corrections in the planning system
become extremely important. An analysis of patients treated on RTOG 0236, which
required homogeneous calculations, found that the true delivered dose was
approximately 10% lower than the homogeneous dose (24). Task Group 101 from the

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American Association of Physicists in Medicine recommends against using pencil-beam
algorithms for lung SAbR planning because of the over-prediction of the dose in low-
density tissues (30). Studies have shown the differences in pencil-beam algorithms and
more sophisticated heterogeneity corrections to be quite significant (31,32).
Plan evaluation is a critical component of SAbR planning and all contours should be
reviewed by the radiation oncologist to ensure that the contours are accurate and that
dose being reported to critical structures as well as the PTVs meet expectations. Table
14.2 contains updated normal tissue constraints for 1, 3, and 5 fraction SAbR regimens
used at UTSW. The spinal cord and brachial plexus constraints take priority and are
always met, even if it requires the tumor to be underdosed. Occasionally, the brachial
plexus constraint can be exceeded if informed consent is given by the patient. As
mentioned previously, 95% of the PTV should be covered by the prescription dose and
99% of the PTV should be covered by 90% of the prescribed dose. Hot spots should
ideally be inside the PTV, but any volume receiving 105% of the prescription dose
should be no larger than 15% of the PTV volume. Guidelines for the use of D2 cm and
R50%, which are used to evaluate the compactness of the intermediate dose, can be
found in the RTOG guidelines (www.rtog.org). The conformality of the prescription dose
can be determined by calculating the ratio of the volume covered by the prescription
dose to the volume of the PTV. Ideally, this ratio will be close to 1.
TABLE 14.2 Normal Tissue Dose Constraints for SAbR Delivery

The critical volume dose is also an important tool in plan evaluation for parallel
tissues, such as the liver and lung. The critical volume represents the volume of an

400
organ that must be spared in order to avoid toxicity. In these tissues, the amount of
tissue damaged or the severity of the damage is not as important as the remaining
functional volume. The traditional DVH has been used to determine how much dose a
structure receives. Shifting this concept to evaluate a structure based on how much of
the structure is spared a certain dose is the goal of critical volume max dose as
illustrated in Figure 14.5. By definition, critical volume max dose is an absolute volume
of an organ that is spared a specific dose in order to avoid an endpoint effect. Dose–
volume constraints for parallel organs can be found in Table 14.2.

FIGURE 14.5 DVH showing the concept of the critical volume maximum, which is the volume of an organ
that must be spared to avoid dysfunction.

COMMISSIONING AND QUALITY ASSURANCE


While the key difference in SAbR and conventional radiation therapy is the dose per
fraction, the safe and accurate delivery of that dose would not be possible without the
technology that has been developed over the last several decades. The quality assurance
activities of the medical physicist ensure that this advanced technology is functioning
properly and will be instrumental in ensuring the success of an SAbR program. Initially,
the physicist will be responsible for commissioning new equipment that will be used for
SAbR, such as immobilization devices, planning systems, and linear accelerators. If
existing equipment will be used, the medical physicist should evaluate its suitability for
use in SAbR. AAPM Task Group 142 provides test tolerances for linacs that will be used
for SAbR (33). As expected, mechanical tolerances for these linacs are stricter than
those that will be used for conventional treatments. Planning systems must be
commissioned to accurately calculate dose distributions and monitor units for small
fields in heterogeneous tissues. Errors made in commissioning of small fields have led to

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serious overdoses (34,35). Guidance for small field measurements is provided in AAPM
Task Group 101 (30) and an average set of small field output factors have been
published by the Imaging and Radiation Oncology Core (IROC), formerly the
Radiological Physics Center, for several linac models (36,37). Institutions can compare
their measurements to the RPC dataset to ensure that there are no major errors in their
data. End-to-end tests using anthropomorphic phantoms such as those available from
the IROC quality assurance centers (Fig. 14.6) for institutions participating in clinical
trials can provide an independent evaluation of the entire SAbR process, including the
simulation, the treatment planning, the image guidance, and the delivery.

FIGURE 14.6 Phantoms from the Imaging and Radiation Oncology Core (IROC) provide an end to end test
for the SAbR process.

Ongoing treatment-specific quality assurance should be aimed at reducing systematic


errors and deviations from normal processes. Analysis of the uncertainties in the end-to-
end process will aid in developing PTV expansions needed to cover targets reliably. The
physicist will also be responsible for developing the patient-specific QA process to
ensure that the entire process proceeds as planned. Items in the SAbR process that
should be part of the patient-specific QA process include verification that normal tissue
constraints are met, that the treatment planning and patient positioning parameters

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have been independently verified and the correct patient is treated. Guidelines for
implementing a safe and high-quality SAbR program can be found in a recent white
paper (38) endorsed by the American Society for Radiation Oncology, the American
Associate of Physicists in Medicine, the American Society of Radiologic Technologists,
and the American Association of Medical Dosimetrists. This white paper also includes
recommendations on personnel, training, and technology requirements and provides
example checklists and forms than can be amended for use according to the individual
institution’s needs.

LUNG CANCER
More than 25% of all cancer deaths every year can be attributed to lung cancer, making
it the leading cause of cancer-related death in the United States (39). Lung was one of
the first sites treated using SAbR (1) and it continues to be the site most frequently
treated with this technique (40). Clinical use of lung SAbR has increased in recent years,
with more than half of surveyed radiation oncologists reporting that they began using
SAbR after 2008 (40). The most common reported fractionation scheme was 18 to 20
Gy × 3 (43%), likely due to the success of RTOG 0236, which showed a 3-year primary
tumor control rate of 98% and overall survival of 56% (41) in medically inoperable
patients with early-stage nonsmall cell lung cancer (NSCLC). Recently reported long-
term results from the trial found rates for 5-year primary tumor control and overall
survival to be 93% and 40%, respectively (42). Excess late toxicities have not been
observed, dispelling fears of such late toxicities with hypofractionation. Results from
RTOG 0236 and similar results from other countries have cemented SAbR as the
standard of care for medically inoperable early-stage NSCLC.
For patients who are medically operable and treated with 54 Gy in three fractions,
RTOG 0618 found that 2-year progression-free survival and overall survival were
65.4% and 84.4%, respectively (43). Only four patients on the trial experienced
treatment–related grade 3 adverse events while no patients had grade 4 to 5 toxicity.
A more definitive examination of SAbR as a lung cancer therapy was published in an
analysis of a Dutch cancer registry (44). They examined the time trend pattern of
treatment for elderly patients with stage I NSCLC from 1999 to 2007. They divided this
period into a pre-SAbR era (1999 to 2001), some SAbR availability era (2002 to 2004)
and a fully available SAbR era (2005 to 2007). They found that the introduction of
SAbR coincided with a 12% decrease in the number of untreated patients and an
increase in overall survival for patients treated with radiation therapy, an increase that
was not seen in patients treated with surgery or those receiving no treatment. While not
a randomized trial and no definitive link can be proved, it is plausible to believe that
the introduction of SAbR offered a more curative treatment option for this population of
patients.
RTOG 0915 investigated less potent fraction schemes for stage I peripheral NSCLC,
with the goal to identify a more favorable fractionation scheme based on the rate of
grade 3 or higher toxicities at 1 year. The trial compared 48 Gy delivered in four
fractions and 34 Gy delivered in one fraction. Results found similar overall survival,
progression-free survival and primary tumor control rates (45) for both arms and the 34
Gy arm met the adverse event criteria and was chosen as the experimental arm for a
planned phase III trial comparing it against 54 Gy in three fractions.
Optimal regimens for centrally located tumors continue to be an area of active
investigation (Fig. 14.7). RTOG 0813, a phase I/II trial to determine the maximal
tolerated dose for central lung tumors in a five-fraction regimen recently closed after

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meeting the accrual goal. Efficacy of SAbR for controlling centrally located tumors has
been shown to be nearly equivalent to control of peripheral tumors (46,47),
demonstrating that SAbR is indicated for these tumors when appropriate fractionation
schemes are used.

FIGURE 14.7 Stereotactic body radiation therapy (SAbR) of a central lung tumor treated on protocol. Panel A
shows the isodose plan. Follow-up scans are shown at 3 months, 6 months, and 1 year in panels B, C, and D,
respectively. There was an excellent initial response with eventual collapse of the downstream lung.

In addition to stage I patients, use of SAbR is being expanded to other patient


populations who historically did not receive radiation therapy or received no therapy at
all. Results from a phase II trial investigating SAbR and erlotinib for patients with
metastatic (stage IV) NSCLC who progressed after chemotherapy were recently
published (48). Patients with fewer than six metastatic extracranial lesions were treated
to all sites of disease with SAbR to a modest tumor debulking equivalent dose. With
median follow-up of 16.8 months, progression-free survival was 14.7 months and
overall survival was 20.4 months, both superior to patients historically treated with
systemic therapy alone. The pattern of failure also changed, from predominantly
existing sites to new sites.

LIVER METASTASES
Approximately 150,000 Americans are diagnosed with colorectal cancer annually,
making it the third most common cancer diagnosed (49). Approximately one-third of
these patients die from the disease, with liver metastases a leading cause of death

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(50,51). The liver receives nutrient-rich blood from the digestive system (stomach,
intestines, spleen, and pancreas) via the portal vein, making it a common site for
trafficking and growth of metastases from gastrointestinal cancers. Other primary
cancers including lung, breast, and melanoma also frequently metastasize to the liver.
Surgery is the treatment of choice because it offers the most established chance of long-
term survival. However, despite advances in surgical techniques, only 10% to 25% of
patients have metastases that are considered resectable due to existing liver disease,
number, and size of the lesions, liver damage from chemotherapy and location of the
metastases within the liver as well as coexisting patient medical comorbidities (52,53).
As a result, there is great interest in minimally invasive ablation technologies to include
radiofrequency ablation (RFA), cryosurgery, and laser-induced thermotherapy (54–60).
However, these treatments are all invasive, efficacy rates are dubious and patients are
frequently not eligible for these procedures for various reasons. RFA, a commonly used
ablation method, is limited in efficacy by tumor size as well as vascular heat sink effects
common in larger tumors (61). Cryosurgery can cause significant morbidity and has a
high local recurrence rate (62). No studies have shown that any one of these therapies
has clear advantages over the others.
Historically, the use of whole or large volume liver radiation therapy has been limited
due to the risk of radiation-induced liver disease (RILD), a variably defined condition
marked by ascites, rapid weight gain, elevated liver enzyme levels, and anicteric
hepatomegaly. Histologically, RILD appears as a form of veno-occlusive disease (VOD)
(63,64) with venous congestion of the central portion of the liver lobules. RILD can lead
to liver failure. The whole liver tolerance of 30 to 35 Gy is insufficient to achieve
reasonable tumor control. In contrast to conventional radiotherapy, SAbR has allowed
radiation oncologists to focally target lesions and deliver high doses of radiation very
accurately to the tumor while sparing the healthy tissue around it. SAbR provides
certain advantages relative to thermal ablations technologies, chief among them the
noninvasive nature of the treatment as well as the lack of a heat-sink problem. Several
groups have published studies using SAbR for tumors in the liver (65–73). Overall,
SAbR has shown to provide excellent local control for patients with liver metastases
with little toxicity. However, patients with larger tumors or treated with lower doses
have been shown to have worse local control and survival (67,74,75), indicating that
increasing the dose in general, but especially to larger tumors, may improve outcomes.
Although prior studies established dose limits for irradiation of the entire liver, dose–
volume limits for partial liver irradiation are less well established. Schefter et al. from
the University of Colorado and Indiana University performed a prospective dose
escalation trial where the maximum tolerated dose (MTD) was not found in the high-
dose ranges investigated (76). Patients treated in this study had tumor diameters less
than 6 cm and at least 700 mL of normal liver (the presumed critical volume) was
restricted to receiving a total dose less than 15 Gy (the presumed tolerated dose). Total
dose was escalated to 60 Gy in three fractions without any RILD or grade ≥3 dose
limiting toxicities. The median gross tumor volume (GTV) was 18 cc and the median
planning target volume (PTV) was 41 cc. Phase II results of this trial using the 20 Gy ×
3 dose regimen have been encouraging; actuarial local control two years after SAbR was
92% and for lesions less than 3 cm in diameter, it was 100% (72). At UT Southwestern,
we have conducted two dose-escalation SAbR liver studies, one using three to five
fractions (73) and another using a single fraction, the preliminary data for which was
presented at the American Society of Radiation Oncology’s annual meeting in 2014 (77)
and has been submitted for publication. The multifraction trial found that 60 Gy can be
safely delivered in five fractions as long as normal liver constraints were met and local

405
control rates at 12 and 24 months were both 100%, respectively (Fig. 14.8). The single
fraction study found 40 Gy in a single fraction to be a tolerable dose and at 1.8 years
median follow-up, no patients had experienced local progression and 50% of the
imaging-evaluable tumors had undergone a complete response. In general, it’s been
determined that local control increases with increased dose, particularly for larger
tumors, and larger tumors can be treated so long as the critical volume is respected.

FIGURE 14.8 Axial, coronal, and sagittal isodoses from liver stereotactic body radiation therapy (SAbR) treated
to 60 Gy are shown in panels A to C, respectively. Panels D to F show 3-month, 6-month, and 1-year follow-
up.

Patients with tumors at or near the hilum of the liver (central liver zone) and thus
near major vessels, such as the portal vein and hepatic artery as well as large-caliber
bile ducts, are ineligible not only for invasive treatments, but are also often excluded
from treatment with thermal ablation and single fraction SAbR courses, including our
own phase I single fraction trial. The tissue at the liver hilum likely has a lower
tolerance to ablative radiation doses, similar to that seen in SAbR treatment of central
lung tumors (78). Biliary sclerosis and jaundice requiring stenting have been seen in
patients treated with SAbR to the central zone of the liver. A better understanding of the
central zone tolerance to ablative radiation doses will be important in order to make this
treatment option available for patients with tumors in the central zone of the liver.

HEPATOCELLULAR CARCINOMA
Experience with SAbR for hepatocellular carcinoma (HCC) is certainly more limited than
that for liver metastases due to the underlying liver disease that accompanies HCC.

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Patients with HCC often are not eligible for curative treatments due to disease stage or
poor liver function (79). However, SAbR is emerging as a potential definitive therapy or
as a bridge to transplant. Researchers from Indiana University published their
experience for Child–Turcotte–Pugh (CTP) Class A and B patients treated with median
of 44 Gy in three fractions and 40 Gy in five fractions, respectively (80). Their median
follow-up was 27 months and the 2-year local control, progression-free survival and
overall survival were 90%, 48%, and 67%, respectively. The reported 2-year local
control was better than that from a previously reported study (81), likely due to the
larger tumor volumes treated in the earlier study. All ≥grade 3 toxicity was
hematologic, but 7 of 36 patients with CTP Class A progressed to CTP Class B and 5 of
24 patients with CTP Class B progressed to CTP Class C. The authors found that
pretreatment CTP Class and development of toxicity were related. Another study treated
patients with more advanced liver disease to a median dose of 34.4 Gy in six fractions
(82). Median survival was 7.9 months and overall survival at 1 year was 32.3%. During
follow-up, no patients experienced progression of irradiated HCC and there were no
grade 3 or higher acute toxicities. In general, studies for SAbR as a definitive treatment
for HCC have found that tumor size and liver function should be carefully considered
before treating these patients. Hypofractionation is also being explored as a bridge to
liver transplants. Radiotherapy can be used to downsize or stabilize tumors prior to
liver transplant. A 10-fraction regimen delivering 50 Gy was found to be very effective
with 12 patients receiving liver transplant or resection following irradiation and were
alive at a median follow-up of 19.6 months (83).

SPINE
The spine is a frequent site of metastases from primary cancers of the prostate, lung,
breast, and kidney. Spine metastases can cause pain and lead to fractures and spinal
cord compression. Historically, spinal metastases have been treated with 30 Gy in 10
fractions for palliation and this dose regimen has provided good pain relief. However,
higher dose are needed to provide durable pain and tumor control. There are a variety
of fractionation schemes being used including single and multifraction regimens. Figure
14.9 illustrates a spine SAbR plan prescribing 20 Gy in one fraction. A recently
published study of a three-fraction regimen with total doses ranging from 27 to 30 Gy
found significant reduction in patient reported pain at 6 months post-SAbR,
progression-free survival was 80.5% at 1 year and 72.4% at 2 years (84). A study of
spine SAbR for renal cell metastases to a median dose of 24 Gy in two fractions found 1-
year overall survival and local control rates of 64% and 83% with oligometastatic
disease status a positive prognosticator for overall survival. The phase II portion of
RTOG 0631 demonstrated that spine SAbR/SRS was feasible, safe, and could be
performed at a high level by a cooperative group (85). The phase III portion of the trial
will compare 3-month pain relief and quality of life for patients treated with single
fraction 16 to 18 Gy SAbR versus patients treated conventionally with 8 Gy in a single
fraction.

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FIGURE 14.9 Panel A shows a stereotactic body radiation therapy (SAbR) isodose plan of a patient treated to
20 Gy in a single fraction with IMRT used to create a sharp dose gradient toward the spinal cord. Panel B
shows follow-up at 6 weeks with radiation pneumonitis corresponding to the 10-Gy line.

Spine SAbR is being used increasingly in the reirradiation setting for patients who
progress through conventional palliative courses (86) but the optimal dose and
fractionation scheme for the reirradiation has been confounded by a poor
understanding of the spinal cord tolerance and its ability to repair previous radiation
damage. Sahgal et al. analyzed myelopathies that occurred after reirradiation with
SAbR and provides guidelines for presumed tolerant SAbR following conventional
treatment for spinal metastases. Preclinical studies in a large animal model have shown
that reirradiation 1 year after a conventional course of radiation therapy had the same
ED50 for paralysis as those that received single fraction therapy alone (87). While
animal data may not be directly applicable for human spinal cord tolerance, it can be
useful in guiding the development of clinical trials. The most common toxicities
following spine SAbR are myelopathy (88) and iatrogenic vertebral compression fracture
(VCF) (89,90) and both are associated with higher doses while probability of VCF is also
correlated with pre-existing tumor-related VCF (90,91).

PROSTATE
Prostate cancer accounts for 27% of new cancer cases diagnosed in men in the United
States and is the second leading cause of cancer-related death in men (39). Prostate
cancer is often diagnosed early due to effective screening programs. Prostate cancer is
conventionally treated to 79.2 Gy in 40+ fractions with IMRT and image guidance,
with the bladder, urethra, erectile tissues, and rectum serving as the most important
organs at risk. Other options for early-stage prostate cancer include watchful waiting,
surgery, and brachytherapy. While all options have excellent survival in low-risk disease
(Gleason <7, PSA <10), cancer death rates increase with intermediate and high-risk
patients.
SAbR is an attractive option for these patients because it can be delivered in fewer
fractions, is noninvasive and has been shown to be more cost-effective than a protracted
course of conventional IMRT, provided that outcomes and quality of life are similar
(92), though longer follow-up and more mature data are needed to determine if that is
the case. A recent analysis of Medicare beneficiaries treated with SAbR for prostate
cancer found more frequent GU toxicity for patients treated with SAbR when compared
to IMRT (93). However, their retrospective analysis was confounded by a lack of
information on grade of toxicity experienced, differences in baseline function, SAbR

408
dose, or treatment technique. In contrast, a multi-institutional report on quality of life
after prostate SAbR found that at 3-year median follow-up SAbR is well tolerated and
that after a decline shortly following completion of therapy, urinary and GI quality of
life returns to baseline and remains high long term (94). These patients received a
median dose of 36.25 Gy in four or five fractions. The same group retrospectively
reported the clinical outcomes of nearly 1,100 patients treated at 8 centers between
2003 and 2011 (95). They reported that with median follow-up of 36 months, 40
patients experienced PSA failure. Their reported 5-year biochemical relapse–free
survival for Gleason score ≤6, 7, and ≥8 were 95%, 83%, and 78%, respectively and
93% for all patients. Updated follow-up from a multi-institutional phase I/II trial
reported excellent PSA control of 99% at median follow-up of 42 months for all patients
(phases I and II) and 54 months for patients treated on the 50 Gy arm in the phase I
study (96). Figure 14.10 shows a sample treatment plan from this trial. The grade 3 late
GI toxicity reported from this trial has been correlated with the volume of rectal wall
receiving greater than 50 Gy and greater than 35% circumference of the rectal wall
receiving 39 Gy, related to vascular and mucosal stem cell injury (97). The grade 2+
acute rectal toxicity was related to treatment of more than 50% of the circumference of
the rectal wall to 24 Gy. It should be noted that the strongly correlated indicator for
rectal toxicities to percent of circumferential irradiation cannot be determined from the
standard dose–volume histogram constraints; rather, prudent examination of the actual
treatment isodose lines is required. This analysis provides the planner with guidance for
plan optimization and organ at risk sparing.

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FIGURE 14.10 Representative treatment plan for prostate SAbR patients treated to 50 Gy in five fractions on
the UT Southwestern phase I/II protocol. A rectal balloon was used to reduce the surface area of the rectum
exposed to the high dose.

PANCREAS
Prognosis for patients diagnosed with pancreatic cancer is extremely poor as it remains
the fourth-leading cause of cancer related death in the United States, and together with
lung cancer, has seen the least improvement in survival over the last three decades (39).
Five-year survival remains below 10%. Surgery is the only potentially curable treatment,
but unfortunately very few patients present with resectable disease. Several recently
published studies have found that SAbR for locally advanced pancreatic cancer is
promising. Potential advantages of SAbR for pancreatic cancer include shorter
treatment courses, better local control, and earlier start of chemotherapy. In as single
institution study, patients were treated with three fractions of 8, 10, or 12 Gy,
depending on the proximity of the tumor to organs at risk, which was followed 1 month
later with 6 months of weekly gemcitabine (98). With median follow-up of 24 months,
local control was 78% and median overall survival was 14.3 months. Eight percent of
patients experienced acute grade 3 toxicities and two patients experienced late toxicity.
A multi-institutional trial examined a single fraction of 25 Gy preceded by three cycles

410
of gemcitabine and followed by three to five cycles (99). All 20 enrolled patients
completed SAbR and received a median of five cycles of systemic therapy. No grade 3 or
greater nonhematologic acute toxicities were seen and one late grade 3 toxicity
occurred. Median survival was 11.8 months and 1- and 2-year survival was 50% and
20%, respectively.
A single institution retrospective review of locally advanced and borderline resectable
patients treated with three cycles of gemcitabine-based chemotherapy followed by SAbR
was recently published (100). SAbR was delivered in five consecutive daily fractions to
a median dose of 25 to 30 Gy to the GTV and a simultaneous integrated boost of 35 to
50 Gy to the region of vessel abutment/encasement. For the borderline resectable
patients, 77.2% underwent an exploratory laparotomy and 56.1% underwent resection,
with 96.9% of those resected having negative margins. Two of the locally advanced
patients underwent surgical exploration but neither was found to be resectable. Median
overall survival and 1-year progression-free survival for borderline resectable patients
was 16.4 months and 42.8% and for locally advanced patients was 15 months and
41%, respectively. Patients who were resected had significantly better median overall
survival and median progression-free survival compared to all patients who remained
unresectable. No acute grade 3 or greater toxicities occurred but four patients
experienced late grade 3 adverse events. The effect of SAbR on local control was clearly
demonstrated in that 37% of patients had distant failure only, indicating the need for
improved systemic therapies for pancreatic cancer. Another multi-institutional phase II
trial using a 33 Gy in five-fraction regimen found 1- and 2-year overall survival rates of
59% and 18% with low toxicity (101).

METASTASES
Patients with metastases are often treated with systemic therapy in an effort to improve
survival and quality of life. Systemic therapy is necessary to reach all sites of known
metastases and to treat microscopic disease that is assumed to be present. However,
certain patients with limited metastatic disease can have excellent long-term outcomes
with surgical resection, even without systemic treatment (102) leading many to believe
that similar results could be achieved with ablative radiotherapy. Long-term follow-up
of a prospective study treating patients with five or fewer metastases from any primary
site found 6-year overall survival and freedom from distant metastasis rates of 20% and
21%, respectively and approximately one-third of patients survived more than 4 years
(103). Doses were determined by the adjacent organs at risk, with a preferred schedule
of 50 Gy in 10 fractions. Patients with metastatic breast cancer experienced
significantly better outcomes than those who had metastases from nonbreast cancer and
nonbreast cancer tumor burden was significant for worse overall survival and local
control.
A dose escalation study from the University of Chicago reported 1- and 2-year
survival rates of 81.5% and 56.7%, respectively for patients receiving SAbR to one to
five metastatic sites (104). They began with 24 Gy in three fractions and escalated 2 Gy
per fraction to a total of 60 Gy. They found that patients tolerated this treatment
regimen and 27% of patients developed no new metastatic lesions during the reported
median follow-up of 20.9 months for all patients and 31.3 months for living patients. A
retrospective review of 14 patients with 74 lung metastases from soft tissue sarcomas
treated with SAbR reported excellent 3-year local control of 82% with a preferred
treatment scheme of 50 Gy in five fractions (105). The median number of lesions treated
per patient was 4 and the median GTV was 5.1 cc. Excluding a single patient treated

411
with 30 Gy in three fractions, the local control rate was 97%. These results are
promising, but determining which patients will benefit the most from local ablative
therapies is still challenging and better systemic treatments are needed.

KEY POINTS
• SAbR requires optimal patient immobilization, motion management, and accurate targeting
to deliver an ablative dose to tumors while sparing surrounding normal tissues.
• The biology of SAbR is not well understood, but the excellent local tumor control is believed
to be a result of vascular damage and abscopal effects are likely a result of an antitumor
immune response to massive cancer cell death in the irradiated tumor.
• A successful SAbR program requires careful commissioning and a comprehensive quality
assurance program developed by the medical physicist.
• SAbR dose distributions are characterized by a highly conformal but heterogeneous high-
dose volume, a compact intermediate dose volume, and a large low-dose volume.
• Treatment plans should be scrutinized carefully to ensure that the attending physician’s goals
are being met for organs at risk and targets.
• SAbR is the standard therapy for early-stage inoperable lung and liver cancer and lung and
liver metastases.
• SAbR is being studied under clinical trials for prostate and pancreatic cancers and for
metastatic disease.

QUESTIONS
1. According to the RTOG 0236 guidelines, which parameters determine the quality
of the dose distribution for a lung SAbR treatment plan?
A. The mean lung dose
B. The maximum lung dose and the volume of lung receiving 20 Gy
C. R50% and D2 cm
D. The PTV volume and the number of beams used
2. Lung tumor motion assessment provides all of the following information except
A. Tumor motion amplitude
B. Tumor size
C. Tumor motion period
D. Tumor motion regularity
3. The concept of the critical volume of an organ that must be spared to prevent
dysfunction would apply to which pair of organs?
A. Lung and liver

412
B. Lung and spinal cord
C. Lung and esophagus
D. Liver and spinal cord
4. In low-density tissues such as the lung, simplistic treatment planning
heterogeneity corrections such as the pencil-beam algorithm
A. Under-predict the actual delivered dose
B. Calculate the correct delivered dose
C. Over-predict the delivered dose
D. Are recommended by the AAPM Task Group 101
5. RTOG 0915 compared the rate of grade 3 or higher toxicities in stage I
peripheral NSCLC patients treated with two different fractionations. The doses
in the trial were
A. 60 Gy in 3 fractions and 54 Gy in 3 fractions
B. 60 Gy in 5 fractions and 60 Gy in 3 fractions
C. 48 Gy in 4 fractions and 60 Gy in 3 fractions
D. 48 Gy in 4 fractions and 34 Gy in 1 fraction

ANSWERS
1. C
2. B
3. A
4. C
5. D

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15 Low Dose-Rate Brachytherapy

Mark J. Rivard

INTRODUCTION
Brachytherapy is a form of radiation therapy in which the source of radiation is placed
close to or within the patient. The origin of the word brachytherapy is from the ancient
Greek word βραχύς or brachys, which means short distance as relating to the proximity of
the radiation source to the patient. As a co-discoverer of radium with Marie Curie (née
Skłodowska) in 1898, Pierre Curie suggested to a fellow Frenchmen, Henri-Alexandre
Danlos, to use the radioactive material for therapeutic purposes. With the assistance of
the physicist Bloch, Danlos proceeded to treat a patient with tuberculosis—this was the
first brachytherapy treatment (1). This form of treatment would be termed
radiumtherapy until Forssell associated the term brachyradium (2), and later simplified
as brachytherapy with the availability of other radiation sources. Aronowitz has
researched much of the early history of brachytherapy, and the interested reader may
examine these readily available summaries (3–16).
Clinical applications of brachytherapy may be applied with the radiation source on
the patient’s skin surface, sometimes referred to as plesiotherapy in historical
documents (think of the plesiosaurus dinosaur that lived on the water’s surface). Other
means of treatment delivery can place the source within a naturally occurring cavity
within the patient (referred to as intracavitary brachytherapy), into a naturally
occurring channel or lumen such as the esophagus (referred to as intraluminal
brachytherapy), into a blood vessel (referred to as intravascular or endovascular
brachytherapy), percutaneously into the tumor volume via a needle (referred to as
interstitial brachytherapy), and within the tumor volume via an open surgical
procedure (referred to as intraoperative brachytherapy). All these delivery methods
require (semi)invasive placement techniques and contrast with teletherapy, nowadays
commonly referred to as external-beam radiotherapy (EBRT), where the radiation source
is positioned relatively far from the patient.
Brachytherapy may be further portioned in terms of the means of delivery. The first
treatments were delivered with 226Ra sources directly inserted into the lesion. This is
now referred to as manual loading. 222Rn sources were subsequently developed to
provide sources with higher specific activity, that is, Ci/g, and allow implantation of
thinner needles. After physicians and surgeons exhibited toxicities such as blackened
digits and subsequent amputations, an alternate method of implantation was developed,
now referred to as manual afterloading. Here, the lesion was implanted with needles
during surgery with the sources implanted afterward. This approach allowed careful
needle positioning without rush, especially important at the academic centers where
brachytherapy was most active at the time. Further, radiation exposure to hospital
personnel was minimized since patients located in recovery rooms were not emitting
radiation. A further advancement was implemented with remote afterloading, where the
placement of the radiation source within the patient was done through
electromechanical means instead of manually, with radiation exposure to hospital
personnel.

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All these delivery methods utilized low dose-rate (LDR) brachytherapy sources, which
are classified to administer radiation at a dose rate of 0.4 to 2 Gy/h (i.e., 0.67 to
3.33 cGy/min). High dose-rate (HDR) sources are classified to administer radiation at a
dose rate exceeding 12 Gy/h (i.e., 20 cGy/min). This categorization of dose rate was
established in Report 38 (17) by the International Commission on Radiation Units and
Measurements (ICRU). ICRU 38 categorization also includes medium dose-rate sources
that administer radiation at a dose rate of 2 to 12 Gy/h (i.e., 3.33 to 20 cGy/min), or
pulsed dose-rate brachytherapy (using HDR sources positioned within the target for a
short time as an in-patient procedure with the treatment course extending over a few
days), but these intermediary approaches have all but stopped and are used now only in
a handful of clinics in the United States.
Key issues with the clinical delivery of brachytherapy is patient safety and implant
quality (18). The European Society for Radiotherapy & Oncology (ESTRO) Booklet 8
established quality standards for brachytherapy equipment and quality assurances
practices (19), but did not offer much guidance on the quality measures governing the
practice of clinical brachytherapy. This topic is covered in greater detail within societal
reports such as the TG-56 (20) and the TG-64 (21) reports by the American Association
of Physicists in Medicine (AAPM), and also the book by Thomadsen (22) dedicated to
the subject of achieving quality in brachytherapy.

LDR BRACHYTHERAPY SOURCES


So what is a brachytherapy source? Brachytherapy sources differ from other internally
placed sources of radiation used in medicine, for example, nuclear medicine, in that the
radiation source does not chemically interact with the patient. Brachytherapy sources
will often have a single or double-layer of encapsulation to contain a radionuclide
whereas nuclear medicine has a radionuclide bound to a chemical that will
preferentially locate within the body after being injected. This difference even applies to
90Y microspheres (23), where the radionuclide is contained within a resin or glass
matrix (24), approximately 30 μm in diameter, and injected for permanently lodging
within the micro vessels of an organ such as a lobe of the liver. Radionuclides used in
nuclear medicine will typically clear the body based on a biologic half-life related to
metabolism and plumbing.
The radiation source for brachytherapy may also be generated through electricity,
such as through an internally or externally positioned x-ray tube (25–27). However,
these radiation sources are designed to deliver a therapeutic dose within a matter of
minutes and are categorized as HDR brachytherapy sources.
This leaves the most popular type of brachytherapy source, which is a radionuclide
contained within an inert encapsulation for temporary or permanent implantation
within a patient. Due to concerns for shielding hospital personnel and the general
public from untoward radiation emitted by patients implanted with LDR brachytherapy
sources, either implanted permanently or in a temporary manner, LDR sources today
contain radionuclides that emit radiation described as low-energy radiation, typically
photons with a mean energy ≤50 keV (28). Some radiologic properties of common low-
energy photon-emitting brachytherapy sources are included in Table 15.1. These three
radionuclides decay via electron capture, in which a proton-rich nucleus absorbs an
electron from an inner atomic shell, subsequently transforming a proton into a neutron.
As the atom relaxes to its ground state, energy is releases as photons are emitted
through x rays generated by electrons from outer atomic shells filling the void of the
inner shell and sometimes also with nuclear relaxation (as is the case for 103Pd and

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125I) with gamma-ray emission from the excited nucleus. These x-ray and γ-ray photons
have discrete energies and intensities for a given radionuclide disintegration. Auger
electrons may also be emitted by the excited atom, but these low-energy electrons are
blocked from exiting the brachytherapy source due to the encapsulation.
TABLE 15.1 Some radiologic properties of low-energy photon-emitting brachytherapy sources.
X-ray transitions are listed after the elemental symbols for the daughter nuclides. The lower
probability x-ray transitions, x-ray transitions <10 keV, and Auger electrons are not listed

Some examples of low-energy LDR brachytherapy sources are included in Figure 15.1
with images adapted from Rivard et al. (28,29). These images depict the various designs
that have been developed to provide source localization with imaging from x-ray
computed tomography (CT) scans, as well as to facilitate a number of novel features
such as localization with ultrasound imaging, thinner diameters to minimize tissue
trauma following interstitial implantation, and source flexibility.

FIGURE 15.1 Examples of low dose–rate brachytherapy sources containing 125I, 103Pd, and 131Cs, as adapted
from Rivard et al. (28,29).

LDR brachytherapy sources have been used, and may still be in use in some clinics,
which contain other radionuclides that emit higher-energy photons. These sources
contained 198Au, 137Cs, or 192Ir. However, their use in LDR brachytherapy sources has
greatly diminished over the past decade due to limited availability from manufacturers

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and excellent clinical results using low-energy brachytherapy sources, which greatly
restrict the radiation exposure to the patient. Further, high-energy photon-emitting
brachytherapy sources may have higher doses in contact with their encapsulation than
low-energy sources due to electrons escaping (30).

DOSIMETRY
The following section describes the current means in which dose distributions are
determined in the vicinity of LDR brachytherapy sources and how these dose
distributions are integrated into clinical treatment planning systems (TPSs). Historical
dosimetry systems (31–34) that came to light before the advent of computerized
treatment planning are available to the interested reader for gaining insight on general
principles that still apply today. Currently, dose specification to water is the standard
for which brachytherapy prescriptions are generally based. This is due to historical
reasons as the earliest brachytherapy sources (i.e., 226Ra, 222Rn, 60Co, and 192Ir) were
high-energy photon emitters and the radiologic equivalence of water and soft tissue was
within about 1% of unity due to similarities in the mass-attenuation coefficients (i.e., μ/
ρ, governing attenuation in medium) and mass-energy absorption coefficients (i.e., μen/
ρ, governing dose deposition) for water and soft tissue (35). For the low-energy photon-
emitting LDR sources, differences between water and soft tissue for μ/ρ and μen/ρ can
exceed a couple percent, such as for 103Pd (36), causing differences between prescribed
and administered dose by over 10% in some instances.
However, a key point to note is that current prescriptions are generally based on trial-
and-error with years of historical data (37,38). The doses prescribed as standard-of-care
are based on the assumption of the water equivalence of human tissue (39). One cannot
simply update the medium for dose calculation without also coordinating a thoughtful
change in the prescription paradigm to correct for the radiologic differences between
water and soft tissue—often a 3D phenomenon and not simply a scalar value.
Given the prevalence of computerized TPSs, the current worldwide standard method
is the AAPM TG-43 formalism, based on the seminal report from 1995 (40), the most
cited publication in the scientific journal Medical Physics (41). This approach sets water
as the reference medium, with a fixed dose calculation formulism, and parameters
within the formulism that are specific to each brachytherapy source model. The TG-43
formalism is based upon prior approaches that also parameterized source-specific terms
(42–47). For clinical dose calculations to occur, the dose distribution must first be
determined in the vicinity of a given brachytherapy source model. From the measured
or calculated dose distributions, brachytherapy dosimetry parameters are obtained. The
TG-43 formulism relies on widespread adoption of dosimetry parameters for a given
source model, resulting in consistent dose calculation for all that utilize accepted
dosimetry parameters. The AAPM is the professional society that establishes consensus
data on brachytherapy dosimetry parameters as they are invested in the safe and
uniform implementation of clinical brachytherapy.
But how are radiation dose distributions around brachytherapy sources determined in
the first place? These are often performed by dosimetry investigators, who use
measurement techniques or computational methods to derive the dose distribution
around a given model for a single brachytherapy source. The dose gradients are
smoother in EBRT than with brachytherapy, where changes in dose exceeding a factor
of two can occur within 1 mm (48). In EBRT, there also is an established infrastructure
of measurement devices and measurement protocols for evaluating the dose distribution

423
under reference conditions from a linear accelerator (49); brachytherapy dosimetry
requires larger detector corrections than for EBRT (50), where the photon energy is
usually a factor of 100 or more higher than that measured in brachytherapy dosimetry.
Prescriptions in brachytherapy are sometimes at a distance of 5 mm from the source,
where a positioning uncertainty of just 0.5 mm can result in a change in dose at that
location of 20%. Issues on the methods of measuring brachytherapy dose distributions
are discussed in detail by Williamson and Rivard (51,52).
The practice of measuring radiation doses in EBRT radiation fields is also supported
due to the electrical nature of radiation generation and the beam tailoring devices that
can alter the dose delivered within the patient. In brachytherapy, the radiation is
almost always generated via radionuclide decay, which is a predictable process that
lends itself to determination through strict computational methods (53,54). Due to the
low-energy photons prevalent in LDR brachytherapy, assumptions of charged particle
equilibrium and the approximation of absorbed dose equivalence to collisional kerma
can simplify the calculations while introducing minimal errors.
Monte Carlo (MC) methods for radiation transport calculations are a crucial
component for brachytherapy dosimetry evaluations performed recently and expected
for the foreseeable future. MC methods have been used for over four decades for this
purpose (55,56). A thorough description of the process is described by Williamson and
by Thomadsen et al. (57,58). Briefly, the dose distribution around a given model for a
single brachytherapy source is determined. Using attributes describing the spatial
distribution of the radionuclide, the brachytherapy dosimetry parameters for that
particular source model are determined. These brachytherapy dosimetry parameters are
then entered into a brachytherapy TPS and used for all subsequent clinical applications
so that there is uniformity in the dosimetry of patient treatments with that source
model.
In practice, one of the following two equations (28,29,59,60) is used for clinical dose
calculations:

where the dose rate at any location is simply the product of a few brachytherapy
dosimetry parameters. If the source orientation is unknown, then Equation 15.1 is used.
This 1D dose calculation formalism is the most popular means of determining dose
distributions for LDR brachytherapy sources, which results in a spherically symmetric
dose distribution.
For the 2D dose calculation formalism, the source is assumed to be designed
cylindrically symmetric with a resultant cylindrically symmetric dose distribution.
Almost always, the source is assumed to be designed with further symmetry about the
transverse plane bisecting the source length. Dose rate is determined as a function of
radial distance r from the source center to the point of interest and the polar angle q as
measured from the source long axis. The polar coordinate system of the TG-43
formalism is depicted in Figure 15.2. Note that the relevant length for dose calculations
is the radioactivity extent and not the length of the encapsulation. The reference
position is at a distance of r0 = 1 cm and a polar angle q0 = 90 degrees.

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FIGURE 15.2 TG-43 brachytherapy dosimetry coordinate system for dose calculations, adapted from Rivard et
al. (28).

The source strength is specified in terms of air-kerma strength, SK. It has units of “U”
where 1 U = 1 μGy·m2· h−1 = 1 cGy·cm2·h−1. For a given source model, this is the
only dosimetry parameter specific to the source inventory within the clinic. Source
strength is reported by the source manufacturer and measured in the clinic. This is
discussed in greater detail in the next section.
The dose-rate constant Λ is specific to a given source model, and is the ratio of the
dose rate at the reference position, , to the source strength. The units of Λ are
cGy·h−1·U−1. Low-energy LDR brachytherapy sources have Λ values near equal to
unity, with Λ approximately equal to 0.68 cGy·h−1·U −1 for 103Pd sources, 0.93 cGy·h
−1·U−1 for 125I sources, and 1.06 cGy·h−1·U −1 for 131Cs sources.
The geometry function is the most important dosimetry parameter toward
approximating the dose-rate distribution using the TG-43 dose calculation formalism. It
can account for a factor of 10,000 gradient in the dose distribution between near and
far positions from the source, that is, positions 0.1 to 10 cm from the source. Use of the
geometry function (and typically coarse evaluation matrices) obscures the fact that
doses exceeding 10,000 Gy may occur at the surface of LDR brachytherapy seeds
following clinical implantation. For the 1D dose calculation formalism, a simple inverse-
square relationship is used to approximate the dose falloff. A complementary term r0 is
in the numerator to balance the units of 1/r2. For the 2D dose calculation formalism,
the spatial distribution of the radionuclide is approximated as a line segment that
typically covers the physical extent of the radioactivity within the encapsulation. The
active length (or effective length for sources containing multiple pellets of radioactivity)
is used for derivation of the 2D geometry function, G(r, q). The geometry function takes
the following form based on polar angle:

The term β is the angle (in radians) subtended by the ends of the radioactive part of
the source and the point of interest. When the point of interest is more than three times
the distance from the center of the source than the active length, any differences

425
between the 1D and 2D dose calculation formalism results amount to less than 5% (61).
For sources with an active length of about 0.3 cm, this occurs at a distance of about 1
cm.
The radial dose function, g(r), is the dosimetry parameter used to obtain the dose rate
in water at positions on the source transverse plane beyond the trend expected by
correcting dose rate at the reference position by the geometry function. For instance, if
the medium were not water but a more attenuating material, the radial dose function
would fall off more steeply than in water due to increased radiation attenuation. While
the radiologic properties associated with this dosimetry parameter are radiation
attenuation and scatter, it is used simply to permit replication of the dose-rate
distribution on the transverse plane beyond any corrections provided by the geometry
function.
In the original (1995) TG-43 report (20), a single radial dose function g(r) was
introduced to account for the deviation from the geometry function on the transverse
plane. However, since there are differences between the 1D and 2D geometry functions,
there should consequently be different radial dose functions for each formalism to
reproduce the original dose-rate distribution. These radial dose functions, gP(r) and
gL(r), were introduced in the 2004 report update (TG-43U1) by Rivard et al. (59).
Because there may be 1D or 2D geometry functions used based on knowledge of source
orientation, it is imperative that the correct radial dose function, either gP(r) or gL(r),
respectively, be used to properly replicate the original dose-rate distribution. Especially
at locations near the source, use of a radial dose function for the wrong formalism can
cause errors in dose by more than a factor of two.
I like to think of the remaining term as “every else” for addressing what is not
accounted for by the combination of the geometry function and the radial dose function
to reproduce dose rates away from the transverse plane. This concept is explained
elsewhere in greater detail (62). Like the geometry function and radial dose function,
the anisotropy function can be for either the 1D or 2D formalism. For the case of the 1D
formalism, the 1D anisotropy function, øan(r), is the ratio of the solid-angle weighted
dose rate, averaged over the entire 4π steradian space, to the dose rate at that same
distance r on the transverse plane. Due to the anisotropy of dose as a function of polar
angle at large distances from low-energy LDR brachytherapy sources (primarily due to
photon attenuation by the encapsulation), values for øan(r) are typically slightly less
than unity. However, the dose rate is higher at locations close to the source off the
transverse plane for a given r value due to the nonspherical geometry of the source.
Consequently, volume averaging of dose over the entire 4π steradian space at these
close distances tends to produce values for øan(r) that are typically greater than unity.
In fact, the volume averaging will include locations within the source for positions
closer than half the encapsulation length. Care must be made by dosimetry investigators
to exclude these locations for øan(r) derivation.
The 2D anisotropy function, F(r,θ), is slightly more complicated in that it is the ratio
of the dose rate at any location off the transverse plane to the dose at the same r on the
transverse plane, after accounting for the geometry function. Consequently, the
perturbing effect on the dose distribution by the spatial distribution of radioactivity will
alter calculations of øan(r) but not F(r,θ). In the end, if properly derived, this difference
does not matter as use of the appropriate geometry function and radial dose function in
combination with the anisotropy function will reproduce the original dose distribution.
Once all the dosimetry parameters are available for a given model of a brachytherapy
source, the AAPM, in concert with other professional societies such as the ESTRO, will

426
review the literature to evaluate candidate datasets and then establish consensus
brachytherapy dosimetry parameters based on robust and unbiased methods (28). These
data will then become available to clinical users through publication in AAPM reports,
posting on the Brachytherapy Source Registry as managed jointly by the AAPM and the
Imaging and Radiation Oncology Core Houston Quality Assurance Center (IROC
Houston, formerly the Radiological Physics Center), through web-based resources under
development, or through inclusion in vendor-provided software by TPS manufacturers.
It is always the responsibility of the clinical medical physicist to evaluate any data used
for clinical applications and to document this evaluation in a methodical manner.
Implementation of new dosimetry parameters can have a profound influence on the
resultant dose distribution that the patient would receive (63–65).

SOURCE CALIBRATIONS
Source strength is typically the only dosimetric quantity measured by a clinical medical
physicist. The practice for establishing calibrations traceable to the US primary
standard laboratory (the National Institute of Standards and Technology) and making
calibrations of clinical instrumentation traceable to the NIST standard is covered in
depth in the AAPM-approved reports by DeWerd et al. (66) and by Butler et al. (67).
The report by the Calibration Laboratory Accreditation subcommittee of the AAPM set
practice standards for LDR brachytherapy source manufacturers and dosimetry
investigators (66). Source manufacturers are to establish internal standards for source
calibrations as used for providing calibration certificates to customers. These
calibrations are to be traceable to NIST on an ongoing basis. Further, measurements of
the dose-rate constant (as performed by brachytherapy source dosimetry investigators)
are taken from a subset of the sources used to establish the calibration standard at
NIST. In this way, the dosimetry parameters used in clinical applications and the seeds
used in patients are both connected through NIST-traceable calibrations. This process
has extended the dosimetric prerequisites (68) necessary for sources to satisfy the AAPM
criteria for placement on the Brachytherapy Source Registry.
The report by the Low Energy Brachytherapy Source Calibration Working Group of
the AAPM set standards for clinical medical physicists on the practice standards for
assaying brachytherapy sources (67). Specific to brachytherapy source strength
measurements, these practice standards supersede those of the AAPM TG-56 report
(20). The responsibility for such calibrations was clearly identified as being that of the
clinical medical physicist. This clarified ambiguity where some source manufacturers
offered calibrations from third-party services where seeds were placed in strands or
prepared with spacers into needle assemblies. Clinical medical physicists are required to
assay sources preceding clinical use because there sometimes is a lack of NIST-
traceability, as well as the increased uncertainties associated with using third-party
calibration services. The report outlined standards for the number of sources to be
assayed, the permissible tolerances between measurements performed by the clinical
medical physicist and the source manufacturer calibration certificate, and actions to be
taken by the end-user medical physicist based on the level of agreement between the two
values of the brachytherapy source strength. Interestingly, the tolerances in this report
can be extended to account for statistical variations in the reported source strength for
a batch of seeds, where the number of sources to be assayed in a given batch can be
derived based on the desired level of agreement with the manufacturer calibration
certificate (69–72). However, this statistical approach was deemed too complicated for
setting widespread use and clinical practice standards.

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For the low-energy photon-emitting radionuclides included in Table 15.1, the LDR
brachytherapy seeds should have a primary calibration standard established by NIST.
This calibration standard is made through measurements performed using the NIST
wide-angle free-air chamber (WAFAC) as described by Seltzer et al. (73), which has been
extended beyond 125I and 103Pd to include 131Cs seeds. A schematic diagram of the
NIST WAFAC device is given in Figure 15.3, where it is indicated that the source rotates
during measurements, radiation is filtered through an aluminum foil, and the chamber
can collapse in length to remove measurement artifacts. As there are photons emitted by
brachytherapy sources with energies less than 5 keV, such as characteristic x-rays from
the frequently used titanium encapsulation, the measurement of source strength
includes corrections to remove these low-energy photons that do not significantly
contribute to absorbed dose in tissue, yet significantly contribute to source strength
measurements (74,75).

FIGURE 15.3 Schematic depiction of the wide-angle free-air chamber (WAFAC) at the National Institute of
Standards and Technology, as adapted from Rivard et al. (28).

The source strength is measured in air at a distance of 30 cm from the source with an
8-cm diameter tungsten aperture that collimates the photons before reaching the
ionization chamber. This collimation results in a high signal due to the sampling angle
(explaining use of the words “wide-angle” in the WAFAC designation), which is about
90 ± 7.6 degrees from the seed long axis. Corrections to the reported source strength
(in terms of air-kerma rate in vacuum) are made for radiation attenuation by the
aluminum filter, attenuation in air, radiation scatter, and several other effects. All these
corrections total to approximately 5% for 125I, 11% for 103Pd, and 4% for 131Cs
sources.
It is important to recognize the robust processes in place for establishing traceable
calibrations of brachytherapy sources, requirements of manufacturers to have their
products included on the Brachytherapy Source Registry, and the clinical practices
standards developed for clinical medical physicists. An example of how the dose
delivered to a patient may vary based on nonrobust calibration methods is given in
Figure 15.4, adopted from Williamson et al. (64), where undesirable dose variations of

428
up to 17% occurred.

FIGURE 15.4 Variations in the delivered dose as a function of time when prescribing either 125 Gy or 115 Gy
with the model 200 103Pd source using the 1D dose calculation formalism in Equation 15.1, as adapted from
Williamson et al. (64). The solid line indicates a prescribed dose of 115 Gy, which initially delivered a dose of
117 Gy in May of 1988. Through changes in the 109Cd calibration source at Theragenics, Corp. (Buford, GA),
the delivered varied from 113 to 125 Gy preceding the establishment of the National Institute of Standards and
Technology (NIST) wide-angle free-air chamber (WAFAC) calibration standard. After implementation of this
calibration standard and correction for a detector response anomaly, a prescribed dose of 115 Gy corresponded to
a delivered dose of 115 Gy through use of the AAPM TG-43U1 brachytherapy dosimetry parameters. For
those physicians that changed their prescription dose from 115 to 125 Gy in the year 2000, as indicated by the
dashed line, the delivered dose ranged from 116 to 125 Gy at present.

There are still some clinics in the United States that use the antiquated unit of
apparent activity (Aapp) for specifying brachytherapy source strength (76). Another
antiquated unit of source strength is the source equivalence to milligrams of radium
(i.e., mg Ra eq). These units of source strength are not traceable to NIST and must not
be used for clinical applications. As a requirement for transportation paperwork to ship
sources to and from the manufacturer to the clinic, the contained source strength in
units of MBq or mCi is specified. However, the clinical medical physicist should not use
this information for the derivation of dose in the patient—this is the role of SK with
units of U. Confusion by clinical medical physicists on this issue has resulted in
numerous medical errors in brachytherapy, with the patient receiving 27% higher dose
than intended for treatment with 125I seeds (64,77), surely resulting in patient harm in
some instances. While the radiation oncologist will be familiar with concepts like
standards of care, he/she will likely not be familiar with concepts like calibration
traceability and it is the responsibility of the clinical medical physicist to convey the

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importance of following the long-standing recommendations of the AAPM (78) for only
using SK with units of U for brachytherapy source when ordering sources,
independently measuring their source strength, and using this in clinical treatment
plans.

TREATMENT PLANNING
The treatment planning process for brachytherapy has advanced considerably over the
past decade. Modern brachytherapy treatment planning relies on computer-based
approaches for dose calculation (58,79,80). Optimization of source strength is not
typically used for LDR brachytherapy, where it is most helpful for HDR brachytherapy
using 192Ir sources when a single source traverses the implant with varying dwell times.
Even with modern computational tools and technologic advances such as the ability to
perform intraoperative brachytherapy treatment planning without a preimplant plan,
all participants in the process must recognize that a poorly executed brachytherapy
implant cannot be salvaged afterward.
Use of film or other 2D means of identifying the spatial relationship between the
brachytherapy sources and the patient is discouraged given the widespread availability
of CT scanners used in the clinic primarily for EBRT treatment planning (81,82). Image-
based, 3D treatment planning for brachytherapy will produce a more realistic
representation of the implant conditions (83,84). 3D imaging is now used for both
identification of structures within the patient as well as guiding the prescription in a
volumetric manner instead of simply prescribing dose to an arbitrary point (85,86).
While CT remains the gold standard in general for brachytherapy imaging, use of
magnetic resonance imaging (MRI) is becoming more prevalent due to its ability to
discern soft issues better than ∼100 kV x-rays (87–90). Ultrasound (US) also has a
strong role for source delivery and postimplant treatment planning in permanent
prostate implants given its nonionization nature and ability to discern soft tissue.
However, probe placement during transrectal US imaging displaces the anatomy and
produces differences in implanted dose distributions and related plan evaluation
metrics. It is now standard practice to perform image fusion of CT with any pertinent
and available dataset(s), for example, MRI or positron emission tomography (PET).
There are many dosimetric uncertainties associated with clinical brachytherapy. The
joint AAPM + ESTRO report TG-138 estimated the total dose calculation uncertainty (k
= 1) to be about 4.4% for a single 125I source (91). The propagation of uncertainties
from source measurement to utilization in the brachytherapy TPS is given in Table 15.2.
TABLE 15.2 Propagation of best practice uncertainties and a standard uncertainty of k = 1
(unless stated otherwise with a coverage factor of 2) for derivation of dose at 1 cm on the
transverse plane for an LDR 125I brachytherapy source (91). The measured source strength SK is
added in quadrature with the Monte Carlo-derived brachytherapy dosimetry parameters and the
uncertainties associated with treatment planning system (TPS) interpolation uncertainties,
yielding a total dose calculation uncertainty of 4.4%. The expanded uncertainty (k = 2) is simply
double the standard uncertainty, and differs slightly from 8.8% due to rounding of the preceding
values.

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These uncertainties increase markedly once other sources of dosimetric uncertainty
are included from the clinical process of source implantation. In a joint ESTRO + AAPM
report, Kirisits et al. (92) described the various uncertainty components. A standard
uncertainty of 7% was associated with contouring structures using CT for permanent
prostate brachytherapy using 125I and postimplant day-0 CT. In combination with all
other uncertainty components, a total uncertainty (k = 1) of 11% was estimated.
The 1985 ICRU Report 38 (17) established criteria for reporting doses and volumes
used in intracavitary brachytherapy for gynecologic disease. This report was later
updated to be generalized to other disease sites requiring interstitial brachytherapy in
the 1997 ICRU Report 58 (93). The AAPM updated these recommendations by
providing specifics for reporting criteria for permanent prostate brachytherapy in the
TG-137 report (39).
As part of its 2009 initiative to update all brachytherapy-related guidelines (94), the
American Brachytherapy Society (ABS) provided updated guidelines in 2012 on
transrectal US-guided permanent prostate brachytherapy (38). These guidelines
included criteria for treatment with brachytherapy as well as contraindications, as well
as an expansion of treatment options for patients stratified by risk grouping. Where
patients were categorized as high risk, the ABS recommended use of brachytherapy in
combination with EBRT and androgen deprivation therapy. Only the three radionuclides
included in Table 15.1 were recommended for this treatment modality. Disappointingly,
the report included recommendations for source strength in terms of apparent activity,
requiring a leap of faith for the clinician to utilize an outdated conversion factor to
correlate apparent activity with the brachytherapy dosimetry parameters. Prescription
doses of 140 to 160 Gy were recommended for 125I, not accounting for the prescription
reset from 160 to 144 Gy due to traceable calibrations excluding titanium K-edge
characteristic x-rays (75,95,96). Similarly, prescription doses of 110 to 125 Gy were
recommended for 103Pd, not accounting for a prescription reset due to changes in
source calibration standards (63,96,97).
The ABS provided guidelines for LDR brachytherapy of cervical cancer in 2012 (98).
These guidelines updated the prior ABS guidelines by Nag et al. (99,100) to expand the
role of brachytherapy to include patients with disease stages IB2 to IVA of the
International Federation of Gynecology and Obstetrics. For definitive treatments using
temporary implants, a cumulative dose of approximately 80 to 90 Gy was
recommended, with two applications to allow for tumor reduction and improved tumor
coverage with the second brachytherapy application. Prescriptions should require dose
delivery to point A or to the 100% isodose line. The D90 and V100 for the high-risk
clinical target volume receiving greater than 90% of the prescribed dose. Sources of

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LDR 137Cs are recommended for intracavitary treatments while LDR 192Ir sources are
recommended for interstitial treatments.
In 2013, the ABS provided new guidelines for brachytherapy of cancer of the penis
(101) and for sarcomas (102). The majority of patients for these two diseases have
historically been treated with temporary LDR 192Ir brachytherapy implants. As use of
HDR 192Ir brachytherapy is becoming more prevalent, LDR brachytherapy for these
diseases is not viewed as a procedure that will be common in the future.
While breast cancer was historically treated with LDR 192Ir wires and ribbons, this
practice has fallen out of favor given the dose modulation possibilities with HDR 192Ir
and its outpatient treatments. However, Pignol et al. have examined the feasibility of
treating breast cancer with permanent implantation of LDR 103Pd seeds (103,104). Dose
to breast tissue differed from dose to water by up to 36% (105). They also examined
feasibility of permanent LDR 125I brachytherapy for the breast, but ruled it out due to
concerns for radiation exposure from this higher-energy photon-emitting radionuclide
(106,107). However, Jansen et al. did not observe the same concerns for radiation
exposure (108).
Other sites of disease that may receive permanent LDR brachytherapy include the
brain (109–111) and the lung (112,113). Cancers of the head-and-neck region, anal
canal, rectum, and skin are all regions that have received LDR brachytherapy over the
years, but have been treated more recently with HDR 192Ir brachytherapy. LDR
brachytherapy of the ocular choroid within the eye is an interesting application where
the patient is often discharged following surgery to return back to the hospital a few
days later for surgical explant of the brachytherapy plaque (114,115). Given the
plaques shielding of the radiation (116), there are radiologic effects that prompt
advancements in clinical practice so that radiation doses are more accurately known
(117–121).

FUTURE DEVELOPMENTS
While this chapter covers the current standards for LDR brachytherapy, it is also
beneficial to the reader to know what lies around the corner as the field of
brachytherapy will continue to advance in a dependable manner as it has over the last
century.
In addition to the three radionuclides included in Table 15.1, several other
radionuclides are being investigated for LDR brachytherapy. 169Yb (122) has a 32-day
half-life and has been considered as a source for both LDR and HDR applications.
Radionuclides such as 170Tm (123,124) with a 129-day half-life, 57Co (125) with a 272-
day half-life, and 153Gd (126) with a 240-day half-life all have mean photon energies of
<0.1 MeV. Sources have even been considered to purposefully contain more than one
radionuclide (127,128). Improved understanding of radiobiology may indicate the
optimal decay in dose (i.e., half-life) needed for a given disease site (129,130).
In the past, there had been advancements with other novel radionuclides for LDR
brachytherapy such as 252Cf, which emits both neutrons and photons. Since its proposal
as a clinical source in 1965 (131), a couple thousand patients had been treated
worldwide with LDR 252Cf brachytherapy (132). However, concerns for radiation
exposure to hospital personnel and increased controls for special by-product materials
have eliminated its use as a brachytherapy source following the tragedies in the United
States on September 11, 2001.
LDR brachytherapy sources have been designed to provide directional radiation

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(133), without the azimuthal symmetry required by the TG-43 dose calculation
formalism. However, this attribute would require a new approach to brachytherapy
treatment planning and the ability to control and monitor the source orientation.
Sources have also been designed (134,135) to be thinner (i.e., 0.5-mm O.D.) than
conventional 0.8-mm O.D. seeds, more flexible through plastic encapsulation and
elongated brachytherapy sources (136–140), and even for the entire LDR source to be
dissolvable within the patient and leave no radiographic trace after 1 year.
The scope of LDR brachytherapy is expanding through development of new
applicators such as for the treatment of disease within the brain (141–143). For the
GliaSiteTM balloon brain brachytherapy applicator, a liquid solution of 125I or 131Cs is
injected into the balloon for a temporary implant of cranial disease.
To remove the variability in human skills for interstitial implantation of
brachytherapy sources, robotic means of delivery (144,145) are being developed. The
AAPM TG-192 report provides an excellent review of the field (146). Algorithms for
automatic identification of LDR seeds are already available (147). Further automation
of the brachytherapy process has focused on the segmentation or contouring of
structures (148) following image acquisition. This is important as structure contouring
has been identified as being the most important contributor to the dosimetric
uncertainties associated with clinical brachytherapy (92,149). Given that
brachytherapy is generally an invasive procedure and perturbs the natural state of
human anatomy, algorithms are being developed in the field of deformable image
registration (150–152) to alter the shape of the imaged anatomy and permit accurate
dose summation of the brachytherapy dose distributions. These algorithms may also
work in combination with results from EBRT treatment plans to estimate the total dose
distribution.
While the current standard for specifying brachytherapy source strength is air-kerma
strength, a more intuitive metric would be the dose rate at some distance in a reference
medium (153). One proposal that is gaining ground in Europe is to calibrate LDR
brachytherapy source strength in terms of the dose rate to water at a specified time
(154–156). A potential advantage of this approach would be lower overall dosimetric
uncertainties since there would be no need to measure the dose-rate constant (153).
However, there would need to be a significant change to the clinical TPSs and to the
calibration traceability available to the clinical medical physicist. Changing to this new
metric would require societal coordination and regulatory changes for this to go
smoothly.
Another advancement in dose calculations for LDR brachytherapy sources is through
improvements in the TG-43 dose calculation formalism (157). Differences between
liquid water and soft tissue can amount to more than 30% (158–161). A simple
approach is to replace the dosimetry parameters for liquid water with the dosimetry
parameters for soft tissue, which can drastically improve the accuracy of dose
determination. As a way to further adjust the means of dose calculation, precalculated
MC-based dose distributions may be used in conventional TPSs for a particular
applicator type (62). Again, these advancements would require societal coordination for
widespread implementation, along with extensions to the current tasks used to
commission brachytherapy dose calculation algorithms preceding clinical use (162).

CONCLUSIONS
The field of LDR brachytherapy was established over a century ago, and there are
established clinical practice standards for the safe and consistent delivery of this

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radiation-based treatment modality. The current standard for dose calculations is the
TG-43 formalism, where dosimetry parameters and prescriptive criteria have dose to
water as its foundation (due to its heritage of 226Ra and 222Rn dosimetry). Source
strength is specified in terms of air-kerma strength, the only traceable quantity for
clinical use as recommended by the AAPM. Brachytherapy has been applied to every
disease site, and the clinical medical physicist should learn proficiency for this manual,
multidisciplinary procedure where the dose gradients and clinical uncertainties are
greater than for EBRT. There are many exciting developments underway to enhance and
extend the field of brachytherapy.

KEY POINTS
• Brachytherapy has been used since the early 1900s
• Brachytherapy is typically an invasive treatment modality with potential for more conformal
dose distributions than other radiation sources
• The AAPM TG-43 dose calculation formalism has been adopted worldwide for consistent
dose calculations
• Air-kerma strength (SK) is the only traceable quantity of brachytherapy source strength
• Clinical brachytherapy requires well-positioned sources for delivering the desired dose
distribution
• Advancements in brachytherapy will further enhance and extend the field

QUESTIONS
1. Which listing of radionuclide (and half-life) is correct?
A. 125I (59.4 days), 103Pd (9.7 days), 131Cs (17 days)
B. 125I (59.4 days), 103Pd (17 days), 131Cs (9.7 days)
C. 125I (17 days), 103Pd (9.7 days), 131Cs (59.4 days)
D. 125I (17 days), 103Pd (59.4 days), 131Cs (9.7 days)
2. Which is the correct format for the 1D format for the TG-43 dose calculation
formalism?

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3. Using the 1D dose calculation formalism, approximately what is the total dose
delivered to the surface of a 1 U 125I seed after 1 year?
A. 11,955 Gy
B. 5,744 Gy
C. 498 Gy
D. 120 Gy
4. Which metric for brachytherapy source strength is recommended for clinical use?
A. Apparent activity (Aapp)
B. MBq
C. mCi
D. SK
E. Dose rate to water at a distance of 1 cm from the source transverse plane
5. For which disease site is LDR brachytherapy most prevalent?
A. Eye
B. Breast
C. Prostate
D. Cervix
E. Lung

ANSWERS
1. B The other answers are incorrect since the half-lives are given in Table
15.1. Section on “LDR Brachytherapy Sources” covers this question.
2. C The other answers are incorrect since calculation of the dose rate would
not replicate the original calculated or measured dose-rate distribution
since the dosimetry parameters are inconsistent. Section on “Dosimetry”
covers this question.
3. A The half-life of 125I is 59.4 days. After 1 year, this amounts to over 6
half-lives and the source may be assumed to have infinitely decayed.
Using Equation 15.1 with a dose-rate constant value of 0.93 cGy·h-1·U-1
for 125I, r = 0.04 cm for the capsule radius, and assuming gP(0.04)

435
equals unity, the initial dose rate in contact with a 1 U seed is about 581
cGy/h. After infinite decay, this amounts to 1,195,460 cGy or 11,955 Gy.
The other answers are incorrect, where (B) is low by a factor of 2.08 based
on incorrectly inverting the ln(2) factor for deriving infinite decay, where
(C) is low by a factor of 24 based on incorrectly converting the half-life
for infinite decay, and where (D) is low by a factor of 100 for tricking the
reader when converting dose to Gy. Sections on “LDR Brachytherapy
Sources and Dosimetry” cover this question.
4. D The other answers are incorrect since only air-kerma strength (SK) is a
quantity traceable to NIST for determination of brachytherapy source
strength. Section on “Source Calibrations” covers this question.
5. C LDR brachytherapy is most frequently performed for the prostate. The
other disease sites have either lower incidence or are treated more
frequently with HDR brachytherapy. Section on “Treatment Planning”
covers this question.

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16 High Dose-Rate
Treatment Planning
Brachytherapy

Bruce R. Thomadsen

GENERAL CONSIDERATIONS OF HIGH DOSE RATE


BRACHYTHERAPY TREATMENTS
High dose rate (HDR) brachytherapy forms a special method of delivering
brachytherapy where the treatment session lasts a short time. What constitutes “a short
time” is considered below, but in the overview, the treatment session takes from 20
minutes to a couple of hours, as opposed to a day to several days for conventional, low
dose rate (LDR) brachytherapy. Most of treatment planning for HDR brachytherapy
remains identical to that for general brachytherapy, which is covered in Chapter 15.
This chapter will only consider those aspects of treatment planning that are either
unique for, or of much greater importance to, HDR planning. The discussion that
follows does not go in order of steps to perform for an HDR application. For example,
planning a brachytherapy procedure, which constitutes the first step, comes late in the
chapter. One reason for not following the procedural order is that the order varies
depending on the nature of the procedure. However, the main reason is that the
principles covered early in this chapter must be understood before applying them in
planning.
Several methods have been used in the past to deliver the treatment in the short time,
but all units currently use the same principle—a very intense radioactive source on a
computer-controlled cable steps through the target volume, pausing for specified
periods at particular locations along the way. The pausing locations are referred to as
dwell positions, and the duration for which the source pauses are dwell times. Often, the
dwell times are normalized to a particular dwell time location or the maximum, in
which case the normalized values are called dwell weights. A unit that operates in such a
manner is called a stepping source device. The radioactive source for most units is 192Ir,
although some new models use 60Co. The operation of HDR units is discussed in detail
in many texts (1,2). Since this chapter deals with the treatment-planning aspect of HDR
brachytherapy, further description of the units properly is left to the reader’s initiative.
HDR brachytherapy offers several advantages over LDR brachytherapy.
1. Improved dose optimization capability. In an HDR brachytherapy application, the
dwell positions perform the same role as the source positions do for LDR
brachytherapy. For example, the same locations where individual iridium sources
would fall in an LDR gynecologic implant, the single HDR source would pause for a
dwell position. Such an LDR implant could, and should, be “optimized.”
“Optimization,” in this context, means adjusting the strength or positions of the
sources to obtain a dose distribution with specified, desired characteristics (3). One
optimization goal often is simply that a specified isodose surface covers a target
volume. Other optimization criteria might include a specified required homogeneity
for the dose through the target volume, or the maximum dose allowed to other

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anatomical structures. Optimization of a medium size LDR implant often requires 8 to
10 different source strengths, which sometimes becomes difficult to obtain from a
supplier. For a similar HDR unit, the dwell times at each dwell position, on the other
hand, commonly may vary in increments of 0.1 second from 0 to 999 seconds. Thus,
satisfying the optimization requirements becomes easier with the great flexibility in
relative strength at each dwell position. Optimization plays such an important part in
HDR treatment planning that a section of this chapter is devoted to this topic.
2. More stable positioning. For intracavitary insertions, HDR applicators usually lock
into their treatment positions through fixation to the treatment couch. With the
patient essentially immobilized (e.g., in stirrups and strapped to the table), the
applicator moves little between imaging for dosimetry calculations and the
completion of the treatment session. One series studying the movement of HDR
tandem and ovoid applications reported an average movement based on skeletal
anatomy of 2 mm (4). This compares with an average of 2 cm movement for LDR
tandem and ovoids (5).
3. Adding distance to normal tissue. For some HDR treatments—notably gynecologic
intracavitary insertions or head and neck interstitial implants—normal tissue
structures can be pushed away from the path of the source during the treatment,
reducing their dose. While not every treatment site can use this technique, in those
for which it applies the dose reduction to normal structures can be marked. In
general, the discomfort that similar tissue displacement would cause over the
multiple-day treatments for LDR brachytherapy would be intolerable.
4. Outpatient treatment. The driving force that led to the wide use of HDR
brachytherapy was the economic shift in reimbursement it produced from the
inpatient hospital to the clinical facility that delivers the HDR treatments. This occurs
because most HDR treatments are delivered on an outpatient basis. In addition to
changing the revenue patterns, outpatient treatments usually are much more
convenient and comfortable for the patients than confinement in a hospital room in
radiation isolation.
5. Smaller applicators. For gynecologic intracavitary applications, the tandem used for
HDR treatment of uterine cancer has only a 3-mm diameter compared with the 7-mm
diameter tandem used for LDR brachytherapy. The dilation required to insert the LDR
tandem forms the most painful part of the treatment procedure. By comparison, the
sound used to measure the length of the uterine cavity before dilation takes place is
also 3 mm in diameter and often requires no anesthesia.
6. Intraoperative and perioperative treatments. For interstitial cases, HRD
brachytherapy treatment can commence immediately following insertion of the
applicator or catheters, localization imaging, and dose calculations. LDR
brachytherapy cases usually require ordering the sources, or if sources were ordered
ahead, performing the implant as planned without the possibility of modifications
based on new information noted during the operative procedure. This ability to treat
immediately after placement, along with the short duration of treatment, opens the
possibility of using HDR brachytherapy during operative cases (intraoperative) for
irradiation of tumor beds during resection or for wider use of image-guided implants
(6).
7. Reduction of radiation exposure to health care providers. The final advantage of
HDR brachytherapy is that all personnel leave the treatment room for the actual
delivery of the radiation, and with adequately shielded walls and doors, the radiation
exposure to staff should remain minimal.

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HDR brachytherapy also has disadvantages compared with LDR brachytherapy.

1. Treatment unit complexity. Compared with the usual LDR brachytherapy situation
of sources manually inserted into an applicator, the HDR situation seems much more
complicated. With the treatment unit, transfer tubes to guide the source between the
unit and the applicator, transferring treatment programs between the treatment
planning computer and the treatment unit computer, HDR brachytherapy entails a
host of considerations not applicable to LDR brachytherapy.1
2. Compressed time frame. Adding to the complexity of HDR brachytherapy, much of
the action takes place in time frames short compared with LDR brachytherapy. For
example, after insertion of a tandem and ovoids for cervical cancer therapy, making
images and calculating the treatment program, the actual delivery of the treatment
frequently takes 10 to 30 minutes. If there were an error in the treatment program, it
would be easy for the error to be executed before detection. The situation with LDR
treatments provides some latitude for detecting errors. The long duration of the
treatment gives more opportunity to spot and correct errors well before the end of
treatment, when corrective actions could prevent serious injury.
3. Radiobiologic disadvantage. The most serious disadvantage for HDR brachytherapy
results from radiobiology. Radiobiology is such an important aspect of HDR
brachytherapy that it has its own section below. In the current discussion, it suffices
to say that compared with LDR brachytherapy, radiation delivered at a HDR
produces a greater increase in damage to normal tissue compared to cancerous tissue.
4. The potential for very high radiation doses resulting from mechanical failure.
The HDR source cable can become stuck or snagged, or the source can break free
from the cable. In either case, the patient could receive an injurious amount of
radiation in about 1 minute. While the operator is unlikely to receive an injurious
amount of radiation removing the stuck source from the patient, there is a real
potential for receiving exposures in excess of allowed limits.

RADIOBIOLOGIC CONSIDERATIONS
Therapeutic Ratio
Accomplishing the goal of radiotherapy requires inflicting more damage to diseased
cells than to normal tissue cells. The therapeutic ratio is an important measure involved
in the planning for the goal of uncomplicated cure of disease. The therapeutic ratio
could be defined as the ratio of the damage to tumor cells to that to normal cells for the
same delivered dose, or

Since it becomes difficult to grade damage, and the damage to cells is not linear with
dose, a more common equivalent expression often forms the basis for the calculation of
this ratio, determining the ratio of the doses required for the same biologic endpoint, for
example, five logs of cell kill. The equation becomes

448
The more effective the radiation is at killing a certain type of cell, the lower the dose
required to reduce a population of cells to a given level.
Figure 16.1 shows a typical curve relating the survival of cells to dose of radiation. In
general, the relationship between cell survival, S, and cell killing can be modeled as

FIGURE 16.1 A cell survival curve, plotting the fraction of cells surviving a single exposure to radiation as a
function of the dose delivered. The curves are based on α = 0.25 Gy −1, βtumor = 0.025 Gy −2, βnormal tissue =
0.083 Gy −2, μ repair = 1.5 h−1. Cell proliferation has been ignored.

where D indicates the dose delivered. Equation 16.3 is just a model, and should not be
taken as the true description of the physical and biologic process. In the figure, the lines
labeled “Normal Acute” and “Tumor Acute” indicate the response of typical normal
tissue and typical tumor cells to a single dose of radiation. For any dose level, the tumor
cells show an increased survival—not a desirable feature for radiotherapy. The other
curves indicate responses for a conventional LDR treatment regimen, delivering the dose
at approximately 0.5 Gy/h. For both tissue types, the survival increases due to repair of
sublethal damage during the radiation delivery. However, the difference in survival
between the two curves at any dose decreases compared with the acute curves. Looking
at it the other way, compared to LDR delivery, the difference in response between
normal tissue and tumor tissues becomes worse for HDR delivery.

449
Figure 16.2 illustrates the loss in therapeutic ratio with an increase in dose rate, and
the loss in therapeutic ratio can be significant. Figure 16.2 also shows another
interesting feature. The therapeutic ratio changes slowly with dose rate over the LDR
portion of the curve (0.4 to 0.8 Gy/h, shown as green vertical lines in the figure), which
accounts for historic LDR treatments giving similar results regardless of the exact dose
rate. In that region, the therapeutic ratio does not change with absolute dose, only dose
rate. At dose rates, above 20 Gy/h, the therapeutic ratio again varies little with the
actual dose rate. Most HDR units deliver a dose at 1 cm at a rate of 100 to 500 Gy/h,
but because much of an implant lies farther away than 1 cm at least some of the
treatment time, the dose rate can fall well below that, but seldom below 12 Gy/h. Over
any realistic HDR application, the dose rates anywhere in a volume of interest remain in
the flat region of the curve. However, the biological dose distribution for an HDR
application depends on the absolute dose level, and so differs from the physical dose
distribution.

FIGURE 16.2 Relative therapeutic ratio as a function of dose rate, normalized to a dose rate of 0.5 Gy/h. Each
line assumes a particular ratio for the α and β in Equation 16.3 for tumor cells and normal cells. The blue line
represents a typical situation, with α/β = 10 Gy for the tumor and 3 Gy for normal tissue. The red line applies to
aggressive tumor, with an α/β of 20 Gy and normal tissue with α/β or 2 Gy. The vertical green lines indicate the
LDR region. The blue dot indicates the normalized therapeutic ratio for fractionated HDR treatments for typical
tumors.

A very different situation obtains in the middle, transition region. In this case, the
biologic effectiveness of the radiation varies greatly with the actual dose rate, and the
biologic effectiveness of a given amount of dose varies with position in the treated
volume. Often, treatments using nominally LDR remote afterloaders actually deliver
doses at this middle dose rate range. High precision is required with these devices to
avoid exceeding tolerance of normal tissues.
The flat response in the HDR region of the curve traces back to the definition of “high
dose rate.” In Equation 16.3 the term α in the exponent does not depend on the rate of
dose delivery. This term is often associated with single-track killing, that is, one charged
particle passing near the DNA strand produces sufficient ionization in the right location
to break both sides of the DNA “ladder.” Such a double-sided break can produce a

450
biologic effect, including cell death.2 The term β can be thought of representing the
situation where the break on each side results from different charged particles. The cell
can repair a single-sided break because the remaining side provides the template for the
missing side. Tr, the half-time for repair of sublethal damage, characterizes this repair
giving the time required to repair half of single-sided breaks. Measured values of Tr vary
widely, but a typical value is 1 to 2 hours for both normal and tumor cells. Some normal
tissues exhibit repair with two components, one with a half-time of approximately the
value above but also a shorter component of about 20 minutes (7), although other
models of repair kinetics fit the data better (8). Tumor cells seem not to have this faster
component of repair, which gives another therapeutic advantage to the use of LDRs. For
the simple, single-component model for repair, the repair coefficient, μ, can be
calculated as

Because the breaks repair over time, the probability for a second-sided break at the
same location as the first depends how compact in time the radiation is delivered. When
all the radiation passes through the DNA in a short period, the likelihood that the
second side will break before the first side repairs increases compared with a long
delivery. In this case, a “short” time relates to the half-time for repair of sublethal
damage. Regardless of the actual dose rate, HDR treatment refers to a treatment where
essentially all the breaks occur before any significant repair takes place. In general,
HDR treatments should be completed within a half hour of commencement.

Fractionation
While reducing the dose rate is one method to improve the therapeutic ratio, another is
fractionation. Figure 16.3 shows survival curves for the same parameters as Figure
16.1, but includes the survival curves for delivering the doses in 2-Gy fractions. The
fractionation reduces the effectiveness of the radiation at killing cells, but it also
reduces the differences between the responses of the tumor and the normal tissues.

451
FIGURE 16.3 Survival curves using the same parameters as in Figure 16.1 for acute (single fraction) exposures
and for 2-Gy acute fractions.

HDR brachytherapy generally fractionates the treatment course to mitigate the


problem of loss of therapeutic ratio with the increase in dose rate. Figure 16.4 shows
the improvement in the therapeutic ratio by using one more fraction. For example, if a
plan is called for the use of three fractions, the therapeutic ratio would improve by
4.7% by using four fractions instead. If five fractions were used instead of four, the
therapeutic ratio would improve another 4% above the 4.7% improvement from
increasing from three to four. As can be seen, each additional fraction improves the
therapeutic ratio, but by less than the addition of the fraction before. In external-beam
treatment, which is definitely HDR therapy, the number of fractions is approximately
35, which would provide a great benefit in the therapeutic ratio, and the addition or
deletion of one or two fractions would not make much a difference. Brachytherapy is
both taxing on the patient and a drain on the personnel and resources of the facility,
and the use of a high number of fractions such as common in external-beam therapy, is
not an option. Thus, a compromise must be made between improved therapeutic ratio
and practicality. The number of fractions selected for curative cases depends on the
amount of work involved and patient discomfort for each fraction. For interstitial cases
with needle-like catheters in place, such as a prostate implant, three fractions are
common. On the opposite extreme, breast implants with soft catheters and little patient
discomfort often use 10, twice-a-day fractions. Intracavitary insertions involving the
placement of a treatment appliance at each fraction often use five or six fractions.
Tandem and ring applications using an indwelling Smit sleeve (a sheath for the tandem)
in the uterine canal simplifies the procedure to the point to which 12 fractions have
been used (9).

FIGURE 16.4 The percentage improvement in therapeutic ratio by the addition of one more fraction than the
number on the abscissa. See the text for an example.

Prescription Doses
Because the biologic effectiveness of radiation changes going from LDR treatments to
fractionated HDR treatments, the absolute dose prescribed also has to change to obtain

452
the same therapeutic endpoint. As Equation 16.3 shows, cell survival has complicated
exponential relationship to dose, so dose proper is not the best variable to use when
evaluating or predicting biologic effects. Of several approaches, one of the most
practical begins by taking the log of both sides of the dose response curves from
Equation 16.3,

and then divided by −α to have at least the first term in dose alone, to give

BED stands for biologic equivalent dose. An equivalent term seen in the literature is
the RDE, radiologic dose equivalent. Equation 16.6 holds for acute, single exposures.
For multiple HDR exposures of n fractions of d Gy/fraction, the BED becomes

Equation 16.7 holds when each fraction is short compared with the half-time for
repair for cellular sublethal damage, and the time between fractions is long compared
with this same half-time. As above, the duration of the treatment should be less than a
half-hour, and the time between should be about 4 half-times, or about 6 hours. The
newly included last term in Equation 16.7 gives the effect of cellular proliferation on
the BED, where T is the total duration of the n fractions and Tpot is the potential
doubling time for the cells. The equation shows that proliferation decreases the
effectiveness of the radiation. This latter factor often is not known well; however, a
compilation of values gleaned from the literature has been published (10).
Conventionally, due to the uncertainty in this parameter, the proliferation is often
ignored. For interstitial cases, the total therapy duration often remains the same; and
therefore also the proliferation effect, whether the treatment chosen is HDR or LDR
brachytherapy, as discussed below.
Protracted LDR therapy with some repair of sublethal damage taking place during
treatment follows Equation 16.8 (11),

where is the dose rate.


Assuming that the dose has been established for LDR treatments, the equation to
produce the same biologic effect with HDR brachytherapy can be calculated. The first
step entails selecting the number of HDR fractions to use. As discussed above, this
selection is an arbitrary compromise between improving the therapeutic ratio and
practical utilization of resources. The next step sets the BED for each modality equal:

453
or

If the total times are similar, then the last terms on each side cancel. Even if they are
not similar, since the values needed for their calculation are not well known, they often
are simply ignored, giving

The remaining unknown term in Equation 16.11 is the dose per fraction, d. Solving
for d gives

BED depends on the tissue characteristics, as embodied in the values for α and β.
Thus, the equivalence between LDR and HDR brachytherapy only applies to a single
type of tissue—tumor or normal tissue. The dose cannot be equivalent for both
simultaneously. An equivalent regimen must be selected to produce the same cure rate
(equivalent for tumor) or the same normal-tissue reaction (equivalent for normal
tissues). If the choice becomes too difficult, a compromise can be made—but at the cost
of not being equivalent to the LDR regimen in any way. In general, making the HDR
regimen equivalent to the LDR regimen for tumor tends to be the more common choice,
since sacrificing cure rate would argue strongly against performing HDR brachytherapy,
and physical techniques often can mitigate the increased effects on the normal
structures. Early in HDR brachytherapy experience, Orton (12) suggested that doses not
exceed 7 Gy/fraction to avoid normal tissue complications. The suggestion came from
the review of a survey asking practitioners about their HDR experience. While the
responses did indicate that complications increase with fraction sizes exceeding 7 Gy,
the total doses for the cases in the survey were not controlled based on the linear-
quadratic equations given here and commonly accepted in the present.
Complicating further the attempt to make an HDR brachytherapy treatment similar to
one performed with LDR brachytherapy, notice that in Equation 16.12 the dose per
HDR fraction, d, depends on the LDR dose to which it should be equivalent. This means
that an HDR brachytherapy dose distribution can never be biologically equivalent to an

454
LDR brachytherapy dose distribution. Thus, to achieve a similar biologic dose
distribution, an HDR treatment should not duplicate the LDR physical dose distribution.
With interstitial implants, higher doses require more fractions to maintain normal
tissues within tolerance doses. If the treatment catheters remain in place for the whole
therapy, treatments frequently are given twice a day (BID). Table 16.1 relates LDR doses
delivered at the rate of 0.5 Gy/h with the equivalent regimen with two HDR fractions
per day. In general, the overall treatment duration—time with the catheters in place—
remains about the same. The patient, however, need not be in radiation isolation with
the HDR treatments.
TABLE 16.1 Equivalent Treatments for LDR and HDR Brachytherapy

For intracavitary insertions, the prescribed dose often falls at an unambiguous


(although often arbitrary) location; for example, Point A for cervical cancer, the surface
of a cylinder for vaginal cancer, or 1 cm from the center of the applicator for
esophageal applications. Interstitial implants are sometimes less well determined. Take,
for example, a post-tylectomy breast implant with a seroma visible on computer
tomography (CT). The clinical target volume (CTV) might be the seroma plus a 1.5-cm
margin, limited to remain 5 mm deep to the skin and not enter the pectoralis major.
During the dosimetry process, the prescription-dose (100%) isodose surface ideally is set
at the CTV. All these seem very straightforward. However, depending on where the
source tracks fall with respect to the CTV, the 100% isodose may lie on the edge of the
more or less uniform dose plateau of the implant or in the rapidly decreasing gradient.
(It should be assumed that the 100% isodose surface would never fall beyond the
rapidly decreasing gradient to where the dose decreases more slowly; that would be a
poor plan indeed.) Thus, in actual cases, some of the CTV may not receive the full dose
and some of the prescription isodose surface may fall outside the CTV. Some guidelines
for specifying the prescription dose are given in the section on “Evaluation.”

OPTIMIZATION
In brachytherapy, “optimization” generally connotes determination of some aspects of
an application in order to achieve particular goals. For example, optimization may have
the goal of delivering a minimum dose to a target volume with a specified homogeneity.
With permanent implants of the prostate, optimization usually generates a pattern for
locations of the sources to deliver 90% of the prescription dose to the entire CTV,3 limit
the volume raised to 300% of the prescription dose, and avoid doses to the rectum and

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urethra that exceed their respective tolerances. In HDR brachytherapy, the most
common optimization process determines the dwell times that produce the desired dose
distribution—rarely does the process determine catheter location, which usually is
given. The assumption is that the planning of the implant, that is, where catheters or
appliances should lie, occurs at a previous stage. This forms the basic difference
between the HDR brachytherapy and the permanent implant cases—for permanent
implants, optimization is a part of planning, while for HDR brachytherapy optimization
is simply a part of dose computation.
The optimization problem in HDR brachytherapy tends to be simpler than for
permanent implants with a single source strength, and can usually come closer to
achieving the goals of the optimization. While the permanent implant problem can only
decide whether or not to place a source in a given location, the HDR brachytherapy
problem can begin assuming activation of all possible dwell locations, and then simply
determine each dwell time. Sometimes, the easiest approach determines the dwell times
relative to either the maximum time or some specific time (dwell weights) for each dwell
position in order to achieve some uniformity, and then set the times in proportion to the
dwell weights required for the dose. If solution for the problem does not require a
particular dwell position, the optimization routine (optimizer) needs only set the weight
to zero. There are several, very different approaches to optimization. Ezzell (13) and
Ezzell and Luthmann (14) present excellent discussion on optimization theory and
characteristics.
The optimization problem usually specifies a goal. A simple goal might be to deliver a
particular dose to a particular location. More specific goals might include delivering the
same dose to a set of points or a surface. Even more complex goals not only specify the
dose to a surface, but the homogeneity of the dose through the bounded volume and
maximum doses allowed to neighboring sensitive normal structures. With the more
involved goals, one of the features of the optimization approach includes how to specify
the problem and determine the importance of all the varied, and often conflicting,
requirements. Many of the optimization approaches use an objective function (OF) to
wrap all the goals into a single measure. An example of an OF for a prostate implant
could be

where D stands for doses and w for weighting for the term. The first term considers the
target voxels, denoted by subscript t. The first goal would be to deliver the prescribed

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dose to the target. Any voxels falling below the prescribed dose would add to the OF.
Homogeneity, indicated by the subscript h, also applies to the target voxels, and in the
second term, voxels exceeding twice the prescribed dose add to the OF. The last two
terms address dose to the rectum and urethra, and increase the OF for voxels that
exceed a specified limit for the respective organ. The goal of an optimization could be to
minimize this OF. OFs (sometimes called cost functions) can be simpler or more
complicated, and can be set such that the goal may be to minimize or maximize the
function.
Considering the function above, there may be many combinations of dwell times that
satisfy all the requirements, so there would not be a unique solution. In the subset of all
solutions, some may be better than others. If the differences in solutions make a
difference in the perceived quality of the treatment plan, then the OF should be
modified to reflect the additional requirements or tighten the specifications. If the
differences in the solution remain unimportant, then the first solution found could be
used.
While there are many approaches to optimization, they tend to fall in general
categories. The actual distinctions between the categories seldom are as clear as it seems
they should be, and into which category a given approach falls often remains debatable.
Nevertheless, the discussion below considers the characteristics of some of the major
categories.

Deterministic Approaches
Deterministic approaches to optimization always find the same solution to the same
problem, and generally solve equations to find the dwell times.

Heuristic Approaches
Heuristic approaches use pragmatic search techniques to construct solutions to the
optimization problem. The search techniques may use surrogates for the optimized
quantities if they are useful. Optimization purists might maintain that heuristics are not
true optimization approaches because they tend not to produce a true optimum but
merely a satisfactory result. For clinical problems, satisfactory results often serve the
patient needs well. In any case, the results of the optimization must be evaluated for
appropriateness.
For HDR brachytherapy, one of the most widely used heuristic approach is geometric
optimization, developed by Edmundson (15). Geometric optimization assumes the goal is
a uniform dose distribution, and further assumes a distribution of dwell positions
through the volume to receive the uniform dose. The first step in the optimization
process recognizes that the dose to the region of the target around a dwell position
results not only from the radiation emanating from that dwell, but from all the other
dwell positions as well. Looking first at what dose is received at a given dwell position
from all the other dwell positions, the weighting of the dwell under consideration
should be inversely proportional to the dose from the other positions. Thus, dwell
positions that receive large doses from the other dwell positions should have shorter
dwell times and those with little contribution from other dwells should have long times.
Mathematically,

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where Dj→i is the dose from dwell position j delivered to dwell position i. The
commercial versions of the programs approximate Dj→i with the inverse square
relationship, using Equation 16.15,

Such an approximation is expedient but not necessary.


One problem with geometric optimization in the form of Equation 16.14 is that the
optimization assumes equal dwell times during the calculation of the dwell weights, but
then uses the calculated weights for the treatment. Thus, the treatment does not match
the conditions for the optimization. This problem could be rectified through an iterative
procedure, where the dwell weights for current iteration used those calculated in the
last, such as

The iteration would continue until the dwell weights changed less than some specified
percentage. Geometric optimization tends to underweight the periphery of implanted
volumes. The iterative procedure could rectify this shortcoming.
A refinement of the approach ignores the contribution of those dwell positions within
a specified radius of the one being calculated, assuming that the influence of very close
dwells may unduly influence the resultant weights. Applying this technique of ignoring
the nearby dwell positions is known as volume optimization. In practical implementation,
often the calculation of the dose to a dwell position ignores the contributions from
dwells along the same catheter track. When optimizing few source tracks, such as single
catheters for esophageal treatments or a tandem and ovoid, all dwell positions would be
included in Equation 16.14—a process then known as distance optimization.

Convergent Searches
Also called “downhill searches,” convergent searches minimize the OF iteratively
(16,17). At each iteration, the program decides which direction to make changes and
how much change to make, based on the differential of the OF with respect to the
parameter being optimized in that pass. These methods tend to get stuck in local
minima if they occur between the starting condition and the true minimum. At the time
of writing, no commercial brachytherapy planning system uses this technique, although
given the popularity of downhill searches in optimization for intensity-modulated
radiotherapy the method may move into HDR brachytherapy.

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Point-Dose Optimization
Geometric optimization works without reference to an actual dose distribution. Point-
dose optimization forms the most direct optimization approach actually to address
doses. For this approach, the operator specifies doses to deliver to particular points
(optimization points). The process then straightforwardly establishes a set of equations
for the doses to the optimization points, of the form

where fi→a denotes the function that describes the dose at optimization point a resulting
from the source at dwell position i per unit dwell time. The dwell time, ti, becomes the
unknown in the equation. Each optimization point forms one equation, and each dwell
time an unknown. Together they form a set of simultaneous equations. Unfortunately,
solution of the set of equations presents two problems. The first problem is nonphysical
solutions. Consider the situation with the same number of unknown dwell times and
optimization points—a determined system. Consider a very simple case, as shown in
Figure 16.5 with 12 dwell positions, separated by 1 cm, and 12 optimization points,
where each point falls 3 cm above the dwell position. Further, to simplify the problem,
approximate the source as a point so the dose rate only depends on the source strength,
SK, the dose-rate constant, Λ, and the inverse of the distance, r. (For 192Ir the other
factors are minor and could be ignored for the example.) Assume that all the
optimization points should receive the same dose. The system of equations becomes

FIGURE 16.5 An example for optimization: a single catheter with 12 dwell positions at 1 cm intervals, and 12
optimization points, each 3 cm below every dwell position.

where every Di = the dose at point i = the prescribed dose, and j indicates the source
dwell position. Solving this system gives relative dwell weights of:
1.00, 0.08, −0.18, 0.26, 0.50, −0.02, −0.02, 0.50, 0.26, −0.18, 0.08, 1.00.
The negative dwell weights are necessary to satisfy the dose requirements. Simply
deleting those dwell times, or increasing all the times by the amount of the most
negative fails to produce the uniform dose.
A method to deal with the potential negative values for the dwell times developed by
van der Laarse adds a constraint to reduce the variation between adjacent dwell times
(18). With control of the variation of dwell times, the equation for optimization becomes

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where wt is the dwell-time gradient weighting factor, a measure of the importance of
minimizing the differences between adjacent dwell times, and n is the number of dwell
positions along a catheter. The first term aims to minimize the differences between the
desired doses at the optimization points and the calculated doses. The optimization
process then becomes minimizing the chi-square, χ2. Delivery of any dose requires the
net dwell time summation to be positive, so there is no concern that the process might
yield all negative times. Minimizing the differences between adjacent dwell times only
makes sense locally, that is, along a catheter. Each catheter starts a new comparison of
times. The best correlation between desired and calculated doses comes with the
smallest value of wt that eliminates negative dwell times. The values for wt have no
limiting range, although increasing the value above approximately 0.8 has little effect
on the dose distribution.
Adding a dwell-time gradient control factor to the problem in Figure 16.5 and
Equation 16.19 produces the dwell weight pattern of:
1.00, 0.31, 0.04, 0.10, 0.37, 0.22, 0.22, 0.37, 0.10, 0.04, 0.31, 1.00.
All the dwell weights have become positive. The value for the dwell weight gradient
control factor in this example was just 0.01. A small amount of control makes a marked
difference. The uniformity suffered slightly in this case. With the negative dwell
weights, the dose at the end optimization points fell −4% below the average dose to the
points, but the remaining points were within ±1%. With the control of the dwell times,
the end points improved to −3%, but the rest of the points varied between −1% and
+3%. The results of any optimization always require evaluation to assure that the
clinical needs are met.
Approaching the problem as a minimization of chi-square also addresses another
problem. While the single catheter example above had the same number of dwell
positions and optimization points, real cases often have more dwell position than
optimization points (making an underdetermined system of equations) or fewer
(overdetermined)—either posing a situation that cannot be solved exactly just by
manipulating the equations. The chi-square approach gives the best approximation to a
solution. Underdetermined cases have many possible solutions. A useful criterion for
selecting the best of the solutions controls the overall treatment time. While simply
selecting the solution that minimizes the sum of the dwell times provides a
straightforward method to achieve this, minimizing the sum of the squares of the dwell
times tends to provide a more uniform distribution of dwell times, and likely of dose
(19).
The results from optimization algorithms always need evaluation. The algorithms, of
course, do what they are instructed, but the instructions may not be exactly the
operator’s intention. Consider the simple example of three dwell positions around a
point, as shown in Figure 16.6, based on an example of van der Laarse. Point
optimization simply specifying the dose to the point could result in the use of only one

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of the dwell positions, when the intention probably was to use all three and cover a
larger volume. Either using a high value for the dwell-time gradient weighting factor or
adding optimization points at locations where the dose is actually desired would solve
the problem.

FIGURE 16.6 Three dwell positions around a point, based on an example case from van der Laarse.

A further reason to review the results of the optimization carefully is that the
optimization requirements may not have a solution. The line problem of Figure 16.5 had
no solution that produced the prescribed dose at each of the optimization points.
Depending on the problem, the solutions may or may not be close to the specifications.
Particularly for underdetermined problems, where the number of optimization points
exceeds the number of dwell positions, the probability of obtaining the desired dose at
all points becomes low. Evaluation procedures are covered in the section on
“Evaluation.”
Modern brachytherapy, as with external-beam radiotherapy, tends to specify doses to
the surface of a target volume rather than a few points. Programs often approximate
surfaces with a collection of closely spaced points. Controlling the dose within a volume
often requires more points. This proliferation of optimization points (equations) takes a
greatly increased amount of computer resources. Direct algebraic approaches become
less appealing.

Polynomial Optimization
A typical (not large) interstitial implant may have 25 catheters, each with 15 dwell
positions, resulting in a total of 375 dwell positions. As noted at the end of the last
paragraph, the number of optimization points in this case may also become exceedingly
large—likely approximating the number of dwell positions. Thus, the system could have
375 equations—each with as many unknowns. This could take some time to solve. Van
der Laarse proposed that with the dwell-time gradient weighting factor, the dwell times
in a catheter could be constrained to the point that a polynomial could describe their
pattern (19). The advantage of fitting the dwell times along a catheter is the reduction
in parameters from the number of dwell times to the fitting parameters. Van der Laarse
suggests that for n dwell positions in a catheter, a polynomial of order p could model
the dwell times, where

Using the polynomials, the dwell time at position i along a catheter, at the distance xi
from the beginning of the catheter, becomes

The optimization then substitutes Equation 16.21 in Equation 16.19, and sets

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to find the optimum fit for the polynomials.

Polynomial optimization as implemented in the Elekta Nucletron4 planning systems


uses geometric optimization to give a first-pass value for the dwell times for volume
implants, sums the resulting dwell times along each catheter, and divvies that time to
each dwell position in proportion to the values resulting from Equation 16.21 divided
by the total of the ti(xi) for the given catheter.

Stochastic Approaches
Stochastic approaches to optimization search for solutions by starting with a possible
solution to the problem (in this case, the dwell times for all dwell positions), but not
necessarily (or likely) the optimum solution. The OF is calculated for this solution. Then
changes are made to the solution, and the OF calculated for the new solution. Another
new solution would then be formed—guided by whether the value for the OF improved
or degenerated. The nature of the search pattern differs for the various optimization
programs, but all the stochastic approaches have some element of randomness in the
search pattern. Because of this randomness, the programs may find different solutions
with each run.
The only stochastic approach currently used in commercial HDR brachytherapy
treatment planning are simulated annealing (20–22) and the genetic algorithm (23,24).
Ezzell (13) and Pouliot (25) present more detail on optimization techniques. For
simulated annealing, the search makes somewhat random changes in the dwell times.
The changes are not truly random, however. At first the changes may be large. With
each iteration, the sizes of the changes decrease. If after the change the OF improves,
the next change pushes toward that same direction. On the other hand, if the OF
becomes worse, a more random change is made. This process hones in on a “best”
solution, but can get stuck in a local optimum, rather than the global optimum. To
prevent a local trapping, occasionally, the program makes a very large change. If the
new region of solutions does not seem promising after some tries, the program goes back
to the place it left off before the big jump. Even though the process is computationally
intensive because of the iterative nature of the search, as implemented commercially at
the time of writing, optimization for a HDR prostate implant only takes a few seconds.

Manual Reoptimization
Optimization programs often satisfy the specified criteria but fail to produce the dose
distribution that the operator had in mind. Manual reoptimization remedies such a
situation. Each commercial planning system for HDR includes a tool for adjusting the
path of the isodose surfaces. With these tools, an isodose curve on a particular image
slice can be grabbed by the cursor and moved to the desired position. The program then
changes the dwell times to produce the change. The operator can choose to have the
changes adjust just a single dwell position (local), all of the dwell positions (global), or
any amount between. Global changes actually just renormalize the dose distribution to
make a new dose as the prescription dose. Figure 16.7 shows manual optimization in
action. Figure 16.7A shows the isodose distribution before adjustment, where the 100%
isodose exceeds the target region of interest. Figure 16.7B shows the result of moving
the 100% isodose curve to the target. For this example the change level was set to
“local.” Even though the change is local, it still affects the dose distributions in other
image cuts. Manual reoptimization must always be practiced iteratively, changing the

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dose distribution through a series of images and going back and adjusting them again,
correcting the first cuts changes for the effects of the later. At some point, the changes
become small enough that further reoptimization becomes unnecessary.

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FIGURE 16.7 An example of manual optimization. A: The isodose distribution before adjustment. B: The
result of the movement. The arrows follow the 100% isodose line (outer of the two darker, thin lines) as it moves
to the edge of the target.

Reoptimization requires caution. Increasing the size of the 100% isodose also
increases the size of all the other isodose surfaces. In particular, the high-dose region
can become large as a result. Manual reoptimization should only be performed with the
high-dose isodose lines visible on the images—following changes in one image, other
images must be checked for unintended consequences.

Cervical Cancer Intracavitary Applications


While interstitial implants may vary in approach between facilities, for the most part
the optimization follows extremely similar criteria. Approaches to optimization for
gynecologic applications very much more widely. Early work in HDR cervical
applications attempted to duplicate the loading of LDR applications (26). As noted in
the discussion above on radiobiology, duplicating the physical dose distribution does not
duplicate the biologically effective dose distribution.
Figure 16.8 shows two approaches. The one on top (from Jason Rownd, Medical
College of Wisconsin) using the tandem and ring starts with the first optimization point
12 mm lateral to the first dwell position. The remaining optimization points each fall
successively 0.5 cm more inferior: the second, the third, and the fourth lateral to the
tandem 14 mm, 16 mm, and 18 mm, respectively. From the fifth point on through Point
A, the points lie 20 mm lateral to the tandem. The ring optimization points fall 6 mm
from the source track at the surface of the cap, specified as 140% of the dose to Point
A. This optimization point pattern produces a slowly tapering pear shape with a narrow
base.

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FIGURE 16.8 Two examples of optimization for cervical cancer intracavitary applications. Top: narrow-top
pear shaped (Courtesy of Jason Rownd, Medical College of Wisconsin). Bottom: squared-off pear (University of
Wisconsin).

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The optimization pattern on the bottom (modified from the Madison System (4) as
practiced at the time of writing) usually leaves the first centimeter of possible dwell
positions inactive to provide space to reduce the dose to the superior bowel, depending
on the patient’s presentation. The first optimization point falls 1 cm below and 18 mm
lateral to the first activated dwell position. From there, the optimization points fall
successively 1 cm more inferior, and all at 20 cm lateral to the tandem. Regardless of
the distance from the previous optimization point, points are added at the position of
Point A and 0.25 cm inferior to Point A. Optimization points are added lateral to the
ovoids at the surface. This optimization pattern produces a more squared-top dose
distribution that is used at the Medical College of Wisconsin that also reaches further
laterally at the position of the ovoids.
The two distributions represent different treatment philosophies. HDR intracavitary
treatments require deciding on the shape of the desired dose distribution before
determining the dwell times. The treatment planning system needs to know the doses to
the optimization points for the dwell time calculation. To perform that optimization,
sufficient number of optimization points need to be entered for the optimization routine
to know how to shape the distribution.

Inhomogeneity Correction
Until recently, the effect of inhomogeneities in brachytherapy had been ignored, mostly
because the effectiveness of heterogeneity corrections in brachytherapy treatment
planning has always lagged behind that of external beam radiotherapy. However, for
several forms of intracavitary treatments, the effects of inhomogeneities have shown to
be important. Sometimes the inhomogeneities result in erroneous dose calculations, such
as from bone or resulting from the shields in vaginal ovoids (27–29). In other cases, the
inhomogeneity may perturb the geometry of the application, such as air pockets trapped
on the surface of a vaginal applicator or on or within intracavitary breast applicator
(30–32). While for many years the hope had been for incorporation of full Monte Carlo
simulations into brachytherapy treatment planning systems, for various reasons this has
not happened. However, recently a discrete-ordinate, grid-based solver for the
Boltzmann’s transport problem became available in a commercial treatment planning
system.5 The evaluations of this program indicate that it compares well with Monte
Carlo simulations and differs importantly from calculations that ignore heterogeneities
(33–35). Figure 16.9 compares treatment plans with and without correction for
heterogeneities. Such programs likely will become common in brachytherapy as they are
in external-beam radiotherapy treatment planning. The use of correction software
requires imaging with CT or magnetic resonance, which also has become more common.
The report of Task Group 186 of the American Association of Physicists in Medicine give
a very comprehensive discussion of inhomogeneity correction in brachytherapy
treatment planning (36).

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FIGURE 16.9 An illustration of inhomogeneity correction using a discrete-ordinates algorithm. A: A plan
performed assuming all space is water. B: The same plan but corrected for the shielding in the ovoids using the
Acuros program. The plans differ in the dose to the rectum due to the rectal shields. Images courtesy of Firas
Mourtada.

A Final Word on Optimization


Optimization assists a planner in achieving the goals of treatment. The first step to
achieving the goals is to place the treatment appliance in the ideal position. While
optimization can sometimes compensate for a less-than-ideal placement, optimization
cannot make a good treatment from a bad placement. Poor placement of an appliance
results in poor homogeneity of the dose distribution, even with the best optimization.

EVALUATION
The generation of a treatment plan involves many steps—some fairly complicated—
presenting many pathways and opportunities for errors to creep into the planning and
be propagated into a treatment error. The next section on “Quality Assurance”
addresses error prevention. The complexity of the treatment plan also presents
situations where choices have to be made or data entered, and on occasion, an entry,
while not obviously wrong, may possibly be less than ideal. As noted in the section on
“Optimization,” the results of the optimization program may not be quite that expected.
For all these reasons, careful evaluation of an HDR treatment plan becomes very
important. A fine line separates quality management and treatment plan evaluation,
and the evaluation serves as the first step in quality assurance (QA).

Dose Prescription
The items to check do not have an unambiguous order. This discussion addresses the
items from the more obvious to the more subtle.

The Absolute Dose to a Reference Location


Often, the dose distribution for brachytherapy shows isodose surfaces of particular
dose. During evaluation, however, considering the absolute dose to a point or a set of
points, and then the isodose distribution as doses relative to the absolute point clarifies
the two-step process involved with most dose prescriptions. Assessing the absolute doses
to specified points forms one of the first checks to perform. For the most part, if the
operator entered particular points for dose specification, the programs will set the
absolute dose to those points accurately. Problems that can arise include the following:
a. Selecting the wrong point from among those entered for dose specification, for
example, accidentally selecting the rectal point instead of Point A for a cervical
treatment.
b. Having entered the specification point incorrectly, either through poor digitization or
through misinterpretation of the anatomy.
c. Specifying the dose to a set of points with a wide variation in dose between.

While the first two problems represent errors, the last may be either a poor judgment
or a bad presentation in the patient. A very simple example would be a treatment with a
tandem and ovoids in a patient with a severely tipped uterus. The dose at Point A on
the right and left side will be very different, and simply specifying the dose to the

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average of the two points could result in excessive dose on one side and too little dose
on the other. A more involved situation would be specifying the dose to a set of points
on the surface of a tumor with catheters running through. Depending on the geometry,
the points may have too wide a variation in doses to provide a good basis for the
absolute dose specification.
In most situations, the reference location should relate to the dose target, rather than
regions of concern for normal tissues. Consideration of normal structures comes later.
Part of checking the prescribed dose includes review of the fractionation schema. The
dose for the fraction should correspond to the total dose divided by the number of
fractions. As part of this verification, the dose should also be checked against any
relevant protocol that may change the dose based on concomitant external-beam
therapy (in an era of satellite facilities and specialty referrals, such concomitant
treatments may not be obvious to the treatment planner) or chemotherapy.

Relative Doses to Specified Volumes


The optimization process required some specification of locations that should receive
some faction of the prescription dose. In intracavitary cases, this may be a few points,
for example, along an esophageal applicator or along a tandem and lateral to a vaginal
ring. For a volume implant, it may be the target volume surface. In any case, these
points define the goal for the treatment and satisfaction of the prescription requires
conformance of the dose distribution to these specifications. For the simpler cases,
review of each optimization point may be performed, but volume implants probably
require a dose–volume histogram (DVH), as discussed below.
The dose to all the optimization points likely will not equal the specified dose, as
noted above, but should be within some defined tolerance of that specified. Failure to
adequately shape the dose distribution raises three possibilities: accepting the results if
compatible with the treatment objectives; changing the optimization parameters and
optimizing the plan again; or manually intervening, as discussed in the section on
“Optimization.”

Limitations
The doses to limiting normal structures should be checked to assure that they remain
below tolerance. Assessment of the doses to normal structures falls under the next
section.

Visual Evaluation of Dose Distributions


Adequate coverage of the target usually involves visual inspection of the isodose lines
on multiple cuts or projections. While a DVH (see subsequent text) shows failure to
include all target within the prescription isodose surface, the DVH does not show where
the failures occur or whether the volumes that fall below the prescription dose are
contiguous (a potentially serious problem) or widely dispersed (often not significant).
The same can be said for high dose volumes (HDVs). When possible, the inspection of
the isodose lines should be superimposed on images, such as from CT.
Much of the evaluation of the dose homogeneity comes in the next section using DVH.
However, two tools that assess the uniformity of the doses only apply when visually
evaluating the isodose distribution for implants. The maximum significant dose (MSD)
refers to the highest-level isodose surface that encompasses more than one needle track.
The dose very near the source track can be very high, but the body seems to tolerate
these local HDVs. The MSD provides a convenient criterion for when small HDVs

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become “significant” and likely to produce biologic consequences. For an implant taken
to normal tissue tolerance, the MSD corresponds to the tolerance dose. For what
fraction of the prescription isodose surface the MSD becomes limiting depends on
several factors. The first is the volume of the implant—the tolerated level for the MSD
decreases with volume. The second factor is where in the gradient around the implanted
volume the prescription dose falls. Much of the modern experience with implants comes
through the use of the Paris System (discussed below). With that system, the
prescription dose (Reference Dose (RD) in the System’s parlance) equaled 85% of the
Basal Dose (BD), that is, the mean of the local minima between needle tracks in the
central plane. The Paris System further defined a HDV as that volume raised to 200% of
the prescription dose (170% of the Basal Dose), and suggested that this dose tightly
conform to the needle tracks. Thus, for Paris System implants, the MSD would be
somewhat less than 200% of the prescription dose. Translating this MSD to HDR
treatments requires a few steps. First, assume an LDR treatment of 60 Gy delivered at
0.5 Gy/h. From Equation 16.8 the BED using an α/β = 10 Gy−1, appropriate for tumor
cells, would be 72.8 Gy10.6 The limitation on high doses in the target volume likely
applies to normal tissue tolerances, since it is normal tissue breakdown that results in
complications. Assuming the MSD is 200% of the prescribed dose, using α/β = 3 Gy−1,
the BED for normal tissue equals 290 Gy3. Many HDR regimens could be used for this
treatment, but this example assumes six fractions of 5.25 Gy each, which gives the same
biologic effect for the tumor. The physical dose that gives the same biologic effectiveness
for normal tissue as the MSD above is 8.45 Gy, or 160% of the prescription dose. This
result highlights a general rule of HDR brachytherapy: the variation in dose through the
treated volume must remain markedly less than with LDR brachytherapy. That rule just
restates the relative increase in the sensitivity of normal tissue with the change to HDR
treatments. The value of MSD of 160% matches well experience with breast implants
that use the 150% isodose surface for the MSD, and that exceeding this level increases
the probability of complications. This also agrees well with experience with large
gynecologic implants that the MSD should stay below 125% of the Basal Dose (3,37).
For small implants, the percentage of the prescription dose selected for the MSD can
increase, but there is not as much data for small volume implant complications as for
the large.
Another tool, developed by Neblett, considers the other boundary of the isodose
distribution, finding the maximum contiguous dose (MCD), or the highest value for an
isodose surface that completely surrounds the implanted needle tracks (38). Isodose
levels higher than the MCD break into small islands of high dose with lower doses
separating volumes enclosed. The prescription dose should not exceed the MCD, but
should not fall much outside the MCD isodose surface.
Evaluation of dose distributions for intracavitary insertions, for the most part,
remains as visual inspection of isodose plots. The concepts that measure uniformity or
HDVs find little relevance in intracavitary applications because the dose always
becomes high near the sources and falls continuously with distance. The question in
evaluating the dose distribution becomes simply whether or not an adequate dose covers
the target or targets and avoids excessive doses to limiting structures. One exception to
this is intracavitary breast treatments with multilumen applicators. In these cases,
tailoring the distribution to the patient often reduces the uniformity of the dose through
the defined target volume, and measures of the homogeneity of the dose, as discussed
below, provide insights into the quality of the treatment.
For intracavitary and interstitial cases, target evaluation should be considered a 3-
dimensional (3D) process. However, 3D views often become difficult to interpret. Figure

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16.10 shows the target for a breast implant and the 100% isodose surface as a veil
draped over the target. This presentation clearly shows where the 100% isodose surface
fails to cover the target (indicated by the white arrows). In many cases, however, the 3D
images may seem confusing to those with little experience looking at them, and
sometimes to those with experience. Limiting the number of structures shown to a
region of interest and one isodose surface helps during the interpretation.

FIGURE 16.10 A three-dimensional view of the target and the 100% isodose surface for a breast implant.

Quantitative Assessment of Implants


The discussion below relates mostly to interstitial implants. For a much more detailed
discussion of evaluation parameters, see Thomadsen (39). Assessment requires precise
terminology. For interstitial implants, the International Commission on Radiation Units
and Measurements (ICRU) defines the following (39):

Recommendations for Interstitial Implant Reporting by the International Commission on


Radiation Units and Measurements

For interstitial implants, the International Commission on Radiation Units and


Measurements (ICRU) defines the following (40):

The Mean Central Dose is defined as the arithmetic mean of the local minimum doses
between all adjacent sources in the implant. This concept is well known in the Paris
System (approximating the basal dose), but is less well known in the USA.
Peripheral Dose is the minimum dose at the periphery of the CTV, and should be the
minimum dose decided upon by the clinician as adequate to treat the target. This dose
is similar to the typical “prescribed dose” used by many American clinicians.
A Low-Dose Region is a region within the CTV where the dose is less than 90% of the
peripheral dose. The maximum dimensions of this volume are reported. This obviously
relates to an underdosed volume of the target, and so should correlate with treatment
failure.
A High-Dose Region should correlate with complications. The high-dose region is defined
as the volume encompassed by the isodose line equal to 150% of the mean central
dose. The maximum dimensions of this volume in all planes calculated should be
reported.

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The ICRU also suggests reporting on the homogeneity of the dose by specifying the
following:
1. Spread—the difference between the maximum and the minimum local minimum doses
divided by the mean central dose
2. Peripheral-mean ratio (PMR)—the ratio of the peripheral dose to the mean central
dose
Hanson points out that the first gives a measure of nonuniformity within the implant
and may be a measure of how well the implant was accomplished (41). The second is
related to proper spacing of the source lines relative to the peripheral reach of the
implant.
Another useful quantifier is the mean peripheral dose (MPD), which equals, as it says,
the mean dose on the periphery of the target volume. The capital “M” differentiates this
from the minimum peripheral dose, simply called the peripheral dose by the ICRU,
which is often denoted by mPD. Neither of these quantities should be confused with the
matched peripheral dose, which was a concept used before imaged-based dosimetry was
available that specified the dose for a distribution of radioactive sources compared with
the dose it would deliver to the periphery of an ellipse with the same average diameter
as the volume implanted (42).

Dose–Volume Histograms
The first step in quantitative evaluation calculates the DVH. Several very different
presentations of very different information fall under the category of DVH. The
histograms in all cases display some function related to volume on the ordinate with
dose (or a function of dose) on the abscissa. Many of the presentations apply to
dosimetry of implants performed without correlation to volume imaging information
(i.e., CT, MR, or ultrasound), and thus have no information regarding the treatment
relative to any target or normal structures. Such DVH consider the implant as a whole,
and are called “unlimited” because they make no reference to a limiting region of
interest. Because the current standard of care would discourage brachytherapy implants
in the absence of imaging information, unlimited DVH will not be considered further.
While they still prove interesting for evaluating the technical execution of an implant,
they find little application in treatment planning. For more information of such DVH,
the reader should consult Thomadsen (39).
Figure 16.11 shows a relative, cumulative DVH for an HDR prostate implant for a
boost following external-beam therapy. The ordinate records the fraction of a structure
that receives at least that dose shown on the abscissa. The normalization of the volume
to the total volume of the region of interest makes the histogram “relative.” Ideally, the
curve labeled “prostate” would run along the top of the graph at 1.0 for all the doses
until the prescription dose, indicating that the entire target receives at least the target
dose, and then the curve rapidly falls. Of course the fall cannot be very sharp because
there will always be HDVs around the source path. The entire prostate may not receive
the prescription dose either. Depending on the limitations on dose to the rectum, and
potentially on the placement of the catheters due to the pelvic arch, some regions of the
prostate may fall shy of the prescription dose.

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FIGURE 16.11 A cumulative, relative, dose–volume histogram (DVH) for an HDR prostate implant.

Figure 16.11 also shows a curve for the rectum. Unlike the target, only part of the
rectal contour usually is entered into the computer. Thus, the histogram actually shows
the fraction of the contoured volume that receives the given dose. Some organs may be
completely contoured during planning, and the fraction of the whole organ receiving
particular doses may relate to complications or other treatment limitations. For long
tube-like organs, complete contouring not only may be unlikely, but unnecessary. Some
evidence indicates that rather than the fraction of the rectum being the critical variable,
that the absolute volume may be important. Various volumes have been proposed from
0.1 to 5 cm3 (43–48). The value of interest for these volumes would be the minimum
dose, since the maximum dose would be just a point, and not change for any of the
volumes. For volumes less than 5 cm3, it makes little difference if the contour simply
encircles the whole rectal cross section or specifically just outlines the wall, as in Figure
16.12 (46).

FIGURE 16.12 Examples of contouring the rectal wall: (A) for planning systems that can designate the region
between the outer wall and the inner wall and (B) for systems that cannot.

Figure 16.13A shows an example of a relative differential DVH. In this case, the
ordinate gives the change in the percent of the volume per dose, which is closely related
to the fractional volume of the region of interest that actually receives the dose on the
abscissa. The differential DVH sometimes proves useful in selecting the prescription
dose, assessing whether the prescribed dose adequately covers the target and the
uniformity of the dose through the target. Figure 16.13B shows the cumulative DVH for
the same implant as figure 16.13A. Information on dose rate is lost but coverage is
clearer.

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Figure 16.13 A: A relative, differential dose–volume histogram (DVH) for a breast implant. This presentation
shows the volume that receives a particular dose. B: The cumulative DVH for the same implant.

DVH assists in evaluation of implants by calling attention to the fraction of the tumor
that may receive less than the treatment dose or whether a neighboring structure
exceeds tolerance. They can also help distinguish between plans that would better
concentrate the dose in the target. However, as noted above, while presenting this
information for rapid detection, DVH loses special information, such as where the target
dose may be low.

Figures of Merit
The DVH distills the information from the isodose distributions to simplify some
evaluations. The DVH still presents much of the data in a 2-dimensional (2D) format,
sometimes complicating some assessments. Figures of Merit provide numerical values for
particular aspects of implants, and can assist in evaluations and facilitate
communication about the treatments. More detailed discussions can be found in Saw
and Suntharalingam (49) and Thomadsen (39). Below are some of the quantities most
useful for HDR treatment planning.

Target Coverage. The first assessment should be whether the plan adequately covers the
target. Several measures for that exist, each telling a slightly different story.
Dx, Vx − Dx% refers to the dose that covers x% of the target volume. Ideally, the
prescription dose covers 100% of the target, although as mentioned before, that often
cannot be the case. Recognizing this, many protocols call for the prescription dose to
cover some particular fraction of the target volume, such as 95%. In such cases, D95%
becomes a value of great interest since it often defines the prescription. The companion
quantity, Vx gives the volume receiving a dose equal or to x. This quantity assumes
different forms depending on the conventions used for a treatment protocol. Most often
the volume refers to the fraction of the CTV receiving the dose x, but at other times it is
the absolute volume. The dose, x, may refer to the absolute dose, or it may be a fraction
of the prescribed dose. The convention in use requires clarification. Again, ideally V100%
should equal 1 in an ideal implant if V equals the fraction of the target volume with x
normalized to the prescribed dose. For the remainder of this discussion, the convention
will specify doses explicitly as either a percent of the prescription dose labeled with “%”

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or an absolute labeled with “Gy.” Reference volumes will be percent, again labeled as
“%” or absolute with units of cm3. Finally, the volume to which the quantity refers will
be a leading subscript, to give quantities such as CTVD90% or rectumV60 Gy. Figure 16.11
shows with red arrows some of the DX and VX values.
The Coverage index (CI) specifies the fraction of the target volume receiving a dose
equal to, or greater than, the target dose (50). The CI corresponds to the value on the
relative, cumulative DVH for the CTV at the prescription dose. Thus, CI = CTVV100%.

Dose Uniformity. After assessing the adequacy of target coverage, the next question
focuses on the uniformity of the dose through the target volume. As discussed above,
the MSD must be controlled, but other measures also can help in this evaluation.
The section on “Quantitative Assessment of Implants” introduced the ICRU term high-
dose region as the volume encompassed by the 150% isodose surface. This concept came
from the HDV of the Paris System, which used a cut-off of 200% of the prescription
dose. Zwicker makes the factor a variable, p, used during optimization (51). In the
discussion above, converting from the LDR treatments to an HDR regimen, the Paris
System’s factor of 200% becomes 160%. Using an LDR factor of 150% leads to an HDR
factor of 123%. Limiting the MSD to 123% is seldom possible in a real implant. The rest
of this discussion uses a value of 150% to define the HDV for HDR implants. Figure
16.14 shows a schematic of a section through the CTV, a prescription isodose surface as
the V100% and the surface corresponding to 1.5 times the prescription dose, V150%. In
this figure much of the V100% and the CTV coincide, but some of the CTV remains below
the prescribed dose while some of the prescribed dose falls outside the target. Some of
the target and normal tissues receive in excess of 150%, which is very undesirable for
the normal tissue and uselessly high for the tumor. Thus, the most desirable region has
the CTV receiving doses between the 100% and the 150%. This figure may be helpful
during the following discussion.

FIGURE 16.14 A schematic showing a section of a clinical target volume (CTV) (light green,) and two isodose
surfaces corresponding to 100% (dark green) and 150% (orange) of the prescribed dose.

The relative dose homogeneity index (HI) measures the uniformity of the dose through
the target volume as the fraction of the target volume receiving a dose between the
target dose and the high dose level, or (52)

In Equation 16.22, both volumes are the fraction of the CTV raised to at least the
percent of the prescription dose given. Originally, the HI referred only to the
prescription isodose volumes without regard to the target, dating from when target
information usually was not available. Most often nowadays, Equation 16.22 is used.
A very similar index, the dose nonuniformity ratio (DNR), equals the ratio of the HDV

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to that volume taken to at least the target dose (53),

This quantity indicates the price paid (in HDV) to set the prescription dose to cover
the target. Obviously, the DNR and HI are related as HI = 1 − DNR, so specification of
both quantities becomes duplicative.
Yu defines a somewhat more comprehensive quantity, the uniformity number (UN)
(54). The derivation begins with defining the harmonic treatment dose (HTD) as

where D(v) is the dose to a voxel element dv, giving a quantity related to the mean dose
through the target, and the harmonic peripheral dose (HPD) as

with D(s) being the dose in a small element on the surface of the CTV, ds. From these, Yu
determines the UN as

The UN tends toward greater stability and robustness in the face of small variations in
the geometry of an implant.

Dose Outside the Target. As a measure of the dose outside the target, the external
volume index (EI) equals the volume of nontarget tissue receiving doses equal to or
greater than the target dose, as a fraction of the target volume (50,55). Thus,

Here, V100% indicates the entire volume enclosed by the prescription isodose surface
and CTVV is the absolute volume of the CTV. Since CTVV100% is the fraction of the CTV
volume raised to at least 100% of the prescription dose, the product CTVV100% . CTVV
gives the absolute volume of the CTV raised to at least 100% of the prescription dose.
Since is the fraction of the CTV volume raised to at least 100% of the prescription
dose, the product, gives the absolute volume of the CTV raised to at least 100% of the
prescription dose.

Conformity. The conformation number (CN) measures the conformance of the


prescription dose to the target (56,57),

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The numerator of each factor gives the total volume of the CTV within the 100%
isodose surface, as the volume of the CTV times the fraction of the CTV raised to the
100% dose. The first factor gives the dose within the CTV as a fraction of the whole
100% dose volume, a measure of the efficiency of the dose deposition. The second
factor is related to the coverage of the target. Together they indicate how closely the
prescription dose matches the target.
The peripheral uniformity number (PUN) also addresses the conformity at the target but
at the periphery, specifying (54)

Figure of Merit Summary. Each of these figures of merit provides useful information
about the implant. Several of them are redundant and which should be used becomes
the user’s preference. None of these quantities tells the entire story for a given implant.
No single index or quantity perfectly characterizes any implant—evaluation requires
consideration of many different aspects, not all of which optimize for the same
conditions. Final decisions and the quality of an implant require consideration of the
large overview of the implant.

QUALITY ASSURANCE
QA for the treatment plan assesses first the adequacy of the generated treatment plan—
the measures which were addressed in the section on “Plan Evaluation.” The evaluation
process includes verification that the plan delivers the right dose to the right location.
The other purpose for QA is to detect and correct errors in the treatment plan before
treatment delivery. QA, by definition, provides indication that the plan contains no
errors and is of the quality intended.
Before performing QA, quality control (QC) works to keep errors from happening in
the first place. For HDR brachytherapy treatment planning, the most useful and
effective QC tool is a form for recording and transmitting the important and requested
information. Such a form may serve as the prescription, since it should contain the
information of the dose—fractionation and normal structure limitation—as well as a
description of the application and any other relevant information. A treatment planning
protocol serves as the other very important QC tool. The protocol is a standard
operating procedure that dictates routine planning decisions for most cases. Examples
of information contained in a protocol include the definition used to find Point A for
cervical intracavitary insertions and the step size for breast implants.7
Independent verification forms an invaluable part of QA. Having someone other than
the person who generated a treatment plan check it increases greatly the probability of
detecting errors. In addition, just as a form for recording and transmission of
information helps prevent errors, forms to guide the plan evaluation also prevent
omissions during the verification. Guidance for developing forms can be found in

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Thomadsen (39). If having an independent person check the plan is not an option at a
facility, the use of forms and a fixed verification protocol becomes even more important.

Indicators of Reasonableness
One major challenge in QA is to judge whether the planner made a significant error.
One approach to assess the plan for errors compares some value related to the plan with
standards or expectations. The standards derive from previous experience or from the
literature. The sections below consider some examples. For a more detailed discussion,
again see Thomadsen (39).

Intraluminal Tests
Intraluminal cases generally use a single catheter, such as for endobronchial,
endoesophageal, or biliary treatments. Some of the tests discussed below also apply for
vaginal cylinder applications. Thomadsen reported an index (58)

where the index should fall between 0.133 and 0.167 ([Gy m2 s]/[Gy cm2 h]).
Obviously, the index actually has no true units since with multiplying by appropriate
constants, the units cancel. However, for convenience, the equation keeps the units most
likely used for each variable. This index increases above these limits for short treatment
lengths compared to the prescription distance.
Kubo (59) and Kubo and Chin (60) calculate the approximate total treatment time
(±2%) based on a linear fit as

where “length” equals the active length along the catheter. They also derived a
quadratic fit for the treatment duration for lengths (L) between 50 and 200 mm and
prescription distance, d (61):

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Ezzell calculates the dose to points 10 cm distant from the approximate center of the
sources, along a line approximately perpendicular to the catheter, in opposite directions
(62). He calculated a dose index, defined as

which should fall between:

• 0.95 to 1.10 for long treatment lengths (such as esophagus)


• 1.10 to 1.20 for short treatment lengths (such as vaginal cylinders)
• 1.05 to 1.20 for endobronchial treatments (lower if highly elongated, higher if curved)

For any of these checks, the source strength should come from a separate table rather
than from the treatment plan.

Tandem and Ovoids


Indices similar to those discussed above have been used in gynecologic applications, but
because the constraints for optimization vary greatly between facilities, the actual
values used with any such index must be developed locally. Two indices developed for
use with the Madison System (4) assess whether a given tandem and ovoid application
falls within the normal range (58):

and

The location for the first index dwell falls far from the ovoids to consider mostly the
loading of the tandem. The dwell times for the tip-most position vary greatly between
patients, and thus do not serve well for measures of application consistency. The dwell
1 cm inferior to the first dwell position used becomes quite stable. Index 1 tells whether
this one position falls within a normal range. Index 2 considers the application as a
whole. The numerator simply gives the integrated reference air kerma (IRAK, which
numerically equals the total reference air kerma, TRAK, of the ICRU (63)). The use of
IRAK parallels the conventional mgRaEq.h customary for evaluating the normalcy of
LDR applications. Following the Madison System optimization pattern, the limits for the
indices in units of ([Gy m2 s]/[Gy h]) become:

• Index 1—0.139 to 0.180


• Index 2

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• For small ovoids—0.098 to 0.123
• For medium ovoids—0.123 to 0.147
• For large ovoids—0.135 to 0.180

The indices also apply to applications using tandem with cylinders in the vagina,
where Index 2 values become:

• For 2.0 cm diameter—0.098 to 0.139


• For 2.5 cm diameter—0.114 to 0.147
• For 3.0 cm diameter—0.109 to 0.160
• For 3.5 cm diameter—0.143 to 0.168

Interstitial Implants
Common optimized HDR implants conceptually tend to follow a cross between
Manchester and Paris implants. The implants behave much like Manchester implants in
that the differential source-strength distribution pattern varies much like in the
Manchester rules. However, unlike the Manchester System, where the dose tends to
correspond to the Paris System’s Basal Dose, most practitioners specify the prescription
to a Reference Dose outside the limits of the implant, much like the Paris System. With
this in mind, the Manchester implant tables can be modified to apply to 192Ir HDR
implants by multiplication of the source strengths by 1.11 to set the Reference Dose to
90% of the Basal Dose, and converting from mgRaeq.h to 192Ir IRAK. For a given
treatment plan, the total duration of the treatment calculated by the planning computer
can be compared with the time given by

where in this equation RV = 0.00321 ManchesterRV, where ManchesterRV is the RV in the


original Manchester tables, so

where E is the longest dimension/shortest orthogonal dimension. Experience with breast


implants shows that this formula generally agrees with the time calculated by the
treatment-planning computer within 5%.
A similar approach holds for modifying the RA values from the Manchester table to
verify the calculations for planar implants. Alternatively, Ezzell (64) developed a
formula that gives the expected time for a dose at a specified distance from an implant
plane as:

where r is the distance from the plane where the prescribed dose falls, E is the
equivalent square of the planar area = 4·area/perimeter, and a, b, and c are fitting
parameters that depend on the distance, r, given in Table 16.2.

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TABLE 16.2 Fitting Parameters for Equation 16.38

Unified Index
Das et al. considered predicting the treatment duration based on the volume of the
prescription isodose surface, V100 (65). Beginning with a point source approximation,
he derived the equation

where EC is the elongation correction, approximated as 1 + 0.06(E − 1)1.26, and K is a


constant depending on the number of catheters:

• 1 catheter, K = 1,267 U s/(cGy cm2)


• 2 or 3 catheters, K = 1,182 U s/(cGy cm2)
• More than three catheters, K = 928 U s/(cGy cm2)

Treatment Unit Programming and Pretreatment Checks


Once the treatment plan passes the evaluation and QA tests, the treatment plan must be
passed to the treatment unit in the form of a treatment program specifying all the
treatment information: channel lengths (distance to the first dwell position), step size or
sizes, and the dwell time pattern for each channel. Verification of the program checks
the items most likely to be in error.
The most likely error is selecting the wrong program for a given patient if there is
more than one program under the patient’s identity. This situation frequently arises in
regimens where new plans are generated at each fraction, such as gynecologic
intracavitary applications. Such plans may differ subtlety, so checking the plan entails
verifying each dwell position. Fortunately, intracavitary plans generally contain few
dwell positions. Large volume implants with more catheters than treatment unit
channels form another common treatment with multiple files under a patient’s identity.
In this case, enough details of the file must be checked to assure selection of the correct
file for the treatment underway. To prevent using the wrong patient’s file for a
treatment, the name on the program must be matched with the patient’s identity.
Regardless of the number of files a patient has, the first fraction for any file must
include a verification of the length for each catheter, particularly if the length differs
from the default value. The most common error with HDR brachytherapy is unintended
treatment with the default length when a customized length was intended. The step size

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also forms a simple but very important parameter to check. Once these have been
verified, and a sampling of the dwell time pattern checked, the program can be
approved. On subsequent treatment fractions, the checks to verify programming with
the correct file suffice.

PLANNING AN IMPLANT
Planning is actually what goes before the action, or at least, what should go before. In
the context of brachytherapy, before performing an implant or an insertion, planning
entails determining the desired location of the treatment appliance. Optimization can
often (but not always) make the prescription isodose surface cover the target in many
cases following a less-than-optimum implant; however, the price paid becomes larger
HDVs, increasing the probability of complication.
The initial steps for planning a brachytherapy procedure follow the same pattern as
for any type of radiotherapy treatment: determining the target volumes. Earlier
chapters discuss target delineation, so it will not be addressed here, other than to say
that in brachytherapy the expansion from the CTV to form a planning target volume
(PTV) usually remains small. Such an expansion needs to consider the ability to place
the applicator in the desired location, and, for implants, the constraints placed on the
location of needles by the implant pattern to conform to the CTV. As an example of the
latter constraint, consider a template guided implant where the edge of the CTV falls
between needle rows. Covering the CTV may require an additional needle in the row
outside of the CTV, thus effectively expanding the CTV to a PTV.

Appliance Selection and Placement


Planning where to place the treatment appliance depends heavily on the form of the
brachytherapy.

Intracavitary Insertions
Intraluminal insertions allow little selection in the treatment appliance or location. For
example, the only variable in endobronchial applications would be how far past the
target to insert the tip of the treatment catheter. Possibly the diameter of the catheter
may be selectable from two sizes, and in some cases the stiffness of the catheter. More
applicators are available for endoesophageal applications because of the size of the
lumen. These applicators have various thicknesses of the walls and number of channels,
running from one in the center (giving a more penetrating dose distribution) to many
around the periphery (allowing some tailoring of the dose distribution to the CTV).
Gynecologic applications present a greater opportunity to select the appliance most
appropriate to the patient from a wide variety. For cervical cancer, the standard
approach places a long tube (a tandem) in the uterus and channels for the source in the
vagina, just as with the LDR treatments. While the tandem for all applicators remains
mostly the same, the vaginal source channels differ greatly between applicators. The
vaginal part of the appliance for four applicators will be compared for examples—
ovoids, a ring, cylinders, and custom molds. Figure 16.15 shows examples of these
applicators. The source travels through ovoids in a tube running axially through either
ellipsoidal (from which the term ovoid derives) or cylindrical piece of plastic. Some
ovoids contain shielding in the direction of the rectum and bladder, as do LDR ovoids,
and some do not. Ovoids come in three sizes, generally 1 cm, 1.25 cm, and 1.5 cm
radius, sometimes with a “mini” size that maintains the 1-cm radius laterally but only a

482
few millimeters medially to fit a smaller vagina. Some of these applicators have no fixed
relationship between the tandems and ovoids while others do. The nonfixed applicators
allow better conformance with the patient’s anatomy, while the fixed systems maintain
a standard geometry. The best dose distribution comes from using the largest size ovoids
that fit in the vagina. This gives the greatest distance between the source track and the
vaginal mucosa and thus, the greatest depth dose, just as increasing the source to
surface distance in external-beam radiotherapy increases the fractional depth dose.
Spreading the ovoids should be avoided because that leads to reduced doses to the
cervix proper.

FIGURE 16.15 Applicators for cervical cancer intracavitary insertions: A: Tandem and ovoid, on the left the
conventional and on the right for CT or MR localization. B: A tandem and ring. C: A tandem and cylinder. D:
A tandem and custom vaginal mold (Picture courtesy Erik Van Limbergen).

In the ring applicator, the vaginal source path follows a circle centered on the
tandem. The ring comes in several diameters (26 to 34 cm). Typical cases only use the
dwell positions in the lateral parts of the ring—somewhat simulating the dwell positions
used in the ovoids. A plastic cap about 5 mm thick slips over the ring to provide spacing
between the source track and the vaginal mucosa, reducing the local dose. Because the
cap provides only half the spacing as the smallest ovoid, the ring projects the dose less
deeply laterally. The fixation to the tandem make insertion easier than ovoids.
Patients with very narrow vagina—not uncommon after high doses of radiation
therapy—may not accommodate a tandem and ovoids. One approach places plastic
cylinders around the tandem where it passes through the vagina. While this approach
allows for treatment, the dose distribution fails to provide the coverage of tandems and
ovoids. The difference results from constraining the source track to the tandem instead
of spreading the tracks laterally, with a concomitant reduction in the coverage to the
lateral aspects of the uterus.
Custom vaginal moulds have been used to provide applications tailored to individual
patients. These applicators use an impression of the patient’s vagina with tracks drilled
to accommodate catheters for the source tubes (60–70). Figure 16.15D shows such a

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mould. In concept, these mould applicators should provide improved fit and stability
for the applicators compared with standard ovoids or a ring. The advantage comes at
the price of increased time commitments for construction of the mould.
Postoperative endometrial cancer treatments form one of the most common
brachytherapy procedures in the United States. The treatment delivers radiation to the
anastigmatic site at the superior end of the vagina following removal of the uterus, with
the goal of preventing tumor recurrences in the surgical site. HDR treatments generally
use either ovoids (without the tandem, since the uterus is gone) or cylinders. The ovoids
tend to produce a dose distribution that conforms closely to the target at risk, while
maintaining relatively low doses to the bladder and rectum. Cylinders give more dose to
the rectum and the bladder than ovoids partially because of the orientation of the
source places these organs near the perpendicular bisector of the sources and the
maximum of the anisotropy of the source. Using cylinders, the axis of the source, where
the anisotropy function is relatively low, points toward the target at the end of the
cylinder. For ovoids, the situation is reversed, with the low values of the anisotropy
toward the bladder and the rectum and the maximum toward the target. However,
Pearcey and Petereit report that relatively low doses (50 Gy10 or an LDR equivalent of
44 Gy) to the target produce control rates of greater than 98%, with complications not
appearing until normal tissue doses of 100 Gy3 (LDR equivalent of 60 Gy) (71).
Uncomplicated control is the norm with this form of treatment. Thus, the differences
between the applicators mean little with regard to the treatment outcome. There are,
however, cylinders with source pathways forming a circle at the top, and rings without
the tandem, that can combine the beneficial orientation of the source with the simplicity
of the cylinder.

Interstitial Implants
Determining the needle pattern for an implant can be the most important decision for
an implant. Many of the older systems developed rules for needle placement that still
provide good guidance (72–77). Most of the rules that apply for LDR implants also
apply for HDR procedures.
Many of the conventional, LDR brachytherapy approaches give rules for implants
with uniform source distribution, that is, source material not differentially distributed.
The Manchester System forms the exception. It becomes more difficult to achieve
relative dose uniformity when all sources have the same strength per centimeter along a
needle track, and rules for needle track placement were developed to produce a dose as
uniform in a plane of volume as possible given that constraint (76,77). Beginning the
planning for needle placement by following these rules generally requires less
modulation of optimized dwell times to achieve the uniformity goals for the plan.
Minimizing the required modulation of the dwell times reduces the likelihood of large
high-dose regions. For most HDR multiplanar and volume implants, a needle separation
of 1.5 cm results in a HDV lower than 1 cm spacing, but larger separations increase the
HDV again.
Most commonly, an approach similar to the Paris System (77,78) is followed
assuming that the prescription dose, as the Reference Dose, falls outside of the actual
implanted volume. The change to optimized HDR treatments carries also the need to
adjust the Paris System’s specifications a bit. Optimization reduces the higher doses that
occur in the interior of the implant, although it also increases the high doses near the
ends of needle tracks. While the Paris System used an RD equal to 85% of the BD,
reducing the higher doses in the interior reduces the variations of the dose minima
inside the implant and lowers the mean. The lower mean requires that the percentage

484
relating the BD and the RD must increase to maintain the same location and value of
the RD. Further, the change to HDRs accentuates differences in dose, so the percentage
must increase further. For a typical optimized HDR implant to give a similar biologic
Reference Dose as an LDR implant, the RD = 93% BD (37). The higher ratio of BD to
RD implies that the needles should be placed slightly closer to the edge of the target
volume for HDR implants.
For planar implants or volumes made from planes, following a strict grid pattern with
uniform loading often results in a region of low dose between the outlying needles and
the rest of the implanted volume, essentially wasting the space implanted near the
outliers, as demonstrated in Figure 16.16A, from Neblett (79). Optimization can fill in
this region but at the cost of increasing the HDV. Neblett recommends moving the
corner needles closer to the main body of the implant than the regular spacing pattern
would dictate, as demonstrated in Figure 16.17—a practice called tight-end loading
(79). Figure 16.16B shows the resultant dose distribution, with the prescription isodose
surface encompassing the whole implant. Tight-end loading increases the MCD,
reducing the HDV.

FIGURE 16.16 A: A planar implant with evenly spaced, uniformly loaded needles showing the failure of the
prescription isodose surface to include the volume between the main body of the implant and the corner needles.
B: The same implant as in (A) except with the corner needles moved inward slightly, eliminating the low-dose
region. (From Neblett D. Clinical techniques and applicators available for interstitial implantation. In:
Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing;
1995, with permission from Medical Physics Publishing.)

485
Figure 16.17 A demonstration of the process for tight-end loading. (From Neblett D. Clinical techniques and
applicators available for interstitial implantation. In: Williamson JF, Thomadsen BR, Nath R, eds.
Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995, with permission from Medical Physics
Publishing.)

Unfortunately, some implants, particularly those with irregular shapes, require


needles outside the target volume to assure adequate coverage. Figure 16.18 shows one
CT image of a breast implant. This implant uses needles outside the target volume to
boost the dose near the edge of the implant in several locations. Optimization would not
need these needles to cover the target except for the restriction to hold the MSD to
150%. Without that restriction, the dwell times near the boundary would simply
increase to extend the dose to the target edge. This case trades the extension of dose to
tissue outside the implant for reducing the HDV inside the implant.

Figure 16.18 A breast implant, showing the necessity for needles outside the target volume in this image.

Dwell Position
Optimization often allows keeping the dwell positions all inside the target volume. The
Paris System and all the derivative systems for LDR treatments using uniform strength
sources require that the sources extend beyond the target volume to assure adequate
coverage. Optimization increases the relative dwell times on the ends of source tracks so
the end dwell positions project the dose to the edge of the target. Increasing the dwell
times at the ends of the tracks does require vigilance to prevent large HDV. This process
simulates the crossing needles of the Manchester System.

486
For those with experience with linear sources, such as 192Ir wire or 137Cs needles,
placing seed-type sources, such as an HDR brachytherapy source to give dose
distributions similar to those from linear sources, requires some care. Figure 16.19
demonstrates that, for equivalency, the dwell positions should not start and stop at the
same location as the ends of the line source. Going to the stepping source, the activity of
the line would be cut into the small pieces that become the dwell positions. Because the
total length of source is smaller with the dwell pattern because of the gaps between
positions, the linear activity density for the dwells has to be greater than for the wire.
Thus, the strength of the wire is condensed into the dwells. Each dwell could be thought
of as having a sphere of influence that commands the space around it until halfway to
the next dwell. For the end dwells, this sphere also projects outward, and it is the edge
of this sphere that should fall at the location equivalent to the end of the wire. While
this concept is well oversimplified and does not account for the fact that all of the wire’s
length contributes to the dose everywhere as do all of the dwell positions, the rapid
gradient in the dose from an element of source does make this learning presentation
useful.

Figure 16.19 Placement of seeds or dwell positions to simulate a line source.

Although an HDR plan can be made equivalent to an LDR plan with continuous wire
or 137Cs needles, usually that would not be desirable. In wire-based implants or those
with uniform linear strength such as used in the Paris System, the sources must extend
beyond the target due to the low doses near the ends. With optimization, the source
material can remain within the target while delivering the dose to the periphery. As a
general guidance for a starting point in planning dwell positions for an optimized
implant, the distance from the surface of the target to the first dwell position in the
target should be half the space between dwell positions (58).

KEY POINTS
• Treatment delivery with HDR brachytherapy occurs over a time that is very short compared
with the half-time of repair of sublethal damage, usually with dose rates in excess of 12 Gy/h.
HDR brachytherapy offers several advantages over LDR brachytherapy including improved
dose optimization capability, more stable positioning, ability to treat as an outpatient, and
reduction in radiation exposure to health care providers. HDR brachytherapy also has
disadvantages to LDR brachytherapy, including a reduction in the therapeutic ratio and the
potential for very high radiation dose errors.
• The therapeutic ratio, defined as the ratio of the damage to tumor cells to that to normal tissue
cells for the same dose, is lower for single-fraction HDR brachytherapy than for LDR
brachytherapy. Fractioning the HDR treatment delivery will increase the therapeutic ratio.
The optimum number of fractions for an HDR course of treatment is selected for
practicality.

487
• HDR brachytherapy allows for improved treatment optimization in that source dwell times
can be adjusted for all possible dwell positions. Two types of computerized optimization
algorithms, deterministic or stochastic, are employed to minimize an objective or cost
function, which represents the difference between the planned and the desired dose
distribution. HDR dose distributions may also be manually optimized by moving an isodose
curve to its desired location, causing the planning system to adjust dwell time(s) accordingly
to produce the change.
• The HDR plan should be evaluated to ensure it meets the treatment objectives. This
evaluation should include verification of the dose prescription (both to the reference location
and to other specified volumes) and of isodose coverage of the target. Additional quantitative
evaluation tools include dose-volume histograms, dose uniformity metrics, conformity and
external volume indices.
• Quality assurance is performed for HDR to detect and correct errors in the treatment plan
before delivery. Independent verification of the plan by someone other than the planner is an
effective method of error detection. A number of indicators have been developed for simple
single-catheter to more complex implants, to ensure the treatment plan is reasonable.
• Applicator selection and placement is an important component of a successful implant. This
is particularly true for gynecologic intercavitary implants, where a number of different
applicators and sizes exist. For interstitial implants, many of the rules governing needle
placement for LDR implants also apply to HDR procedures.

QUESTIONS
1. High dose rate (HDR) brachytherapy typically involves dose rates greater than
A. 100 Gy
B. 0.5 Gy/h
C. 0.5 cGy/h
D. 12 Gy/h
2. Compared to LDR brachytherapy, HDR brachytherapy offers the advantage(s) of:
A. Improved therapeutic ratio for a single-fraction treatment
B. Higher energy radiation sources with better tissue penetration
C. Less applicator movement over the course of the implant
D. Reduction of radiation exposure to personnel
3. The cell survival curves for HDR brachytherapy:
A. Show a larger variation between tumor and normal tissues than those for a
conventional LDR treatment regimen.
B. Are substantially changed with considering normal tissue and tumor repair.
C. Become closer to LDR cell survival curves when increasing fractionation
D. Demonstrate a therapeutic ratio which is very dependent on dose rate.
4. Compute the biologic equivalent dose (BEDHDR) to point A for a five-fraction
tandem and ovoid implant delivering 6 Gy/fraction over a period of 28 days.

488
Assume α = 0.35 Gy-1, α/β = 10 Gy, and Tpot = 7 days.
A. 25 Gy10
B. 30 Gy10
C. 35 Gy10
D. 40 Gy10
5. Repeat the calculation in question 4 for a LDR tandem and ovoid implant
delivering 0.5 Gy/h to point A for a period of 80 hours. Assume Tr = 1 hour:
A. 27 Gy10
B. 33 Gy10
C. 39 Gy10
D. 45 Gy10
6. Which of the following figures of merit may be used to evaluate the quality of an
HDR implant?
A. Relative dose homogeneity index
B. Coverage index
C. Peripheral uniformity number
D. Harmonic peripheral dose
7. Which of the following QA measures should be performed prior to initiation of
each HDR treatment delivery?
A. Failure mode and effects analysis
B. Independent verification of the plan, ideally by someone other than the
planner
C. Room shielding and barrier survey
D. Verification of the treatment unit plan information

ANSWERS
1. D
2. C and D
3. A and C
4. D
5. C
6. A, B, C, and D
7. B and D

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1The exception to this generalization is the use of a LDR remote afterloader—a device that
moves LDR sources into applicators while the patient lies in a hospital bed. Since marketing of
these units recently terminated, remote afterloading LDR brachytherapy will not be considered
in this chapter.
2For more information, the reader may consult any basic radiobiology textbook, such as Hall
EJ, Giaccia AJ. Radiobiology For Radiologists, 6th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2005.
3Definitions for the CTV and related terms can be found in Chapter 1.
4Elekta Nucletron BV, Veenendaal, The Netherlands.
5The program Acuros in BrachyVision, Varian Associates, Palo Alto, CA, based on Attila,
Transpire Inc., Gig Harbor, WA.
6Convention dictates that the units for BED indicate the α/β as a following subscript.
7The step size becomes very important in many implant cases. Large step sizes give less ability to
optimize the dose distribution. Small step sizes with very short dwell times cause some unit to
void a treatment plan following a source change if the automatically recalculated dwell times
become shorter than the shortest time programmable.

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17 Electron Beam Treatment Planning

John A. Antolak

High-energy electron beams were first available for use in radiotherapy in the 1930s
using Van de Graaff generators (1). In the 1940s, the betatron became the machine of
choice because higher energies allowed more than just the treatment of skin lesions
(1,2). Electron linear accelerators became commercially available in the 1950s, but were
not commonly used until about a decade after their introduction (1,2). Adding electron
beam capability to a medical linear accelerator added to the expense and complexity of
the machine, and the use of electron beams for radiotherapy was not well understood
for many years. Cobalt irradiators, which were used starting in the 1950s, were widely
available and very reliable, so it took many years for the use of medical linear
accelerators to gain traction in the radiotherapy clinic. It took even longer for groups
such as the one at MD Anderson Hospital and Tumor Institute (3,4) to demonstrate the
usefulness of megavoltage electron beams, which gradually led to their increased use in
the general radiotherapy community. Currently, most medical linear accelerators are
purchased with electron capabilities and it has become an expected capability in the
modern radiotherapy clinic.
The most common energy range for electron beams in current medical linear
accelerators is 6 to 20 MeV, which can treat tumors up to approximately 6 cm in depth.
Primary clinical applications for electrons include skin cancers, chest wall irradiation
for breast cancer, administration of boost treatments (i.e., breast, head, and neck), and
intraoperative radiation therapy (IORT). All of these regions can be successfully treated
with x-rays, however, electrons offer the distinct advantage of sparing dose to deeper,
possibly critical, tissues, as well as delivering higher surface doses.
The purpose of this chapter is not to provide a comprehensive review, but to provide
a practical understanding of the properties of electron beams used in radiation therapy
so that the reader can confidently apply that knowledge in the clinic to plan electron
beam treatments. In order to limit the scope of this chapter, it will be assumed that the
reader has a modern 3D treatment-planning system (TPS) and uses it for electron beam
treatment planning, or that they are considering making better use of the TPS for
electron beam treatment planning. The next section on basic physics and beam
properties provides an overview of the most important properties of electron beams as
applied to patient treatments. An understanding of electron beams is key to being able
to apply them effectively in the clinic. The next section on basic treatment-planning
builds on that understanding to provide a qualitative description of how electron beams
can be used to solve some basic treatment-planning problems. The next section on
advanced treatment planning discusses more advanced techniques, which may not be
easily accomplished using most commercial planning systems. For a more
comprehensive review of clinical electron beam dosimetry, the reader is encouraged to
consult the two AAPM reports available on the subject (5–7), and the excellent review
article by Hogstrom and Almond (1).
Electrons are arguably under-utilized in the modern radiation therapy clinic (8), for a
variety of reasons. Electron beam radiotherapy is a minority technology, and therefore
some training programs give little thought to teaching about the utility of electron

495
beams. In the 1990s, intensity-modulated radiation therapy (IMRT) and image-guided
radiation therapy (IGRT) technology started to become readily available. Until then, one
of the more common treatment sites for electron beams was treating the posterior neck
region for head-and-neck tumors, after the spinal cord had received its tolerance dose
from the lateral photon fields. This created a dose distribution that wrapped around the
spinal cord. Using IMRT, it was possible to create a similar dose distribution without the
additional complexity of the added electron fields. The addition of IGRT technology
contributes to even better accuracy and precision, so it is doubtful that older patched-
field approaches will make a comeback.

BASIC PHYSICS AND BEAM PROPERTIES


Electrons are negatively charged fundamental particles with a small mass,
approximately 2,000 times lighter than a nucleon (proton or neutron). Because of the
electric charge, they readily interact with positively charged atomic nuclei and the
negatively charged electrons that orbit the nuclei. The electric field of the nucleus can
change the direction of the incident electron, which is called Coulomb scattering.
Because this scattering occurs on a microscopic scale, it is not practical to try to follow
each scattering event. If we look at this effect on a macroscopic scale, it is called
multiple Coulomb scattering since we are including multiple scattering events at each
step. The material that the electrons are passing though can be characterized by a
scattering power, which is a measure of how easily a given material can change the
angular distribution of the electrons passing through the material. Occasionally, the
nuclear scattering interaction is strong enough that the incident electron loses energy in
addition to scattering, and the lost energy is emitted as an x-ray. This is called
bremsstrahlung production, and is the primary process for producing x-rays in the
anode of a diagnostic x-ray tube or in the target of a linear accelerator. Bremsstrahlung
events remove energy from the beam, but this energy is not deposited locally and hence
contributes very little to the deposited dose.
Incident electrons also interact with atomic electrons. This generates heat and causes
ionization of the atoms in addition to scattering. This is where the majority of the
energy deposition occurs. The material that the electrons are passing through can be
characterized by a mass collisional stopping power, which is the energy lost to
collisional interactions per unit length divided by the density of the material. The dose
deposited is the product of the electron fluence (number of electrons per unit area) and
the mass collisional stopping power. For biologic materials, the mass stopping power is
relatively constant, so the energy deposition is determined primarily by the electron
fluence, or the number of electrons passing through a given volume. The scattering
power of the materials that the beam passes through determines how the electrons
redistribute themselves, so calculating the dose deposition due to electron beams is
primarily a problem of calculating the fluence distribution of the electrons in the
material. While this is a somewhat simplified description of the electron interactions in
matter, it is good enough to be able to qualitatively understand some of the basic
properties of electron beams used in radiation therapy.

Percent Depth Dose


Most of the energy loss for an incident electron beam involves transfer of energy to
orbital electrons in the medium (e.g., patient), and the rate of collisional energy loss
depends primarily on the electron density of the material, which is closely related to the

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physical density for low-Z (biologic) materials. For the energy range used in electron
radiation therapy, the energy loss is approximately 2.0 MeV per cm of water. Figure
17.1 shows percent depth dose (PDD) curves for a Varian TrueBeam linear accelerator
(Varian Medical Systems, Palo Alto, CA). The practical range is at the depth of the
intersection of the linear portion of the distal dose falloff and the line representing the
level of bremsstrahlung contamination. At depths shallower than the practical range,
the dose is primarily due to the electrons, and it is readily apparent that the energy of
the beam is approximately double the practical range. Very few electrons are able to
reach the depth of the practical range due to multiple Coulomb scattering deflecting the
electrons, and this gives rise to the distal slope of the electron PDD. The therapeutic
depth of the electron beam increases with energy almost linearly, and a general rule of
thumb is that the energy of the beam is approximately 3.3 times the depth of R90.

Figure 17.1 Electron central-axis percentage depth dose profiles for a Varian TrueBeam linear accelerator, 10 ×
10 cm2 applicator, 100-cm SSD. The practical range, Rp, and therapeutic depth, R90, for the 20-MeV beam
are illustrated.

Ideally, we would like to select the electron energy such that the target is shallower
than R90, and the critical structures are deeper than Rp. This implies that as the energy
is increased, the separation between the target and critical structures also needs to
increase if full sparing of the critical structures is to be maintained. Using the above
rules of thumb for R90 and Rp, the optimal separation in depth (in cm) between the
target and critical structures is approximately the beam energy (in MeV) divided by 5
(e.g., for the 20-MeV electron beam, this separation is about 4 cm). If the target to
critical structure separation is less than that, an alternative might be to use IMRT with
x-rays to get a sharper distal falloff. If particle therapy (e.g., protons) is available, the
distal falloff can be even sharper.
The central-axis depth dose curve, for the same nominal stated energy, may be
different depending upon equipment manufacturer. Factors contributing to these
differences include, but are not limited to, differences in the materials used in the
construction of scattering foils and ionization chambers, location of the scattering foils,
and the geometry and materials of the tertiary collimation system (applicator or cone).

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Therefore, the depth dose curves and associated isodose distribution should be
measured for each clinical treatment unit.
The surface dose for electron beams is higher than for x-ray beams, which can be an
advantage for targets near the skin surface. The primary reason that the dose increases
in the buildup region between the surface and R100 (dmax) is increased path length per
unit depth caused by multiple Coulomb scattering. Since lower-energy electrons scatter
more readily than higher-energy electrons, the slope in the buildup is steeper for lower
energies and the surface dose is lower as well. This is contrary to the case for
megavoltage x-rays, where the relative surface dose is lower for higher energies. As
shown in Figure 17.1, the surface dose for the 6-MeV beam is less than 90%. If full dose
at the skin surface is desired, approximately 0.5 cm of additional bolus is needed to
have 90% dose at the surface. As a consequence, the therapeutic depth (in the patient)
is reduced, in this case to 1.2 cm.
The bremsstrahlung tail (or x-ray contamination) is what is left over after all of the
electrons have stopped in the patient. In a modern medical linear accelerator, about
half of the bremsstrahlung tail is due to x-rays generated in the high-Z components of
the treatment head (e.g., scattering foils) and about half is due to x-rays generated in
the patient. Because the relative dose in the bremsstrahlung tail is generally smaller
than 5% of the maximum dose, it has little effect on how the electron beams are used
clinically.

Isodose Distributions
Figure 17.2 shows isodose distributions for 9-MeV and 16-MeV beams at 100-cm SSD
and 110-cm SSD. On the phantom surface, the penumbra width is proportional to the
width of the angular distribution of the electrons at the level of the final collimation
(cutout is at 95-cm SSD) multiplied by the gap between the final collimation and the
phantom. Because lower-energy electrons are more readily scattered in the treatment
head and air above the cutout, the width of the angular distribution of the 9-MeV
electrons at this level is larger (more diffuse) than the 16-MeV electrons and hence the
penumbra at the surface is larger for the 9-MeV beam. Comparing the 100-cm SSD
isodose curves to the 110-cm SSD isodose curves, you can easily see that the penumbra
at the surface is approximately three times larger because the gap between the final
collimation and the surface is three times larger. However, there is less effect at R100
and R90 because the scattering in the phantom dominates relative to the contribution of
the air gap.

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Figure 17.2 Isodose distributions for a 10 × 10 cm2 applicator. (A) 9 MeV, 100-cm SSD. (B) 9 MeV, 110-cm
SSD. (C) 16 MeV, 100-cm SSD. (D) 16 MeV, 110-cm SSD.

Figure 17.3 Isodose distribution for a 10 × 10 cm2 applicator, 100-cm SSD, 12-MeV electron beam. Distance
measurement is shown from the projected beam edge to the 90% isodose line.

Similar to x-ray beams, the beam edge in the lateral direction does not correspond to
the therapeutic region (e.g., 90% isodose volume). When drawing the beam portal in the
TPS, a good starting point is to add 1.0 cm to the PTV in the beam’s eye view. For a 12-
MeV electron beam, Figure 17.3 shows that the distance between the 50% and 90%
isodose lines at R100 is 0.8 cm. After computing the dose in the planning system, the
difference between the prescription isodose line and the target volume can then be used
to adjust the beam portal if needed for better conformality. For a clinical setup, where
the TPS is not used, it is important to remember to include this dosimetric margin when
creating the beam portal. For example, if the clinical target measures 8 cm in dimension
on the skin surface, the beam portal should be a minimum of 10 cm, depending on what
other structures might be present and must be avoided.

Field Shaping and Shielding


Field shaping on most modern medical linear accelerators is accomplished using a
combination of an electron applicator (or cone) and a field-defining insert (or cutout).
Figure 17.4 shows an example of a 10 × 10 cm2 applicator for a Varian 2100C linear
accelerator (Varian Medical Systems, Palo Alto, CA) and a patient-specific insert. The
applicator is usually constructed as a series of two to three scrapers with apertures that

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gradually shrink down to the size of the final collimation. The size of the opening of the
photon jaws for each specific energy is integral to the proper functionality of the device,
so specific jaw openings are automatically set when the applicator is inserted and a
given energy is chosen. The thickness of the final insert must be enough to stop the
highest-energy electrons. The AAPM Task Group #25 tabulated the thickness of lead
required to stop various energy electrons and found a linear relationship with the
minimum required thickness of lead in millimeters being equal to half of the energy in
MeV (5). They also recommended adding 20% to the thickness if a lead alloy was used
instead. Adding 1 mm of lead for uncertainty is prudent, so the recommended thickness
of lead as a function of energy is

For a linear accelerator with a maximum energy of 20 MeV, the thickness required to
stop the electrons is approximately 11 mm of lead, or 13 mm of lead alloy. It is not an
accident that the standard thickness of lead alloy electron inserts is approximately 13
mm. It is also possible to have these inserts commercially made to order from a copper
alloy by sending the block outline from the treatment-planning computer to the vendor
(.decimal, Inc., Sanford, FL), where they are manufactured using computerized
machining and shipped to the customer.

Figure 17.4 Electron applicator for cutouts up to 10 × 10 cm2, and a patient insert made from low melting
point alloy.

In addition to being used for field shaping, lead and other high-density materials can
be used for shielding normal tissues that need to be spared. For example, when treating
a lesion near the eye, shielding the eye might be desirable. As shown in Figure 17.2, the
penumbra of the beam is sharper when the applicator is placed closer to the patient.
However, because of the size and shape of the applicator device, it is often necessary to
treat at extended distances. In this case, shielding in the form of lead sheets can be
placed on the patient surface. This usually requires making a positive mold of the
patient so that the lead sheets can be formed to fit the patient surface. The required
thickness is given by the above formula. Eye shields are commercially available (Civco
Medical Solutions, Coralville, IA) that are fabricated from tungsten and coated with
dental acrylic. The thickness of the tungsten is sufficient to shield up to 9-MeV

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electrons. The coating serves two purposes; one is to provide a smoother surface less
prone to scratching sensitive tissues, and the other to absorb some of the backscattered
electrons. Klevenhagen et al. (9) measured electron backscatter as a function of atomic
number and showed that the amount of backscatter increases for higher atomic number
materials and lower-energy electrons. These backscattered electrons generally have a
spectrum of energies with a very low mean energy, and therefore, a relatively thin layer
of lower atomic number material will absorb much of the backscattered energy. If the
eye shields are placed under the eyelid, for example, the dental acrylic coating of the
shield will greatly reduce the backscattered dose on the inside of the eyelid. Whenever
shielding is placed inside the body to shield distal tissues, it is a good idea to place a
layer of lower atomic number material upstream of the higher atomic number shielding.

Field Size Effects


When field sizes are smaller than the lateral scatter equilibrium field size, the
percentage depth dose can change shape, and the dose output (dose per monitor unit)
can change significantly. Understanding lateral scatter equilibrium is key to
understanding how depth dose and dose output change as a function of field size. We
will use a TPS to understand lateral scatter equilibrium. The planning system allows us
to create very accurate block openings, and to create complementary island blocks (even
though they are not physically realizable). In this case, the treatment-planning
algorithm being used is Eclipse Electron Monte Carlo (EMC 10.0.28, Varian Medical
Systems, Palo Alto, CA), which has been shown to accurately calculate doses in
heterogeneous materials under a variety of conditions (10). Figure 17.5 shows the dose
distributions for a 3 × 3 cm2 field in a 10 × 10 cm2 applicator, the same field with a
central block (instead of an opening), and the summed dose distribution. The summed
dose distribution shows a dose distribution that looks very much like the normal open
applicator dose distribution, other than a little bit of extra leakage dose through the
block material (same number of electrons put into the phantom with double the monitor
units).

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Figure 17.5 Isodose distribution for a 12-MeV electron beam at 100-cm SSD. The horizontal dashed line shows
the location of R100 for the 10 × 10 cm2 applicator field. (A) 3 × 3 cm2 field in a 10 × 10 cm2 applicator. (B)
10 × 10 cm2 applicator with 3 × 3 cm2 central block. (C) Sum of (A) and (B).

Another way to look at the same data is shown in Figure 17.6, where the central-axis
depth dose profiles are shown for the blocked fields and complementary central-blocked
fields. Looking at the depth dose profiles for the 6 × 6 cm2 field in a 10 × 10 cm2
applicator and its complementary central-block field, you first see that the depth dose
for the 6 × 6 cm2 field is almost the same as the 10 × 10 cm2 field. This is indicative
of almost having lateral scatter equilibrium. Looking at the central-axis depth dose
profile for the 6 × 6 cm2 central-block field, the amount of dose on the central axis is
very small, indicating that very few electrons from the outer part of the field contribute
to dose on the central axis. Looking at the data for the 3 × 3 cm2 field and the 3 × 3
cm2 central-block field, the situation is not quite the same. The depth dose in the initial
part of the buildup for the 3 × 3 cm2 field follows the depth dose for the 10 × 10 cm2
field for only about 1 cm before it starts deviating significantly. At shallow depths,
electrons from outside the 3 × 3 cm2 central area do not contribute dose on central

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axis. As you go deeper, more of the dose on central axis is due to electrons that started
outside the 3 × 3 cm2 central area. At 4-cm depth, which is past R100 for this energy,
the contribution from electrons outside the 3 × 3 cm2 central area reaches a maximum.
It is easy to see that re-normalizing the depth dose for the 3 × 3 cm2 field will give a
depth dose that looks quite different from the original 10 × 10 cm2 field. The surface
dose will be higher relative to the maximum dose, and the therapeutic depth will be
about 1-cm shallower. The curves for the 1 × 1 cm2 field and the 1 × 1 cm2 central-
block field clearly show that lateral scatter equilibrium is not present at any depth.

Figure 17.6 Calculated central-axis electron depth dose profiles for 12-MeV electron beams at 100-cm SSD.
Thicker lines are for open-field sizes of 1 × 1 cm2, 3 × 3 cm2, 6 × 6 cm2, and 10 × 10 cm2. Thin lines are for the
corresponding open fields with central blocks, and the dashed line is the sum of the open field and centrally
blocked field. All fields use the same monitor units and the dose axis is in cGy per MU.

Figure 17.7 shows the same open-field depth dose data normalized to the maximum
dose on central axis. Other than very small differences in the buildup region, there is
very little difference between the 6 × 6 cm2 field and the 10 × 10 cm2 field. The
output in dose per monitor unit is a little bit lower, but using the same PDD for both
fields would be very reasonable. For the 3 × 3 cm2 field, the relative surface dose has
increased, the depth of maximum dose has shifted toward the surface, and the
therapeutic depth has decreased. In this case, we no longer have lateral scatter
equilibrium. It is very important to keep this in mind when deciding on the energy to
use. If the field size is smaller than the lateral equilibrium field size, the therapeutic
depth may shift far enough toward the surface that a higher energy may be needed to
treat to the desired depth. For circular fields, the minimum radius for lateral scatter
equilibrium is approximately , where is the most probably energy of the
electrons at the patient (phantom) surface (11). If we approximate the most probably
energy with the nominal energy, the minimum radius is approximately 3.0 cm for 12
MeV. This is approximately the same size as the 6 × 6 cm2 field, which is consistent
with the observations made about Figures 17.6 and 17.7.

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Figure 17.7 Calculated electron central-axis depth dose profiles for 12-MeV electron beams at 100-cm SSD, for
open-field sizes of 1 × 1 cm2, 3 × 3 cm2, 6 × 6 cm2, and 10 × 10 cm2 in a 10 × 10 cm2 applicator.

For the 6 × 6 cm2 field in the 10 × 10 cm2 applicator (Fig. 17.7), the percent depth
dose is almost same as the open 10 × 10 cm2 field, so the depth coverage is about the
same. However, as shown in Figure 17.6, the output (maximum dose per monitor unit)
of the 6 × 6 cm2 field is not the same. Figure 17.8 shows measured dose output (output
factors) for cutouts in three different size applicators for the 12-MeV beam on a Varian
TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA). Each curve is in
dose per monitor unit, so the difference in dose output of the open applicator is
included in this graph. Because the 15 × 15 cm2 applicator has larger openings, the x-
ray jaw opening for this applicator is also larger to ensure that the electron field profile
is uniform. Therefore, more electrons get through the x-ray jaws and larger applicators
tend to have slightly greater dose output. Similarly, the jaw opening for the 6 × 6 cm2
applicator is smaller, which tends to give less dose output. The actual magnitude of the
output of the open applicator is a complicated function of the design of the applicator,
the energy of the beam, and the x-ray jaw opening. The x-ray jaw openings for each
energy-applicator combination are usually fixed by the vendor to provide good dose
uniformity for the open applicator and, in general, should not be changed by the end
user. The dose output should be measured and entered into the TPS.

504
Figure 17.8 Measured output factors for 12-MeV electron beams at 100-cm SSD. For each electron cone, the
dose output (cGy/MU) for the cutout field size is plotted.

There are two features that can be seen in Figure 17.8 that are consistently seen in
measured output factor data. The first is the slight rise in dose output, as the field size
gets slightly smaller than the open applicator field size. As the field size gets smaller,
the field edges get closer to central axis. Electrons scattering from the edges of the
aperture are able to reach central axis more easily and the dose output rises slightly.
When the field size gets smaller than the field size required for lateral scatter
equilibrium (about 6 cm for 12 MeV), the dose output drops quite dramatically as
electrons that would normally contribute dose to central axis are removed from the
beam. In addition, the shape of the depth dose is also changing, as seen in Figure 17.7.
If planning clinical electron treatments (without the planning system), the change in
dose output can be accounted for using tabulated output factors. However, the change
in percent depth dose is not so easy to deal with. Therefore, when dealing with field
sizes smaller than the equilibrium field size, a good TPS is recommended to ensure that
the treatment goals are met.
When delivering an electron beam, it is generally possible to deliver the same field
shape using different applicators. The shape of the dose distribution primarily depends
on the shape and size of the final collimation, as shown by Shiu et al. (12), and the dose
output depends on the chosen applicator. Referring to Figure 17.8, the dose output for
a 5 × 5 cm2 field in a 6 × 6 cm2 applicator is approximately 3.5% smaller than the
dose output for the same field size in a 10 × 10 cm2 applicator. Most TPSs are able to
model the change in depth dose as the field size changes, either using tables of percent
depth dose as a function of field size or an appropriate physics model. For the former
(PDD tables), changes in dose output with different applicators may or may not be
included and it is important for the radiotherapy team to be aware of how to convert
the planning data to monitor units at the machine, if necessary. For the latter (physics
model), the absolute dose output and percent depth dose for each applicator is usually
entered as part of the beam data, and the physics model takes care of modeling changes
to the dose deposition as the field size is changed. While it is preferable for the TPS to
provide the monitor units directly, it is not crucial as long as the radiotherapy team is
aware of how the treatment-planning data needs to be transferred to treatment and this

505
is done correctly. In both cases, the formalism to calculate monitor units should be
consistent with AAPM recommendations (6,13). The AAPM also recommends that a
second check of the monitor units be carried out prior to treatment (preferable) or
before 10% of the treatment has elapsed (14,15).

Extended SSD
In addition to changes in penumbra shown in Figure 17.2, increasing SSD can affect the
shape of the depth dose distribution as well as the dose output (per monitor unit). To
account for the change in the depth dose distribution, AAPM TG-25 (5) recommended
using a divergence factor (F-factor or Mayneord factor) to calculate the relative depth
dose at extended SSD from the relative depth dose at the nominal SSD. As pointed out
by Shiu et al. (12), these changes in relative depth dose are expected to be relatively
small because the electron penetration is small compared to the SSD. They evaluated
this approach for a 20-MeV electron beam at 110-cm SSD for a 15 × 15 cm2 field and a
6 × 6 cm2 field. For the larger field size, they found the divergence factor worked well,
but there were significant differences for the smaller field size. They hypothesized that
these differences were due to a large number of low-energy electrons scattered from the
edges of the final aperture. The number of scattered electrons depends on the design of
the applicator. Modern applicators tend to simply remove electrons at the field edge,
while older applicator designs had walls that contributed scattered electrons.
As shown in Figure 17.9, there are a few competing factors that affect the shape of
the depth dose curve as the SSD is changed. For the 15 × 15 cm2 field, the therapeutic
depth (R90) of the electron beam is hardly affected, but there is a deficit of electrons in
the buildup region, which is consistent with the hypothesis of Shiu et al. (12). For the
smaller 6 × 6 cm2 field, we can see a few competing effects. First of all, the therapeutic
depth of the 6 × 6 cm2 field is smaller than the therapeutic depth of the 15 × 15 cm2
field, as would be expected because of the loss of lateral scatter equilibrium (discussed
previously). If we do an inverse square (divergence) correction for the 6 × 6 cm2 field
to get to 110-cm SSD (as recommended by AAPM TG-25), then you can see that the
depth dose does not change significantly. However, in reality, the shape of the depth
dose and the magnitude of the dose output do change significantly. We no longer have
side scatter equilibrium for the 6 × 6 cm2 field, so the simple inverse square correction,
which assumes side scatter equilibrium, is not sufficient to calculate the change in depth
dose with SSD. In addition to the small reduction in dose output, we can see a small
increase in the therapeutic depth, which is consistent with the slightly larger field size
at the extended SSD. Similar to the case with x-ray beams, a simple divergence
correction is inadequate for smaller fields because of differences in scatter conditions,
and lateral scatter is arguably more important for electron beams.

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Figure 17.9 Calculated electron central-axis depth dose profiles for 20-MeV electron beams at 100- and 110-
cm SSD, for open applicator field sizes of 6 × 6 cm2, and 15 × 15 cm2. The vertical axis is absolute dose in cGy,
and the monitor units for beams at 100-cm SSD were set to obtain 100 cGy maximum dose on central axis. For
the beams at 110-cm SSD, the monitor units were increased using an inverse square factor and an effective
source distance of 90 cm (scattering foil position for this linear accelerator). The curve labeled “inverse square” is
the PDD for the 6 × 6 cm2 field size at 110-cm SSD, calculated from the 100-cm SSD depth dose using just
an inverse square correction.

Virtual Point Source


The virtual point source, as defined by AAPM TG-25 (5), is a useful concept for
calculating the divergence of the electron beam. The basic idea is to determine the 50%
width of the electron beam under conditions of lateral scatter equilibrium. The task
group recommended a field size of 20 × 20 cm2 or larger. For most linear accelerators,
the virtual source position is close to the position of the primary scattering foil, which is
not necessarily at the same position as the x-ray target. While useful for calculating
beam profiles using a pencil-beam algorithm (Hogstrom et al. (16)), it is less useful for
calculating the dose variation with SSD (5).

Effective Point Source


The effective SSD concept was introduced by Khan (17) to facilitate calculation of the
dose output as a function of SSD. There is no assumption of lateral scatter equilibrium
in this case. The dose output is tabulated as a function of the air gap between the final
collimation and the phantom surface. A plot of the inverse square root of the output as
a function of the gap is fit to a straight line and extrapolated to an effective point
source where the inverse square root of the output is zero (or the output is infinite). The
range of air gaps used for the measurement should be representative of those used in
the clinic. In practice, the effective point source is usually tabulated as a function of
square or circular field size. The effective point source position and can vary
systematically from 50 cm (for very small fields) to approximately the position of the
primary scattering foil (90 cm for Varian, and 100 cm for Siemens). The output at the
nominal SSD (100 cm) is corrected by an inverse square correction factor, ISCeff, to give
the output at the treatment SSD.

507
where r is the field size, d0 is the normalization depth for the electron beam, and g is the
air gap difference between the nominal (calibration) SSD and the actual SSD. If the air
gap is larger than what was used to determine the effective point source, a
measurement of the dose output may be needed since the inverse square dependence of
the dose output is only approximate and may not hold for larger air gaps.

Effective Versus Virtual Point Source


For larger field sizes, where lateral scatter equilibrium exists, the effective point source
and virtual point source are approximately the same. The electron beam appears to be
emanating from a point near the primary scattering foil in the linear accelerator. As the
size of the beam is reduced and lateral scatter equilibrium is lost, the effective source
position of the electron beam appears to move toward isocenter. It is important to note
that the effective source is not a true electron source position; it is only a result of the
fact that the output of the beam is varying with distance as if the source was at a
different location than the primary scattering foil. This is purely a product of the loss of
lateral scatter equilibrium. In fact, one can show theoretically that the electrons in the
middle of the beam are still diverging from a position near the primary scattering foil; it
is just the output that is being reduced more quickly. In other words, the beam is
geometrically diverging from the primary scattering foil, but the output is decreasing as
if the source was closer to isocenter.
In Equation (17.2), g is the additional air gap between the nominal SSD (usually 100
cm) and the actual treatment SSD. It is not important how these effective source
positions are measured, only that they exist and can be used for distance corrections. A
drawback of this method is that finding (interpolating) the SSDeff for an irregular field
is not well defined.

Air Gap Factor


One of the more significant issues with the effective point source method of correcting
the dose output is that the effective SSD quickly moves toward isocenter for small field
sizes because of the loss of side scatter equilibrium. Small uncertainties in field size may
lead to relatively large uncertainties in effective SSD and dose output. If the field shape
is not the same as those used to measure the effective point source, then the field size
used in the inverse square correction has even more uncertainty.
An alternative approach for determining the output of the electron beam at extended
distance is to use the virtual SSD method from AAPM TG-25, which uses the virtual
SSD, SSDvir , and an air gap factor, fair , to calculate the output at extended SSD.

It is important to note that this is an alternative to the effective point source method,
and must not be used in addition to the effective point source method. The physical
interpretation of this equation is that the electrons are diverging from the virtual point
source (inverse square term), and the air gap factor, fair , describes the deviation
between inverse square dependence from the virtual point source and the true dose

508
output. Note that the inverse square term no longer depends on field size, and that the
field size dependence is fully contained in the air gap factor.
The effective point source and air gap factor methods have both been shown to give
clinically acceptable results, provided the calculations are not made beyond the range of
measured commissioning data. Either method is acceptable for determining electron
beam monitor units in accordance with TG-71 (13), although the author prefers the air
gap factor method.

Irregular Fields
In general, data for square or circular fields is collected when commissioning linear
accelerators, but clinical electron fields are irregularly shaped. If data is collected for
square fields, which is probably more common, it is useful to approximate the clinical
irregular field by a rectangular field size (13,18). Similar to what is done for x-ray
beams, the basic idea is to find a rectangular field with approximately the same amount
of scatter as the irregular field. Small portions of the irregular field that are more than
from the point of interest (the minimum radius for lateral scatter equilibrium
as given by Khan et al. (11)) can be ignored. For a more detailed explanation of the
rules for constructing equivalent rectangular fields for electrons and some examples, see
the description by Hogstrom and Steadham (19), which is reproduced by Gibbons et al.
(13).
Multiple Coulomb scattering theory (16) gives several useful results that can be used
to calculate dosimetric quantities for rectangular fields, given the same data for square
fields. For percent depth dose, the PDD for a rectangular X × Y cm2 field is given by
the geometric mean of the PDD for the square X × X cm2 field and the square Y × Y
cm2 field.

Mills et al. (20) showed that a similar equation for output factors was more accurate
than using 4A/P for the effective field size.

Similarly, there is a similar rule for the air gap factor (12).

There is no similar rule for the effective point source method. However, if you
acknowledge that both methods should give the same result, the following equation can
be derived for the effective source inverse square correction for the rectangular field.

Similar to sector integration methods for x-ray beams, Khan et al. (11,21–23)
developed methods to be able to predict changes in depth dose and output factors for

509
irregular fields. When applying these methods, it is more natural to use input data for
circular fields, although square field sizes can be converted to equivalent circular field
sizes to get the necessary input data. The methods presented are more suitable for
computer implementation than for hand calculations, and will not be discussed here.

Sloping Surfaces
When the electron beam is incident on a sloping surface, the isodose curves are affected
in several ways. Figure 17.10 shows isodose curves for 12-MeV electron beams at
normal incidence and 40° oblique incidence. The SSD along central axis and monitor
units are the same for both beams. There are three main effects on the dose distribution
as the beam angle is moved away from normal incidence. First, the penetration of the
electron beam relative to the phantom surface is reduced, reducing the therapeutic
depth. Second, the maximum dose along the central axis is increased. This is due to
electrons being scattering toward central axis by the phantom material upstream of the
beam entry point (patient left in the figure). The last major effect is that the penumbra
of the beam on the upstream side (patient left in the figure) is sharper (isodose lines are
closer together) than the penumbra on the downstream side. The last effect is basically
the same as what was shown previously in Figure 17.2 for normally incident beams with
different source to surface distances.

Figure 17.10 Calculated dose for 12-MeV 10 × 10 cm2 fields at 110-cm SSD for (A) 0° incidence
(perpendicular) and (B) 40° angulation. The beam weights were set to obtain 100% at the depth of maximum
dose for the beam at 0° incidence.

Figure 17.11 shows calculated central-axis depth dose profiles for 12-MeV electron
beams at different angles of incidence. The therapeutic depth along central axis is

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reduced, the maximum dose along the central axis is increased, and the practical range
of the electron beam increases. On one side of the beam, we have phantom material
upstream of the central-axis beam entry point, and on the other side the phantom
material is further away than the central-axis beam entry point. The upstream portions
of the phantom scatter electrons toward the central axis that contribute more dose at
shallower depths on the depth dose curve. The downstream portions are not scattered
until farther distances (relative to central axis) and those scattered electrons contribute
dose at deeper depths along the beam’s central axis, which leads to what appears to be
an increased range. Figure 17.12 shows depth dose data for the same beams, but in this
case, the depth dose is perpendicular to the phantom surface. In this case, you see an
increase in dose at shallower depths as the angle of incidence increases, as well as a
decrease in the depth of penetration relative to the skin surface. Because it maximizes
the penetration of the electron beam, we generally try to place the electron beams at
normal incidence relative to the skin surface.

Figure 17.11 Calculated central-axis electron depth dose profiles for 12-MeV electron beams at 110-cm SSD.
The beam weights were set to obtain 100% at the depth of maximum dose for the beam at 0° incidence. The
entry point of the beam is fixed, and the depth dose is along the beam axis.

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Figure 17.12 Calculated electron depth dose profiles for 12-MeV electron beams at 110-cm SSD.The beam
weights were set to obtain 100% at the depth of maximum dose for the beam at 0° incidence. The entry point of
the beam is fixed, and the depth dose is perpendicular to the phantom surface, or the depth from the phantom
surface.

Surface Irregularities
Real patient surfaces are not flat. That can be rounded (e.g., extremities or skull) or
very irregular (e.g., nose or surgical defect). The former is basically a more complicated
sloping surface; the beam penetrates further where it has normal incidence, and less
where the surface is sloping away from perpendicular incidence. The latter is perhaps
more interesting in that it introduces us to heterogeneity effects.

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Figure 17.13 Calculated dose for 16-MeV 8 × 8 cm2 field at 100-cm SSD incident on a nose phantom, (A)
without and (B) with heterogeneity corrections. The monitor units were set to deliver 100% dose for a water
phantom at the same SSD.

Figure 17.13A shows the dose distribution for a nose phantom irradiated with an 8 ×
8 cm2 field of 16-MeV electrons at 100-cm SSD. The monitor units were set to deliver
100% maximum dose on central axis for the same field incident on a water phantom at
the same SSD. The density of the external contour was set to unity to highlight the
effect of the surface geometry. The resulting dose distribution looks very different
compared to an open-field dose distribution (see Fig. 17.2), with hot spots of up to
120% of the dose for the open field on a water phantom. To explain why this is
happening, let’s look at the situation a small distance into the nose portion of the
phantom. The electrons in the nose are scattered away from the nose. The electrons in
the air tend to stay in the air, so the number of electrons just lateral to the nose
increases as the electron beam penetrates the nose. As described earlier, more electrons
means more dose, which is the primary reason why there are significant hot spots just
lateral to the nose. Because the electrons have been redistributed laterally from the
nose, there are fewer electrons directly behind the nose, which leads to a cold spot. In
general, any time there is a hot spot due to electron scattering, there will be a
corresponding cold spot in the dose distribution.

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Figure 17.14 Calculated dose for 16-MeV 19 × 12 cm2 field at 100-cm SSD incident on a water phantom with
1-cm cylindrical bone (patient right) and air (patient left) heterogeneities. The heterogeneities are at 1-cm depth
and the monitor units were set to deliver 100 cGy at the depth of maximum dose for a uniform water phantom.

Heterogeneities
Electron dose distributions can also be significantly affected by tissue heterogeneities
such as bone, lung, and air cavities. Figure 17.13B shows the dose distribution for the
same nose phantom as Figure 17.13A, except that the dose calculation now includes the
effect of the CT densities (same electron field and monitor units). Compared to the
homogeneous calculation, you can see that the hot spots just lateral to the nose are
slightly reduced in magnitude. Inside the nose, we have air cavities and some of the
electrons in the tissue portions of the nose are scattered into the internal air cavities
and so fewer electrons scatter out of the nose and hence the hot spot lateral to the nose
is slightly reduced. Just behind those hot spots, there is another air cavity. The large
number of electrons in the lateral hot spots can now penetrate deeper into the phantom
because of the air, in addition to other electrons scattering into those air cavities.
Directly behind the nose, the electrons tend to scatter into the long, narrow air cavities
and hence are able to penetrate much further. Overall, the electron beam is able to
penetrate much further into the phantom because of the air cavities.
It is not easy to see in Figure 17.13, but electrons in bone tend to scatter more readily
(because of the higher density). Figure 17.14 shows the calculated dose distribution for
cylindrical bone and air heterogeneities in a water phantom, and the hot spots
streaming off the side of the bone are readily apparent. In most patient cases, the
difference in density between the bone and normal tissue gives hot spots on the order of
3% to 5% as shown in the figure. For air cavities, the density difference is much larger,
so hot spots of 10% or greater, as shown in the figure, are not uncommon.

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Figure 17.15 Dose for a 9-MeV chest wall boost field (A) calculated without heterogeneity corrections and (B)
calculated with heterogeneity corrections.

Another common situation is shown in Figure 17.15, where we have an electron boost
field on the chest wall. Without heterogeneity corrections, the dose appears to not
penetrate very far in the lung tissue. However, once the reduced density of the lung
tissue is accounted for, it is readily apparent that the electron beam penetrates much
farther into the lung tissue. Fortunately, this is just a boost field so relatively little of the
total dose is given using this field.

Bolus
Bolus is a specifically shaped material, which is usually tissue equivalent and is
normally placed either in direct contact with the patient’s surface, close to the patient’s
surface, or inside a body cavity. In electron beam radiotherapy, the most common uses
for bolus are to flatten out an irregular surface, reduce the penetration of the electrons
in all or part of the field, and/or increase the surface dose.
A very common type of bolus material available in most clinics is superflab, which is a
synthetic oil gel with a density very close to that of water. It is available in a variety of
thicknesses from 0.2 to 3.0 cm in sheets that are typically 30 × 30 cm2 in size. It can
be easily cut using scissors or a utility knife and conforms reasonably well to patient
surfaces. As seen in Figure 17.1, lower-energy electron beams may have a surface dose
less than 90% of the maximum central-axis dose and this dose may be lower than
desired, depending on the location of the target relative to the skin surface. In this case,
adding superflab (or equivalent) to the skin surface over the entire treatment field
increases the surface dose. The desired bolus thickness depends on the desired skin dose
and the energy of the beam being used for treatment. The penetration of the beam into
the patient will be reduced by the thickness of the bolus, so higher electron energy may
be needed depending on the depth of the target. Using a higher energy has the
disadvantage that the slope of the distal dose falloff is not as steep, which means more
radiation dose to underlying normal tissues. Another reason to use constant thickness
bolus is to reduce the range of the beam in the patient. For a typical linear accelerator,
the energy spacing is such that the therapeutic depth spacing is approximately 1 cm.
Combining these energies with 5-mm sheets of superflab bolus material, it is relatively
easy to achieve 0.5-cm spacing in therapeutic depth.

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Figure 17.16 Calculated dose for a 16-MeV 19 × 12 cm2 field at 100-cm SSD incident on a water phantom
with 1-cm unit density bolus in only a portion of the field. The edge on the patient right is cut square, and the
edge on the patient left is cut at a (A) 45° angle, or (B) 30° angle.

When using superflab bolus to reduce the overall range of the beam or increase the
skin dose, it is important that the bolus cover the entire electron field with some margin.
Similar to what was seen with the nose phantom (Fig. 17.13). Figure 17.16 shows that
sharp bolus edges within the field (or close to the field edge) will lead to significant hot
and cold spots. If only partial coverage is desired (e.g., target depth variable across the
field), then it is recommended that the edge of the bolus that is inside the electron field
be tapered to not have a sharp edge as this will reduce the magnitude of the hot and
cold spots. As shown in Figure 17.16, shallower angles (e.g., 30°) are preferable; the
dose calculation shows almost no difference between cutting the bolus material square
or at a 45° angle. As noted by Gerbi et al. (6), the minimum width of the bolus for a scar
boost treatment should be at least 2 cm to ensure dose buildup occurs instead of getting
a cold spot due to out-scattering (e.g., as seen with the nose phantom).

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Figure 17.17 Calculated dose for a 16-MeV 8 × 8 cm2 field at 100-cm SSD incident on a nose phantom with
customized bolus, (A) without heterogeneity corrections and (B) with heterogeneity corrections. The monitor
units were set to deliver 100% dose for a flat phantom at the same SSD.

Figure 17.17A shows the dose distribution for the same nose phantom as shown in
Figure 17.13A, again with CT density set to unity. The bolus was shaped to conform to
the shape of the nose and provide a flat surface for the electron beam using algorithms
developed by Low et al. (24). In years past, similar results were achieved by molding
beeswax (or similar material) around a positive impression of the patient. There are
some residual hot spots remaining (<103%) as a result of imperfect construction of the
bolus material in the planning system, but the dose distribution for the 8 × 8 cm2 field
is almost restored to what would be expected for a flat phantom.
Unfortunately, the dose distribution in the phantom is changed significantly as a
result of internal heterogeneities, as shown in Figure 17.17B, and it is obvious that a
simple flat bolus may be inadequate if internal heterogeneities are significant. The dose
distribution in the patient can be customized by changing the thickness of the bolus as a
function of position in the field. Because of complex interplay between surface
irregularities and internal heterogeneities, doing this by trial and error would be
difficult at best. That was the motivation for Low et al.’s bolus design investigations
(24), to provide a framework to systematically design an electron bolus to conformally
treat the target volume and/or spare distal normal tissues. This technology has been
further developed (25–27) and is now commercially available (BolusECT, .decimal, Inc.,
Sanford, FL, http://dotdecimal.com/). Clinically, the technology has been used in the
treatment of paraspinal muscles (28), post-mastectomy chest wall (29), and head-and-
neck target volumes (30). When using this technology, there is generally a tradeoff
between target conformality and dose homogeneity. One way to decrease the impact of

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this tradeoff (improved dose homogeneity for the same conformality, or improved
conformality for the same homogeneity) is to modulate the intensity of the electron
beam within the field (31), although technology for intensity modulation of electron
beams is not readily available.

Calibration and Monitor Units


In radiation therapy, calibration of the linear accelerator refers to the establishment of a
relationship between the measured dose under reference conditions and the monitor
units set on the treatment machine. The calibration protocol currently used in the
United States and Canada is TG-51 (32), while the very similar TRS-398 (33) is used
almost everywhere else. While the calibration protocols are quite specific when
describing how the measurements are to be performed, the measured dose at the
reference depth (in the protocol) is usually transferred to the R100 depth using the
clinical percentage depth dose. A typical calibration statement for an electron beam
might be 1 cGy per MU at a depth of R100 for a 10 × 10 cm2 field size in a 10 × 10
cm2 applicator at an SSD of 100 cm. The calibration and reference conditions are
entered into the TPS by the physicist as part of the commissioning process. Other data,
such as dose rates for other applicators, dose rates for different inserts, percent depth
doses, and virtual and/or effective SSDs for each energy may also be needed. The
physicist needs to consult the documentation for the TPS to determine the required
input data so that it can be measured at the time of machine commissioning.
Because surface irregularities and internal heterogeneities have a very significant
effect on the dose distribution, the use of heterogeneity corrections in the TPS is highly
recommended. Ideally, the treatment planner should be able to create the treatment
plan to cover the target volume and have the TPS provide the monitor units required to
deliver the treatment. If the planning system is capable of doing this, it is good practice
to have an independent second check of the monitor units using either a hand
calculation or another computer program (13,15). If the planning system is not able to
directly provide monitor units, the physicist will need to create a process to convert the
beam weight in the TPS to monitor units that can be delivered on the treatment machine.
The physicist will also need to determine the range of treatment over which the
planning system provides adequate clinical accuracy (e.g., ±3%) by comparing to
measured commissioning data.
The ability of the TPS to adequately handle surface irregularities and internal
heterogeneities is determined more by the algorithm implementation, although the
quality of the input data may also affect the results. Shiu et al. (34) made an attempt to
provide a standard set of measured data to test electron dose calculations, but there
were some small but significant inconsistencies in the data due to measurements being
carried out at different institutions on different machines. Boyd et al. (35) repeated the
measurements on a single linear accelerator and validated the results using EGS4 Monte
Carlo calculations (36), creating a much more consistent and reliable dataset. The data
is available from the authors and has been used to validate the accuracy of the pencil-
beam redefinition algorithm (37) and the Varian Eclipse electron Monte Carlo algorithm
(10).

BASIC TREATMENT PLANNING


Electron Dose Prescription

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Recommendations for prescribing and reporting electron radiotherapy can be found in
ICRU Report 71 (38), and the recommendations of the AAPM (5,6) are consistent with
those recommendations. The basic concepts of gross tumor volume (GTV), clinical target
volume (CTV), and planning target volume (PTV) that are used for x-ray therapy and
recommended by ICRU Reports 50 and 62 (39,40) can be used for electron beam
treatment planning. ICRU Report 71 recommends that dose be reported for a reference
condition of the same beam incident on a homogeneous phantom. In general, this
reference point should be in the center of the target volume; if not, then the reference
dose in the center of the target volume should also be reported. In addition, the
maximum and minimum dose to the PTV should be reported, as well as doses to organs
at risk and/or dose–volume histograms.
Within the TPS, the treatment planner must enter a dose prescription for the electron
treatment plan. While the precise details of how this is done in every TPS are beyond
the scope of this work, there are a couple of general methods for accomplishing this
task. Before the use of TPS for electron beams became ubiquitous, a common old-style
prescription would be something like a dose to 90% of the central-axis maximum dose.
It is assumed that the central-axis maximum dose is in a water phantom at the same
SSD as the patient’s plan. If the beam weight in the TPS is directly related to the
maximum dose in a water phantom for that beam at the same SSD, then it is possible to
calculate the beam weight for the given prescription. However, it is more likely that the
monitor units need to be calculated first and entered into the planning system. In other
words, the second check is setting the beam weight, which is not the most desirable
situation.
A more modern approach is to adjust the beam weight (or monitor units) until the
prescription isodose line covers the target volume appropriately with the maximum dose
inside the target volume approximately 10% higher than the prescription dose. In this
case, the secondary monitor unit calculation or hand calculation is a true independent
check. However, it is not entirely clear what dose should be entered into the second-
check calculation. As described above, the dose in the electron beam is greatly affected
by the patient surface and internal heterogeneities. There is no easy accurate
heterogeneity correct method available for electron beams, so a method to estimate the
dose for that same beam incident on a flat water phantom is needed. Similar to what is
commonly done for IMRT verification, the treatment plan can be cast onto a water
phantom to extract the desired dose. This removes the patient surface and internal
heterogeneity effects, allowing the central-axis maximum dose to be obtained more
reliably.

En-face Beams
The simplest situation to deal with is treatment planning for a single field (e.g., scar
boost for a breast treatment). We’re dealing with target volumes that are small enough
to be treated with a single field cutout in a single applicator. All of the effects that were
described above can come into play, which is why so much effort was put into
describing how electron beams behave.
The first steps are to choose the energy, field size, and beam direction to use. The
energy is primarily determined by the maximum depth of the target, with a good first
approximation for the energy (in MeV) being 3.3 times the maximum depth of the target
(in cm). The beam direction should be chosen to be approximately perpendicular to the
skin surface that is nearest the target volume, because this maximizes the penetration of
the electrons relative to the skin surface.

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One strategy for choosing the SSD is to make it as close as possible to the skin surface
to minimize the spreading of the electrons in the air gap between the final collimation
and the skin surface. This allows the penumbra to be as sharp as possible, for sparing
normal tissues lateral to the target volume. However, there is a risk to aggressively
choosing a shorter SSD since potential collisions of the bulky applicator with the patient
are not easily visualized in most TPSs. Therefore, another common strategy is to choose
a safe SSD (e.g., 110 cm) that is very unlikely to cause a collision problem. The former
strategy (choosing a shorter SSD) can give slightly better lateral penumbra at the
expense of having to occasionally replan the patient treatment if the shorter SSD can’t
be realized on the treatment machine. Proponents of the latter strategy would also
argue that using the same SSD for all electron beams could potentially reduce setup
errors that could occur if the norm was to use a different SSD for each patient. The
author favors using a standard SSD that is slightly shorter than the safe SSD. Evaluating
the plan for potential collision issues should be a standard part of the treatment-
planning process, and the SSD could be extended for potential problem cases.
Once the beam direction, SSD, and energy are chosen, the beam aperture needs to be
created in the TPS. As described above, the penumbra of the electron beam necessitates
that there is a margin between the PTV and the beam portal, and a margin of 1 cm is a
good starting point. This is very much like treatment planning for x-ray beams. The
exact details of how these steps are accomplished differs from one system to another, so
a step-by-step description of the process will not be given and it will be assumed that
the treatment planner is familiar with the tools available for positioning beams, defining
beam properties, and creating beam apertures. After setting the beam parameters, the
dose can be calculated and the beam weight set to get (or verify) the desired coverage.
The next task is for the treatment planner and/or physician to evaluate the dose
distribution to determine if the goals of the treatment plan have been met. For example,
the magnitude of hot and cold spots due to the external patient contour and internal
heterogeneities should be compared to the planning objectives, and the conformality of
the prescription isodose line should be compared to the PTV. It may be necessary to add
a bolus to the patient surface, as described above, to make the dose more homogeneous
and/or make the dose coverage more conformal. Field-size effects may have reduced the
depth dose of the electron beam and the electron beam energy may need to be
increased. An understanding of all of the effects described above will allow the planner
to determine if the dose calculation results make sense and what can be done to improve
the dose distribution to meet the treatment-planning goals.

Skin Collimation
In Figure 17.3, it was shown that the therapeutic portion of the beam can be on the
order of 1 cm smaller than the field aperture, and the precise relationship between the
therapeutic treatment volume and the total irradiated volume depends on the energy of
the beam and the SSD. When the target is very small (e.g., 2 to 3 cm), the field size may
need to be double the size of the target or greater to be able to give a uniform dose to
the target. This means that the volume of significant dose extends well beyond the
target. If a critical structure is located close (laterally) to the target volume, it is then
very difficult to irradiate the target volume while sparing the critical structure.
For a given energy, the width of the penumbra depends on the distance between the
final collimation and the patient surface, and the amount of scattering inside the
patient. There isn’t a lot that can be done about patient scattering. However, the
component of the penumbra due to the collimator distance can be reduced if the patient

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can be moved closer to the final collimation. Unfortunately, that is often not possible
and one still has to consider setup uncertainty and its contribution to being able to
spare the critical structure. Collimation can also be placed on the skin surface, in the
form of lead sheets. The required thickness of lead was given by AAPM TG-25 (see Field
Shaping section above) and the adequacy of the lead shielding should be verified before
the skin collimation is used in the clinic. Lead shielding can be placed over a portion of
the treated area, to shield a critical structure, or around the entire treated area to
provide a more conformal treatment. The width of the lead shielding needs to be greater
than the width of the penumbra. The projection of the aperture edge needs to be placed
such that the edge of the lead is at approximately the 90% point on the beam profile if
the lead were not there. The width of the lead needs to extend far enough to block the
entire penumbra, extending out to the 5% level on the beam profile without the lead
(for example).
Figure 17.18 illustrates some of the issues involved when using skin collimation. In
Figure 17.18A, a high-density material is placed on the skin surface with a 4 × 4 cm2
opening. It is relatively easy to see that using skin collimation in this way can give a
nice sharp penumbra, and because placing it on the skin can be very reproducible, skin
collimation can be used to shield structures that are quite close to the target region.
Figure 17.18B shows the dose distribution for the 6 × 6 cm2 electron field without the
skin collimation. Note that the width of the 90% dose region is approximately the same
size as the opening of the skin collimation. This is required so that the dose can be
relatively uniform in the volume exposed by the skin collimation. The lateral extent of
the dose distribution without the skin collimation gives you an idea of how far the
shielding needs to be extended. The dashed horizontal line is at the depth of R100, and
it is readily apparent that the depth penetration of the beam with skin collimation is
less than the beam without skin collimation. It is also apparent that electrons scatter
from the skin collimation and contribute to hot spots near the edge of the skin
collimation. Because lateral scatter is the dominant factor determining the depth dose
characteristics, the depth dose for the beam with skin collimation is determined by the
size of the opening. The dose output, however, is determined by the size of the
applicator insert. To illustrate this point, the same monitor units were used with and
without skin collimation.

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Figure 17.18 Calculated dose for a 9-MeV 6 × 6 cm2 field at 110-cm SSD incident on a water phantom (A)
with and (B) without skin collimation. The monitor units for each beam are the same and set to deliver 100% at
the depth of maximum dose for the beam without skin collimation. The skin collimation was approximated by a
bolus of density 5 g cm−3, and has an opening of 4 × 4 cm2 on the skin surface. The lower panels show the
calculated dose for a 9-MeV beam with (C) a field size of 4 × 4 cm2 on the skin surface, and (D) a field size of
4.6 × 4.6 cm2 on the skin surface. The monitor units for the beams in the lower panels were set to deliver 100%
at the depth of maximum dose for the blocked beam.

For comparison, Figure 17.18C shows the dose distribution if we used just an
applicator insert that projected to 4 × 4 cm2 on the skin surface (without skin
collimation). The first observation about this dose distribution is that the size of the
therapeutic region is significantly smaller than the dose distribution with skin
collimation. In Figure 17.18D, the insert size was increased to 4.6 × 4.6 cm2 to
increase the size of the therapeutic region. In both of these cases, the therapeutic dose
coverage is arguably inferior to the case with skin collimation, and the total volume of
irradiated tissue is larger.
Currently, there are no commercially available TPSs that support skin collimation,
which means that planning these treatments is not easy. Assuming that you have a way
to fabricate the skin collimation in the first place, the planner will have to figure out a
way to enter the skin collimation into the TPS, and then design the electron cutout to
place the 90% point (or greater) of the beam profile at the edge of the lead collimation,
keeping in mind that the outer edge of the lead collimation needs to block the rest of the
penumbra. All of these margins depend on the beam energy and SSD, so if it is desired to
do this on a regular basis, it might be worthwhile to tabulate some of these values in
advance to assist in planning. Obviously, some tools available in the TPS could be
potentially very useful, but we’ll just have to keep our hopes up.

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Electron–Electron Field Junctions
Electron field sizes using standard applicators are generally limited to 25 × 25 cm2 by
the size of the largest applicator. Rotating the collimator by 45° will allow for a slightly
longer field that can be useful for treating the craniospinal axis (41). Even then, it may
be necessary to join multiple electron fields together to treat the entire spinal axis.
There may also be scenarios where it may be desirable to treat different portions of the
field with different energies because of the target depth differences. The scattering of
the electrons complicates the dosimetry of the field junction.
Figure 17.19A shows the resulting dose distribution for two adjacent 12-MeV 10 ×
10 cm2 fields where the field junction is at the phantom surface, and it is obvious that
this beam arrangement would not be desirable for a real patient case. The hot spot due
to the field overlap at depth is greater than 25% of the delivered dose for each beam.
This problem is not unique to electron beams however, and a similar hot spot (different
magnitude) would be seen if x-ray beams were used instead. Figure 17.19B shows the
same fields, but with a slightly larger separation between the beams to create a smooth
junction at the R100 depth. Unfortunately, it is pretty obvious that the dose near the
surface is significantly colder than each electron beam, and if there were target tissue at
that location, the dose would be inadequate.
A better geometry for field junctions (photon or electron) is to maintain a common
source position for the fields and match the field edges at the junction. The simplest
case is shown in Figure 17.20A, with two electron beams with half-beam blocks. Since
the block is the only thing that is changed and the energy is the same, the dose in the
junction is quite smooth. Another way to junction the fields is to angle the fields away
from each other, as shown in Figure 17.20B, where the beams have been rotated by 2.9°
such that the edges of the beams, as drawn by the TPS, are aligned with each other.
Unfortunately, the field junction hot spot is almost 109%, so it is obvious that aligning
the TPS field edge is not the correct way to do this. In this case, the TPS draws the field
edge as if the source of the electrons was at the same position as the photon (or light-
field) source. However, the actual source of the electron beam for this particular linear
accelerator is approximately 90 cm from isocenter. Allowing for this difference in source
position, the angle of the beam away from vertical and the separation of the beams both
need to be increased slightly (3.2°) to create a smoother junction, as shown in Figure
17.20C. In this case, the magnitude of the hot spot is less than 103%, so this is quite
close to aligning the actual edges of the electron beams. While not shown here, the
virtual source position used by the dose calculation is approximately 82 cm from
isocenter, so the ideal beam angulation is a little more than shown in Figure 17.20C.

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Figure 17.19 Calculated dose for two adjacent 12-MeV 10 × 10 cm2 fields at 100-cm SSD incident on a water
phantom. The monitor units for each field were set to deliver 100% dose at R100 for each field, and the central
axes of the fields are separated by (A) 10 cm to junction the fields on the phantom surface, and (B) 10.4 cm to
junction the fields at the depth of R100. Note that the dose scale for the colorwash is not the same in each panel.

To further complicate matters, it is not uncommon for the energies of the electron
beams to be different. Figure 17.20D shows the dose distribution for a junction between
a 12-MeV and 16-MeV electron beam, using the same beam parameters as Figure
17.20C. Because penumbra of the two beams is no longer matched, even though the
beam edges are matched, there is a hot spot on the higher-energy side that is probably
larger than we would like for a patient treatment.

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Figure 17.20 Calculated dose distributions for electron beam field junctions incident on a water phantom at
100-cm SSD. (A) Two adjacent 12-MeV 10 × 5 cm2 fields, with monitor set to deliver 100% dose at R100 for a
10 × 10 cm2 field. (B) Two adjacent 12-MeV 10 × 10 cm2 fields, with monitor set to deliver 100% dose at
R100. The beam angles are 2.9° from vertical and the central axes of the fields on the phantom surface are
separated by 9.99 cm to align the field edges (as drawn by the TPS) with each other. (C) Two adjacent 12-
MeV 10 × 10 cm2 fields, with monitor set to deliver 100% dose at R100. The beam angles are 3.2° from vertical
and the central axes of the fields are separated by 10.04 cm. (D) Adjacent 12-MeV and 16-MeV 10 × 10 cm2
fields, with monitor set to deliver 100% dose at R100. The beam angles are 3.2° from vertical and the central axes
of the fields are separated by 10.04 cm.

A fairly standard solution for this problem is to feather the junction, as shown in
Figure 17.21A. In this case, we started by aligning the beams vertically as shown in
Figure 17.19B (matching field edges at R100), and moving the junction edge by ±1 cm.
The monitor units for each original field are equally divided into the sub-fields, and the
resulting junction is quite smooth at all depths. There are still three fairly small low-
dose regions near the skin surface. This could be improved further by starting with the
beam arrangement with the virtual source at the same position (see Fig. 17.20C), but
depending on the dosimetric requirements, the simpler method shown in Figure 17.21A
is probably adequate. In many cases, using an extended SSD (e.g., 110 cm) is fairly
common, and Figure 17.21B shows that this relatively simple approach works quite well
even if the energies of the adjacent beams are not the same.
At this point it would be useful to review why this method works as well as it does.
Figure 17.22 shows a dose profile at a depth of 3 cm for the junction as shown in Figure
17.21B. For each beam, the penumbra of the feathered edge is much wider than the
nonfeathered edge and the width of the feathered penumbra is more dependent on the
amount of feathering (±1 cm) than the penumbra width of the electron beam. With a
wide penumbra, the summed dose profile does not change significantly for small
changes in the junction position, which also explains why the junction is relatively
smooth at all depths. A more practical problem is the number of cutouts and the
sequence of treatment. One choice is to treat each sub-field every day, dividing the
monitor units equally as shown in the figure. However, this involves several trips into
the treatment room to change the field cutout, which is inconvenient. It is also possible
to change the cutouts once per week (for example), which reduces trips into the
treatment room. However, there will be a cold spot near the patient surface on a daily

525
basis. If the cold spot was a concern, the adjacent field could be matched on the patient
surface before feathering the junction, or perhaps be matched at an intermediate depth.
It would obviously be nice to have a device and algorithm to automate the edge
feathering such as that proposed by Eley et al. (42).

Photon–Electron Field Junctions


It is also possible to have a junction between an electron field and a photon field, an
example of which would be the junction between the whole-brain photon fields and the
spinal electron field for the craniospinal technique described by Maor et al. (41). A more
common example is the internal mammary chain (IMC) electron field commonly used
with tangent photon fields for treating chest wall or whole breast. The traditional
wisdom about the IMC electron field is that it should be angled a few degrees away from
the anterior tangent field because of the bowing of the electron isodose lines. However,
it should be angled away from the tangent because, even if the penumbra of the electron
field was the same as the photon field, the angle is needed to match the divergence of
the electron beam to the posterior edge of the tangent beams.

Figure 17.21 Calculated dose for two adjacent feathered 10 × 10 cm2 fields (15 × 15 cm2 applicator) incident
on a water phantom. Each field has two additional sub-fields with the junction edge moved by 1 cm. The
monitor units for each field are equally divided between the sub-fields, and the total number of monitor units
for each field-set was set to deliver 100% dose at R100 for a single field. (A) Feathered field junction for 12-
MeV fields at 100-cm SSD, where the central axes of the fields are separated by 10.4 cm to junction the fields
at the depth of R100. (B) Feathered field junction for 12-MeV and 16-MeV fields at 110-cm SSD, where the
central axes of the fields are separated by 11.4 cm to junction the fields at the depth of 3 cm.

526
The difference in penumbra between the photon and electron beams makes a good
junction very difficult to achieve. Figure 17.23 shows the result of blindly applying the
feathering technique that worked for electron–electron beam junctions. The resulting
dose across the junction is not very homogeneous, and clearly another approach is
needed. Figure 17.24 shows a lateral dose profile at a depth of 2.8 cm for this junction,
and it is a little clearer why this naive approach doesn’t work as well as it did for the
electron–electron junction. Feathering the junction for the electron beams produces a
penumbra that is broad and fairly linear, while feathering the junction of the photon
beam produces a stepped profile. While the hot and cold spots are reduced compared to
a nonfeathered junction, it is clear that this is not an optimal solution.

Figure 17.22 Calculated lateral dose profile for two adjacent feathered 10 × 10 cm2 fields at 110-cm SSD
incident on a water phantom (16-MeV on patient right, 12-MeV on patient left) at a depth of 3 cm (see Figure
17.21B).

The basic field junction problem boils down to matching the field edges and the
penumbral profile. Because the photon beam has a very sharp penumbra relative to the
electron beam, the amount of feathering (smoothing) required to match the penumbral
shape is greater for the photon beam. Figure 17.25 shows one possible approach where
the penumbra of the photon beam is feathered to try to match the penumbra of the
single electron beam (without feathering). While not as smooth as the electron–electron
junction, hot and cold spots in the junction are less than 10%. Further improvements
could be made by feathering the electron field edge, and more feathering of the photon
field edge to match that. In principle, IMRT optimization could be used to optimize the
photon fluence to more accurately match the electron field edge with much less trial
and error in planning.

527
Figure 17.23 Calculated dose for two adjacent 10 × 10 cm2 fields at 110-cm SSD incident on a water phantom
(12-MeV electrons on patient right, 6 MV photons on patient left). Each field has two additional sub-fields
with the junction edge moved by 1 cm. The monitor units for each field were set to deliver 100% dose at a
depth of 2.8 cm, and the monitor units for each field were equally divided between the sub-fields.

Figure 17.24 Calculated lateral dose profile for two adjacent feathered 10 × 10 cm2 fields at 110-cm SSD
incident on a water phantom (12-MeV electrons on patient right, 6 MV photons on patient left) at a depth of
2.8 cm (see Fig. 17.23).

528
Figure 17.25 Calculated dose for two adjacent 10 × 10 cm2 fields at 110-cm SSD incident on a water phantom
(12-MeV electrons on patient right, 6 MV photons on patient left). The photon field has four additional sub-
fields with the junction edge moved by 0.4 cm and 0.9 cm. The monitor units for each field were set to deliver
100% dose at a depth of 2.8 cm, and the monitor units for each field were equally divided between the sub-
fields.

Energy Mixing
There are usually five to six choices for electron beam energy on a modern medical
linear accelerator, and the typical energy range is 6 to 20 MeV. This gives a maximum
therapeutic depth of approximately 6 cm and the spacing between beams is
approximately 1 cm in therapeutic depth, as shown in Figure 17.1. There are a couple
of ways to deal with target depths that are between the available therapeutic depths.
The first method is to add bolus to the patient, either a constant thickness bolus such as
superflab, or a commercially available customized electron bolus (BolusECT, .decimal,
Inc., Sanford, FL, http://dotdecimal.com/). A second method is to use a weighted
mixture of two energies to get the desired depth coverage. Advantages of this technique
are slightly lower surface dose (if that is desired) and not having to deal with a
treatment accessory.

Mixing with Photon Beams


Given a situation where an electron beam provides adequate depth penetration but too
much skin dose, combining an x-ray beam with an electron beam from the same
direction provides a depth dose distribution that is similar to an electron beam with
lower surface dose, transitioning to an x-ray depth dose after the electrons range out.
Where this transition occurs depends on the electron and x-ray energies, and the beam
weights. Modern TPSs should give a reasonable representation of the dose distribution
for this situation, except for perhaps the immediate surface, which tends to be
problematic for most TPSs. For a more accurate surface dose, measured surface doses
are probably required.

MONITOR UNIT VERIFICATION


As mentioned above, it is recommended that the monitor units from the TPS be verified
using an independent system, and most commonly this is done using a separate
computer program. The current AAPM recommendations are contained in the TG-71
report (13) and the formalism used by the monitor unit verification system should be

529
compatible with current recommendations. There are several different ways to
accomplish this and it is beyond the scope of this chapter to provide an overview.

SPECIAL TECHNIQUES
Total Skin Electron Irradiation
Total skin electron irradiation (TSEI) was developed to treat the entire skin surface to a
homogeneous dose (generally within ±10%) to treat mycosis fungoides, or cutaneous T-
cell lymphoma. Once the treatment technique has been designed, there is generally very
little treatment planning to be done. AAPM Report 23 (43) describes the technique and
dosimetry for this technique. Antolak and Hogstrom (44) provided more details on how
TSEI beams can be designed for standard techniques, and the dosimetry that can be
expected for such a technique was described by Antolak et al. (45). For patients that are
unable to stand, a lying-on-the-floor technique, such as that described by Deufel and
Antolak, can be considered.

Electron Arc Therapy


As pointed out in the AAPM TG-70 report (6), commercial TPSs do not implement the
tools necessary to be able to do electron arc therapy. In particular, while some
treatment machines are capable of delivering the treatment fields, there are no
commercial TPSs that can calculate the dose distribution for those beams, or deal
appropriately with the skin collimation that is necessary for this technique. As such, the
reader is referred to the AAPM report if they are interested in this historic technique.

Total Limb Irradiation


Wooden et al. (46) described a technique for treating the entire circumference of a limb.
In their case, the patient had Kaposi sarcoma, although other indications for such a
technique might include melanoma or lymphoma. In some ways, the treatment goal is
similar to electron arc therapy in that the target volume is 2 cm or less around the
circumference of an extremity. However, the technique that they described uses
standard electron fields with a virtual isocenter in the center of the limb, and six to
eight fields around the limb. Similar to TSEI, the fields should be larger than the limb so
that the electron beams can wrap around the limb and each point around the limb is
irradiated by multiple beams. Wooden et al. described a methodology where the monitor
units could be determined from the prescribed dose and output factor of the open field
using a body factor, in their case 2.55, although the exact value will depend on the
electron energy and the delivery equipment. Using a modern TPS, with the capability to
accurately determine monitor units to deliver the required dose, planning becomes more
straightforward, although it might be useful to do some sort of in vivo dosimetry to
verify that the dose delivery is accurate. Using the TPS, it would also be possible to
perhaps use different energies from different beam angles to vary the depth of the
therapeutic dose region.
The most significant problem when delivering this type of treatment is the setup and
immobilization of the patient. The extremity needs to be extended away from the body
so that beams can be placed around the extremity. The immobilization can make it
difficult or impossible to get the patient into the bore of the CT scanner to get images
for treatment planning, so it might be necessary to resort to alternative methods of
obtaining or estimating the patient contour for treatment planning, which will not be

530
discussed here. To see how the immobilization might work for such a technique, the
reader is referred to the original publication or to the AAPM TG-70 report (6).

THE FUTURE
After intensity-modulated techniques became available for high-energy x-ray beams, a
natural progression for electron beams was the development of modulated electron
radiation therapy (MERT) by several investigators (47–50). Intensity modulation can be
done with the x-ray MLC (51–53) or an add-on electron MLC (42,54,55). The former
device is available on virtually every conventional linear accelerator in use today, while
the latter device is only available as a research tool. Seuntjens et al. are developing a
few leaf electron collimator (FLEC) as a simpler device that is capable of some degree of
intensity modulation (56–58). This device is less flexible than a dedicated electron MLC,
but has the advantage of being lighter and simpler, which could make it easier to
integrate with the treatment machine. Unfortunately, there are no commercial TPSs that
are currently able to deal with such devices, so while promising, it will require many
more years before we start seeing MERT in the clinic.
Despite the fact that electron beam radiotherapy has been around for many decades,
its use in the clinic has been declining over the past several years. Competing
technologies include conventional IMRT (including VMAT), helical tomotherapy, proton
therapy, and HDR brachytherapy, and many of these technologies have seen major
improvements in the last couple of decades. Delivery technology for electron beams is
much the same as it was decades ago and has not seen the same kind of development. In
order to be able to more fully utilize the unique advantages that electron beam
radiotherapy offers, we need to convince commercial partners to make improvements to
both electron delivery and planning systems.

KEY POINTS
• Megavoltage electron beams are useful for treating target volumes within a few centimeters of
the patient surface.
• Understanding scatter effects, in-air and in-patient, is key to understanding the properties of
electron beam dose distributions.
• Surface irregularities and heterogeneities scatter and redistribute electrons, giving rise to hot
and cold spots in the dose distribution.
• Improved treatment-planning tools are needed to increase the clinical utility of electron beam
radiotherapy, and treatment-planning vendors need to be made aware of this need.
• Improved electron delivery tools (e.g., electron MLC, bolus ECT) are needed to allow
electron beam radiotherapy to contribute to more effective delivery of conformal radiation
therapy, and treatment machine vendors need to be made aware of this need.

QUESTIONS

531
1. For an electron beam incident on a chest wall with rib heterogeneities, what is
the approximate magnitude of the hot spots caused by the ribs?
A. 3%
B. 10%
C. 15%
D. 20%
2. A 9-MeV electron beam (Rp = 4.5 cm) is incident on a chest wall of thickness 2
cm. Assuming a lung density of 0.33, what is the total range of the electron
beam (from the skin surface)?
A. 2.5 cm
B. 5.0 cm
C. 7.5 cm
D. 10.0 cm
3. What is the thickness of lead required for skin collimation in a 16-MeV electron
beam?
A. 3 mm
B. 5 mm
C. 7 mm
D. 9 mm
E. 11 mm
4. An electron beam is incident on the patient surface at an angle of 30° relative to
perpendicular incidence. Compared to the same beam delivered at perpendicular
incidence, the therapeutic depth of the electron beam is
A. larger
B. smaller
C. the same
D. not enough information
5. As the air gap between the final collimation and the patient increases, the output
of an electron beam (dose per MU) decreases
A. and follows the inverse square law
B. more slowly than the inverse square law
C. more rapidly than the inverse square law

ANSWERS
1. A
2. C
3. D
4. B
5. C

532
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18 Proton Beam Therapy

Hanne M. Kooy and Judy A. Adams

INTRODUCTION
Proton beam radiotherapy further advances a central aim of radiation therapy:
significant reduction in healthy tissue dose and, as a corollary, significant safe increase
in malignant tissue dose. Proton beam radiotherapy is not new and was used as a
definitive modality as early as 50 years ago. Its recent emergence as a viable, and even
necessary, technology is a consequence of its historical success in treating otherwise
incurable disease, the present desire for increased conformal radiation therapy, and the
commercial availability of proton beam equipment.
The evolution of proton and photon radiotherapy is diametrically opposite. Proton
radiotherapy was, ab initio, a conformal modality but only sparsely available;
radiotherapy was a therapeutic analog to planar x-ray imaging and broadly available.
Of course, brachytherapy also was, and is, a local conformal modality but has its own
application and is in equal competition to proton and photon radiotherapy.
Proton radiotherapy from its inception required careful attention to detail as a
consequence of the intrinsic precision afforded by the proton beam itself even while the
supporting technologies were minimal. As a result, the early adopters of proton beam
radiotherapy were neurosurgeons: Lars Leksell in Stockholm, Sweden and Raymond
Kjellberg in Boston, USA. Neurosurgeons, by training, have an exquisite understanding
of the cranial anatomy as visualized on x-rays, as CT was not yet available. The early
use was in abnormalities visible on those x-rays such as pituitary and arteriovenous
abnormalities. The x-ray information allowed effective use of the advantageous
properties of the proton beam. Easy access to a proton beam, at the Harvard Cyclotron
Laboratory at Harvard University, allowed Kjellberg to establish a proton radiosurgery
program that continues to date. Leksell did not have this convenience and out of
necessity looked for alternative conformal methods, which culminated in the gamma
knife.
Treatment of ocular melanomas was another early adopter of proton beam therapy.
Again, the orbital anatomy and the use of x-ray opaque markers at the target margin
provided sufficient information to apply proton beams.
These early adopters used existing, postnuclear research cyclotrons. Many of these, at
Clatterbridge, UK, for example, were of low energy and could only be used for ocular
targets. A few cyclotrons, those at Harvard University (USA) and later in Orsay
(France), for example, had sufficiently high energy to treat internal targets. The
treatment of those targets, however, did not commence until the late 1970s when
volumetric imaging with CT was available and the treatment planning tools for using
those images had been developed (1). It is the treatment of those targets that introduced
proton radiotherapy to the general practice of radiotherapy. Proton radiotherapy, as an
intrinsically conformal modality, introduced many elements of “modern” conformal
radiotherapy: attention to the details of imaging, setup, treatment planning, and
delivery.

537
CLINICALLY EFFECTIVE PROPERTIES OF THE PROTON BEAM
The clinical potential of a proton beam was recognized by Robert R. Wilson, then at the
Harvard Cyclotron Laboratory, in his article of 1947 (2), in which the geometric and
dosimetric localization properties of a monoenergetic proton beam were proposed for
treating targets inside the body. The practicalities were in doubt, as available proton
beams had insufficient penetrating energy: the first Harvard Cyclotron, built in 1937,
had an energy of 12 MeV equal to 17 mm range! This cyclotron was moved, by Wilson,
to Los Alamos for the Manhattan project in 1943, which allowed the construction of the
second Harvard Cyclotron in 1947 with an initial energy of 90 MeV (6.4-cm range in
water) and later upgraded to 160 MeV (17.7-cm range in water) in 1955. It was
another 12 years before Wilson’s vision became a reality (3).
A proton beam, as any charged particle, loses energy along its track as a function of
the local stopping power. The stopping power, the energy loss per unit length, increases
rapidly as the proton in water slows down and equals 5.2 MeV/cm at 160 MeV, 12.4
MeV/cm at 50 MeV, and 26.1 MeV/cm at 20 MeV. This rapid increase in energy loss per
unit length results in a very large dose enhancement at the end of the particle track and
results in the characteristic Bragg peak beyond which no dose is deposited (see Fig.
10.2). The large mass of the proton (938.3 MeV/c2) results in tracks that deviate little
from the initial proton direction, and thus all protons along the same direction yield
Bragg peaks at the same depth and the overall dose distribution is, in essence, a simple
addition of the dose distribution along a single track. This is in contrast to a beam of
electrons where the small mass of the electron (0.511 MeV/c2) results in tracks that lose
any correlation with the initial direction and as a consequence the electron Bragg peak
is “smeared” throughout the effective treatment volume and only a distinct distal fall-
off remains (see Fig. 18.1). The intact or pristine Bragg peak characteristic of heavy
charged particles and its large peak to entrance dose ratio offers the opportunity for
localizing dose at a point in a target volume. Thus, a proton beam has intrinsic three-
dimensional (3D) shaping features, in depth and laterally, compared to the two-
dimensional (2D) lateral controls in a photon beam.

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Figure 18.1 The use of range-compensators requires two steps, smearing and tapering, to achieve satisfactory
target coverage. Smearing considers each point on the range-compensator and replaces the thickness of that point
with the minimum thickness found at other points within a smearing radius of the point under consideration.
This has the effect to “throw” the dose deeper into the patient (see bottom right compared to bottom left). The
middle inset illustrates the example where the CT represents the unsmeared compensator, while (B) is the
compensator if a shift was to occur. The composite compensator considers positions (CT) and (B). Smearing,
originally, was introduced to compensate for geometric uncertainties by considering the “worst”-case penetration
range within a region. Tapering considers range-compensator gradients along the aperture edge and applies a
smoothing to those gradients to remove scattering artifacts. In general, support for smearing and tapering is poor
within existing treatment planning systems and requires considerable knowledge on the treatment planner to
achieve a satisfactory result.

The depth of the Bragg peak is a function of the initial proton beam energy and there
is a direct correspondence between energy E (in MeV) and penetration depth or range R
(in g/cm2). The terms “energy” and “range” are interchangeable although the range is
more effective in clinical communication. A consequence of the energy–range
relationship is that the energy loss can be equated to material thickness. Thus, inserting
a material of certain thickness in a proton beam results in a proportional energy
reduction and a known shift downward of the range. The proton beam intensity,
however, does not change: all entering protons exit. This is in contrast to a clinical
photon beam where the mean energy is minimally affected while the intensity reduces
exponentially as a function of thickness.
The near-straight tracks of the protons produce a beam whose penumbral edge is
intrinsically sharp. The individual protons undergo (primarily) many multiple Coulomb
scattering events, which result in a Gaussian-shaped broadening of an initially parallel
proton beam. The Gaussian spread increases with depth and results in a depth-
dependent penumbra (80/20%) (see Fig. 18.2 where the penumbra profile increases per
depth).
The proton beam penumbra is intrinsically sharper compared to a single photon beam
penumbra at depths below ~18 cm (in water). This single beam penumbra is relevant
when one wishes to achieve the sharpest lateral fall-off of dose between the target and a
critical structure. Thus, proton beam treatments in the head and neck achieve a sharper
lateral fall-off, for example, in a target around the brainstem compared to a photon
(intensity-modulated radiotherapy [IMRT]) beam treatment. On the other hand, a
prostate or other deep-seated target does not show a penumbral advantage for a proton
beam. Of course, other benefits may still favor the proton beam dosimetry.
In practice, however, it is the composite penumbra of multiple fields that is of
relevance as it determines not only the sharpest achievable penumbra but also the
integral dose “bath” throughout the patient. Photon beams have no localization ability
along depth and “pass” through the target. Proton beams, in contrast, deposit no dose
beyond the distal edge of the Bragg peak. This simple difference means that a composite
of multiple proton beams will have approximately half the integral dose of a similarly
arranged set of photon beams (see Fig. 18.3).
A single proton field, as the composite of multiple individual dose-weighted Bragg
peaks, can deliver an arbitrary dose distribution to a target volume. Scattered proton
fields, in clinical practice, are shaped to deliver homogeneous dose to all or part of the
target volume. In the case of partial target coverage, a second field is used to fill-in or
“patch” (see below) the remainder. Thus, a single proton field can achieve the desired
dose description. Such a single proton field can achieve superior dose shaping by virtue
of the lateral penumbra and the distal fall-off that spares distal tissues. A single-

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scattered proton field cannot control the entrance dose, given the fixed modulation
width of a spread-out Bragg peak (SOBP). An example of such a field is shown in Figure
18.3 in comparison to an IMRT treatment.

Figure 18.2 The effect of increasing the air gap in a scattered field results in an increase in penumbra because
the projection of the effective source size, on the order of 7 cm in scattered proton fields, in the patient increases.
The penumbra also increases, but much less so, as a consequence of the scatter in patient as a function of depth
(depths of 0, 5.3, and 10.5 cm are shown for a field of 14-cm range and 8-cm modulation). The initial
penumbra at a depth of 0 equals the projected source size only as the proton beam has not yet scattered in the
patient. The inset (top left) shows the penumbra for this field as a function of depth for an air gap of 5 cm.

Figure 18.3 Treatment plans, intensity-modulated radiotherapy (IMRT) and scattered fields (DS) for

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endometrial nodal disease are compared. The IMRT plan uses seven fields and has an unavoidable dose bath
(yellow between 50% and 80% isodose lines). The DS plan, in contrast, achieves superior coverage with a single
posterior aperture and range-compensator field (examples of these devices, not those used for this treatment, are
shown on the right). The aperture, as for a photon beam, achieves lateral beam’s-eye-view conformance. The
range-compensator shifts the proton penetration range in proportion to the local thickness to conform the dose
to the distal surface of the target volume. Note that for a scattered field, the entrance dose cannot be controlled
and results for this case in near, full skin dose.

The distal fall-off of the Bragg peak has the sharpest dose gradient (about half of the
lateral penumbra) and should offer the best opportunity to achieve a dose differential
between target and healthy tissues. In practice, however, the range in patient has an
uncertainty estimated on the order of 3.5%. This uncertainty arises from the
uncertainty in (relative) stopping power in the patient as derived in practice from CT.
CT data measures, per voxel, the electron density in Hounsfield units. For proton
radiotherapy treatment planning, the Hounsfield unit in each voxel is converted to
stopping power using a tissue-dependent conversion curve (Fig. 18.4). This conversion
is empirical and global, and ignorant of patient-specific variations. Proton radiotherapy
planning assumes the worst-case scenarios concerning the possible position of the distal
edge of the Bragg peak. In practice, the distal edge is extended beyond the target
volume by 3.5% of the distal range. The modulation, that is, the difference between
distal and proximal (90% to 98%, in our practice), is extended by 7%. Most
significantly, it means that the distal edge cannot be used to achieve a dose gradient
between the target and a critical structure—doing so could imply a direct overshoot into
the critical structure!

Figure 18.4 The radiosurgery beamline uses a single-scattered proton beam. A stack of lead and lexan absorbers
shift and scatter the proton beam (of R = 20.7 cm) to the desired energy and fixed scattering angle. The
reference ionization chamber (IC) counts the appropriate number of MU to create spread-out Bragg peaks
(SOBPs) of the desired modulation. The patient is positioned on the patient positioner (PPS) at 450 cm from
isocenter (the dot in the lamination pattern on bottom left). The position is verified with x-ray and the snout
(SN) allows imaging of the full cranial anatomy and with the aperture. The beam energy is verified by a

541
multilayered Faraday cup (FC). A thick neutron absorber (white) between the FC and IC reduces the neutron
dose well below the required levels at the patient.

Proton dose distributions are biologically equivalent to photon dose distributions


except for a constant relative biologic effect (RBE) factor of 1.1. That is, a photon dose
of 54 Gy (Co-60 equivalent) equals a physical—as measured in an ionization chamber
(IC)—proton dose of 54/1.1, or 49.1 Gy. Proton dose distributions are, therefore, stated
as 54 Gy (RBE) (4) to indicate that the physical dose has been corrected by the RBE
factor and can be compared directly to an equivalent photon dose distribution of 54 Gy.
Dose effect knowledge from photon radiotherapy can thus be transferred to proton
radiotherapy. This is a major advantage in the clinical application of proton
radiotherapy. In contrast, the RBE of heavier charged particles, that is, for lithium and
beyond, introduces significant complexities and unknowns in dose reporting.

GENERATION OF CLINICAL PROTON FIELDS


The proton pristine Bragg peak is too narrow, on the order of 6 mm, to be clinically
useful. Thus, many Bragg peaks must be added and distributed through the target
volume to achieve a clinical dose distribution.

Accelerators
The generation of a clinical proton beam requires an accelerator to achieve a desirable
clinical energy range of up to about 250 MeV. The latter corresponds to about 38 cm in
water and is considered good maximum choice, given the deepest seated targets. The
lowest minimum range is about 3 to 4 cm (60 MeV) and is needed for orbital and other
shallow targets.
Current accelerating technologies are cyclotrons and synchrotrons. A cyclotron
accelerates a proton beam when it crosses repeatedly over a gap over which a strong
cyclical (of a period equal to the proton traversal time between gap crossings) electrical
field is applied. The proton beam is in a constant magnetic field B = BT and the
accelerating proton beam assumes an ever-increasing radial orbit R, that is, R = R(E).
At the highest design energy, that is, at the maximum radius T = R(Emax) of the
cyclotron cavity, the proton beam is extracted from the cyclotron. Thus, a cyclotron
produces a single energy beam Emax and the proton beam must pass through a carbon
or beryllium (i.e., a low scatter material) variable thickness degrader to achieve the
desired clinical energy. A synchrotron accelerates the proton beam by passing it through
an accelerating cavity and keeps the beam in a constant-radius orbit T by synchronizing
(and increasing) the magnetic field with the proton energy, that is, B = B(E) such that
the proton bending radius equals T. A synchrotron can produce any energy E,
proportional to the number of passes through the cavity and limited by the maximum
magnetic field B, without the need for postextraction degradation.
The primary difference between a synchrotron and cyclotron is the need for energy
degradation of the latter. The degrading material, however, scatters the beam, which
results in a large emittance, that is, the position and momentum phase space, for a
cyclotron. This, in turn, affects the beam transport design and the ability to achieve a
narrow beam at the patient. The choice of cyclotron was preferred due to their simpler
operation and higher beam current. The latter is to compensate for proton loss in
scattered fields where a large portion of protons (between 50% and 90%) is lost to
scatter and field collimation within the scattered-field radius. The emerging preference

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for scanned beam technology, however, places different requirements on the beam
parameters compared to scattered beams, and the choice between synchrotron and
cyclotron may shift in favor of the synchrotron.
The generated beam is transported to the treatment delivery device using a magnetic
beamline. A distributed beamline allows a single accelerating device to supply multiple
treatment rooms which reduce the overall facility cost.

Scattered Proton Fields


An initially narrow proton beam of a given energy is shifted to lower energies and
spread in depth by different thickness absorbers, broadened and flattened laterally by
carefully designed scatterers, and “stacked” with appropriate weights by synchronizing
absorber insertion with monitor units (MU) or another integrated beam-current measure
(see Fig. 18.4). Such composite and scattered proton fields are labeled SOBP fields and,
in general, produce homogeneous dose per field over a desired modulation width up to
a maximum range.

Single Scattering
A proton beam scattered by a series of flat absorbers is labeled a single-scattered beam.
The scattered beam profile is Gaussian and, with a large SAD and sufficiently large
scattering angle, a near-uniform collimated field can be created over a radius at the top
of this profile. An example of such a system is the radiosurgery beamline at the F. H.
Burr Proton Therapy Center (see Fig. 18.4). An incoming proton beam of 185 MeV (22-
cm range in water) is centered on a binary stack of lexan and lead absorbers. Lexan is a
low-Z material and is an efficient energy absorber with low relative scatter (1 g/cm2 has
a mean angle of 0.0072 radian at 130 MeV) while lead is a high-Z material with high
scatter (1 g/cm2 has a mean angle 0.021 rad) and low relative absorption. The stack
has 10 lexan absorbers with thicknesses from 0.022 to 11.5 g/cm2, where each
subsequent thickness is twice the previous, and five lead absorbers from 0.088 to 1.403
g/cm2, again with doubling of thickness. Combinations of lexan and lead produce
pristine Bragg peaks between 4 and 22 cm, where each emerging beam is scattered into
a Gaussian profile within which a 10-cm diameter field has a minimum intensity of 95%
relative to the center. By switching combinations of lexan and lead absorbers for
appropriate beam-on times, as measured in an IC, for example, SOBP fields of arbitrary
modulation widths can be created.

Double Scattering
A common mechanical method for creating SOBP fields uses a rotating wheel where the
thickness of a particular angular interval encodes the pullback of the pristine peak in an
SOBP and the width of the angular interval encodes the weight of the pristine peak (see
Fig. 18.5). Such a wheel can be constructed of a lexan and lead combination to create a
constant-scatter angle as a function of rotation and combined with a second scatterer to
increase the efficiency of the proton beam and to broaden and flatten the field. The
second scatterer, again, is constructed of two, low-Z/high-Z, materials and is contoured
along its radius to uniformly absorb the proton energy. The scatterer is shaped
differentially to scatter the protons to create a uniform field. A photon scatterer, in
contrast, is shaped differentially to absorb photons.
Dual-scattering systems have been the primary technology, up to now, for proton-
radiotherapy field delivery. Here we summarize, briefly, the operation of the IBA* dual-
scattering nozzle at the F. H. Burr Proton Therapy Center as an example (see Fig. 18.5

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top). In such a system, one wishes to minimize the number of scatterers and modulators
to reduce complexity. The system is fully automated, efficient to operate, but not
necessarily optimal in terms of proton efficiency or field parameters due to pragmatic
operational considerations. The IBA nozzle offers SOBP ranges between 3 and 30 cm in
water with a field diameter of up to 24 cm for ranges <25 cm and up to 12 cm for
ranges >25 cm.
The nozzle has three rotating modulator wheels, each of which has three tracks. The
nozzle defines eight combinations of modulator wheel track and scatterer where each
combination, called an option, covers a particular clinical-range interval of about 3 to 4
cm. A total of eight options thus cover the desired clinical minimum and maximum
ranges. In theory, a pair of modulator wheel track and scatterer only produces a flat
field, laterally and in depth, for the design energy. Below that energy, the field is “over”
scattered, and above it “under” scattered. The nozzle has a set of thin-foiled lead
insertable scatterers upstream from the modulator track that increases the mean scatter
angle and flattens the field, as the energy increases in the option interval.

Figure 18.5 Patching of fields is a necessary technique in scattered fields to wrap the dose distributions around a
target. In the above example, the through-field (top left where the circle is a 12-cm aperture) covers the anterior
part of the GTV and the patch field covers the posterior “horns.” The top right three figures show the dose
distributions for the scattered (DS) fields. The bottom right three figures show the result using the DS-field
approaches and using the pencil-beam scanning (PBS) optimization to achieve a total dose distribution without
the benefit of either apertures or range-compensators. In the PBS optimization, all fields are optimized as an
ensemble. The desired prescription dose is 14.4 Gy (RBE). The construction of patching fields in DS is tedious
as the field parameters—range, modulation, and aperture size—must be carefully tweaked to achieve a dose
distribution that covers the partial volumes to yield coverage of the total volume. For example, the through-field
for the DS plan shows a distinct softening at its distal edge, which makes it harder for the patch field to cover
that volume. The PBS patching, by virtue of its simultaneous optimization of all fields and its ability to vary
local intensity, achieves a much more satisfactory result. In addition, the posterior lateral gradient of the PBS

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through-field is not as sharp compared to the DS through-field. The PBS gradient is defined by the varying
pencil-beam intensities while the DS gradient is defined by the field edge. Thus, the PBS patch is probably less
sensitive to errors. The PBS fields used a total of 1,600 pencil-beams with an initial spread of σ = 5 mm and
with ranges between 4.5 and 14.5 cm (in water). The bottom right figure shows the 1,103 spots for each of 24
energy layers for the through PBS beam. The color indicates the number of gigaprotons (Gp) in each spot.

The SOBP depth dose plateau flatness (better than ±1% in our practice) can be
controlled by modulating the cyclotron beam current during the rotation (at 10 Hz) of
the modulator track. This is a convenient property of a cyclotron which acts as a
continuous and variable current source. The SOBP flatness is determined by the set of
weights for each of the pristine Bragg peaks in the SOBP. These weights of each peak’s
contribution to the SOBP are hard-coded in the modulator track but are not “exact” for
a particular SOBP range. The modulation of the beam current adjusts the weight by
varying the number of protons that pass through an angular segment. The use of
current modulation reduces the complexity of modulator track design, which now can
be “corrected,” and allows a particular track to be applied well outside its initial design
interval (see Fig. 18.6).
The beam-current control also controls the width of the SOBP field. The modulator
track, over its full rotation, achieves a maximum constant pullback SOBP width. The
current can be turned off at an angle within the full rotation to allow for arbitrary
modulation up to the maximum pullback to deliver the desired modulation width for a
particular patient field.

Figure 18.6 The ability to control the current (relative to the current I0 set for a specific dose rate) as a function
of the rotation time (100 ms) of the modulator wheel allows a track to be “tuned” to produce a perfectly flat
spread-out Bragg peak (SOBP) (blue) compared to that produced with a constant current (red).

Field-Shaping Devices
Scattered fields are shaped laterally by apertures, as photon fields, and in depth by
range-compensators (Fig. 18.3). Apertures are collimated to the beam’s-eye-view
projection of the target volume and require a distance of 7 to 10 mm between the target
and aperture edges to account for the depth-dependent penumbra. The apertures must
have sufficient thickness to absorb the incident range as a proton field does not change
in intensity as it passes through an absorber. Thus, insufficient thickness will result in

545
full dose to the patient! The range-compensator is unique to proton and heavy charged
particles. The range-compensator adjusts the range across the lateral field profile such
that the resultant distal dose surface closely matches the distal target volume surface. A
range-compensator thus spares tissues distal to the target.
The thickness of the target volume, measured as the difference between the deepest
and shallowest radiologic path-lengths in the target volume, determines the desired
maximum range of the SOBP field and the modulation width. The combination of an
aperture and range-compensator can thus achieve, for a single SOBP field, lateral and
distal conformation and homogeneous dose in the target volume (see Fig. 18.3).
The aperture is placed as close as possible to the patient to reduce the effect of the
large effective proton source, whose size is on the order of 5 to 10 cm, due to scattering
material in the beam, compared to 1 to 2 mm for a photon beam! The penumbra of this
source can only be mitigated by, first, placing it as far as possible from the patient,
typically at an SAD ∼300 cm, and demagnify it by the aperture–patient distance over
the aperture–source distance. Thus, in clinical practice, the effective source size is
demagnified 40-fold and its contribution to the penumbra for double-scattered fields is
on the order of 5% (see Fig. 18.2).
The design of the range-compensator considers individual radiologic path-lengths
from the source to the distal surface and sets the range-compensator thickness such that
the distal fall-off of the SOBP is just beyond the target distal surface. Consider an
“open” field of range Rd that reaches, as measured from the source to that point, just
beyond the deepest point Pd on the target distal surface. We wish to insert material for
every other point Pi on the target distal surface equal to Ti = Rd − Ri, where Ri is
radiologic path-length to point Pi. The range-compensator is constructed with the
thicknesses Ti. The result is that the range Rd as it passes through the range-
compensator is shifted along each ray from the source such that the distal edge of the
proton composite dose distribution lies just beyond the target distal surface (see Fig.
18.3).
Known uncertainties in the patient or target position, caused by setup errors or
otherwise, create variations in path-lengths that could lead to an underdose of the
target or an overshoot into the healthy tissues. The range-compensator profile is,
therefore, “smeared” where each point is assigned the largest range (or least thickness)
from among the points in its neighborhood within a radius corresponding to the total
expected variation (see Fig. 18.1). This ensures worst-case coverage of the distal target
surface in the presence of these variations. It does, however, push the distal fall-off dose
further into the healthy tissues. This, and the inherent uncertainty in range stated
above, means that the distal fall-off of the SOBP cannot be used to shape a gradient
between the target volume and a critical structure.

Absolute Dosimetry
The relationship between dose in patient and number of protons produced by the
cyclotron is not trivial for scattered fields. The number of protons, as usual, is
monitored by a reference IC placed upstream of the collimated field, which produces a
signal proportional to the proton flux. In general, we can refer to proton beam flux in
terms of absolute number of protons, that is, gigaprotons or Gp; or in terms of the IC
response in MU as the two are related by the stopping power Sair, that is, MU ∝ Sair ×
G for G protons passing through the collection volume of the IC. For scanning beams,
discussed below, the use of Gp is recommended. For scattered fields in a continuous
system such as a dual-scattered system with a rotating modulator wheel, the target

546
volume receives the fractional prescription dose at every wheel rotation interval (i.e.,
0.1 seconds). Thus, MU is proportional to the fraction of prescription dose in patient. A
delivery interruption (within 0.1 seconds) results in the whole volume receiving partial
prescription dose. For the single-scattered system described above, however, an IC count
interval corresponds to the delivery of an individual pristine peak in the set of peaks of
the SOBP. In such a system, a delivery interruption results in some parts of the target
volume receiving full dose, while other parts receive incomplete dose. Resumption of
such fields must be accurately handled in the delivery system.
The relationship between physical dose (in Gy) in the SOBP plateau and MU is
complicated. In principle, one could calibrate each pristine Bragg peak in units of Gy
per number of protons (or MU). This relationship for scattered fields is impractical
except for the simplest beamlines. In general, the complex secondary interactions in a
dual-scattering system and the variability of mechanical device settings preclude such a
calibration or derivation.
One can establish a semitheoretical relationship for the output factor Ψ (in Gy/MU)
between MU and physical dose in water. The SOBP output factor is the ratio between
dose DP in the plateau and dose (i.e., MU) measured in the IC. The latter, in turn, is
proportional to the entrance dose D0 of the SOBP. Thus Ψ is proportional to the ratio of
DP/D0, which can be derived from a mathematical description of the Bragg peak and
equals

where D0R is the SOBP entrance dose of the reference SOBP which has an output factor
ΨR, and the entrance dose of the SOBP of interest, with range R and modulation M, is
D0(R, M) and described by the two-parameter function characterized by a form factor r
= (R, M)/M. The function parameters, a and b, have the theoretical values of 0.44 and
0.6, respectively. In practice, these differ due to the secondary effects in the nozzle.
In clinical practice, the applicability of Equation 18.1 depends very much on the
construction details of the delivery system. In our practice, the formula is successfully
applied to both the single-scattering beamline and our dual-scattering gantry nozzle.
The parameters a and b are obtained from calibration and are constant for each option.
In general, Equation 18.1 will apply to a constant configuration of a nozzle where the
SOBP-shaping devices do not change, which is the case in the IBA nozzle for each
option.

Scanned Proton Fields


The clinical practice of proton radiotherapy, about 50,000 patients to date, has been
based almost exclusively on scattered-field technology. The use of scattered fields to
achieve complex dose distributions requires considerable manual planning and time.
Scanned proton beam technology is clinically viable, as by the PSI team, and should
become the future of proton radiotherapy. Only scanned proton fields can match the
level of automation and complexity integration that now is expected in photon
radiotherapy considering technologies enabled by IMRT and treatment planning
optimization.
Scanned proton fields use a narrow beam of protons of variable energy, to control
depth penetration, and which is moved in the lateral dimensions by magnetic fields (Fig.

547
10.8 bottom). Thus, an almost arbitrary 3D dose distribution can be created inside the
patient without the aid of mechanical beam modifiers or field-shaping devices such as
apertures and range-compensators. The latter, however, may continue to have clinical
use or benefit and their use should not be considered void.
There are two clinical modes of using pencil-beam scanning (PBS) technology. The
first mode, labeled single-field uniform dose (SFUD) (5), is analogous to the clinical use
of SOBP fields. In this mode, each PBS field is designed to deliver a homogeneous dose,
like an SOBP field, to the target volume. Unlike an SOBP field of constant modulation
width, the dose to the volume proximal to the target volume now conforms as well. This
offers further healthy tissue sparing compared to scattered SOBP fields. The second
mode uses two or more fields and optimizes the dose as a composite for all fields. This
mode is analogous to IMRT field optimization, where each individual field delivers
inhomogeneous dose, and is labeled intensity-modulated proton therapy (IMPT).
The clinical application of PBS to date (at PSI) has been primarily with SFUD fields
and not with IMPT fields. The reason is twofold. First, IMPT fields have uncertainties in
the precise knowledge of the end-of-range of the pencil-beam and also require precise
knowledge of the sources of geometric errors. These uncertainties could cause the
individual fields not to “mesh” correctly to yield the desired composite dose. Second,
the optimization problem for IMPT is significantly more complex compared to IMRT
optimization. In IMPT optimization, the number of variables is one or two orders of
magnitude larger compared to IMRT and requires a substantial increase in numerical
computing power which only has become available recently with the advent of 64-bit
computing architectures.
The optimization unit for IMPT, that is, the pencil-beam itself, also complicates the
convergence of conventional optimization algorithms as it presents to the optimizer a
sharp distal fall-off and a coarser (by a factor of two) lateral fall-off. This causes
conventional optimization algorithms, that is, those based on squared dose differences,
to prefer the distal edge fall-off which exacerbates the problem of distal edge
uncertainty. SFUD field optimization only considers a single field at a time and avoids
these problems.
Thus, the successful clinical introduction of IMPT requires new optimization
technologies that consider the robustness of the final treatment plan. The robustness of
a treatment plan measures its invariance against the known and specified sets of
uncertainties that have been included in the optimization methodology. For IMPT plans,
this set includes range and positional uncertainties, including those of target motion
(6). The positional uncertainties, especially, are significant for SOBP fields in general
and for IMPT in particular. For both, the local motion of a target volume, such as may
be present, in the lung, causes significant changes in radiologic path-lengths and cannot
be considered by a simple expansion of the clinical target volume (CTV) into a planning
target volume (PTV). Such an expansion can be used for the lateral extent, that is, in the
Beam’s Eye View (BEV) plane. Along the depth dimension, however, the final beam
profile, managed with a range-compensator for SOBP fields and by differential pencil-
beam intensities for IMPT, must ensure coverage of the target for all phases of motion.
The correct consideration of these effects requires a computation over all phases instead
of a geometric assumption such as the Imaging Target Volume, the composite volume
from all imaging sets, concept.

Multicriteria Optimization
In current clinical practice, optimization algorithms use a quadratic cost-function F of
the form

548
which specifies, for each organ of interest, the prescription dose Dk and weight factor ak
as an indicator of the significance of meeting the prescription dose. The function F is
minimized for all dose point dj that contribute dose to the organ k. This methodology, in
practice, yields treatment plans that approximate the desired solution, that is, the
“optimal” treatment plan, but often requires arbitrary recalculations that “tweak” the
parameters ak and Dk to achieve the physician’s intent. This intent is typically not
specifiable as it depends on a trade-off analysis by the physician which can only be
done given the actual possibilities.
Recent developments in optimization introduce the use of multicriteria optimization
(MCO) which considers multiple trade-offs simultaneously (7). The MCO approach, at
least in our practice, computes all “possible” treatment plans, each of which is optimal
within the choice of trade-offs. In MCO, the physician specifies a set of absolute
constraints, such as minimum and maximum doses allowed to the target and/or
structures, and a set of objectives, such as “minimize the mean to the lung” or
“minimize the maximum to the GTV.” The MCO optimizer generates a set of plans, each
of which meets the constraints, of sufficient number to sample all the possibilities of the
stated objectives. These optimal treatment plans lie on the Pareto trade-off surface,
which is a multidimensional surface (of dimension proportional to the number of
objectives) formed by those points whose values are the optimal trade-offs. That is,
changing one trade-off (such as increasing the target dose) will decrease another trade-
off (such as higher critical structure dose). The user traverses this surface to select the
desired set of trade-offs. Consider the example in Figure 18.7 that shows the Pareto
surface (a curve in this case of two objectives) of a chest wall target volume with a
desired optimal dose of 70 Gy (RBE) but where a minimum of 40 Gy (RBE) was set to
allow sufficient “room” to assess lung dose. The two objectives are “minimize the mean
lung dose” and “maximize the minimum dose to the GTV.” An optimal plan that lies on
the curve means that improving lung dose will degrade target dose and vice versa.

Absolute Dosimetry
PBS dosimetry is, in essence, simple as one only considers the interaction of a pure
proton beam in medium. The proton pencil-beam control parameters are its lateral
deflection as defined in the reference plane and measured in a positional IC, its energy
as defined by the accelerator, and its instantaneous or integrated current. All these
parameters must be specified by the treatment planning system as the final dose
calculation must consider, at a minimum, the exact relative dose contribution from each
pencil-beam. Figure 18.8 shows a set of pristine Bragg peaks as a function of range
which have been carefully calibrated for treatment planning to match those delivered
on the equipment. The peaks are specified in units of Gy (RBE) mm2/Gp. These units
allow the treatment planning system to relate the dose in patient directly in terms of a
delivery system control parameter, that is, the number of protons (in Gp). This relation
between dose in patient and the beam charge (assuming a pure Gaussian model, see
Chapter 10, Proton Dose Calculations) is

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where σi(z) is the spread of pencil-beam i at depth at z (in the pencil-beam coordinate
system with z equals to pencil-beam axis), ri(x, y, z) is the lateral displacement of the
calculation point with respect to the pencil-beam axis, Gi is the number of protons in the
pencil-beam, and Di∞(z) is the pristine Bragg-peak depth dose. The index i includes
summation over pencil-beams of different energies and positions. The pencil-beam
spread σi(z) includes both the inpatient scatter due to (primarily) multiple Coulomb
interactions and the initial spread of the pencil-beam prior to entering the patient as
produced in the delivery equipment. The final dose thus has the correct units of Gy. It is
the responsibility of the treatment planning optimization system to compute the set Gi
to be delivered by the delivery equipment. The pencil-beam energies and deflections are
typically precomputed, given the target shape and location.

CLINICAL CASE ANALYSIS


Our example is a pediatric cervical chordoma. This site has as critical structures:
brainstem, cord, cochlea, and chiasm. The prescription dose is 50.4 Gy (RBE) to the CTV
and 79.2 Gy (RBE) to the GTV, while keeping the chiasm below 62 Gy (RBE), brainstem
and cord center (surface) below 55 (67) Gy (RBE), and the cochlea below 60 Gy (RBE).
The treatment approach reflects a long experience in sequencing the fields.

Figure 18.7 The challenge of selecting the “optimal” plan is illustrated by the above hypothetical, proton pencil-
beam scanning (PBS) irradiation of a chest wall. The PBS treatment uses three beams: a posterior (gantry 170),
anterior (gantry 350), and right posterior oblique (gantry 225). The GTV (red) is constrained to a dose range of

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40 to 70 Gy (RBE) and the competing objectives are to “maximize the minimum GTV dose” and to “minimize
the mean to the right lung” (note that there is no contralateral lung dose concern as the proton beams have no
exit dose). The top right figure shows the Pareto surface of optimal plans (a curve in this case given two
objectives). The Pareto optimizer computes a mathematical representation of all plans that lie on the curve. This
representation allows a rapid computation of any plan that corresponds to a point on the curve. The “red” plan is
a suboptimal plan because, given its mean RT lung dose, it should allow a GTV dose of 68 Gy (RBE; arrow); a
Pareto optimizer would not yield such a plan by definition. The “cyan” and “green” plans (labeled 18,48 and
23,60 for the curve coordinates) are Pareto-optimal plans. Note how the GTV dose can be significantly
increased in the central curve region with only a modest increase in lung dose. The analysis afforded by the
multicriteria optimization (MCO) is essential for PBS, given the higher level of variability in a treatment plan
because of the large number of PBS pencil-beams (on the order of 10 3 to 10 4). The corresponding dose
distributions and DVHs are shown on the left and bottom right, respectively.

The first set of five fields to the CTV have gantry angles of 70, 100, 230, and 260 at a
couch angle of 0, and a gantry angle of 155 at a couch angle of 90. The main objective
of this field arrangement is to reduce the dose to the parotid glands but little to the
spinal cord. Each field, in the scattered-field (DS) delivery, covers the CTV to
homogeneous dose. The DS fields are not all delivered at each treatment session.
Instead, triplets of rotating combinations are used. Figure 18.8 shows the normalized
dose distribution for a single field and the composite dose distributions for all five
fields.
The GTV fields, as a consequence of the full CTV dose inclusion, must avoid the
brainstem and spinal cord. For DS fields, this can only be achieved by patch
combinations. A patch combination is the proton equivalent of field edge matching.
Given the finite range of the proton, one can now also patch the distal edge of one field
to the penumbral edge of another field. Each field delivers full dose within its subtarget
volume and the combination of patch fields achieves full dose to the target volume. As
noted before, however, the uncertainty in the distal range can lead to a cold or a hot
spot. As a consequence, patch combinations are always “switched” around to feather
this hot or cold spot. The construction of patch-field combinations for scattered SOBP
fields is cumbersome in spite of some available support in treatment planning systems.
For illustration purposes (Fig. 18.5), we use one of the three DS patch-field combination
(in fact a “double” patch) and use the PBS optimization engine to “auto-patch” the field
without the use of an aperture and range-compensator. The result is (probably) more
robust to cold or hot spots as the individual field dose distributions present a more
gradual distal fall-off compared to the “true” pristine peak dose fall-off. Thus, any over-
or undershoot effect is minimized by the lower gradient. We expect, in the clinical
practice of PBS and subject to further validation, to continue to use the DS-field
approaches as these have inherent robust properties such as target avoidance with the
penumbral edge and distal edges away from critical structures. Even with available
robust optimization techniques, these DS-field approaches retain their use.

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Figure 18.8 The figure shows a near-symmetric chordoma wrapping around the spinal cord in this transverse
image. The GTV is shown in red, the spinal cord in purple, and the parotid glands in cyan and purple. Isodose
values are shown in Gy (RBE). The desired prescription dose for the GTV is 78 Gy (RBE). The left half of the
picture shows an IMPT treatment plan, and the right half shows a scattered-field (DS) treatment plan. Both
plans used the identical beam angles, as created for the DS plan. The choice of the DS beams inherently selects
“robust” approaches (see text). Distinctive features in favor of the intensity-modulated proton therapy (IMPT)
plan are (1) tighter and more complete coverage of the GTV especially into the posterior tails (see 78-Gy [RBE]
isodose), (2) better sparing of the parotid (see 30-Gy [RBE] isodose), (3) significantly less spinal cord dose (see
55 Gy [RBE] isodose), and (4) lower integral dose as apparent from the 30- and 40-Gy (RBE) isodose lines.
Overall, however, the scattered-field approach achieves a very comparable treatment plan.

Figures 18.9 and 18.10 show the total, CTV + GTV, dose distributions for both the
IMPT and DS plans. The IMPT plan does significantly improve on the parotid glands,
which are primarily located in the integral dose region, which—as stated before—can be
reduced on an average by 50% with protons and even more with IMPT compared to
photons. In general, however, the DS plan is competitive with the IMPT plan and, in
general, we do not expect as dramatic a change between IMPT and DS compared to
IMRT and 3D conformal. Instead, we expect PBS to significantly reduce the treatment
planning overhead required to create the numerous fields (12 for this case) required to
achieve superior DS dose distributions in patient.

Figure 18.9 An example of a double-scattered field delivery to the clinical target volume (CTV) (green). Each of
the five fields achieves full target coverage (>98% isodose line—not shown). Note how each field arrangement
(one of which is shown on the left) spares the contralateral parotid. The full complement of five fields reduces
the parotid dose to about 20% of 50 Gy (RBE) as only one field passes through each parotid. Note that the

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fixed modulation of the DS SOBP cannot control the entrance dose (as visible in the left figure where the 95%
isodose line crosses the parotid). The composite dose distribution (in Gy [RBE]) is on the right. The maximum
dose to the CTV is 51 Gy (RBE) and indicates the high degree of homogeneity achievable with SOBP fields.

Figure 18.10 The dose–volume histograms for the parotid glands and brainstem show significant reduction in
dose. This is primarily a consequence of the fact that pencil-beam scanning (PBS) fields reduce the proximal
dose that cannot be controlled in a scattered field. The spinal cord does not show an overall reduction for the
PBS approach as the field approaches deliberately, per convention and per need to avoid the parotids, pass
through it.

KEY POINTS
• A monoenergetic pristine narrow proton beam is modified by a double or single scattering
system to produce a lateral flat field (within a desired diameter) and is modified by a set of
range-shifters (either a set of individual shifters or mechanically constructed as a single
device) to produce a depth-modulated spread-out Bragg peak (SOBP) such that the
composite pristine peaks in the SOBP produce a flat depth-dose profile over a depth interval
(labeled modulation width) up to the deepest pristine peak penetration.
• The SOBP field, either produced in a scattering system or by uniform scanning, is
characterized by an unbounded (within a maximum diameter) flat field and by a constant
radiologic depth penetration set by the maximum energy of the SOBP pristine peak. The flat
field needs to be tailored to the BEV projection of the target by an aperture. The constant
depth penetration needs to be modulated by a variable thickness range-shifter or range-
compensator such that the penetration depth can be adjusted across the field to minimize
penetration distal to the target volume.
• Apertures in SOBP fields are characterized by a sharp penumbra due to the large SAD and

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close placement of the aperture to the patient. This geometry affects a source size penumbra
on the order of 10. Pencil-beam scanning of narrow proton beams without an aperture may
still have a large penumbra in comparison to the SOBP penumbra. Thus, the use of an
aperture in a pencil-beam scanning field will yield a 10-fold reduction in source penumbra.
• The PTV concept in photon radiotherapy is valid because geometric perturbations in the
patient have a negligible effect on the physical dose distribution. Thus, geometric alignment
corresponds to dosimetric alignment. Proton fields, however, are very sensitive to geometric
perturbations and the dose distributions can become a strong function of the geometric
perturbation. Thus, a simple geometric expansion of the CTV will not suffice to a priori
account for the dosimetric effect of these perturbations.
• The number of optimization variables, the individual pencil-beam intensities, in pencil-
beam scanning fields is very large and on the order of 1,000 to 5,000. One can therefore
expect that given multiple clinical competing objectives, multiple plans should be considered
to evaluate the best trade-off. Multicriteria optimization aims to provide a model where,
instead of producing a single “optimal” plan, many optimal plans can be considered, each of
which is optimal given an actual choice of objective values.
• Uncertainties in proton treatment plans include geometric setup errors, anatomical changes,
and physical uncertainties in the stopping power determination in the patient and thus in the
range penetration into the patient. Such uncertainties affect the dose distribution directly and
cannot be mitigated by geometric solutions such as the PTV concept. Instead, uncertainties
need to be considered in the treatment planning dosimetry directly to establish that, given the
uncertainty extents, dose constraints remain clinically acceptable.

QUESTIONS
1. A Pareto-optimal plan defines a set of objective and their values. If an objective
value improves,
A. all other objective values worsen
B. some improve, some worsen
C. some worsen, some remain the same
D. some worsen, some reach a limit
2. Compared to an SOBP treatment plan, a PBS plan will always show (indicate all
that are correct):
A. Improved proximal dose reduction
B. Better distal penumbra
C. Worse distal penumbra
D. Better lateral penumbra
3. Why do proton plans significantly reduce integral dose?
A. Proton treatments use less fields
B. Protons deposit no dose beyond the distal edge
C. The proton Bragg peak deposits much more dose in the target compared to
the rest of the tissues

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ANSWERS
1. A Every Pareto-optimal plan is a “point” on the Pareto surface whose
dimensionality is determined from the plan objectives and where each
point is a set of optimal objective values. Any change that improves one
objective worsens all other objectives.
2. A An SOBP field has a fixed modulation and therefore cannot control the
dose proximal to the target (C), the SOBP field has a range-compensator
that ensures that every proton “stops” at the distal surface and thus the
distal penumbra is the distal penumbra from the pristine peak (which is at
least two times sharper than the lateral penumbra). A PBS field whose
spots are rather random with respect to the distal surface does not expose
the pristine distal fall-off.
3. B Protons deposit no dose beyond the distal edge. This (almost) reduces the
integral dose by a factor of two.

REFERENCES
1. Goitein M, Abrams M, Rowell D, et al. Multi-dimensional treatment planning: II.
Beam’s eye-view, back projection, and projection through CT sections. Int J Radiat
Oncol Biol Phys. 1983;9:789–797.
2. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–491.
3. Richard W. A Brief History of the Harvard University Cyclotrons. Cambridge: Harvard
University Press; 2004. Available from http://physics.harvard.edu/
∼wilson/cyclotron/history.html.
4. Prescribing, recording, and reporting proton-beam therapy: contents. J ICRU.
2007;7(2):NP.
5. Lomax A. Intensity modulation methods for proton radiotherapy. Phys Med Biol.
1999;44:185–205.
6. Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment
uncertainties 2: the potential effects of inter-fraction and inter-field motions. Phys
Med Biol. 2008;53:1043–1056.
7. Monz M, Küfer KH, Bortfeld TR, et al. Pareto navigation—algorithmic foundation of
interactive multi-criteria IMRT planning. Phys Med Biol. 2008;53:985–998.

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19 Role of Protons Versus Photons in
Modern Radiotherapy: Clinical
Perspective

Darwin Yip, Yi Wang, and Thomas F. DeLaney

INTRODUCTION AND OVERVIEW


Radiation therapy remains a cornerstone for the curative treatment of a broad range of
malignancies. It can serve as a less toxic alternative to surgery for local tumor control in
a number of critical anatomic sites where radical surgery is functionally or cosmetically
debilitating (i.e., head and neck, spine), can be combined with surgery +/− systemic
therapy to allow more conservative surgery (i.e., breast, extremity), and may have a
more favorable toxicity profile for some patients than surgery (prostate, early-stage lung
cancer) (1). It is expected to continue to be important for the treatment of cancer for
some years to come, and recent data suggest that it can be combined for therapeutic
gain with both targeted systemic therapies (2) and immunotherapy (3). Hence, optimal
radiation therapy will continue to be an important component of a major cancer
treatment program.
Protons are charged particles with mass that travel a fixed distance in tissue that is
related to the accelerating energy. They have a physical advantage over x-rays (i.e.,
photons) because they deposit the bulk of their energy in a narrow range at the depth
related to the accelerating energy; this nidus of energy deposition is referred to as the
“Bragg peak,” beyond which there is no energy delivered, hence sparing the normal
tissues distal to the Bragg peak of any radiation dose (Fig. 19.1). Protons can deliver
similar or higher radiation doses to the tumor target with up to 50% to 60% less
integral or “total-body” radiation dose compared to the highest technology photon (i.e.,
x-ray technique), namely intensity-modulated radiation therapy (IMRT) (4). The current
generation of proton equipment can also perform intensity modulation, which is
referred to intensity-modulated proton therapy (IMPT) which yields both highly
conformal radiation doses around the tumor with integral radiation doses that are 50%
to 60% lower than photons. Because of the substantially lower total-body radiation
doses, protons are already felt to be optimal for treatment of children with solid tumors
who require radiation therapy. Protons are FDA-approved for treatment of patients in
the United States. Medicare and commercial payers provide coverage for proton
treatment for selected indications, which are not standardized and are evolving.
Randomized phase II or III studies comparing IMRT versus protons are currently in
progress or planned for brain tumors, head and neck, nonsmall cell lung,
hepatocellular, prostate, and breast cancers (clinicaltrials.gov; NRG Oncology;
Massachusetts General Hospital [MGH]/M. D. Anderson U19 Grant; PCORI). There are
14 operating proton centers in the United States with another dozen or so in various
stages of construction and planning (5).
Proton facilities have traditionally entailed a particle accelerator (cyclotron or
synchrotron) and magnetic beam line(s) to steer protons into three to five treatment

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rooms, using either fixed beams or more versatile but expensive rotational gantries. The
cost of these facilities is generally in the range of $125 to $200 million depending on
the size and configuration of the facility. The cost for proton treatment has been
estimated to be ∼2.7 to 3.2 times more than IMRT, much of it related to the upfront
capital expenditure, which could be ameliorated by charitable contributions toward the
construction of the facility, since the treatment costs otherwise (i.e., physician
consultation, CT simulation, treatment planning, treatment delivery) are comparable,
although ongoing maintenance is also higher with a proton facility (6,7). Single room
proton facilities have recently opened with lower cost, ∼$30 million per gantry-based
room, which represents a significant cost reduction and also allows a “modular”
concept, namely starting with one room but leaving space for the addition of additional
beam lines and rooms to the accelerator at a later date (8). Even with the more costly
traditional multi-room proton facilities, and certainly for the newer, less-costly single
room facilities, protons have been estimated to be cost-effective for some
diseases/anatomic sites, primarily pediatric, because of the reduction in medical costs
associated with the treatment of late effects related to the larger radiation treatment
volumes associated with radiation therapy with photons (9–11).
Because of ongoing concern about rising medical costs, it is increasingly likely that a
societal acceptable cost benefit for protons be demonstrated if they are to be a viable
technology. A legacy physics research facility at University of Indiana, which was
modified for medical proton therapy and began patient treatments in 2004, was closed
in 2014, in part because of high staff-to-patient ratio and high fixed operating costs.
Although the other operating proton facilities in the United States currently appear to
be financially viable and new lower cost single-room facilities have more favorable
financial projections than the larger centers, cost-effectiveness remains an issue that
will need to be addressed.

Figure 19.1 Proton Bragg peaks of increasing energy and range. (Courtesy of Hanne Kooy, PhD, Massachusetts
General Hospital, Boston, MA.)

Carbon ions are heavier charged particles, with 12 times the mass of a proton.
Physically, their greater mass and charge produce a denser track of ionization and,
biologically, more double-stranded DNA breaks. They have a higher relative biologic
effect (RBE) that is estimated to be ∼2.5 times greater than that of protons, which,
however, changes over the course of the carbon particle track and requires very
sophisticated modeling for patient treatment (12). Carbon ions do have a sharper lateral
penumbra than protons, particularly at deeper ranges, although they also produce some
spallation products distal to the Bragg peak that give some unwanted dose distal to the

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target. Interesting data from Japan and Germany suggest some encouraging results for
sacral chordomas, pelvic recurrences of rectal cancer, peripheral nonsmall cell lung
cancer (NSCLC), and cancer of the pancreas (12). Because the radiation dose schedules
for carbon ions have tended to be hypofractionated and not strictly comparable to those
generally used with protons, it is not clear in the absence of randomized comparative
studies whether the clinical results to date represent a clinical advantage over protons,
and, if so, is it related to simply higher doses, the alternative fractionation schedules
tested for carbon ions, or reflective of the higher RBE for carbon ions. Higher RBE by
itself is not an advantage, proven by the use of neutrons which had a higher RBE but
poor physical dose distribution and resulted in much greater normal tissue side effects
than x-rays (13); that is, the higher RBE has to be confined to the tumor volume because
higher RBE particles releasing energy in normal tissue may result in normal tissue
injury.
There are randomized studies comparing carbon ions with protons underway in
Heidelberg, Germany, looking at skull base chordomas and chondrosarcomas, as well as
sacral chordomas, and glioblastomas (clinical trial information available at
clinicaltrials.gov). Skull base chondrosarcomas have ∼95% local tumor control at
10 years with protons (14); so from a clinical trial perspective carbon ions cannot
realistically be shown to be superior to that, although it is theoretically possible that
carbon ions cause less toxicity than protons related to the sharper penumbra. The
randomized studies of skull base chordoma and sacral chordoma may yield the most
enlightening data, although the fractionation scheme chosen for sacral chordomas, 4
GyRBE × 16 = 64 GyRBE, has been used with carbon ions without much experience
with that schedule for protons; so if there is a difference between the arms of the sacral
chordoma study, it will not be clear whether the optimal radiation fractionation scheme
was used in the proton arm. In the glioblastoma study, patients receive 50 Gy with x-
rays in each arm to the tumor with several centimeter margin followed by a boost of 10
GyRBE/5 fractions of 2 GyRBE with protons versus 18 GyRBE/6 fractions of 3 GyRBE
with carbon ions. In our opinion, the glioblastoma study presents a design problem; if
the carbon arm is superior, it will not be clear if this is related to a difference in total
dose or to the use of carbon ions, although any improvement in the outcome for patients
with glioblastoma will of course always be welcome.
Some facility designs allow delivery of both protons and carbon ions, but these are
more costly than a proton facility (see below). There are also other charged particles
which are intermediate in weight and charge between protons and carbon ions (i.e.,
helium, neon, lithium), which may have some advantages over either protons or
carbons. While these have not been studied extensively to date, these have been
discussed in the charged particle literature as possible candidates for future
consideration for clinical trials (15). The design of some charged particle facilities may
allow the future use of variable charged particles, although the additional cost would
need to be weighed against what is currently an uncertain future utility.
The cost of a combined carbon–proton facility was estimated in 2010 as €138 million
compared to €94.9 million a proton-only facility and €23.4 million for a photon (i.e., x-
ray)-only facility (7). The estimated cost ratio for the combined-particle facility
compared to photons was 4.8 and for the proton-only facility compared to photons was
3.2. These cost ratios depend upon how these facilities are configured, including
whether they have gantries. Gantries, which rotate around the tumor and allow
treatment from multiple angles to optimally deliver dose to the tumor and avoid normal
tissue, are standard for photons (x-rays) and comprise the majority of treatment rooms
in proton centers. Most carbon ion facilities have only fixed beam lines, generally from

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superior, lateral, and/or 45-degree directions, because of the weight of a carbon ion
gantry. The carbon ion gantry in Heidelberg is 670 tons, compared to ∼120 to 200 tons
for a proton gantry. One other carbon facility in Japan is currently developing a gantry,
with a plan for a compact superconducting design that is projected to weigh less than
300 tons.
Carbon ion therapy is not currently FDA-approved in the United States, so it is
currently considered an investigational therapy. The NCI has awarded two recent
carbon-ion facility planning grants with the thought that it would be of scientific
interest to have a carbon or other heavy charged particle facility in the United States for
comparative studies with protons, but there are currently no operating carbon or other
heavy charged ion facilities in the United States.

HISTORY OF PROTON BEAM THERAPY


Dr. Robert Wilson first proposed the clinical use of proton beam, as well as heavier
charged particle therapy for treatment of cancer (16). His proposal was based on the
characteristic Bragg peak of the proton and heavier charged particles, whereby the
majority of a particle’s energy is deposited in the final few millimeters of the proton’s
track in tissue at a depth proportional to its energy. This would eliminate “exit” dose
beyond the tumor target, resulting in a marked reduction in integral dose of up to
∼60% compared to photons. This reduction in normal tissue dose could reduce the
possible side effects of radiation and offered the possibility of better concentrating the
radiation dose in the tumor, and hence the possibility of increasing the radiation dose to
the tumor and improving local tumor control. Dr. J. Lawrence and associates at
Lawrence Berkeley Laboratory launched a phase I trial in 1954 of proton irradiation of
the pituitary gland to suppress hormone productions in breast cancer patients (17).
Radiation doses of 140 to 300 Gy were administered in three fractions over
approximately 2 weeks using a crossfire technique in which multiple small 340-MeV
proton beams intersected at the pituitary. Interestingly, because of the high proton
energy, the treatments in fact used the plateau region of the beam rather than the Bragg
peak and the beams exited the skull. Some of the treated patients had good responses to
treatment.
Proton beam therapy (PBT) began in Europe in 1957 in Uppsala (18). The MGH
Neurosurgical Department and the Harvard Cyclotron Laboratory (HCL) developed a
clinical program in 1961 using, primarily, single fraction treatments to treat pituitary
adenomas (19) and arteriovenous malformations (20). The Bragg peaks of multiple
narrow beams were targeted at the tumor. Herman Suit and Michael Goitein started a
program of fractionated proton treatment of cancer patients in 1974 designed to test
the hypothesis that protons would allow dose escalation to improve local tumor control
with acceptable clinical toxicity in clinical sites where (1) local control (LC) was poor
with photons and (2) dose could be escalated with protons in a facility with that was
limited by a fixed, horizontal beam of limited energy (160 MeV). They were successful
for treatment of uveal melanomas in the eye (21), skull base chondrosarcomas and
chordomas (22), and prostate cancer (23). From a technical perspective, the facility
pioneered many of the treatment techniques that serve as the foundation for passively
scattered proton therapy.
Their results were confirmed at other centers in Europe (Orsay in France (24), PSI in
Switzerland (25)). These encouraging clinical results provided the impetus for the
development of hospital-based facilities. The first hospital-based proton therapy center
was opened at Loma Linda University Medical Center in 1990 (26). This facility utilized

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a synchrotron from which protons were magnetically steered to three gantry-based
rooms and a single fixed beam room. Additional hospital-based facilities opened in the
United States at MGH (2001), Indiana (2004), University of Florida (2006), and
Houston (2006); as of April, 2015, there were 14 centers operating in the United States
(http://www.ptcog.ch/index.php/facilities-in-operation).

DEVELOPMENT OF PROTON THERAPY TECHNIQUES


The stepped rotating absorber to generate a spread-out Bragg peak (SOBP) that was
broad enough to treat a human tumor was first proposed by Wilson (16). Koehler and
Schneider from the HCL described variable thickness rotating propellers that readily
achieved the planned distributions of proton energies that resulted in the desired SOBP
(27). They then developed a method for double scattering that achieved a relatively flat
lateral dose distribution (28), further refined by Gottschalk and Wagner by the
utilization of contoured bi-material filters (29). Techniques for distal edge compensation
(32) were also developed at the MGH and the HCL (30–32). These latter beam
modification systems and techniques or variants thereof are still widely used in broad
beam energy-modulated proton beam therapy. Larsson at Uppsala developed a
technique of ridge filters to generate the required SOBPs (33). He was the first to
employ magnetic beam scanning for broad-beam SOBP on the 187-MeV proton beam
(33). Kanai et al. developed beam scanning for use in the proton beam line in Chiba,
Japan (34).
Verhey et al. quite early developed methods of dosimetry (35) and accurate patient
positioning (36) at the HCL. Goitein made a series of major conceptual and practical
contributions to proton therapy that are equally applicable to photon therapy. These
include the first 3D treatment planning systems (37), DVHs (dose–volume histograms)
(38), DRRs (digitally reconstructed radiographs) (30), and the display of uncertainty
bands around isodose contours (30,39–41).
Even early in the history of PBT, it was recognized that the proton charge would also
enable magnetic scanning of narrow proton pencil beams through the target. The first
case of proton pencil beam scanning was reported from Chiba in Japan (34). The
scanning was achieved with a 70-MeV proton beam, too low in energy to be attractive
for clinical application and the system was not used in patient treatments. Clinical beam
scanning, however, was employed in the pion program in Switzerland between 1981
and 1992 (42) and led to its adoption for the proton therapy program at the Paul
Scherer Institute. Magnetic beam scanning permitted the development of IMPT, which
has emerged as the preferred technique for PBT in many anatomic sites (43).

Protons versus 2D Photons


It must be recognized that protons developed initially in the 2D radiation treatment
planning era; in fact, 3D treatment planning was developed by Michael Goitein to
facilitate clinical proton radiation therapy (39). Protons could successfully deliver
higher radiation doses with lower integral dose than was achievable with 2D or 3D
photons, explaining, in part why the majority of clinical studies that were initially
conducted were nonrandomized phase I and then phase II studies of protons, because
one could not deliver the same radiation dose(s) with 2D or 3D photons that were
achievable with protons.
Indeed, in the phase III study of protons versus photons for prostate cancer at the
Harvard Cyclotron, patients received 50.4 Gy using conventional 2D photons via a four-

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field box beam arrangement to a CTV that included the prostate, seminal vesicles, and
pelvic nodes, with one half randomized to receive a boost to 67.2 Gy using conventional
photons through lateral portals and the other half to a total dose of 77.2 GyRBE using
perineal protons (23). This study was really asking whether the higher proton radiation
dose of 77.2 GyRBE (established as safer in an earlier phase I dose escalation study)
improved patient outcome; it was judged not clinically feasible to deliver this radiation
dose with conventional photons. A similar dose question was asked in a second
randomized study conducted by MGH and Loma Linda investigators for earlier stage
prostate cancer diagnosed in the PSA era (44).

PROTON THERAPY IN THE AGE OF IMRT AND ADVANCED


TECHNOLOGY PHOTON THERAPY
It was only after the development of IMRT which permitted dose escalation with
photons that we were really able to frame the current question about the role of protons
versus photons in modern radiotherapy. IMRT may achieve similar target doses as
protons, and may in fact be more conformal than 3D passively scattered protons in the
high-dose region but will almost always have higher integral doses (45). IMPT should
theoretically be as conformal as IMRT in the high-dose region (46) but current studies
are looking to ensure that IMPT is “robust” so that the planned dose distribution is
actually realized in the patient (47). Hence, the relevant questions currently revolve
around (1) whether the lower integral dose which can be achieved in most patients with
protons compared to IMRT and other advanced technology photon techniques (i.e.,
image-guided stereotactic radiation) results in measurably lower acute or late toxicity,
and if so, which patients derive the most benefit and (2) whether the higher cost of
protons (based on the fact that protons are 1,800 times heavier than the electrons used
for photon generation, resulting in higher costs for acceleration and steering) can be
justified in terms of higher LC or survival or less toxicity within a societally acceptable
cost-effectiveness framework.
From first principles, it would follow that the largest benefit for protons will be in the
youngest patients (who will be at risk for the late effects of radiation for the longest
period of time) with potentially curative (either localized or oligometastatic) tumors
who require treatment to large target volumes (where a larger volume of normal tissue
would be spared exit dose) or to a large proportion of a critical organ (i.e., eye, liver)
and need high doses of radiation. Some additional clinical scenarios such as re-
irradiation and large target volumes where critical organs can be injured with
irradiation such as lymphomas and breast cancers near the heart may also benefit from
protons (48).
Patients with benign tumors, because of the greater likelihood of their long-term
survival, may also derive benefit from PBT. Winkfield et al. evaluated eight different
radiation techniques for treatment of pituitary adenoma and found that PBT achieves
the best therapeutic ratio when evaluating treatment plans (49). Limiting the irradiated
volume of normal brain was desirable to minimize excess risk of radiation-associated
second tumors (49).
Systems for allocating patients for treatment with protons have been developed based
on ethical principles for allocation of scarce resources, perceived benefit based on the
best available evidence and expert opinion, patient age, and eligibility for research
protocols (50,51). In spite of a PBT allocation system based on these principles, the
practical reality of proton treatment assignment was also related to whether a patient’s
insurance would cover the costs of proton treatment (51).

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Because the lower integral dose associated with protons is judged to offer the largest
potential benefit in pediatric patients, a substantially higher proportion of these
patients currently receive protons than adult patients. In 2012, it was estimated that
∼10% of pediatric cancer patients in the United States were treated with proton
radiation therapy (52). This contrasts with the use of protons in the adult patient
population, where ∼0.85% of adult patients are treated with protons. Between 2010
and 2012, there was a steady increase in the number of pediatric patients receiving
protons in the United States. In 2010, 465 pediatric patients were treated with proton
radiation; 613 patients in 2011, and 694 patients in 2012. This represents an increase
from ∼10% of the total number of proton treatments in the United States in 2010 to
12% in 2011 and 13% in 2013. There are currently over 5,000 patients per year in the
United States receiving protons, although this remains <1% of the patients undergoing
radiation therapy each year in the United States.

Acute Toxicity
There are data documenting a reduction in acute toxicity in patients undergoing
protons compared to photons. These include a study by Brown et al. demonstrating less
acute gastrointestinal and hematologic toxicity in adult patients undergoing
craniospinal irradiation (CSI) with protons compared to photons (53). Because CSI is
such a large target volume, it is a patient population where one would a priori expect
an advantage for protons; that is, the larger the target, the larger the volume beyond
the target that would be spared with protons (Fig. 19.2). Proton CSI patients lost less
weight than photon patients (1.2% vs. 5.8%; p = 0.004), fewer proton patients had
>5% weight loss compared with photons (16% vs. 64%; p = 0.004). Proton patients
experienced less grade 2 nausea and vomiting (26% vs. 71%; p = 0.004) as well as a
smaller reduction in peripheral white blood cells, hemoglobin, and platelets (white
blood cells 46% vs. 55%, p = 0.04; hemoglobin 88% vs. 97%, p = 0.009; platelets 48%
vs. 65%, p = 0.05). Patients treated with photons were more likely to require medical
management of esophagitis (57% vs. 5%, p < 0.001).

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Figure 19.2 Craniospinal irradiation with protons, illustrating sparing of tissues anterior to the vertebral bodies
including heart, mediastinum, thyroid, and lungs. (Courtesy of Judy Adams, CMD, Massachusetts General
Hospital, Boston, MA.)

Potential Late Toxicity


The MGH and M. D. Anderson Cancer Center conducted a joint phase II trial of
passively scattered PBT for treatment of pediatric rhabdomyosarcoma. Between 2005
and 2012, 54 patients were enrolled and treated with proton therapy. As part of the
study, IMRT plans for comparison were also generated for each patient (54). The
median number of beams for IMRT plans were 7 versus 3 for proton therapy. The mean
integral dose was 1.8 times higher for IMRT (range 1.0 to 4.9) in comparison to proton
therapy. By site, the mean integral dose was 1.8 times higher for head/neck and
genitourinary (p < 0.01), 2.0 times higher for trunk/extremity (p < 0.01), and 3.5
times higher for orbit (p < 0.01) in comparison to proton therapy. The authors argued
the reduction of dose in the low-to-medium dose region could result in a clinically
important difference in late effects. Specifically, they cited the reduction of dose to
hypothalamus in the patients treated for head and neck rhabdomyosarcoma, since
Merchant et al. (55) have reported that growth hormone deficiency is seen in 50% of
patients receiving 16 Gy and 99% receiving 35 Gy to the hypothalamus. Ladra et al.
observed dose above 16 Gy to the hypothalamus in 15% of proton therapy plans versus
30% of the IMRT plans (54).

Secondary Malignancy
Lower integral dose with protons could also reduce the risk of radiation-associated
secondary malignancies. Chung et al. compared 558 patients treated with proton
radiation from 1973 to 2001 at the Harvard Cyclotron in Cambridge, MA, with 558
matched patients in the SEER registry who were treated with photons (56). The median

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follow-up was 6.7 and 6.0 years, respectively, in the proton and photon cohorts.
Median age at treatment was 59 years for both cohorts. They observed 6.9 cancers per
1,000 person-years for the proton patients, and 10.3 cancers per 1,000 person-years for
the photon patients. There was no significant difference in proportion of second
malignancies within the primary field of radiation between the proton patients (10%)
and photon patients (16.7%). The authors suggest that the fewer observed cancers with
protons may be due to reduction of second cancers outside of primary radiation field,
possibly due to less integral dose from proton radiation.
Modeling studies suggest a significant reduction in the risk of second malignancies
with protons compared to photons (57–59). Proton beams reduced the expected
incidence of radiation-induced secondary cancers for a pediatric patient with an orbital
rhabdomyosarcoma by a factor of ≥2 and for a medulloblastoma patient undergoing
CSI by a factor of 8 to 15 when compared with either intensity-modulated or
conventional x-ray plans (57). Notably, protons provided more risk reduction for larger
radiation target volumes than smaller ones.
Nevertheless, secondary malignancies are relatively uncommon with modern
radiotherapy. An analysis of SEER data by Berrington de Gonzalez et al. estimated that
five excess cancers per 1,000 patients could be attributed to radiotherapy 15 years after
diagnosis, that is, 0.5% risk at 15 years (60). Therefore, a very large number of patients
would be required to show a difference in the rate of secondary malignancies after
proton versus photon radiation therapy. Assuming an 80% power to detect a target of
60% reduction in radiation-associated second malignancies with a significance level of
0.05, Dr. Beow Yeap (Harvard Medical School, personal communication) estimated that
13,509, 6,759, or 4,510 patients would be needed in each arm if there were 5, 10, or
15 years average follow-up available in the studied patients using one-sided statistics
(with the assumption that protons could only lower the risk of radiation-associated
malignancy); if a two-sided test were used (with the assumption that protons could
either decrease or increase the risk), those numbers would increase to 17,280, 8,646,
and 5,768 patients. These numbers are prohibitively large for any randomized clinical
trial looking to use protons to reduce the risk of radiation-associated second
malignancy, although this question might be amenable to a registry or database
assessment.
However, selected patient populations are known to carry a higher risk of a second
malignancy. Kuttesch et al. estimated the cumulative risk of a second malignancy in
young patients treated for Ewing sarcoma as 9.2% at 20 years (61). In this patient
population, Dr. Yeap (Harvard Medical School, personal communication) estimated that
only 1,264, 638, and 430 patients (with 5, 10, or 15 years average follow-up) would be
needed in the proton and in the photon cohort to have an 80% power to detect a 60%
reduction in second malignancy risk with a p-value of 0.05. Dr. Torunn Yock is leading
an ongoing multi-institutional Pediatric Proton Consortium Registry (62). The goal of
the registry is to determine the acute and late effects in the children enrolled at the
participating proton facilities. It is hoped that the collected data, when compared to
photon-treated patients, will help clarify whether protons can contribute to second
malignancy reduction in a high-risk patient population.

Cost-Effectiveness
Mailhot Vega et al. performed a cost-effectiveness analysis from a societal perspective
using a Monte Carlo simulation model, based on a population of 18-year-old patients
treated at age 5 for a medulloblastoma and who were at risk for developing 10 possible

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adverse events including growth hormone deficiency, coronary artery disease,
ototoxicity, secondary cancers, and death (63). Costing data included the cost of
investment and the costs of diagnosis and management of adverse health states from
institutional and Medicare data. Longitudinal outcomes data and recent modeling
studies informed risk parameters for the model. Incremental cost-effectiveness ratios
were used to measure outcomes. Results from the base case demonstrated that proton
therapy was associated with higher quality-adjusted life years and lower costs;
therefore, it dominated photon therapy. In one-way sensitivity analyses, proton therapy
remained the more attractive strategy, either dominating photon therapy or having a
very low cost per quality-adjust life year gained. Probabilistic sensitivity analysis
illustrated the domination of proton therapy over photon therapy in 96.4% of
simulations, demonstrating that proton therapy is a cost-effective strategy for the
management of pediatric patients with medulloblastoma compared with standard of
care photon therapy.
Cost-effectiveness seems reasonably assured in the pediatric population. In the adult
patient population, however, cost-effectiveness determinations are still emerging,
hampered in part by the lack of comparative clinical outcome data. However, it is
expected that the results will depend on the particular cancer, the anatomic site, the
size of the target volume, and the available alternatives. In a systematic review of the
cost-effectiveness of radiation therapy for prostate cancer, PBT was not judged to be
cost-effective (64). On the other hand, Lundqvist et al. found that proton therapy for
breast cancer could be cost-effective if appropriate risk groups, such as those with left-
sided breast cancer at risk for cardiac disease, are chosen as candidates for the therapy
(9).
For countries without their own facilities for proton therapy, the cost of referral
abroad for their patients can be substantial. For example, the Alberta Health Service
estimated that Canada sent 96 patients abroad at a mean cost of $200,000 per patient
in 2013. In addition to the specific diagnosis, the Alberta guideline also requires
patients to be treated with curative intent, to have good performance status, and life
expectancy >5 years (65). While the upfront cost of building a proton facility may be
relatively high, there may be long-term economic benefit by investing in such facilities.
Worldwide, there are 56 particle therapy centers in operation as of the beginning of
2015, of which 48 are PBT centers, and eight offer carbon ion therapy (5).
Proton radiation therapy, especially with more advanced techniques such as IMPT
and in vivo dosimetry, can offer superior dose distribution versus photon radiation.
However, the substantial difference in cost between proton therapy and photon therapy,
and the lack of direct comparison of clinical outcome, prevent more widespread
adaption of proton therapy. With more clinical evidence, and continued reduction in
cost, proton therapy is likely to play an increasingly important role in radiation
therapy.
This discussion, of course, also raises the question of whether the cost of proton
therapy can be reduced, as this would improve its cost-effectiveness. Indeed, Newhauser
et al. were able to document cost reduction for proton treatment of prostate cancer with
passively scattered protons by using a multi-leaf collimator instead of custom-fabricated
apertures as well as modest hypofractionation strategies (66). Hong et al. were able to
deliver a well-tolerated five-fraction hypofractionated course of preoperative proton
chemoradiation of 5 GyRBE/fraction concurrent with capecitabine in a week (67); the
radiation therapy charges for this regimen were lower than those for a standard 28-
fraction, 5.5-week course of 3D conformal or IMRT photon course of radiation (T. Hong
MD, personal communication). The initial, hospital-based proton centers generally

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included a proton accelerator and multiple treatment rooms, generally with multiple
gantries (26). More recently, smaller single-room facilities have been developed with
markedly reduced initial capital costs and lower estimated cost per patient (8). These
efforts to reduce the costs of proton therapy will improve its cost-effectiveness and make
it cost-effective for a broader group of adult patients.

Requirements for the Radiation Oncologist and Radiation Physicist


The American College of Radiology (ACR) and ASTRO have published a Practice
Parameter for the Performance of Proton Beam Radiation Therapy (68). The guideline
calls for specific training in proton therapy for the physician prior to performing any
such treatments. Specifically, the radiation oncologist must understand the spatial
distribution of the proton beam, with particular attention given to sharp dose fall-off at
the distal and lateral edges, which can lead to underdosing of target, or overdosing of
critical structures.
Details regarding the qualifications and responsibilities of the qualified medical
physicist for proton therapy are enumerated in the ACR–American Association of
Physicists in Medicine (AAPM) Technical Standard for the Performance of Proton Beam
Radiation Therapy (69). Notably, the qualified medical physicist must have proton-
specific training before assuming responsibility for the technical aspects of patient care
for patients receiving proton therapy.

ASTRO Recommendations Regarding Proton Beam Therapy


There is currently no uniform consensus on whom should be treated with PBT. ASTRO
considers protons reasonable in instances where sparing the surrounding normal tissue
cannot be adequately achieved with photon-based radiotherapy and are of adequate
clinical benefit to the patient (70). Examples of such advantages might be (1) when the
target volume is in close proximity to one or more critical structures and a steep dose
gradient outside the target must be achieved to avoid exceeding the tolerance dose to
the critical structure(s); (2) a decrease in the amount of dose inhomogeneity in a large
treatment volume is required to avoid an excessive dose “hotspot” within the treated
volume to lessen the risk of excessive early or late normal tissue toxicity; (3) a photon-
based technique would increase the probability of clinically meaningful normal tissue
toxicity by exceeding an integral dose-based metric associated with toxicity; or (4) the
same or an immediately adjacent area has been previously irradiated, and the dose
distribution within the patient must be sculpted to avoid exceeding the cumulative
tolerance dose of nearby normal tissue. ASTRO indicated that the final determination of
the appropriateness and medical necessity for PBT resides with the treating radiation
oncologist who should document the justification for PBT for each patient.
Based on these considerations and published data, ASTRO noted that disease sites
that frequently support the use of PBT include for ocular tumors including intraocular
melanomas, skull base tumors including chordoma and chondrosarcomas, primary or
metastatic tumors in the spine where spinal cord tolerance may be exceeded with
photons or where the spinal cord has previously been irradiated, hepatocellular
carcinoma treated in a hypofractionated regimen, primary or benign solid tumors in
children treated with curative intent as well as occasional palliative treatment of
childhood tumors where at least one of the four considerations noted above apply. In
addition, proton therapy should be considered for patients with certain genetic
syndromes.

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For other disease sites and patients, ASTRO suggested that there was a need for
continued evidence development and comparative effectiveness analyses for the
appropriate use of PBT for various disease sites. Other anatomic sites would be
considered appropriate for insurance coverage as long as the patient was enrolled in
either an IRB-approved clinical trial or a multi-institutional registry adhering to
Medicare requirements for Coverage with Evidence Development. These latter would
include but not be limited to head and neck, thoracic, abdominal, and pelvic
malignancies, including genitourinary, gynecologic, and gastrointestinal tumors. ASTRO
felt it was essential to develop additional evidence for the use of PBT for prostate
cancer, in particular, its effectiveness compares with IMRT and brachytherapy, calling
for the use of PBT for prostate cancer only within the context of a prospective clinical
trial or registry, with a plan to revise its recommendations as evident from these studies
emerged.
ASTRO also outlined clinical scenarios for which PBT is rarely indicated, including (1)
situations where PBT does not offer an advantage over photon-based therapies that
otherwise deliver good clinical outcome and low toxicity; (2) spinal cord compression,
superior vena cava syndrome, malignant airway obstruction, poorly controlled tumor
hemorrhage, and other urgent scenarios; (3) inability to accommodate tumor or organ
motion; and (4) palliative treatment in a clinical situation where normal tissue tolerance
would not be exceeded in previously irradiated areas.

Highlights of Clinical Results with Proton Beam Therapy


Some salient results achieved with PBT are discussed below. Given the limitations of
space, the reader is referred to a monograph dedicated to this subject (71) or published
reviews (72–80).

Pediatric Tumors
Retinoblastoma. A retrospective review was performed on retinoblastoma patients, 55
of whom were treated with PBT at the MGH and 31 were treated with photon therapy
at Boston Children’s Hospital. With median follow-up of 6.9 years in the proton cohort,
and 13.1 years in the photon cohort, the 10-year in-field secondary malignancy rate
was 0% in the proton group versus 14% in the photon group (p = 0.015) (81).
Ependymoma. Seventeen pediatric patients with ependymoma who were treated with
PBT at Francis H. Burr Proton Center and Harvard Cyclotron had comparative IMRT
plans generated. These demonstrated substantial sparing of normal tissue with proton
beam therapy (82). At a median follow-up of 26 months from the start date of radiation
therapy, LC, progression-free survival, and overall survival rates were 86%, 80%, and
89%, respectively.
Rhabdomyosarcoma. Yock et al. reported seven children who were treated for
orbital rhabdomyosarcoma with proton irradiation and standard chemotherapy (83).
Local and distant disease control compared favorably to those in other published
accounts. Conformal 3D photon and proton radiotherapy plans with dose–volume
histograms were generated for the patients and compared for important orbital and
central nervous system structures. Protons provided a dosimetric advantage in limiting
the dose to the brain, pituitary, hypothalamus, temporal lobes, and ipsilateral and
contralateral orbital structures. Tumor size and location affected the degree of sparing
of normal structures.
Kozak et al. compared tumor and normal tissue dosimetry of PBT with intensity-

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modulated radiation therapy (IMRT) for 10 patients with pediatric parameningeal
rhabdomyosarcomas. Proton and IMRT plans provided acceptable and comparable
target volume coverage but proton therapy resulted in significant sparing of all
examined normal tissues except for ipsilateral cochlea and mastoid; ipsilateral parotid
gland sparing was of borderline statistical significance (p = 0.05) (84).
Ewing Sarcoma. Rhombi et al. reported 30 children with Ewing sarcoma treated with
chemotherapy and PBT to a median dose of 54 GyRBE. The 3-year actuarial rates of
event-free survival, LC, and overall survival were 60%, 86%, and 89%, respectively
(85). PBT was acutely well tolerated, with mostly mild-to-moderate skin reactions. At
the time of the report, the only serious late effects were four hematologic malignancies,
which are known risks of topoisomerase and anthracycline exposure.
Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors.
Jimenez et al. reported on early outcomes for 15 children aged <5 years treated with
induction chemotherapy followed by 3D conformal craniospinal PBT followed by
involved-field PBT or involved-field PBT alone for these tumors (86). At a median of 39
months from completion of radiation, 2 of 15 had died, one after a local failure and one
from a non–disease-related cause, while the remaining 13 patients were alive without
evidence of disease recurrence. Ototoxicity and endocrinopathies were the most
common long-term toxicities, with two children requiring hearing aids and three
requiring exogenous hormones.

Central Nervous System Tumors


Benign. PBT may be especially beneficial for patients with benign CNS tumors because
of the potential for very long survival, and thus, greater period at risk for developing
secondary malignancy. Single fraction proton beam stereotactic radiosurgery for
cerebral arteriovenous malformations has shown 5- and 10-year cumulative incidences
of total obliteration of 70% and 91%, with median time to total obliteration of 31
months (87). Winkfield et al. evaluated eight different radiation techniques for
treatment of pituitary adenoma and found that PBT achieves the best therapeutic ratio
when evaluating treatment plans (49).
Intracranial Meningioma. The Paul Scherrer Institute used scanning-based proton
therapy to treat 39 patients with meningioma, with median GTV size of 21.5 cc. The 5-
year actuarial LC was 84.8% for entire cohort, and 100% for benign histology. With a
mean follow-up of 62 months, the cumulative 5-year grade 3 late toxicity-free survival
was 84.5% (88).
Adult Medulloblastoma Craniospinal Irradiation. M. D. Anderson conducted a
retrospective review of 21 patients treated with photon CSI, and 19 patients treated
with proton CSI. As noted above, PBT patients experienced significantly less acute
weight loss, nausea and vomiting, esophagitis, and cytopenias (53).

Ocular Tumors
Fifty-nine patients were treated with 54 GyRBE or 60 GyRBE in Vancouver with PBT for
ocular melanoma. The treatments were delivered in four fractions on four consecutive
days at TRIUMF cyclotron facility, with the proton beam energy set at 74 MeV. The 5-
year actuarial LC rate was 91% (97% in patients treated with 60 GyRBE). The eye
conservation rate was 80%. At median follow-up of 63 months, there was a 31% rate of
neovascular glaucoma, and 74% rate of retinopathy (89). Princess Margaret Hospital in
Toronto, Canada, treated 64 patients with ocular melanoma with stereotactic photon

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radiation, 70 Gy in five fractions over 10 days. With a relatively shorter 37-month
follow-up period, there were higher rates of neovascular glaucoma (42%) and
retinopathy (81%) reported (90).

Bone and Soft Tissue Sarcomas


Skull base chordoma and chondrosarcoma can be a challenge to manage with
conventional photon radiotherapy, due to the inherent relative radioresistance of the
tumors, as well as the proximity of the tumors to neurologic structures. A retrospective
review of 621 patients with spinal and skull base chordomas or chondrosarcomas
treated at the HCL reported 5-year local relapse-free and overall survival rates of 73%
and 80%, respectively, for chordoma and 98% and 91% for chondrosarcoma (91).
Chordomas have traditionally to be considered very radioresistant, and surgical
resection was considered the only curative treatment. A retrospective review reported
24 patients with spinal chordomas treated with definitive combined proton/photon
radiation to a median total dose of 77.4 GyRBE after biopsy and without surgical
resection. At median follow-up of 56 months, the 5-year overall survival rate was
78.1%, chordoma specific survival rate was 81.5%, local progression-free survival rate
was 79.8%, and metastases-free survival rate was 76.3% (92).
DeLaney et al. reported the long-term results of a prospective phase II clinical trial
incorporating high-dose proton-based RT for patients with primary or locally recurrent
thoracic, lumbar, and/or sacral spine/paraspinal chordomas or sarcomas (93).
Treatment included pre- and/or postoperative photon/proton RT +/− radical
resection. Fifty patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross
total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). Radiation dose was
≤72.0 GyRBE in 25 patients and 76.6 to 77.4 GyRBE in 25 patients. With 7.3-year
median follow-up, the 5- and 8-year actuarial LC rates were 94% and 85% for primary
tumors and 81% and 74% for the entire group. Local recurrence was less common for
primary tumors, 4/36 (11%) versus 7/14 (50%) for recurrent tumors, p = 0.002. The
8-year actuarial risk of grade 3 to 4 late RT morbidity was 13%. No myelopathies were
seen. No late neurologic toxicities were noted with radiation doses ≤72.0 GyRBE while
three sacral neuropathies appeared after doses of 76.6 to 77.4 GyRBE. The authors
concluded that LC with this treatment was high in patients with primary tumors with
acceptable late morbidity (93).
Ciernik et al. reported the results of PBT for unresectable or incompletely resected
osteosarcoma (94). Fifty-five patients were treated to a mean dose of 68.4 GyRBE. LC
rates after 3 and 5 years were 82% and 72%, respectively. The 5-year DFS was 65%,
and the 5-year OS was 67%. Risk factors for local failure were ≥2 grade disease (p <
0.0001) and prolonged treatment time (p = .008). Grade 3 to 4 late toxicity was seen in
30.1% of patients. One patient died from treatment-associated acute lymphocytic
leukemia, and another from secondary carcinoma of the maxilla. The authors concluded
that PBT allows locally curative treatment for some patients with unresectable or
incompletely resected osteosarcoma.

HEAD AND NECK TUMORS


An M. D. Anderson dosimetric study of IMRT versus spot-scanned PBT for five patients
with head and neck cancer showed lower mean dose to oral cavity, brainstem, spinal
cord, and contralateral parotid and submandibular glands using protons. The maximum
doses to the spinal cord and brainstem were also lower with scanned PBT than with

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IMRT (95). The University of Pennsylvania reported a dosimetric study comparing IMRT
versus pencil beam-scanned PBT in a series of eight patients receiving postoperative
radiation therapy for parotid gland carcinoma. The prescription target dose was 60
Gy(RBE). Scanning beam PBT had a lower mean dose to the ipsilateral cochlea and
temporal lobe, as well as the contralateral parotid gland. The maximum brainstem dose
was 22.9 Gy with IMRT versus 1.6 GyRBE with scanning beam PBT (96).
A phase II trial of chemoradiation using PBT for nasopharyngeal carcinoma enrolled
23 patients, stages IIB to IVB (61% T3–4, 75% EBV positive) from 2006 to 2012. With a
median follow-up of 4 years, the investigators reported 92% 4-year locoregional control,
91% overall survival, and 87% distant-metastasis-free (97). A randomized phase II
study of IMRT versus IMPT for chemoradiation of nasopharyngeal cancer has been
proposed (http://grantome.com/grant/NIH/U19-CA021239–35). Figure 19.3 illustrates
oral cavity sparing that can be achieved with IMPT versus IMRT.

Figure 19.3 Comparative plans illustrate oral cavity sparing that can be achieved with IMPT (A) versus IMRT
(B).

A randomized phase II study of IMRT versus IMPT of oropharyngeal cancer


(NCT01893307) is now underway at M. D. Anderson and collaborating centers
(https://clinicaltrials.gov/ct2/show/NCT01893307?
term=oropharynx+and+proton&rank=2).

Lung Cancer
Chang et al. enrolled 44 patients in a phase II study of concurrent weekly carboplatin
and paclitaxel with 74 GyRBE in 37 fractions of passively scattered PBT for treatment
of stage III NSCLC (98). Median overall survival time was 29.4 months and no patient
experienced grade 4 or 5 proton-related adverse events. Nine (20.5%) patients
experienced local disease recurrence, but only 4 (9.1%) had isolated local failure. The
overall survival and progression-free survival rates were 86% and 63% at 1 year. This
led to a phase II study comparing photons versus photon chemoradiation for locally
advanced NSCLC (NCT00915005, https://clinicaltrials.gov/ct2/show/NCT00915005?
term=lung+cancer+and+proton&rank=13), the results of which are pending, and
an ongoing NRG Oncology phase III study (NCT01993810) comparing photons versus
protons in these patients (https://clinicaltrials.gov/ct2/show/NCT01993810?term =
lung+cancer+and+proton&rank=4).

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Esophageal Cancer
Investigators at Tsukuba University evaluated 40 consecutive patients with esophageal
cancer treated with chemotherapy and concurrent passively scattered PBT to a total
dose of 60 GyRBE/30 fractions, with additional 4 to 10 GyRBE boost when residual
tumors were suspected. No cardiopulmonary toxicities of grade 3 or higher were
observed. Recurrences were observed in 16 patients, and the 2-year rates of disease-
specific survival and locoregional control were 77% and 66%, respectively (99). A
randomized Phase III study of protons versus IMRT for esophageal cancer is currently
underway (NCT01512589, https://clinicaltrials.gov/ct2/show/NCT01512589?
term=proton+radiation+esophageal+ cancer&rank=2).

Hepatocellular Carcinoma
High rates of local tumor control with low rates of toxicity have been reported for
hepatocellular carcinoma with PBT by several groups (100–102). The group at Tsukuba
University reported LC rates after 1, 3, and 5 years of 98%, 87%, and 81%, respectively
(100). An ongoing study is currently comparing transarterial chemoembolization versus
proton beam radiotherapy for the treatment of hepatocellular carcinoma
(NCT00857805, https://clinicaltrials.gov/ct2/show/NCT00857805?
term=proton+radiation+hepatocellular&rank=6).

Breast Cancer
The use of hypofractionated regiments in proton therapy may be a potential option to
balance the relatively high cost of proton therapy. Loma Linda University treated 50
patients with 40 GyRBE in 10 fractions over 2 weeks after lumpectomy for early-stage
breast cancer. Actuarial 5-year overall survival and disease-free survival were 96% and
92%, respectively. There was near complete elimination of dose to contralateral breast,
lung and heart, thus, allowing hypofractionation to be done safely. There were no
reported cases of fat necrosis, rib fractures, radiation pneumonitis, or cardiac events
(103).
Long-term risk of cardiovascular events such as congestive heart failure, coronary
artery disease, and myocardial infarction can be increased following postmastectomy
radiation therapy, especially for left-sided breast cancer. The relatively risk of these
events have been estimated to be 1.2 to 3.5 (104). The MGH conducted a phase I trial
on postmastectomy radiation therapy with PBT for 12 patients. Eleven of the patients
had left-sided breast cancer, and one patient had right-sided breast cancer with bilateral
implants. All patients were treated to 50.4 GyRBE to chest wall and regional
lymphatics. Proton therapy allowed excellent coverage of target volume, with D95 of
46.3 GyRBE to combined CTV, while limiting average V20 (GyRBE) of heart to 0.01%,
and mean V20 of lung to 12.7% (105).
The Patient-Centered Outcomes Research Institute has recently funded a study in
which The Radiotherapy Comparative Effectiveness (RADCOMP) Consortium will
conduct a pragmatic randomized clinical trial in which 1,716 patients with stage II and
III breast cancer involving axillary or supraclavicular lymph nodes will be randomized
after surgery to either proton therapy or photon therapy
(http://www.pcori.org/research-results/2015/pragmatic-randomized-trial-proton-vs-
photon-therapy-patients-stage-ii-or-iii).

571
Glioblastoma
The RTOG-NRG is currently conducting a trial of dose escalated IMRT or proton therapy
versus conventional photon radiation with concurrent temozolamide in patients with
newly diagnosed glioblastoma. The higher dose arm will receive 75 Gy CTV2/50Gy
CTV1 via simultaneous integrated, dose-painted technique in 30 fractions by proton or
IMRT, and the conventional arm will receive 60 Gy CTV2/50Gy CTV1. This phase II
study will permit indirect comparison of photon IMRT to proton therapy for overall
survival, neurocognitive function and patient-reported quality of life (106).

Prostate
A study utilizing Medicare data argued that there was no significant difference in
toxicity for treatment of prostate cancer utilizing IMRT versus proton therapy in 2008
and/or 2009, with proton therapy being significantly more costly than IMRT (107).
However, one may argue that there are limitations when extrapolating from
retrospective Medicare data, and that the proton therapy techniques have evolved since
that time. The MGH and the University of Pennsylvania are leading a multi-center phase
III randomized trial, Prostate Advanced Radiation Technologies Investigating Quality of
Life (PARTIQoL), comparing IMRT versus proton therapy for treatment of prostate
cancer (108). The trial plans to enroll 400 patients.

KEY POINTS
• Proton radiation allows a reduction in integral dose compared to photons of up to 60%.
• In the era of 2D and 3D photons, protons were able to deliver higher radiation dose to the
target in clinical studies that included prostate, ocular melanoma, and skull base sarcomas.
• Image-guided IMRT can often deliver comparable target doses to protons, although integral
dose with protons may be up to 60% lower.
• Protons are increasingly the preferred radiation dose for children, where the lower integral
dose is acknowledged to have the highest potential benefit.
• The clinical significance of the lower integral dose of protons compared to IMRT is currently
being tested in adults in multiple randomized controlled clinical trials.
• The original mode of proton delivery, passively scattered protons, is being replaced by spot-
scanned proton treatment, which also allows IMPT. Some new proton facilities only have
spot scanning technology available.
• The clinical use of protons may require the use of adaptive re-planning as well as “robust”
treatment planning to ensure that the planned dose distribution is actually realized in the
patient.
• Carbon ions are charged particles with a mass 12 times heavier than protons with a higher
RBE. They are being compared in randomized clinical trials to see if they offer any clinical
advantage over protons.

572
QUESTIONS
1. What is a potential disadvantage of passively scattered protons compared to
spot-scanned protons?
A. Higher RBE.
B. Lower RBE.
C. Higher scattered neutron dose.
D. Lower scattered neutron dose.
2. The potential clinical advantage for protons compared to photons is:
A. Biologic, related to higher oxygen enhancement ratio with protons
B. Biologic, related to higher LET than carbon ions
C. Physical, related to the photoelectric effect
D. Physical, related to lower integral dose than photons
3. Magnetically spot-scanned proton beams
A. Are being replaced by passively scattered protons in new proton facilities
B. Allow for intensity modulated proton therapy
C. Are available in only one energy
D. Require range modulators to spread out the Bragg peak.
4. The higher RBE of the carbon ion
A. Has been shown to improve clinical outcome
B. May provide a clinical advantage for tumors not well treated by protons
C. Fortunately does not change over the course of the range of the ion
D. Prevents the use of spot scanning with carbon ions.
5. The greatest potential normal tissue sparing with protons compared to photons
A. Is with the largest target volumes
B. Is with the smallest target volumes
C. Is at the highest energies
D. Is at the lowest energies

ANSWERS
1. C
2. D
3. B
4. B
5. A

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20 Fractionation: Radiobiologic Principles
and Clinical Practice

Colin G. Orton

INTRODUCTION
Radiotherapy for the treatment of cancer was first started in 1896 but it was not
realized that fractionation was essential if cancerocidal doses were to be delivered
without exceeding normal tissue tolerance until 1932. It was then that Henri Coutard
published the excellent results he had obtained using fractionated radiotherapy (1) and
fractionation was thereafter established as the standard of practice. However, it took
many decades before the radiobiologic rationales for fractionated radiotherapy were
fully understood.

RADIOBIOLOGIC PRINCIPLES OF FRACTIONATION


The basic principle of radiotherapy is the destruction of all cancer cells without killing
so many normal cells as to exceed tolerance. Thus, cell survival and the shape of cell-
survival curves is of utmost importance in radiotherapy.

Cell-Survival Curves
A plot of the fraction of surviving cells as a function of dose for acutely irradiated cells
is shown in Figure 20.1. Note that surviving fraction is plotted on a log scale. This is
partly because, as we will see later, the shape of the log-linear survival curve for specific
cell types tells us something about the important radiobiologic properties of these cells,
and partly because much of the important information about cell survival is contained
within the low- and high-dose extremes of the survival curve (regions A and B in
Fig. 20.1). Plotting cell survival on a log scale helps us visualize and study the shape of
the survival curve in these regions. It is low doses per fraction (in region A) that are
commonly used for fractionated radiotherapy (1 to 3 Gy/fraction) and, to cure a tumor
with typically 108 to 1010 cells, cell-surviving fractions as low as 10−8 to 10−12 are
required (region B).
Since the shapes of cell-survival curves are so important, it is necessary to have a
mathematical model that can predict these shapes. Currently, the model of choice is the
linear quadratic (LQ) theory of cell survival.

Linear Quadratic Theory


The basis of the LQ theory is that a cell is inactivated only when both strands of a
deoxyribonucleic acid (DNA) molecule are damaged in close proximity. Actually, this is
a gross oversimplification of the highly complex chemical and biologic responses
triggered by irradiation of cells, but this was the basic assumption made when the LQ
model was first devised (2) so, for simplicity, we will adopt this approach here. Readers
interested in a more thorough (and accurate) discussion of the complex events that

580
occur when cells are irradiated are referred to an excellent review by Wouters and Begg
(3).
On this simple model, double-strand breaks in close proximity can be produced either
during the passage across the cell of a single ionizing particle or by independent
interactions by two separate ionizing particles. Such events are random and, because
there are large numbers of cells, the probability that any specific DNA molecule will be
damaged will be extremely low. Under such conditions, the statistics of rare events
(Poisson statistics) prevails. According to Poisson statistics, the probability, P0, of there
being no such events, is given by the expression (4):

where p is the mean number of hits per target molecule. For single-particle events, p is a
linear function of dose, D, so the mean number of lethal events per DNA molecule can be
expressed as αD and P0 represents the probability of there being no single-particle–
induced lethal events, that is, it is the surviving fraction of cells, S. Then, Equation 20.1
can be written as:

where α is the average probability per unit dose that such a single-particle event will
occur. In order for a single particle to damage both arms of the DNA in its passage
across the molecule, it has to be fairly densely ionizing, that is, high linear energy
transfer (LET). With photon and electron irradiation, it is only the slow electrons that
are responsible for most of these interactions. Conversely, when cells are irradiated with
high-LET radiations, such as α-particles and heavy ions, almost all the events will be by
single particles, so cell survival will be governed by Equation 20.2 and cell survival will
be an exponential function of dose so that survival curves plotted on log-linear scales
will be practically linear.
For the two separate ionizing particle events of the LQ theory, the mean probability of
one particle causing damage in one arm of a DNA molecule in any specific cell is
linearly proportional to dose, as also is the mean probability that a second particle will
have such an interaction in the adjacent arm of this same DNA molecule. Therefore,
unless the damage to the first arm of the DNA is repaired before the damage to the
second arm occurs (see section on Repair later), the mean probability of both arms being
damaged at any one time is βD 2, so the probability that no such two-particle events will
occur, that is, the surviving fraction S, is given by:

Figure 20.1 Graph showing the surviving fraction of cells (log scale) as a function of dose. The two shaded areas

581
represent the regions of most interest in fractionated radiotherapy for which doses per fraction normally range
from 1 to 3 Gy (region A) and the cell-surviving fraction required to control a typical tumor containing 10 8 to
10 10 cells must be on the order of 10 −8 to 10 −12 (region B). This hypothetical graph has been constructed
according to the linear quadratic (LQ) model with parameters α = 0.4 Gy −1, α/β = 10 Gy.

where β is the mean probability per unit square of the dose that such complementary
events will occur.
The overall LQ equation for cell survival is therefore:

This is illustrated in Figure 20.2, which shows how the two components of cell killing,
α-damage and β-damage, combine to form the cell-survival curve. It will be shown later
that α-damage and β-damage relate to irreparable and repairable damage, respectively.
For two-particle events (β-type), if the damage from the second particle occurs before
the lesion from the first particle has been repaired, the cell will be inactivated (“killed”).
Since cellular repair half-times are of the order of 1 hour, this gives rise to the dose-rate
effect: the higher the dose rate, the greater the effect.

Figure 20.2 Linear-quadratic cell-survival curve, with α = 0.22 Gy −1 and α/β = 2.5 Gy, and d is the
dose/fraction. Note that the log cell kill for α-type damage equals that for β-damage at a dose equal to α/β.

Figure 20.3 Typical survival curves for cancer and late-reacting normal tissue cells, superimposed for comparison.
Compared with the cancer curve, the normal tissue cell-survival curve has a shallower initial slope (lower α) and is
“curvier” (lower α/β). Note that there is a “Window of Opportunity” below ∼ 4 Gy (with the parameters used
here) where normal tissue cells exhibit a higher survival than cancer cells. Parameters used to draw these
hypothetical curves are as follows: tumor, α = 0.4 Gy −1, α/β = 10 Gy; late-reacting normal tissues, α = 0.22 Gy

582
−1, α/β = 2.5 Gy.

Of special interest is the dose at which the log-surviving fraction for α-damage (e−ad)
equals that for β-damage ( ), that is, αd = βd2, or d = α/β. This is also illustrated in
Figure 20.2. This parameter, α/β, represents the curviness of the cell-survival curve.
Specifically, the higher the α/β, the straighter the survival curve. A high α/β is
characteristic of a type of cell that exhibits considerable irreparable damage and/or
little repair (high α and/or low β). In contrast, a low α/β (low α and/or high β) indicates
little irreparable damage and/or a high capability of repair. Here lies the major
difference between the cells of tumors and those of late-responding normal tissues: α/β
values tend to be high for cancers and low for late-reacting normal tissues. For example,
typical α/β values determined for cancer cells range from 5 to 20 Gy (mean ∼10 Gy),
but for late-responding normal tissues the range is 1 to 4 Gy (mean ∼2.5 Gy). There
appear to be some exceptions, however. For example, the α/β values for prostate and
breast cancer cells have been reported to be about 1.5 and 4 Gy, respectively (5,6).
Figure 20.3 shows typical survival curves for tumor and late-reacting normal cells,
superimposed for comparison. The difference in the shapes of cell-survival curves of
cancer and normal cells provides the major rationale for fractionated radiotherapy.

Rationale for Fractionation


Radiotherapy, in general, is governed by the four Rs: repair, reoxygenation,
repopulation, and redistribution, and so also is fractionation. Following is a discussion
of how each of the four Rs affects the practice of fractionation.

Repair
Of the four Rs, repair is the most important in terms of the rationale for fractionation.
As discussed in the preceding section, late-reacting normal tissue cells tend to exhibit a
greater propensity for repair than do tumor cells. This is exhibited by their low α/β
values and hence their curvier survival curves, as shown in Figure 20.3. In this
illustration, the normal tissue and tumor cell curves cross at doses of the order of 4 Gy.
At doses below the crossover point, cell survival for late-reacting tissues is greater than
that for tumors, and the reverse is true above the crossover. This means that delivery of
doses greater than ∼4 Gy will be more destructive to normal tissues than to cancer
cells. There is essentially a “Window of Opportunity” centered at ∼2 Gy within which
normal cells have a greater survival than cancer cells. However, doses far in excess of 4
Gy are needed to control tumors. There are two ways to safely deliver such high doses.
One is to deliver much higher doses to the tumor than to the normal tissues, such as
with stereotactic radiosurgery (SRS), intensity-modulated radiation therapy (IMRT), and
various other forms of conformal therapy. This will be discussed in detail later. The
second option is to fractionate with doses/fraction within the “Window of
Opportunity.”
If a course of fractionated radiotherapy is delivered with time between fractions
sufficient for complete repair (which clinical evidence has shown to be about 6 hours or
more), all the cells that have been sublethally (but not lethally) damaged during the first
fraction (i.e., only one DNA strand has been damaged or both arms are damaged but the
lesions are far apart), will have repaired before the second fraction is delivered, and so
on. This relates to the β-type damage in the LQ model. Then, at least to a first
approximation, cell-surviving fractions for each successive treatment will be identical
and the shape of the survival curve will simply repeat for each fraction. Then the cell-

583
surviving fraction equation becomes:

where N is the number of fractions and d is the dose/fraction. Then, if the dose per
fraction is below the crossover point shown in Figure 20.3, the resultant cell-survival
curves gradually separate, with tumor cells suffering more damage than normal cells, as
illustrated in Figure 20.4, which has been derived using Equation 20.5.
At least as far as repair is concerned, the optimal dose per fraction is that which will
produce the maximum separation of the two fractionated radiotherapy curves in Figure
20.4. However, the LQ model predicts that this maximum separation occurs with an
infinite number of infinitely small dose fractions, each separated by sufficient time for
complete repair. Clearly, this is not a realistic fractionation scheme, and in any event it
ignores the influence of the other three Rs of radiotherapy, especially repopulation (see
later discussion). With this in mind, a better definition of the optimal (or at least the
most efficient) dose per fraction might be where the rate of increase in separation of the
two fractionated radiotherapy curves in Figure 20.4 per unit number of fractions is a
maximum. It can be shown that this occurs at the point of maximum separation between
the cancer and normal tissue curves shown in Figure 20.3, which turns out to be at
exactly 50% of the dose at the crossover point. For the parameters used to plot the
survival curves in Figure 20.3, this dose is ∼2 Gy. Hence, the optimal dose per fraction
is about 2 Gy. If the α and β values for normal tissues and tumor were known for each
patient, it would be possible to design patient-specific fractionation regimens but,
unfortunately, the technology to do this is not refined enough at present. The
alternative is to determine the optimal dose per fraction for specific types of disease for
the average patient, and this has been the objective of numerous clinical trials of altered
fractionation (2,6–17).

Figure 20.4 How fractionation with dose per fraction below the crossover point of the late-responding normal
tissue and tumor cell-survival curves in Figure 20.3 results in higher cell survival for the normal tissue cells as the
total dose increases.

The situation is somewhat different for SRS and other types of highly conformal
radiotherapy because the effective dose to normal tissues is usually kept well below that
to the tumor, where the “effective dose” may be defined as the dose that, if delivered
uniformly to the tissue in question, would result in the same probability of local control
or complication as the actual inhomogeneous dose distribution in that tissue. Several
methods to determine such effective doses from dose–volume data have been published
(18–24) and these are reviewed in Chapter 23. For example, if f (the geometrical

584
sparing factor) is the ratio of the effective dose in normal tissues to effective dose in
tumor, even a modest sparing represented by f = 0.8 moves the crossover point to
considerably higher doses and significantly widens the “Window of Opportunity,” as
shown in Figure 20.5. In this example, the crossover point moves from 4 Gy all the way
out to about 14 Gy, so the optimal tumor dose per fraction becomes ∼7 Gy.

Figure 20.5 How the crossover point for single (acute) irradiations shown in Figure 20.3 moves to considerably
higher tumor doses if there is even a modest amount of “geometrical sparing” of the normal tissues (the normal
tissue curve moves 20% to the right). In this example, a 20% sparing (f = 0.8) causes the crossover point to move
from ∼ 4 Gy out to 14 Gy. The same linear quadratic (LQ) model parameters as for Figure 20.3 are used here.

For SRS, single doses of the order of 20 Gy are used. It is readily shown that with the
parameters used to plot Figures 20.3 to 20.5, this will be optimal if f equals ∼0.6, not
too unlikely, especially for small tumors. For large tumors, f may exceed 0.6, so
fractionated radiotherapy might be required.
One concern with SRS and other types of radiotherapy such as IMRT, CyberKnife, and
so on, for which the time it takes to deliver a treatment session can be of the same order
of magnitude as the half-time for cellular repair, is that repair during irradiation might
reduce the effectiveness of the treatment. Studies have shown that this effect might
cause reductions in effective dose by as much as 12% if the time to deliver the
treatment is as high as 0.5 hours, with concomitant reductions in tumor control as
much as 30% (25). Fortunately, it is possible that protraction of irradiation time during
a treatment might reduce the effect on normal tissues more than on cancers (26).
Hence, it might be possible to increase the total dose sufficiently to offset the effect of
this intrafraction repair without increasing the damage to normal tissues.
All the foregoing discussions, and especially the dose per fraction estimates are, of
course, highly dependent on the α and β values assumed. They also totally ignore the
effect of the other three Rs of radiotherapy.

Reoxygenation and the Oxygen Effect


Oxygen is the most powerful of all radiation sensitizers, so cells deprived of oxygen are
relatively resistant to radiation and require approximately three times as much dose as
well-oxygenated cells to destroy them. Such doses in a course of radiotherapy will likely
exceed normal tissue tolerance unless highly conformal therapy is used. Furthermore,
there is evidence that a significant proportion of human cancers contain hypoxic cells
(27–32). For such tumors it would be expected that, immediately after exposure, the
fraction of the surviving cells that are hypoxic should increase because the sensitive,
well-oxygenated cells will be killed preferentially. Indeed, this is exactly what has been

585
observed in many animal in vivo experiments. However, in some of these experiments,
the hypoxic-cell fraction rapidly returned to the much lower pre-irradiation levels, and
this has been interpreted as reoxygenation (33). In that case, if enough time is allowed
for reoxygenation between exposures in a course of fractionated radiotherapy (typically
24 hours is sufficient), the number of hypoxic cells in a tumor gradually decreases.
Hence, fractionation takes on added importance when treating tumors with a significant
hypoxic-cell fraction. However, because cell kill is reduced during each fraction due to
the presence of some resistant hypoxic cells, it is possible that, even with reoxygenation,
delivery of a high enough dose to kill all the cancer cells without exceeding normal
tissue tolerance might not be possible. For example, several clinical trials have
demonstrated that pre-irradiation hypoxia significantly reduces local control even after
an extended course of fractionated radiotherapy long enough to ensure reoxygenation
(27–32).
Another aspect of the effect of oxygen on fractionated radiotherapy relates to the
effect of LET. When cells are exposed to high-LET radiation, the protective effect of
hypoxia is greatly reduced (33). Hence, in the part of the cell-survival curve where α
(i.e., high-LET) damage predominates, at low dose or low dose/fraction (see Fig. 20.2),
the effect of hypoxia should be less than where β-damage predominates, which is at
high dose or high dose/fraction. This effect of dose or dose/fraction has been
demonstrated by cell-survival experiments (34,35) and has been shown to be consistent
with clinical data (30).
The effect of O2 is represented by the oxygen enhancement ratio (OER), where:

to produce the same biologic effect, for example, the cell-surviving fraction. Low OER
means that the protective effect of hypoxia on cell survival is little, and high OER means
that the effect is great. The potential magnitude of the effect of dose/fraction on the
OER can be illustrated using the LQ model in Equation 20.5 and taking the natural logs
of both sides giving:

Then, if subscripts a and h represent aerobic and hypoxic irradiation conditions,


respectively, and equating values of −ln S for N fractions of dose d/fraction for equal
biologic effect:

Then,

586
Figure 20.6 Illustration of the increase in oxygen enhancement ratio (OER) with increase in dose/fraction.
Parameters used (see text) are those derived to fit clinical data for the treatment of prostate cancers by Nahum et
al. (30).

Figure 20.6 shows how OER varies with dose/fraction for prostate cancer using
values of α and β that have been shown to fit clinical data (36,37): αa = 0.26 Gy−1, βa
= 0.0312 Gy−2, αh = 0.149 Gy−1, and βh = 0.00293 Gy−2. This figure shows the
trend of increasing OER as dose/fraction increases but it should be realized that the
actual numbers depicted here represent just a single study for a single type of cancer.
Data from other analyses of clinical results for prostate and other cancers will yield
different OER versus dose/fraction curves, but the trend should be as shown in Figure
20.6.
Similar observations of increasing OER with dose/fraction above 1 Gy/fraction have
been made using modified versions of the LQ model and different parameters (38,39).
This would indicate that, for the treatment of cancers that might contain significant
numbers of hypoxic cells, low dose/fraction techniques, with the order of 1 Gy/fraction,
might have an advantage over conventional (about 2 Gy/fraction) and high
dose/fraction (>2 Gy/fraction) regimes. The inappropriateness of high dose/fraction
radiotherapy for hypoxic cancers was demonstrated by Carlson et al. (40) who modified
the LQ model to take into account the effect of oxygen partial pressure, the change in
OER as a function of dose/fraction, and reoxygenation. As illustrated for head-and-neck
cancers in Figure 20.7, they showed that cancer cell survival should increase with
increase in dose/fraction, especially above 5 Gy/fraction.
In summary, fractionation is essential for reoxygenation but, even with fractionated
radiotherapy, it may not be possible to deliver doses high enough to control cancers
without exceeding normal tissue tolerance. Also, with high doses/fraction above about 5
Gy, the OER is high and reoxygenation between fractions is reduced because of the
fewer number of fractions, so survival of cells in hypoxic cancers is increased. It would
appear that the use of high doses/fraction for hypoxic cancers is contraindicated, but
this ignores the effect of the third R of radiotherapy, repopulation.

587
Figure 20.7 Surviving fraction of tumor cells as a function of the number of fractions and the dose/fraction to
yield equivalent tumor control under normoxic conditions for hypoxic fractions 0.1 (red), 0.2 (blue), and 0.3
(green), assuming daily fractionation, full reoxygenation, and no repopulation. Modified from Carlson DJ, Keall
PJ, Loo BW, et al. Hypofractionation results in reduced cell kill compared to conventional fractionation for
tumors with regions of hypoxia. Int J Radiat Oncol Biol Phys. 2011;79:1188–1195.

Repopulation
By their very nature, all cancers contain dividing cells, with viable cancer cells usually
dividing much faster than those of late-reacting normal tissues. Hence, during a course
of radiotherapy, there is considerably more repopulation of cancer cells than cells of the
late-responding normal tissues, so the longer a course of radiotherapy, the more
difficult it becomes to control the tumor without exceeding normal tissue tolerance.
Furthermore, some studies show that repopulation of cancer cells might accelerate
during a course of fractionated radiotherapy (accelerated repopulation), with the faster
rate of division kicking in after the first 2 to 4 weeks of treatment (the so-called kick-in
time Tk) (41). On these grounds, therefore, repopulation appears to dictate that courses
of radiotherapy should not be overly protracted and that accelerated repopulation, if it
exists—there is some controversy about this (42)—even indicates that optimal schedules
of treatment might be as short as 2 to 4 weeks, or even less. However, repopulation is
not entirely detrimental. Acutely responding normal tissues need to repopulate during a
course of radiotherapy to avoid exceeding acute tolerance. Hence, the length of a course
of radiotherapy, and therefore the fractionation, must be controlled so as to not allow
too much time for excessive repopulation of tumor cells, at the same time not treating so
rapidly that acute tolerance is exceeded.
One problem with shortening the course of therapy is that this probably means
increasing the dose/fraction unless multiple fractions are to be delivered each day,
which is very inconvenient (see later). But, as shown in the previous section, increasing
the dose/fraction will reduce the effectiveness of the treatments if hypoxic cells are
present in the tumor (Fig. 20.7). A delicate balance has to be struck between too few
fractions (less opportunity for reoxygenation) and too many fractions (increased

588
repopulation of cancer cells). Carlson et al. demonstrated this for the head-and-neck
cancers shown in Fig. 20.7, and showed that there ought to be an optimal number of
fractions and dose/fraction (40), as shown in Figure 20.8. With the parameters used in
this study, this occurs at about 15 fractions of 3.7 Gy, but the actual optimal
fractionation is highly dependent upon the parameters used and the accuracy of the
model. For example, in this study a kick-in time Tk of 21 days was assumed for five
fraction/week treatments. Hence, accelerated repopulation kicked in after 15 fractions.
But, as shown in Figure 20.7, after 15 fractions the decrease in surviving fraction of the
cancer cells due to OER and reoxygenation effects has practically saturated. Hence the
effect of accelerated repopulation kicking in causes the cell-survival curve to increase
suddenly, thus making 15 fractions the apparent optimal fractionation. The optimal
fractionation is, therefore, highly dependent upon the value of Tk assumed. For Tk less
than 15 days, the optimal number of fractions should be less than 15, and high
dose/fraction regimes will not, after all, be contraindicated for hypoxic cancers.

Figure 20.8 Surviving fraction of tumor cells as a function of the number of fractions and the dose/fraction at
five fractions/week to yield equivalent tumor control under normoxic conditions for hypoxic fraction 0.2,
including repopulation with a kick-in time Tk of 21 days. Modified from Carlson DJ, Keall PJ, Loo BW, et al.
Hypofractionation results in reduced cell kill compared to conventional fractionation for tumors with regions of
hypoxia. Int J Radiat Oncol Biol Phys. 2011;79:1188–1195.

Redistribution
According to the cell cycle effect, cells irradiated during the mitotic (M) phase of the
cell cycle are most sensitive, and during late synthesis (late S) they are most resistant,
with a second peak of resistance in G1 in some cells (43). For cells irradiated in the M
phase, the survival curve is practically linear, indicating minimal repair. In contrast, for
cells irradiated in late S, survival curves exhibit the greatest curvature, representing
considerable repair. Consequently, when tumors are treated with fractionated
radiotherapy, cells surviving the first fraction tend to be partially synchronized, with an

589
overabundance of surviving cells in late S moving into early G2 immediately after
exposure. If a second exposure is delivered sometime after the first, the number of cells
inactivated depends on how far this surviving bolus of cells has traveled around the cell
cycle. For example, if they have reached the M phase at the time of the second fraction,
they will be most sensitive. It is this radiation-induced partial synchronization of cells
that is known as redistribution (or reassortment).
TABLE 20.1 Fractionation Schemes with Typical Parameters

Redistribution can be a benefit in a course of fractionated radiotherapy if the cancer


cells can be caught in mitosis after each fraction, or detrimental if they have reached a
resistant phase of the cell cycle. In theory, it ought to be possible to adjust the interval
between fractions so as to gain maximum benefit from redistribution, but to date there
has been no evidence that such an advantage can be obtained in practice. Consequently,
potential effects of redistribution are generally ignored when designing fractionation
strategies.

Fractionation Strategies
The radiobiologic principles discussed in the foregoing sections have been used
extensively to guide in the design of numerous clinical trials of altered-fractionation
regimens. In this section, the rationale for various fractionation schemes will be
presented. Table 20.1 lists a variety of fractionation schemes, their typical parameters,
and some brief comments. Following is a detailed description of each of these
fractionation schemes.

Conventional Fractionation
The most common fractionation for curative radiotherapy is about 1.8 to 2.2
Gy/fraction delivered at five fractions a week. This has evolved as the conventional
fractionation regimen because it is convenient (no weekend treatments), efficient
(treatment every weekday), and effective (high doses can be delivered without
exceeding either acute or chronic normal tissue tolerance). The principal rationale for
the prescription of conventional fractionation for a particular patient or disease is that
most experience is with this type of fractionation, for which both tumoricidal and
tolerance doses are well documented. Unless there is a good reason to change, radiation
oncologists are reluctant to deviate from this tried-and-true method of treatment.

Hyperfractionation

590
A hyperfractionated course of radiotherapy is one in which more than one fraction is
delivered each day but the overall treatment time remains similar to that for
conventional fractionation. Typically, this means 1.2 to 1.3 Gy/fraction, two fractions a
day, with an increase in total dose of the order of 20% to account for increased repair
at the lower dose per fraction.
The major rationale for hyperfractionation is to take full advantage of the difference
in repair capacity of late-reacting normal tissues compared with tumors. This was
illustrated by the curvier cell-survival curves for these normal tissues (Fig. 20.3) and the
concomitantly lower α/β values. If conventional radiotherapy is not producing
particularly good clinical results and no obvious reasons for this are evident, maybe the
reason is that the dose per fraction that adequately separates the two fractionated
radiotherapy curves in Figure 20.4 is below that used in conventional fractionation.
With such a low dose per fraction, more than one fraction per day is necessary to keep
the course of therapy short enough to avoid the risk of excessive tumor cell
repopulation. Such hyperfractionation regimes will have to be delivered at about 1.2 to
1.3 Gy/fraction, two fractions a day. To treat with higher than 1.3 Gy/fraction at more
than one fraction per day may exceed acute tolerance, and to use <1.2 Gy/fraction will
require three fractions per day in order to not overly increase overall treatment time,
with at least 6 hours between fractions required for complete repair, a treatment
schedule that would be highly inconvenient.
Another potential advantage of hyperfractionation might be the reduced OER at low
dose/fraction compared with that with conventional fractionation (see Fig. 20.6). This
could be important for cancers that might be expected to contain significant numbers of
hypoxic cells.

Accelerated Fractionation
For rapidly growing tumors with short potential doubling times of the viable cycling
cancer cells (Tpot), accelerated treatment is desirable.
There are several ways to achieve reduced overall treatment time. The simplest is to
treat 6 or 7 days a week instead of the normal 5, keeping the dose per fraction the same
as with conventional fractionation. This produces a modest acceleration that may be
enough to influence clinical outcome. A more drastic acceleration can be achieved by
treating twice a day at 1.4 to 1.6 Gy/fraction, but only at the risk of exceeding acute
normal tissue tolerance. Such accelerated fractionation regimens have been tried but
have usually been unsuccessful because many patients had to be given a rest of 1 to 2
weeks during the course of therapy to allow acute reactions to subside, negating the
intent to accelerate the treatments.
Another possibility is to increase the dose per fraction to about 2.5 Gy (often called
rapid fractionation), but this risks losing the repair advantage of late-responding
normal tissues. Increased late reactions usually occur unless the dose to the normal
tissues can be reduced, such as with conformal therapy. Alternatively, for rapidly
growing cancers it is possible to exploit the difference in repair between late-reacting
normal tissues and tumors by hyperfractionating while accelerating the course of
therapy by treating with three fractions per day. Such treatment is known as
accelerated hyperfractionation.

Accelerated Hyperfractionation
A major problem with accelerated fractionation is that cancerocidal doses delivered in
such short overall times are likely to exceed acute tolerance unless a rest period is
included part way through treatment to allow early reactions to subside. One way

591
around this is to complete the treatments in such a short time that the acute reactions
reach their peak only after the radiotherapy has been completed. This was the rationale
for the development of the continuous hyperfractionated accelerated radiotherapy
(CHART) regimen at Mount Vernon Hospital in London (10). With CHART, treatments 6
hours apart are delivered three times a day, 7 days a week. With a dose/fraction of
1.5 Gy, a total dose of 54 Gy can be delivered in 36 fractions over 12 successive
treatment days including weekends. With this schedule, patients can complete
treatment without a break because peak acute reactions occur approximately 2 weeks
after the start of therapy. Although clinical results for the treatment of lung and head-
and-neck cancers have been promising with CHART, they have been achieved with
considerable trauma to the patients: many of these patients developed grade 3 or worse
acute complications (44). CHART is also difficult for the staff, since delivery of three
fractions per day 6 hours apart for 12 successive days, including weekends, is very
inconvenient. Some of this inconvenience is reduced with an alternative form of CHART
called CHARTWEL (CHART weekend less), wherein the 54 Gy at 1.5 Gy/fraction at
three fractions per day is delivered over a total of 16 days without the weekend
treatments (13). Clinical trials have shown that CHARTWEL is a viable alternative to
CHART (45).

Hypofractionation
All the fractionation regimes presented above require the delivery of many fractions
over many days. They are costly in terms of resources and are inconvenient for patients.
These fractionation schemes were necessitated by the desire to “cure” cancers without
exceeding normal tissue tolerance. However, not all radiotherapy is aimed at “cure.” For
many patients, the aim is to simply palliate, so there is no need to employ the very high
doses required for “cure” and hence no need to approach tolerance of normal tissues.
For these patients it is, therefore, possible to design much more convenient and cost-
effective treatments, which use far fewer fractions, that is, to employ hypofractionation.
Typical hypofractionation schemes used for palliation range from as many as 10
fractions of 3 Gy to as few as a single fraction of about 10 Gy, with anything from 1 to
5 fractions per week.
With conformal radiotherapy, because there is considerable geometrical sparing of
normal tissues, the “Window of Opportunity” (Fig. 20.5) is widened such that the high
doses/fraction needed for hypofractionated treatments can be used for curative
radiotherapy. This has led to the development of many clinical trials of
hypofractionation, especially for prostate and breast cancers for which the α/β ratio is
lower than the 10 Gy typically assumed for most cancers (9,14,16,46).
As discussed earlier, potential disadvantages of hypofractionation relate to the
increased OER and decreased reoxygenation that might be expected with high
dose/fraction schedules (Fig. 20.6). But this disadvantage might be mitigated for
rapidly dividing cancers if the hypofractionation allows the course of treatment to be
shortened. All this depends significantly on radiobiologic properties of the cancer cells
that are difficult to predict. Hence, it seems prudent to not apply hypofractionation for
the treatment of cancers thought to contain significant fractions of hypoxic cells
without extensive clinical trials.
One possible advantage of hypofractionation for cancers with a high α/β that might
be exploited is the increase in intrafraction repair that takes place with long treatment
times, which should benefit late-reacting normal tissues because of their lower α/β
(prostate cancer might be an exception). This would require increasing the total dose to

592
account for this increased repair just enough so as to not increase the risk of late
complications. This could be determined by, for example, a carefully controlled dose-
escalation clinical trial or, maybe, calculation of the appropriate dose using a bioeffect
dose model. This exemplifies a major challenge with most modified fractionation
regimens for which there is no previous experience: the determination of the
appropriate total dose to use. Rather than just guessing, it has been a common practice
to use mathematical bioeffect dose models to calculate these doses. The most popular of
these is the biologically effective dose (BED) model.

The Biologically Effective Dose Model


The BED model for fractionated radiotherapy can be derived directly from the LQ
equation for cell survival for fractionated irradiations presented earlier (Equation 20.7):
.
This equation could be used to calculate treatment regimes that are equally effective
biologically (constant − ln S) but, to do so, we would need to know the values of the
two parameters α and β for each tissue involved. Unfortunately, it is difficult enough to
determine a single biologic parameter from clinical data, let alone two. However, it is
possible to reduce the number of unknown parameters to one by dividing both sides of
Equation 20.7 by α to derive the BED, originally called the extrapolated response dose
(ERD) (47,48):

Fractionation schemes for which BEDs are equal will be equally effective biologically.
Here, we have just one biologic parameter, α/β, to determine from clinical data for each
type of tissue involved where, as we saw earlier, α/β is the dose at which α-type and β-
type damages are equal (Fig. 20.2).
Equation 20.10 was derived assuming acute radiation conditions (i.e., no time for
repair during each fraction) and complete repair between fractions. This does not
always prevail, however, since there may be occasions when the time between fractions
is not sufficient for full repair, or the time to deliver each fraction is long enough for
some repair to occur during irradiation. The former has been observed clinically with
some of the early three fractions per day patients, for example, when less than 6 hours
between fractions was used (49), and the latter probably occurs for some of the highly
conformal therapy techniques such as with SRS, IMRT, SBRT, and CyberKnife
treatments (25,26,50). For these situations, a more complex form of the BED equation is
needed that takes into account both the rate at which cells repair, the rate at which
each part of the tissue is irradiated, and the time between fractions. The full BED
equation for such fractionated therapy has been published (25,51,52) but it is extremely
complicated and outside the scope of this chapter.
Equation 20.10 accounts for repair only, but cells, especially cancer cells, are known
to repopulate during a course of therapy. If tumor cell repopulation is assumed to be an
exponential function of time, with doubling time for repopulation of the cycling cells
Tpot, then ln S will be increased by (0.693/Tpot)T, so (53):

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and hence the BED equation becomes:

However, since the two additional biologic parameters Tpot and α are very difficult to
determine from analysis of clinical data, it is useful to replace 0.693/αTpot by a single
repopulation rate parameter, k, estimated from loss of local control when radiotherapy
is prolonged (54). For example, if retrospective analysis of data shows that a patient has
a rapidly repopulating type of tumor, a value of k = 0.6 BED units/day might be used.
At the other extreme, for a slowly proliferating disease like prostate cancer, k = 0.1
BED units/day might be more appropriate. Note that it is usual to assume that k = 0 for
late-responding normal tissues, since little or no repopulation of these cells would be
expected to occur during a course of therapy. For acutely responding normal tissues,
the value of k is probably in the range of 0.2 to 0.4 BED units/day (54).
One further refinement of the BED equation is required if cells are believed to exhibit
accelerated repopulation after a kick-in time Tk. If it is assumed that repopulation is
negligible before Tk and after that proceeds at a rate represented by k BED units/day
(54):

where k = 0 for T < Tk.


A further useful application of the LQ model for comparison of different fractionation
regimes is to calculate the equivalent dose at 2 Gy/fraction, because much of the clinical
data used to represent tumor control and normal tissue complication probabilities has
been published for 2 Gy/fraction treatment schedules (55–57). This is achieved by
equating BEDs. For example, if we ignore repopulation effects, the 2 Gy/fraction total
dose, D2, equivalent to a regime of Dd Gy delivered at d Gy/fraction, is given by:

Then

Another useful application of the LQ model is to correct for errors in dose/fraction.


For example, if the wrong dose/fraction is delivered for the first several fractions, Joiner
showed that it is possible (with some obvious exceptions) to use the LQ model to
calculate a treatment schedule to complete the course of treatment and achieve the
same biologic effects that were originally planned for both tumor and normal tissues,
provided repopulation effects can be ignored (58). He showed that, if the planned total

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dose was Dp Gy at dp Gy/fraction but, due to an error, the first De Gy was delivered at
dose/fraction de Gy, the course could be completed with dose Dc delivered at dc
Gy/fraction, where Dc = Dp − De and

Note that the total dose is unchanged (Dp = De + Dc) and that the solution is
independent of the α/β of the tissues involved, which is why the effects on both tumor
and normal tissues are the same as originally planned. Also, although not stated in
Joiner’s paper (58), it can be shown that the solution is independent of any geometrical
sparing of normal tissues, that is, it is independent of geometrical sparing factor, f.

The LQ Model in Clinical Practice


It is important to realize that the LQ model is an approximation. How could such a
simple mathematical model account for all the complex changes that occur in tissues
and cells when they are irradiated? But, like all models, it can be useful and has been
shown to provide an adequate fit to clinical data in many studies. Problems with the
model, apart from the over-simplicity of the model itself, include lack of accurate values
for the biologic parameters α, α/β, k, Tpot, and Tk, and a concern that there may be an
upper limit to the dose/fraction above which the model no longer applies.
As far as the biologic parameters are concerned, studies of tumor and normal tissue
effects in clinical trials are gradually providing better and better estimates of their
values. Of special interest as far as normal tissues are concerned are the studies being
analyzed as part of the Quantitative Analyses of Normal Tissue Effects in the Clinic
(QUANTEC) program (59). Hopefully, this will provide reliable estimates of the
parameters for a whole variety of normal tissues.
The problem of a possible upper limit in dose/fraction for the LQ model is a concern
for uses of the model for extreme hypofractionation with doses/fraction above about 7
Gy. One concern relates to the shape of cell-survival curves at high doses. Many have
claimed that these straighten out at doses above about 7 Gy, whereas the LQ model
predicts that they continue to curve downward (60). This would mean that the LQ
model would predict more cell kill than really occurs at high doses, that is, it
overestimates radiation effects. On the other hand, many claim that the LQ model
underestimates the effect at high doses above about 10 Gy because it ignores indirect cell
death due to vascular damage (61,62). This is discussed in depth in Chapter 21. Maybe
because the LQ model overestimates the direct effect on cells but underestimates it in
tissues, these two “errors” at least partially cancel and the LQ model can be used at
doses well above 10 Gy. Only carefully designed clinical trials are likely to give us a
clear answer to this conundrum. Regardless, the LQ model is always an approximation.
It should be applied with caution when designing or modifying fractionation schemes
and, if used for patients, it is important to watch out for signs of unexpected tissue
reactions or poor tumor control.
The following examples illustrate how these models can be applied to the solution of
practical radiotherapy problems.

Examples
Problem 1: Gap in treatment: A patient with a rapidly growing cancer is planned to

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receive a course of 70 Gy in 35 fractions in 7 weeks. After 25 fractions the patient
develops a severe acute reaction that necessitates a 2-week rest period. To complete the
treatment in 10 more fractions in 2 weeks, what dose per fraction should be delivered?

SOLUTION
Application of the LQ model to problems such as this is complicated since different
solutions are possible for different tissues considered and several tissue-specific
parameters have to be assumed. For this problem, assume the following parameters for
this patient:
For tumor:

For late-responding normal tissues:

Tumor solution. Before the break the BED is (using Equation 20.13):

After the break this reduces to:

The planned BED was:

Therefore, the residual BED that needs to be delivered is:

If d is the dose per fraction required to complete the treatment in 10 fractions over 2
weeks:

Therefore:

Solving this for d gives:

Late-responding normal tissue solution. Since no repopulation is assumed for late-


responding normal tissues (k = 0), the break should have no effect, so the dose to
complete the course of therapy should be unchanged. Therefore:

If it is assumed that the original course represented the maximum dose that could be
delivered safely to this patient then, in order not to increase the risk of late normal
tissue injuries, the treatment should be completed in 10 fractions of 2 Gy. However,
since the dose per fraction required for the tumor (2.58 Gy) is much higher than this, it

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might be necessary to compromise in order to not reduce tumor control too much. It
might be decided to treat with more than 10 fractions of 2 Gy, but less than the number
that would be required for the full tumor effect. This illustrates the undesirability of
allowing rest periods during the treatment of rapidly proliferating cancers.

Problem 2: Hyperfractionation: A hyperfractionation regimen consisting of 2 fractions


per day, 6 hours apart, for a total of 60 fractions in 6 weeks is designed to be
equivalent to 60 Gy in 30 fractions in 6 weeks. What dose per fraction is required?

SOLUTION
Assume all the same parameters as in the first problem. However, since the overall time
is unchanged, no account need be taken of repopulation.

Tumor solution. Equating the conventional to the hyperfractionated regimens, the


dose/fraction d is determined using Equation 20.10:

or

Solving for d gives:

Late-responding normal tissue solution. Equating the two regimens gives (using Equation
20.10):

or

The solution to this is:

Note that the late-reacting tissues can tolerate doses much higher than that required
for the tumor. This is a consequence of the low dose per fraction and is the major
rationale for hyperfractionation. However, even though a course of 60 fractions at 1.21
Gy/fraction in 6 weeks is tolerable as far as late reactions are concerned, the risk of
acute reactions might be higher than that for the conventional course of treatment
because a total of 2.42 Gy will be delivered each day. But this might not be a problem if
the risk of acute injuries is negligible for the conventional course. If these calculations
are to be used as the basis for the design of a hyperfractionation regime for real
patients, it might be prudent for the radiation oncologist to develop some experience by
treating the first few patients with slightly fewer fractions and, if the acute reactions
appear tolerable, to escalate the number of fractions to the required 60. Several national
clinical trials of hyperfractionation have been designed using dose escalation in this

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way.

Problem 3: Accelerated fractionation: An accelerated fractionation scheme consisting of


40 treatments, twice a day for 4 weeks is to be equivalent to 60 Gy in 30 fractions in 6
weeks. What dose per fraction is required? Assume the same parameters as in Problem
1.

Tumor solution. The accelerated regimen is completed before the kick-in time for
repopulation (28 days), and equating BEDs using Equation 20.13 to determine the
dose/fraction d:

or

Solving this for d gives:

Late-responding normal tissue solution. No repopulation correction is needed, so (using


Equation 20.10):

or

The solution is:

According to these calculations, it would be safe to deliver the treatment at 1.63


Gy/fraction, which means that the effect on the tumor should be greater than that for
the conventional fractionation scheme. This is the rationale for accelerated fractionation
for such rapidly proliferating cancers. Note that the daily dose for the accelerated
regime is 3.26 Gy, which might not be tolerated acutely. As in the previous problem, it
might prudent to start out using less than the desired 40 fractions of 1.63 Gy/fraction
and to dose-escalate with this accelerated radiotherapy schedule, carefully watching out
for excessive acute reactions.

Problem 4: Hypofractionation: What is the appropriate dose/fraction required for


hypofractionated total breast radiotherapy in 13 fractions over 5 weeks in order for this
to be equivalent in terms of tumor control to standard radiotherapy with 25 fractions of
2 Gy delivered over 5 weeks assuming α/β for breast cancer is 4 Gy?

SOLUTION
Since the overall time is unchanged, there is no need to take repopulation into account,
so Equation 20.10 can be used.
For the standard treatment the BED is 50(1 + 2/4) = 75. Then, if d Gy is the

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dose/fraction needed for the hypofractionated treatments:

Therefore:

Solving this for d gives:

Note that hypofractionation regimes consisting of 13 fractions of about 3.2 Gy


delivered over 5 weeks have been studied in clinical trials and found to be acceptable in
terms of both tumor control and complications (7).

Problem 5: Correction of treatment error: A patient is planned to receive 30 daily


fractions of 1.8 Gy but, due to an error, the first 5 fractions are delivered at 2
Gy/fraction. How can the treatment continue so as to result in the same effects on
tumor and normal tissues as originally planned?

SOLUTION
According to Equation 20.16, the remainder of the treatments should be delivered at a
dose/fraction dc given by:

The total dose remains as planned at 54 Gy, so the remaining 44 Gy has to be


delivered in 44/1.75 = 25.1 fractions. Since we cannot deliver 0.1 of a fraction,
25 fractions of 44/25 = 1.76 Gy should be used.

Problem 6: Accelerated hyperfractionation: A CHART scheme consisting of 36


treatments, 3 times a day for 12 successive days with at least 6 hours between fractions
is to be equivalent to 70 Gy in 35 fractions in 49 days as far as tumor control is
concerned. What dose per fraction is required? With this treatment regime, will the
effect on late-responding normal tissues exceed that expected from a conventional
course of 30 fractions of 2 Gy in 42 days?

SOLUTION
Assume the same parameters as before, except for the repopulation kick-in time for the
tumor, which is assumed to be 0 (assume CHART is being tried for these patients
because their cancers are rapidly proliferating right from the start of treatment).
For tumor: equating BEDs, the CHART dose/fraction d is given by (using Equation
20.13):

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or

Solving this for d gives:

For late-reacting normal tissues: the BED for the conventional regime is (using Equation
21.10):

and for the CHART treatments it is:

Hence, the CHART treatments should be far more tolerable as far as late reactions are
concerned. One would expect that, compared to conventional therapy with 60 Gy at 2
Gy/fraction, CHART should provide equivalent tumor control without the added risk of
severe late reactions. However, because the daily dose is about 4.5 Gy, one would
expect acute reactions to be very severe, as clinical results have demonstrated (13).

SUMMARY
Treatments have been fractionated from the very inception of radiotherapy a century
ago, although it was not until the early 1930s that it was generally accepted that
curative therapy required fractionation. Recent studies of the radiobiologic principles of
cell survival demonstrate that the major reason fractionation is so important is the
difference in the capacity of tumor and late-responding normal tissue cells to repair
damage at low doses per fraction. Specifically, normal tissue cells are more capable of
repair than are tumor cells. This causes their cell-survival curves to be curvier than
those for tumors which, according to the LQ model, correspond to a lower value of the
α/β ratio.
A second difference between tumor and late-reacting normal cells is repopulation.
These normal cells repopulate little, if at all, during a course of fractionated
radiotherapy, whereas tumor cells, especially those with a short potential doubling time,
exhibit significant repopulation.
These repair and repopulation differences between normal and tumor cells provide
the major rationale for clinical trials of several types of modified fractionation schemes,
such as hyperfractionation, accelerated fractionation, and accelerated
hyperfractionation.
One problem encountered whenever fractionation regimens are modified is how to
decide on an appropriate total dose when little prior clinical experience is available. The
most common way this has been done is by the use of the BED model. However, it must
be realized that this model provides only approximate solutions to clinical problems. It
represents a grossly oversimplified view of the extremely complex biologic changes that
occur during a course of fractionated radiotherapy. It is useful for demonstration of the
effects of fractionation but, if applied to actual patient treatment calculations, it should
be used with caution, preferably only when previous clinical experience is not available.

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KEY POINTS
• The clinical need to fractionate treatments first became accepted in the 1930s.
• Late-reacting normal tissue cells are better able to repair damage than are cancer cells.
• There is a “Window of Opportunity” at low dose and low doses/fraction within which
cancers can be controlled without exceeding normal tissue tolerance.
• The “Window of Opportunity” widens with geometrical sparing of normal tissues, thus
allowing much higher doses/fraction to be used for curative therapy.
• Radiobiologic effects are regulated by the four Rs of radiotherapy: repair, reoxygenation,
repopulation, and redistribution.
• Different fractionation strategies have been investigated to try to find the best treatment for
specific types of cancers.
• The linear quadratic model can be used to compare different fractionation schemes but,
because it is an approximation, it has to be used with caution.

QUESTIONS
1. The principle radiobiologic rationale for fractionating radiotherapy at low
doses/fraction is that
A. this improves utilization of treatment machines
B. cells of late-reacting normal tissues are better able to repair than those of
most cancers
C. this gives the staff time to rest between treatments
D. survival curves for cancer cells are typically “curvier” than for normal cells
E. cancer cells repair faster than normal cells so session times have to be kept
short
2. One reason why the CHART technique might be better for reducing the overall
time of a course of treatment than conventional accelerated fractionation is that,
with CHART
A. there will be increased probability of reoxygenation of hypoxic cancer cells
B. treatments are more convenient to deliver
C. there is a comparable risk of severe acute complications with increased tumor
control
D. there is a reduced risk of severe acute complications
E. severe acute reactions peak after the course of radiotherapy has been
completed
3. Hypofractionation might better than other forms of fractionation because
A. with fewer fractions, reduced reoxygenation will protect late-reacting normal
tissues

601
B. longer treatment times will allow some cancer cells to repair
C. fewer fractions will be more cost-effective
D. shorter courses of radiotherapy will reduce the risk of acute reactions
E. shorter courses of radiotherapy will reduce the risk of late complications
4. The major radiobiologic rationale for hyperfractionation is to take
A. full advantage of the difference in repair capacity of late-reacting normal
tissues compared with tumors
B. full advantage of the difference in repair capacity of acutely reacting normal
tissues compared with tumors
C. advantage of the higher OER for tumors at low dose/fraction
D. advantage of the short time between fractions to “catch” the cancer cells in a
sensitive phase of the cell cycle
E. advantage of the short time between fractions to “catch” the normal tissue
cells in a resistant phase of the cell cycle
5. In the 1930s it was realized that treatments needed to be fractionated because
A. repair at low doses/fraction was known to be better for normal tissue cells
than for tumor cells
B. repair at low doses/fraction was known to be better for tumor cells than for
normal tissue cells
C. it was known that reoxygenation improved as fractionation was increased
D. it was known that the OER of tumor cells was lower for fractionated as
opposed to single dose treatments
E. clinical experience had demonstrated that, only by fractionating, could
cancerocidal doses be delivered without exceeding normal tissue tolerance

ANSWERS
1. B. At low doses and doses/fraction, cell survival is greater for late-reacting
normal tissue cells than for cancer cells due to their better ability to repair,
thus giving rise to the “Window of Opportunity.”
2. E. With accelerated radiotherapy regimens, acute reactions tend to reach a peak
after about 2 weeks of treatment, and this often makes it impossible to
complete the course of therapy without giving the patient a rest period, thus
negating the benefit of accelerated treatment desired. With CHART, this peak
in acute reactions occurs after the completion of treatment.
3. C. “Fewer fractions” is clearly more cost-effective and the other potential
answers either have no significant effect or make the treatments worse.
4. A. At low doses/fraction, the surviving fraction of both late-reacting normal
tissue and tumor cells will both be increased but, because the normal tissue
cells are better able to repair, the differential advantage will increase. The
other potential answers either have no significant effect or make the
treatments worse.
5. E. It was the excellent clinical results Coutard published in 1932 that
demonstrated that fractionation was needed if cancerocidal doses were to be
delivered without exceeding normal tissue tolerance. Answer B is wrong and

602
the rationales given in the A, C, and D are now known to be good reasons to
fractionate but they were not understood for several decades after Coutard’s
results were published.

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61. Song CW, Mi-Sook K, Cho C, et al. Radiobiological basis of SBRT and SRS. Int J Clin
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21 Radiobiology of Stereotactic
Radiosurgery and Stereotactic Ablative
Radiotherapy

Paul W. Sperduto and Chang W. Song

INTRODUCTION
The previous chapter focused on treatment planning for stereotactic radiosurgery (SRS)
and stereotactic ablative radiotherapy (SAbR), which is also known as stereotactic body
radiation therapy (SBRT). This chapter complements that work with a concise primer on
the evolving radiobiologic principles and current understanding of the mechanism of
action of SRS/SAbR. While direct tumor cell death remains important, recent research
shows indirect cell death from the vascular and immunologic effects of SRS/SAbR may
be equally or more important. This chapter will also briefly summarize how hypoxia-
inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) impact
tumor progression and how inhibition of these factors may enhance indirect cell death,
thereby further improving the efficacy of SRS/SAbR. Finally, this chapter will revisit the
enduring debate regarding whether the linear quadratic (LQ) model, or any modified
version thereof, is applicable to SRS/SAbR.
A major paradigm shift in cancer biology came with the realization that cancer is not
merely a normal cell gone awry but the result of a complex process by which the cell
responds to intercellular signals, the surrounding microenvironment and the therapies
directed against it. The importance of the tumor microenvironment and specifically
hypoxia was highlighted by Gray, who suggested in 1953 that hypoxic cancer cells are
resistant to radiation therapy (1). Hypoxia, hypoxic cell radiosensitizers, hypoxic
cytotoxins, and reoxygenation have since been the focus of extensive research in
radiation oncology (2). A key advance was the discovery that angiogenesis is a critical
factor in cancer progression (3,4). It was later shown by multiple investigators that not
only are hypoxic cells resistant to radiation but that hypoxia is the principal physiologic
stimulus for angiogenesis (5,6). The subsequent discovery that HIF-1α regulates
hypoxia-induced angiogenesis through activation of multiple angiogenic growth factors,
including VEGF, suggests that to the extent that radiation causes endothelial cell death
resulting in indirect tumor cell death, it may also activate HIF-1α, which may contribute
to radiation resistance (7,8). Thus, more recent work has focused on the effects of
radiation on tumor vasculature and potential methods for inhibiting HIF-1α and VEGF
which, in turn, should enhance cell death (9,10). Figure 21.1 shows a schematic
representation of the current understanding of the radiobiologic mechanisms of action
of SRS/SBRT, which are different than the traditional radiobiology principles that have
been used to describe the effects of conventionally fractionated radiation therapy.

Evidence of Indirect Cell Death from Vascular Damage by SRS/SAbR


Recent clinical experience has demonstrated high local control rates in patients treated

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with SRS/SAbR (11–17) and other work (18–20) has suggested that the mechanism of
SRS/SAbR is different than conventional radiobiology. Park et al. recently published a
comprehensive review of the literature on the effects of radiation on tumor vasculature
and concluded that extensive vascular damage may lead to indirect cell death (21).
Both recent and remote data clearly indicate that secondary or indirect cell death
resulting from vascular damage plays an important role in the response to tumors to
high dose per fraction SRS or SAbR. Song et al. published a series of investigations in
the 1970s showing irradiation of experimental tumors with 10 Gy or higher doses in a
single dose induced severe vascular destruction and such vascular damage caused
considerable indirect tumor cell death in Walker tumors of rats or SCK tumors of mice
(22). Other investigators have reported similar observations that radiation-induced
endothelial cell death and vascular dysfunction by high-dose irradiation induced
secondary cell death in various types of tumors (23,24).
The number of viable tumor cells in 1 g human tumor is known to be as many as 108
to 109 implying that 8 to 9 logs cancer cells have to be killed for complete control of a 1
g tumor (25). Traditional radiobiologic principles would indicate that the radiation
doses used for SRS and SAbR are supposed to sterilize only 3 to 4 logs of tumor cells,
assuming 10% to 20% of tumor cells are hypoxic. Leith et al. reported that a single dose
of irradiation with as high as 80 to 90 Gy in a single treatment is needed to control 3-
cm diameter brain tumors, assuming 20% of the tumor cells are hypoxic (26). However,
SRS with only 18 to 25 Gy in a single fraction has been shown to be highly effective to
control primary or metastatic brain tumors by a number of investigators (11,12).
Likewise, SAbR with doses less than 60 Gy in three to five fractions has also been shown
to be highly effective to achieve local control of various types of large tumors (13–18).
For example, SAbR of 5- to 7-cm diameter liver tumors with only 54 Gy in three equal
fractions resulted in more than 90% local control for 2 years (15). Taken together, it is
highly likely that mechanisms other than direct killing of cancer cells through DNA
double-strand breaks are involved in the response of tumors to high dose per fraction
SRS and SAbR.

Figure 21.1 A schematic representation of the current understanding of the mechanism of action for
SRS/SBRT.

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Figure 21.2 The effect of dose on indirect cell death in fibrosarcoma. Effect of 10-, 15-, 20-, and 30-Gy
irradiation in a single dose on the surviving cell fraction in FSaII fibrosarcoma tumors grown in the hind limb of
C3H mice. The cell survival was determined immediately after irradiation or after leaving the irradiated tumors
in situ for 1 to 5 days. The cell survival in individual irradiated tumors was normalized to the mean cell survival
of unirradiated control tumors (15 tumors).

Recent in vivo experiments using animal tumor models by Song et al. confirm that
indirect cell death is induced when tumors are irradiated with high-dose irradiation
(27). Figure 21.2 shows the effect of 10-, 15-, 20-, and 30-Gy irradiation in a single
dose on the surviving cell fraction in FSaII fibrosarcoma grown in the hind limb of C3H
mice. The cell survival was determined immediately after irradiation or after leaving the
irradiated tumors in situ for 1 to 5 days. The cell survival in individual irradiated
tumors was normalized to the mean cell survival of unirradiated control tumors (15
tumors). Figure 21.3 shows radiation survival curves of FSaII fibrosarcoma cells in vivo
obtained immediately (Day 0) and 5 days (Day 5) after irradiation with various doses,
based on the data from Figure 21.2. These data show that the surviving cell fractions on
day 5 were significantly smaller than those immediately after irradiation with 15 to 30
Gy due to the secondary cell death within 5 days after high-dose irradiation. The
radiation doses at which the indirect death is triggered may vary depending on various
factors including tumor type. For example, 10-Gy irradiation induced considerable
indirect cell death in Walker mammary tumors of rats whereas few cells died of indirect
effect after 10-Gy irradiation in FSaII mouse fibrosarcoma (Figure 21.2) (22).
When all the aforementioned literature and the representative data presented here, it
is evident that irradiation with high dose per fraction (>10 Gy) causes indirect death in
tumor cells by causing vascular damage. It may be further concluded that such
additional cell death through indirect mechanisms play an important role in the
response of tumor to high-dose SRS/SAbR and that fraction size is important to exploit

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the radiation-induced vascular damage.

Hypoxia-Inducible Factor 1-alpha and Vascular Endothelial Growth Factor


The role of HIF-1α and VEGF in the response of tumors to radiotherapy has become the
focus of much research (7–10). Colbert et al. (9) studied 98 patients with
adenocarcinoma of the pancreas and found HIF-1α expression correlated directly with
recurrence. Those patients with high HIF-1α expression were more likely to develop
distant metastases whereas those with relatively low HIF-1α expression were more likely
to have local recurrence (9). Lee et al. showed trimodality therapy (radiation and
inhibition of both HIF-1α and VEGF-A) was highly effective in blocking sarcoma growth
in a murine model by maximizing DNA damage and apoptosis in tumor endothelial cells,
leading to loss of tumor vasculature (10).

Figure 21.3 Cell survival curves by dose and time. Radiation survival curves of FSaII fibrosarcoma tumor cells in
vivo obtained immediately (Day 0) and 5 days (Day 5) after irradiation with various doses. The data points are
from Figure 21.2. These data suggest indirect cell death is dose dependent.

As discussed above (27), the secondary cell death in FSaII tumors progressed for
about 3 days after 15- or 20-Gy irradiation and then the surviving cell population
began to increase in some tumors whereas no such recovery of cell survival was evident
after 30-Gy irradiation. These results suggested that indirect cell death in FSaII tumors
is limited after irradiation with doses lower than 10 Gy. In these experiments,
irradiation of FSaII tumors with 20 Gy significantly increased the expression of both
HIF-1α and VEGF (Figs. 21.4 and 21.5). Such increases in HIF-1α and VEGF may
account for the recovery of surviving cell population following the initial indirect cell
death in the tumors irradiated with 15 or 20 Gy (Fig. 21.2). As shown in Figure 21.1,
eradication of the surviving hypoxia cells with hypoxic cytotoxins, and suppression of

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HIF-1α with small molecule inhibitors may prevent relapse and metastases caused by the
cells which escaped the direct and indirect insults of SRS/SAbR.

Evidence of Radiation-Induced Immune Enhancement with SRS/SAbR


Immunotherapy is an attractive therapeutic approach that harnesses the power of the
immune system to eliminate malignant disease. Many tumors express tumor-associated
antigens that can be recognized by T cells and have the potential to mount an immune
response that would cause tumor destruction (28). However, ionizing radiation is often
immunosuppressive because lymphoid tissues, including lymphocytes, are
radiosensitive. When patients are treated with conventional fractionated radiotherapy,
the multiple radiation exposure for a prolonged period may cause suppression instead
of augmentation of antitumor immunity. On the other hand, accumulating evidence
suggests radiation-induced immune enhancement in that high-dose local irradiation of
tumors elicits antitumor immune reactions (29–35). Indications are that extensive
injury and death of tumor cells caused by high-dose irradiation induces a massive
release of tumor-specific antigens as well as various pro-inflammatory and pro-oxidant
cytokines, leading to improvement of priming of tumor-specific T cells. In addition,
irradiation promoted the antigen presentation by increasing the activation and
maturation of dendritic cells (DCs), and also increased the traffic of effector T cells to
tumors. Finkelstein et al. showed SAbR can induce cellular expression of major
histocompatibility complex (MHC), adhesion molecules, costimulatory molecules, heat
shock proteins, inflammatory mediators, immunomodulatory cytokines, and death
receptors to enhance antitumor immune responses (33).
Although large field radiation has been historically associated with
immunosuppression, targeted radiation in SRS/SAbR doses has been shown to induce
changes in the tumor microenvironment beyond cellular cytotoxicity that evoke immune
enhancement, including changes in proinflammatory cytokines, chemokines, effector,
and immunosuppressive T-cell subsets as well as in immune receptors on tumor cells.
These changes have been linked to expansion of tumor-reactive T cells, improved
clinical responses, and increased overall survival in both preclinical and clinical models
(34). Thus, combination of SRS and/or SAbR with immunotherapy may be synergistic by
promoting the release and processing of antigens that can be presented by DCs. This
may then augment the response to treatments that expand or activate antitumor T cells
(35).
Postow et al. reported the abscopal effect, a phenomenon in which local radiotherapy
is associated with the regression of metastatic cancer in unirradiated locations, in a
patient with metastatic melanoma treated with SBRT (9.5 Gy × 3) and an immune
checkpoint inhibitor (ICI), ipilimumab, an inhibitor of cytotoxic T-lymphocyte–
associated antigen (CTLA-4), an immunologic checkpoint on T cells. The abscopal effect,
rare with conventionally fractionated radiation therapy, may be more common and
predictably induced with SRS/SAbR, which can cause massive antigen release from the
irradiated tumor, which then promotes the immunologic attack on other tumors (the
abscopal effect) (36). Just as the aforementioned vascular damage may vary by tumor
cell type, we hypothesize the extent of antigen release may vary by both dose and
volume of tumor irradiated. In summary, as shown in Figure 21.1, the ability of SRS or
SAbR to elicit antitumor immunity may be potentiated with the use of immune agents
targeting various steps of antigen processing, generation of effector cells, and
trafficking the effector cells into tumors.

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Figure 21.4 Immunohistochemical study for CA9, HIF-1α, VEGF, and CD3. FSall tumors grown in the hind
limb of C3H mice were irradiated with 20 Gy in a single exposure and tumors were dissected 1, 3, and 5 days
later. Tissues were sectioned and processed for immunohistochemical staining for CA9, HIF-1α, VEGF, and
CD31. Representative samples from control tumors and those 3 days after irradiation are shown. Results show
increased expression of HIF-1α and VEGF suggesting tumor response to radiation-induced hypoxia. A: Brown:
CA9 (Carbonic anhydrase 9). B: Dark brown: HIF-1α. C: Reddish brown: VEGF. D: Dark brown: CD31-
labeled micro vessels. E: Immunofluoresence assessment: Green: CD31-positive endothelial cells. Red: HIF-1α.
Blue: Nucleus stained with DAP1. D: Brown: VEGF.

The Debate Regarding the Applicability of the Linear Quadratic Model to SRS/SAbR
Given the aforementioned evidence of the vascular and immunologic changes associated
with SRS/SAbR, it is not surprising that many, if not most, investigators now believe the
traditional radiobiologic principles do not apply to SRS and SAbR (19,37,38,41).

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Nonetheless, the debate endures (37–41). First, the LQ model and the modified LQ
models are based on the assumption that radiation-induced cell death in tumors is due
solely to DNA double-strand breaks. The many seminal and recent articles cited herein,
however, strongly suggest that high dose/fraction (>10 Gy) radiation causes
devascularization in tumors, which then induces delayed indirect tumor cell death. The
massive cell death directly and indirectly caused by SRS/SAbR then would release large
amounts of tumor antigens leading to tumor-specific immune stimulation, thereby
inducing further indirect cell death. Thus it is reasonable to hypothesize that the doses
routinely delivered in SRS/SAbR would induce indirect cell death via both vascular and
immunologic effects. The cellular alpha/beta ratio in the LQ model is directly quantified
by an in vitro survival curve, which simply does not account for vascular or immune
responses. Therefore, we assert that applying the LQ model, which has been very useful
and extensively used for conventionally fractionated radiotherapy, to high
dose/fraction SRS and SAbR is conceptually flawed.

Figure 21.5 Hypothetical model of cell survival by dose. 0 to 5 Gy correlates with death well-oxygenated tumor
(curve a); 6 to 10 Gy correlates with death of hypoxic tumor (curve b); doses of >10 Gy correlate with indirect
delayed death of hypoxic cells by devascularization and possibly radiation-induced immune enhancement (curves
c and d).

Figure 21.5 illustrates hypothetical radiation cell survival curves of tumors irradiated
in vivo, which account for both high-dose radiation-induced vascular damage and
immune enhancement resulting in increased indirect cell death and improved tumor
control. If it is assumed that about 10% of tumor cells are hypoxic and that the
radiation-induced cell death occurs only by the classical radiobiologic principle, the
survival curve of tumor cells will be biphasic denoted by “a” and “b”: the initial rapid
decrease in cell survival “a” represents the death of oxic cells and the subsequent
gradual decline in cell survival with the increase in radiation dose indicated by “b”
corresponds to the death of hypoxic cells. However, it is likely that irradiation of tumors
with doses above 10 to 12 Gy causes vascular damage, thereby triggering indirect death
of hypoxic cells, as shown by the downward curve “c” or d (41).

CONCLUSION
Stereotactic radiation (both SRS and SAbR) is now more frequently used in the

613
treatment of intracranial and extracranial tumors. The rapid adoption of these
techniques is due largely to the technologic advances in positioning and targeting that
have made the precise delivery of such high doses both safe and effective. Multiple
clinical trials have confirmed dramatic improvement in tumor control for many
different types of tumors with SRS and SAbR. Even though SRS and SAbR are now
widely accepted as established treatment modalities in modern radiation oncology, the
radiobiologic rationale for SRS and SAbR has been unclear until recent laboratory
studies indicated that vascular damage and immune reaction may be responsible for the
high response rate of tumors to SRS and SAbR. It is well known that newly formed
tumor blood vessels are exquisitely sensitive to ionizing radiation. Various lines of
experimental evidence indicate that the high-dose radiation, that is, >10 Gy, per
fraction, causes marked vascular damage leading to deterioration of the intratumor
environment, which then causes secondary or indirect tumor cell death. In tumors
treated with SRS and SAbR, extensive initial cell death through direct effect and
vascular damage leads to release of antigens, which may be dose and volume
dependent. Conventional radiobiology principles cannot account for the high rates of
tumor control produced with high dose per fraction SAbR and SRS. The LQ model is for
cell death caused by DNA breaks, and thus the usefulness of this model for SAbR and
SRS is limited. Recent and future research will focus on methods to enhance indirect cell
death. This work will include the discovery and delivery of hypoxic cell cytotoxins,
inhibitors of HIF-1α, VEGF, and immune checkpoint inhibitors.

ACKNOWLEDGMENT
This work was supported by research funds from Elekta and the University of Minnesota
Foundation.

KEY POINTS
• While direct cell death remains important, recent research shows indirect cell death from
vascular and immunologic effects of high dose/fraction radiation (SRS/SAbR) play a key role
in the overall effect of these modalities.
• Hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and
various immune checkpoint inhibitors (ICI) may enhance indirect cell death associated with
SRS/SAbR.
• Radiation-induced immune enhancement (abscopal effect) is mediated by antigen release
from irradiated tumors, which then causes indirect cell death in un-irradiated tumors.
• Early results suggest the combination of SRS/SAbR and immunotherapy may be synergistic
by promoting the release and processing of antigens that can be presented by dendritic cells,
which may activate antitumor T cells and result in radiation-induced immune enhancement.
• The linear-quadratic model, although very useful for predicting the effects of conventionally
fractionated radiation therapy, does not take into account the indirect effects of SRS/SAbR,
and thus application of the LQ model to SRS/SAbR is conceptually flawed.

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QUESTIONS
1. Which of the following are possible mechanisms for indirect cell death in
SRS/SAbR?
A. DNA strand breaks
B. Tumor hypoxia from vascular effects of radiation
C. Radiation-induced immune effects
D. All of the above
2. Which of the following does not occur when fibrosarcoma in mice is irradiated
with 20 Gy?
A. Reduced blood perfusion of tumor.
B. HIF-1α is upregulated.
C. CA9 expression is increased.
D. VEGF expression is decreased.
3. True/False: Cell survival studies of fibrosarcoma treated with 30 Gy in a single
dose show that relative to day 1, no further cell death occurs by day 5.
4. True/False: Radiation-induced immune enhancement (abscopal effect) is a
phenomenon in which local radiotherapy is associated with regression of other
unirradiated tumors. This effect is rare with conventionally fractionated
radiotherapy. This effect has not been demonstrated in both preclinical and
clinical case reports in response to SAbR?
5. Although large field radiation therapy with conventional fractionation has
historically been associated with immunosuppression, targeted radiation in high
doses has been shown to induce immune enhancement, including changes in
proinflammatory cytokines, chemokines, effector, and immunosuppressive T cell
subsets as well as immune receptors on tumor cells. These changes have been
linked to which of the following?
A. Expansion of tumor-reactive T cells
B. Improved clinical responses
C. Increased survival in both preclinical and clinical models
D. All of the above

ANSWERS
1. D
2. D VEGF is increased. All of the above effects indicate increasing tumor
hypoxia.
3. False. Cell survival continues to decrease over that time period suggesting
both direct and subsequent indirect cell death.
4. False. The abscopal effect has been shown in response to SAbR in both
preclinical research and clinical case reports.
5. D

615
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22 Tolerance of Normal
Therapeutic Radiation
Tissue to

Bahman Emami and Fiori Alite

INTRODUCTION
Radiation therapy is an integral part of the treatment of patients inflicted with cancer.
It is estimated that over 60% of patients with cancer will have radiotherapy as part of
their total course of treatment (1). Radiation therapy affects both tumor cells and
uninvolved normal cells; the former to the benefit and the latter to the detriment of
patients. With the goal of achieving uncomplicated local regional control of cancer,
balancing between the two is both the art and science of radiation oncology.
Unfortunately, after over 100 years of practicing radiation oncology and in spite of
much recent progress, knowledge of either of the two is far from complete.
From a historical point of view, the first formal attempt to address at least one of the
goals, namely normal tissue tolerance to radiation, was carried out by Rubin and
Cassarett (2). Even though this publication was a collection of anecdotal reports, it has
served radiation oncologists as a raw reference to build on their own experience. The
decade of the 1980s represents a quantum leap of progress in the field of radiation
oncology. With the work of researchers on four National Cancer Institute multi-
institutional contracts, the science and practice of radiation oncology changed from a
two-dimensional to a three-dimensional/volumetric process (3). During the work on
these contracts it became apparent to the clinicians that information on the tumoricidal
doses of radiation as well as normal tissue complication doses, especially on partial
volumes, is mostly empirical and totally inadequate. A committee was formed to address
a part of this dilemma by comprehensively reviewing the available published data. In
the process of this review by the committee, it became clear that much of the data was
nonexistent and they would have to rely on the collective experience of eight clinicians
from major institutions in the United States. Moreover, in order to shed some light on
the volumetric aspect of these issues, it was decided that organs be divided into one-
third, two-thirds, and whole-organ volumes. In spite of the clear indication in the
manuscript on the paucity of solid experimental/prospectively driven data, this
publication by Emami et al. gained much popularity. Obvious limitations of the
publication include: (1) It was literature review up to 1991. (2) It completely pre-dated
the 3DCRT-IMRT-IGRT era. Even at that time dose–volume histograms were not in
routine clinical use. (3) It was a tabulation of the estimates for three of the
aforementioned arbitrary volumes. (4) It was only for external beam radiation with
conventional fractionation. (5) Only one severe complication was chosen as an
endpoint.
During the last two decades, the practice of radiation oncology has been completely
revolutionized. Multidisciplinary management of cancer has become the standard of
care. The choice of an endpoint for complication analysis and modeling has
significantly changed. There has been a major change in technology with the routine
use of CT simulation and the incorporation of other modalities such as MRI, PET, 4D-

619
CT, etc. In addition, 3D-CRT/IMRT/IGRT has become standard with an array of
evaluation tools. There has also been a vast amount of published information that has
become available to address the relationship between dosimetric parameters and the
clinical outcomes of normal tissues. Due to different analytic methodologies, calculation
methods, endpoints, grading schemes, etc., the data is noisy and sifting through these
data for practicing radiation oncologists represents a nearly impossible task. Realizing
this difficulty and the obvious need for a simplistic format, a group of physicians and
researchers were formed with the name “The Quantitative Analysis of Normal Tissue
Effects in the Clinic” (QUANTEC). The first goal was to review the available literature of
the last 18 years on volumetric/dosimetric information of normal tissue complication
and provide a simple set of data to be used by the busy community practitioners of
radiation oncology, physicists, and dosimetrists. The second goal of the QUANTEC
group was to provide reliable predictive models on relationships between dose–volume
parameters and the normal tissue complications to be utilized during the planning of
radiation oncology. The results of several years of data collection since the original
work by Emami et al. culminated in the publication of the so-called QUANTEC “white
papers” in 2010 (4–6,27). Although these publications contain a comprehensive review
of published information and can serve as a guide for future research on this issue, they
still have many shortcomings mainly due to the basic complexity of the subject (26–27).
This shortcoming has been clearly indicated in the QUANTEC publication and the need
for much more data in the future has been emphasized. However, the presented data in
the publication is still cumbersome and lacks the “user-friendliness” required for it to be
used in the day-to-day practice of a busy community clinician. As shown in Table 22.1,
there are numerous factors that affect the radiation-induced complications of normal
tissues on any given clinical situation (23–25). Thus, the experience and judgment of
the clinician still plays the most important role in treating patients.
After reviewing the publication by the QUANTEC group, we attempt to provide the
clinicians and the practitioners of radiation oncology a comprehensive but simpler,
more user-friendly set of data (Tables 22.2 and 22.3). Several additional organs/tissues
are also reviewed that were not discussed in the QUANTEC publication, as well as our
constraints for hypofractionated regimens. It should be noted that the data is not
intended to be extrapolated to pediatric patients. The data should be used only as a
guide and does not substitute for a physician’s clinical judgment. We believe, as
indicated in the QUANTEC publication, there is an urgent need for systematic research
on this issue which we hope will be forthcoming.
TABLE 22.1 Variables That Can Impact Normal Tissue Tolerance

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TABLE 22.2 Normal Tissue Tolerance for Standard Fractionation

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TABLE 22.3 Normal Tissue Dose Tolerances for Hypofractionated Regimens Synthesized from
Available Literature

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623
624
Word of Caution About BED
Recently it has become popular (as in many sections of QUANTEC publication) to
convert the dose–fractionation to a biologically effective dose (BED) in order to compare
various dosimetric parameters. A practical version of isoeffect formula based on the
linear-quadratic (LQ) model is:

The index of α/β is calculated based on information from cell survival curves and has
been extrapolated and extended to human tumor and normal tissues by some computer
scientists. Unverified assignment of an α/β ratio and using it to calculate a normal
tissue tolerance dose can be misleading, or at least should be experimentally validated
before being recommended for routine clinical use (7,9,10). The following are some
basic facts based on current knowledge:

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The following example depicts the basic fallacies of using BED, calculated from the
above formula, in clinics.

If we arbitrarily choose 1 Gy/fraction/day of brain tissue, then the conversion of BED


to dose/fractionation of 1 Gy/day:

In the authors’ limited informal survey, no radiation oncologists would use 90 Gy at 1


Gy/day or 45 Gy at 3 Gy/day (despite being the same BED as 60 Gy in 30 fractions
using an α/β of 1), thus limiting the applicability of BED for routine clinical use.
The following descriptive paragraphs of Tables 22.2 and 22.3 are presented as
general guidelines.
Note: Evolution of Dose Calculation and Treatment Planning System
As treatment planning systems continue to evolve in their ability to calculate planned
dose with higher precision, significant dose discrepancies between calculation

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algorithms have been reported in the literature that will require a reevaluation of organ
at risk tolerance doses. For example, we have demonstrated that utilizing Monte Carlo–
based treatment optimization to achieve constraints previously developed in an era of
pencil-beam algorithms without heterogeneity corrections results in significant
differences from normal tissue RTOG constraints (80). As an era of higher accuracy
Monte Carlo treatment planning is ushered in, it is important that normal tissue
constraints be reevaluated to reflect this change.

Standard Fractionation

Central Nervous System


Brain. Radiation necrosis of the brain typically occurs 3 months to several years after
radiotherapy (median 1 to 2 years) (3,7). The original Emami publication estimated a
5% risk of radionecrosis at 5 years with a dose of 60 Gy to 1/3 of the brain with
standard fractionation (3). More recently, QUANTEC conducted an extensive review of
the modern literature and published new dose constraints for the brain (6,7). The
review was based on a heterogeneous group of studies with varied dose and
fractionation schemes. Studies were compared using the biologically effective dose
(BED) with an α/β ratio of 3. A dose–response relationship was found to exist. For
standard fractionation, the incidence of radionecrosis appears to be <3% for a dose of
<60 Gy. The incidence increases to 5% with a dose of 72 Gy and 10% with a dose of
90 Gy. However, these doses were based on studies with widely varying parameters
(target volumes, sample size, brain region, etc.). It should be noted that an α/β ratio of
3 is greater than the values frequently used in the literature and caution should be used
when converting to BEDs (see above discussion). In our practice, we strive to achieve
very homogeneous dose distributions with a Dmax (point dose) ≤65 Gy with only rare
occurrences of symptomatic radiation necrosis (personal data, unpublished).

Brainstem. RT-induced brainstem toxicity can be incapacitating and potentially lethal.


The initial estimates by Emami et al. (3) were of a TD 5/5 of 50 Gy to the entire
brainstem and 60 Gy to 1/3 of the brainstem. These estimates were based on the scant
amount of data in the literature at that time and on clinical experience. The QUANTEC
review identified additional modern series focusing on brainstem dose and dose–volume
measures (6,9). The review included series that treated patients with either photons,
protons, or both. The QUANTEC review concluded the original Emami constraint of 50
Gy was overly conservative. The entire brainstem can tolerate up to 54 Gy with a <5%
risk of brainstem necrosis or neurologic toxicity. Small volumes (1 to 10 cc) can tolerate
up to 59 Gy while a point (<<1 cc) may receive up to 64 Gy.

Spinal Cord. Spinal cord injury due to irradiation, though rare, can be extremely
debilitating resulting is paralysis, sensory, deficits, pain, and bowel/bladder
incontinence (10,30). Schultheiss (30) published an extensive review of the literature
regarding de novo irradiation of the spinal cord. Among the reviewed studies, a wide
range of fractionation regimens were used (2 to 9 Gy/fraction). An α/β ratio of 0.87 was
estimated for the spinal cord and corresponding 2-Gy equivalent doses were calculated.
The review estimated the risk of myelopathy to be 0.2% at 50 Gy and 5% at 59.3 Gy.
Similar conclusions regarding α/β ratio and dose–volume limits were published by
QUANTEC (6,10). It should be noted that an α/β ratio of 0.87 is less than the values
frequently used in the literature and caution should be used when converting to BEDs
(see above discussion).

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Chiasm and Optic Nerves. Radiation-induced optic neuropathy (RION) is infrequent
but usually results in rapid painless visual loss (8). The initial Emami review listed a TD
5/5 of 50 Gy to the whole organ without partial volume tolerance data (3). Again, this
was based primarily on clinical experience and sparse published data. Many more
studies are now published and were reviewed by QUANTEC (6,8). Based on the
QUANTEC review, a Dmax of 50 Gy is associated with a “near-zero” risk of blindness. In
fact, blindness was quite rare (<3%) until a Dmax of ≥55 Gy. Between 55 and 60 Gy,
the risk of blindness is approximately 3% to 7%, although it must be noted that except
for patients being treated for pituitary tumors where there is optic nerve compression,
in standard fractionated patients none experienced RION at doses less than 59 Gy (see
Figure 1 in Mayo et al. (8)). At doses >60 Gy, the risk of RION greatly increases.

Head and Neck


Retina. Radiation retinopathy, resulting in loss of vision or visual acuity, presents
similarly to diabetic retinopathy often within 5 years of radiotherapy. Parsons (31,32)
reported only one instance of retinopathy with a dose <50 Gy to at least half the
posterior pole of the eye with a steep dose–response curve at doses >50 Gy.
Subsequently, Parsons et al. (33) demonstrated no cases of retinopathy at doses below
45 Gy but a steep dose curve at doses >45 Gy. More recently, Monroe et al. reported a
4% rate of retinopathy after <50 Gy was received by at least 25% of the globe with
conventional fractionation and modern conformal techniques (34). Using
hyperfractionation, the rate of retinopathy decreased from 37% to 13% with doses ≥50
Gy. Takeda et al. reported no cases of retinal complications when the Dmax was <50
Gy (35). Clearly, the dose tolerance of the retina is dependent upon multiple factors
including predisposing comorbidities, the fractionation schema employed, and the
volume that is irradiated. Multiple publications have demonstrated a steep dose–
response curve for doses >50 Gy (33–35). Using modern treatment planning techniques
and standard fractionation, we recommend limiting the retina to a Dmax <50 Gy
consistent with current RTOG protocol guidelines (76–78).

Lacrimal Gland. Severe dry eye leading to visual compromise can develop in patients
receiving head-and-neck radiation. In a review of 78 patients, Bhandare et al. noted 40
cases of severe dry eye syndrome, with incidence increasing from 6% at mean total
doses of 35 to 40 Gy to 50% at 45 to 50 Gy and 90% at 60 to 65 Gy. Higher total doses
and dose per fraction to the lacrimal gland also correspond to faster time to the onset of
severe dry eye symptoms (81,82).

Cochlea. Damage to the cochlea may result in sensorineural hearing loss (SNHL). As
summarized by QUANTEC, high-frequency hearing loss is much more common than low-
frequency hearing loss (11). Cisplatin-based chemotherapy can have an additional
adverse effect on SNHL. The definition of clinically significant SNHL varies throughout
the literature but is generally considered to be an increase in bone conduction threshold
of 10 to 30 dB. The QUANTEC review examined several series and suggested a mean
dose constraint of ≤45 Gy (6,11). Chan et al. conducted a longitudinal study of 87
consecutive patients treated for nasopharyngeal carcinoma, mostly treated with
cisplatin-based chemoradiotherapy (36). A mean dose of ≤47 Gy to the cochlea resulted
in <15% rate of SNHL. Therefore, based on a review of the literature with modern
treatment planning techniques and concurrent cisplatin chemoradiotherapy, we believe
a cochlear mean dose constraint of ≤45 Gy will result in a <15% rate of SNHL.

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Parotid. Late salivary dysfunction is a common toxicity from radiotherapy for head-
and-neck cancer that can take up to 2 years to recover (37,38). Xerostomia has been
widely defined in the literature from patient-reported outcomes to objective salivary
flow. Quantifiably, xerostomia is defined by the LENT-SOMA scale. Grade 4 xerostomia
consists of an objective reduction of ≥75% of baseline salivary function. The QUANTEC
review (6,12) summarized the literature including the Washington University
experience (37). Blanco demonstrated that sparing (mean dose <20 Gy) of at least one
parotid gland minimized the incidence of grade 4 xerostomia. Likewise, limiting both
parotids to a mean dose <25 Gy resulted in minimal of grade 4 xerostomia. Dose to the
parotids should be reduced as much as clinically allowable as lower mean doses
generally result in better salivary function (12).

Mandible. The rates of osteoradionecrosis (ORN) of the mandible have decreased over
the past few decades (39). The risk of ORN is dependent on several factors including
radiation dose, use of chemotherapy, dental hygiene, tumor location, mandibular
surgery, and radiation technique (39–44). Ben-David et al. (40) demonstrated a steep
dose fall-off across the mandible when IMRT is employed. In their study, 50% of the
patients in their study received ≥70 Gy to ≥1% of the mandibular volume with no
cases of grade ≥2 ORN. Additional studies, including IMRT for oral cavity cancers,
demonstrate a rate of ORN near 5% (41–43). Therefore, we recommend limiting the
mandible to a Dmax (point dose) ≤70 Gy when using IMRT. However, there may be
clinical scenarios where, based on the judgment of the clinician, it may be necessary for
larger volumes of the mandible to receive higher doses of radiation in order to achieve
adequate tumoricidal dose and target coverage.

Pharyngeal Constrictors. Treatment intensification for head-and-neck cancer has


resulted in an increased rate of late sequela including dysphagia and aspiration.
Modern treatment planning has allowed the study of various components of the
swallowing apparatus. The results in the literature in this burgeoning area of research
are variable as summarized in the QUANTEC review (6,13). Several groups have found
the dose to the superior and/or middle pharyngeal constrictor muscles to be of
paramount importance. Others have demonstrated the dose to the inferior pharyngeal
constrictors or larynx to be of importance. Feng et al. (45) found no patients to have
aspiration when the pharyngeal constrictors were limited to a mean dose <60 Gy. We
base our practice primarily on the findings from the University of Michigan and limit
the superior pharyngeal constrictors to a mean dose <60 Gy whenever clinically
possible after maintaining appropriate tumoricidal dose and target coverage.

Larynx. Toxicity from radiotherapy to the larynx can include vocal dysfunction and
laryngeal edema. The original Emami publication (3) addressed the risk of cartilage
necrosis; however, this is rarely seen in modern radiotherapy and is not as relevant of
an endpoint as vocal function and laryngeal edema. The QUANTEC publication
reviewed several studies involving vocal dysfunction, concluding doses to multiple
structures (larynx, pharynx, oral cavity) play an important role in voice function (6,13).
Radiotherapy is commonly used for the treatment of early-stage glottic cancer,
employing doses >60 Gy, with a good voice outcome. A single publication (46) on
laryngeal edema was reviewed, which found <20% incidence of ≥grade 2 edema when
the mean laryngeal dose was <43.5 Gy and the V50 <27%.

Thyroid. Radiation-induced clinical hypothyroidism is a documented late effect after


tumor-directed radiation therapy to the region of the neck. Reports of incidence have

629
varied based on clinical definition and extent of cancer-directed therapies employed. A
recently published normal tissue complication probability (NTCP) model for radiation-
induced biochemical hypothyroidism (TSH >4) has related mean thyroid dose to
irradiated thyroid volume. Dose constraints for a 25% risk of hypothyroidism were 26,
38, 4,8 and 61 Gy for thyroid volumes of 10, 15, 20, and 25 cc, respectively (83).

Thorax
Brachial Plexus. Brachial plexopathy can manifest as pain, paresthesias, or motor
deficits of the upper extremity (47). Muscular atrophy and edema may develop. Emami
et al. (3) suggested the TD 5/5 to the entire brachial plexus was 60 Gy. More recently,
several studies with over 20 years of follow-up have suggested that the incidence of
brachial plexopathy continues to rise after 5 years and may not be apparent for up to
20 years after radiotherapy (47,48). The brachial plexus appears to be especially
sensitive to fractionation schedules, with the risk of injury much higher for larger
fractions despite equivalent BED (49). With standard fractionation the risk of clinically
apparent nerve damage seems to be <5%, after 5 years of completing radiotherapy,
when the brachial plexus is limited to 60 Gy.

Lung. Symptomatic radiation pneumonitis (RP) is one of the most common toxicities in
patients treated with radiation for cancers of the lung, breast, and mediastinal
lymphatics. The risk of RP often limits the dose delivered for the treatment of these
malignancies. Since the initial Emami publication (3) there has been an extensive
amount of research attempting to relate many different dose–volume parameters to RP.
The QUANTEC publication reviewed >70 published articles looking at both mean lung
doses and Vx parameters (6,14). This comprehensive review demonstrated no clear
threshold dose for symptomatic RP. The compiled data showed a mean dose–response
curve with a 20% risk of RP for a mean lung dose of 20 Gy. In addition, multiple Vx
values have been investigated for predicting RP but the data are not as consistent as the
data for mean lung doses. Using 3D techniques, Graham found the V20 to be the most
useful parameter for predicting the risk of RP (50). When Vx values are used, the V20 is
the most commonly incorporated parameter.

Esophagus. Acute esophagitis commonly occurs during radiotherapy for thoracic


malignancies and can lead to hospitalizations, procedures, and treatment breaks (16).
Most series in the literature report rates of RTOG grade ≥2 esophagitis. The QUANTEC
review summarized 11 studies that used three-dimensional treatment planning (6,16). A
single best parameter was not identified due to the diverse range of dose–volume
metrics that correlated with acute esophagitis (51–53). As demonstrated in the
QUANTEC publication, there appears to be a trend demonstrating increased rates of
acute esophagitis for volumes receiving >40 to 50 Gy. Currently, the ongoing RTOG
0617 is collecting V60 data on all patients and recommends keeping the mean dose
<34 Gy (54).

Heart. Clinical pericarditis and long-term cardiac mortality are the two most relevant
cardiac toxicities. Since the original Emami publication (3), there remains a paucity of
data reporting rates of pericarditis with dose–volume parameters. Indeed, several
current RTOG protocols continue to use constraints similar to the original Emami TD
5/5 dose–volume estimates for the heart (54–56). As reviewed by QUANTEC (6,15), two
esophageal cancer studies (57,58) assessed 3D-derived data with both studies
demonstrating a rate of pericarditis <15% when the mean pericardial dose was <26

630
Gy. In addition, Wei found the pericardial V30 <46% to be significant on multivariate
analysis. Long-term cardiac mortality has been demonstrated in multiple studies, most
commonly in the treatment of breast cancer and Hodgkin lymphoma (15). A joint
analysis of the Hodgkin and breast cancer data (59,60), summarized by QUANTEC,
produced a dose–response curve for cardiac mortality. QUANTEC proposed a
conservative approach, predicting a V25 <10% of the heart will be associated with a
<1% probability of cardiac mortality at 15 years after radiotherapy.
A recently published population-based case-control study analyzing over 2,000
women treated for breast cancer in Sweden and Denmark from 1958 to 2001
demonstrated a dose–response relationship for mean heart dose and major coronary
events including myocardial infarction, coronary revascularization, and death from
ischemic heart disease (84). The study noted an increase of 7.4% risk for major
coronary events for each additional Gray to mean heart dose, and no threshold for
initiation of increased risk was found. Current RTOG protocols have placed an
unacceptable deviation for mean heart dose of greater than 500 cGy, and per protocol
goal of V20 less than 5% for left-sided treatments (85,86).

Abdomen
Liver. Radiation-induced liver disease (RILD) typically occurs between 2 weeks and 3
months after radiotherapy. Pre-existing liver disease may render patients more
susceptible to RILD (17). The findings by QUANTEC (6,17) are very similar to the
original estimates by Emami et al. (3), suggesting a <5% rate of RILD when the mean
liver dose is ≤30 Gy in patients without pre-existing liver disease or primary liver
cancer. The mean liver dose should be ≤28 Gy in those patients with pre-existing liver
disease.

Kidney. Radiation-induced renal dysfunction can be expressed in various ways


including symptomatic expression, biochemical changes, or radiologic findings. As
summarized by QUANTEC, a wide array of endpoints has been used in the literature
from a decrease in creatinine clearance to renal failure (6,19). For bilateral whole
kidney irradiation, a pooled analysis by Cassady (61) concluded a mean dose of 18 Gy
corresponded to a 5% risk of injury at 5 years. For bilateral partial kidney irradiation,
the data is less clear with a multitude of dose–volume metrics studied by several
investigators (19). Small volumes of the kidney can tolerate relatively high doses of
radiation. QUANTEC estimated a <5% risk of injury for the combined kidney when V20
<32%. A recent RTOG protocol limited the combined kidney D50 <18 Gy and the
mean dose <18 Gy (79). In addition, the current common practice of limiting the
equivalent of one kidney to <20 Gy seems to be reasonable and is frequently used in
our practice.

Stomach. Late radiation-induced toxicity to the stomach can include dyspepsia and
ulceration. Since the original Emami publication (3), few studies have reported severe
RT-related gastric toxicity. The QUANTEC publication reviewed these studies, primarily
pancreatic cancer trials, and concluded a whole-organ dose of 50 Gy has been
associated with a 2% to 6% risk of severe late toxicity (6,18) (similar to Emami et al.).

Small Bowel. Small bowel toxicity can be greatly affected by the use of concurrent
chemotherapy and prior abdominal surgery. In particular, concurrent chemotherapy
can impact the rates of acute small bowel toxicity. Modern series employing 3D-
conformal RT or IMRT have demonstrated that the volume of small bowel receiving

631
relatively low doses of radiation plays a significant role in the rate of acute toxicity
(18). When contouring individual bowel loops, the most robust dose–volume metric is
the V15. The rate of grade ≥3 acute toxicity is <10% when the V15 <120 cc (62,63).
When the entire potential space within the peritoneal cavity is contoured, a V45 <195
cc results in <10% acute toxicity (64). Late small bowel toxicity, consisting of
obstruction or perforation, can be influenced by prior abdominal surgery. Modern series
reviewed by QUANTEC generally confirm the Emami et al. (3) TD5/5 estimate for
partial organ irradiation (6,18). In practice, we limit the volume of the small bowel
receiving 50 Gy to much less than 1/3. We generally limit the V50 <5% based on the
clinical scenario.

Pelvis
Rectum. The treatment of prostate cancer has evolved such that the great majority of
patients will be alive for many years after radiotherapy. Late rectal toxicities from
radiotherapy can significantly impact quality of life. Since Emami et al. (3), numerous
studies have employed dose escalation using 3D-CRT or IMRT for the treatment of
prostate cancer. These trials have resulted in the publication of many dose–volume
analyses as summarized by the QUANTEC review (6,21). The dose–volume results are
surprisingly consistent suggesting that high doses are most important in determining
risk of toxicity.

Bladder. The bladder frequently receives radiation during the treatment of commonly
encountered pelvic malignancies such as prostate, cervical, and bladder cancer. Due to
the distensibility of the bladder it is difficult to conduct robust dose–volume analyses.
The QUANTEC publication was unable to find any reliable data for partial bladder
volume constraints in the treatment of prostate cancer and recommended using RTOG
0415 dose limits (6,20,65). In the treatment of bladder cancer, where the entire organ
is targeted, rates of severe late bladder toxicity are varied (20). Shipley et al. (66)
reported the pooled results of multiple RTOG trials demonstrating a grade ≥3 toxicity
rate of ≤6% when treating the bladder to a dose of 64 to 65 Gy.

Penile Bulb. Erectile dysfunction can have a significant detrimental effect on quality of
life after treatment for prostate cancer. QUANTEC summarized the published studies
correlating the dose and volume of the penile bulb that is irradiated with rates of
erectile dysfunction (22). The results for various dose–volume parameters are
conflicting. There is some data to support limiting the D70 <70 Gy and D90 <50 Gy.
However, the strongest data support the recommendation of limiting the penile bulb to
a mean dose <52 Gy without compromising target coverage (67).

Femoral Head. Toxicity of radiation treatment to the pelvis includes femoral head
necrosis, femoral neck fracture, or long-term sequela resulting in hip replacement
surgery. Besides radiation dose and volume, additional risk factors may include pre-
existing osteoporosis/osteopenia and androgen deprivation therapy (68–70). Emami et
al. (3) suggested a TD 5/5 of 52 Gy to the whole femoral head. Grigsby et al. published
the Washington University experience and documented a 4.8% incidence of femoral
neck fracture following groin irradiation (68). Of note, there was only one case of
femoral neck fracture when the whole femoral neck received ≤50 Gy. There is little
data describing femoral toxicity when higher doses are delivered to small volumes of the
femoral head or neck (71–74). We generally limit the entire femoral head to <50 Gy in
an attempt to limit femoral head/neck toxicity to <<5%.

632
Hypofractionation
Some of the earliest radiotherapy treatments were delivered using hypofractionated
dose regimens. As technology and radiobiology advanced, protracted fractionation
schemes became the norm. Eventually, hypofractionation was again pursued and used
to treat intracranial lesions. Stereotactic radiosurgery (SRS) has been used for decades
and its success led to the use of hypofractionated treatment outside of the brain. Over
the past 15 years, the use of stereotactic body radiotherapy (SBRT) has become
widespread and utilized to treat a number of cancers. Its role continues to expand,
especially in the setting of early-stage NSCLC, prostate adenocarcinoma, and treatment
of oligometastases. The QUANTEC group reviewed the literature pertaining to SRS and
published tolerance doses for some CNS organs at risk (6–11). The most comprehensive
review to date has been published by Timmerman, and reviewed by Grimm et al.
(75,87). In Table 22.3 we provide a synthesized data of this table, and in Table 22.4 we
provide an example of standardized dose constraints used in our clinic for lung SBRT.
Both intracranial and extracranial organ tolerances were reviewed and adjusted for
either single-fraction, three-fraction, or five-fraction treatments. Because the data in this
burgeoning modality is relatively limited, the dose constraints are largely not validated.
Rather, they are based on a combination of published data, clinical observations,
modeling, and educated guessing. Despite these caveats, the dose constraints adapted
from the Timmerman and Grimm reviews provide an excellent starting point for
adaptation in the clinic (see Table 22.3). The QUANTEC steering committee has
expressed interest in developing a similar set of guidelines in setting of SBRT and
hypofractionation as data in these fields evolves.
TABLE 22.4 Guidelines Employed by Loyola University Medical Center for 50 Gy in Five-
Fraction Thoracic Stereotactic Body Irradiation

633
Conclusion
From the pioneering work of Rubin and Cassarett, to the historic work by Emami et al.
and now the exhaustive review by QUANTEC, great progress has been made in the field
of normal tissue tolerance to therapeutic radiation. Despite these efforts, many
questions still remain. Normal tissue tolerance is an extremely complex issue and
multifactorial in nature. There continues to be an urgent need for comprehensive and
collaborative research. The preceding dose–volume parameters should only be used as a
guide. For instance, there are clinical scenarios where a 5% rate of a particular toxicity
is unacceptable. In contrast, there may be cases where one is willing to accept the risk a
20% rate of a particular side effect in order to obtain a desired clinical outcome.
Therefore, it is imperative that the clinical judgment of the treating physician prevails
in the treatment decision-making process.

KEY POINTS
• Multiple clinicopathologic, treatment, and reporting variables can impact normal tissue
tolerance.

• The history and evolution of normal tissue tolerance to radiation therapy culminated with the
publication of the Emami estimates of normal tissue constraints (3).

634
• The normal tissue compatibility models of the quantitative analysis of normal tissue effects in
the clinic (QUANTEC) was developed to integrate additional studies providing
dose/volume/outcome data.

• Radiobiologic dose and fractionation principles that guide tumor control probability can
affect normal tissue tolerances, but there are limitations to applying these principles in the
clinic.

• Table 22.3 provides normal tissue constraints for each organ at risk site, integrates the most
up-to-date literature, and provides dose constraints for several hypofractionated regimens.

QUESTIONS
1. According to Darby et al., the increase per Gray (Gy) of Mean Heart Dose (MHD)
resulted in an increase of what percentage of risk for major coronary event?
A. 1%
B. 7%
C. 15%
D. 35%
E. 50%
2. Which of the following variables can affect the rate of risk of development of
clinically relevant radiation pneumonitis in a patient undergoing
chemoradiation for stage IIIA lung cancer?
A. Age
B. Smoking status
C. V20
D. Previous contralateral lobectomy
E. All of the above
3. According to QUANTEC, what is the maximum brainstem dose that results in
<5% risk of neuropathy for patients undergoing single-fraction stereotactic
radiosurgery?
A. 5 Gy
B. 12.5 Gy
C. 27 Gy
D. 25 Gy
E. 50.4 Gy
4. How many cubic centimeters of normal liver must be spared at least 17 Gy in
order to maintain normal liver function in three-fraction stereotactic body
radiation therapy?
A. 100 cc
B. 300 cc

635
C. 700 cc
D. 1,000 cc
E. 1,300 cc
5. The alpha/beta ratio for most tumors and normal tissues is empirically derived
from which of the following?
A. Large retrospective datasets comparing dose per fraction and local control
and tissue toxicity.
B. Large prospective datasets comparing dose per fraction and overall survival
and tissue toxicity.
C. Large case-control datasets comparing dose delivered and risk of normal
tissue complication.
D. For a particular cell line, plotting the log of the surviving fraction versus
dose, and calculating the dose at which the linear and quadratic
contributions to cell killing are equal.

ANSWERS
1. B 7%. According to recently published case cohort review by Darby et al.
(84), with each Gy increased of MHD, there was a 7.4% increase in risk of
major coronary event, which included myocardial infarction, coronary
revascularization, and death from ischemic heart disease.
2. E All of the above. Several clinicopathologic as well as treatment
characteristics can affect the rates of risk of developing normal tissue
toxicity. See Table 22.1.
3. B 12.5 Gy. According to Mayo et al. (9) maximum brainstem dose of 12.5
Gy is associated with low (<5%) risk of brainstem toxicity.
4. C 700 cc is an important partially spared volume of liver that has been
shown to correlate with radiation-induced liver disease. See Table 22.3.
5. D For a particular cell line, plotting the log of the surviving fraction versus
dose, and calculating the dose at which the linear and quadratic
contributions to cell killing are equal. It is important to note that BED
calculations are dependent on alpha/beta ratios, which are derived from
colony assays performed on individual cell lines. Unverified assignments
of an alpha/beta ratio and using it to calculate a normal tissue tolerance
dose can be misleading, or at least should be experimentally validated
before being recommended for routine clinical use (7,9,10).

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1431.

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23 Treatment Plan Evaluation

Ellen D. Yorke, Andrew Jackson, and Gerald J. Kutcher

Since the previous edition of this book, the basic tools of plan evaluation—dose–volume
histograms (DVHs) and high-quality graphic dose displays—have not changed except
for increase in calculation speed. These tools are available on all modern treatment
planning systems and are almost universally used. A variety of dose–volume metrics
that have been shown to correlate with outcomes are applied in daily clinical practice.
“Biologic models” which condense the entire dose distribution into a single number that
represents the probability of a specified outcome are not widely used in clinical practice
but are still of interest, and increasingly sophisticated statistical techniques are being
used to extract model parameters and significant dose–volume points from clinical data.
The report of AAPM’s Task Group 166, “The Use and QA of Biologically Related
Models for Treatment Planning,” (1) includes a thorough review of current models and
their implementations in commercial treatment planning systems for planning and plan
evaluation.

INTRODUCTION: WHAT IS NEW?


Since the late 1990s, three-dimensional conformal radiation therapy (3DCRT) has gone
from novel to passé, use of intensity-modulated radiation therapy (IMRT) has burgeoned
and other delivery techniques—volumetric-modulated arc therapy (VMAT),
tomotherapy, “CyberKnife”—are now routinely used. Greatly increased computer speed
and graphic capabilities make it possible to routinely plan these treatments in busy
clinics—indeed, many planners find it easier to generate an IMRT or VMAT plan than a
3DCRT plan. Registered positron emission tomography (PET) and magnetic resonance
imaging (MRI) studies are routinely used to supplement the planning computerized
tomography (CT) scan. Treatment accuracy has been greatly increased by readily
available tools for online image guidance. Partly thanks to this image-guided radiation
therapy (IGRT), it is now possible to safely and effectively deliver highly
hypofractionated treatment schedules to tumors anywhere in the body using stereotactic
body radiotherapy (SBRT) (also called stereotactic ablative body radiotherapy [SABR]).
SBRT consists of a small number (1 to 10) of daily fractions, each delivering a high dose
per fraction (5 to 30 Gy). SBRT is perhaps the greatest change in radiation therapy
since the advent of IMRT and its use has grown explosively (Fig. 23.1). It provides
superior tumor control with a remarkably low rate of serious complications, although
some new and unexpected complications have been observed (2,3). There is incomplete
mechanistic understanding of the excellent tumor control but the rarity of serious
complication is at least partly due to very accurate setup with online image guidance
(IGRT) and the fact that many applications of SBRT are to small tumors (<100 cc).
Thanks to the combination of 3D IGRT and increasing planning computer speed,
clinicians are more seriously considering both online and off-line “adaptive
radiotherapy,” where plans are changed during a treatment course to accommodate
anatomical changes such as tumor shrinkage or growth.
Knowledge of relationships between dose distributions, medical variables, and normal

643
tissue complications continues to grow as researchers take advantage of electronic
medical records to more readily analyze outcomes from single and multi-institutional
patient cohorts. The systematic reviews of publications on normal tissue complications
by the “QUANTEC” (Quantitative Analysis of Normal Tissue Effects in the Clinic) group
have provided updated treatment planning dose–volume guidelines and impetus for
new studies to address areas where information is lacking (4). Members of the American
Association of Physicists in Medicine (AAPM) can access the QUANTEC reports through
the AAPM website.

INTRODUCTION: NOT NEW BUT NECESSARY


Inspecting isodose distributions superimposed on a patient’s planning CT scan (or on a
registered PET or MRI scan) remains an important plan evaluation tool that can rapidly
inform the planner of deficiencies in the dose distribution. The rapid volumetric dose
calculations of modern planning systems allow users to rapidly scroll through the
treated volume for a complete picture of the dose distribution in relation to anatomy
and locate hot and cold spots with a single mouse click. For complex plans, this is a
great improvement over the traditional “three principal planes through isocenter”
displays. Clinicians often prefer uniform target dose distributions unless there is a
deliberate effort at nonuniform target coverage—called simultaneous integrated boost
(SIB) or “dose painting” (5). The planner can deal with unintended high-dose regions by
changing beam number or directions, using higher-energy beams and using dose-
controlling “dummy structures” in optimization to arrive at a final plan. Graphic
displays also provide useful geometric information such as whether a beam enters
through a support device where attenuation must be considered or unnecessarily
through an organ at risk (OAR), or whether the planning scan was acquired with an
inadequate field of view such that a beam appears to traverse a shorter path length
than it does in reality. However, for most people, graphic displays are hard to interpret
in a comprehensive manner. For optimum plan evaluation, they should be used in
parallel with the two general sets of tools described below: DVHs, based on either
physical or biologically equivalent doses, and metrics derived from biologic models of
tumor control probability (TCP) and normal tissue complication probability (NTCP).

Figure 23.1 Growth in the number of Radiation Oncology articles dealing with SBRT and in PubMed. There
were approximately 1,500 articles in 2014. Data from Dr. Jimm Grimm.

The questions posed in the previous edition of this book still plague clinicians:
Conventional evaluation of treatment plans, which judges a “best treatment plan”

644
using tradition, inspection of graphic isodoses and practical knowledge alone, is no
longer adequate to answer the issues that continually arise in modern practice. For
example, should we escalate the dose to the prostate to the highest nonuniform dose or
to a lower, more uniform, target dose? Can the rectum and bladder tolerate a high
localized dose to a small volume? And if so, how small a volume and how high a dose?
And finally, how should we balance tumor control and the risk of normal tissue
complications?
Recent developments lead to new, unsolved questions in plan evaluation. Under what
conditions might nonuniform target doses be more effective? When applying TCP
models, should one look at the gross target volume (GTV), the clinical target volume
(CTV) of suspected disease or the planning target volume (PTV) within which the CTV
might be found under conditions of setup error? What normal tissue evaluation metrics
should be used for hypofractionated treatment?
Below, we describe briefly the basic structure and some applications of DVHs and
modeling. We also describe some of the QUANTEC normal tissue guidelines and
compare them with previous consensus recommendations.

Dose–Volume Histograms
DVHs may be represented in either differential or integral form. The former represents
the volume of the organ receiving a dose within a specified dose interval, whereas the
latter is defined as the volume receiving at least dose D as a function of D. The volume is
either represented as the percent (or fraction) of the total volume of the organ or as the
volume in cubic centimeters. The differential form lends itself well to rapid visual
inspection of the range and uniformity of dose. This works well in finding cold spots in
the target volume or hot spots in normal organs. The integral form facilitates the
assessment of the total volume of tissue in such hot or cold spots and is the preferred
format. A major deficiency of DVHs is that they give no information as to the
anatomical location of hot or cold spots. In clinical plan evaluation, this is partly
resolved by parallel inspection of the graphic dose distribution.
In traditional radiation therapy, the ideal target integral DVH is a step function—
uniform dose to the entire target (Fig. 23.2). Since that is not physically achievable, a
“good” target DVH is considered to be one where the bulk of the target receives
prescription (e.g., D95 = prescription dose to 95% of the target receives prescription
dose or higher) while restricting the minimum and maximum point doses (often to
approximately 90% and 110% of prescription, respectively). For dose-painting
treatments, the deliberate nonuniformity is reflected in the target DVH (Fig. 23.2B). The
ideal DVH for a normal tissue is a delta-function at zero dose, which is also
unachievable. OAR DVHs are analyzed in two ways. Most often, key dose–volume points
on the integral DVH which are correlated with treatment outcome are evaluated (Fig.
23.3). For example, in conventionally fractionated therapy (1.5 to 2.5 Gy/treatment),
the maximum spinal cord dose (Dmax) is usually restricted to below 50 Gy in order to
avoid the very serious complication of radiation myelitis. The limit is based on clinical
experience and numerous publications: a 0.2% rate myelitis is estimated at Dmax = 50
Gy in 2-Gy fractions (6). The maximum organ dose is also significantly related to
complication for the brainstem and optic nerves. The fraction of lung volume receiving
over 20 Gy at standard fractionation (V20) is often held below 35% to limit the
incidence of symptomatic radiation pneumonitis. Similarly, intermediate DVH points are
correlated with complication for other organs such as esophagus and rectum. Mean
organ dose—the area under the integral DVH (with percent volume)—is another

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commonly used evaluation criterion, as it is strongly related to symptomatic
complications for organs such as lung, parotid, liver, and kidney (4).

Figure 23.2 A: An ideal target DVH (dashed) to treat target to 5,400 cGy with uniform dose and (solid) an
actual target DVH. B: DVHs for a dose-painting case—PTV 7,000 (dashed) is inside PTV 5940 (solid).

The second approach is to use the entire DVH of the OAR as input to a model which
estimates NTCP. Several models are described in this chapter, as well as in an AAPM
task group report (1) and many primary source papers. At present, despite their
potential, use of models to evaluate treatment plans in routine clinical practice is
largely confined to major academic centers where radiation oncologists and planners
are sufficiently confident in models—sometimes ones developed at their center—to use
them comfortably. An exception to this is the use of mean dose which is directly
evaluated in many planning systems and with which there is known strong correlation
with several complications (e.g., xerostomia or radiation pneumonitis). Models are
sometimes used in treatment planning studies to evaluate possible effects of changes in
treatment practice (7) or to compare proposed and existing techniques (8). They also
provide essential support for responsible extrapolation of treatments to new regimes
(e.g., dose escalation) under phase I protocols (9,10). In that context it is not necessary
for the model to be correct in all details, provided it gives a reasonable estimate of how
far the current treatment may be modified without excessive risk. Finally, models are
used in advanced methods for optimization of treatment plans, where they enable
quantification of tradeoffs (11,12).

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Figure 23.3 Normal organ (parotid) DVH with different dose–volume points indicated. Dmax ∼ 7,500 cGy,
V40 ∼ 33%, D20 ∼ 5,400 cGy.

A robust model might determine the optimal DVH between two similar plans. For
example, suppose an integral DVH for plan A lies to the left of one for plan B. If the
organ is a nontarget tissue, then plan A is better; if the organ is the target, then plan B
is better. A more complex comparison is given in Figure 23.4 where integral DVHs for a
normal organ planned with a parallel-opposed (traditional) and multifield 3D plan are
shown. Although the volume irradiated to any dose level can be used to quantitatively
compare the treatment plans, the location of high-dose (or other) regions cannot be
determined from the DVHs. Moreover, in the example shown, the DVHs cross one
another so that it is not obvious which DVH is better.
Because SBRT is now widely used, it is necessary to be able to interpret both graphic
distributions and DVHs of treatment plans for hypofractionated treatments and to
rationally compare hypofractionated with conventionally fractionated plans. In order to
do this, a detour to classical radiobiology is needed. Hypofractionation has a strong
effect on biologic responses and using physical DVHs for SBRT may be misleading.

Cell Survival Models


Decades of clinical and experimental experience show that the same dose delivered over
a small number of daily fractions (e.g., 20 Gy × 3 fractions) has a greater cell-killing
effect than if delivered over a large number of daily fractions (e.g., 2 Gy × 30
fractions). This is well known to radiation oncologists and medical physicists, for whom
a course in radiobiology is a standard part of training (13,14). Many mathematical
models describe this behavior, but the Linear-Quadratic (LQ) model is by far the most
used because of its mathematical simplicity and because, over decades, its parameters
have been measured for many cell types and under many conditions (7–10). According
to the LQ model, if a collection of identical cells receives a uniform dose D delivered in n
acute fractions spaced several hours apart, the surviving fraction (SF) of cells is

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Figure 23.4 Dose–volume histograms (DVHs) for the mandible. (Reprinted from Kutcher GJ. Quantitative
plan evaluation. In: Purdy JA, Simpson LR, eds. Advances in Radiation Oncology Physics: Dosimetry, Treatment
Planning, Brachytherapy. New York, NY: American Institute of Physics; 1992:998–1021, with permission.)

α and β depend on the cell type and environment (e.g., oxic or hypoxic) and the type of
radiation (e.g., heavy ions vs. megavoltage photons) but are independent of dose.
Typical cell survival curves are found in many texts (13,14). Because the range of SF
over an experimentally achievable dose range covers 5 to 6 orders of magnitude, it is
typical to use semilog plots.
The solid curve in Figure 23.5 shows the SF predicted by the LQ model for single
acute doses to cells with α = 0.33 Gy−1 and α/β = 8.6 Gy (chosen to agree with α/β in
a competing model (29)).
A mechanistic interpretation of the LQ model is that α describes irreparable DNA
damage due to a single radiation “hit” while β describes the effect of two lesions,
neither of which is lethal on its own but which can interact to produce lethal damage.
Overall cell radiosensitivity is dominated by α, which is measured at low doses (when
the quadratic term is negligible) or at low dose rates, when most double-hit lesions are
repaired. Typical in vitro values of α range between about 0.05 Gy−1 (radioresistant, SF
due to single-hit alone at 2 Gy ∼90%) through 1.5 Gy−1 (radiosensitive, single hit SF
at 2 Gy = 5%) (15–17).
The parameter α/β is of particular clinical interest in clinical radiotherapy (and it is
much easier to find tabulations of it) because it captures, with reasonable accuracy,
changes in biologic response for different dose fractionation schedules. Knowing α/β
allows clinicians to find treatment schedules with the same TCP or NTCP (isoeffective
dose schedule) by assuming that isoeffective schedules result in the same SF of the
relevant cells. From Equation 23.1, a total dose D given in n fractions and total dose D′
given in n′ fractions to an identical tissue are isoeffective if

The quantity D(1 + (D/n)/(α/β)) is called the biologically effective dose (BED); it
depends on the total dose, the number of fractions, the type of radiation, and the tissue
of interest (13,14). For clinical photon beams, many—but not all—tumors and “acutely
responding” normal tissues, like skin, have high α/β of 10 Gy or more while “late

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responding tissues,” where complications occur months to years after treatment, have
low α/β, typically 1 to 5 Gy, depending on the tissue and the complication. Possible
reasons for this difference are given by Thames and Hendry (18).

Figure 23.5 Semi-log plot of surviving fraction of cells predicted by the LQ model (solid) and the Universal
Survival Curve (USC dotted). At high doses the LQ curve is “curvier” due to the effect of the β term. (Parameters
were taken from Park C, Papiez L, Zhang S, et al. Universal survival curve and single fraction equivalent dose:
useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70:847–852.)

For a tumor with α/β = 10 Gy, the BED of a typical fractionated schedule of 60 Gy in
30 fractions is 72 Gy while for a hypofractionated schedule of 60 Gy in 3 fractions, the
tumor BED is 180 Gy. A nearby normal tissue with α/β = 3 Gy receives a BED of 100
Gy for conventional fractionation and 460 Gy for the hypofractionated schedule. In
order to express LQ corrected doses on a scale that is more comparable to clinical
experience, the LQ-corrected dose is often presented as the equivalent dose in 2-Gy
fractions (EQD2) (19,20) where

Regardless of α/β, EQD2 for dose delivered at 2 Gy/fraction must equal the physical
dose. For dose/fraction less than 2 Gy, EQD2 is less than the physical dose and for
dose/fraction above 2 Gy, EQD2 is greater. In the hypofractionation example above, the
tumor EQD2 is 150 Gy while the normal tissue EQD2 is 276 Gy. It is very clear that
hypofractionation calls for extreme protection of normal tissues.
In the interest of clarity, the International Commission on Radiation Units and
Measurements (ICRU) recently introduced the symbol and term “Equieffective dose” =
EQDXα/β to describe the dose delivered at an arbitrary dose per fraction X to a tissue
with a specified α/β that is equivalent to the dose D delivered to the same tissue in n
fractions (21) (at dose per fraction d = D/n). Thus

The first equality is as stated in Reference (21) while in the second, numerator and
denominator are in more typical LQ model form. Until ICRU nomenclature is generally

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accepted, when reading publications, it is important to know whether the authors are
reporting physical dose, BED, EQD2, or something else, and that for “biologically
corrected” doses, they have specified α/β.
An important recent result of the isoeffective concept is the realization that α/β for
prostate cancer is much lower than the generic α/β = 10 Gy usually assumed for
tumors. For prostate cancer, α/β is now considered to be ∼1.5 Gy. This has important
consequences for hypofractionated treatment of prostate cancer, the most common male
cancer in the United States, with ∼221,000 new cases per year. The initial discovery
was prompted by work by Brenner and Hall and was motivated by the observation that
prostate cancer cells—like many late-responding normal tissues—replicate slowly (22).
They started from the common hypothesis that the TCP of a uniformly irradiated tumor
containing N clonogenic cells is achieved if zero clonogenic cells survive the treatment,
that the SF, SF(D), is determined by the LQ model, and that cell killing is a random
process that is well described by a Poisson distribution (23).
Under these conditions,

They extracted the radiobiologic parameters from two large clinical studies of
“biochemical failure” after treatment for prostate cancer; one after a course of external
beam therapy and the other after low dose-rate brachytherapy. Biochemical failure is a
rise in the blood concentration of prostate-specific antigen (PSA) following a drop to a
nadir in the months after therapy. PSA rise can be detected by a blood test long before
clinical evidence of recurrence and freedom from biochemical failure (FFBF) is clinically
equated with TCP at a chosen time point. In the external beam dataset (233 patients),
the dose per fraction was 2 Gy and the number of treatments was escalated from 30 to
40. For these patients, the LQ model was directly applied. The second dataset consisted
of 134 patients who had received I-125 brachytherapy with known peripheral dose D.
Because of the extremely low dose rate of such implants (∼6 cGy/hr), two-hit damage is
completely repaired so the SF was exp-(αD). Each patient’s initial PSA level and
dosimetry (approximated as uniform tumor dose) was known and the endpoint was
FFBF at 3 years in both studies. The pretreatment PSA was taken as indicative of the
initial number of cancer cells (N); N and α were determined by fitting the FFBF of
groups of brachytherapy patients with the same initial PSA to their delivered doses.
Knowing these parameters, β was determined from external beam patients with similar
initial PSA. The study concluded that α/β was 1.5 Gy with 95% CI (0.8 to 2.2 Gy).
There have since been numerous papers comparing PSA outcomes for prostate cancer
patients treated under well-defined conditions with different fractionation schedules.
Fowler et al. (24) summarized three large reviews (each involving thousands of patient
records) which were all statistically consistent with α/β ∼1.5 Gy and concluded that
“high fractionation sensitivity is an intrinsic property of prostate carcinomas.”
The clinical impact of this realization is that SBRT is feasible for a large population of
patients with prostate cancer because the tumor α/β is lower than that of the closest
critical normal tissue—the rectum—for which α/β is believed to be ∼3 Gy (25). A major
problem in prostate cancer treatment planning is that the prostate and the anterior
rectal surface are in contact with each other and that rectal complications are
associated with the high-dose region of the dose distribution. Therefore, tumor control
and rectal sparing are strongly competing treatment goals. The minimum biologic target
dose cannot be too low, yet it must be consistent with rectal sparing where the two

650
organs are in contact. Given the excellent results and clinical efficiency of SBRT at other
disease sites and the high prevalence of prostate cancer, it is desirable from medical and
economic perspectives to safely treat prostate cancer with SBRT.
Figure 23.6 shows the physical DVHs for the PTV and the rectal wall from the dose
distribution of a hypofractionated external beam prostate cancer treatment (8 Gy × 5
fractions). In Figure 23.6, the rectal maximum dose is clearly less than the physical dose
to most of the PTV and, at conventional fractionation, would be well tolerated.
However, at conventional fractionation, 40 Gy is totally inadequate to control prostate
cancer; prescriptions for definitive conventionally fractionated prostate cancer
treatments, which have both good tumor control and normal tissue sparing range from
∼80 to 86 Gy. DVHs can be converted to EQD2α/β_VHs by transforming the dose at the
midpoint of each dose bin using Equation 23.3. The large dashes in Figure 23.6 show
the PTV EQD2α/β_VH assuming that the tumor α/β is 10 Gy and the smaller dashes are
the PTV EQD2α/β_VH for α/β = 1.5 Gy. The rectum EQD2α/β_VH is calculated for α/β
= 3 Gy (small, light dashes). If the tumor α/β were 10 Gy, SBRT would not be feasible
because target equivalent dose (∼60 Gy) is still much lower than what is curative at
conventional fractionation while the high equivalent doses to the rectum far exceed
those to the target. Increasing the target dose would raise the rectal maximum dose well
beyond its tolerance level. But because it is well confirmed that prostate cancer has a
low α/β, the EQD2α/β-VHs for the same dose distribution with the prostate α/β = 1.5
Gy show a favorable therapeutic ratio because rectal complications are most correlated
with maximum dose. Hypofractionated external beam treatment of prostate cancer is
now widely and safely used (26) although longer follow-up is needed to determine
whether long-term TCP is comparable to conventionally fractionated treatment. The
fractionation of Figure 23.6 is a realistic schedule, though some groups treat on
alternate days to improve OAR sparing. As a general rule, hypofractionation is favored
if the tumor has a smaller α/β than the most important adjacent critical normal
structures and the dominant complications depend strongly on the structure maximum
dose.

Figure 23.6 DVHs and EQD2_VHs from a hypofractionated prostate plan of 8 Gy × 5 fractions. Solid curves
are the PTV and rectal wall DVHs using physical dose. The medium-dashed curve is the rectal wall EQD2_VH

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taking α/β = 3 Gy, which is typical for a late-responding normal tissue. The dark dashes are the EQD2_VH for
the PTV assuming that α/β = 10 Gy, a value often used for tumors. The small-dash curve is EQD2_VH for the
PTV assuming that α/β = 1.5 Gy, as is currently believed to hold for prostate cancer. The dose distribution is
the same for all the curves but their biologic effects are quite different.

There is considerable controversy as to the validity of the LQ model for large fraction
doses based on in vitro evidence that LQ overestimates cell killing for fraction doses
above ∼10Gy (27,28). The dotted curve in Figure 23.5 compares the SF predicted by
the LQ model with predictions of one of the competing models, the Universal Survival
Curve (29). But to date, no model has replaced LQ, because of its mathematical
simplicity, the availability of model parameters acquired over many decades and the
lack of definitive evidence that it is wrong in cases of clinical interest (16). Further
investigations are needed for a definitive answer.

Biologic Models
Biologic models are an alternative method of evaluating treatment plans that use the
complete DVH as well as other information to predict treatment outcomes. Although
models are not currently in common use for plan evaluation, they may ultimately prove
to be more effective than predictions based on single or a small number of dose–volume
points. In general, TCP and NTCP are thought to increase sigmoidally from 0% to 100%
as a function of dose or a combination of dose and other factors (e.g., smoking, age,
chemotherapy, genetics (30)). The parameters that determine the midpoint and slope in
the middle region of the curve are obtained from analyses of clinical outcomes. This
section further describes some approaches to modeling TCP and NTCP.

TUMOR CONTROL PROBABILITY


The central assumption of most TCP models is that a tumor is destroyed if all viable
clonogenic cells within it are killed (23).
From this assumption, Brahme (31) and Goitein (32) derive TCP from the product of
probabilities that individual clonogens (or tumorlets) are killed. The simplest form of
these models assumes that clonogens in a tumor have identical radiosensitivities,
respond independently to radiation damage, are uniformly distributed, and that the
tumorlets are small enough so that the dose D in each tumorlet is homogeneous. Under
these conditions, the TCP for a tumorlet with partial volume v can be inferred from the
TCP for uniform irradiation of the whole tumor,

It then follows that the TCP of an inhomogeneously irradiated tumor is given by the
product of tumorlet TCPs,

where TCP(vi, Di) is the TCP for the ith tumorlet receiving dose Di and N is the number
of tumorlets.
Several features of the model emerge immediately. The probability of controlling a
tumor is dominated by any clonogens with low probability of being killed, thus TCP is
very sensitive to cold spots in the dose distribution. Given the large numbers of

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clonogens in a tumor, when the dose is uniform the probability of destroying any
individual clonogen must be very close to one for TCP to be appreciable. Given
reasonable values for radiosensitivities of tumor cells, the model implies a very sharp
dose response not seen in clinical studies. This discrepancy is not explainable by
variations in tumor size (33,34). One way the observed shallow dose response might
occur is if only a small number of clonogens can repopulate the tumor is small
(approximately 200, which is many orders of magnitude less than the overall cell
density of ∼108/cc (35)). But definitive evidence for this hypothesis other than the
shallow dose response, for which there are other explanations, has not been presented.
Goitein and others (36–40) propose that the radiosensitivity of tumors differs from
patient to patient and that the averaging over this difference results in the relatively
broad dose response seen in clinical studies of TCP. which are always population
averages. Site-, stage-, and grade-specific parameters that describe the radiosensitivity
of individual tumors and their variation in the patient population have been collected
from clinical studies and summarized by Okunieff et al. (41). Webb (42) adopted a
similar approach, using it to fit four clinical tumor control datasets while assuming
large (∼107 cells/cc) clonogen density and Webb and Nahum (43) included the
possibility of variations in clonogen density within a tumor. As a consequence of a
distribution in radiosensitivities among patients, Zagars et al. (40) and Thames et al.
(44) point out that an escalation in dose is most effective for patients with intermediate
sensitivity. Those whose tumors are most sensitive do not require such a high prescribed
dose, and those who are least sensitive rarely require a dose in excess of normal tissue
constraints. This implies that assays predicting radiosensitivity would be useful in
identifying patients who would benefit from dose escalation. Such a personalized
approach is under investigation for HPV-positive H&N cancers, which have superior
survival at the high-dose levels (45) possibly due to increased radiosensitivity.
As was shown by Brahme (31) for a tumor with identical clonogens, the highest TCP
for a given mean dose is achieved by a uniform tumor dose distribution. Perhaps partly
for this reason, a historical treatment planning goal is uniform PTV coverage. But there
is mounting evidence for intratumoral heterogeneity due to both genetic (46) and
environmental factors such as hypoxia (17,47,48). Although this does not broaden the
dose–response, it is increasingly important in treatment planning, as it suggests that
nonuniform target coverage which places hot spots in regions that are known to be
radioresistant or at high risk for failure for other reasons should be advantageous. IMRT
can quite easily achieve such distributions and is instrumental to the now widely used
technique of dose-painting (simultaneous integrated boost or SIB). Here the physician
identifies tumor subvolumes at different degrees of risk and specifies the dose to be
delivered to each by a single treatment plan. Usually the regions painted to higher or
lower doses are determined by characteristics such as natural history of disease spread,
surgical margins, and pretreatment (18) FDG imaging. In theory, high-dose regions
could also be identified by hypoxia imaging using the positron-emitting tracer 18F-
misonidazole though instability of hypoxic regions, which tend to reoxygenate during
treatment, may be confounding (49–52).
It is likely that clinical TCP observations are due to a combination of intratumoral
and population distributions of tumor characteristics and that both dose painting and
methods of predicting radiosensitivity within the patient population will be useful
strategies.
The uncertainties in defining tumor boundaries, clonogenic tumor cell densities, the
distribution of heterogeneous clonogen radiosensitivity, and the interaction between
these uncertainties and the uncertainties in delivered dose distributions—setup error,

653
physiologic motion, and anatomy changes over a treatment course—make it difficult to
test model predictions of the effects of dose inhomogeneity against clinical TCP data.
Nonetheless, a growing number of studies indicate effects of inadvertent target dose
inhomogeneity on TCP. Terahara et al. (53) studied the effects of dose inhomogeneity
on local control using DVH and outcome data from 115 patients treated for skull base
chordomas with combined photons and protons. In these patients, with relatively small
positional uncertainties and relatively large dose inhomogeneities in the target, a Cox
multivariate analysis showed that models including gender and the minimum target
dose were significantly associated with the outcome. A case report (54) described
treatment failure near a parotid gland in three patients treated with parotid-sparing
IMRT and suggested that future patients receive pretreatment PET imaging to assure
that the parotid region is free of suspicious nodules. A study that reviewed records of
23 consecutive orbital lymphoma patients treated with 3DCRT, of whom 12 were
treated to only the partial orbit, found that 4 of these had an intraorbital recurrence in
volumes that had not been covered while no patient treated with whole orbit RT had
such recurrence (55). A study of the GTV dose distribution of 91 tumors (79 patients)
treated with single-dose SBRT for paraspinal tumors reported 7 local failures. All were
significantly correlated with the low dose regions and no failures were observed if the
minimum PTV dose exceeded 15 Gy (56). The target dose distributions in paraspinal
SBRT are deliberately nonuniform in order to protect the spinal cord which abuts the
GTV. There were similar observations in a 332 paraspinal SBRT dataset where 1-year
local control was 88%. The minimum GTV BED was the only variable to remain
correlated with local failure under multivariate Cox analysis and the authors
recommended maintaining the minimum GTV dose above 14 Gy in 1 fraction and 21 Gy
in 3 fractions (57). In contrast, Levegrun et al. (58,59) found that the mean, but not the
minimum, PTV dose was significantly correlated with biopsy outcome in a series of 132
patients treated with 3DCRT for prostate cancer. PTV coverage in this population was
fairly homogeneous and the CTV was defined as the prostate gland and seminal vesicles,
although it is likely that the tumor clonogens were confined to subvolumes of the
prostate. Setup uncertainty was greater for these patients than those in the other
studies, as they were treated before the era of image-guided RT. Random positional
uncertainty on the order of 1 cm can be expected in the CTV location during treatment
due to setup error and organ motion and the location of resulting underdoses with
respect to tumor clonogens was unknown. The possible influence of setup uncertainty
which may introduce tumor underdoses, on TCP of prostate cancer is suggested by a
much later study from the same institution comparing outcomes for 186 patients
treated with conventionally fractionated IMRT for prostate cancer using IGRT with 190
patients who also received IMRT to the same dose and the same planning and delivery
technique but without IGRT. The image guidance consisted of setting the patients up by
registering the images of radiopaque fiducials implanted in the prostate with their
location at simulation using kilovoltage orthogonal radiographs. This assured that the
planned high-dose region was delivered to the prostate rather than partially missing on
some days due to physiologic changes such as bladder or rectal filling. The high-risk
patients treated with IGRT had significantly better FFBF (PSA relapse-free survival) than
those without IGRT (97% vs. 77.7%) (60).

Normal Tissue Complication Probability


The goal of NTCP models is to predict the probability of a complication as a function of
the dose (or BED) distribution; more recently other factors such as smoking,

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comorbidities, and chemotherapy may also be included in the function. Intuitively, the
modeled NTCP should increase in a roughly sigmoidal fashion (Fig. 23.7) as a function
of the organ dose distribution, going from zero at no dose up to 100% with the model;
the model parameters determine the location and shape of the curve. A given organ may
have several different types of complications with different dose–volume parameters.
For example, most organs have acute (during or within a few months of treatment) and
late complications. Rectal complications include rectal bleeding (most analyzed
complication), fecal incontinence, and stool frequency (61).

Figure 23.7 Sigmoidal dose responses that are expected for both TCP and NTCP. The “metric” might be
purely dosimetric (e.g., mean dose or Dmax) or might be a combination of dosimetric and other factors (smoker
or nonsmoker). The location and shape of the curve is obtained by analysis of clinical data.

All NTCP models must deal with the volume effect. Some complications are most
sensitive to “hot spots” in the OAR, others to the mean organ dose, and yet others
depend on the entire DVH in a more complex way. The phenomenologic model of Lyman
(62) augmented by Kutcher and Burman (LKB model) (63,64) seeks to describe NTCP in
terms of four parameters. They introduced the idea of “partial organ irradiation,” where
a fraction of an organ, v, receives a uniform dose D while the rest receives zero dose.
This is not completely artificial—dose distributions of parallel opposed fields are good
approximations to partial organ irradiation and such treatments were the clinical norm
prior to 3DCRT. In the Lyman model, partial volume tolerance doses are related to each
other through a power law in volume fraction. Specifically, if a complication rate c% is
produced by uniform dose D to a whole organ, the same complication rate is produced
by partial irradiation to a dose D′ of a fraction v of the total organ or a chosen reference
volume to a dose if

where n ≥ 0. If n is very small, vn is approximately 1 and the complication has little


volume dependence. The larger n, the stronger the volume dependence. A feature of the
Lyman model is that there is always a partial volume dose for which complication will
occur at a specific rate, no matter how small the irradiated partial volume is. The
Lyman model is widely used in outcomes analysis, but much less so in clinical plan
evaluation though it is implemented on some planning systems (1).
In the 1990s, there were efforts to develop other models based on the tissue
architecture of organs. Withers (64) hypothesized that the work of an organ is carried
out by “functional subunits” (FSUs) and that the volume effect of a complication is
determined by how the FSUs combine to carry out the organ function. Nephrons in the

655
kidney and alveoli in the lung are sometimes used as possible examples of FSUs.
Architectural models are thoroughly described in the previous edition of this book, part
of which is quoted here. Serial (critical element) models assume that certain organs are
organized like chains; when one link (a functional subunit or FSU) is damaged the entire
chain is broken (65). A candidate for a serial organ is the spinal cord. Organs with this
architecture have a small volume effect. For the parallel model (also called critical
volume), a complication does not occur until a significant fraction of independent
functional subunits (functional reserve) have been incapacitated (66–68). The volume
effect in these tissues is large, because a complication does not occur if less than the
functional reserve is irradiated. This behavior is not reflected in the LKB models unless
augmented by an additional parameter such as a critical volume below which there is
no complication.
The serial and parallel models are conceptually attractive and it was hoped that they
might lead to mechanistic understanding of NTCP, but this goal has not been achieved.
The models are seldom used in clinical plan evaluation although the names prevail.
“Serial” is used for complications that depend mostly on the highest doses to the organ
(small n in the Lyman model) and “parallel” for complications with a strong volume
dependence (large n). However, a variant (also nonmechanistic), the “relative seriality”
model (69), is almost as widely used for NTCP calculation as the Lyman model, mostly
in Europe. There is currently no definitive evidence that would lead users to prefer one
of the three NTCP model types (Lyman, tissue architecture, relative seriality) in the
clinic. For further discussion, see the references cited here and the earlier edition of this
book.

Uniform Irradiation
Lyman (62) represents the NTCP for uniform partial volume irradiation of an organ
with an error function of dose and volume.

The model contains four parameters: TD50 (62), the tolerance dose for whole organ
irradiation; m, the steepness of the dose–response curve; Vref, the reference volume,
which in some cases may be the whole volume of the organ; n, which relates the
tolerance doses for uniform whole and uniform partial organ irradiation. This latter
parameter represents the volume effect. When n is near unity, the volume effect is
large1 and when it is near zero, the volume effect is small. A value of n ∼ 1 implies that
NTCP correlates with the mean dose, whereas a small volume effect implies a correlation
with the peak organ dose. The NTCP for partial organ irradiation in the Lyman model
was originally based on clinical estimates of partial organ tolerance doses. An early
compilation by Emami et al. (70) was fitted to the model by Burman et al. (71).
Although many of the parameter values he obtained are still in use, values resulting
from maximum likelihood fits of DVH and complication data from 3D conformal dose
escalation protocols are available for a growing list of organs. This will be described in
more detail in the section “Current Supporting Data for NTCP”.

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Nonuniform Irradiation—Histogram Reduction and Equivalent Uniform Dose
The approach in the preceding text has been extended to inhomogeneous irradiation by
converting the organ’s DVH into an “equivalent” uniform one using the effective volume
method (63). The DVH is transformed into one in which the partial volume, veff, which
is equal to or less than the whole organ volume, receives a dose equal to the peak organ
dose. This effective volume transformation is self-consistent with the power law model
for uniform irradiation in that it can be derived from just two hypotheses: The organ is
homogeneous in response and each element of the organ obeys the same power law
relationship as the whole organ. Moreover, there is a family of equivalent uniform DVHs
with effective volume and dose related through the defining power law relationship.
This method was extended to calculate the effective whole volume dose (deff) by Mohan
et al. (72). More recently, use of the generalized equivalent uniform dose (gEUD,
sometimes simply called EUD) (1,5,73), has become popular. This quantity is calculated
in an identical fashion to deff (in the EUD formalism, the LKB model parameter n is
replaced by the parameter a, they are related by n = 1/a).
While the LKB model was designed only for NTCP, gEUD is also used as a surrogate
for TCP. Given the DVH for an organ or tumor, gEUD is calculated as

where the sum runs over all the dose bins of the DVH, Di is the dose at the center of the
ith bin, and vi is the fraction of the organ volume in that bin. To describe complications,
a ≥ 0 while to describe TCP, a < 0. Serial complications (small n or large a) depend
strongly on the high-dose part of the DVH while the entire DVH affects the gEUD for
small a (large n); for n = 1, gEUD is the mean dose. If a is large and negative, gEUD
accentuates the low-dose portion of the DVH—the cold spots which are important for
tumor control. gEUD is useful for relative ranking of treatment plans in regard to a
chosen organ or target without the “judgmental” character of a full TCP or NTCP
calculation.2
Although the original formulations of the Lyman model and gEUD used physical dose,
EQD2α/β (or a similar reduction to any desired reference dose) can replace physical
dose if the DVH is converted to EQD2α/β-VH. Within the simplest form of the LQ model,
this biologically equivalent EUD has only two parameters (a and α/β) and can
potentially incorporate fractionation and volume dependence in a single number that
can rank dose distributions delivered at nonstandard fractionation schedules in terms of
their risk.

CURRENT SUPPORTING DATA FOR NTCP


Both models and dose–volume plan evaluation criteria are based on clinical data,
although for many complications, data is still quite sparse and unreliable. This is due to
several factors, including: treatments are designed to be “safe” so many reported series
have low numbers of complications; publications use qualitatively different criteria for
reporting complication severity; for some organs, publications use different definitions
of the reference volume; doses are often not clearly specified—for example, a
publication might report the number of complications and the prescription dose but give
minimal details of an organ dose distribution. Developments such as computerized

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planning, accurate dose calculation algorithms, electronic record keeping, and
prospective collection of dose distribution and complication data allow more
opportunities for data collection, but radiation oncology still has a long way to go (75).
The 1991 compilation of normal tissue tolerance doses and volume effects by Emami
and eight co-authors (70) is one of the most cited articles in radiation oncology and its
guidelines are still in use. It was the product of an NCI Collaborative Group charged
with investigating the then-new tools and potentials of 3D, CT-based treatment
planning. Most of the literature they reviewed was from the “2D” era when most
treatments were simple (often parallel opposed), simulation images (if taken) were plane
radiographs and, if patient-specific dose distributions were generated, they were often
superimposed on a manually acquired, two-dimensional contour. In 2010, a group of
physicists and physicians performed a systematic review that included more recent
publications on dose and volume dependence of clinically reported normal tissue
complications for 16 organs. They reviewed many studies that were published in the
“3D” era, where patients were treated with the benefit of 3DCRT (and occasionally
IMRT) and modern delivery tools (though most studies preceded IGRT). This group
named itself QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic). It
received funding from both AAPM and ASTRO, but was not a formal part of either
organization. Its reports are published in a supplement to the International Journal of
Radiation Oncology, Biology and Physics (4). Surprisingly, QUANTEC found it difficult to
extract dosimetric guidelines even from modern published literature for reasons
summarized in Reference (75).
However, the QUANTEC groups were able to make recommendations and, for some
complications, develop NTCP models for several organs. These are summarized in a
large table in the QUANTEC issue (76). These recommendations involve mean doses or
one or a few DVH points and do not include more complex models. However, many of
the organ-specific articles developed models based on the reviewed clinical data and in
some cases recommended their use to limit toxicity. QUANTEC repeatedly urges caution
in applying its guidelines to IMRT, since much of the reviewed literature described
outcomes of 3DCRT, but not IMRT, treatment.
Here we briefly compare the QUANTEC and the 1991 guidance for several
complications. For some organs, guidelines are similar although the modern
complication endpoints may be less severe (perhaps thanks to guidance from the 1991
study as well as to improved dose conformality with 3DCRT).
Spinal cord (6): The QUANTEC endpoint (grade 2 or greater myelopathy) includes
complications that are less severe than “transverse myelitis,” used in the 1991 study.
The QUANTEC spinal cord group reviewed 16 publications covering 2,281 patients
without prior irradiation, 14 papers with prior spinal radiation, and 10 papers
reporting on patients who received SBRT. All reported complications were,
understandably, at the low end of the dose–response curve—myelitis is the most feared
radiation therapy complication and even slightly risky treatments are usually avoided.
Using a logistic function model developed by Schultheiss (77) based on his earlier
review of publications extending back into the 1970s, the QUANTEC group concluded
that irradiation of the full cord cross-section to a maximum dose of 50, 60, and 69 Gy
was associated with 0.2%, 6%, and 50% rate of myelopathy. The spinal cord is narrow
and visualizing it requires a myelogram or an MRI. Therefore, dosimetrists often
contour the spinal canal and the dose distribution within the cord itself (or even the
canal) is rarely closely examined in clinical plans. Also, many conventionally
fractionated treatments have setup uncertainty that can blur the delivered dose
distribution on the 0.5 to 1 cm scale of the cord diameter. Therefore, the QUANTEC

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guidelines (76) are to keep the cord point maximum dose ≤50 Gy, similar to the 1991
recommendation. For the increasingly common situation of retreatment of a volume
which includes the spinal cord, QUANTEC found that when more than 6 months
elapsed between two treatments, myelopathy was not seen for cumulative doses less
than 60 Gy. For SBRT, they recommended that the point maximum be ≤13 Gy in a
single fraction and 20 Gy in 3 fractions to keep the complication rate below 1%.

Figure 23.8 QUANTEC rate of symptomatic pneumonitis as a function of mean lung dose—comparison of
data from 10 institutions. The dashed line is a logistic fit to the form f/(1 + f) where f = exp(b0+b1 × mean lung
dose). The best fit values (95% CI) are b0 = −3.87 (−3.33, −4.49), b1 = 0.126 (0.100, 0.153) corresponding to
TD50 = 30.75 (28.7, 33.9) Gy and γ50 = 0.969 (0.833, 1.122) where γ50 represents the increase in response
(measured as percentage) per 1% increase in dose near the 50% dose–response level. (Reprinted with permission
from Marks, LB, Bentzen, SM, Deasy, JO, et al., (2010). Radiation Dose-Volume Effects in the Lung. Int J
Radiat Oncol Biol Phys 2010;76(3):S70–S76.)

Lung (78): For lung, the QUANTEC and the 1991 recommendations were again
similar. Lung, regarding the complication of radiation pneumonitis (RP), is considered a
“parallel” organ with a large volume effect. The 1991 paper (71) set the Lyman volume
parameter n = 0.87 and TD50 = 24.5 Gy, m = 0.18. The QUANTEC group reviewed
∼70 publications (all conventional fractionation), most of which had more statistically
elegant analyses of institutional data than the “by eye” fits used in 1991. Their best
estimate of n was 1.03, indicating that the mean lung dose is significantly correlated
with RP. This correlation is robust across institutions, as shown in Figure 23.8. The
QUANTEC team developed logistic and probit fits to the data in Figure 23.8, from which
they recommended mean doses for keeping symptomatic RP between 5% and 40%.
Rectum (25): Rectum is one of the organs which is defined differently in different
studies: rectal wall, rectum including the lumen, anatomical rectum, and lengths
determined by the high-dose region. The shape and volume of the rectum change
between, and sometimes during, treatment fractions; thus the delivered rectal dose—
which determines the outcome—may differ in an unknown way from the planned dose.

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QUANTEC’s preferred definition is the anatomical rectum on the planning scan,
including the lumen. Most of the papers the QUANTEC team reviewed dealt with rectal
complications following prostate external beam treatment (other cancers which give
substantial rectal dose have a large brachytherapy component or are treating rectal
disease). The QUANTEC endpoints were ≥ grade 2 and ≥ grade 3 late rectal toxicity,
mostly bleeding and usually defined according to the RTOG grading scale (79). These
include milder complications than the 1991 study (“severe proctitis/necrosis/fistula”)
despite the higher doses used for modern prostate treatments. This reflects improvement
in rectal protection with the use of 3DCRT. Both QUANTEC and the 1991 studies found
that rectal complications have a weak volume dependence. In the 1991 Lyman model
parameters, “n” is 0.12 (71) while the QUANTEC n is 0.09 with 95% CI 0; 04–0.14.
Both find rectum to be fairly radioresistant; the 1991 TD50 is 80 Gy, QUANTEC’s is
76.9 Gy or 78.5 Gy, depending on the publications they included in analysis. However,
rather than simply specifying a maximum rectal point dose, QUANTEC recommends five
intermediate DVH points, thus defining the upper limit of the DVH between 50 and 75
Gy.
Rectal complications other than bleeding may be better correlated with the dose
distribution in specific parts of the rectum (61). Because rectal dose distributions for
IMRT treatment of prostate cancer look quite different from those from 3DCRT and the
rectal complication rate following IMRT prostate treatment is much lower than for
3DCRT (80), QUANTEC made no recommendations for IMRT. However, a recent
publication confirmed the QUANTEC Lyman parameters (7) as a secondary aspect of the
research in that paper while another study on a large, different dataset found a large
discrepancy between Lyman parameters for rectal toxicity in 3DCRT versus IMRT (81).
Deciding whether or not the QUANTEC parameters describe rectal toxicity in IMRT and
modeling rectal complications for SBRT prostate treatment remains to be done.
Optic structures (optic nerves and chiasm) (82): The endpoint for the 1991 study
was blindness while QUANTEC included less severe complications as well (visual
impairment or optic neuropathy). The optic structures are very small and both
contouring and dose delivery accuracy confound efforts to find a volume effect. The
1991 guidelines are a 5% probability of blindness for a whole organ dose of 50 Gy and
a 50% probability of blindness for 65 Gy. In general, QUANTEC finds that the optic
structures are more radiation tolerant than suggested by the 1991 study, which may
allow better target coverage in some brain and head and neck (H&N) cases.
QUANTEC’s recommendations are for three point maximum values with the caveat
that the Dmax values are often very close to the dose to the whole organ. The QUANTEC
maximum dose points are Dmax < 55 Gy for NTCP < 3% (the 1991 model predicts
13.6%); Dmax 55 to 60 Gy, NTCP 3% to 7% (the 1991 model predicts up to 29%). The
third Dmax point involves only upper limits above 60 Gy (NTCP > 7% to 20%) which
doesn’t allow comparisons.
1991 models more aggressive: For parotid, cochlea, kidneys, heart, and stomach,
using the 1991 constraints is likely to lead to a higher complication rate than expected
from subsequent literature; the QUANTEC recommendations are more conservative. For
example, the parotids are key risk organs for H&N treatment: these cancers have a high
cure rate and the nonlethal complication of xerostomia, with great impact on quality of
life, is a concern. The parotids are “parallel” organs, with the 1991 Lyman model
assigning an n of 0.7 while QUANTEC (83), based on more recent information, focuses
on the mean parotid dose. The 1991 Lyman model predicts <20% complication for
mean parotid dose below 39 Gy, while today most H&N treatment protocols advise
keeping the mean bilateral gland dose below 25 Gy if possible or, if high dose must be

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given to one parotid to achieve tumor control, keeping the spared parotid mean dose
below 20 Gy.
Finally, for esophagitis and radiation-induced liver disease, the dose–volume behavior
extracted by QUANTEC from modern studies is simply different than reported in the
1991 publication. And for the bladder, the quality of available data was inadequate to
support guidelines. The 1991 report gives Lyman model parameters for several organs
not included in QUANTEC (brachial plexus, external ear, rib cage, femoral head,
thyroid, TM joint, and mandible) while QUANTEC makes recommendations on the
penile bulb.
For many organs, QUANTEC made no recommendations for hypofractionated
treatment because literature at that time was scarce. Also, most of the literature
reviewed by QUANTEC dealt with complications in adult patients. There are now two
efforts patterned after QUANTEC—one to make literature-based recommendations for
pediatric radiation therapy (PENTEC), and one to make similar recommendations for
hypofractionated treatment (WGSBRT). These groups hope to make recommendations in
the near future.

Fitting Clinical Complications Data to a Model: An Example


Thanks to the knowledge gained from over a century of radiation therapy and to
advanced planning and delivery techniques, radiation-induced normal tissue
complications are infrequent. Differences between patient populations, local preferences
for certain treatment methods and dosing schedules, and local variations in
accompanying therapies (surgery, chemotherapy) make the study of NTCP an exercise
in extracting a weak signal from a noisy background. Controlled randomized clinical
trials might provide high-quality data, but they are often cost-limited to small patient
numbers and are aimed at answering a few specific questions that the funding
organization deems important. Increasingly, sophisticated statistical methods are being
applied to the problem of mining institutional databases or using peer-reviewed clinical
data to develop and validate NTCP models.

Statistical Model of a Parallel Organ


In parallel element tissues, which have been modeled using binomial statistics (66–68),
a complication occurs if the fraction of eradicated FSUs exceeds a threshold fraction,
the functional reserve of the organ. The kidney, liver, and lung are conjectured to
behave as parallel organs. Because the number of FSUs is always large in these organs,
the functional reserve can be defined by the fraction rather than the number of
eradicated FSUs. Furthermore, as with TCP, the large number of FSUs leads to
unrealistically large gradients of NTCP with dose in the region of NTCP = 50%. To
remedy this, population averaging is invoked, which requires additional parameters. For
example, if the functional reserve and the FSU radiosensitivity (defined by the dose
required for 50% FSU death) vary among a population of patients, then two additional
parameters are required to represent the widths of these distributions. In addition,
intraorgan variation in radiosensitivity may also be considered. Fortunately, it can be
demonstrated that intraorgan variability has a negligible effect on the slope of the local
dose–response curve (84).
A further simplification is possible if the width of the distribution of radiosensitivities
is narrower than that of the functional reserve. In this limit the NTCP is given by the
integral of the functional reserve up to the mean fraction of eradicated FSUs, that is, up
to the fraction damaged (84). This form is quite useful for fitting clinical complication

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data.

Fitting the Parallel Model to Clinical Complication Data


The method described here is now widely used in fitting biophysical models to clinical
data. Such an approach is a starting point to suggest further developments in the
collection and analysis of clinical data. We describe here one example in which a
parallel model (described in preceding text) and the method of maximum likelihood is
used to fit DVHs and complication data for radiation hepatitis of 93 patients treated for
tumors of the liver (84–86).
The method of maximum likelihood can be applied as follows. The DVH for each
patient is used to calculate NTCP by first assigning a best guess for the model
parameters. The predicted probability of a complication for each patient is then
compared against the observed grade of complication in that patient. The overall
likelihood L of the observations is then modeled according to:

where

where L is the likelihood, O(tm) is the probability that a complication will manifest itself
after the follow-up time tm for the mth patient—calculated from complication and
follow-up time data with the Kaplan–Meier method (87) and γ1, γ2, . . . indicates the
model parameters. The likelihood function is then maximized with respect to the model
parameters. Note that the likelihood is essentially the probability in the model of the
observed complication pattern.
Furthermore, it is convenient to assume, as described earlier, that the organ has a
functional reserve described with two parameters (whose values are to be obtained from
the maximum likelihood fit) and that NTCP is given by the integral of the functional
reserve up to the mean fraction of eradicated FSUs, that is, up to the fraction damaged
(84). For each patient, the fraction damaged is calculated by summing up the product
of the fractional volume of each voxel of the organ and the probability of damage. The
latter can be calculated using each patient’s DVH and an assumed local response
function with two parameters (whose values are to be obtained from the maximum
likelihood fit).
The results of applying such an analysis to the hepatitis data is shown in Figure 23.9
for observed complication rate as a function of the calculated fraction of the liver that is
damaged. The observed complications for this dataset show a threshold effect with a
steep response, which is described well with the parallel model. In this application, the
best-fit functional reserve distribution and their confidence intervals predict that
irradiation of less than one-third of the liver volume leads to negligible complications
(84). That is, the threshold volume is about one-third. A more detailed analysis of the fit
revealed that the uncertainties in the width of the functional reserve distribution and

662
radiosensitivity of functional subunits were correlated. This arose because complications
were seen only in the cohort of patients who received a whole liver irradiation as part of
the treatment course. The lack of complications among patients given only partial
volume irradiation suggested that an attempt to increase local control through dose
escalation was feasible. After follow-up of subsequently treated patients, some of whom
had received 90 Gy, Dawson et al. analyzed data from 138 patients, including 19 with
radiation-induced liver disease (RILD). Observation of complications in patients with
only partial volume irradiation helped to resolve the correlated uncertainties in the
model parameters and the threshold limit was revised down from one-third to one-
fourth (88,89).

Figure 23.9 Observed complication rate for radiation hepatitis versus calculated fraction damaged. (Reprinted
from Jackson A, Ten Haken RK, Robertson JM, et al. Analysis of clinical complication data for radiation
hepatitis using a parallel architecture model. Int J Radiat Oncol Biol Phys. 1995;31:883–892, with permission.)

Current and Future Clinical Use of Normal Tissue Dose–Volume Criteria


Treatment plans are often designed to meet competing goals of target coverage and
protection for nearby normal organs. These goals have been refined through experience
so that they are relatively safe and effective (“acceptable” complication and control
rates) and can be satisfied by plans that can be done by skilled planners (dosimetrists)
within clinically reasonable times using acceptable beam arrangements (no mechanical
collisions, not too many beams, none passing through strongly attenuating support
structures). There are protection goals that must be satisfied (e.g., spinal cord) even if
target coverage is compromised. For example, for conventionally fractionated
treatments of patients without prior radiation, the maximum permitted spinal cord dose
is below 50 Gy, which is often too low to achieve durable tumor control. A compromise
for mediastinal tumors (devised long before the advent of 3DCRT, but still in use) is to
treat to 40 to 45 Gy with AP/PA beams that cover the entire PTV and then “cone down”
to “off cord” oblique beams which treat part of the PTV to 60 Gy but spare the spinal
cord from further direct dose. IMRT often allows a plan that treats the tumor to 60 Gy
in a single phase because intensity modulation decreases target dose from some beams
to protect the cord but fills in target dose from other beam directions. In paraspinal
SBRT, target coverage is usually compromised to achieve sufficient cord protection; with

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minor compromise, the treatments remain effective (56,57). In some situations, it may
be possible to make a clinical decision of priority between protection and coverage
goals. In these cases, it is valuable for the planner to have guidance as to whether both
can be satisfied before he starts. As an early example, Hunt et al. (90) retrospectively
analyzed the treatment plans of 51 H&N cancer patients treated with dose-painting
IMRT (PTVs for dose levels 54, 59.4, and 70 Gy or 54 to 60 Gy and 66 Gy). One or both
parotid glands overlapped PTVs. To maintain a <25% risk of xerostomia, the mean
parotid gland dose should be below 26 Gy but for tumor control, the plan should give
each PTV full dose according to its level. The study derived the maximum fraction of
parotid-PTV overlap and the necessary mean dose to the non-overlap region to achieve
an overall mean parotid dose of 26 Gy without underdosing the PTV. These doses could
be used as optimization goals for parotid portions outside the PTV. If a mean dose below
26 Gy cannot be achieved for a gland, a clinical decision must be made.
A more elaborate version of this approach is now being applied to “knowledge-based
planning” (91,92). For a particular disease site and perhaps beam arrangement, a
database of previous “good” plans is used as a training set to parameterize a treatment
plan model. The “best” (as defined by the model) achievable OAR DVHs are then
predicted for a new patient based on his anatomy. Of course users must agree on an
appropriate training set. Knowledge-based planning is in its infancy, but in the future,
it may reduce planning time, improve plan quality, and allow for more objective plan
evaluation by comparison with high-quality reference plans that meet established
treatment standards. On the down side, developing the plan model (commissioning the
knowledge-based system) will require much work and institutions with different
treatment goals would not be able to share models.
In a novel application of the knowledge-based approach (7), treatment plans from an
RTOG prostate IMRT treatment protocol were replanned using a knowledge-based
model. The training set was 20 high-quality plans from one of the collaborating
institutions. These plans satisfied all the RTOG protocol constraints and were selected
for best OAR (rectum and bladder) sparing. The model was further tuned on the RTOG
plans with the smallest difference between the plan rectal NTCP and that predicted by
the knowledge-based program. Finally, for 30 RTOG plans (10 with the smallest NTCP
difference from predicted, 10 with the largest difference, and 10 intermediate cases)
model-predicted rectal DVHs were obtained. Each case was then replanned to give
approximately the same PTV coverage as the original (in all cases meeting protocol
requirements), to maintain or improve the bladder DVH and to use the rectal DVH
predicted by the model as a guide for the new plan. The QUANTEC Lyman model
parameters were confirmed as a separate part of the study and the improvement in plan
quality was evaluated as the reduction in Lyman NTCP achieved by the new plan.
Although all the original plans had met the protocol’s constraints, they were not
“optimal” in that the rectal NTCP was reduced in all the replanned cases without
sacrificing coverage or other planning objectives. Should this or related methods become
readily accessible and efficient, one would expect treatment complication rates, as well
as planning time to decrease. Evaluation of individual plans would be partly based on
their similarity to the plans in the model knowledge base. Models themselves might be
evaluated by periodic institutional plan intercomparisons, though there would
undoubtedly be debates about the gold standard. And of course with better quantitative
understanding of plan outcome, plan quality metrics will change.

CONCLUSIONS

664
Dose–volume criteria are now widely used in planning and plan evaluation; models are
available and interesting, but in order to come into general clinical use, proponents will
have to demonstrate that they add something to the clinical process—more efficient
planning or more efficient or objective plan evaluation. Especially the latter will require
stringent model validation and education of physicians, physicists, and dosimetrists as
to their appropriate use. Clinical data is being mined to update evidence-based
guidance, which is particularly needed to address new treatment paradigms. Currently
we are focused on hypofractionation but future developments may include combined
modalities or molecular personalized medicine. Peer-reviewed clinical data should be
presented in a format that allows “data pooling” (93) so that these efforts move forward
more rapidly. Improved models and dose–volume constraints combined with knowledge-
based planning may make it easier and more likely to arrive at superior plans to the
benefit of future patients.

KEY POINTS
• Both volumetric graphic dose distributions and dose-volume histograms (DVHs) are
required for evaluation of complex modern treatment plans. The quality of treatment plan
dosimetry must achieve a balance between the probability of local tumor control (tumor
control probability or TCP) and the probability of normal tissue complications (NTCP).
• The rapid growth of stereotactic body radiotherapy (SBRT) makes it necessary to account for
the greater biologic potency of hypofractionated treatments in planning and plan evaluation.
The Linear Quadratic (LQ) cell survival model is most often used for this purpose, although
other models have been proposed.
• Some dose–volume metrics that can be read directly off a DVH (D_volume, V_dose) have
been shown to correlate with outcomes but predictive models have also been devised. Both
TCP and NTCP are approximately zero at low doses and rise to close to 100% at high doses
but “low,” “high,” and the rate of increase with dose depend on the tissue. Ideally the key
parameters that determine response are obtained and validated by analysis of clinical
outcomes.
• Most TCP models are based on the hypothesis that a tumor is controlled only if the radiation
course kills all clonogens (cells capable of regrowing the tumor). This approach, combined
with the LQ cell survival model, led to recognition that SBRT can be safely delivered to
prostate cancer.
• For NTCP, it is noted that different complications have different dependences on the
radiation distribution in the organ. The two extremes are called “serial” and “parallel”
responses. Serial responses depend on the highest dose in the organ while parallel responses
depend on the overall organ dose, often approximated by the mean organ dose. NTCP models
must account for these effects. A classical collection of NTCP dose–response information was
published in 1991 (Emami et al., Burman et al.). Recently, the QUANTEC group
(Quantitative Analysis of Normal Tissue Effects in the Clinic) reviewed modern papers and
provided guidelines and models for 16 organs. There is mixed agreement between
QUANTEC and the 1991 studies.
• Models may be effectively used in comparing rival plans and delivery techniques, in dose–
escalation trial design and in plan optimization and they are used in this way at large

665
academic centers. However, for general use, they must be validated sufficiently for many
clinicians to have confidence in them.

QUESTIONS
1. Tumor type A has radiobiologic parameter α/β = 10 Gy while tumor type B has
α/β = 1.5 Gy. Both tumors have 108 clonogens and have radiobiologic
parameter α = 0.1 Gy−1. Which tumor type has the larger change in TCP when
the treatment fractionation is changed from 60 Gy in 30 fractions to 60 Gy in
3 fractions?
A. A
B. B
C. Equal response
D. Neither tumor responds to such low doses
2. The complication probability for a normal tissue is said to be of “serial” type.
What part of the dose distribution is most important in determining its NTCP?
A. The mean organ dose
B. The low-dose part of the distribution
C. The high-dose part of the distribution
D. The % volume receiving 20 Gy
3. The complication probability for a normal tissue is said to be of “serial” type.
Which is most likely to be the Lyman model volume effect parameter, n?
A. n = 0.05
B. n = 0.35
C. n = 0.75
D. n = 1.0
4. A recent analysis of published NTCP data up to approximately 2010 was
conducted by
A. Emami_Burman
B. QUANTEC
C. NRC
D. NTQABS
5. One way to use biologic models in treatment planning is
A. Comparing rival treatment plans
B. Reducing planning time
C. Reducing plan delivery time
D. All of the above
6. The gEUD is
A. The mean dose to an organ
B. The equivalent uniform dose that, when applied to the organ, has the same

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biologic (TCP or NTCP) effect as the actual dose distribution
C. The uniform radiation dose that has the same effect as a specified
chemotherapy dose
D. Applicable only to parallel normal tissues

ANSWERS
1. B Tumor B: For Tumor A, the BED changes from 72 Gy to 180 Gy and TCP
(Equation 23.4) changes from ~0 to 0.218 (approximately 21.8%). For Tumor
B, the BED changes from 140 to 860 Gy and TCP changes from ~0 to 1 (or
100%).
2. C (the high-dose part) “Serial” is used for complications that depend mostly on
the highest doses to the organ (small n in the Lyman model) and “parallel” for
complications with a strong volume dependence (large n).
3. A (n = 0.05)—see explanation above.
4. B (QUANTEC) “In 2010, a group of physicists and physicians performed a
systematic review that included more recent publications on dose and volume
dependence of clinically reported normal tissue complications for 16 organs.”
5. A (comparing rival treatment plans). Biologic models have no effect on plan
delivery time and at present, there’s no definitive evidence that they reduce
planning time.
6. B (see section “Nonuniform Irradiation—Histogram Reduction and Equivalent
Uniform Dose”).

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SECTION II
Treatment Planning for Specific Cancers

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24 Cancers of the Gastrointestinal Tract

Jordan A. Torok, Bradford A. Perez, Brian G. Czito, Christopher G.


Willett, Fang-Fang Yin, and Manisha Palta

INTRODUCTION
Radiotherapy in combination with chemotherapy has a significant role in the treatment
of cancers of the esophagus, stomach, pancreas, rectum, and anus. The role of combined
modality therapy in the treatment of these diseases has been defined largely as a result
of numerous prospective clinical trials conducted over the past 20 years. This chapter
highlights the technical aspects of treatment of gastrointestinal cancer, with particular
emphasis on anatomic target definitions and modern treatment planning techniques.

ESOPHAGEAL CANCER
In 2015, there will be an estimated 16,980 new cases of esophageal cancer in the
United States and 15,590 deaths (1). While esophageal and gastric cancers are often
described together, they are quite distinct malignancies—anatomically, etiologically,
and therapeutically. Squamous cell carcinoma and adenocarcinoma are the
predominant histologies in esophageal cancer, each attributable to specific risk factors
(2). A dramatic increase in adenocarcinoma incidence has been seen in the United States
for the past several decades, which only recently appears to have plateaued (3).
Internationally, there is significant geographic variation in the incidence of esophageal
cancer (4) where the predominant histology in endemic regions is squamous cell
carcinoma (5,6). Radiation therapy (RT) plays an important role in the management of
esophageal cancer, particularly in the neoadjuvant setting for locally advanced disease.

DIAGNOSTIC EVALUATION
A complete diagnostic workup is crucial in defining the maximal extent of locoregional
disease prior to treatment. Due to the limitations of diagnostic imaging in staging this
disease, no single study should be relied on solely to define the extent of tumor during
treatment planning.
Description of the mucosal extent of disease is best defined visually by upper
endoscopy and frequently this will define tumor beyond what is appreciated by imaging
modalities. Review of endoscopy reports and/or discussion with the gastroenterologist is
imperative. Measurements of tumor extent in the esophagus are referenced by
endoscopic distance from the incisors and location of the tumor in reference to the
gastroesophageal junction (GEJ). These measurements may be inconsistent and
imprecise between examinations, but they should be noted and compared to radiologic
findings to ensure general consistency between modalities. The distance from the
incisors to the thoracic inlet is generally 18 cm (beginning of upper thoracic
esophagus), the carina is located at ∼24 cm (demarcating the beginning of the mid-
esophagus), and the lower esophagus begins at 32 cm and ends at ∼40 cm (GEJ) (7).
Endoscopic ultrasound (EUS) is an established modality for local staging in

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experienced hands. The accuracy of EUS for T stage is generally reported to be between
80% and 90% for esophageal cancer, with higher accuracy for tumors which penetrate
the muscularis propria (T3) (8). Regional staging by EUS, which characterizes both
nodal size and architecture, has been reported to have ∼75% accuracy. Fine-needle
aspiration may augment the accuracy of the procedure for determining lymph node
involvement by tumor.
Axial imaging of the chest and abdomen with computed tomography (CT) or magnetic
resonance imaging (MRI) can detect lymphadenopathy beyond the range of EUS, but
more importantly evaluates for distant metastases. Positron emission tomography (PET)
is more accurate than CT or EUS in detecting distant metastases, and may increase
diagnostic specificity for regional and distant lymphadenopathy (9,10). Integrated
PET/CT takes advantage of the improved spatial resolution of CT, making this a
complementary study to the local staging provided by EUS.
Among patients with concerning respiratory symptoms at presentation, or any patient
with a cervical or upper esophageal tumor, bronchoscopy should be considered to
evaluate for fistula within the tracheobronchial tree prior to treatment planning.
Although the presence of a fistula has traditionally been considered a contraindication
to radiotherapy, there are multiple reports of irradiating these patients successfully
(11–13). At times, the fistula may even close with treatment and the survival of
irradiated patients appears superior to patients treated with chemotherapy or
supportive care alone (13). Consideration should be given to endoscopically stenting
these patients (12).

TREATMENT OPTIONS
The optimal coordination of surgery, chemotherapy, and radiotherapy continues to be
studied by large multi-institutional studies in patients with esophageal and GEJ cancers.
Surgical resection has long been the foundation of curative strategies for locoregionally
confined esophageal and GEJ cancers, but is inadequate as monotherapy for most cases
(14). Adjuvant treatment of GEJ tumors in the United States has largely been informed
by Intergroup 0116, which demonstrated an overall survival benefit of
chemoradiotherapy (CRT) compared to surgery alone (15). All patients had
adenocarcinomas, the majority of which were gastric cancers, with GEJ tumors making
up about 20% of the population. Similarly, phase II data supports the adjuvant CRT
approach, particularly in patients with pT3+ and/or node positive disease (16).
Retrospective evidence suggests adjuvant CRT is also beneficial for esophageal
squamous cell carcinoma (17). Adjuvant RT alone is of uncertain benefit. Dated trials
using antiquated techniques and/or unusual fractionation schemes showed either no
improvement or even a possible detrimental effect to RT alone (18,19).
More recently, neoadjuvant CRT has supplanted the traditional adjuvant paradigm
for potentially, resectable cancers of the esophagus, largely as a result of the CROSS
trial. In this trial, patients with T1N1 or T2–3N0–1 esophageal or GEJ cancer were
randomized to preoperative CRT or surgery alone. Trimodality therapy was associated
with improved complete resection rates, a pathologic complete response rate of ∼30%
as well as an overall survival benefit (median survival 49.4 vs. 24 months) (20). Early-
stage esophageal cancer (particularly T1N0) may not benefit from a trimodality
approach (21), and are more appropriately managed with upfront surgery or definitive
CRT. The accuracy of preoperative staging is therefore critical in determining the
appropriate management for these patients.
Surgical resection may not benefit all patients with potentially resectable disease after

675
CRT. Randomized trials of the addition of surgical resection to initial CRT for locally
advanced squamous cell carcinomas of the esophagus have shown improved
locoregional control but no significant improvement in patient survival (22,23). Outside
of medically inoperable patients, it is currently unclear which patients may be best
suited for this approach. In patients with unresectable disease, CRT represents the
standard of care (24).

TREATMENT PLANNING
Simulation
Patients are generally simulated in the supine position with arms extended over the
head using a wing-board or similar device to ensure reproducibility and to allow
treatment with oblique or lateral fields. Although prone positioning may be less
reproducible, it may be advantageous for some patients with middle or lower
esophageal lesions. Prone positioning is reported to move the esophageal lumen
anteriorly, an average of 1.7 cm away from the spinal cord, compared to supine
positioning (25). It should be noted that despite such maneuvers, periesophageal tissue
posterior to the esophagus still remains fixed to the vertebral column. If treatment fields
will encompass any stomach, the patient should be both simulated and treated with an
empty stomach (minimum 3 h NPO) to reduce gastric distension and improve target
reproducibility. Although CT-based planning is essential, fluoroscopic simulation may
also be a useful step for identifying surgical staple lines, clips, and respiratory motion.
Administration of oral contrast, whether at the time of simulation or flouroscopy, aides
in localizing the mucosal extent of esophageal cancers. In addition, respiratory
movement of the left hemidiaphragm can be noted and incorporated into parameters of
the planning target volume (PTV) for GEJ tumors. Studies of 4DCT-simulation (4DCT) of
esophageal cancers have demonstrated significant primary tumor as well as nodal
(celiac) movement with respiration in all directions (26,27). Given wide patient
variation in such target motion, individual assessment of target motion is preferred to
standardized internal target margins for all patients.

Radiotherapy Target
For patients treated neoadjuvantly or definitively with radiotherapy, the gross tumor
volume (GTV) includes the maximal extent of gross disease as defined by the
combination of all staging modalities. Dependence on upper gastroesophageal
radiography alone at the time of simulation will likely underestimate both the radial
tumor margin and regional nodal disease. CT may be better at defining the radial and
regional extent of gross disease, but longitudinal tumor boundaries may not be distinct.
In addition, small tumors (T1 or T2) are often not discernable on CT. Oral contrast may
assist in defining an area of mucosal irregularity. Upper endoscopy may provide the
most accurate assessment of longitudinal mucosal tumor boundaries, but is often not
possible to precisely correlate these measurements with a planning CT. EUS is probably
the best modality for defining both longitudinal and radial extent of the primary tumor.
By coordinating with the endoscopist, the superior and inferior boundaries of tumor can
be referenced to an intrathoracic structure such as the top of the aortic arch or GEJ
rather than just the incisors (28).
PET imaging is also useful in defining the GTV. With clinical judgment, the GTV may
be expanded to include FDG-avid tissue not appreciated as tumor with other imaging.

676
At times, other imaging modalities may define greater extent of tumor volumes than
defined by PET. For example, the longitudinal extent of tumor is often perceived greater
on CT than PET (29). However, given the risks of false-negative imaging, target
contours should not be reduced to include only abnormal volumes defined by PET (30).
While PET may improve target delineation, its contribution to improving treatment
efficacy seems limited (31).
The clinical target volume (CTV) includes areas of microscopic risk of disease from
either primary tumor extension or nodal metastases not detected by clinical staging. The
lymphatic drainage of the esophagus is primarily longitudinal with channels extending
some distance before perforating the muscularis propria to communicate with
adventitial lymphatics (32). Autopsy studies in patients dying of esophageal cancer
have found lymphangitic carcinomatosis of the esophageal wall in up to one-third of
patients, with in situ or invasive skip lesions at a distance of 2 to 10 cm in 13% of
patients (33). Thus, in the preoperative or definitive setting, radiotherapy ports for
esophageal cancer have traditionally included a generous longitudinal margin of
mucosa. Although initial ports in RTOG 85–01 treated the entire esophagus for 30 Gy
(34), subsequent trials have limited the longitudinal margin to 5 cm (35).
With 3D target definition, this 5-cm margin is comparable to a 3- to 4-cm CTV of
longitudinal margin of esophagus from the GTV (assuming 1-cm PTV and 0.5 to 1 cm to
block edge for dosimetric buildup). For tumors of the lower esophagus and GEJ, a 3 to 4
cm inferior extension of the CTV often includes proximal stomach. Pathologic study of
resected squamous cell carcinoma and adenocarcinoma has shown the risk of
microscopic extension to be limited to 3 and 5 cm, respectively (36). In addition to
longitudinal extension, the CTV includes radial expansion from the GTV as well.
Although this radial expansion of CTV around the GTV should include 1 to 2 cm of
adjacent soft tissue, generally this is well within the CTV boundary required for regional
nodal coverage. In the CROSS trial, longitudinal margins were 4 cm with the distal
margin shortened to 3 cm when tumor extended to the stomach (20). A radial margin of
1.5 cm around the GTV was used. It is important to note that these expansions formed a
PTV, and a CTV was not utilized. Recurrences at the border of the treatment fields were
rare (∼2%), suggesting these margins are adequate at least when followed by
esophagectomy (37).
The regional lymphatics included within the CTV depend on the anatomic location of
the primary tumor. Huang et al. examined the pattern of lymph node metastases based
on location of the primary tumor in patients undergoing esophagectomy and
lymphadnectomy (38). To summarize, upper thoracic tumors more commonly involved
cervical, upper and middle mediastinal lymph nodes while lower thoracic tumors more
commonly involved middle to lower mediastinal and abdominal nodes. For primary
tumors of the esophagus, the CTV should be extended radially to include periesophageal
lymph nodes around the GTV and along the longitudinal extent of the normal
esophagus included within the CTV (see Fig. 24.1). The periesophageal lymph nodes lie
in the posterior mediastinum in the soft tissue immediately surrounding the esophagus.
Although conventional radiotherapy fields have accommodated these nodes by a 2- to
2.5-cm margin on the esophagus, such guidelines do not account for the often
asymmetric and variable distribution of this tissue surrounding the esophagus. Thus,
the CTV should be contoured based on individual patient anatomy. Given a >40% rate
of subclinical metastases to the supraclavicular lymph nodes for upper esophageal
cancers as defined by surgical dissections (39), extension of the CTV to this region is
indicated for tumors in this location. Similarly, if the upper esophagus is within the
CTV, adjacent paratracheal lymphatics should be included in addition to periesophageal

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tissue. In the mid-esophagus, the subcarinal lymph node region should be included in
the CTV if esophagus or tumor is included to this axial level as a target volume.
Treatment of the thoracic hilar or anterior mediastinal lymph nodes is not indicated
unless they are grossly involved on pretreatment imaging.
Distal esophageal tumors that extend to or involve the GEJ pose a threat to upper
abdominal lymph nodes. Pericardial lymph nodes (medial and lateral borders of gastric
cardia) and celiac lymph nodes are included in the CTV. While splenic hilar lymph
nodes may be at risk for T3 or T4 GEJ tumors (40), failure rates were low in the CROSS
study where ∼25% had GEJ tumors and these lymph nodes were not electively treated
(37). With extension of tumor inferiorly/laterally into the gastric cardia, lymph nodes of
the entire celiac axis and splenic hilar nodes are at risk and should be covered as
described in the gastric cancer section.
Target identification is inherently more challenging in the postoperative setting.
Using preoperative staging studies and operative findings, the original extent of the
primary cancer (and gross nodal disease) must be reconstructed on the planning CT and
included within the CTV. In addition, the gastroesophageal anastomosis must be
identified and included. Although there may be temptation to exclude the anastomosis
among patients where it lies high in the thorax or even lower neck, such an omission
has been associated in one series with a 29% anastomotic recurrence rate (compared to
0% with treatment) (41).

Normal Tissue Tolerances


The percentage of total lung receiving >20 Gy should be kept to <30%, and preferably
<25%. Among patients treated neoadjuvantly, postoperative pulmonary complications
have been inversely associated with the absolute volume of lung spared 5 Gy (42,43).
The whole heart should not receive beyond a mean dose of 30 Gy. One-half of the heart
should be restricted to 40 Gy or less. Doses of 50 Gy or slightly beyond may be delivered
to a maximum of 30% of heart volume, but an attempt should be made to limit high
doses to the left ventricle when possible. The spinal cord should not receive >45 Gy.

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Figure 24.1 A 63-year-old woman with a cT2N0 adenocarcinoma of the distal esophagus treated with
neoadjuvant chemoradiotherapy utilizing a four-field technique. AP (A) and right lateral (B) fields, GTV (red).
Axial (C) and sagittal (D) dosimetry, with GTV (red) and 45 Gy (yellow), 42.75 Gy (orange), 40.5 Gy (dark
blue), 36 Gy (dark green) and 18 Gy (pink) isodose lines.

Radiotherapy Dose
RTOG 95–05 (35) evaluated the radiotherapy dose for definitive treatment of
esophageal cancer in conjunction with concurrent chemotherapy. No difference in
locoregional control or overall survival was detected between the 50.4 and 64.8 Gy
arms of the trial, with a trend toward inferior outcome with high-dose CRT. Thus, 50.4
Gy given at 1.8 Gy/fraction is the recommended dose for patients with esophageal
cancer treated definitively with radiation. In the neoadjuvant setting, the CROSS trial
utilized a lower total dose of 41.4 Gy in 1.8 Gy/fraction to a single volume (20). It is
important to note that this was in a well-selected patient population fit for surgery, with
94% of patients subsequently undergoing esophagectomy. In practice, many patients
may not ultimately go to surgery, where a total dose of 41.4 Gy may be inadequate. An
alternative approach is to deliver 45 Gy at 1.8 Gy/fraction to the initial CTV with
consideration of a 5.4-Gy boost to gross disease. In this manner, a definitive dose has
been administered even if the patient ultimately does not go for surgery. Whether this

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additional dose results in enhanced perioperative complications compared to that used
in the CROSS regimen is unknown.
In the postoperative setting, 45 Gy at 1.8 Gy/fraction is considered standard based
on Intergroup 0116 (15). Boost treatment beyond 45 Gy for such indications as close or
involved surgical margins may be considered cautiously in the setting of normal tissue
and patient tolerances.

RADIOTHERAPY FIELDS AND TECHNIQUES


Common field arrangements for the treatment of esophageal cancers are influenced by
the total dose limits of the spinal cord. AP–PA techniques irradiate the least amount of
normal lung, but care must be taken with lower esophageal/GEJ tumors where such a
field arrangement can include a significant amount of heart. Supplementation with
lateral or oblique fields which avoid the spinal cord are required to deliver doses beyond
45 Gy to the thorax, but will generally lead to increased doses to the lung. A four-field
technique (AP, PA, and laterals) usually enables a satisfactory dose distribution when
the weighting of lateral fields is limited according to lung tolerance (see Fig. 24.1).
Oblique ports include less lung than lateral fields, but depending on orientation may
include more heart (25). Another option is to treat the patient with a three-field
technique (AP and posterior oblique fields), with at least one field not contributing to
spinal cord dose.
Traditional field borders for esophageal cancers have generally been defined with 2-
cm lateral (radial) margins beyond the esophagus and a 5-cm longitudinal margin from
tumor (superior–inferior) (35). 3D treatment planning allows for further optimization of
field shaping and orientation based on individual patient anatomy compared to 2D
techniques. However, the transition from 2D to 3D field definitions of target must be
done with caution in order to avoid undertreatment of tissues at risk, which were
previously included in multi-institutional trials. Target motion should be assessed, either
with 4DCT or fluoroscopy and upper gastrointestinal contrast. Internal motion can then
be added to the CTV to create an internal target volume (ITV). The PTV should be
expanded by a minimum of 5 mm to 1 cm, depending on the frequency of image
guidance, to account for setup uncertainty. Conforming field borders should then be
devised that allow dosimetric coverage of the PTV (usually another 5 to 10 mm to the
field edge).
Given the complex geometric targets associated with esophageal cancers and the
proximity of critical normal tissue, the increased conformality of IMRT may provide
dosimetric advantages compared to standard radiotherapy techniques. However, this
technology must be employed with care, given the challenges of respiratory and cardiac
motion, the intolerance of large volumes of the lung to even modest doses of radiation,
and the undesirability of dose inhomogeneity within the PTV. There is limited
prospective clinical experience with the use of IMRT in the treatment of esophageal
cancer. Its careful implementation has been associated with decreased exposure of the
lungs and heart compared to traditional techniques (44–47), with one retrospective
series suggesting improved clinical outcomes compared to 3D conformal RT (48).

Chemotherapy
Based on Intergroup 0116, 5-fluorouracil (FU)–based CRT is typical for adjuvant CRT
(15). Patients initially received 5-FU (425 mg/m2) with leucovorin (20 mg/m2) for 5
days. CRT began 28 days later with reduced doses of 5-FU (400 mg/m2) and leucovorin

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on the first 4 days and last 3 days of radiotherapy. Two more monthly cycles of
chemotherapy were given a month after completion of radiotherapy. Grade 3 or higher
hematologic and gastrointestinal toxicity associated with this regimen was seen in 54%
and 33% of patients, respectively.
For patients treated with definitive CRT of the esophagus, both cisplatin and 5-FU are
used concurrently with radiation. RTOG 85–01 established the clear superiority of CRT
over radiotherapy alone for patients with squamous cell carcinoma of the esophagus
(34). Cisplatin (75 mg/m2) was administered on the first and fifth weeks of
radiotherapy with 5-FU (1,000 mg/m2) for 4 days. Two additional cycles of cisplatin
and 5-FU were administered after completion of radiotherapy. Rates of grade 3 or
higher hematologic and gastrointestinal toxicity were comparable to those seen in the
Intergroup trial. Initial randomized trials of neoadjuvant CRT have similarly included
various schedules of concurrent cisplatin, generally with 5-FU as well (49–52). The
more recent CROSS regimen included carboplatin at an area under the curve of 2
mg/mL/min and paclitaxel 50 mg/m2, both given weekly (20) with preoperative
radiotherapy. Acute toxicity was considerably less compared to earlier trials containing
5-FU, with grade 3+ hematologic, and all other nonhematologic toxicity reported in 7%
and 13% of patients, respectively. The optimal agent(s), dose and schedule are
currently unknown.

PROGNOSIS
The outcome of patients with esophageal cancer treated with curative intent has been
defined by randomized clinical trials. For locally advanced, unresectable esophageal
cancers, the 5-year overall survival after definitive CRT was 26% in RTOG 85–01 (24).
Five-year survival among patients undergoing trimodality therapy has been reported as
high as 47% (20). Surgical or endoscopic treatment of T1 esophageal cancer results in a
5-year survival of ∼80% (53).

GASTRIC CANCER
In 2015, there will be an estimated 24,590 new cases of gastric cancer in the United
States, with 10,720 deaths attributed to the disease (1). As with esophageal cancer,
there is marked variation in the incidence of gastric cancer based on geographic region
(54). Gastric cancers are predominantly adenocarcinomas, with diffuse and intestinal
subtypes. Distal gastric cancers have been decreasing in incidence, while more
proximal/cardia lesions have become more common (55). While often used in the
adjuvant setting in North America, the role of RT in the management of gastric cancer
in Europe is somewhat controversial and remains to be defined by ongoing trials.

DIAGNOSTIC EVALUATION
Similar to esophageal cancer, upper endoscopy is critical in delineating the location and
extent of mucosal disease involvement. The location of the tumor “epicenter” and its
extension to the GEJ/distal esophagus should be determined based on endoscopy
reports and/or discussion with the gastroenterologist. The Siewert classification can be
useful in differentiating true gastric cancers from GEJ cancers (56). As with esophageal
cancer, EUS may play an important role in the local and regional staging of gastric
cancer. EUS accuracy in determining both correct T and N stage is ∼80% (57–59).

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A contrast-enhanced CT of the chest, abdomen, and pelvis is done to evaluate for
regional lymph node and distant metastases, but is limited in the detection of peritoneal
implants (60). The addition of PET to CT can improve accuracy of staging, primarily as
a result of increased specificity in diagnosing lymph node metastases (61) and in the
detection of distant metastases (62). An important limitation of PET is that diffuse
type/signet-ring gastric cancers can be associated with false-negative results (63–65). In
addition, PET also has limited sensitivity in the diagnosis of peritoneal metastases (66).
As a result, the role of PET is not as clearly defined in gastric cancer.
The use of routine staging laparoscopy for gastric cancer is evolving. In a large series
from the Memorial Sloan Kettering Cancer Center, 30% of patients without CT-evidence
of distant metastases were found to have metastatic disease at laparoscopy (67). In
patients without obvious metastatic disease and EUS-staged T1–T2N0 disease, occult
metastatic disease is rarely found at laparoscopy (68), suggesting the procedure can be
safely omitted in these patients. Laparoscopy is therefore more likely to change
management in advanced cases and should be considered in these patients (69).

TREATMENT OPTIONS
The optimal treatment paradigm for gastric cancer remains an active area of
investigation. Upfront surgical resection is indicated for early-stage gastric cancers
(T1N0). For more advanced cases, local recurrence and/or regional failure occurs in a
significant number of patients following a curative resection (70). As a result, two
multimodality approaches have evolved in parallel. Intergroup 0116 investigated the
use of adjuvant CRT in a heterogeneous patient population including T1N+, T2–4N0–2
gastric cancers as well as a smaller proportion of GEJ cancers (15). The addition of
adjuvant CRT to surgical resection resulted in a significant reduction in local regional
failure and an improvement in survival (median survival 35 vs. 27 months) (71). As a
result, adjuvant CRT became the standard treatment for patients with gastric cancer in
North America. Critics have suggested the survival benefit of CRT was a result of
inadequate lymphadenectomy, as the majority of patients underwent a D0 resection
(72). Retrospective evidence suggests adjuvant CRT is still beneficial for patients
following D2 resection compared to surgery alone (73). The Korean ARTIST trial
compared the use of adjuvant chemotherapy to CRT in patients undergoing a D2
resection. A recent update of this trial found a significant reduction in locoregional
relapse with CRT, but no difference in overall survival (74). Subset analysis of the
results suggested patients with node positive disease were more likely to benefit from
CRT, leading to an ongoing trial in this population.
Perioperative chemotherapy has also been investigated for advanced gastric cancer,
primarily in European countries. The UK MAGIC trial compared this approach to
surgical resection alone in a heterogeneous patient population of mostly gastric (∼75%)
but also GEJ and distal esophageal cancers. The perioperative chemotherapy regimen
was associated with tumor downstaging and a significant improvement in overall
survival (5-year 36% vs. 23%) (75). A meta-analysis of perioperative chemotherapy
compared to surgery alone (including the MAGIC trial and several other similarly
designed trials) demonstrated a small, but significant, improvement in survival (76).
Perioperative chemotherapy has subsequently become the preferred approach in
Europe. Whether the addition of neoadjuvant RT to perioperative chemotherapy will
improve outcome is currently under investigation. The role of neoadjuvant CRT was
evaluated in the RTOG 9904, a single-arm phase II study. This study demonstrated the
feasibility of this approach with a pathologic complete response rate in greater than

682
20% of patients (77).
For unresectable disease, some patients can be downstaged with neoadjuvant therapy,
but the optimal approach is unknown. Therapy for the majority of these patients is
typically palliative. The role of RT in this setting is largely based on historical trials. The
addition of chemotherapy to RT improved survival (78), while the comparison of CRT to
chemotherapy alone appeared to result in more long-term survivors (79). Most
contemporary trials have focused on improving combination chemotherapy efficacy for
these patients.

TREATMENT PLANNING
Simulation
As with esophageal cancers, patients are generally simulated in the supine position with
arms extended over the head using a wing-board or similar device. Patients should be
both simulated and treated with an empty stomach (minimum 3 h) to reduce gastric
distension and improve target reproducibility. Oral contrast can be given, which in the
preoperative or definitive setting can help identify mucosal extent of disease. In the
postoperative setting, oral contrast helps identify anatomical structures, including the
gastric remnant and anastomosis. IV contrast is routinely given to assist in the detection
of lymphadenopathy. 4DCT may be useful in terms of organ motion related to
respiration which can be incorporated into parameters of the treatment volumes (80).
Fluoroscopic imaging with contrast agent or fiducial markers may also be an effective
approach to estimate the extent of organ motion (81).

Radiotherapy Target
In the neoadjuvant and definitive setting, the GTV includes the maximal extent of gross
disease as defined by upper endoscopy and imaging modalities, primarily CT and EUS.
The CTV includes areas at risk for microscopic disease from either primary tumor
extension or nodal metastases not detected by clinical staging. Areas at risk for local
and regional recurrence have been identified, most notably from a seminal re-operation
series (70). The CTV includes all the perigastric lymph nodes along the lesser and
greater curvatures of the stomach. Adequate longitudinal normal mucosal margin
within the CTV should be generated (∼5 cm). For proximal gastric tumors, extension of
CTV cranially may include distal esophagus with associated periesophageal lymphatics.
For very distal gastric cancers, similar caudal extension including a portion of the
duodenum is appropriate. Tumors of the gastric cardia or fundus (especially if T3)
should include the medial left hemidiaphragm.
In addition to the perigastric lymph nodes, nodal stations to be included in the CTV
for gastric tumors include the celiac, porta hepatis (including gastrohepatic and
hepatoduodenal), suprapancreatic (along the splenic artery), splenic hilar, supra- and
infrapyloric (above and below the pylorus), pancreaticoduodenal (tissue around and
posterior to the pancreatic head), and local paraaortic/retroperitoneal lymph nodes
(along the cranial-caudad extent of the stomach). Similar principles for target
identification exist in the postoperative setting. Using preoperative staging studies and
operative findings, the original extent of the primary cancer (and gross nodal disease)
must be reconstructed on the planning CT and included within the CTV. A recently
published contouring atlas helps identify these regional nodes on CT in patients with
both intact and postoperative anatomy (82). Among gastric tumors that involve only the

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upper one-third of the stomach and who have minimal lymphatic tumor involvement
pathologically, cautious consideration can be given for exclusion of the infrapyloric and
pancreaticoduodenal lymph nodes (83). Similarly, lesions of the lower one-third of the
stomach may have a lower propensity for involvement of the splenic hilar lymph nodes
(83).

Normal Tissue Tolerances


The amount of small bowel receiving over 45 Gy should be minimized without
compromising target coverage. Any small bowel within a possible boost volume of
treatment should be limited and not receive beyond 50 Gy. At least 75% of one kidney
or the composite of one whole kidney should be kept below 18 to 20 Gy. If the large
majority of one kidney will receive doses beyond 20 Gy, consideration should be given
to a quantitative renal scan prior to treatment to ensure sufficient function of the other
kidney. Sixty (and preferably less) percent of the liver should be kept below 30 Gy and
the whole liver should not receive >25 Gy. Heart and spinal cord constraints are
similar to those described for esophageal cancer.

RADIOTHERAPY DOSE
In the neoadjuvant setting, 45 Gy at 1.8 Gy/fraction was utilized in RTOG 9904 and is
the dose being used in the ongoing TOPGEAR trial. In the postoperative setting, 45 Gy
at 1.8 Gy/fraction is the standard dose based on Intergroup 0116 (15). Boost treatment
beyond 45 Gy for such indications as close or involved surgical margins may be
considered cautiously, with regard given to normal tissue and patient tolerances.

Radiotherapy Fields and Techniques


The PTV is in part based on organ motion assessment and should be individualized
based on 4DCT. For 3D planning, a minimum 5-mm margin is necessary for dosimetric
coverage of the PTV. Postoperative field design continues to be influenced by Intergroup
0116. Smalley et al. (83) describe the traditional borders as follows: the superior field
border includes the left hemidiaphragm, though it may be significantly higher for
proximal gastric tumors whose anastomoses are in the thorax. In order to include the
infrapyloric and pancreaticoduodenal nodes, the inferior field border is generally
located at L3. The left lateral border extends sufficiently to include the lateral border of
the perigastric lymph nodes of the greater curvature and the splenic hilum. The medial
border is placed to include the porta hepatis and the medial extent of the preoperative
tumor volume. Using this technique, the addition of lateral or oblique fields to AP–PA
ports may have some benefit. The gastric fundus and adjacent perigastric lymph nodes
often extend posteriorly enough that straight lateral fields are unable to spare the entire
spinal cord or a significant amount of kidney. In addition, more liver is irradiated with
such fields, and so if used they must be weighted to ensure their contribution is <20
Gy. The anterior borders of lateral and oblique fields must cover the preoperative extent
of the ventral gastric wall.
Modern 3D conformal treatment planning should incorporate CT-defined volumes
while taking into account volumes included in traditional ports to avoid
undertreatment. Customized field technique may be advantageous for some patients
depending on the anatomic extent of target. Oblique fields optimized to avoid spinal
cord or kidney while covering the PTV may often prove superior to straight lateral

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fields. 3D treatment planning with five or more fields has been studied in comparison to
the AP–PA technique used in Intergroup 0116 with reported dosimetric gains in regard
to normal structures (84) and favorable clinical assessment of toxicity (85). The
dosimetric benefit achieved was from reduction in kidney and spinal cord doses, at the
expense of small increases in dose to the liver.
Dosimetric studies of IMRT in the postoperative treatment of gastric cancer have
reported a possible improvement target coverage and sparing of critical structures (86),
most notably in reducing kidney exposure (87–89) compared to conventional
techniques. However, clinically apparent renal dysfunction has not been described as a
common problem after treatment with more conventional techniques, such as among
patients treated in Intergroup 0116 (15). Preoperative IMRT is associated with excellent
target coverage and normal tissue sparing but appeared to have similar acute toxicity to
patients treated with 3D CRT (90).

Chemotherapy
Intergroup 0116 employed an adjuvant/concurrent regimen of 5-FU as described in the
esophageal section. This has subsequently served as the backbone for most CRT
regimens. The RTOG investigated combination and alternate regimens in both the
preoperative and postoperative settings. RTOG 9904 utilized an induction regimen of 5-
FU (200 mg/m2) by continuous infusion on days 1 to 21 and cisplatin (20 mg/m2) on
days 1 to 5 for two cycles followed by concurrent 5-FU (300 mg/m2) 5 days a week and
paclitaxel (45 mg/m2) weekly during radiotherapy (77). RTOG 0114 conducted a
randomized phase II study comparing an intensified regimen of paclitaxel, cisplatin,
and 5-FU (PCF) induction followed by PF CRT to a non–5-FU containing regimen of PC
induction followed by PC CRT (91). The PCF arm closed early due to excess toxicity,
while the PC arm did not improve outcomes compared to INT 0116. Intergroup trial
CALGB 80101 compared the INT 0116 5-FU regimen used before and after CRT to a
regimen similar to that used in the MAGIC trial containing epirubicin (50 mg/m2 d1),
cisplatin (60 mg/m2 d1), and 5-FU (200 mg/m2/d1–21, ECF). The CRT component was
the same in both arms with 5-FU given via continuous infusion at a dose of 200
mg/m2/d. Results presented at the 2011 ASCO meeting revealed no significant
difference in survival between the arms. A possible alternative to intravenous 5-FU is
daily oral capecitabine (825 mg/m2 BID) as used in the ARTIST trial (74), although
there is no prospective evidence comparing the two in gastric cancer. Additional agents
used in the adjuvant setting not previously mentioned include S-1 and oxaliplatin.
While fluoropyrimidine-based CRT has been a consistent theme across trials, the optimal
perioperative and adjuvant regimen remains an area of active investigation.

Prognosis
The outcome of patients with gastric cancer varies depending on the geographic region
treated. The 5-year overall survival from the ARTIST trial based in South Korea was
∼75% (74), compared to a 5-year survival of ∼40% in the combined modality arms
from INT 0116 (71) and the MAGIC trial (75). The 5-year survival rate was <30% in
the surgery alone arms from the latter two trials, while it was 60% to 70% in the
surgery alone arms from recent Japanese and Korean studies (92,93). This may be
explained in part by more advanced patients included in the North American and
European trials, but may also reflect differences in the biology of the disease, surgical
experience, and screening practices resulting in stage migration between the countries.

685
PANCREATIC CANCER
In the year 2015, the American Cancer Society estimated 48,960 new pancreatic
cancers in the United States (1). They also predicted 40,560 deaths from this disease,
highlighting the unfavorable prognosis of this cancer at any stage and the need for
more effective therapies.

DIAGNOSTIC EVALUATION
The pretreatment diagnostic evaluation is crucial for selection of patients who are
candidates for surgical resection, those with unresectable disease, and patients with
distant metastases. Abdominal CT or MRI remains the most useful modality for defining
local extent of disease and to detect metastasis within the abdomen. Resectability
criteria are based on tumor involvement along nearby arteries and veins which can be
assessed with these imaging modalities (94). Refinements in abdominal CT imaging,
such as acquisition of thin sections, dual-phase contrast imaging, 3D reconstruction,
and use of multi-detector CT, have greatly improved the accuracy in defining local
tumor extension. With these techniques, accurate prediction of resectability has been
reported in up to 87% of patients (95). In addition to CT or MRI, EUS in experienced
hands may add further information regarding tumor extent, vascular involvement, and
regional adenopathy, but probably is most useful in obtaining cytologic diagnosis.
Endoscopic retrograde cholangiopancreatography (ERCP) is a useful technique as it can
be utilized as a diagnostic tool to collect brushings which can confirm malignancy
within the biliary and/or pancreatic ducts, and as a therapeutic tool to place a biliary
stent which can relieve extrinsic compression from the pancreatic tumor. Imaging from
ERCP should also be reviewed as it may assist in defining tumor boundaries during
treatment planning based on abnormalities of the biliary and/or pancreatic ducts.
Although PET imaging has been reported to have a high sensitivity in detecting
pancreatic carcinomas, its poor anatomic resolution limits its usefulness for local
staging (surgical resectability or nodal involvement) (96). Some studies suggest PET/CT
may be more sensitive than other modalities in detecting distant metastases (97),
although currently this approach is not commonly utilized for pancreatic cancer
staging.

TREATMENT OPTIONS
When a patient is medically fit and their tumor is anatomically resectable, surgical
resection is clearly indicated as it is the only strategy that contributes to long-term
survival in this disease. After surgical resection, patients not only have a high-risk
distant metastasis development, but local failure as well. A high rate of local recurrence
has been reported after surgery (98,99). A small randomized trial conducted by the
GITSG reported a doubling in median survival (10.9 vs. 21.0 months) among patients
treated with adjuvant CRT compared to patients undergoing surgical resection alone
(100). Two subsequent randomized trials from Europe (EORTC 40891 and ESPAC-1)
failed to detect a survival benefit for adjuvant chemoradiation (101,102). These studies
should be interpreted with caution given the split course radiotherapy in all three trials,
the small numbers of the GITSG trial, the inclusion of favorable periampullary tumors in
the EORTC study, and the lack of radiotherapy quality assurance or standardized
specimen review in the ESPAC-1. Recent retrospective analysis of large cohorts of
patients from Mayo Clinic and Johns Hopkins Hospital strongly support the use of

686
postoperative CRT in the management of resected pancreas cancer (103,104). Thus,
postoperative CRT may be considered part of the overall adjuvant treatment plan in
medically fit patients.
Multiple series have reported the feasibility and outcome of patients with resectable
tumors treated with preoperative CRT (105–108). Preoperative CRT, however, has not
been established as a treatment standard by prospective randomized trials. Some of the
theoretic advantages of this strategy include local tumor downstaging to facilitate an R0
resection, better oxygenation of the target tissues during radiation and chemotherapy,
reduced risk of intraoperative seeding, and improved treatment tolerance compared to
adjuvant therapy in the postoperative setting. Practically, neoadjuvant therapy may
also allow for identification of those patients not likely to benefit from curative intent
surgical resection, particularly pancreaticoduodenectomy, which carries a high degree
of associated morbidity (109). A course of neoadjuvant therapy followed by restaging
may select patients who benefit from resection and conversely avoid surgery in those
patients with adverse biologic features leading to early development of metastatic
disease.
Patients with unresectable cancers who have a favorable functional status can be
considered for noncurative approaches including CRT or chemotherapy alone. Two
randomized studies including preliminary results of a large, recently presented
European study (LAP-07) have not shown any benefit with the addition of RT to initial
chemotherapy among patients with unresectable disease (110,111). In contrast, other
studies reporting on use of combined modality therapy have been associated with
improved overall survival compared to radiotherapy alone (112), chemotherapy alone
(113,114), or supportive care (115). In light of this conflicting data, one approach for
patients without local symptoms is to offer initial systemic therapy followed by
combined modality therapy in patients without disease progression. Among
symptomatic patients, local therapy with radiation is likely to be an effective palliative
tool, and therefore consideration should be given to upfront combined modality
therapy.
Patients who present with metastatic disease are generally best managed with
systemic chemotherapy, although short palliative courses of radiotherapy for symptoms
such as pain may be beneficial in some instances.

TREATMENT PLANNING
Simulation
Patients should be simulated in the supine position with arms over the head using a
wing-board or similar device to ensure reproducibility and to allow treatment with
lateral fields. Use of oral contrast is helpful to identify the duodenal C-loop as an
important reference for field design. Intravenous contrast during CT planning aids in
detection of vascular landmarks and target definition, but generally, planning CT
images are inferior to diagnostic scans optimized for pancreas imaging (acquisition
during arterial and portal-venous phases of contrast). Therefore, diagnostic films should
be reviewed in conjunction with planning CT images. Respiratory motion can be
significant within the radiation target areas and such variation can be accounted for by
use of 4DCT and/or use of oral contrast during fluoroscopic simulation. These
approaches allow for quantification of duodenal C-loop motion and ensure appropriate
coverage of the target regions.

687
Radiotherapy Target
Accurate target definition is important not only to impact locoregional control with
radiation, but also to reduce toxicity of treatment. For unresectable tumors or those
treated neoadjuvantly, the GTV includes the primary tumor (including vessels involved
by tumor) and any radiographically enlarged lymph nodes. The CTV includes the
primary tumor and involved nodes plus margin for microscopic extension and any at-
risk abdominal lymph nodes. A 1- to 2-cm margin of soft tissue around the primary
tumor should be included in the CTV. This margin, however, is usually within the
volume required to include the peripancreatic lymph nodes. Given the proximity of the
pancreatic head to duodenum, the adjacent medial wall is included. The entire
circumference of duodenum should be included for tumor with gross duodenal invasion.
For patients to be treated postoperatively, surgical and pathologic information should
be carefully reviewed at the time of treatment planning to assist with target delineation.
The postoperative CTV includes the postoperative bed, anastomoses, and the abdominal
lymph nodes at risk. Often a postoperative boost volume (CTV2) is delineated which
attempts to reconstruct the preoperative tumor volume. The RTOG has published a
contouring atlas to assist with postoperative target delineation which is also useful for
identifying nodal areas at risk when radiation is delivered neoadjuvantly (116).
Brunner et al. (117) have provided an excellent analysis of nodal regions at risk based
on pathologic specimens from 175 cancers of the pancreatic head. Peripancreatic nodal
regions at >5% risk of nodal metastasis include (in order of decreasing frequency):
posterior pancreaticoduodenal area, superior/inferior border of the pancreatic head,
anterior pancreaticoduodenal area, hepatoduodenal ligament (porta hepatis), superior
margin of pancreatic body, and superior mesenteric artery. Thus, a CTV that includes a
small rim of peripancreatic soft tissue in all directions of the pancreatic head and neck
will include all but the nodes along the porta hepatis, SMA, aorta, and celiac artery,
which should also be included within the CTV. Attention to a biliary stent may assist in
locating the porta hepatis during target contouring. Although the location of the celiac
artery and SMA has traditionally been described in relationship to T12 and L1,
respectively, data from angiography (118) suggests that there is enough individual
variability that identification should be based on CT imaging rather than relying solely
on boney landmarks. Although the paraaortic lymph nodes are considered a distant site
of disease for staging purposes, given the over 20% risk of subclinical metastases (117),
they should be included in the CTV. With respect to the inferior vena cava and aorta, in
>90% of cases, retroperitoneal metastases are anterior to these vessels, between them,
or lateral to the aorta (<5% metastases are retrocaval/retroaortic or lateral to the cava)
(119). In the craniocaudad dimension, the majority of paraaortic nodal involvement is
between the celiac artery superiorly and the level of the renal veins inferiorly (except
for tumors >3 cm, where the CTV volume should extend inferiorly to the level of
inferior mesenteric artery) (120). For tumors involving the pancreatic tail, inclusion of
the suprapancreatic lymph nodes (along splenic vessels) and splenic hilum is
recommended. In addition, elective treatment of inferior pancreaticoduodenal lymph
nodes may be excluded in these patients, which allows for relative sparing of the right
kidney.
Given the predominance of tumor recurrence within radiotherapy ports even when
small local fields are used (121), some have questioned the value of treating the
regional lymph nodes in patients with unresectable pancreatic cancer. Initial reports
have described treating the primary tumor only with stereotactic body radiotherapy
(SBRT) (122–125). Local control rates using this approach are encouraging and

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significant toxicity is rare with careful attention to duodenal wall dose constraints.
SBRT has also been used as a boost after initial standard fractionation (126). Given that
pathologic nodal involvement is reported in up to 76% of patients undergoing surgical
resection (117,120), elective treatment of regional lymphatics seems justified, unless
directed otherwise on an investigational trial. SBRT techniques in the setting of
pancreatic cancer are still best performed in the context of a clinical trial.

Normal Tissue Tolerances


The amount of small bowel receiving 45 Gy should be minimized without compromising
target coverage. Any small bowel within the boost volume of treatment should be limited
and not receive beyond 50 Gy, though up to 55 Gy may be cautiously delivered to small
portions of the duodenum wall if clinically indicated. At least 75% of one kidney or the
composite of one whole kidney should be kept below 18 to 20 Gy. If the large majority
of one kidney will receive doses beyond 20 Gy, consideration should be given to a
quantitative renal scan prior to treatment to ensure sufficient function of the other
kidney. Our bias is keep 60% of the liver below 30 Gy and the whole liver should not
receive >25 Gy. The spinal cord should not receive >45 Gy.

Radiotherapy Dose
The only data from randomized trials regarding radiotherapy dose in pancreatic cancer
is the GITSG trial for unresectable tumors. No difference in patient outcome was
detected between 40 and 60 Gy (split course schedule with concurrent 5-FU) (112). The
radiotherapy and imaging techniques of this trial would be considered outdated by
current standards, and so current radiotherapy dose guidelines are based on normal
organ tolerance to upper abdominal radiation rather than the results of this trial.
Elective nodal stations (CTV) are treated to 45 Gy at 1.8 Gy/fraction. A subsequent
boost of 5.4 Gy is delivered to the GTV or CTV2 (postoperatively). Higher boost doses
may be considered for unresectable patients or those with positive margins when dose
can be delivered within the constraints of normal organs (especially small bowel).

Radiotherapy Fields and Techniques


The pancreas is commonly treated with a four-field technique with disproportionate
weighting of the anterior and posterior fields to reduce dose to the liver from the lateral
fields (see Fig. 24.2). While maintaining a 2- to 3-cm margin on the primary tumor (or
tumor bed), traditional fields typically encompass T11 superiorly through L3 inferiorly.
The left field edge is at least 2 cm from the left vertebral body edge (or past the splenic
hilum for pancreatic tail lesions). The right field border is extended to cover the
duodenum and porta hepatis. With the lateral fields, the posterior border generally
splits the vertebral bodies, while the anterior border is placed at least 2 cm anterior to
the tumor, maintaining a 3- to 4-cm margin anterior to the vertebral bodies to ensure
coverage of paraaortic lymph nodes. These boundaries should be customized based on
patient differences in target volumes as well as normal structure location. Boost fields
generally encompass unresected tumor or original tumor bed with 1.5- to 2-cm margins.

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Figure 24.2 A 62-year-old woman with a cT2N1 borderline resectable adenocarcinoma of the pancreas treated
with neoadjuvant chemoradiotherapy utilizing a four-field technique. AP (A) and right lateral (B) views
showing primary (yellow) and boost (red) fields with MLC blocks targeting GTV (red), PTV_45 Gy (dark blue)
and PTV_50.4 Gy (light blue). Sagittal (C), axial (D) and coronal (E) dosimetry, with GTV (red) and 50.4 Gy
(yellow), 45 Gy (dark blue), 40 Gy (cyan) and 15 Gy (light green) isodose lines.

With a 3D reconstruction of carefully defined CT-based target volumes, field borders


can be refined, which reflect individual tumor and patient anatomy. A four-field
technique is often still appropriate with optimization of field weighting with computer
dosimetry. To account for setup error and target movement, a PTV margin of 1 cm
beyond the CTV is advised. If respiratory motion and image-guided setup techniques are
utilized, PTV margins as small as 5 mm can be considered. Given the movement of
upper abdominal organs due to respiration, greater margin in the superior to inferior
dimension may be prudent (127). Field edges are devised at an additional 5 to 10 mm
beyond the PTV to provide dosimetric coverage. The use of highly conformal
radiotherapy techniques should be used cautiously due to substantial inter- and
intrafraction variations in the pancreas position. Study of pancreas movement by cine
MRI has shown that changes in pancreas position are larger and more variable than
often appreciated, especially in the craniocaudad dimension, and do not necessarily
correlate well with the diaphragm location (128). Similarly, image guidance based on
boney landmarks has been found to correlate with accurate pancreas target setup in
only 20% of treatments when compared to tumor fiducial markers even when using
respiratory gating (129).
Radiation treatment using a traditional four-field technique remains standard in the
treatment of pancreatic cancer. 3D treatment planning with four to six noncoplanar
beams has been objectively compared to traditional four-field techniques and may
provide some dosimetric advantages, particularly in sparing the kidneys (130).
Alternative field orientations may be considered for patients with dosimetric challenges
due to atypical target volumes or normal organs (e.g., one kidney). The use of IMRT for
pancreatic cancers may also provide some dosimetric advantages by sparing kidneys,

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bowel, and liver (131–133) as well as enabling possible dose escalation to the GTV
(134). A few institutions have reported patient outcomes after treatment with IMRT
with favorable tolerance and expected survival (131,135). Care must be taken when
employing this modality to account for target motion, avoid dosimetric hot spots, and
be certain the devised plan is clinically superior to that which could be achieved with
less advanced techniques.
Although there is no high-level evidence to date supporting the use of SBRT, there are
multiple single-institution experiences describing SBRT techniques for the treatment of
pancreatic cancer (122,123,125) in addition to one prospective, multi-institutional
Phase II study (136). Due to variability in target volume delineation and limited
experience with SBRT for pancreatic cancer, prescription doses using SBRT have varied
widely. A recent phase II retrospective multi-institution experience prescribed 6.6 Gy in
five fractions with concurrent gemcitabine (124). SBRT planning typically consists of
4DCT simulation and consideration of advanced respiratory motion management
techniques such as inspiratory/expiratory breathhold or abdominal compression to
minimize the size of target volume while accounting for organ motion. Fiducial markers
can be placed and utilized as part of image guided radiation therapy (IGRT) to assist
with treatment setup. Treatment delivery with linear accelerator–based RT typically
utilizes volumetric-modulated arc therapy or IMRT with multiple noncoplanar beams to
maximize dose gradients and minimize high dose to nontarget normal tissues in close
proximity to the target.

Chemotherapy
Given the high rates of distant metastatic disease, systemic treatment with
chemotherapy is a critical component to the management of all patients with pancreatic
cancer. Recent studies have shown improved survival with the use of newer, multi-drug
regimens. Conroy et al. showed improved survival among patients with good
performance status and metastatic pancreatic adenocarcinoma treated with oxaliplatin,
irinotecan, FU, and leucovorin (FOLFIRINOX) compared to gemcitabine alone (137).
Van Hoff et al., recently published a phase III randomized study demonstrating
improved 1- and 2-year survival rates among patients with metastatic pancreatic
adenocarcinoma treated with nab-paclitaxel and gemcitabine compared to gemcitabine
alone (138). The role of these multi-drug regimens has not been as well established in
nonmetastatic patients, although retrospective series suggest these agents may also be
more active among patients with locally advanced pancreatic cancer (139,140) and
among those patients with borderline resectable disease (141).
Chemotherapy has a long history of utilization as a radiosensitizer for patients with
pancreatic cancer. Among unresectable patients, a randomized trial conducted by the
GITSG established the superiority of bolus 5-FU concurrent with radiotherapy over
radiotherapy alone (113). In current practice, continuous venous infusion 5-FU or oral
capecitabine are now more commonly utilized with RT although the data to support this
is extrapolated largely from randomized studies of patients treated with combined
modality therapy for rectal cancer (142,143). Gemcitabine has been studied
concurrently with radiation both among unresectable patients and in the postoperative
setting with conflicting data from small randomized studies regarding its efficacy
compared to 5-FU–based regimens (144,145). Toxicity with combined modality therapy
using gemcitabine is dependent on an inverse relationship between gemcitabine
schedule/dose and radiation field size/dose (146). Without standardized parameters or
large trials showing benefit over 5-FU–based therapy and radiation, gemcitabine

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delivered concurrently with radiation should be approached with caution.

Prognosis
The overall prognosis for patients with pancreatic cancer is poor. Approximately 40% of
patients have distant metastatic disease at presentation and an additional 30% to 40%
have locally advanced, unresectable tumors. Only about 15% to 20% of patients with
pancreatic cancer have potentially resectable disease at diagnosis. The median survival
for patients presenting with metastatic disease treated with modern chemotherapy
techniques remains less than 1 year (137,138). Among locally advanced, unresectable
patients who receive chemotherapy alone or combined modality therapy, median
survival is about 15 to 16 months (110). Long-term survival is not anticipated in
patients with inoperable tumors. For patients with resectable pancreatic cancer, the
median survival is 20 months, with a 5-year overall survival rate of 8% to 20% (101).
Innovative approaches are necessary to change the natural progression of this disease
before significant improvements in outcomes can be made.

COLORECTAL CANCER
In 2015, an estimated 93,090 cancers of the colon and 39,610 cancers of the rectum
will be diagnosed in the United States (1). Radiotherapy plays an important
neoadjuvant or adjuvant role in the management of rectal cancers, but is uncommonly
indicated in the treatment of colon cancer.

DIAGNOSTIC EVALUATION
Careful diagnostic evaluation is essential not only for accurate staging and selection of
patients for neoadjuvant strategies, but also to assist appropriate target definition
during treatment planning. During the patient history, careful attention should be given
not only to bowel-related symptoms, but also to indicators of local tumor extension into
other pelvic structures (bladder/prostate or pelvic wall). The radiation oncologist’s
digital rectal examination should assess the distance of the tumor from the anal verge,
size and location, degree of circumferential involvement, and palpable morphology. The
mobility of palpable lesions is described as mobile, tethered, or fixed, the latter implying
initial unresectability. Proximal rectal cancers that are not palpable are referenced to
the anal verge by endoscopy. Measurements from flexible endoscopies should be relied
upon with caution as they are notoriously imprecise and inconsistent between
examinations. Measurements from rigid proctoscopy tend to be more reliable.
Pretreatment imaging is not only important to rule out distant metastases, but also to
determine patients who are candidates for neoadjuvant radiotherapy. EUS or MRI has
been reported superior to CT in both determination of tumor depth of penetration (T
stage) and detection of perirectal adenopathy (147). High-resolution MRI may be of
particular benefit in predicting involvement of circumferential resection margin
(148,149). Pelvic CT or MRI is indicated for the evaluation of pelvic lymphatic stations
beyond perirectal lymph nodes. Among patients with locally advanced disease, PET has
detected liver metastases in up to 8% of patients, which were not identified by other
modalities (150). PET without CT registration generally does not have sufficient spatial
resolution to determine depth of tumor penetration nor consistently distinguish
perirectal adenopathy from adjacent tumor.

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TREATMENT OPTIONS
The use of adjuvant or neoadjuvant RT is generally reserved for patients whose tumors
penetrate the bowel wall (≥T3) or are node positive. Among such patients, randomized
trials clearly support the benefit of adjuvant combined modality therapy (pelvic
radiotherapy and 5-FU–based chemotherapy) in regard to both local control and overall
survival (151–153). The presence of node positivity, penetration of tumor through the
bowel wall and involvement of adjacent structures needs to be determined by EUS or
MRI in order to justify a neoadjuvant approach. Two paradigms have emerged in the
neoadjuvant treatment of rectal cancer: a short course of hypofractionated RT and a
long course of CRT. The German Rectal Cancer Study Group found a significant
downstaging effect and higher rate of sphincter preservation with long-course
preoperative CRT (154). A significant improvement in local control was seen with
preoperative CRT versus similar postoperative treatment (10-year local relapse rate of
7% vs. 10%, p = 0.048) (155). Alternatively, Dutch investigators found that a short
course of preoperative hypofractionated RT improved local control compared to
patients undergoing total mesorectal excision (TME) alone (10-year LR 5% vs. 11%, p <
0.0001) (156). Two trials have directly compared short- and long-course neoadjuvant
RT. In the Polish trial, the long-course CRT group was given bolus 5-FU (157). The more
recent Australian trial utilized a more contemporary dosing of continuous infusion 5-FU
in the CRT arm (158). Neither trial showed a significant difference in clinical outcomes
between treatment arms. While either approach is acceptable in resectable disease, long-
course CRT should be administered in unresectable cases due to the known downstaging
effect of the treatment (159).
Adjuvant radiotherapy for patients with colon cancer is not routinely indicated.
Although retrospective series have shown favorable local control outcomes with the use
of adjuvant radiotherapy among patients with T4 tumors and selected T3 tumors with
positive lymph nodes (160,161), this has not be corroborated in clinical trials. Among
such patients, Martenson et al. (162) reported the results of a randomized trial
investigating the use of adjuvant CRT. This study did not detect a benefit to CRT for
patient survival, however, this study was underpowered for the primary endpoint.
Preoperative treatment may be considered in patients whose tumors are considered
unresectable at presentation.

TREATMENT PLANNING FOR RECTAL CANCERS


Simulation
Proper patient positioning can significantly reduce the amount of small bowel within
the pelvis and limit toxicity from treatment. In addition to decreasing the volume of
bowel receiving maximal organ tolerance (45 to 50 Gy), reduction of bowel receiving
doses as low as 5 Gy has been associated with improved patient tolerance to pelvic
radiation (163–165). Maximal displacement of small bowel out of the pelvis is achieved
with prone positioning and bladder distension. Without the use of a belly-board or
lower abdominal wall compression, however, ∼25% of patients will have more small
bowel in the pelvis with supine positioning (166). Multiple studies have documented
significant reduction in pelvic small bowel volume with use of a belly-board device
(167–169) or lower abdominal wall compression (166). Bladder distension may actually
contribute more to bowel displacement than a belly-board, but the effect of each method
appears additive (170) and concurrent use of both techniques should be considered.

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Efforts displace bowel from the pelvis may be less reproducible and associated with
variation in patient setup, which should be accounted for when employing highly
conformal radiation techniques.
Simulation in the prone position enables verification of lower and middle rectal lesion
location in relationship to the anal verge based on findings on digital examination. The
anal verge should be marked with a radiopaque marker and rectal contrast may be
instilled into the rectum to assist radiographic identification of the primary lesion.
Taping the buttocks laterally may reduce their self-bolusing effect on the perianal skin
during treatment. Patients who have undergone abdominoperineal resection (APR) must
have the perineal scar marked and included in the initial pelvic fields, with appropriate
bolus utilized posteriorly if exposed. Perineal recurrence has been described in 8% to
30% of patients in the absence of adjuvant RT (171–173), but as low as 2% when the
scar is adequately treated (174). CT-based planning has replaced conventional
fluoroscopic imaging as the preferred simulation technique.

Radiotherapy Target
For patients treated preoperatively, the GTV includes the primary tumor and any
radiographically enlarged lymph nodes. All clinical, endoscopic, and imaging
information must be used to define the maximal extent of the rectal tumor. Relying
solely on one modality risks underestimation of the tumor extent and inaccurate field
design (especially within boost portals). Although not mandatory in treatment planning,
the addition of PET to CT in GTV contouring has been shown to increase the target size
by an average of 25% (175) and lead to a change in treatment fields in 17% of patients
(176). Soft tissue extension or suspected infiltration of rectal tumors into adjacent
mesorectal fat should be included within the GTV, particularly posteriorly.
The CTV encompasses all the perirectal tissue/mesorectum, presacral space, and
lymphatics of the internal iliac chain (which are not commonly dissected at the time of
surgery). A report of 269 cases of rectal cancer that recurred in the pelvis after surgery
alone emphasized the predilection for rectal cancer recurrence in the posterior pelvis,
specifically the presacral space. Among patients undergoing anterior resection, 93%
recurred at or posterior to the colorectal anastomosis (177). Other studies of rectal
cancer failure patterns have shown infrequent recurrence above the S1–S2 interspace,
lateral pelvic nodes, or in the anal sphincter (178,179).
Accurate contouring of the pelvic CTV involves more than simply identifying the
internal iliac vessels. A study comparing locations of external and common pelvic
lymphatics (by lymphangiography) to vessel location revealed that lymph nodes are not
directly superimposable upon vasculature (180). Myerson and Drzymala (181) and
Roels et al. (182) provide a review of CT-based treatment planning for rectal cancer. In
the upper pelvis, the CTV should extend cephalad to include the sacral promontory,
posteriorly to include the anterior wall of the sacrum, and laterally it should encompass
vasculature and presacral soft tissue to the border of the iliopsoas muscles. In the mid-
pelvis, the CTV includes similar tissues with care taken to include perirectal fat anterior
to the rectum. In addition, 1 to 2 cm of posterior bladder or uterus may be included if
at risk of subclinical extension of disease for patients who have adjacent, locally
advanced lesions. In the lower pelvis, the CTV includes all the perirectal fat inferiorly
and laterally extending to the levator ani muscles. It should extend to the posterior wall
of the prostate or vagina as well. A larger margin of anterior pelvic organs is indicated
for tumors with documented invasion (T4). The inclusion of the external iliac lymph
nodes is generally reserved for patients with T4 tumors, which extend into anterior

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organs of the pelvis (prostate, bladder, vagina, and cervix/uterus) for whom these nodes
are at risk. This modification is supported by failure patterns (177) from patients
treated with surgery alone. However, in a series of patients with T4 rectal cancers
where external iliac lymph nodes were not routinely included within RT portals,
regional recurrence of disease still occurred almost exclusively within the radiotherapy
field (183).
The CTV should also include a minimum of 2 cm of normal rectum cephalad and
caudad to the primary tumor. A subsequent PTV expansion of at least 1 cm (without
IGRT) around the CTV will provide a minimum 4-cm longitudinal margin from GTV to
block edge (assuming an additional 0.5- to 1-cm margin beyond PTV to block edge for
dosimetric buildup). With the use of daily image guidance, smaller CTV to PTV margins
may be utilized. Given the distensibility of the rectum, more PTV margin may be
indicated anteriorly, especially for anterior wall tumors of the mid- and upper rectum.
Bladder, small bowel, and femoral heads should also be contoured for evaluation of
normal tissue tolerance.
Tumors of the lower rectum, which extend to the dentate line of the anal canal, have
a theoretical risk of failure in the inguinal lymph nodes. A report of 184 patients with
such lesions revealed only six groin failures (5-year actuarial rate of 4%) without
elective radiotherapy to the inguinal lymph nodes (184). Thus, for patients with low-
lying rectal cancers, careful attention should be given to the groins during initial
staging, but the added toxicity of treatment does not seem justified if the inguinal nodes
are clinically negative.
In the postoperative setting, treatment volumes are similar except that with the
removal of the primary lesion, the entire preoperative tumor bed must be reconstructed
and included within the CTV (often identified separately as a boost volume—CTV2).
Review of preoperative imaging, operative reports, and surgical clip placement is
imperative. As mentioned above, the perineal scar must be included in the initial fields
for patients who have undergone APR.
To account for internal target motion and patient setup variability, a PTV is
delineated beyond the CTV. In the absence of IGRT, a PTV margin of at least 1 cm is
appropriate. However, a retrospective study of interfraction variability has shown that
patient setup without IGRT can easily approach these margins, especially among
patients with a large body mass index treated in the prone position (185). Intrafraction
movement of the mesorectum has also been evaluated and found on average to move
<4 mm in various dimensions, but significant individual variability is observed (186).

Normal Tissue Tolerances


The amount of small bowel receiving 45 Gy should be minimized without compromising
target coverage. Any small bowel within the boost volume of treatment should be limited
and not receive beyond 50 Gy. In addition to maximum dose, acute intestinal side
effects from pelvic radiotherapy have been found to correlate with volume of bowel
receiving all dose levels to as low as 5 Gy (164,165). Thus, bowel exposure at any dose
should be minimized. The femoral heads and necks should receive <45 to 50 Gy (187),
and preferably <40 Gy. Blocking in the lateral fields excludes the anterior genitalia in
addition to small bowel and bladder.

Radiotherapy Dose
There is very little data in the literature regarding the optimal radiotherapy dose in the

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treatment of rectal cancer. One retrospective study supporting current dosing guidelines
is from Brizel and Teppererman (188) who observed superior local control with
adjuvant radiotherapy doses ≥45 Gy compared to patients who received lower doses.
Forty-five Gray, given in 1.8-Gy fractions, is the currently accepted dose and
fractionation for initial pelvic fields in the adjuvant setting based on its repeated use in
clinic trial designs (153,189). After the initial 45 Gy, a boost of 5.4 to 9 Gy is generally
given to the tumor bed and adjacent lymphatics (CTV2). In the neoadjuvant setting, the
radiotherapy dose depends on the use of short- or long-course radiation therapy. In the
former approach, five daily 5-Gy fractions are administered to a single volume for a
total cumulative dose of 25 Gy (190). Long-course CRT doses are similar to those used
in the adjuvant setting, typically 45 Gy with a 5.4-Gy boost to the GTV (158,191) or
treatment of the entire volume to 50.4 Gy (154). In any case, careful attention should
be made to minimize small bowel within the field. Treating beyond a cumulative dose of
50 Gy should only be considered when small bowel can be completely excluded from the
high-dose region of treatment.

Figure 24.3 A 41-year-old woman with a cT3N+ adenocarcinoma of the distal rectum treated with a three-field
technique. Beam’s eye view of PA (A) and lateral (B) fields. Note the GTV (red) and CTV (orange) including
mesorectum and rectal contrast. Axial view (C) showing field arrangement and dosimetry (red and light green lines
denote the 98% and 95% isodose lines, respectively). Prescription dose was 4,500 cGy in daily 180-cGy
fractions.

Radiotherapy Fields and Techniques


Patients are commonly treated with a three-field technique consisting of a PA and

696
laterals (see Fig. 24.3). When inclusion of the anterior pelvis is indicated (e.g.,
treatment of the external iliac lymph nodes or larger habitus patients), an additional AP
field may be advantageous to improve dose homogeneity. High-energy photons and
appropriate beam wedging and weighting are mandatory to ensure a homogeneous dose
distribution within the pelvis.
Traditional field design has been based on boney landmarks, the location of contrast-
enhanced bowel/rectum and the anal verge. The superior border of the PA (and AP)
fields generally covers the sacral promontory while the inferior border is placed at least
3 to 4 cm distal to the rectal cancer. For upper rectal cancers, the distal border need not
include the entire anal canal, but should extend to approximately the level of the
dentate line (about 2 to 3 cm from the anal verge) so that all the mesorectum is
encompassed. The lateral borders of the PA field should include 1.5- to 2-cm margin
beyond the pelvic brim, with appropriate blocking of almost all of the femoral head.
Lateral fields should cover the anterior bony margin of sacrum with 1.5- to 2-cm margin
posteriorly to allow for setup error and dosimetric coverage. Anteriorly, the field
includes the internal iliac lymph nodes by placing its border at approximately the
posterior edge of pubic symphysis. Care is taken, however, when devising this border to
ensure at least 3-cm coverage of the primary tumor anteriorly. In the superior–anterior
portion of the field, it is usually possible to block a portion of small bowel. Similarly, the
anterior genitalia in most patients should be blocked in the lateral fields. Custom boost
fields are devised that include the GTV (or tumor bed) with a 2- to 3-cm margin. A
three-field technique or laterals alone will often suffice.
While traditional field orientations (PA and laterals) are usually adequate for three-
dimensional reconstructed targets, they do not fully account for the variability inherent
in individual patient anatomy. In addition, more conformal techniques including IMRT
require delineation of a CTV in 3D. Consensus guidelines have been reported to assist in
contouring these volumes (192). The caudad extent of the CTV should be a minimum of
2-cm caudad to gross disease, including the entire mesorectum to the pelvic floor. The
lateral CTV should include the mesorectum and only a few millimeters of the levator
muscles unless radiographically involved. Involvement of adjacent organs and/or pelvic
sidewall requires a more generous margin (1 to 2 cm). In the mid-pelvis, the CTV
extends to the pelvic sidewall and musculature posterolaterally. Anteriorly, the
posterior 1 cm of the bladder is included to account for variation in bladder position
(193). The superior extent of the rectal CTV is a minimum of 2-cm cephalad to gross
disease, including the rectosigmoid junction. A minimum 7- to 8-mm margin around the
internal iliac vessels is included up to the common iliac bifurcation including at least 1
cm anterior to the sacrum. CTV expansion to create a PTV depends on treatment
technique and the use of IGRT. The PTV margin should be 0.7 to 1 cm when using IMRT
with IGRT. Conventional field borders are generally expanded another 5 to 10 mm in
order to achieve sufficient dosimetric target coverage.
Possible benefits of treatment of rectal cancer with IMRT include dose escalation to
the GTV and construction of a concave dose distribution that reduces small bowel dose,
in addition to bladder and bone marrow. Dosimetric studies comparing IMRT to
traditional techniques in rectal cancer have shown clinically significant reductions in
dose to bowel (194–196) as well as bladder, pelvic bones, and femoral heads while also
achieving superior target coverage, homogeneity, and conformality (197). The
successful implementation of IMRT in the management of rectal cancer has been
reported from multiple institutions, generally with dose escalation to the GTV with
favorable outcomes (198–200). A retrospective review of 92 patients treated at the
Mayo Clinic in Arizona demonstrated a 32% incidence of ≥grade 2 gastrointestinal

697
toxicity among patients treated with IMRT compared to 62% (p = 0.006) among
patients treated with conventional fields during the same era (201). In view of the
challenges of internal movement, distensibility of pelvic organs (rectum, bowel, and
bladder) as well as the dose inhomogeneity produced by some treatment planning
systems, caution should be used before undertaking IMRT in rectal cancer.

Chemotherapy
Adjuvant or neoadjuvant radiotherapy has traditionally been delivered with concurrent
5-FU. In the postoperative setting, protracted venous infusion (PVI) of 5-FU
(225 mg/m2/d) throughout the course of pelvic radiotherapy has been shown to
decrease tumor recurrence and improve overall survival compared to the administration
of bolus 5-FU (189), although not confirmed in a subsequent trial (202). Despite this,
continuous infusion 5-FU became the standard in subsequent neoadjuvant trials (154).
More contemporary studies have found the use of capecitabine, an orally administered
premetabolite of 5-FU, is at least equivalent if not superior to PVI 5-FU in conjunction
with pelvic radiation for rectal cancer (203,204). Multiple studies have attempted to
integrate additional chemotherapeutics, namely oxaliplatin, into the neoadjuvant and
adjuvant fluoropyrimidine backbone. The majority of these studies found no
improvement in clinical outcome at the expense of added toxicity (204–206).

Treatment Planning for Colon Cancer


Patients treated with radiotherapy for colon cancer are treated with the same
chemotherapeutic and radiation principles as rectal cancer. Decubitus positioning at
simulation and during treatment may reduce the amount of small bowel in the
treatment field. The initial CTV generally includes the tumor bed and adjacent
pelvic/retroperitoneal lymphatics, with a subsequent boost to the tumor bed (or tumor
preoperatively). Review of preoperative imaging, operative reports, and identification of
surgical clips demarcating the tumor bed are essential in order to define targets and
design fields that may impact local control and the prognosis of this disease.

Prognosis
The incidence and mortality of colorectal cancer in the United States has been declining
in recent years, most likely as a result of screening practices (1). Based on the Dutch
TME results, 10-year overall survival for TNM stages I, II, and III patients are ∼70%,
55%, and 40%, respectively (156). The inclusion criteria for the German rectal cancer
study more closely approximates those patients eligible for neoadjuvant CRT (cT3–4
and/or N+; TNM stages II to III), where 10-year overall survival was ∼60% (155).

ANAL CANCER
In 2015, there will be an estimated 7,270 new cases and approximately 1,010 deaths
from anal cancer in the United States (1). Historically, APR was the standard of care in
the management of anal cancer (207,208). Although this procedure resulted in cure for
many patients, there were significant drawbacks including permanent colostomy and
high rates of morbidity and mortality. In 1974, Nigro et al. introduced chemotherapy
and radiation as a novel treatment approach in the management of anal cancer (209).
Since Nigro’s publications, phase III randomized trials have examined different

698
strategies of chemotherapy and radiation administration (210–215). Given the
favorable results of definitive chemoradiation, a sphincter-preserving approach is the
standard of care for this disease.

DIAGNOSTIC EVALUATION
Patients who are being considered for RT and chemotherapy should undergo a complete
history and physical examination. Risk factors for HIV infection should be reviewed,
with a low threshold for ordering laboratory testing. Careful review of gastrointestinal
and genitourinary symptoms may indicate extension of tumor beyond what is clinically
or radiographically detected. It is necessary to perform a thorough clinical evaluation of
inguinal lymph nodes, digital rectal examination, and proctoscopy to determine tumor
extent. Thorough examination of the perianal skin is imperative for accurate treatment
planning as it often reveals disease beyond what is visible on imaging studies alone.
When patients have severe anal discomfort that inhibits adequate examination, such
examinations should be scheduled under anesthesia. In females, a pelvic examination to
rule out vaginal extension is indicated as well as identification of synchronous
gynecologic cancers (HPV related).
Axial CT imaging of the chest, abdomen, and pelvis is critical for appropriate staging.
Anal cancer most commonly spreads by local and lymphatic invasion, however, in about
13% of cases distant metastases are present at initial presentation (216). Distant
metastases are most commonly seen in the liver and lungs (217). An alternative to CT or
MRI is PET/CT, which can be useful for assessing disease extent and often assists in
treatment planning. Multiple, small studies have shown that PET/CT alters staging in
about 20% of patients compared to conventional imaging due to improved sensitivity in
detection of primary tumor, involved regional lymph nodes, and distant metastases
(218–222). Winton et al. reported that initial diagnostic PET/CT altered design of
radiation treatment fields in 8 of 61 (13%) of patients with anal cancer (218).
Similarly, a series of 50 patients from Australia reported 19% of cases underwent
treatment planning revision based on pelvic or nodal inguinal involvement on PET/CT
(221). All patients should have a biopsy to confirm invasive malignancy at the primary
site. In patients with suspicious inguinal adenopathy, biopsy may be performed to
clarify the diagnosis as it can alter radiation treatment volumes and doses.

TREATMENT OPTIONS
Patients with anal carcinoma in situ (anal intraepithelial neoplasia or AIN) and tumors
of the perianal skin (which do not extend to the anal verge), should initially be
considered for local excision in selected cases. When these lesions cannot be excised
adequately without significantly compromising anal function, definitive RT alone or
chemoradiation is an efficacious option. Patients with invasive carcinoma of the anal
canal should generally be treated with definitive CRT. The addition of mitomycin-C and
5-FU to radiotherapy has been shown to improve local control and colostomy-free and
disease-free survival (210–212). Multiple subsequent phase III randomized trials have
examined different strategies of chemotherapy administration including use of cisplatin
in place of mitomycin-C (213–215). Despite these efforts, mitomycin-C and 5-FU with
concurrent radiotherapy remains the standard treatment for patients with anal cancer.
APR is usually reserved as salvage treatment for patients with persistent or recurrent
disease after radiotherapy. It should be noted that there can be significant delays in
tumor regression after CRT and a recent randomized study of chemoradiation for anal

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cancer indicates that tumor regression can occur up to at least 26 weeks after
completion of therapy (214). Therefore, in the absence of progression, a decision to
proceed with APR for persistent disease should usually be delayed until at least 6
months and perhaps up to 1 year after completion of therapy in selected circumstances.

TREATMENT PLANNING
Simulation
After clinical and radiographic staging, CT-based simulation is performed for radiation
treatment planning. If available, PET/CT at the time of simulation may be helpful to
define local and regional target structures. Patients can be simulated in the supine or
prone position and there are benefits to each approach in the appropriate clinical
setting. Prone setup with a false tabletop allows for improved small bowel avoidance
and may be useful in individuals with a large pannus and pelvic node involvement.
Supine setup is usually more reproducible, potentially allowing for reduced PTV
margins and smaller treatment fields. Typically for IMRT patients should be simulated
in the supine position with legs slightly abducted (frog-legged) with semi-rigid
immobilization in vacuum-locked bag or alpha-cradle. Patients are instructed to
maintain a full bladder for simulation and treatment to decrease the amount of small
bowel within the pelvis. In males, the external genitalia are typically positioned
inferiorly such that setup is reproducible. In females, a vaginal dilator can be placed to
help delineate the genitalia and displace the vulva, vagina, and urethra away from the
primary tumor. A radiopaque marker should be placed at the anal verge. The clinical
extent of any visible or palpable perianal tumor should be demarcated with radiopaque
catheters as it may not be apparent on simulation imaging. It may be helpful to place a
catheter with rectal contrast in the anal canal at the time of simulation for tumor
delineation. In patients with adequate renal function, IV contrast facilitates
identification of the pelvic and groin vasculature (which approximates at-risk nodal
regions). Oral contrast identifies small bowel as an avoidance structure during
treatment planning. For tumors involving the perianal skin or superficial inguinal
nodes, bolus should be placed as necessary for adequate dosing of gross disease in these
areas. Routine use of bolus may not be necessary as the tangential effect of IMRT may
minimize skin sparing. In situations where adequate dosing of superficial targets is
uncertain, in vivo diode dosimetry with the first treatment fraction can ensure
appropriate dose at the skin surface.

Radiotherapy Target
Target volume definition should be performed per ICRU 50 recommendations (223).
GTV should include all primary tumor and involved lymph nodes, utilizing information
from physical examination, endoscopic findings, diagnostic imaging, and simulation
planning study for delineation. CTV should include the GTV plus areas at risk for
microscopic spread from the primary tumor and at-risk nodal areas. If the primary
tumor cannot be determined with available information (such as after local excision),
the anal canal may be used as a surrogate target. Ortholan et al. (224) published a
study of 181 patients with anal cancer without inguinal nodal involvement at
presentation. Seventy-five patients received elective inguinal irradiation compared to
106 patients who did not receive elective inguinal irradiation. With a median follow-up
of 61 months, rates of inguinal recurrence were 2% in patients receiving inguinal

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irradiation compared to 16% in patients without inguinal irradiation. Given these
recurrence rates, pelvic and inguinal nodes should be routinely treated in most patients.
At-risk nodal regions include the mesorectum, presacral, internal and external iliac, and
inguinal nodes (225). The presacral nodal volume is typically defined as an
approximately 1-cm strip over the anterior sacral prominence. To contour the internal
and external iliac nodes, our practice generally is to contour the iliac arteries and veins
with approximately 0.7-cm margin (1 to 1.5 cm anteriorly on external iliac vessels) to
include adjacent lymph nodes. In order to include the obturator lymph nodes, external
and internal iliac volume contours should be joined parallel to the pelvic sidewall. The
inguinal node volume extends beyond the external iliac contour along the femoral
artery from approximately the upper edge of the superior pubic rami to approximately
2-cm caudad to saphenous/femoral artery junction. The medial and lateral borders may
be defined by adductor longus and sartorius muscles, respectively. Several recently
published atlases are helpful to review when defining elective nodal CTVs (226–228).
The above descriptions are generalizations and target volume should be individual
based on the anatomy of each patient and tumor distribution.
When using IMRT, a separate CTV volume for each planned treatment dose tier is
contoured. Our approach has been to define three tiers: a gross disease volume, a high-
risk elective nodal volume (including gross disease), and a low-risk elective nodal
volume (including gross disease and high-risk elective nodal volume) (229,230).
Alternatively, a gross disease volume with a single elective nodal volume can be used to
deliver the prescribed course (231–238).
In defining the gross disease CTV around the primary tumor, approximately 2.5-cm of
margin the around GTV should be used with manual editing to avoid muscle or bone at
low risk for tumor infiltration. To define the gross disease CTV around involved nodes, a
1-cm expansion should be made beyond the contoured involved lymph node(s) with
manual editing to exclude areas at low risk for tumor infiltration. In addition, the entire
mesorectum is included within the volume defined as gross disease CTV for the purposes
of treatment planning. The mesorectal volume encompasses the rectum and surrounding
lymphatic tissue.
The high-risk elective nodal volume typically includes the gross disease CTV including
the entire mesorectum, presacral nodes, and bilateral internal and external iliac lymph
nodes inferior to the sacroiliac joint as per conventional field definitions utilized in
RTOG 98–11 (213). In patients with gross inguinal nodal involvement, the bilateral or
unilateral inguinal nodes may be included in the high-risk elective nodal volume.
The low-risk elective nodal volume should include the gross disease CTV, high-risk
elective nodal CTV as well as presacral, bilateral internal, and external iliac nodes above
the inferior border of the sacroiliac joint to the bifurcation of the internal and external
iliac vessels at approximately L5/S1 vertebral body junction. If there is no obvious
involvement of the bilateral inguinal nodes, these are only included in the low-risk
elective nodal volume.
The PTVs should account for effects of organ and patient movement and inaccuracies
in beam and patient setup. PTV expansions should typically be about 0.5 to 1.0 cm from
CTV depending on use of image guidance and physician practice with treatment setup
for each defined CTV. To account for differences in bladder and rectal filling, a more
generous CTV to PTV margin is applied in these regions. Future development of real-
time adaptive RT will potentially reduce this margin. When using IMRT, especially with
small PTV margins, use of daily image guidance with kV orthogonal imaging to ensure
excellent alignment of the bony anatomy is recommended. In addition, cone-beam CT
should be performed prior to the first treatment and periodically to ensure target soft

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tissue volumes remain within the appropriate PTV and ensure bladder filling is
relatively stable.

Normal Tissue Tolerances


It is important to accurately define organs at risk (OARs) so that dose to these structures
can be minimized during treatment. With IMRT, dose to small bowel, bladder,
pelvic/femoral bones, and external genitalia can be sculpted and minimized despite
close proximity of these organs to target volumes. When contouring these structures, it
is typically best to demarcate normal tissues on axial CT at least 2 cm above and below
the PTV. Contouring atlases offer excellent guidance on defining OAR (226,227). Once
the OARs have been identified, the chief aim of IMRT planning is to limit the dose to
these structures without compromising PTV coverage. The extent to which OARs can be
avoided largely depends on the location and extent of tumor involvement at
presentation as well as the extent to which the bowel extends into the lower pelvis and a
given individual’s anatomy.
While there is significant variability in how to contour the small bowel, one approach
entails contouring the entire volume of peritoneal space in which the small bowel can
move. Oral contrast is helpful to delineate small bowel. The amount of small bowel
treated to >45 Gy should be minimized. Although this is generally achievable due to
the inferior location of the boost target volume, large volumes of bowel receiving even
moderate doses of radiation (as low as 15 to 30 Gy) contribute to acute toxicity and
should be minimized when possible. Devisetty et al. published a multi-institution,
dosimetric analysis which found that limiting the volume of bowel receiving 30 Gy (V30
Gy) to less than 450 cc significantly reduced acute GI toxicity (8% vs. 33%) (239).
DeFoe et al. have published retrospective data correlating lower rates of acute GI
toxicity with V30 Gy less than 310 cc and V40 Gy less than 70 cc (240). Emami et al.
estimate a dose of 50 Gy to one-third of the small bowel is associated with 5% likelihood
of obstruction or perforation at 5 years (241). To minimize late small bowel toxicity, the
Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) analysis
reviewed available clinical data for small bowel dose and recommends minimizing
volume receiving greater than 45 Gy to less than 195 cc when contouring the entire
potential peritoneal space (242).
There are limited clinical data correlating bladder dose-volume relationships with
increased GU toxicity in anal cancer. Extrapolating from other cancer treatment sites,
normal tissue complication probability models suggest that the risk of serious GU
complications with bladder doses below 65 Gy is low (243). The risk of clinical
complications appears to increase with larger volumes of bladder receiving high dose.
Marks et al. estimate that limiting 50% of the bladder to less than 40–50 Gy will limit
complications to less than 5–10% (based on cervical cancer clinical literature) (244).
Despite limited available data for anal cancer, many patients experience acute grade 1–
2 GU toxicity during RT and limiting dose to the bladder, without compromising PTV
coverage, may help minimize these symptoms further.
Reduction in radiation dose to the proximal femoral and pelvic bones is also
important. A retrospective cohort study using Surveillance, Epidemiology, and End
Results (SEER) cancer registry data linked to Medicare claims reported that in women
treated for anal cancer, the cumulative 5-year pelvic fracture rate was 14.0% among
women receiving radiation treatment versus 7.5% among women who did not receive
RT (245). There is limited empirical data on dose–response relationships for femoral
neck complications. Emami et al. reported a tolerance dose of 52 Gy to the entire

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femoral neck to limit the risk of complication to less than 5% (241). Bedford et al. have
recommended limiting the volume of femoral neck receiving 52 Gy to less than 10%
(246). The femoral heads and necks should receive <45 to 50 Gy (187), and preferably
<40 Gy.
Studies indicate that sexual dysfunction is a late effect of RT for anal cancer with
significant impact on quality of life (247,248). Pelvic radiotherapy has been associated
with high rates of impotence, sterility in young men, as well as dyspareunia, vaginal
bleeding, and vaginal dryness in women. Limited data on dose–response relationships
between late sexual toxicity and genitalia dose are available. As with other pelvic OARs
where data are limited, it is advisable to minimize genitalia dose without compromising
PTV coverage.
The perianal skin develops significant moist desquamation as a result of combined
modality therapy. Dosimetric hot spots in this region should generally be avoided.
Prolongation of overall treatment due to treatment breaks for skin toxicity time have
been associated with a detriment in local control (249,250). In the absence of infection,
treatment breaks for skin toxicity should be avoided by instituting early, aggressive
supportive measures.
Given patient variation with respect to OAR position and areas of tumor involvement,
practical dose constraint guidelines are challenging. In tumors without gross nodal
involvement it is often possible to limit OAR doses even further. Alternatively, in tumors
with gross nodal involvement within the pelvis, compromise of PTV coverage may be
necessary to limit doses to the small bowel. Normal tissue dose constraints from RTOG
05–29 are a reasonable guide to assist with IMRT treatment planning (232).

Radiotherapy Dose
The appropriate dose for elective nodal sites has not been well defined. In RTOG 87–04,
30.6 Gy in 1.8-Gy fractions was delivered to initial pelvic fields with the superior
border placed at the L4–L5 interspace (212). Subsequently, the superior field borders
were reduced to the bottom of the sacroiliac joints, and the pelvis and inguinal nodes
continued treatment to 36 Gy. Finally, 10- × 10-cm fields which included the primary
tumor and lowermost pelvis were treated to cumulative doses of 45 to 50.4 Gy. In RTOG
98–11, the initial pelvic fields were treated to 30.6 Gy with the superior border placed
at L5–S1 (213). Reducing the superior border to the bottom of the sacroiliac joints, the
lower pelvis was treated to 45 Gy. The inguinal lymph nodes electively received 36 Gy.
In the ACT II study, all patients received a dose of 30.6 Gy in 1.8-Gy fractions to the
pelvis and inguinal nodes with the superior border placed at least 3 cm above the SI
joints (214). A second volume including the gross primary tumor plus 3-cm margin was
prescribed an additional 19.8 Gy for a total dose of 50.4 Gy. Among patients with
macroscopic nodal involvement on CT, all gross disease plus margin was prescribed
50.4 Gy.
RTOG 05–29 is the first phase II prospective study utilizing IMRT for the treatment of
anal cancer (232). The prescription parameters designate a single elective nodal volume
inclusive of mesorectum, presacrum, bilateral internal and external iliac, and bilateral
inguinal regions as outlined in the RTOG atlas (228). A simultaneous integrated boost
(SIB) plan was utilized to treat the elective nodal volume plus areas of gross tumor and
nodal involvement with slightly different dose prescriptions depending on tumor stage
and nodal volume. T2N0 tumors received 42 Gy elective nodal and 50.4 Gy to the anal
tumor in 28 fractions. T3–4N0–3 tumors received 45 Gy elective nodal and 50.4 Gy for
involved nodes <3 cm, 54 Gy for involved nodes >3 cm and 54 Gy to the anal tumor

703
in 30 fractions.
Although successive pelvic field reductions probably address the gradient of risk for
micrometastatic disease within lymph nodes, retrospective series suggest that doses as
low as 30 Gy with concurrent chemotherapy may be sufficient to achieve control of
subclinical disease within nodes or at the primary site after excisional biopsy of small
lesions (251–253). The SIB approach offers the convenience of developing a single
treatment plan with reduced planning complexity, albeit with a lower biologic dose
delivered to the elective nodal areas. Utilization of SIB dose painting implements 1.5 Gy
per fraction to the elective nodal region, and such doses are not well studied. When
concurrently treating multiple targets at different doses per fraction (i.e., IMRT), higher
total doses may be indicated for regions receiving <1.8 Gy/d (232). Only small primary
tumors that have completely responded to radiation should be treated to 45 to 50.4 Gy.
Larger tumors (T3/T4) and incompletely responding tumors should receive at least 50.4
to 54 Gy. Multiple retrospective series have reported superior local control rates in this
dose range compared to lower doses (251,254,255).

Radiotherapy Fields and Techniques


The treatment of patients with anal cancer can be technically challenging given the
complex geometric distribution of targets, particularly the inguinal nodes, in
relationship to normal pelvic structures. By reducing radiation to normal structures,
IMRT minimizes toxicities and treatment interruptions. Institutional experiences
(229,230,233–238,256) and a single phase II, multi-institutional prospective study
(232) have shown the feasibility of IMRT with improvements in acute toxicity compared
to historical studies. Although no direct comparison of IMRT to conventional
radiotherapy planning has been performed, utilization of IMRT is recommended to
minimize treatment toxicity and associated treatment breaks. Due to the high precision
of IMRT, planning and delivery of RT require a thorough understanding of the local and
regional progression patterns to define PTVs and surrounding normal organs. A
knowledgeable treatment planning team is required to optimally utilize IMRT planning
algorithms, ensuring homogeneous dose to target areas while reducing dose to normal
tissues (see Fig. 24.4).
If IMRT planning is not available, alternative approaches utilizing treatment field
design based on bony anatomy may be feasible. A wide AP photon field, which includes
the inguinal lymph nodes, is simulated with a narrow PA field that excludes the femoral
neck (may include a small portion of the medial femoral head for margin on the
obturator nodes). Due to divergence, it is sometimes possible to match the lateral exit of
the narrow PA beam with the surface entrance of the wide AP photon beam and provide
sufficient dosimetric coverage of the groins (257). More commonly, however,
supplemental anterior electrons are indicated. The lateral exit of the narrow PA field is
marked anteriorly on the patient’s groins (done at time of fluoroscopic simulation). This
serves as the medial border for each electron supplement. The lateral border of each
electron supplement is placed at or 1 cm lateral (due to beam constriction) to the
surface entrance of the wide anterior photon beam. Particular attention must be made
during treatment to any shifts made with the PA field to ensure similar movement in the
anterior electron field junctions. Radiopaque wire placed on these junctions may assist
proper setup when porting the PA field. To reduce the complexities associated with
electron groin setups, photons have also been used to supplement the lateral inguinal
lymph nodes using the same AP photon field and setup. This can be achieved with
multileaf collimation (258,259).

704
Figure 24.4 A 60-year-old male patient with T2N2 squamous cell carcinoma of the anal canal. Diagnostic CT
(A) and with PET (B) indicate abnormal FDG avidity in left inguinal lymph node and anal canal. Sequential
nine-field IMRT treatment plans were delivered. Axial (C, D, E), coronal (F, G) and sagittal (H) dosimetry,
with GTV (red) and 54 Gy (green), 45 Gy (magenta), 30.6 Gy (cyan) isodose lines.

For patients treated with conventional radiotherapy techniques, gross tumor should

705
be boosted with reduced fields encompassing primary tumor and involved nodes with a
2- to 3-cm margin to the field edge. When possible, a composite representation of dose
between the initial and boost treatments should be created to ensure normal organ
tolerance is not exceeded during the boost phase of treatment. A variety of beam
arrangements may be used. Separate boost fields for involved inguinal lymph nodes are
usually necessary, but care should be taken not to concurrently overlap any tissues
irradiated by the boost treatment to the anus.

Chemotherapy
Careful coordination of the timing of concurrent chemotherapy with the delivery of
radiation is important for successful treatment of anal cancer. The addition of
mitomycin-C (10 mg/m2 on days 1 and 29 of radiotherapy) to 5-FU (1 g/m2/d for 96
hours on days 1 to 4 and 29 to 32 of radiotherapy) was established as the standard of
care by the results of RTOG 87–04 (212), which compared both drugs to concurrent 5-
FU alone. With this approach, treatment should generally begin on a Monday or
Tuesday so that radiotherapy may be given on each day of chemotherapy delivery (4
days of 5-FU). As an alternative to mitomycin-C, multiple institutions have reported
excellent results with cisplatin and 5-FU concurrent with radiation (260,261). The
recently reported ACT II study reports similar outcomes in their randomized comparison
of cisplatin + 5-FU versus mitomycin-C + 5-FU with concurrent radiotherapy (214).
However, in RTOG 98–11, cisplatin and 5-FU, given as induction therapy and
concurrent with RT, has been shown to be inferior to RT concurrent with mitomycin-C
and 5-FU with a reported overall survival detriment reported after 10 years of follow-up
(262).

Prognosis
The outcome of patients treated with combined modality therapy is well described from
the results of randomized trials. More recent series utilizing combined modality therapy
with mitomycin-C, 5-FU, and radiotherapy indicate that outcome is somewhat
dependent on the clinical stage. ACT II, the largest recent randomized controlled trial of
940 patients, reports 5-year progression-free survival, colostomy-free, and overall
survival rates of 69%, 68%, and 79%, respectively among patients receiving radiation
therapy concurrent with mitomycin-C and 5-FU (214). Among patients who experience
local failure, approximately 50% may be salvaged with surgical resection (212).

KEY POINTS
• Esophageal cancers are most commonly treated with neoadjuvant chemoradiation with
carboplatin/paclitaxel followed by surgical resection. The role of surgical resection in
squamous cell carcinoma is less clear with no associated improvement in overall survival.
• Gastric cancers are most commonly treated with resection followed by adjuvant chemotherapy
or chemoradiation.
• Pancreatic cancers are practically classified into resectable, unresectable, and metastatic. The
data for adjuvant chemoradiation is less robust and the subject of ongoing clinical
investigation.

706
• Rectal malignancies are treated with neoadjuvant 5-FU–based chemoradiation or
hypofractionated short-course radiation alone prior to surgical resection.
• For anal cancers, sphincter sparing is achieved with radiotherapy combined with 5-FU and
mitomycin.

QUESTIONS
1. Which of the following nodal areas would not be routinely included in a cT3N1
rectal adenocarcinoma?
A. Presacral
B. Internal iliac
C. External iliac
D. Mesorectum
2. For a T2N1 gastric cardia cancer, which of the following regions may be
excluded from the RT treatment fields?
A. Gastric remnant
B. Splenic hilum nodes
C. Celiac axis
D. Porta
E. Pancreaticoduodenal nodes
3. The following nodal areas are encompassed in both anal cancer and rectal cancer
treatment volumes with the exception of which of the following?
A. Inguinal nodes
B. Mesorectum
C. External iliac
D. Presacral
4. Which of the following are appropriate adjuvant therapies for resected
pancreatic cancer? Select all that apply.
A. Adjuvant chemotherapy
B. Adjuvant chemoradiation
C. Clinical trial
D. All of the above
5. The appropriate concurrent chemoradiation regimen for resectable esophageal
cancer is which of the following?
A. CDDP/5-FU and RT
B. Carboplatin/paclitaxel and RT
C. CDDP/mitomycin and RT
D. Capecitabine and RT

707
ANSWERS
1. C
2. B
3. A
4. D
5. B

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25 Gynecologic Malignancies

Anthony Paravati, Daniel R. Simpson, Loren K. Mell, Catheryn M.


Yashar, and Arno J. Mundt

INTRODUCTION
Gynecologic cancers arise from organs throughout the female reproductive tract,
including the ovaries, uterus, cervix, vagina, and vulva. Gynecologic cancers represent
the fourth most common malignant tumors diagnosed in women in the United States
each year, with nearly 95,000 cases expected in 2014 (1). Worldwide, gynecologic
cancers represent approximately 20% of all cancers, with nearly 1 million cases
diagnosed per year (2).
Radiation therapy (RT) occupies an important role in the treatment of nearly all
gynecologic malignancies. Radiation is commonly used as definitive treatment in many
early-stage patients and in conjunction with surgery and/or chemotherapy in women
with locally advanced disease. It is also frequently used to palliate patients when cure is
not possible.
This chapter provides an overview of the role of RT in the treatment of gynecologic
malignancies, with a focus on the planning of various radiotherapeutic approaches used
in these patients, including external-beam RT and brachytherapy. Technologies to be
discussed include intensity-modulated RT (IMRT), image-guided RT (IGRT), and image-
guided brachytherapy.

RADIOTHERAPEUTIC MANAGEMENT
Cervical Cancer
Radiation is commonly used in the treatment of nearly all stages of cervical cancer.
Selected early (microscopic) tumors (stage IA) are treated primarily with surgery;
however, when such patients are unable to undergo surgery due to advanced age
and/or significant comorbidities, RT can be used and is associated with excellent results
(3). Early-stage patients with gross disease (stages IB to IIA) are managed well with
either radical surgery or definitive RT, with cure rates exceeding 80% following either
approach (4).
The choice of surgery versus radiation in early-stage cervical cancer depends on a
number of factors, including patient age, comorbidities and various tumor
characteristics. Older women, particularly those with multiple comorbidities, are
generally treated with RT whereas younger women receive surgery. A common reason
for favoring surgery in young women is the ability to preserve ovarian function.
However, it may be possible to preserve ovarian function in premenopausal patients by
performing an ovarian transposition prior to RT (5). Another oft-stated reason for
favoring surgery in young women is the commonly held belief that sexual function
would be less adversely affected. However, prospective quality of life analyses have
found equivalent sexual function following surgery compared to RT (6).
In general, RT is recommended over surgery in early-stage cervical cancer patients as

724
lesion size and vaginal involvement increase. As tumor diameter exceeds 4 cm, there is
increased likelihood of tumor spread to surrounding organs and regional lymph nodes,
necessitating the need for adjuvant RT following surgery. Randomized trials conducted
by the Gynecologic Oncology Group (GOG) and other cooperative groups have found
that postoperative RT is beneficial in many cervical cancer patients following surgery.
GOG 92 noted an improved 2-year recurrence-free survival rate (88% vs. 79%, p =
0.008) comparing adjuvant RT versus no further therapy in node negative patients with
high-risk features (deep stromal invasion, bulky primary disease, and/or
lymphovascular invasion) (7). GOG 109 compared adjuvant pelvic RT versus pelvic RT
plus chemotherapy in women found to have involved pelvic nodes, parametrial invasion
and/or positive margins and noted a superior 4-year overall survival (81% vs. 71%, p
= 0.007) with the combined approach (8). Whether concomitant chemoradiotherapy is
superior to RT alone in node negative patients with high-risk features is currently being
evaluated by GOG 263, whereas the benefit of adjuvant chemotherapy following
chemoradiotherapy in high-risk node positive patients is the subject of GOG 0724.
While a treatment option in early-stage patients, radiation has long been the
cornerstone of treatment in cervical cancer patients with locally advanced (stages IIB to
IVA) disease. In these women, radiation is combined with concomitant chemotherapy in
light of multiple prospective randomized trials demonstrating a survival advantage to
the combined approach (9–11). Surgery is typically not utilized in patients with locally
advanced disease, albeit some investigators have advocated pelvic exenteration in cases
with bladder and/or rectal invasion (stage IVA) (12). Metastatic (stage IVB) patients
may also undergo RT, particularly those with a good response to chemotherapy or those
requiring palliative treatment due to uncontrolled vaginal bleeding.
Definitive RT in cervical cancer is administered with a combination of pelvic RT and
brachytherapy, except in earliest-stage patients in whom brachytherapy alone is
sufficient (3). Early-stage patients (stage IB1) are standardly treated with radiation as
there are currently no randomized trials demonstrating improved outcomes with the
addition of chemotherapy. Early-stage patients with bulky (>4 cm) tumors (stage IB2)
are treated with a combination of pelvic RT and chemotherapy (13), with or without an
adjuvant hysterectomy (14). Hysterectomy increases local control but does not alter
survival. When delivered adjuvantly, most patients receive pelvic RT with or without
chemotherapy. In women with locally advanced disease, pelvic fields are also used,
except in those with documented paraaortic lymph node involvement in whom extended
field RT (EFRT) is administered. In the past, there was considerable interest in
prophylactic paraaortic RT in locally advanced patients, following the superior survival
rates reported on the Radiation Therapy Oncology Group (RTOG) trial using this
approach (15). Today, however, EFRT is rarely used without evidence of paraaortic
involvement, except at some centers in woman with involvement of common iliac lymph
nodes. Pelvic fields are extended to include the inguinal lymph nodes in patients with
lower vaginal involvement and additional external-beam RT is often delivered in
patients with significant parametrial involvement and/or gross nodal disease.
Brachytherapy is commonly delivered in conjunction with pelvic RT in cervical cancer
patients undergoing definitive treatment. In the adjuvant setting, brachytherapy is less
commonly performed, except when patients are treated preoperatively. If brachytherapy
is prescribed, most patients receive intracavitary brachytherapy (ICB). However, at
some centers, interstitial brachytherapy is favored in women with unfavorable anatomy
and/or significant parametrial involvement. See “Radiotherapy Techniques” below for a
full discussion of the various RT techniques used in cervical cancer patients.

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Uterine Cancer
Although radiation has traditionally been delivered prior to surgery in many uterine
cancer patients (16), the majority of patients today undergo upfront surgery, consisting
of total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO), with
RT delivered postoperatively to selected patients based on pathologic features in the
surgical specimen. In the United States, many uterine cancer patients undergo extended
surgical staging (ESS) at the time of surgery as well, consisting of pelvic and paraaortic
lymphadenectomies, despite the results of two randomized trials questioning its benefits
in terms of survival (17,18).
The most common pathologic features used to determine the need for adjuvant RT in
early-stage (stages I to II) uterine cancer are tumor grade, histology, depth of
myometrial invasion (MI), lymphovascular invasion (LVI), and cervical involvement.
Some investigators also use tumor size and lower uterine segment (LUS) involvement.
However, the prognostic significance of such features, particularly in the absence of
other more established adverse features, remains unclear (19). Multiple randomized
trials have been performed by the GOG and other groups demonstrating that adjuvant
RT in early-stage uterine cancer patients with adverse pathologic features significantly
reduces locoregional failure (20–23). Whether it improves survival, however, remains a
matter of intense debate, despite the results of two large Surveillance Epidemiology and
End Results (SEER) studies suggesting a survival benefit in most patients (24,25).
At many centers today, low-risk early-stage uterine cancer patients (stage I, grade 1,
no or minimal MI) are treated with surgery alone, while those with intermediate risk
factors (grade 3 with superficial MI or grade 1–2 with deep MI, especially combined
with advanced age and LVI) receive adjuvant RT. In the latter group, pelvic RT is
currently reserved for patients who do not undergo ESS and vaginal brachytherapy is
delivered in those who do (provided all nodes are negative), a trend that appears to be
increasing in the United States (26). It may be possible, however, to treat selected
intermediate risk patients with adjuvant vaginal brachytherapy alone even when ESS is
not performed (27). In the adjuvant setting, either pelvic RT or vaginal brachytherapy
is delivered. While commonly delivered together in the past, the routine use of both
appears to only increase the risk of serious toxicity without improving local control and
thus should be avoided whenever possible (28).
The optimal approach in high-risk early-stage uterine cancer patients (deep MI and
grade 3 disease, cervical stromal invasion, LVI) remains controversial. In Europe, the
Postoperative Radiotherapy for Endometrial Carcinoma (PORTEC)-3 trial is comparing
pelvic RT versus pelvic RT plus concomitant and adjuvant chemotherapy in these
patients. In the United States, GOG 0249 is randomizing patients to pelvic RT versus
vaginal brachytherapy plus chemotherapy. Preliminary results of GOG 0249 which
randomized 601 patients with stage I endometrial carcinoma with high-risk features,
stage II endometrial carcinoma, and stages I to II serous or clear cell to either pelvic
radiation or vaginal brachytherapy followed by chemotherapy with paclitaxel and
carboplatin were published in abstract form in 2014. The vaginal recurrence rate after
pelvic radiation was 5% versus 2% with VCB/C. Pelvic recurrence was 2% with pelvic
radiation and 19% after VCB/C. There was no difference in distant failure, recurrence
free survival, or overall survival. The preliminary conclusion from GOG 0249 is that
VCB/C was not demonstrated to be superior to pelvic radiation. In early-stage uterine
cancer patients unable to undergo surgery due to advanced age and/or multiple
comorbidities, radiation can be used with curative intent and typically consists of a
combination of brachytherapy with or without pelvic RT in grade 3 patients and

726
brachytherapy alone in those with grade 1–2 disease (28). Pelvic magnetic resonance
imaging (MRI) may be helpful in these women to evaluate MI and extrauterine spread.
In stage III and IV uterine cancers, the standard approach has been for many years
surgery followed by adjuvant RT, using a variety of techniques including pelvic RT,
EFRT, and whole abdominal RT (WART). Historically, selected locally advanced patients
with positive peritoneal cytology received intraperitoneal radioactive phosphorus (32P)
(29). Outcomes varied considerably in stage III to IV patients depending on the type
and number of extrauterine sites involved, with the best results seen in patients with
isolated adnexal involvement (30) and poorer outcomes in those with involvement of
multiple extrauterine sites, nodal involvement, and/or residual disease (31).
Today, WART is rarely used in the United States following the publication of the GOG
122 trial randomizing stage III to IV patients to either WART or chemotherapy, which
noted a superior 5-year survival (55% vs. 42%) with adjuvant chemotherapy but
inferior pelvic control (32).
A secondary analysis of GOG 122 conducted to determine whether the number of
positive pelvic nodes (PPNs), cervical stromal involvement (CSI), and/or
lymphovascular space involvement (LVSI) were prognostic factors in terms of PFS and
OS among women with advanced endometrial carcinoma treated with adriamycin plus
cisplatin (AP) or whole abdominal irradiation (WAI). This analysis revealed the presence
of CSI and increasing number of PPN were associated with poor prognosis. For patients
with CSI improved PFS and OS was achieved with AP compared to WAI (33). However,
the question remains whether adjuvant RT has a role in conjunction with
chemotherapy. Patterns of failure studies suggest that it does, given the high risk of
locoregional recurrence in women undergoing surgery and chemotherapy (34). At many
centers today, stage III and selected stage IV patients are treated with chemotherapy
combined with limited volume RT (pelvic RT, EFRT, and/or vaginal brachytherapy
based on pathologic features), an approach known as “tumor volume–directed” RT
which was used in the GOG 184 trial (35). Of note, GOG 258 is currently randomizing
locally advanced patients to chemotherapy versus chemoradiotherapy. The results of
this important trial will help define the role of RT in these patients.
The role of RT in the treatment of patients with unfavorable histologies, notably
papillary serous and clear cell tumors, is controversial. However, RT may help reduce
the risk of locoregional recurrence in such patients who receive adjuvant chemotherapy
following surgery (36). Patients with early-stage uterine sarcomas, except those with
low-grade endometrial stromal sarcoma, have traditionally been treated with adjuvant
pelvic RT. Locally advanced sarcoma patients are treated at many centers with adjuvant
chemotherapy without RT, due to the superior outcomes in patients undergoing
chemotherapy compared to WART on the GOG 150 trial (37). Nonetheless, adjuvant RT
still remains a common treatment of choice in these patients, particularly in elderly
women and others who are unable to undergo adjuvant chemotherapy. See the
“Radiotherapy Techniques” below for a full discussion of the various RT techniques
used in patients with uterine cancer.

Ovarian Cancer
For many years, RT occupied an important role in the treatment of ovarian cancer.
Following upfront surgery, consisting of an omentectomy, TAH-BSO, peritoneal
sampling, and cytoreduction of extra-ovarian disease throughout the abdomen and
pelvis, and often pelvic and paraaortic lymph node dissection, adjuvant RT was
routinely delivered in the form of intraperitoneal 32P in high-risk early stage and WART

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in locally advanced disease patients.
Several randomized GOG studies have compared adjuvant 32P versus chemotherapy
(melphalan or cisplatin-cytoxan) in early-stage high-risk disease (stages IA to B grade 3,
stages IC to II) and found no differences in either relapse-free or overall survival rates
(38,39). Moreover, in GOG 7602, chemotherapy was associated with higher toxicity
rate compared to RT, including a higher rate of second malignancies (38). Despite these
favorable results, few patients receive intraperitoneal 32P today, apart from its use at
some centers in selected elderly high-risk early-stage patients unable to receive
chemotherapy, partly due to the development of peritoneal adhesions in some patients.
In locally advanced ovarian cancer patients who were optimally cytoreduced
(previously defined as <2 cm residuum remaining following surgery), WART was long
considered the standard adjuvant approach at many centers throughout the world.
Published long-term outcomes have been highly favorable in such patients treated with
WART, particularly in those with microscopic or no residual disease after cytoreductive
surgery (40,41). Investigators at Stanford University reported a 15-year relapse-free
survival rate of 50% in stage I to III optimally cytoreduced patients undergoing
adjuvant WART (40). Despite these favorable results and even a prospective phase III
M. D. Anderson Hospital randomized trial demonstrating identical survival rates
following WART or chemotherapy (42), adjuvant WART has been largely abandoned at
most centers today, at least in the United States. The standard adjuvant approach is
currently combination chemotherapy. Unfortunately, a randomized trial comparing
WART and chemotherapy regimens popular today will most likely never be performed.
Although no longer used alone following surgery, the question remains whether
adjuvant RT has a role in conjunction with chemotherapy and surgery in ovarian
cancer. Several prospective trials have evaluated the role of “consolidative” RT in stage
I to III patients following upfront surgery and adjuvant chemotherapy (43,44). No
benefit was seen using intraperitoneal 32P compared to observation in a GOG trial
focused on stage I to III patients with microscopic residual disease following surgery
and chemotherapy (43). In contrast, the Swedish-Norwegian Ovarian Cancer Study
Group trial compared WART versus cisplatin-doxorubicin-epirubicin versus observation
in stage III patients achieving a pathologic complete response and noted 5-year
progression-free survivals of 56%, 36%, and 35% in the WART, chemotherapy, and
observation groups, respectively (44). Although favorable results have been reported
combining adjuvant RT with modern taxane-based adjuvant chemotherapy (45),
whether adjuvant RT is truly beneficial in this setting remains unclear.
RT is occasionally used in the management of patients with nonepithelial ovarian
cancers. Given its exquisite radiosensitivity, ovarian dysgerminoma may be treated with
RT; however, in these patients as well, the standard practice today is adjuvant
chemotherapy, particularly in those desiring fertility-sparing treatment. As in other
gynecologic cancers, RT has an important role in the palliative treatment of ovarian
cancer patients (45). See “Radiotherapy Techniques” below for a discussion of the
various RT techniques used in ovarian cancer.

Vulvar Cancer
The treatment of vulvar cancer at most centers today consists of upfront surgery,
typically radical vulvectomy or radical wide local excision in selected patients with
small well-lateralized tumors (46), with RT delivered adjuvantly in patients with high-
risk features including LVI, tumor invasion >5 mm, surgical margins <8 mm, grade 3
disease, and microscopic positive margins (47,48). Most patients also undergo bilateral

728
inguinofemoral dissections, particularly those found to have tumor invasion >3 mm,
LVI and/or high-grade disease, due to their high risk of nodal involvement.
Although commonly used in many other gynecologic cancers, prophylactic nodal
irradiation is rarely used to treat clinically negative regional lymph nodes in vulvar
cancer. This practice is based on the GOG 88 trial which compared prophylactic
inguinofemoral RT versus lymphadenectomy in clinically node negative patients and
found a significantly higher rate of recurrence (p = 0.03) and death (p = 0.04) in the
RT group (49). See “Radiotherapy Techniques” below for critique of this influential
study.
In women with locally advanced but resectable disease, surgery is typically performed
followed by adjuvant radiation or chemoradiation. Over 20 years ago, the GOG
completed a landmark trial (GOG 37) comparing adjuvant RT versus pelvic node
dissection in patients found to have involved inguinal nodes at the time of surgery (50).
A significantly higher survival rate was noted in the RT group, with the greatest benefit
seen in women with clinically suspicious and/or ≥2 pathologically involved nodes.
Moreover, adjuvant RT significantly reduced the risk of recurrence in the inguinal
nodes (5% vs. 24%, p = 0.02). This trial established adjuvant RT as the treatment of
choice in these patients.
In unresectable vulvar cancer patients, RT has been used preoperatively with
promising results (51,52). Considerable interest has been focused on further
augmenting these results by combining RT with chemotherapy (48,53,54). GOG 101
evaluated preoperative chemoradiotherapy in locally advanced unresectable patients
and found that nearly all patients (97%) became resectable, with only 16% ultimately
failing locally (55).
Adjuvant RT in vulvar cancer is delivered using a variety of techniques, ranging from
small electron fields directed solely at the primary site to generous fields encompassing
the primary, pelvis plus one or both groins. The most common approach, however, is
pelvic-inguinal irradiation, delivered with or without a midline block. Brachytherapy
has a limited role in vulvar cancer, apart from patients with a positive vaginal margin
or in medically inoperable patients in whom high doses are required to control the
primary tumor. However, at most centers, high-dose central boosts are delivered in such
patients using external-beam techniques. A description of the various RT techniques
used in vulvar cancer is provided below (see “Radiotherapy Techniques”).

Vaginal Cancer
The treatment of choice in all stages of vaginal cancer is definitive RT. However,
selected early-stage patients, such as those with small volume disease limited to the
upper vagina, can be treated with a variety of surgical approaches, including partial or
radical vaginectomy (56).
Early-stage vaginal cancer patients typically receive brachytherapy alone or combined
with external beam when tumors invade the paravaginal tissues (57,58). Some
investigators advocate the use of combined external beam and brachytherapy even in
patients without paravaginal invasion (59). Overall, definitive RT is associated with
excellent outcomes in most early-stage vaginal cancer patients, particularly in those
with stage I disease in whom locoregional control rates exceed 85% (58). Patients with
locally advanced disease undergo pelvic RT and brachytherapy (57–59). At some
institutions, chemotherapy is delivered concomitantly in these patients in an effort to
improve tumor control and potentially survival extrapolating from cervical cancer
studies. Given the low number of vaginal cancer patients diagnosed each year, it is

729
unlikely that randomized trials evaluating such approaches will ever be successfully
conducted.
Brachytherapy in early-stage vaginal cancer typically involves ICB, but in women
with >0.5 cm tumor invasion or thickness, interstitial brachytherapy is recommended.
Some investigators favor interstitial brachytherapy combined with ICB even in patients
with superficial tumors to reduce the total vaginal dose and, in distal vaginal tumors,
the rectal dose (59). If external beam is also delivered, vaginal cancer patients receive
either pelvic irradiation, or in cases involving the lower one-third of the vagina, pelvic-
inguinal RT. See “Radiotherapy Techniques” below for a discussion of the various RT
techniques used in patients with ovarian cancer.

RADIOTHERAPY TECHNIQUES
External-Beam Therapy

Whole Pelvic Radiotherapy


Pelvic RT is used in many gynecologic cancers to irradiate multiple target tissues within
the pelvis, including the uterus/cervix (or the postoperative bed), the upper vagina,
paracervical/parametrial tissues, and the pelvic (internal, external, and common iliac)
lymph nodes. Pelvic RT fields have traditionally been designed using fluoroscopic
simulation based on bony landmarks and are delivered with either two-field (opposed
anterior–posterior:posterior–anterior [APPA] fields) or four-field (APPA plus opposed
lateral fields) techniques (Fig. 25.1). In recent years, however, most centers have moved
away from APPA treatment (60), since four-field approaches allow considerably more
normal tissue sparing, notably the anterior small bowel and posterior rectum. Some
investigators still favor opposed APPA fields, however, in patients with locally advanced
cervical cancer.
For many years, the superior border of the pelvic RT field was placed at the L5–S1
interspace; however, most investigators currently favor the L4–L5 interspace to include
the common iliac lymph nodes. It is important to note, however, that the common iliacs
in some patients may extend considerably higher, requiring an upper border as high as
L2–L3 to ensure their full coverage. The lower pelvic RT border is typically placed at the
inferior obturator foramen while the lateral borders are set 1 to 1.5 cm beyond the
pelvic brim. The anterior border of the lateral field is at (or 1 cm anterior) to the pubic
symphysis to ensure coverage of the external iliac nodes; the posterior border is at the
S2–S3 interspace. Previously, the posterior border was commonly set at the S1–S2
interspace; however, concerns were raised about adequate coverage of the attachment
of the uterosacral ligament to the sacrum with this approach, particularly in locally
advanced cervical cancer patients (61). Customized blocking is added to each field
using either cerrobend or multi-leaf collimation to reduce dose to the surrounding
normal tissues including the small bowel and rectum. Oral and rectal contrast may be
administered at simulation to aid in the design of these blocks.

730
Figure 25.1 Anterior–posterior (AP) (A) and lateral fields (B) in a representative gynecologic cancer patient
undergoing whole pelvic radiation therapy.

Various modifications can be done to the traditional pelvic RT fields, depending on


the clinical scenario. In cervical or uterine cancer patients with significant vaginal
involvement, the lower border can be extended to the introitus, ensuring irradiation of
the entire vaginal canal. In such cases, it is helpful to place a radiopaque marker in the
vagina at the time of simulation marking the inferior extent of disease. The superior
border may be extended superiorly to fully encompass the common iliac lymph nodes,
particularly in women with involvement of the external iliac lymph nodes, or may be
lowered to the L5–S1 interspace in patients undergoing ESS and found to have negative
pelvic nodes. The posterior border of the lateral field can also be moved posterior to the
sacrum in cervical cancer patients with bulky disease, whereas the anterior border may
be moved anteriorly in women with an anteverted uterus and/or bulky external iliac
nodes.
At many centers, patients undergoing pelvic RT are immobilized and simulated in the
supine position. Prone positioning with a “belly board” is favored by some investigators
to help reduce the volume of small bowel irradiated. Similarly, at some centers, patients
are simulated and treated with a full bladder to displace small bowel. Whatever
approach is used, it is important to strive for consistent bladder and rectal filling
throughout treatment, given that the volume of these organs may impact the position of
the cervix/uterus (or vaginal cuff) (62,63).
Although pelvic RT fields have traditionally been designed based on bony landmarks,
multiple investigators have demonstrated that such an approach may underdose the
target tissues and/or inadequately shield surrounding normal tissues in many patients
(64,65). Finlay et al. assessed the adequacy of nodal coverage of conventional pelvic RT
fields in 43 cervical cancer patients (64). Pelvic vessels were contoured following
computed tomography (CT) simulation and used as surrogates for the pelvic lymph
nodes. In 41 patients (95%), conventional fields inadequately covered various lymph
node groups. Of note, in 24 (56%), conventional fields and blocks were found to be too
generous. Others have similarly used three-dimensional (3D) imaging and found that
conventional fields and blocking may result in inadequate target coverage in up to 50%
of patients, particularly with the placement of the posterior field border of the lateral
pelvic field at S2–S3 (65). These results strongly support the design of pelvic RT field

731
using CT simulation, which is now the preferred approach throughout the United
States.

Figure 25.2 Treatment plan with isodose lines in a representative gynecologic cancer patient treated with whole
pelvic radiation therapy.

Conventional pelvic RT fields are typically delivered using moderate–high energy


(≥10 MV) photon beams. However, lower energies can be used in selected thin patients.
Wedges may be added to the lateral fields to reduce “hot spots” in the treatment plan.
As example pelvic RT plan is shown in Figure 25.2. Total doses prescribed typically
range from 39.6 to 50.4 Gy delivered in 1.8 to 2 Gy/fractions, the higher doses used in
patients undergoing external beam alone and lower doses in those treated with both
external beam and brachytherapy.
In the past, there was considerable interest in the use of altered fractionation
schedules in gynecologic cancer patients, including accelerated hyperfractionated RT as
a means of escalating the pelvic radiation dose. However, the RTOG 88–05 trial using
this approach in locally advanced cervical cancer patients failed to demonstrate a
benefit in terms of tumor control or complications (66). Others have also reported high
complication rates using a hyperfractionated approach (67). Moreover, twice daily
treatment in an effort to boost the cervical tumor prior to brachytherapy has also been
associated with increased complications (68). In contrast, hypofractionated approaches,
for example, 2.5- to 3-Gy daily fractions (total doses 30 to 35 Gy), have been used
successfully in patients treated with palliative intent. Higher dose per fraction (up to 10
Gy) palliative regimens have also been explored (69,70).
Various blocks can be added to the conventional pelvic RT field. At some centers, a
midline block is utilized allowing a higher proportion of the total dose to be delivered by
brachytherapy in cervical cancer patients, typically placed after approximately 20 Gy
(71). A midline block may also be placed following brachytherapy in cervical cancer
patients with significant parametrial involvement and/or involved pelvic lymph nodes
allowing an additional boost to be delivered, typically 10 to 12 Gy in five to six
fractions.
At many centers, midline blocks are often standardized, but at others the midline
block may be customized based on the brachytherapy isodose distributions (Fig. 25.3).
In 1997, Wolfson et al. performed a survey of GOG institutions and reported that the
percentages of centers using standard and customized midline blocks were 76% and
21%, respectively, at that time (72). Only 3% utilized step-wedge blocks as popularized
by Perez et al. (71). The width of the midline block should fully encompass the ovoids
(colpostats) on the anterior radiograph plus a margin since narrow midline blocks
inadequately shield the ureters and are associated with increased complications 75(73).

732
The inferior edge of the block should be coincident with the lower border of the pelvic
field. However, various superior block edges can be used. In the GOG survey, the upper
border of the midline block was set at the top of the pelvic field, the tip of the tandem
plus a 1- to 2-cm margin, or the level of the sacroiliac joint by 29%, 38%, and 33% of
respondents, respectively (74).
IMRT is increasingly used in the treatment of gynecologic cancers. Investigators at the
University of Chicago were the first to compare conventional and IMRT planning in
gynecologic cancer patients undergoing pelvic RT and found that IMRT reduced the
volume of small bowel irradiated by a factor of two and the volume of both the bladder
and rectum irradiated by 23% (75). Subsequently, others have confirmed these results,
with reductions up to 70% seen with IMRT planning in terms of the volume of small
bowel receiving the prescription dose (73,76). More recently, IMRT planning has been
shown to be an effective means of reducing the volume of pelvic bone marrow irradiated
in patients undergoing pelvic RT, an appealing approach particularly in patients
receiving concomitant chemotherapy (77). The ongoing International Evaluation Of
Radiotherapy Technology Effectiveness In Cervical Cancer (INTERTECC) is a phase
II/III trial which randomizes patients with biopsy-proven stage I to IVA invasive cervical
carcinoma either in the post-hysterectomy setting with high-risk features OR is locally
advanced, in the intact setting to either pelvic radiotherapy with IMRT or with
conventional 3D-conformal techniques with concurrent cisplatin followed by
brachytherapy to test whether IMRT will reduce the rate of acute grade ≥3 hematologic
or clinically significant grade ≥2 gastrointestinal toxicity. Patients undergoing pelvic
IMRT are typically immobilized in the supine position and undergo CT simulation with
thin (5 mm) slices, although at selected centers prone positioning is favored (78).
Contrast may be administered to aid in the delineation of the target and normal tissues;
intravenous contrast is particularly useful since the pelvic vasculature is used as a
surrogate for the lymph nodes in the planning process.

Figure 25.3 Example midline blocks used in patients with cervical cancer: (A) standard block and (B)
customized block based on brachytherapy isodose distribution. From Wolfson AH, Abdel-Wahab M, Markoe
AM, et al. A quantitative assessment of standard versus customized midline shield construction for invasive
cervical carcinoma. Int J Radiat Oncol Biol Phys. 1997;37:237–242.

733
Following simulation, a gross tumor volume (GTV) and clinical target volume (CTV)
are contoured on the planning CT scan, based on ICRU 50 guidelines (79). The GTV
should include all demonstrable disease, including involved regional lymph nodes. A
variety of imaging modalities can be used to aid in target design, with growing attention
on positron emission tomography (PET) and MRI (80). Investigators at Washington
University in St. Louis base their target volume definition on PET and contour a
metabolically active tumor volume (MTV), specified at the 40% threshold level (81).
The CTV in most patients undergoing pelvic IMRT consists of the upper half of the
vagina, uterus/cervix (if present), parametria, presacral region, and pelvic lymph nodes
(internal, external, and lower common iliac nodes). The most superior extent of the CTV
is typically placed 1 to 1.5 cm inferior to the L4–L5 interspace to account for planning
target volume (PTV) expansions. In uterine cancer patients without cervical
involvement, the presacral region need not be included. At some centers, a single CTV is
drawn, whereas at others several CTVs are delineated. In a postoperative patient, for
example, two CTVs may be delineated: the CTVnodes includes the common, external, and
internal iliac nodes and presacral space, whereas the CTVvagina includes the vaginal cuff
and paravaginal/parametrial tissues. At some centers, an integrated target volume (ITV)
is generated by fusing empty and full bladder planning CT scans, encompassing
contours of the cervix (or vaginal cuff in postoperative patients) on both scans, with
patients treated with a full bladder or, at other centers, an empty bladder as
maintaining a full bladder has not been shown to be reproducible. Normal tissues are
contoured as well, including the small bowel, bladder, rectum, and, at some centers, the
sigmoid colon. The pelvic bones are used as a surrogate for the pelvic bone marrow in
patients undergoing chemoradiotherapy. In the past, only the iliac crests were
contoured; however, recent data suggest that the pelvic bones are a better surrogate for
the bone marrow in the optimization process (78).

Figure 25.4 Mid-pelvic computed tomography (CT) image illustrating a clinical target volume (CTV)
delineated in a patient with cervical cancer treated postoperatively based on guidelines developed for the
Radiation Therapy Oncology Group (RTOG) 0418 trial. Upper external and internal iliac (red) and presacral
region (blue). From Small W Jr, Mell LK, Anderson P, et al. Consensus guidelines for delineation of clinical
target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical
cancer. Int J Radiat Oncol Biol Phys. 2008;71:428–434.

Consensus guidelines regarding CTV design in gynecologic cancer patients


undergoing postoperative pelvic IMRT were developed for the RTOG 0418 phase II trial

734
(Fig. 25.4) (82). These guidelines were based, in part, on work of Taylor et al. who
mapped pelvic lymph node regions using iron oxide-enhanced MRI, a method to
visualize benign lymph nodes (83). In an analysis of 20 patients using this technique, a
modified margin of 7 mm around the major pelvic vessels was found to encompass 99%
of the visualized lymph nodes. More recently, consensus guidelines have been developed
for cervical cancer patients treated with an intact uterus based on MRI (Fig. 25.5) (83).
The next step in the IMRT planning process involves the expansion of the CTV to
generate a PTV, accounting for patient setup uncertainty and organ motion. The
optimal PTV expansion remains a matter of debate, particularly in patients with intact
cervical cancer in which there may be considerable organ motion (62,63). A reasonable
approach is to provide generous expansions around the cervical tumor (definitive
patients) and the vaginal cuff (postoperative patients) on the order of 1.5 to 2 cm.
Tighter expansions can be placed around the CTV in the upper pelvis (0.7 to 1 cm).
Daily in-room IGRT techniques, notably cone-beam CT (CBCT) imaging, may help ensure
adequate coverage of the target tissues on a daily basis (62).
No consensus exists regarding many IMRT planning parameters used in gynecologic
cancer patients. At many centers seven to nine equally spaced 6 MV beams are used;
however, others favor volumetric-modulated arc or tomotherapy approaches. As in
conventional RT, the total dose prescribed is a function of the tumor site, stage, and
treatment volume. Most investigators deliver 45 Gy in 1.8-Gy daily fractions,
particularly in women subsequently undergoing brachytherapy. Higher doses (50.4 Gy)
can be used in patients treated with pelvic IMRT alone (84). Some investigators are
exploring the use of more sophisticated simultaneous integrated boost (SIB) approaches,
particularly in women with grossly positive nodes (85).
Given the potential ability to safely deliver higher and potentially more efficacious
doses, some investigators have explored using IMRT as a substitute for brachytherapy in
cervical cancer (75,86). Investigators at the Princess Margaret Hospital presented a case
study of a stage IIB cervical cancer patient unsuitable for brachytherapy treated with an
IMRT boost (87). Using MRI guidance, a GTV was delineated consisting of the cervix
and LUS. The GTV was expanded by a 10-mm margin (7 mm posteriorly) generating the
CTV which was subsequently expanded by 5 mm (10 mm anteriorly) to generate the
PTV. Six static 6 MV fields were used to deliver 25.2 Gy in 1.8-Gy daily fractions to the
PTV. The resultant treatment plan was highly conformal; average doses delivered to
50% of the rectum, bladder and small bowel were 21 Gy, 13 Gy, and 5 Gy, respectively.
Treatment was tolerated well without significant sequelae. Given the paucity of data
using IMRT in lieu of brachytherapy, this approach should be considered experimental
at the present time and only used in women unable to undergo brachytherapy.

735
Figure 25.5 Axial view of a T2-weighted magnetic resonance (MR) images illustrating contours of the gross
tumor volume (GTV) (red), cervix (pink), vagina (yellow), parametria (green), and uterus (blue) in a patient with
intact cervical cancer undergoing intensity-modulated radiation therapy (IMRT) based on the Radiation
Therapy Oncology Group (RTOG) consensus conference. From Lim K, Small W, Portelance L, et al.
Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the
definitive treatment of cervical cancer Int J Radiat Oncol Biol Phys. 2011;79:348–355.

The optimal dose–volume constraints for the PTV and normal tissues in gynecologic
cancer patients undergoing pelvic IMRT remain unclear. Investigators at Washington
University reported the use of the following constraints: PTV (100% to receive 95% of
the prescription dose), small bowel (<40% to receive ≥30 Gy), rectum (<40% to
receive ≥40 Gy), and femoral heads (<40% to receive ≥30 Gy) (88). In the original
series from the University of Chicago, <40% of the small bowel, rectum and bladder
were constrained to receive ≥36 Gy, ≥40 Gy, and ≥40 Gy, respectively. Moreover,
>95% of the PTV needed to receive >95% of the prescribed dose (89).
Preliminary clinical outcome studies in gynecologic cancer patients undergoing pelvic
IMRT have been extremely promising, with lower rates of acute and chronic toxicities
reported compared to conventional techniques (9,89–93). Recent outcome studies have
also reported excellent tumor control rates in both cervical (88,90) and uterine (94)
cancers. Favorable outcomes have also been reported using adjuvant pelvic IMRT on the
RTOG 0418 prospective clinical trial (95). As described earlier in this chapter, an
international cooperative group trial (INTERTECC) evaluating pelvic IMRT in cervical
cancer is currently enrolling patients (96).
In recent years, detailed normal tissue complication probability (NTCP) studies have
been performed in gynecologic cancer patients undergoing pelvic IMRT which shed light
on the optimal dose–volume constraints for various normal tissues (Fig. 25.6) (97–99).
In update of the combined University of Chicago/University of California San Diego
experience, the small bowel volume receiving ≥45 Gy was constrained to 250 cc and
the volume of pelvic bone marrow (defined as entire pelvic bones) receiving ≥10 Gy
and ≥20 Gy were constrained to receive ≤90% and ≤75%, respectively (90). The
normal tissue dose constraints used in the previously mentioned INTERTECC trial which
is ongoing are small bowel volume receiving >45 Gy (V45) ≤250 cc; maximum dose
<115%, rectum maximum dose <115% of the prescription dose, and bone marrow
volume receiving 10 Gy and 2 Gy <90% and 75%, respectively. The Normal tissue
planning goals are small bowel volume receiving >45 Gy (V45) ≤200 cc; V40 <30%;
maximum dose <50 Gy, rectum V45 <50%; V30 <60%; maximum dose <50 Gy, bone

736
marrow V10 <80%; V20 <66%, bladder V45 <50%; maximum dose <50 Gy, femoral
head V30 <15%; maximum dose <50 Gy (96). There is also substantial interesting
focused on the use of more sophisticated image-guided approaches in an effort to
further optimize IMRT planning (91).

Figure 25.6 Plot of white blood cell count log (WBC nadir) versus bone marrow volume receiving 20 Gy or
more (V20) in a cohort of cervical cancer patients treated with combined chemoradiotherapy, supporting the use
of bone marrow V20 as a constraint in the optimization process. Pelvic bones were used as a surrogate for pelvic
bone marrow in this analysis. Regression coefficient (b) = –0.021 k/mL/%, p = 0.002. From Rose BS, Aydogan
B, Liang Y, et al. Normal tissue complication probability modeling of acute hematologic toxicity in cervical
cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2010; 78:912–919.

Extended Field Radiotherapy


EFRT is used to treat the pelvic and paraaortic regions. A variety of techniques are
currently utilized. At some centers, the entire volume is treated with large opposed
APPA fields, extending from pelvis to the T12–L1 interspace. The paraaortic portion of
these fields is typically 8 to 10 cm wide, depending on the patient’s anatomy and
disease extent. CT or PET/CT-based planning is helpful to ensure coverage of all
enlarged lymph nodes. To reduce the small bowel dose, some favor using four-field
approaches (APPA plus opposed laterals). However, when using such approaches, care
needs to be taken to minimize the dose to the kidneys with variable weightings between
the APPA and lateral fields ensuring a maximum kidney dose of 18 Gy or less. At some
centers, the pelvis and paraaortic regions are treated separately with a place “gap”
between fields. Selected patients may need to be treated at an extended distance given
the length of the fields treated.
Whichever field arrangement is used, moderate–high energy beams (≥10 MV) are
indicated except in selected thin women; all patients are simulated and treated in the
supine position. Prescribed doses range from 39.6 to 45 Gy delivered in 1.8 to 2 Gy per
fractions. In women with involved paraaortic nodes, a 5- to 10-Gy boost may be
delivered via reduced fields. Selected involved sites may be treated to 60 Gy or higher;
however, care needs to be given to minimize the dose to the surrounding bowel and
other normal tissues including kidneys and spinal cord.
Multiple centers have explored the use of IMRT planning in gynecologic cancer
patients undergoing EFRT (100–102). Compared to an APPA approach, investigators at

737
Washington University noted that intensity-modulated EFRT (IM-EFRT) reduced the
volume of small bowel, bladder, and rectum receiving the prescription dose by 61%,
96%, and 71%, respectively (100). Compared to a four-field approach, corresponding
reductions were 60%, 93%, and 56%, respectively. The following normal tissue
constraints were used in the IM-EFRT planning: small bowel (<50% to receive ≥30
Gy), kidneys (<33% to receive ≥10 Gy), and spinal cord (<5% to receive ≥45 Gy).
Lian et al. compared 3D conformal EFRT plans in 10 endometrial cancer patients to
IMRT and helical tomotherapy (HT) plans (101). The following constraints were used in
the IMRT and HT optimization process: bladder (<50% to receive ≥40 Gy), rectum
(<40% to receive ≥40 Gy), bowel (<35% to receive ≥35 Gy), kidneys (<35% to
receive 16 Gy), and spinal cord (maximum dose, 40 Gy). Overall, both IMRT and HT
resulted in superior target coverage and significantly reduced normal tissue doses
compared to 3D conformal planning; however, the HT achieved the best normal tissue
sparing (Fig. 25.7).
A potentially important role for IMRT in gynecologic cancer patients undergoing
EFRT is the ability to safely deliver higher than conventional doses to involved
paraaortic lymph nodes. Using conventional techniques, doses above 60 Gy, except in
patients with small volume disease, are difficult to deliver. However, the likelihood of
controlling bulky paraaortic nodes with such doses is quite low. Multiple investigators
have demonstrated that higher doses may be possible using SIB IMRT approaches in
patients with involved paraaortic lymph nodes. Two different approaches have been
proposed. Some investigators recommend that the entire paraaortic region be treated
with conventional fraction sizes (1.8 Gy/day, 45 Gy total dose) and an SIB technique
used to irradiate the involved nodes with higher than conventional fraction size (2.4
Gy/day, 60 Gy total dose) (103). Alternatively, conventional fractions can be used for
the SIB portion (1.8 Gy/day, 59.4 Gy total dose) and lower than conventional fractions
used to treat the paraaortic region (1.53 Gy/day, 50.4 Gy total dose) (85).

Figure 25.7 Comparison of planning target volume coverage by the 95% (green line) in three-dimensional
conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (HT)

738
plans in a stage IIIC uterine cancer patient undergoing extended field irradiation. Blue indicates the 50% isodose
line; red line or red area indicates planning target volume. From Lian J, Mackenzie M, Joseph K, et al.
Assessment of extended-field radiotherapy for stage IIIC endometrial cancer using three-dimensional conformal
radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy. Int J Radiat Oncol Biol Phys.
2008;70:935–943.

Limited outcome data exist using IM-EFRT. Salama et al. treated 13 women to a total
dose of 45 Gy in 1.8-Gy fractions (104). While 84% of patients experienced acute grade
2 bowel toxicity, no grade 3 or higher bowel or bladder sequelae were noted. Using the
SIB approach with higher than conventional daily fractions (2.2 Gy/day, 55 Gy total
dose) to PET-defined paraaortic nodes, investigators at the University of Pittsburgh
noted acute grade 2 and 3 bowel sequelae in 10% and 0% of patients, respectively
(105). The University of Pittsburgh group also published an expanded experience using
IM-ERFT with the same SIB technique in 61 consecutive women either with PET positive
paraaortic disease or with PET PPNs alone siting the false-negative rate of FDG-PET for
paraaortic metastases of approximately 20% to 25% (106). In this series, at a mean
follow-up time of 29 months, 8 patients experienced recurrence. However, 10 patients
(16.3%) had persistent or recurrent local disease, 3 (4.9%) involving the regional
nodes, and 14 patients (23%) progressed distantly. The rate of paraaortic failure in
patients with pelvic-only PET positive nodes was 2.5%. Grade 3+ adverse events
developed in only two patients (4%). Du et al. randomized 60 cervical cancer patients
with involved paraaortic nodes to either IMRT or conventional RT to the paraaortic
region (107). While the IMRT patients received a higher prescribed dose (58 to 68 Gy
vs. 45 to 50 Gy) than the conventional RT patients, they experienced less acute and
chronic toxicity. Moreover, IMRT patients had a superior 3-year survival (36.4% vs.
15.6%, p = 0.016) compared to the conventional RT patients.

Pelvic-Inguinal Radiotherapy
In women with vulvar cancer and other gynecologic cancer patients involving the lower
vagina, pelvic-inguinal irradiation is used to irradiate the pelvis, vagina, vulva, and
bilateral inguinofemoral regions. Such patients are immobilized and simulated supine in
the “frog-leg” position to minimize skin folds and thus the risk of acute perineal
toxicity. Moderate–high energy beams (≥10 MV) are used.
The upper border of the conventional pelvic-inguinal field differs between institutions
and is based on the disease extent. In vulvar cancer patients, some advocate the
treatment of reduced pelvic fields (“true pelvis”) with the upper border placed inferiorly
to the sacroiliac joints. Others place the upper border at the L5–S1 or L4–L5 interspace.
In a survey of members of the Gynecologic Cancer Intergroup (GCIG), the most common
upper border was L5–S1 followed by L4–L5 (48). In women with upper pelvic
adenopathy, the upper border may need to be even higher. The lower border is typically
placed approximately 5 cm inferior to the vulva/perineum to ensure coverage of the
inguinofemoral lymph nodes.
A variety of treatment approaches have been used in patients undergoing pelvic-
inguinal RT. One common approach is to use opposed APPA fields, with a “wide” AP
field encompassing the pelvis and groin regions and a “narrow” PA field treating only
the pelvis. Supplemental electron fields are used to treat the groins, reducing the dose
received by the femoral heads. Alternatively, APPA fields can be equally wide with
partial transmission blocks placed on the PA field minimizing dose to the femoral heads.
A third approach is to prescribe high-energy photons (10 to 24 MV) for the PA field and
low-energy photons (4 to 6 MV) for the AP field. A novel modified segmental boost

739
technique has been developed using a wide AP field, narrow PA field, and two angled
photon fields encompassing the bilateral groins (108). Whichever technique is used,
attention needs to be given to avoid underdosing the vulvar region, particularly in
patients treated preoperatively. Bolus is typically used with doses confirmed via
thermoluminescence dosimetry (TLD). Total prescribed doses in patients undergoing
pelvic-inguinal RT range from 45 to 50.4 Gy in 1.8- to 2-Gy daily fractions. Additional
boosts may be delivered to the inguinal region in patients with involved lymph nodes. In
the GCIG survey, the mean pelvic and groin node doses were 48.1 Gy and 49.9 Gy,
respectively (47).
When treating the inguinal lymph nodes with electrons, care needs to be taken to
ensure the proper selection of beam energy. Routine use of low-energy electron beams
will likely underdose the groin nodes in a significant number of patients, particularly
obese women. The depth of treatment should be tailored to the individual patient based
on CT imaging, since the depth of the inguinofemoral nodes is highly variable with an
average depth of 6.1 cm reported in one study (109). The high rate of nodal failures
observed in the RT patients treated on GOG 88 comparing prophylactic RT versus
lymphadenectomy in clinically node negative vulvar cancer patients was likely due, at
least in part, to the fact that the groins were treated via a single anterior field
prescribed to a depth of 3 cm (48). Such an approach would significantly underdose the
inguinal nodes in many patients. Prophylactic groin irradiation in clinically node
negative patients has been shown to be highly effective if properly planned and
delivered (110). Care must also be taken to also ensure an adequate volume is irradiated
given inguinal nodal metastases can occur throughout the groin region. Thus, small
volume fields designed to irradiate the vessels with a limited margin are not
recommended.
Considerable controversy exists regarding the use of a midline block in vulvar cancer
patients undergoing pelvic-inguinal RT. In one highly quoted report, Dusenbery et al.
noted a 48% central recurrence rate in 26 women treated with a midline block (111).
However, all patients in this study had pathologically positive lymph nodes and many
did not have wide negative margins. Of note, central recurrences were rare in the GOG
37 trial despite the use of a midline block (50). Thus, in the properly selected patient, a
midline block may be reasonable, particularly in elderly, frail patients who are at high
risk of requiring treatment breaks due to perineal toxicity if treated without a midline
block.
Limited experience is available evaluating IMRT in gynecologic cancer patients
undergoing pelvic-inguinal RT, with largest experience to date from the University of
Pittsburgh. Beriwal et al. compared IMRT and conventional planning in terms of normal
tissue sparing in 15 vulvar cancer patients (112). Various IMRT techniques were used,
with a median number of seven beams (range 5 to 8). Normal tissue planning
constraints included: small bowel (<35% to receive ≥35 Gy), rectum (<40% to receive
≥40 Gy), and bladder (<40% to receive ≥30 Gy). The plans were considered
acceptable if <5% of the PTV received <100% of the prescribed dose and <10%
received >110%. Mean preoperative and postoperative prescribed doses were 46.4 and
50.4 Gy, respectively. IMRT planning resulted in better sparing of the small bowel,
rectum, and bladder; however, unlike other reports (113), no significant difference was
seen in volume of the femoral heads irradiated. Treatment was well tolerated, with only
one patient experiencing acute grade 3 toxicity and none developing a grade ≥3 late
toxicity. Two patients ultimately recurred locally, both were treated postoperatively.
Investigators at the University of Pittsburgh also reported their experience with
preoperative chemotherapy and intensity modulated pelvic-inguinal RT in 18 vulvar

740
cancer patients (114). IMRT was delivered twice daily during the first and last
treatment weeks. Overall, treatment was well tolerated with no grade ≥3 late toxicities.
Moreover, no recurrences were seen in the nine patients achieving a pathologic
complete response, whereas three of five partial responders failed locally.

Whole Abdominal Radiotherapy


WART involves the treatment of the entire peritoneal cavity. While in the past, due to
the limitations of machine field size, treatment was delivered with a “moving strip”
technique (115), WART is currently delivered at most centers using large opposed APPA
techniques. Care needs to be taken at simulation to ensure that the upper border is
placed sufficiently high (1 to 1.5 cm superior to the dome of the diaphragm) to cover
the full excursion of the diaphragm during respiration. Laterally, the field borders are
set 3 to 4 cm beyond the peritoneal reflection. Inferiorly, fields extend to the inferior
obturator foramen. CT-based planning is particularly helpful to ensure complete
coverage of the entire peritoneal cavity. Given the large volumes treated, selected
patients may need to be treated at an extended distance.
Patients undergoing WART are simulated in the supine position and immobilized with
their arms overhead. Prescribed doses range from 25 to 30 Gy in 1.5-Gy daily fractions,
generally followed by a boost to the pelvis (total pelvis dose, 45 to 50 Gy). Low–
moderate beam energies are recommended (6 MV) to avoid underdosing the anterior
peritoneal structures. At many centers, partial transmission blocks (2 to 5 half-value
layers) are placed on the posterior field over the kidneys (with a 0.5-cm margin) to limit
the kidney dose to ≤18 Gy. Some centers elect to limit the kidney dose to ≤15 Gy,
particularly in women previously treated with chemotherapy. If the total prescribed
dose exceeds 25 Gy, blocks are added at some centers to limit the liver dose to 25 Gy.
Various modifications to the conventional WART technique have been introduced over
the years to boost selected intra-abdominal and pelvic sites. Martinez et al. at Stanford
developed a technique incorporating progressively shrinking fields delivering 30 Gy to
the abdomen, 42 Gy to the paraaortics and medial diaphragm surface, and 51 Gy to the
pelvis (40). Others have focused on hyperfractionated techniques, delivering 0.8 to 1 Gy
twice daily to 30 to 30.4 Gy (116).

741
Figure 25.8 Isodose distributions from an intensity-modulated whole abdominal radiotherapy (IM-WART)
plan with five gantry angles in a patient with locally advanced uterine cancer. Isodose levels in %: (A) sagittal
plane and (B) coronal plane. Also shown are isodose distributions from a conventional WART plan delivered
with opposed anterior–posterior:posterior–anterior (APPA) fields in the patient: (C) sagittal plane and (D)
coronal plane. From Hong L, Alektiar K, Chui C, et al. IMRT of large fields: whole-abdomen irradiation. Int J
Radiat Oncol Biol Phys. 2002;54:278–289.

Limited data are available evaluating IMRT in gynecologic cancer patients undergoing
WART. Investigators at Memorial Sloan Kettering Cancer Center compared IMRT using
5 equally spaced static fields and conventional large field APPA techniques in 10
endometrial cancer patients treated with WART (117). The target volume included a 1
cm rim of liver but completely excluded the bilateral kidneys, which were constrained to
receive a maximum dose of 18 Gy. IMRT planning was associated with significantly
better coverage of the peritoneal cavity and a 60% reduction in the volume of pelvic
bones (a surrogate for pelvic bone marrow) irradiated (Fig. 25.8). Others have reported
equally favorable early clinical results using volumetric arc IMRT techniques (118,119).

Stereotactic Body Radiotherapy


SBRT is a novel treatment approach used to deliver high, ablative doses of radiation in a
limited number of fractions (typically three to five) to extracranial targets. Popularity is
rapidly growing for this technique in the treatment of primary and metastatic tumors,
particularly in the liver, lung, and spine tumors (120). Initially delivered on
conventional linear accelerators, SBRT today is currently delivered using specialized
machines such as the Cyberknife (Accuray Inc., Sunnyvale, CA), Novalis (BrainLab AG,
Feldkirchen, Germany), and the Trilogy or TrueBeam (Varian Medical Systems, Palo
Alto, CA). Moreover, while originally developed using stereotactic localization methods,
most SBRT approaches today instead rely on image guidance, using either planar- or
volumetric-based imaging techniques (121).

742
Figure 25.9 Treatment plan of a gynecologic cancer patient with an isolated paraaortic recurrence treated with
stereotactic body radiation therapy (SBRT). The gross tumor volume (GTV) was defined as the visible tumor in
the paraaortic lymph node region on computed tomography (CT) (innermost red line). The radiation dose was
prescribed to the 81% isodose line of the maximum dose to cover the GTV + 2-mm margin (sky-blue line
indicated by the long arrow). The outermost line is the 30% isodose line (blue line indicated by the short arrow).
From Choi CW, Cho CK, Yoo SY, et al. Image-guided stereotactic body radiation therapy in patients with
isolated paraaortic lymph node metastases from uterine cervical and corpus cancer. Int J Radiat Oncol Biol Phys.
2009;74:147–153.

In recent years, several investigators have begun exploring the potential of SBRT in
gynecologic cancers. Choi et al. reported their experience using SBRT to treat recurrent
paraaortic lymph nodes with the Cyberknife system (121). A total of 30 patients were
treated with 33 to 45 Gy in three fractions, prescribed to the 73% to 87% isodose line.
Prior to treatment, fiducial markers were placed in adjacent vertebral pedicles and used
for online image guidance. In all patients, the GTV consisted of the involved lymph
node defined by either CT or PET/CT imaging and was expanded by 2 mm to generate
the PTV. Treatment was well tolerated with few acute and chronic sequelae. Local
control was excellent, particularly in small volume (≤17 cc) disease. A treatment plan
in a representative patient from this series is shown in Figure 25.9.
The use of SBRT as a possible alternative to brachytherapy was reported by Molla et
al. (122,123). In their studies, the CTV was defined as the vaginal vault,
uterus/parametria, residual or recurrent tumor and was expanded by 6 to 10 mm to
generate the PTV. Following external-beam RT, patients were immobilized and simulated
in the supine position with an endorectal probe in place to minimize internal organ
motion (which was also used during treatment). Using 5 to 15 static IMRT fields,
postoperative patients received 7 Gy × 2 while those with intact disease underwent 4
Gy × 5 using the Novalis System. At a median follow-up of 12.6 months, 15 of 16
patients remained locally controlled. Only one patient developed a late grade 3 or
higher toxicity.

743
Figure 25.10 Tandem and ovoid applicator used for high dose rate (HDR) brachytherapy in patients with intact
cervical cancer.

Brachytherapy

Intracavitary Brachytherapy
ICB in gynecologic cancer patients was initially performed by placing radioactive
sources directly within the vagina and/or uterus. However, by the 1960s, afterloading
techniques were introduced whereby an applicator was first positioned within the
patient while the sources were placed at a later time, typically after the patient had
been transferred to an isolated (and often shielded) hospital room. Using this approach,
radioactive sources were initially inserted manually but, more recently, remote-
afterloading techniques have been developed, significantly reducing the exposure of the
radiation oncologist and staff.
Various ICB applicators have been used in gynecologic cancer patients, depending on
the specific clinical scenario. In cervical cancer patients treated with an intact uterus,
the Fletcher–Suit–Delclos device based on the original Manchester system (124) is
typically used, consisting of a curved tandem inserted into the uterus and two
colpostats (ovoids) placed in the vaginal fornice. Various tandem lengths and colpostat
diameters are available; most colpostats used today include shielding along the medial
aspects of the anterior and posterior colpostat faces, reducing dose to the bladder and
rectum (Fig. 25.10). A popular variation of the traditional tandem and ovoid system
consists of a tandem and ring, a system particularly useful in patients with asymmetric
fornices. Another ICB applicator used in the treatment of cervical cancer is the
Henschke device (125). Interstitial applicators include the Vienna combined
intracavitary and interstitial devices (126), the Syed–Neblett template (127), and the
Martinez Universal Perineal Interstitial Template (MUPIT) (128).
While medically inoperable uterine cancer patients have historically been treated with
intrauterine Heyman–Simon capsules (129), newer applicators have been developed,
including the dual-tandem Rotte “Y” device (130). In patients treated postoperatively, a
variety of applicators can be placed within the vagina, typically either a vaginal
cylinder or colpostats. The MIRALVA vaginal applicator consists of two ovoid sources
and a central tandem (131). The Capri vaginal applicator is a multi-channel balloon
applicator that consists of a single central channel surrounded by two concentric arrays
of channels (132).
Gynecologic cancer patients undergoing ICB can be treated using either low dose rate

744
(LDR) or high dose rate (HDR) techniques. According to the ICRU Report 38, LDR is
defined as dose rates ranging from 0.4 to 2 Gy/h while HDR utilizes dose rates of >12
Gy/h, with modern HDR systems capable of delivering dose rates exceeding 400 Gy/h
(133). A variety of radioactive sources are used; however, the most popular are Cesium-
137 (137Cs) for LDR and high activity Iridium-192 (192Ir) for HDR. Unlike LDR, which
is delivered in the hospital over several days, HDR is performed in the outpatient setting
over several minutes obviating the need for anesthesia and prolonged bedrest, making it
an ideal approach in women with multiple medical comorbidities. Other advantages of
HDR include increased ability to optimize treatment plans, reduced radiation exposure
of personnel, and better stability of the applicator during treatment. Disadvantages
include increased number of treatment sessions and greater equipment cost. While some
have argued that LDR is radiobiologically superior to HDR in terms of normal tissue
effects, particularly in patients with an intact uterus (134), prospective randomized
trials have demonstrated that the two techniques are similar in terms of both tumor
control and toxicity (135,136). Some investigators favor the use of pulsed dose rate
(PDR) brachytherapy whereby intermittent “pulses” of radiation (10 to 30 minutes/h)
are delivered using a machine similar to an afterloading HDR system. Proponents argue
that PDR combines the logistic advantages of HDR with the potential radiobiological
advantages of LDR. However, outcome data remain limited (137,138). Others have
explored the use of HDR electronic brachytherapy in gynecologic cancer patients (139).
Various doses and prescription points have been used for HDR and LDR ICB. In
patients with intact cervical cancer, dose is typically prescribed to a reference point
known as Point A. In the original Manchester formulation (124), Point A was defined as
2 cm lateral to the center of the intrauterine canal and 2 cm superior to the mucosal
surface of the lateral fornix, presumably at the medial edge of the broad ligament where
the uterine artery crosses the ureter. In the early 1950s, however, the definition of Point
A was modified to be 2 cm superior to the external cervical os and 2 cm lateral to the
intrauterine canal. A second specified reference point in the Manchester system was
Point B (3 cm lateral to Point A) which was felt to represent the location of the
obturator lymph nodes, although CT-based studies reveal that this is rarely the case
(140). Currently, the American Brachytherapy Society (ABS) recommends using a
sidewall dose point rather than Point B and, in intact cervical cancer patients
undergoing HDR ICB, Point H is the recommended prescription dose point (Fig. 25.11)
(141). At selected centers, alternative prescription points are used including Point M
(135) and Point T (136). In postoperative cervical or uterine cancer patients or patients
with vaginal cancer, ICB is prescribed to either the vaginal surface or at 0.5 cm depth.
In uterine cancer patients treated with an intact uterus (either preoperatively or
definitively), ICB was traditionally prescribed in terms of milligram-hours, but more
recently most radiation oncologists prescribe to 2 cm from the midpoint of the
intrauterine sources (142).

745
Figure 25.11 Relevant geometry for intracavitary brachytherapy dosimetry for a tandem and ovoid insertion.
Finding Point H begins with drawing a line connecting the mid-dwell positions of the ovoids. From the
intersection of this line with tandem, move superiorly along the tandem 2 cm plus the radius of the ovoids, and
then 2 cm perpendicular to the tandem in the lateral direction. The figure also shows variations in the position
of the conventional Point A based on its evolving definition. Ao located Point A in the original Manchester
formulation. The positions of Af1 and Af2 follow the revised definition and Point M is based on the Madison
System. Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for
high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2009;48:201–211.

Additional points used in the planning of ICB of gynecologic cancer patients include
bladder and rectal reference points. The bladder point is defined on planar orthogonal
radiographs as the point on the surface of the Foley balloon (pulled snugly into the
bladder trigone) receiving the highest dose, although volumetric studies have
demonstrated that this point consistently fails to capture the true maximum bladder
dose (143). A rectal reference point is defined 0.5 cm posterior to the posterior vaginal
wall.
Intact cervical cancer patients undergoing LDR ICB are typically treated with two
separate insertions, although comparable tumor control and complication rates have
been reported with a single insertion, particularly in early-stage patients (144). The first
insertion should be performed as soon as pelvic geometry allows, typically during the
second to fourth weeks of pelvic RT; the second 1 to 2 weeks later. Care should be taken
to complete the entire course of treatment within 8 weeks, since more protracted
courses have been associated with poorer outcomes (145).
Intact cervical cancer patients undergoing HDR typically receive four to six
insertions. Given the increased number of fractions, HDR necessitates interdigitating
pelvic RT and the initial HDR insertions to ensure that treatment is completed within 8
weeks, with the first treatment delivered as soon as pelvic geometry allows. However, it
is not recommended that both ICB and external-beam RT or chemotherapy be delivered

746
on the same day. For postoperative cervical and uterine cancers, vaginal cancer and
medically inoperable uterine cancer, ICB is delivered with one to two LDR or three to
five HDR insertions.
Treatment planning for patients undergoing ICB has traditionally been based on 2D
radiographs. More recently, CT-based planning with computerized dosimetry has come
into wider use. In LDR patients, given the limited overall number of source activities
and positions, treatment planning is typically performed manually by varying the
various source activities and positions, focusing on the doses to Point A as well as
normal tissues. Many radiation oncologists typically start with a “standard” loading, for
example, 15–10–10 milligram radium equivalents (mg-Ra-eq) in the tandem and 10 to
15 mg-Ra-eq in both colpostats in a patient with intact cervical cancer. The goal is to
deliver a total Point A dose (including the pelvic RT) of approximately 80 to 85 Gy for
small tumors and 85 to 90 Gy for bulky tumors, while limiting the rectal and bladder
doses to <80% of the Point A dose. Different investigators recommend different
maximum acceptable rectal and bladder doses, typically <75 to 80 Gy for the bladder
and <70 to 75 Gy for the rectum. Dose rates of 40 to 60 cGy/h to Point A are used at
most centers. Care must be taken not only to optimize the doses and dose rates at the
various reference and normal tissue points, but also to review the isodose distributions
themselves in an effort to obtain a classic “pear shape.” Patients treated postoperatively
to the vaginal cuff are typically treated with surface dose rates of 80 to 100 cGy/h or
50 to 80 cGy/h to 0.5 cm. Dose distributions in these patients should conform to the
shape of the cylinder.
Given the increased number of potential dwell positions and times, HDR
brachytherapy optimization lends itself to more sophisticated optimization approaches.
In fact, several inverse planning approaches have been described in these patients
(141). The ABS has provided detailed guidelines on the optimization of HDR
brachytherapy treatments in patients with cervical cancer, using multiple optimization
points along the tandem and vaginal surface (141).
TABLE 25.1 American Brachytherapy Society Guidelines Definitive Radiation Therapy for
Cervical Cancer LDR Intracavitary Brachytherapy

A large variety of dose–fractionation schemes have been used for gynecologic cancer
patients undergoing LDR and HDR brachytherapy. The ABS has published guidelines for
LDR and HDR ICB for both cervical and uterine cancers (Tables 25.1 to 25.4)

747
(141,142,146). No guidelines are available for ICB dose–fractionation schemes for
vaginal cancer. Fortunately, a variety of LDR and HDR approaches have been published
using these techniques (56–59,147,148). The ABS has published guidelines for
interstitial brachytherapy for vaginal cancer and recurrent endometrial cancer, which
will be discussed in a later section (149,150).
TABLE 25.2 American Brachytherapy Society Guidelines Definitive Radiation Therapy for
Cervical Cancer HDR Intracavitary Brachytherapy

TABLE 25.3 American Brachytherapy Society Guidelines Postoperative Radiation Therapy for
Uterine Cancer HDR Intracavitary Brachytherapy

748
Considerable interest has recently focused on the use of volumetric image-based
treatment planning in intact cervical cancer patients. European investigators have
pioneered MRI-based approaches in these patients. T2-weighted MRI using a pelvic coil
provides excellent soft tissue resolution and differentiation between tumor and normal
tissues, allowing more accurate assessment of parametrial and uterine tumor extension
(151,152) and improved sparing of the bladder and rectum (153). Controversy exists,
however, whether MRI is needed at every insertion or whether CT imaging during
subsequent insertions is sufficient. Comparison studies have demonstrated that CT may
overestimate tumor width (154,155). However, if MRI with each implant is infeasible,
MRI may be used at the first insertion with CT-based planning at subsequent implants
for normal tissue delineation, relying on the initial MRI for tumor delineation, especially
in small tumors treated with ICB (155,156).
TABLE 25.4 American Brachytherapy Society Guidelines Radiation Therapy for Inoperable
Uterine Cancer HDR Intracavitary Brachytherapy

749
Both the Group Européen de Curiethérapie-European Society for Therapeutic
Radiology and Oncology (GEC-ESTRO) and North American IGRT Working Group have
published recommendations for MRI-guided brachytherapy in cervical cancer
(157,158). The nomenclature that has been adopted worldwide for treatment planning
in these patients is based on work primarily performed by GEC-ESTRO (Fig. 25.12).
GEC-ESTRO recommendations are to contour the GTV, high-risk CTV (HR-CTV),
intermediate-risk CTV, (IR-CTV), and normal tissues including the bladder, rectum,
sigmoid colon, and small bowel. The HR-CTV includes the entire cervix as well as any
macroscopic disease that persists in the parametria, uterus, rectum, bladder, or vagina
(but not to cross these anatomic boundaries without clear rationale). The prescription
goal is 80 to 95 Gy to the HR-CTV. The IR-CTV includes the HR-CTV, with the intent to
deliver 60 Gy to this volume. HR and IR-CTV contours in a representative cervical
cancer patient are shown in Figure 25.13.

750
Figure 25.12 Group Européen de Curiethérapie–European Society for Therapeutic Radiology and Oncology
(GEC-ESTRO) working group concepts and terms used for image-guided brachytherapy. Schematic diagram
with coronal (A, C) and transverse (B, D) sections of an optimized treatment plan for limited (A, B) and
advanced (C, D) disease with partial remission after external irradiation. GTV, gross tumor volume; HR CTV,
high-risk clinical target volume; IR CTV, intermediate-risk clinical target volume. From Haie-Meder C, Pötter
R, Van Limbergen E, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group
(1): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis
on MRI assessment of GTV and CTV. Radiother Oncol. 2005;74:235–245.

Recommendations for reporting and quality assurance in patients undergoing MRI-


guided brachytherapy include calculation and reporting of the minimum dose to 90%
and 100% of the contoured target volume (D90, D100). In addition, for evaluation
within a single treatment scheme, the volume encompassed by the 100% isodose line
(IDL) (V100) should also be determined. For the normal tissues, reporting of the ICRU
reference bladder and rectal points should continue for comparison with the dose–
volume (DVH) data. The minimum dose received by the maximally irradiated contiguous
0.1 cm3, 1 cm3, and 2 cm3 of the bladder, rectum, sigmoid and small bowel,
respectively, should also be calculated and reported. Dose should be expressed as
bioequivalent doses given at 2 Gy per fraction, using the linear quadratic model, to
standardize for different dose rates. Provisional dose–volume constraints for the normal
tissues are to maintain the bladder below 85 to 90 Gy and the rectum and sigmoid
below 75 Gy. There has been validation for the recommendation for rectum, but there is
a weaker basis for recommendations for bladder, sigmoid, and vagina (159,160).
Several promising outcome reports have been published in cervical cancer patients
undergoing MRI-guided HDR brachytherapy using the GEC-ESTRO guidelines
(160–164). In a series of the first 145 patients (predominantly stages IIB to IIIB) treated

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at the University of Vienna, the 3-year actuarial local control was 85%. Local control
was dependent on tumor size with best results (>90%) seen in 2 to 5 cm tumors.
However, evaluating the most recent locally advanced patients with tumors >5 cm, the
local control rate was 82%. Low rates of chronic treatment-related toxicities were also
seen.
MRI-guided brachytherapy in cervical cancer is the subject of the multi-national
observational EMBRACE study (165). The goal of the study is to introduce MRI-guided
brachytherapy to multiple centers in a prospective setting and correlate DVH
parameters for the tumor and normal tissues with clinical outcomes. The results of the
EMBRACE study will then be used to design the interventional trial EMBRACE II.

Figure 25.13 Target and organs at risk (OAR) delineation at the first magnetic resonance imaging (MRI)-
guided brachytherapy insertion. (A) Volume delineated on a coronal view, using clinical drawings at the time of
the first brachytherapy application. (B) Target and OAR delineation on the MRI according to the GEC
ESTRO guidelines, axial cut, and the corresponding sagittal level identification (dotted line). From Sturdza A,
Dimopoulos J, Potter R. MR-guided target delineation in a patient with locally advanced cervical cancer
undergoing brachytherapy (Case Study). In: Mundt AJ, Roeske JC, eds. Image-Guided Radiation Therapy: A
Clinical Perspective. Shelton, CT: People’s Medical Publishing House—USA; 2011:430–435.

Investigators at Washington University have conducted several studies on PET-guided


brachytherapy planning for cervical cancer, demonstrating the feasibility and
dosimetric advantages of this approach over conventional techniques (Fig. 25.14)
(166–168). The procedure involves scanning patients after both intravenous delivery of
18F-fluorodeoxyglucose (18F-FDG) and insertion of tubes containing 18F-FDG into the
tandem and colpostats. To date, no outcome data are available using this novel
approach.

Interstitial Brachytherapy

752
Interstitial brachytherapy involves implanting radioactive sources directly within the
target tissues. Unlike ICB, interstitial implants may be temporary whereby sources are
removed after the treatment, or permanent with limited half-life sources left in place. In
gynecologic cancer patients undergoing interstitial brachytherapy, the great majority
are treated with temporary implants. Similar to patients undergoing ICB, interstitial
brachytherapy was previously performed using “live” sources but is now performed
primarily using afterloading techniques. As noted in the ICB section above, afterloading
approaches significantly reduce the radiation exposure of the medical and ancillary
staff, particularly when performed using remote afterloading techniques.
While the great majority of gynecology patients undergoing brachytherapy receive
ICB (169), interstitial brachytherapy is recommended in women in whom ICB would
result in suboptimal dose distributions (141). Interstitial brachytherapy should also be
considered in patients with extensive parametrial involvement, bulky primary tumors,
narrow or distal vaginal involvement, post-hysterectomy central recurrence, or a history
of prior RT. Other indications are distal or extensive vaginal involvement (>0.5 cm
thickness) or persistent disease following external-beam RT and ICB. The ABS has
published guidelines describing potential candidates and proper techniques for
interstitial brachytherapy in various gynecologic malignancies including vaginal cancer,
vulvar cancer, and vaginal recurrence (149,150).

Figure 25.14 Positron-emission tomography (PET)-guided brachytherapy planning in a patient with cervical
cancer. From Malyapa RS, Mutic S, Low DA, et al. Physiologic FDG-PET three-dimensional brachytherapy
treatment planning for cervical cancer. Int J Radiat Oncol Biol Phys. 2002;54:1140–1146.

Multiple afterloading commercial applicators are currently available for interstitial


brachytherapy, the most popular of which are the Martinez Universal Perineal
Interstitial Template (MUPIT) and the Syed–Neblett template. The MUPIT consists of
two acrylic cylinders, an acrylic template with an array of equally spaced holes through
which hollow needles are inserted, and a cover plate (170). The Syed–Neblett template
is comprised of a vaginal cylinder, 2 lucite plates with 38 holes through which hollow
needles are introduced; 6 additional needles can be inserted into groves along the

753
vaginal cylinder (171). The Vienna ring applicator allows placement of interstitial
needles along with ICB brachytherapy (Fig. 25.15) (164).

Figure 25.15 The Vienna Ring applicator that allows placement of interstitial needs in patients with residual
parametrial involvement in conjunction with intracavitary brachytherapy. From Sturdza A, Dimopoulos J, Potter
R. MR-guided target delineation in a patient with locally advanced cervical cancer undergoing brachytherapy
(Case Study). In: Mundt AJ, Roeske JC, eds. Image-Guided Radiation Therapy: A Clinical Perspective. Shelton,
CT: People’s Medical Publishing House—USA; 2011:430–435.

Pre-planning using CT and/or MRI can be used in patients undergoing interstitial


brachytherapy to help determine source number and placement, particularly in patients
treated with LDR techniques which required ordering of radioactive seeds and/or wires.
However, at the time of implant with the patient under anesthesia, physical
examination should be performed to determine optimal applicator and needle
placement, based on the patient’s individual anatomy and tumor extent (Fig. 25.16)
(164,172). Care needs to be taken to avoid perforation of adjacent organs including the
small bowel, bladder, and rectum. Intraoperative digital transrectal palpation is
recommended not only to assess tumor extent but also to help avoid implanting needles
into the rectum. Today, interstitial implants are performed at many centers under image
and/or laparoscopic guidance (173,174). Investigators at the University of Vienna have
also reported on the use of intraoperative ultrasound guidance for transvaginal or
transperineal needle placement in advanced gynecologic malignancies (175). Care
should be taken to avoid excessive doses to the vaginal mucosa. If needles are inserted
along the periphery of the central cylinder of a Syed–Neblett template, vaginal dose can
be reduced with the placement of a sleeve over the cylinder (175).

754
Figure 25.16 Example customized implant plans for uterine cancer patients with (A) a vaginal vault recurrence
and (B) recurrence in the right lateral vaginal wall. Redrawn from Nag S, Yacoub S, Copeland LJ, et al.
Interstitial brachytherapy for salvage treatment of vaginal recurrences in previously unirradiated endometrial
cancer patients. Int J Radiat Oncol Biol Phys. 2002;54:1153–1539.

As with ICB, interstitial brachytherapy can be delivered using LDR, HDR, or PDR
techniques (see earlier section on ICB for a discussion of the advantages and
disadvantages of each approach). 192Ir is the most common isotope currently used, with
high activity sources used for HDR. Limited data are available using permanent 198Au
or 103Pd interstitial implants in gynecologic cancer patients (176,177).
Various doses and prescription points have been used for interstitial brachytherapy in
gynecologic cancer patients. The treatment volume is typically defined by the peripheral
needles with or without an additional 5-mm margin, with the dose prescribed to an IDL
encompassing this volume. Growing interest is focused on MRI-based treatment
planning using the GEC-ESTRO guidelines in patients undergoing interstitial
brachytherapy (178).
Computerized dosimetry is useful to ensure dose homogeneity throughout the
implant. Maximum doses to the adjacent normal tissues should be calculated and efforts
made to spare the surrounding bladder and rectum as much as possible. In a series of
locally advanced cervical cancer patients treated with interstitial brachytherapy,
Demanes et al. recommended bladder and rectal maximum doses <75% and <65% of
the prescribed dose, respectively (179). Nag et al. treated 13 locally recurrent uterine
cancer patients with salvage interstitial brachytherapy and optimized the treatment
plans to ensure maximum rectal and bladder doses of 60% and 100% of the prescribed
dose (146). Total rectal doses of >76 Gy were noted in one study to be highly
correlated with the development of severe gastrointestinal toxicity including

755
rectovaginal fistulae (180). The ABS recommends equivalent cumulative doses in 2-Gy
fractions (EQD2) of ≤70 to 75 Gy to 2 cm3 of the rectum and sigmoid colon and ≤90
Gy to 2 cm3 bladder for the entire course of therapy (149).
Given the invasive nature of interstitial brachytherapy, an effort is made to minimize
the number of implants performed. Most patients undergoing LDR interstitial
brachytherapy are treated with a single insertion, which requires several days of bedrest
in the hospital. Patients undergoing HDR interstitial brachytherapy undergo one to
three implants, often with multiple fractions delivered during each implant. If multiple
implants are performed in patients with intact cervical cancer, it is recommended to
initiate brachytherapy during external-beam RT to avoid unnecessary treatment
protractions (141). As with ICB, interstitial brachytherapy should not be performed on
the same day as either external-beam RT or chemotherapy.
The ABS published guidelines on appropriate dose–fractionation schedules to be used
for gynecologic cancer patients receiving HDR interstitial brachytherapy with
cumulative EQD2 doses ranging from 71.5 to 81.5 Gy delivered with a combinations of
EBRT and 3 to 10 HDR fractions (Table 21.5) (150). In a series of 69 locally
advanced/recurrent gynecologic cancer patients undergoing a single LDR interstitial
implant, Gupta et al. at William Beaumont Hospital prescribed median doses of 32 and
35 Gy in patients treated with and without external-beam RT, respectively (181). Five-
year actuarial local control rates were 54% and 44% in the entire group and the subset
of primary cervical cancer patients, respectively. Severe complications (grade 4) were
noted in 14% of patients. Demanes et al. at the California Endocurietherapy Cancer
Center (CET) presented the outcomes of 62 previously untreated locally advanced
cervical cancer patients undergoing HDR interstitial brachytherapy (six fractions of 5.5
to 6 Gy) combined with external-beam RT (179). Overall, the local control of the entire
group was 94%, with rates exceeding 90% even in stage IIB to IIIB patients. Severe
(grade 3 to 4) late sequelae were seen in 6.5% of patients.
TABLE 25.5 American Brachytherapy Society Guidelines Interstitial HDR Brachytherapy for
Gynecologic Cancer

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Other groups have published outcomes of patients treated with a variety of interstitial
dose–fractionation regimens, including in cervical (178,182,183), vaginal (183–187),
vulvar (183–189), and locally recurrent uterine cancers (172,190), using
predominantly HDR techniques. More limited data exist regarding PDR dose–
fractionation regimens for interstitial brachytherapy (191).

FUTURE DIRECTIONS
Radiotherapeutic approaches and treatment planning in gynecologic cancer patients are
rapidly evolving. Long-held techniques and concepts are rapidly giving way to ever
newer ones. One area of current intense research is the development of adaptive RT in
gynecologic patients. It is well known that in selected patients, particularly woman with
bulky cervical cancer, tumors rapidly regress throughout treatment and re-planning
may be beneficial (192). However, sophisticated high-speed techniques are needed
before adaptive RT can be introduced clinically (193,194). Novel image-guided
approaches are also currently being explored which may further enhance IMRT
treatment in these patients, including bone marrow–sparing techniques which reduce
dose to functionally active bone marrow sites (195). It is also possible in the future that
novel approaches including SBRT (120,195,196) and even proton therapy, (197) which
are both growing in popularity throughout the world, will be increasingly applied to
gynecologic cancer patients.

KEY POINTS
757
• Radiation is commonly used as definitive treatment in early-stage gynecologic cancer and in
conjunction with surgery and/or chemotherapy in women with locally advanced disease.
• Radiation therapy is recommended over surgery in early-stage cervical cancer patients as
lesion size and vaginal involvement increase. As tumor diameter exceeds 4 cm, there is
increased likelihood of tumor spread to surrounding organs and regional lymph nodes, which
would necessitate adjuvant RT following surgery.
• In patients with locally advanced (stages IIB to IVA) cervix cancer, radiation is combined
with concomitant chemotherapy: multiple prospective randomized trials have demonstrated a
survival advantage to the combined approach.
• Definitive RT in cervical cancer is administered with a combination of pelvic RT and
brachytherapy, except in earliest-stage patients for whom brachytherapy or surgery alone is
sufficient.
• The majority of patients with uterine cancer undergo upfront surgery, consisting of total
abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO), with RT
delivered postoperatively to selected patients based on pathologic features in the surgical
specimen: depth of invasion, tumor grade, and lymphovascular invasion, cervical involvement.
• Following publication of GOG 122, stages III to IV endometrial cancer is treated with
adjuvant chemotherapy. GOG 258 is currently randomizing locally advanced patients to
chemotherapy versus chemoradiotherapy. The results of this important trial will help define
the role of RT in these patients.
• Treatment of vulvar cancer consists of upfront surgery (radical vulvectomy or radical wide
local excision in selected patients with small, well-lateralized tumors) with RT delivered
adjuvantly in patients with high-risk features including LVI, tumor invasion >5 mm, surgical
margins <8 mm, grade 3 disease, and microscopic positive margins.
• In a patient with intact cervical cancer: The goal is to deliver a total Point A dose (including
the pelvic RT) of approximately 80 to 85 Gy for small tumors and 85 to 90 Gy for bulky
tumors, while limiting the rectal and bladder doses to <80% of the Point A dose.
• Both the Group Européen de Curiethérapie-European Society for Therapeutic Radiology
and Oncology (GEC-ESTRO) and North American IGRT Working Group have
published recommendations for MRI-guided brachytherapy in cervical cancer. MRI-guided
brachytherapy in cervical cancer is the subject of the multi-national observational
EMBRACE study. The goal of the study is to introduce MRI-guided brachytherapy to
multiple centers in a prospective setting and correlate DVH parameters for the tumor and
normal tissues with clinical outcomes. The results of the EMBRACE study will then be used
to design the interventional trial EMBRACE II.
• Interstitial brachytherapy should be considered in patients with extensive parametrial
involvement, bulky primary tumors, narrow or distal vaginal involvement, post-hysterectomy
central recurrence, or a history of prior RT.

QUESTIONS
1. What structures comprise the CTV for stage IIIA cervical cancer when using

758
definitive IMRT?
A. GTV, cervix, uterus, and parametria, including the ovaries
B. GTV, cervix, uterus, and parametria, excluding the ovaries
C. GTV, cervix, uterus, parametria excluding the ovaries and entire vagina
D. GTV, cervix, uterus, parametria including the ovaries and entire vagina
2. Which examination best delineates the high-risk CTV when performing image-
based contouring with IV contrast for cervical cancer brachytherapy?
A. CT scan before the implant only
B. CT scan before and at the time of the implant
C. MRI before the implant only
D. MRI before and at the time of the implant
3. What is considered to be a close surgical margin in fixed tissue for carcinoma of
the vulva?
A. 8 mm
B. 10 mm
C. 15 mm
D. 18 mm
4. When treating cervical cancer with EBRT and HDR brachytherapy, the EQD2 D2
cc for the bladder (the minimum dose in the MOST irradiated 2 cm3 normal
tissue volume) should not exceed:
A. 60 Gy
B. 70 Gy
C. 80 Gy
D. 90 Gy
5. What was the HDR brachytherapy boost regimen (following 45 Gy in 25
fractions of EBRT) used in RTOG 0921?
A. 6 Gy × 3 to the vaginal mucosa
B. 6 Gy × 2 to the vaginal mucosa
C. 7 × 3 to 0.5 cm depth
D. 5.5 × 4 to 0.5 cm depth

ANSWERS
1. D The CTV includes the entire GTV as determined by the intermediate/high
signal seen in T2-weighted MR images; the entire cervix if not included
within the GTV contour; the entire uterus; the entire parametrium
including ovaries. The entire mesorectum should be included if the
uterosacral ligament is involved; for the vagina: if there is minimal or no
vaginal extension of disease include the upper half, if there is upper
vaginal involvement include the upper two-thirds, and if there is extensive
vaginal involvement then include the entire vagina.
Reference: Lim K, Small W, Portelance L, et al. Consensus guidelines for
delineation of clinical target volume for intensity-modulated pelvic

759
radiotherapy for the definitive treatment of cervix cancer. Int J Radiat
Oncol Biol Phys. 2011;79(2):348–355.
2. D The advantage of MRI compared to CT with IV contrast is that MRI
allows for distinction between the corpus and the cervix.
CT with IV contrast can delineate the cervicouterine junction at the
intersection of the uterine vessels and the cervix which allows
demarcation of the upper border of the cervix. However, only MRI before
and at the time of brachytherapy can accurately delineate the superior
border of the HR-CTV for patients with tumor extending beyond the
cervix. If MRI is unavailable, the initial tumor extension into the corpus,
or the entire canal, must be contoured to ensure that the CTV covers the
entire extent of the areas at risk. Delineation of the HR-CTV and IR-CTV is
also best informed by gynecological examination with drawings at the
initial evaluation and at the time of brachytherapy.
Reference: Viswanathan AN, Dimopoulos J, Kirisits C, et al. Computed
tomography versus magnetic resonance imaging based contouring in
cervical cancer brachytherapy: results of a prospective trial and
preliminary guidelines for standardized contours. Int J Radiation Oncology
Biol Phys. 2007;68(2):491–498.
3. A Surgical margin is the most powerful predictor of local vulvar recurrence.
Combining factors in a stepwise logistical regression does not significantly
improve this predictive value. Accounting for specimen preparation and
fixation, a 1-cm tumor-free surgical margin on the vulva results in a high
rate of local control, whereas a margin less than 8 mm is associated with a
50% chance of recurrence.
These data come from a series of 135 patients with vulvar squamous
cell carcinoma treated at UCLA and City of Hope Medical Centers between
1957 and 1985. Sixty-two cases were stage I, 48 stage II, 18 stage III, and
7 stage IV. Twenty-one patients developed a local vulvar recurrence after
primary radical resection. Ninety-one patients had a surgical tumor-free
margin ≥8 mm on tissue section and none had a local vulvar recurrence.
Forty-four patients had a margin less than 8 mm; 21 had a local
recurrence and 23 did not (p ≤ 0.0001).
Reference: Heaps JM, Fu YS, Montz FJ, et al. Surgical-pathologic
variables predictive of local recurrence in squamous cell carcinoma of the
vulva. Gynecol Oncol. 1990;38(3):309.
4. D The EQD2 D2 cc of bladder is = 90 Gy.
Reference: Viswanathan, Beriwal S, De Los Santos JF, et al. American
Brachytherapy Society consensus guidelines for locally advanced
carcinoma of the cervix. Part II: High-dose-rate brachytherapy.
Brachytherapy. 2012;11(1):47–52.
5. A Choices C and D are both dose/fractionation schemes for HDR
intracavitary brachytherapy when used adjuvantly without EBRT.
Reference: RTOG 0921 Protocol.

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26A Cancer of the Genitourinary Tract:
Prostate Cancer

Jason Chan and Albert Chang

INTRODUCTION
Epidemiology
Prostate cancer is the most common solid malignancy in men in the United States with
233,000 new cases diagnosed and 29,480 dying of prostate cancer in 2014 (1). Since
PSA screening in the 1990s, prostate cancer mortality rates have dropped dramatically
(2). Because of earlier diagnosis from screening with the majority of cases being
localized, only one in seven men will die from their disease (3). Even so, prostate cancer
is a heterogeneous disease with a highly variable natural history. Advanced prostate
cancer is not only a serious threat to life expectancy but also to quality of life. It is
therefore paramount to discern the difference between aggressive and indolent disease
to personalize treatment for patients.

Clinical Anatomy

Anatomy
The prostate consists of four anatomic zones: peripheral, central, transitional, and the
anterior fibromuscular zone. The prostate gland lies posterior to the pubic symphysis,
anterior to the rectum, inferior to the bladder neck, and superior to the urogenital
diaphragm. A normal prostate gland is 20 to 30 cc and the peripheral zone represents
two-thirds of this volume. Prostate cancer is often multifocal with the majority of
tumors arising from the peripheral zone. The urethra penetrates the prostate as it
descends from the bladder neck to the urogenital diaphragm. Nerve and vessel bundles
course along the lateral surfaces of the prostate in the superior–inferior direction and
attach to the base at the superior pedicles, and to the apex at the inferior pedicles.

Local Growth Patterns


The prostatic capsule has an inner layer of smooth muscle and an outer layer of
connective tissue though the capsule is ill-defined at the apex. Tumor that extends
beyond the capsule of the prostate may involve the periprostatic fat, seminal vesicles,
bladder neck, and neurovascular bundles (superior and inferior pedicles). Tumor that
invades superiorly from the base of the prostate may cause bladder neck obstruction
and cause frequency, urgency, incomplete bladder emptying, and weak urinary stream.
Prostate cancer in the apex that extends to the membranous urethra may cause similar
obstructive urinary symptoms. Seminal vesicle invasion may manifest as
hematospermia. Extracapsular extension is most common posterolaterally where the
superior pedicles course along the prostate base, which may result in erectile
dysfunction. While some patients present with symptoms of bulky tumors, many
patients are diagnosed with prostate cancer without ever developing symptoms.

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Regional and Distant Metastasis
Prostate cancer metastasizes through the blood and lymphatic systems. The prostate
gland is predominantly drained by the obturator and internal iliac nodes (4). The
external iliac, presacral, and presciatic nodes are also involved with prostatic lymphatic
drainage. Distant metastasis most commonly results in osteoblastic bone lesions to the
axial skeleton.

Principles of Radiation Therapy in Prostate Cancer


Radiation therapy plays a critical role in the treatment of many of the clinical stages of
prostate cancer including (1) definitive treatment of localized disease, (2) adjuvant
treatment following radical prostatectomy (RP), (3) salvage therapy following disease
recurrence, and (4) palliation of locally advanced and metastatic disease.
Modern radiation therapy techniques for prostate cancer include external photon and
particle beam treatments, as well as low dose rate (LDR) and high dose rate (HDR)
brachytherapy radioisotope implantation. External radiation now routinely consists of
3-dimensional (3D) planning with CT and/or MRI, conformal treatment delivery with
inverse planning and IMRT, and image localization with various techniques utilizing
fiducial markers, ultrasound, and cone beam CT. These improved treatment techniques
have allowed for safe delivery of higher radiation doses, which correlate with improved
PSA control (5,6) and overall survival (7) with only modest changes in toxicity (8) and
patient-reported quality of life (9). Brachytherapy, either performed alone or in
combination with EBRT, is another method of delivering escalated doses of radiation
therapy to the prostate.
The prostate is a moving target and delivery of higher radiation doses not only
require smaller treatment margins but accurate target tracking. The unpredictable
position and motion of the prostate gland puts neighboring structures, most importantly
the rectum and bladder, at risk during radiation treatments. Inadequate target tracking
can also lead to underdosing of the tumor and inferior therapeutic outcomes and
increased toxicity (10). Therefore, target volume delineation, tumor localization, patient
immobilization and simulation, and treatment delivery must be carefully considered.

CLINICAL ASSESSMENT
Diagnosis
A nodule palpated on digital rectal examination (DRE) warrants further evaluation with
a transrectal ultrasound (TRUS)-guided biopsy to rule out cancer. With routine PSA
screening, it is often an elevated absolute PSA level or abnormal PSA kinetics that
prompts a biopsy as a palpable nodule is often not present at the time of diagnosis. An
extended sextant biopsy consisting of at least 12 biopsy cores is typically recommended
(11,12). A pathologist makes the definitive diagnosis and assigns a Gleason primary and
secondary grade to the biopsy specimen as an indication of tumor aggressiveness.
Unfortunately, TRUS-guided biopsies tend to underdiagnose and understage prostate
cancers. Roughly one-third of prostate cancers are not detected on first biopsy and
roughly half of detected cancers are less than the final Gleason scores assigned on
prostatectomy samples (13). Recent implementation of MRI-guided or MRI-ultrasound
fusion biopsies has been suggested to improve the staging accuracy of biopsies (14). The
extent of the primary tumor, PSA level, and Gleason grade are used to determine the
patient’s risk group, which guides decision-making regarding treatment.

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Risk Stratification
At least 130 different algorithms or nomograms have been developed to predict
clinically relevant outcomes for counseling patients on appropriate treatment strategies
(15). As previously mentioned, the clinical T stage, Gleason grade, and pretreatment
PSA level are the most important prognostic indicators that determine a patient’s risk
group. The NCCN stratification system groups patients into five risk categories (Table
26A.1): very low, low, intermediate, high, and very high (although most typically only
low, intermediate, and high risk groups have been used). Similarly, the AJCC prognostic
groups are based on T stage, Gleason score, and pretreatment PSA. However, broad
heterogeneity can exist within a particular risk group and newer classification systems
incorporating factors such as age and percentage of positive biopsies (16) and genetic
testing (17) are increasingly used to further risk stratify patients.
TABLE 26A.1 2010 American Joint Committee on Cancer (AJCC) Clinical Primary Tumor
(T) Staging for Prostate Cancer (7th Edition)

Staging

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The clinical T stage represents the size and extent of detectable tumor. DRE has
previously been the main tool in making this determination but with routine PSA
screening, prostate cancers are predominantly diagnosed at earlier stages and T1c
(nonpalpable disease) now represents the most common clinical stage. As such, many
imaging modalities are used as adjuncts to provide more accurate staging information.
The American Joint Commission on Cancer (AJCC) clinical staging system for primary
tumor (T staging) is shown in Table 26A.2 (18).

Ultrasound
TRUS most commonly identifies a tumor as a hypoechoic lesion in the peripheral zone
but is unreliable in evaluating the full extent of disease. The hypoechoic lesion has a
cancer detection sensitivity of 85.5% and specificity of 28.4%. Nearly one-third of
prostate cancers are not identifiable on TRUS (19). Its most important role is to provide
visual guidance for prostate biopsy.

CT
Similar to TRUS, pelvic CT does not provide adequate soft tissue contrast discrimination
and may only accurately predict local tumor extent up to 65% of the time (20).
Multiparametric MRI has improved accuracy for delineating the primary tumor. In one
study of low- to intermediate-risk patients undergoing prostatectomy, endorectal coil
MRI predicted local extraprostatic extension and seminal vesicle invasion with
sensitivity and specificity of 65% and 100%, respectively (12). Nevertheless, CT
remains valuable in determining lymph node involvement and bone metastases.
TABLE 26A.2 Prostate Cancer Recurrence Risk Group by NCCN Criteria (2015 Version)

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MRI
Multiparametric MR imaging with high-resolution T2-weighted imaging, diffusion
weighted imaging (DWI), and dynamic contrast enhanced MRI (DCE-MRI), and MR
spectroscopy (MRS) play an important role in the assessment of prostate cancer. High-
resolution T2-weighted imaging provides exquisite definition of the prostate zonal
anatomy. Endorectal coil MRI may have a role in predicting extracapsular extension or
seminal vesicle invasion for imaging at 1.5T, although 3T MRI scanners have superior

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signal-to-noise ratio (SNR) such that excellent image quality can be achieved even
without endorectal coils. DWI helps differentiate benign from malignant tissue by
inferring cellular density by measuring Brownian motion of interstitial water molecules.
DCE-MRI adds information about prostatic vascularization through a series of high
temporal resolution T1-weighted images following the administration of contrast.
Finally, proton MRS is another useful functional imaging technique to help localize
prostate cancer by detecting levels of choline and citrate, which accumulate in prostate
cancer and benign prostate tissues, respectively.

Bone Scan and PET


In patients with intermediate–high-risk disease, imaging evaluation is indicated to
identify and localize occult metastatic disease. Pelvic CT and MRI are recommended in
either of the following: (1) T3 or T4, (2) T1–T2, and nomogram indicated probability of
lymph node involvement greater than 10%. Similarly a bone scan would need to be
ordered only in select scenarios: T1 and PSA >20 ng/mL, T2 and PSA >10 ng/mL,
Gleason score ≥8, T3 or T4, or symptomatic disease. However, bone scans and pelvic
CT or MRI scans are limited in their sensitivity for detecting occult disease. Bone scans
have limited sensitivity for detecting osseous metastases and are not able to detect soft
tissue metastases. The sensitivity, specificity, PPV, and NPV of detecting metastatic
lymph node involvement by CT is 7%, 100%, 85%, and 100%, respectively (21). The
same limitations for detecting lymph node involvement in CT also hold for standard
pelvic MRI examinations. Newer imaging modalities including Sodium Fluoride, 11C-
and 18F-choline, 11C-acetate, and PSMA PET imaging hold promise for improving the
detection of occult metastases and are being studied in the clinic.

Gleason Grade
The Gleason system is based on the morphologic architecture of the prostate cancer and
is the most common method for histologic grading (22). The Gleason grade applies to
adenocarcinomas and squamous cell carcinomas but not to sarcomas or transitional cell
carcinomas of the prostate. The scale ranges from 1 (most differentiated) to 5 (least
differentiated). The Gleason score is the sum of the two most prevalent Gleason grades
observed within a tissue sample and ranges from 2 to 10 with 2 being the most indolent
and 10 being the most malignant. In contemporary clinical practice, GS is broken down
into three main partitions: well-differentiated (GS 2 to 6), moderately differentiated (GS
7), and poorly differentiated (GS 8 to 10). A GS of <6 is rarely encountered on needle
biopsy due to a prevailing change in Gleason grading by pathologists which has led to a
shift in GS over time with higher GSs being more prevalent in the PSA era even as other
clinical risk features have declined (23).

PSA
PSA screening should be discussed with men over the age of 40, whether PSA is right for
them based on health and family history risk factors. An elevated PSA may prompt a
biopsy. However, in addition to prostate cancer, elevated PSAs may result from recent
ejaculation, BPH, and prostatitis and may lead to false positive results. There are other
supplementary tests and considerations that can help decide if a biopsy is necessary
including free PSA levels, PSA velocity, PSA density, family history, and digital
examination results. A PSA above 10 ng/mL correlates with a 50% to 75% chance of
diagnosis. A moderately elevated PSA between 4 and 10 ng/mL correlates to only a 20%

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to 30% risk of prostate cancer and can be difficult to interpret especially if BPH is also
present. In this range, a PSA density (serum total PSA level divided by prostate volume)
greater than 0.15, a free PSA below 10% of total serum PSA level, and a PSA velocity
above 0.75 ng/mL/yr should further heighten suspicion for prostate cancer and prompt
TRUS-guided needle biopsies of the prostate to be performed by a urologist.
Prostate cancer antigen 3 (PCA3) is increasingly being utilized for screening in
addition to PSA testing. PCA3 is overexpressed in prostate cancer. PCA3 has a lower
sensitivity but higher specificity and a better positive and negative predictive value
when compared to PSA. PCA3 is measured in the urine after prostate massage with
DRE. PCA3 testing has been suggested to be clinically useful to predict the presence of
prostate cancer in patients with prior negative biopsies.

TREATMENT OPTIONS
Treatment Algorithms
Treatment recommendations are determined by the extent of disease: localized, lymph
node positive, and distantly metastatic. This section will focus on the treatment
paradigms for localized prostate cancer. The treatment scheme used at UCSF is shown
in Table 26A.3.

Watchful Waiting
Watchful waiting, or passive observation, is an appropriate strategy in asymptomatic
patients who do not to expect to derive a survival benefit from treatment either due to
advanced age or advanced co-morbid illness. This approach forgoes upfront treatment
with the expectation to deliver palliative therapy for symptomatic disease. Two
randomized trials have compared RP with watchful waiting. The Scandinavian Prostate
Cancer Group Study Number 4 (SPCG-4), a trial that predated routine PSA screening,
found a disease-specific and overall survival benefit for RP in patients younger than 65
years, but no survival benefit in patients 65 years or older (24). The US-based Prostate
Cancer Intervention Versus Observation Trial (PIVOT) found no overall survival benefit
for RP in low-risk patients, but a benefit was observed in patients with high-risk disease
(25). In some clinical contexts, monitoring should still include routine DRE and PSA as
changes in examination or PSA level may prompt patients to start therapy in
anticipation of new symptoms.
TABLE 26A.3 A Risk Stratification System for Clinically Localized Prostate Cancer with 3D
Conformal or Intensity Modulated External Beam Radiation Therapy Treatment Guidelines
Utilized at the University of California San Francisco

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Active Surveillance
In contrast to watchful waiting, active surveillance involves serial DRE, PSA, and
surveillance biopsies with the expectation to intervene with definitive treatment at the
time of disease progression. Active surveillance is an alternative to definitive treatment

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for low-risk disease. A prospective cohort from the University of Toronto is one of the
most mature and comprehensive data sets to date, which demonstrates the safety and
feasibility of active surveillance. In this series, patients were offered definitive
intervention with a PSA doubling time of <3 years, Gleason upgrade (to 4+3 or
greater), or unequivocal clinical progression. The 10-year estimate of prostate-cancer
specific death was 1.9% and the risk of death due to other causes in this cohort was 9.2
times greater (26). Comparison of active surveillance to RP and definitive radiation
therapy is the subject of the ongoing UK-based Prostate testing for cancer and
Treatment (ProtecT) (27).

Radical Prostatectomy
Approximately 40% to 50% of patients select to undergo an RP initially (28). RP
involves removal of the prostate, the surrounding capsule, seminal vesicles, and the
ampullae of the vas deferens. There are a variety of approaches to the procedure:
retropubic, perineal, and laparoscopic, which may be robot-assisted. The advent of the
nerve-sparing RP in the early 1980s, increasing chances for retaining sexual potency, as
well as more recent refinements in surgical techniques such as laparoscopic or robotic
RP, have ensured that RP remains a popular treatment option.
Prostatectomy results in a substantial risk of impotence, and at least some degree of
urinary incontinence is common (29,30). Nerve sparing techniques may decrease these
rates although most patients still report significant sexual dysfunction even following
nerve sparing RP (9,30,31). Laparoscopic prostatectomy techniques have decreased
acute surgical morbidity, with decreased blood loss, shorter hospital stays, and more
rapid postoperative recovery (32). More recently, there has been an increased use of
surgery for locally advanced disease, which may necessitate a higher rate of utilization
of adjuvant RT for residual disease, particularly among surgeons new to the technique
(33). In addition, patients with clinical evidence of extracapsular (T3) disease or high-
risk features such as high GS or PSA may be at increased risk of residual disease after
nerve-sparing surgery. Although there are currently no completed prospective,
randomized trials comparing RP to radiation therapy, it appears that cure rates are
similar.

External Beam Radiation Therapy


External beam radiation therapy (EBRT) is commonly utilized to treat men with
clinically localized or locally advanced prostate cancer. EBRT alone may be applied to
any clinical stage—T1 to T4—but is also often used with adjunctive antiandrogen
therapy for selected higher-risk patients. EBRT is also commonly utilized as either
adjuvant or salvage therapy in the postprostatectomy setting for patients with clinical
high-risk features or with a rising PSA following RP.
In the past, EBRT for prostate cancer consisted of a 4-field box or bilateral 120-degree
arcs that were delineated using bony landmarks or a single CT slice to include the
prostate, seminal vesicles, and pelvic lymph nodes. Using these nonconformal
techniques, prescription doses to the prostate were limited from 64 to 70 Gy due to
significant volumes of normal tissues that were also irradiated, in particular rectum and
small bowel. Conformal radiation therapy simulation, planning, and treatment became
increasingly available in the late 1980s, and one analysis estimated that a 10% increase
in minimum tumor dose could be achieved without increasing acute or chronic toxicity
(34). Intensity-modulated radiation therapy (IMRT) was introduced in the mid-1990s

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and is now routinely utilized in the treatment of prostate cancer. IMRT allows for the
safe delivery of dose-escalated radiation therapy over 74 Gy, which has shown to
improve biochemical free survival (7).

Androgen Deprivation Therapy


For high-risk prostate cancer patients, long-term ADT and RT is the standard-of-care.
The question of ADT added to RT was first evaluated in a series of randomized trials,
which revealed that for patients with locally advanced (T3–T4) or high-grade prostate
cancer (Gleason 8 to 10), the addition of ADT to conventional dose EBRT increased
biochemical control and decreased risks of metastasis, death from prostate cancer, and
all cause mortality (35–38). For patients with the highest risk disease, the use of 28 to
36 months of ADT along with conventional dose EBRT appears better than either EBRT
alone or EBRT delivered with shorter duration ADT (4 to 6 months) (37,38). For
example, on RTOG 9202 the addition of 24 months adjuvant ADT in addition to 4
months neoadjuvant ADT resulted in an absolute 16% increase in biochemical control at
10 years (p < 0.0001) along with improvements in local control (10% improvement, p
< 0.0001), metastasis (8% improvement, p < 0.0001), and disease-specific survival
(5% improvement, p = 0.004). Overall survival, however, was not increased for all
patients, but was significantly improved for those with Gleason 8 to 10 disease (32% vs.
45%, p = 0.006). EORTC 22961 also randomized patients with high-risk prostate
cancer to 6 months versus 3 years of ADT. Patients receiving 3 years of ADT had a
significant improvement in overall survival and prostate cancer specific survival (38).
More recently it was also demonstrated that for node-negative men with high-risk
prostate cancer the addition of conventional dose RT dramatically increased disease
outcome when combined with long-term ADT as compared to long-term ADT delivered
alone (39). There was an absolute risk reduction of 50% for biochemical failure at 10
years (75% vs. 26%, p < 0.0001) with the addition of RT. More importantly, the
cumulative incidence at 10 years for prostate cancer-specific mortality was 24% in the
ADT alone group and 12% in the ADT plus RT group (p < 0.0001), while the
cumulative incidence for overall mortality was 39% in the endocrine alone group and
30% in the endocrine plus RT group (p = 0.004).
For intermediate-risk prostate cancer, short-term ADT and RT is recommended. The
role of ADT in intermediate-risk disease has been addressed in two randomized trials
which would suggest a benefit to shorter course antiandrogen therapy (4 to 6 months)
when treated with a conventional dose RT of ≤70 Gy (44,45). The role for ADT in
patients treated with higher dose RT (particularly if intermediate risk) is an area of
active evaluation at this time and is the subject of RTOG 0815. Finally, there does not
appear to be meaningful benefit with the addition of short-term ADT in either cancer-
specific or overall survival in men with clinical low-risk disease by NCCN risk criteria
even when treated with RT dose <70 Gy (40).
In addition, there is emerging data on the benefit of ADT in the postoperative setting.
RTOG 9601 compared salvage radiation therapy (SRT) with SRT plus ADT with high
dose bicalutamide in post-RP patients and updated results were recently presented at
the American Society for Radiation Oncology (ASTRO)’s 57th annual meeting in San
Antonio. The study randomized post-RP patients with pT3N0 or pT2N0 with positive
margins who had developed elevated PSA from 0.2 to 4.0 ng/mL to RT + placebo (64.8
Gy in 36 fractions of 1.8 Gy) versus RT plus AAT (24 months of bicalutamide, 150 mg
daily). Actuarial overall survival at 10 years was 82% for RT plus AAT and 78% for RT
+ placebo and a hazard ratio of 0.75 with a two-sided p-value of 0.036.

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Brachytherapy
Interstitial brachytherapy is appropriate definitive treatment to the intact prostate for
low-risk patients and selected patients with intermediate-risk cancers. Brachytherapy as
monotherapy has several advantages over EBRT, including the convenience of
undergoing a 1-day outpatient procedure, rapid dose fall-off outside the prostate, and
less problems presented by organ motion in planning and treatment delivery. Prostate
brachytherapy is also commonly used in combination with EBRT to 45 to 50.4 Gy,
particularly for patients with adverse risk features. As risk of disease extending beyond
the prostate capsule increases, other modalities should be considered for definitive
treatment. LDR radioisotopic implants are performed using I-125, Pd-103, or more
recently Cs-131 seeds which are placed transperineally through a template. HDR
brachytherapy involve needle placement of catheters that are used for afterloading of
an Ir-192 source. Brachytherapy performs comparably to surgery or EBRT for low-risk
patients. There is also a mounting body of literature supporting the use of
brachytherapy for locally recurrent prostate cancer after prior definitive radiation
therapy. Early results of the ASCENDE-RT study showed that the 7-year biochemical
control estimate was 82% for men who received LDR boost compared to 39% for those
who received dose-escalated EBRT (p = 0.0022).
Since the incidence of urethral stricture can be high after transurethral prostatic
resection (TURP), implant is usually not recommended for stage T1a and T1b tumors.
Other relative contraindications to brachytherapy include large prostate size, a
prominent median lobe, or significant preexisting obstructive urinary symptoms, as
these may be associated with technical difficulty in performing an adequate implant or
increased risks of complications. Patients with locally extensive tumors—clinical stages
T3 and T4—are generally not suitable candidates for isotope therapy. Brachytherapy is
also starting to have a role in salvage treatment after localized recurrence for patients
treated with definitive RT although the results from this form of treatment at this time
are still limited (41–46).

Other Treatments
Cryotherapy and other local therapies lack long-term data comparing these treatments
to radiation or RP and are therefore not recommended as routine primary therapy for
localized prostate cancer. A Canadian randomized trial did compare short-term ADT
followed by either EBRT or cryotherapy in men with localized prostate cancer where
most (80%) had NCCN high-risk disease (47). Sexual dysfunction was significantly
higher in those treated with cryotherapy. There were no significant differences in
clinical outcome between the two treatment arms although a number of treatment
features were suboptimal for the RT group including low RT dose (most 70 Gy or less),
no pelvic RT, and only a short course of ADT. Each of these has been demonstrated
alone to increase the rate of biochemical control for men treated with EBRT for prostate
cancer. Furthermore, early repeat cryotherapy was not considered a treatment failure,
and a modest number of patients were retreated after biopsy-proven residual disease in
the cryotherapy arm. Cryotherapy may be an option for patients with biopsy-proven
recurrence after previous RT.

TREATMENT PLANNING FOR DEFINITIVE EBRT


Target Volume Definition

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Prostate
The International Commission on Radiation Units and Measurements (ICRU) has
defined volumes for treatment planning that take into account the extent of the known
gross tumor, the areas of likely microscopic extension, and daily variations in patient
setup and tumor position. Definitions of GTV, CTV, and PTV are shown in Table 26A.4.
The prostate is most commonly identified on a treatment planning CT. The use of MRI is
increasingly utilized to aid in delineation of the prostate gland especially at the apical
region (48). In addition, the penile bulb is well delineated on MRI. The GTV and CTV is
the extent of gross tumor identified on DRE and imaging. Additional margin is added to
the CTV to account for variation in daily treatment setup and organ motion to define
the PTV.
TABLE 26A.4 International Commission on Radiation Units and Measurements Designated
Tumor Volumes and Definitions

The amount of margin added to the CTV to define the PTV has been the subject of
extensive study and discussion. While it is important to make margins generous enough
to consistently encompass gross and microscopic tumor by the prescribed dose, there is
also a compelling reason to keep the margins as small as possible near organs of limited
tolerance, such as the rectum posteriorly, the bladder superiorly, and (possibly) the
penile bulb inferiorly. In general, 0.5 to 1 cm is added around the prostate (and seminal
vesicles) to ensure coverage of extracapsular microscopic tumor extension and to
account for setup variability and organ motion. As an example, treatment guidelines
from RTOG 0924 suggest that the PTV be defined as the CTV plus a 0.5 to 1.0 cm
margin depending on institutional policy. These volumes are then used for treatment
planning using either 3D-CRT or IMRT techniques.
A CT simulation is obtained while the patient is supine with a comfortably full
bladder and an empty rectum. The prostate should be contoured between the
genitourinary diaphragm to the bladder neck without the surrounding pelvic muscles.
Gold seed fiducials or Calypso beacon transponders are often utilized to improve the
accuracy of daily patient setup. At UCSF, three gold markers are placed into the
prostate transrectally, typically with one in the apex and two on both sides of the base.
Daily prostate position can then be confirmed and positional adjustments made based
on 2-dimensional (2D) alignments between digitally reconstructed radiographs (DRRs)
with EPID or 3D alignments between CT and MV CBCT.
Rigid immobilization devices such as the Alpha Cradle or thermoplastic body casts
may increase setup accuracy. Rosenthal et al. (49) found that with immobilization only
1 of 10 patients had >0.5 cm variation in patient positioning for treatment, whereas 8

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of 12 patients had more variation than this without immobilization. Improved
positioning accuracy with rigid immobilization has been demonstrated in prospective
randomized comparisons as well (50,51). Intrarectal balloons may be expanded within
the rectum to stabilize the prostate position, reducing the concerns over inter- and intra-
fraction organ motion (52) (Fig. 26A.1). However, use of these devices may be
inconvenient for daily treatment and somewhat uncomfortable for the patient.

FIGURE 26A.1 An intrarectal balloon device (top panel) can be used for stabilization of prostate position
during external beam radiation therapy (bottom panel). Courtesy Dr. Mark Ritter.

Daily imaging for prostate localization including daily CT (53), ultrasound (54),
radiographic imaging of implanted radiopaque fiducial markers (55,56), or
electromagnetic transponders (57,58) are also utilized (Fig. 26A.2). Adjustments can
then be made on a daily basis, ensuring accurate localization and targeting of the PTV
at the start of treatment. These techniques fall under the category of a collection of
adaptive RT practices termed IGRT (59).
Prostate movement and the margin necessary to compensate for it have been studied
in detail. Ten Haken et al. (60) reported maximal superior, inferior, anterior, and
posterior prostate movement of 1, 1.25, 2, and 0.75 cm, respectively. The overall
average movement was 0.5 cm, most often in the anterior and superior direction, while
the average left-to-right movement was <0.05 cm. Nevertheless, residual errors in
prostate position of over 7 mm after pretreatment localization and adjustment of
prostate position clearly demonstrate the influence of intratreatment movement. In a
limited trial using fluoroscopy, Dawson et al. (61) demonstrated breathing-related

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movement of the prostate, the magnitude of which increased with the amplitude of the
breathing cycle (deep breathing vs. shallow), which even varied in the same patients
based upon prone or supine positioning with greater movement in those evaluated
prone. Just as observed by others, the magnitude of movement was greatest in the
anterior–posterior and cranial–caudal directions while minimal lateral movement was
seen (62,63) using non-IGRT techniques.

FIGURE 26A.2 Gold fiducial marker seeds (A), can be implanted into the prostate. The position of the
implanted markers, shown in a digitally reconstructed radiograph (DRR) (B), can be used for daily localization
of the prostate, shown with the proper alignment of a daily portal image (C).

Seminal Vesicles
While the prostate gland is always in the CTV, a decision must be made as to whether
the seminal vesicles and pelvic lymph nodes are included. The seminal vesicles are
superior and posterior to the prostate gland, attaching at the base. The clinical risk
factors of stage, GS, and PSA can be related to risk of seminal vesicle involvement,
similar to lymph node risk (64). Ninety percent of seminal vesicle involvement is limited
to the proximal 2 cm and therefore some argue that only the proximal portion of the
seminal vesicles adjacent to the prostate needs to be included in the target volume (65).
Seminal vesicle involvement is associated with a relatively high risk of lymph node
disease and a worse clinical outcome (66). Some advocate for the CTV to include the
base of the seminal vesicles if the risk of seminal vesicle is less than 15% and for the
CTV to include the entire seminal vesicles if risk of SV involvement is above 15%. To
date no study documents improved local control or survival if seminal vesicles are
electively irradiated for the risk of clinically undetected microscopic disease; however,
intuitively it seems important to include these structures in higher-risk patients, so that
likely potential sites of local disease in its entirety is treated. Including the seminal
vesicles, lymph nodes, or both within the target volumes increases the field size and
may likewise increase the acute side effects and long-term complications (67). The
ongoing RTOG 0924 clinical trial, which randomizes patients with unfavorable
intermediate or favorable high-risk disease to high dose radiotherapy with or without
whole pelvic radiation, requires the entire seminal vesicles to be treated at least to 45
Gy in both arms and for the proximal 1.0 cm of the seminal vesicle tissue to be included
in the boost target volumes.

Lymph Nodes
The benefit of pelvic lymph node irradiation has been a controversial topic over many
years (68). Lymph node irradiation is not standard for low- or intermediate-risk prostate
cancer and is controversial for high-risk disease. Whole pelvis radiotherapy is generally

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recommended for T4 tumors, lymph node involvement, and seminal vesicle invasion.
RTOG 9413 suggested that patients with a risk of lymph node involvement of at least
15% may benefit from pelvic lymph node irradiation. Patients were randomized to
whole pelvic radiation versus prostate-only radiation, as well as to short-term
neoadjuvant and concurrent ADT versus adjuvant ADT starting at the completion of RT.
No statistically significant differences were found in progression-free or overall survival
between the two study questions that patients were randomized to: neoadjuvant ADT
versus adjuvant ADT and pelvic RT compared with prostate only RT. Nevertheless, a
trend toward improved progression-free survival was found in favor of the pelvic and
neoadjuvant ADT arm compared with the other three arms. In addition, when the size
of the pelvic field was separately evaluated, it appeared that there was a direct benefit
when using a whole pelvic field as compared to a mini-pelvic field or prostate-only
treatment with 7-year progression-free survival of 40%, 35%, and 27%, respectively (p
= 0.02) (80). The benefit of whole pelvic irradiation is the subject of RTOG 0924,
which randomizes patients with unfavorable intermediate-risk disease and favorable
high-risk disease to ADT with prostate-only irradiation or ADT with whole pelvis
irradiation.
Current imaging technology, including CT, MRI, and lymphangiograms, has limited
accuracy for detecting pelvic lymph node metastasis. Therefore, until improved methods
for detecting pelvic lymph node metastases are developed, clinicians will be limited to
using risk factor assessment and clinical judgment in deciding whether pelvic lymph
nodes should be encompassed in the target volumes.
Accurate targeting is critically important if 3D conformal or IMRT-based treatment
techniques are utilized to treat the pelvic lymph nodes, yet there is significant
heterogeneity in how pelvic lymph nodes are contoured even amongst experienced
genitourinary radiation oncologists (69). A consensus definition was established to make
pelvic nodal volumes more uniform (70). Based upon this consensus, the pelvic lymph
node volumes to be irradiated include: distal common iliac, presacral lymph nodes (S1–
S3), external iliac lymph nodes, internal iliac lymph nodes, and obturator lymph nodes.
Lymph node CTVs include the vessels (artery and vein) and a 7-mm radial margin
without extending into bowel, bladder, bone, and muscle. Volumes begin at the L5/S1
interspace and end at the superior aspect of the pubic bone (70). The treatment of
presacral lymphatics is somewhat controversial as these nodes are infrequently
problematic clinically and are rarely an isolated site of recurrence if left untreated, and
are not included in the standard pelvic lymph node dissection. Their inclusion in the
radiation field necessitates that the posterior margin be expanded significantly,
encompassing additional rectum and large bowel, and unless using 3D conformal or
IMRT techniques may result in increased irradiation of the rectum with increased risk of
acute and long-term side effects. The role of RT in patients with known pelvic lymph
node positive disease is less clear. However, as both RTOG 8531 and the EORTC studies
of high-risk prostate cancer allowed positive pelvic lymph nodes at diagnosis, treatment
of patients with positive lymph nodes with both irradiation and ADT is a reasonable
course of action.

Field Setup

Localization, Immobilization, and Simulation


Day-to-day setup variations can result in significant treatment errors (71). Volumetric
planning with CT simulation is recommended and thin axial slices of 3 mm or finer is
preferred. There are many options for image guidance, including CBCT, ultrasound

788
localization system, or implanted fiducials. Selection of image guidance methods
depends on patient factors and institutional experience. For instance, hip prosthesis
may limit CBCT due to artifact.
A comfortably full bladder and empty rectum minimizes dose to critical structures.
Patients lie supine, with arms folded on the chest. They are immobilized with a body
mold, such as a vacuum-lock bag or Alpha Cradle. Intrarectal balloons may be expanded
within the rectum to stabilize the prostate position, reducing the concerns over inter-
and intrafraction organ motion (52) (Fig. 26A.1).

FIGURE 26A.3 A “dumbbell”-shaped clinical target volume (CTV) is outlined to encompass the “prostate bed”
between the bladder and rectum to facilitate treatment planning in the adjuvant or salvage situation after radical
prostatectomy. Surgical clips are visible and also aid in defining the CTV.

Instead of focusing on immobilization, many centers use daily imaging for prostate
localization (Fig. 26A.2). Adjustments can then be made on a daily basis, ensuring
adequate localization and targeting of the PTV at the start of treatment.
Simulation involves a CT scan from the mid-abdomen to mid-femur. Contrast agents,
such as IV contrast, a retrograde urethrogram, and oral contrast are optional. MRI
fusion with T2-weighted scans also can be done to provide better soft tissue resolution
of the apex, EPE, SVI, and penile bulb. Target volumes and OARs can then be defined
(Fig. 26A.3).

Treatment Technique
In the past, a four-field technique was generally used to treat pelvic lymph nodes (Fig.
26A.4): anterior, posterior, right, and left lateral portals. Blocks can be drawn manually
on simulation films or BEV DRRs from CT planning software. Construction of these
blocked fields can be facilitated by reviewing the pelvic CT scan and entering lymph
node volumes that track along the course of the iliac vasculature (Fig. 26A.4).
Depending on the external contour, which can be done manually or automatically by CT
scan, small angle wedges on the lateral fields may help to produce a more symmetrical
dose distribution.

789
IMRT is currently the most common method of treatment planning for prostate
cancer. The prostate, seminal vesicles, pelvic lymph nodes, and OAR must all be defined
for appropriate treatment planning and optimization. Examples of recommended OAR
tolerances are provided (Table 26A.5) (70).

FIGURE 26A.4 Three axial treatment planning computed tomography (CT) images are shown at the levels of
the seminal vesicles (A), mid-prostate (B), and lower-prostate (C). The outlined clinical target volume (CTV)
encompassing the seminal vesicles and the prostate is shown along with the planning target volume (PTV)
expansion around the CTV. The normal bladder and rectum are also contoured.

For CT-based planning, CT images are entered into a treatment planning software
package. The lymph node regions, prostate, and seminal vesicles are outlined by the
physician, and can be expanded by adding appropriate margins to establish the CTVs
and PTVs. As noted previously, margins may vary between institutions and individual
physicians and by the use of IGRT. Normal structures are also outlined including
bladder, rectum, penile bulb, femoral heads, loops of small bowel, or any other
structures to which the physician may wish to limit dose. Treatment planning software
packages allow manipulation of virtual 3D reconstructions of these volumes, providing
a variety of views for the planner, including “beam’s eye view” (BEV) perspectives.
These features are designed to allow the user to manipulate beam orientation (gantry,
table, and collimator angles) and shaping (blocking or multileaf collimation) to
encompass targets and avoid normal structures.
For forward-planned 3D conformal treatment planning, high-energy beams from 6 to
18 MV are routinely used for pelvic lymph node and prostate irradiation. The software
allows rapid calculation of the dose that can be displayed on the overlying images in the
form of isodose lines or surfaces (Fig. 26A.5). Additional tools including dose–volume
histograms (DVHs) help the clinician to compare treatment plans to determine the
optimal plan for coverage of target volumes and avoidance of normal tissue structures

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(Fig. 26A.6).
TABLE 26A.5 Dose Volume Histogram Constraints for Organs at Risk (87)

Forward planned 3D CRT beam arrangements for prostate cancer treatment may
include the standard axial anterior, posterior, and lateral beams common to 2D prostate
plans, but can also easily make use of oblique and nonaxial beam angles. Rotation of the
collimator is commonly used to place the orientation of the multileaf collimator
appropriately so as to maximize normal tissue blocking and target coverage. Segmental
fields, physical wedges, and dynamic wedge techniques can be used to improve target
coverage and dose homogeneity. In addition to the classic four-field box technique, 3D
CRT beam configurations include a six-field conformal technique (72) as well as a four-
field variation using lateral and anterior obliques that eliminate the posterior-oblique
beams. Marsh et al. (73) have found that the four-field technique, using laterals and
anterior–inferior obliques, often improves the rectal DVH compared with axial plans
(Fig. 26A.7). This technique requires supine patient positioning to achieve table
clearance for the anterior–inferior beams.

791
FIGURE 26A.5 Digitally reconstructed radiograph (DRR) images are shown demonstrating typical anterior (A)
and lateral (B) treatment fields encompassing the prostate, seminal vesicles, and regional pelvic nodes.

FIGURE 26A.6 Axial (A), reconstructed sagittal (B), and coronal (C) computed tomography (CT) images are
shown with contoured normal tissue structures (bladder and rectum) and target volumes (prostate and seminal
vesicles). Isodose lines conforming to the planning target volume (PTV) are overlaid, depicting the dose
distribution of a three-dimensional (3D) conformal radiation treatment plan.

792
FIGURE 26A.7 A typical dose–volume histogram (DVH) plot is shown for bladder, rectum, and planning
target volume (PTV) from a three-dimensional (3D) conformal radiation treatment plan.

The application of IMRT technology to prostate cancer EBRT planning has enabled
further improvements in normal tissue DVHs, mainly due to the ability of this
technology to achieve convex dose distributions, reducing rectal dose (Fig. 26A.8). The
clinical significance of this advance toward reducing rectal toxicity remains
undetermined although some groups have suggested that with the combination of IGRT
and IMRT high-dose EBRT can be delivered without increases in toxicity as compared to
that observed in historical control groups treated to lower doses with less sophisticated
techniques (8). For instance, Zelefsky et al. noted an actuarial rate of grade 2 or greater
rectal toxicity at 10 years of 13% in patients using 3D CRT and 5% using IMRT (p <
0.0001) (116). Of note, IMRT patients received higher doses of RT than 3D conformal
patients, but IGRT was also used with much greater frequency in the IMRT group. The
inverse planning process starts with the contouring of target and normal tissue volumes
on an axial CT image set—just as for 3D CRT planning. However, instead of inputting a
candidate beam arrangement into the planning software and calculating a dose
distribution for that plan, the IMRT software package uses an optimization algorithm to
find a beam “solution” that maximizes a set of “cost functions.” Typically, the process
begins with a certain number of axial beam angles for the algorithm to utilize. Each
beam is subdivided into square “beamlets” that represent the incremental movement of
multileaf collimator leafs across the field in 1 cm or less increments. The algorithm
“modulates” the fluence through each of these beamlets in an iterative process,
evaluating and comparing each candidate plan to identify a better one. Each plan is
evaluated for dose coverage of target volumes, as well as dose avoidance for normal
tissue structures. Target coverage and normal tissue structure sparing is prioritized
based on clinical judgment, and a cost for achieving or failing to achieve each objective
is assigned. The algorithm will iterate until it identifies a plan that best achieves the
stated objectives. Once the optimization algorithm produces a plan, a formal dose
calculation is performed, and a quality assurance procedure is followed to ensure that
the delivered dose will be within a desired level of accuracy. For the prostate, where the
target shape and volume are relatively consistent from patient to patient, a template
can be established to make the treatment planning process more efficient. Examples of
typical dose constraints for rectum, bladder, femoral heads, and both large and small
bowel are given in Table 26A.5. The sparing of the penile bulb is controversial as

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different authors have come to differing conclusions about the utility of sparing the
penile bulb in preserving sexual function (74). However, it is clear that if a penile bulb
dose constraint is observed that it should not be at the cost of decreasing dose to the
PTV. An example of an IMRT plan as well as DVHs for both an IMRT plan and a 3D-CRT
plan are given in Figure 26A.9.

FIGURE 26A.8 An axial computed tomography (CT) image with isodose lines is shown from a three-
dimensional (3D) conformal radiation treatment plan utilizing a four-field technique with lateral and anterior
inferior oblique beams.

In the past, the sharp dose gradients that can be created using highly conformal
techniques such as IMRT created a concern for missing the target due to inter- and
intrafraction setup uncertainty and organ motion. However, careful delineation of
treatment volumes, patient setup and immobilization, and implementation of IGRT will
ensure the accuracy of treatment delivery to minimize marginal misses due to setup
error or changes in prostate position.

794
FIGURE 26A.9 An axial computed tomography image is shown from a seven-field intensity modulated
radiation therapy (IMRT) plan (A). The dose distribution is demonstrated using a dose “color-wash” and
depicts the concave dose distribution achieved for the rectum. This results in the improved normal tissue dose
volume histogram (DVH) for the IMRT plan (B) as compared with a four-field, three-dimensional (3D)
conformal treatment plan DVH for the same patient (C).

Treatment planning software packages allow manipulation of virtual 3D


reconstructions of these volumes, allowing a variety of views for the planner, including
BEV perspectives. These features are designed to allow the user to manipulate beam
orientation (gantry, table, and collimator angles) and shaping (blocking or multileaf
collimation) to encompass targets and avoid normal structures. High-energy beams from
6 MV to 18 MV are routinely used for pelvic lymph node and prostate irradiation. The
software allows rapid calculation of the dose that can be displayed on the overlying
images in the form of isodose lines or surfaces (Fig. 26A.5). Additional tools including
DVHs helps the clinician to compare treatment plans to determine the optimal plan for

795
coverage of target volumes and avoidance of normal tissue structures (Fig. 26A.6).
Once the process of defining the patient positioning and localization have been
determined, the process of treatment planning can commence. Most centers currently
use inverse-planned IMRT. If the decision is made to treat the pelvic nodes, the classical
superior bony landmarks in the AP view include the bottom of the L5 vertebral body to
encompass the common, internal, and external iliac nodes, midway through the
sacroiliac joints to encompass the distal common, internal, and external iliac lymph
nodes, or the bottom of the sacroiliac joints to encompass the internal and external iliac
lymph nodes. The inferior margin is often set 1 cm below the ischial tuberosities
inferiorly, and 1.5 to 2 cm to either side of the lateral bony pelvis laterally. In the
lateral projection the anterior border is placed at the most anterior point of the pubis
symphysis. The posterior border generally falls along the posterior ischium, although
the field is usually shaped to bisect the rectum when filled with 20 to 30 mL barium GI
contrast, administered via rectal tube. Retrograde urethrography may be performed
using a small-gauge catheter to administer 5 to 10 mL of 30% Hypaque into the urethra
with immediate penile clamping. The narrow point, or beak, in the contrast column
denotes the level where the urethra passes through the urogenital diaphragm (75,76).
The most inferior aspect of the prostate gland is typically located 1 cm above the
urethral apex, and the inferior field margin is placed 1 cm below the apex or beak,
allowing a 2-cm inferior margin on the prostate.
In most practices, CT planning has now largely supplanted the setting of fields using
2D fluoroscopic techniques. CT images facilitate the identification and localization of
both target and normal tissue structures (70). Lymph node regions follow the path of
the common iliac artery and its bifurcation into the internal and external iliac arteries,
and can usually be easily traced even without intravenous contrast administration.
Compared with the estimated general localization provided by bony landmarks in 2D
planning, the size, shape, and location of the prostate and particularly the seminal
vesicles can be visualized and defined more precisely with CT planning. The seminal
vesicles drape around the rectum in some patients, and standard blocking in 2D fields
set using rectal contrast may not provide adequate coverage of these structures.
Identification of the prostate apex on axial CT is sometime difficult and may be
facilitated with MRI or with sagittal and coronal reconstruction of CT data sets (77).
Normal tissue structures including the rectum, bladder, loops of small bowel, penile
bulb, and even important anatomic anomalies such as pelvic or horseshoe kidneys can
be readily identified and localized with CT planning.
Fluoroscopic or CT simulation for treatment planning may be performed with the
patient either supine or prone, with or without customized immobilization as discussed
above. External marks are placed on the patient or immobilization device, often chosen
to designate a preliminary isocenter position. These locations may be delineated with
radiopaque markers taped to the patient in the x, y, and z axes that can be referenced to
the image set, facilitating the transposition of the isocenter from the treatment plan to
the patient at the time of treatment. For CT-based planning, CT images are obtained at
1- to 5-mm intervals through the levels to be encompassed within the treatment fields.
Target and normal structures can then be defined and expanded to create the relevant
PTVs on axial CT images within specialized treatment planning software (Fig. 26A.3).
The issues regarding immobilization technique, patient positioning, and image
guidance were discussed above. Common choices for immobilization include the Alpha
Cradle, thermoplastic cast material similar to Aquaplast, and “vacuum lock” molds. The
CT scan must be done with the patient in the planned treatment position in the
immobilization device, with attention toward patient comfort and maximization of daily

796
reproducibility. Alternatively, for ease of position adjustment, some practitioners utilize
supine position without an immobilization device if daily prostate localization
techniques are employed (see above). An advantage of the prone position is to shift the
seminal vesicles forward, away from the rectum, potentially improving rectal sparing
(78). On the other hand, prone positioning may be associated with more internal organ
motion, including respiratory motion particularly in men with any degree of obesity
(61). Roach et al. (34) advocated nonuniform expansions around the prostate because
of the variation in prostate movement depending on direction, the status of rectum and
bladder filling, as well as radiation tolerance of these two structures. The
recommendations included anterior and inferior margins of 2 cm, lateral and superior
margins of 1.5 cm, a posterior margin of 0.5 to 0.75 cm, and that CT planning be
performed with the rectum empty and the bladder full. If bladder fullness is
inconsistent from treatment to treatment, superior and inferior margins are more
generous and accommodating, and this also helps to keep small bowel out of the field. If
the rectum is empty when fields are planned, a rectum that is fuller during treatment
only pushes the prostate further into the field, and 2-cm anterior margins should still
provide adequate coverage of the CTV. However, with the use of image-guided therapy
smaller margins may be appropriate (6).
TABLE 26A.6 Long-Term Follow-up of the MD Anderson Dose Escalation Trial:
Biochemical Freedom from Recurrence (Phoenix Definition) at 8 Years (121)

Dose Fractionation
Prophylactic dose to the pelvic LN is 1.8 Gy/fx to 45 Gy. At UCSF, involved LN is
typically treated to 54 to 60 Gy, with consideration of normal organ dose tolerance.
Comedown boosts cover the prostate to at least 74 Gy. Dose escalation has shown to
significantly improve biochemical cure rates (Table 26A.6). The rationale for IMRT
versus 3D-CRT is to allow for smaller CTV–PTV margins as well as creating step
gradients between the PTV and adjacent structures, namely the bladder and rectum.
This is the motivation behind all forms of IMRT, such as step and shoot, sliding window,
helical fan beam, and volumetric modulated arc therapy (VMAT).
As advances in treatment techniques have allowed more conformal treatment of the
target volumes with decreased dose to normal tissues, improved outcomes have been
documented with increased doses of >74 Gy to the prostate. However, the optimal
treatment doses for various risk categories of prostate cancer remain unknown. In the
past, with 2D treatment techniques, doses of 45 to 50 Gy to the pelvis, 55 to 65 Gy to

797
the seminal vesicles, and 65 to 72 Gy to the prostate were typical. With the advent of
3D CRT, IMRT, and other highly conformal techniques, doses have been escalated
without significant increases in acute side effects or late complications (79).
In a landmark trial, the MD Anderson Cancer Center compared 70 to 78 Gy using 3D
CRT techniques and found that patients receiving the higher dose had significant
improved biochemical failure-free survival, particularly those patients with a
pretreatment PSA above 10 ng/mL or with higher-risk clinical features (Table 26A.6)
(80). Toxicity, however, was increased as a function of the volume of rectum treated to
higher doses. Another significant randomized trial of dose escalation used a
combination of external beam photon radiotherapy with a proton beam boost. Zeitman
et al. have reported that mostly low–intermediate-risk prostate cancer patients receiving
79.2 Gy had a 15% absolute reduction in the risk of biochemical recurrence at 10 years
as compared to those receiving 70.2 Gy (32.4% vs. 16.7%) (2). Given the lack of
biologic difference between protons and photons, there is no reason to presume that
these results are unique to the use of a proton boost. Using this technique, although
there was a slight increase in mild acute rectal toxicity, there was no significant
difference in clinically substantial toxicity rates or patient reported quality of life (9).
These randomized trials as well as others (81,82), combined with many retrospective
studies, give strong evidence that dose escalation above 70 Gy may significantly
improve prostate cancer biochemical cure rates. However, at present, dose escalated
radiation has not resulted in clear differences in rates of metastasis, prostate cancer-
specific death, or overall survival. When dose-escalation is performed using conformal
techniques toxicity rates seem to be acceptable (5,30,82).
Most treatments have used conventional fraction sizes of 1.8 to 2.0 Gy/day. The use
of a smaller number of treatments delivered at a higher daily dose (hypofractionation)
has been suggested as a means to improve prostate cancer control and decrease overall
cost and treatment time, while still achieving acceptable long-term rates of toxicity.
Recent reports have supported modest hypofractionation with daily fractions of 2.5 to
3.1 Gy (83–87) as being efficacious without increased risks of toxicity. Nevertheless, the
impact of hypofractionation on late toxicity has not been clearly established at this time
and most practitioners await long-term results before adopting these shorter regimens.
Evidence supporting this more cautious approach comes from the RTOG 9408 dose
escalation study, which was a sequential phase II trial that evaluated increasing doses
between 70 and 79.2 Gy in fractions of 1.8 or 2.0 Gy. Interestingly, the rate of late
rectal toxicity was higher in those treated with 78 Gy in daily fractions of 2 Gy than in
any of the other arms including those receiving 79.2 Gy in daily fractions of 1.8 Gy
(88).
A number of reports have retrospectively analyzed biochemical control of prostate
cancer using EBRT, LDR, or HDR brachytherapy, or the combination of these modalities
(88–91). Based on α/b corrections that take into account different radiation fraction
sizes, it has been suggested that the α/b for prostate cancer is not actually in the range
of 10 Gy (as commonly used for most tumor cells) but in the range of 1.2 to 3.0 Gy.
Therefore, treating prostate cancer with larger fraction sizes, but to an appropriate total
lower dose, would theoretically result in an increase in the therapeutic ratio. Thus, by
using larger radiation fraction sizes, one might decrease overall treatment dose, time,
and cost with a similar rate of late toxicity and an increase in expected biologic efficacy
for prostate cancer. Extreme hypofractionation with doses in excess of 6 to 7 Gy
delivered in four to five fractions has been reported from a number of limited single
institutions’ experiences (92–94). At present, however, follow-up on these studies is
short, and the use of extreme hypofractionation or stereotactic radiotherapy for

798
prostate cancer should be considered experimental and is most appropriately utilized as
part of prospective clinical trials (95).

TREATMENT PLANNING FOR ADJUVANT OR SALVAGE EBRT


Adjuvant versus Salvage EBRT Following Radical Prostatectomy
Adjuvant radiation (ART) refers to immediate postoperative EBRT following
prostatectomy. No studies have directly compared ART (delivered 10 to 12 weeks after
surgery) due to the presence of high-risk pathologic features even with undetectable
PSA to salvage RT delivered at the time of rising PSA. Three phase III randomized trials,
ARO 96-02, The South West Oncology Group (SWOG) 8794, and EORTC 22911,
support the use of ART (96–98). Furthermore, a number of retrospective reviews have
suggested an improved rate of biochemical control using ART as compared to salvage
RT (99,100). However, a blanket approach of adjuvant treatment for all pT3 patients
would needlessly irradiate men who either have no disease or occult metastatic disease.
The balance between ART and early salvage RT remains to be determined.
For adjuvant therapy there is now level I evidence from randomized trials supporting
a decline in biochemical failure, metastasis, and prostate cancer-specific death with an
improvement in overall survival with the use of ART (97,101). SWOG 8794 randomized
men (stage pT3N0M0 disease or positive surgical margins) to observation or ART arms
where the RT dose ranged from 60 to 64 Gy, with treatment portals including the
prostatic fossa and paraprostatic tissues. With >12 years of follow-up the use of ART
was associated with a 50% relative reduction in the risk of PSA recurrence in the ART
group (p < 0.001). The use of ART yielded an absolute 10% improvement in metastasis-
free survival at 10 years (71% vs. 61%, p = 0.016) and an 8% improvement in overall
survival (66% vs. 74%, p = 0.023). Interestingly, the magnitude of benefit was similar
for those with or without detectable PSA postoperatively although the utility of super-
sensitive PSA remains to be determined (102). Two additional randomized trials support
similar benefit in biochemical control of prostate cancer using ART although follow-up
in these studies is insufficient to address more clinically meaningful end-points (96,98).
The role of salvage RT for patients with a rising PSA after RP has not been evaluated
in randomized trials (although certainly a significant portion of patients on both the
SWOG and EORTC trials had detectable PSA at the time of irradiation and as such
would be consistent with salvage therapy). In general, approximately 30% to 40% of
patients given salvage RT will have long-term disease control (103,104). Preoperative,
pathologic, and other clinical features have been utilized to construct a nomogram
predicting the likelihood of PSA control (104), which was subsequently validated in a
large multi-institutional data set (103). In addition, others have presented data
supporting an improvement in prostate cancer-specific survival with the use of salvage
RT particularly in those with the most rapidly rising PSA (105). Den et al. (106)
reported a validation study for the use of a genetic test to predict for the occurrence of
clinical metastasis and which patients might be spared from early postoperative RT.
While promising, their primary endpoint of clinical metastasis 5 years after RT may be
premature for basing management decisions considering that the median actuarial time
from a rising PSA after RP to metastasis is 8 years (107).

Target Volume Definition


Postprostatectomy target volume delineation is subject to significant variation,

799
especially in the posterior and superior aspects. Several target volume definition
guidelines were created to improve interobserver variability. The randomized trials of
ART in general utilized large fields and 2D treatment techniques; therefore, there was
not a need to precisely define target volume (96,98,101). Consensus guidelines have
been published defining recommended anatomic boundaries of the CTV for RT delivered
in the postoperative setting (108–111). The definition of treatment volumes for ART or
salvage RT for patients who have undergone previous RP is difficult as there is usually
no palpable or visible disease on imaging to constitute a GTV. The vesicourethral
anastomosis (VUA), periurethral, and perivesicular tissues should all be treated as these
are the most common sites of recurrence following RP (112–114). Some practitioners
also encompass lymph node regions (as described above) but pelvic nodal irradiation in
the postoperative setting is controversial. Residual microscopic disease within the
“prostate bed” is targeted by delineating the CTV at the preoperative location of the
prostate and seminal vesicles. This can be accomplished using CT planning, and
contouring an elongated “dumbbell-shaped” volume encompassing the plane between
the posterior bladder and anterior rectum (Fig. 26A.3). Surgical clips remaining from
prostatectomy, preoperative staging information, and postoperative pathology report
information that are valuable in delineating the CTV.
The VUA can frequently be identified in relationship to the urinary diaphragm on a
CT scan sagittal reconstruction; alternatively, either ultrasound or MRI may aid in this
process. Given the prior location of the prostate at the level of the pubic symphysis, the
region extending anteriorly to posteriorly from the pubic symphysis to the rectum
should be included in the CTV. The most recent consensus guidelines are only to include
the seminal vesicles if they were pathologically involved at the time of the surgical
resection. If not including the seminal vesicles the superior border should be either at or
5 mm above the cut of the vas deferens, or alternatively, at the level of the most
superior surgical clip. In addition, ∼1.5 cm of posterior bladder and bladder wall are
also included to account for the shifting of the bladder into the space previously
occupied by the prostate. The inferior border should be ∼10 mm below the VUA;
however, if there is concern that the initial prostate tumor may have been apical, then
the inferior border of the CTV should end immediately superior to the penile bulb (109).

Dose Fractionation
Doses of 64.8 to 70.2 in 1.8 to 2.0 Gy/fraction are used postoperatively. To date, there
have been few studies investigating the role of dose escalation in the adjuvant or
salvage setting. Valicenti et al. (115) suggested that doses of RT in excess of 64.8 Gy
were associated with improved outcomes. In addition, Ost et al. (116) reported on the
clinical outcome and safety of ART in 104 patients treated with IMRT and a median
dose of 74 Gy. The 3- and 5-year actuarial biochemical relapse-free survival (bRFS) was
93%, a 20% gain as compared to the bRFS rate seen in the randomized trials with doses
of 60 to 64 Gy. These results are limited by the study’s retrospective nature, the short
follow-up, and the impact of stage migration as compared to the randomized ART trials
which enrolled patients from the late 1980s to early 1990s. Despite the higher dose,
acute and late toxicities were rare, with only 4% of patients experiencing late grade 3
toxicities (all GU). These toxicity results are similar to those reported from a multi-
institutional analysis using more conventional doses of radiation (117). It is possible
that the use of IMRT allowed dose distributions that partially spared the posterior and
lateral rectal walls, thus minimizing late rectal toxicity. King et al. (118) recently
evaluated a series of retrospective reviews to assess the impact of RT dose on outcome in

800
the adjuvant and salvage setting. The authors found that the dose–response
relationships were suggestive of a larger burden of disease for salvage patients with a
detectable PSA and approximately one-tenth of this disease burden for adjuvant
patients. They estimated an increase in the bRFS rate of ∼3%/Gy over the range of 60
to 70 Gy. Of note, this is similar to the 2% to 3% improvement in bEFS observed per 1
Gy increase in radiation in the four randomized trials of dose escalation for definitive
radiation of the prostate. At present, however, no prospective trials have directly
compared different doses of EBRT in the adjuvant or salvage setting. Therefore, at
present most practitioners will utilize RT doses of at least 64.8 Gy in the adjuvant and
salvage setting with some considering doses even up to 66 to 70.2 Gy.

Treatment Technique
Several IGRT methods have been developed to provide consistent localization of the
prostate bed and reduce daily setup error, including Calypso beacon localization (119),
daily portal imaging with implanted gold seed fiducials (120), ultrasound (121), and
daily cone-beam imaging or kilovoltage imaging (122). The use of IGRT in the
postoperative setting is not as clearly established as that in the definitive setting
although the fundamental principles and rationale remain the same. These techniques
are useful in detecting the location of the VUA, which in turn depends on variability in
rectal and bladder distention. Similarly, the use of IMRT in the postoperative setting has
not been well studied at present. Given the somewhat poorly defined treatment volume
that includes a large portion of bladder and rectum as well as the typically utilized RT
doses of <70 Gy, the benefit of IMRT may be limited. However, use of both IGRT and
IMRT may allow dose escalation in the postoperative setting, which some have
suggested will correlate with improvements in outcome just as it has in the definitive RT
setting (118).

TREATMENT PLANNING FOR RADIOISOTOPE IMPLANT


Indications
Advances in brachytherapy techniques have made it a popular, effective, and safe
treatment for localized prostate cancer. Brachytherapy is categorized by dose rates
defined in ICRU report 38. LDR brachytherapy ranges between 0.4 and 2.0 Gy/h,
medium dose rate (MDR) between 2.0 and 12.0 Gy/h, and HDR above 12.0 Gy/h.
Radioactive seed implant alone is effective in treating low-risk prostate cancer and
indicated in select patients with intermediate risk disease (123). Men with larger,
higher-grade tumors with higher PSA levels have a substantial risk of having disease
outside the prostate. These patients may be best treated by a combination of external
beam radiation and brachytherapy. Compared to external beam radiotherapy,
brachytherapy implants follow the daily motion of the prostate and dosimetry primarily
depends on source arrangement within the prostate.

Target Volume Definition


The prostate gland itself, with minimal margin, is the target for radioisotopic implant.
Candidates for implant are chosen carefully since pelvic lymph nodes are not treated
with implant techniques. Coverage of seminal vesicles and extracapsular areas vary
depending on the operator and institution.

801
Localization and Treatment
The present era of low-energy permanent radioisotopic implantation for prostate cancer
traces its origins to Scardino and Carlton at Baylor College of Medicine in the 1960s
and Whitemore and Harris at Memorial Sloan-Kettering Cancer Center in the 1970s,
where an open, retropubic approach was used to perform implants using freehand
placement of needles containing gold or iodine radioisotopes (124). Unfortunately, this
technique was associated with inhomogeneous dose distribution, inexact dosimetry, and
disappointing local control and disease-free survival, and by the mid-1980s, the
retropubic technique was largely abandoned in favor of a transperineal approach (125).
Soon thereafter ultrasonography and a transperineal implant approach using a rigid
template guidance system was developed (126). Two ultrasound-based planning
approaches are generally used, either a preplan designed with the prostate in treatment
position, or an intraoperative plan approach. With the preplanned technique,
transverse TRUS images are recorded at 5-mm intervals from the base to the apex of the
prostate gland using a stepping device attached to the ultrasound probe and the patient
in the dorsal lithotomy position. The physician may evaluate the pubic arch during this
procedure to determine any potential for bone interference with needle insertion. The
ultrasound software projects the template grid over each successive prostate image.
Typically, seven to nine images are displayed at 5-mm increments, and the prostate
volume is contoured by the physician on each image. The prostate itself or the prostate
with a margin of 2 to 5 mm around the prostate may be defined as the PTV. Various
software packages can be used for planning of a 3D implant volume, determining the
number of needles, their placement according to template coordinates, and the number
of seeds inserted per needle, prior to the actual implant.
With intraoperative planning, all these steps are performed in one setting in the
operating suite, tailoring the plan to the individual. Without a preplan, there may be a
risk of ordering too few or too many seeds; however, the intraoperative planning
approach has the significant advantage in that the planning images are of the patient
under anesthesia, minimizing discrepancies between the planning images and the actual
anatomy and geometry. Furthermore, some treatment planning software packages now
allow the users to register the location of sources as they are implanted and recalculate
dosimetry in “real-time,” allowing further adjustments and refinements to be made in
the treatment plan to accommodate inaccuracies in needle placement and intraoperative
prostate shift and swelling.
Seeds are usually spaced 0.5 to 1 cm apart in the transverse (right to left), anterior–
posterior, and the superior–inferior planes. Computer-generated isodose curves predict
the delivered dose, assuming the implant is completed as planned (Fig. 26A.10). During
the implant process each needle is guided to its predetermined position with the
template placed against the perineum by the use of an on-screen template grid system
and direct ultrasound visualization (Fig. 26A.11). The specified number of radioactive
seeds is implanted from the base to the apex of the gland as each needle is withdrawn,
using either individual seeds—seeds linked together with custom-assembled spacers—or
fixed-space seeds embedded within a polymer strand cut to the desired length. After
completion of the seed placement, cystoscopy or fluoroscopy may be utilized to assess
for inadvertent seed localization within the bladder or urethra and a Foley catheter may
be placed. After anesthesia recovery and proper assessment of exposure rates outside
the patient, most patients are safely released home and instructed to return for
subsequent postimplant dosimetry studies.

802
FIGURE 26A.10 A typical preoperative or intraoperative prostate ultrasound is shown with the central urethra,
prostate (clinical target volume), and prostate + 2 mm (planning target volume) contours. The loading positions
and number of intended I-125 seeds to be implanted in each position are indicated at specific template
coordinates, and the 290 Gy, 217.5 Gy, and 145 Gy isodose lines are shown. Courtesy of Dr. Vrinda Narayana.

FIGURE 26A.11 Transperineal prostate brachytherapy with transrectal ultrasound visualization and seed
placement via needle insertion using template guidance.

FIGURE 26A.12 An axial computed tomography image is shown in a postimplant patient. Based upon the
positions of the seeds and the contour of the prostate clinical and planning target volumes, one can assess the
adequacy of the dose distribution, as shown by the overlaid 290, 217.5, and 145 Gy isodose lines. Courtesy of

803
Dr. Vrinda Narayana.

A postimplant CT scan and dosimetry should be done on each patient to evaluate


implant quality, thereby detecting any consistent underdosing or inhomogeneities. The
positions of all seeds are identified, the target and normal tissues are contoured
(prostate, urethra, bladder, rectum, bowel, penile bulb), and dose distributions are
calculated (Fig. 26A.12). This allows calculation of various dose–volume metrics, such
as the D90 and D100, the doses that cover 90% and 100% of the prostate volume,
respectively, as well as the V100, the volume of the prostate receiving at least 100% of
the prescribed dose. The reporting of these metrics is important in the medical literature
to enable comparisons between treatment results and also for individual prostate seed
brachytherapy programs to enable ongoing assessment of implant quality and
correlation with disease and toxicity outcomes. This enables any necessary adjustments
to treatment techniques and procedures. Postimplant bleeding and edema can have
significant effects on prostate volume. Given that this is a dynamic process, it can have
significant implications for postimplant CT dosimetry. Practitioners may have varying
preferences for the time interval between the implant procedure and when to perform
postimplant dosimetry imaging, but it is important that implant programs remain
consistent in their planning and dosimetry procedures to apply their dosimetry lessons
toward quality improvement.

Isotopes and Dose


Several isotopes have been used for prostate LDR—permanent interstitial prostate
brachytherapy (Table 26A.7). The most extensive experience with permanent
interstitial, LDR implants has been with iodine-125 (I-125), which has been used for
>40 years. Some radiobiologic evidence raised concerns that the dose-rate of ∼8 cGy/h
from I-125 was too low for prostate cancer doubling times, so palladium-103 (Pd-103),
with a higher dose rate near 20 cGy/h, has been advocated (155).. Since the energy of
Pd-103 is still low and similar to that of I-125, 21 versus 28 keV, this isotope retains the
advantage of delivering a relatively low dose to surrounding organs and minimal
exposure to medical personnel. Clinical comparisons between the two isotopes have
revealed no significant difference in biochemical control (127). More recently, Cesium-
131 has been FDA-approved for permanent prostate brachytherapy. Cs-131 has an
energy (29 keV) similar to I-125, but a shorter half-life (9.7 days). Although early
experience with this isotope has been positive, the follow-up is short, and there is no
data to suggest superiority over I-125 or Pd-103 (128). Although given the shorter half-
life of Pd-103 and Cs-131, these two isotopes may be associated with greater short-term
urinary toxicity with the potential to also have earlier resolution of urinary irritative
and obstructive symptoms.
The American Association of Physics and Medicine (AAPM) Task Group 43 (TG-43),
published in 1995, altered the dose calculation algorithm used for I-125, and its
recommendations have been broadly implemented (129). As a result, prescription doses
previously described as being 160 Gy have been lowered to 145 Gy as calculated under
TG-43 with no change in implant activity, distribution, or geometry. This has
consequently divided the prostate brachytherapy dosimetry literature into “pre-TG-43”
and “TG-43” eras, an important consideration for clinicians’ interpretation of older I-
125 publications. Similarly, the dose for Pd-103 implant was 115 Gy before the
National Institute of Standards and Technology 1999 Guidelines (NISTG-99) and 125
Gy afterward (130).

804
Analysis of matched peripheral dose calculations within the Memorial Sloan-Kettering
Cancer Center I-125 implant experience found that the 5-, 10-, and 15-year local
relapse-free survival was 78%, 56%, and 30% among patients receiving doses of at least
140 Gy (126 Gy by TG-43), compared with 64%, 38%, and 21% among those receiving
<140 Gy (126 Gy by TG-43) (125). Using modern transperineal prostate brachytherapy
techniques with CT-based postimplant dosimetry, Stock et al. reported that patients
receiving a D90 140 Gy (using TG-43 criteria) had a 92% rate of 4-year biochemical
control compared with only 68% for patients receiving a D90 < 140 Gy (131). Wallner
demonstrated that both dose and volume of normal urethral and rectal tissue are
related to toxicity from prostate implants (132). Based on these experiences and others,
the American Brachytherapy Society has published guidelines for transperineal
permanent brachytherapy for prostate cancer, recommending prescription doses of 145
Gy (TG-43) for I-125 and 125 Gy for Pd-103 (after NISTG-99) as monotherapy (156).
For combination therapy, an EBRT dose of 40 to 50 Gy should be combined with 100 to
110 Gy (TG-43) I-125 or 90 to 100 Gy (NISTG-99) Pd-103 implantation. For Cs-131, an
experienced group of users has developed consensus recommendations for prostate
implantation, which includes a monotherapy prescription dose of 115 Gy and a boost
prescription dose of 85 Gy, with special attention to urethral and rectal dosing (128).
TABLE 26A.7 Isotopes Used for Interstitial Prostate Implant

Use of HDR iridium-192 (Ir-192) brachytherapy has become increasingly popular at


many centers either as monotherapy or as a boost in combination with EBRT. As with
LDR brachytherapy, the HDR technique employs TRUS-guided transperineal placement
of needles and catheters either via a template or by freehand, which is fixed to the
perineum. Real-time, ultrasound-based dose planning software may be utilized.
Planning may be accomplished using CT, ultrasound, or MRI images taken with the
catheters in place. Targets and normal structures are contoured, and dwell times for
source positions can be calculated to optimize delivery of the desired dose to the PTV
while minimizing normal tissue dose. The hollow catheters can then be loaded by remote
afterloading Ir-192 HDR unit either in single or in multiple insertions. Treatment is
hypofractionated, generally using two or more large fractions delivered at dose rates of
∼100 Gy/h. This HDR, which approximates that delivered with a linear accelerator
during EBRT, is the main theoretical advantage of HDR brachytherapy and may result
in a superior radiobiologic effect compared with LDR brachytherapy, particularly for
disease with adverse risk features (133).
Although several centers (134) and multi-institutional experience (135) have been
published on HDR brachytherapy, no randomized trials have compared outcomes of
HDR monotherapy with other primary treatment modalities. The follow-up is still
insufficient to establish the role of HDR monotherapy for treatment of men with
localized disease. HDR brachytherapy is more commonly utilized as a boost in
combination with EBRT. A variety of dose and fractionation schedules have been

805
reported. As one example, the most recent RTOG study for intermediate risk patients
prescribed 45 Gy of conventional EBRT followed by an HDR prostate boost dose of 19
Gy given in two 9.5 Gy fractions with a minimum 6-hour interfraction time interval
(135).

PROGNOSIS
The likelihood of biochemical, local, and distant failure as well as disease-specific
survival after RT for prostate cancer is related to tumor stage, grade, and pretreatment
PSA level (136–141). As discussed above, additional factors also contribute to long-term
prognosis including radiation dose, the use of adjunctive androgen ablative therapy,
PSA kinetics, and tumor volume. Posttreatment factors such as PSA nadir also have
predictive value in estimating biochemical and distant failure (142). Provider
experience and treatment volume have also been demonstrated to influence the
likelihood of recurrence and the need for salvage hormonal therapy for both
brachytherapy (143) and external beam radiation.
At a RTOG symposium in Phoenix, numerous candidate definitions of biochemical
failure were evaluated, and a definition was endorsed of the posttreatment nadir PSA
plus 2 ng/mL as being the threshold for defining clinically meaningful biochemical
failure after primary EBRT for prostate cancer (144). The Phoenix definition was
initially only defined for those receiving EBRT or brachytherapy with at most short-term
androgen therapy (145). However, others have suggested that it is applicable to those
treated with EBRT along with long-term ADT (146). Biochemical failure by the Phoenix
definition has been demonstrated to correlate with patient survival although the risk of
death from prostate cancer following biochemical failure is dependent upon both the
clinical features of the cancer as well as patient age (146,147), and as a result it is not a
reasonable surrogate for patient survival in most patients. Following biochemical failure
patient risk group, the time to PSA failure (148,149) and the PSA kinetics during failure
may help further elucidate those patients at high risk of distant metastasis and prostate
cancer-specific mortality (149,150).
Long-term follow-up of the MD Anderson randomized trial of 70 versus 78 Gy
(without ADT) revealed 8-year freedom from biochemical failure using the Phoenix
definition of 88%, 86%, and 63% for low, intermediate, and high-risk prostate cancer,
respectively (Table 26A.7) (80). Radiation dose did appear to predict for improved
outcome as well with freedom from biochemical or clinical failure at 8 years greater in
the 78 Gy arm as compared to the 70 Gy arm (78% vs. 59%, p = 0.004). Distant
metastasis had only been observed in a small number of patients; however, freedom
from distant metastasis after 70 Gy versus 78 Gy was 95% versus 99% with a trend
toward statistical significance (p < 0.06). The difference in metastasis as a function of
radiation dose was greater in those in the high-risk group (83% vs. 96%, p < 0.04).
With a median of 8 years of follow-up there were few deaths due to prostate cancer, as
a result to date there was no difference in either prostate cancer-specific or overall
survival (80).
Brachytherapy outcomes have also improved significantly with enhanced techniques,
and multi-institutional and randomized trial data are now becoming available in the
literature which should provide more generalizable experiences as opposed to single-
institutional case series which are more prone to selection, individual practitioner
experience/technique, and other biases. RTOG 9805 examined LDR monotherapy for
patients with low-risk prostate cancer treated at 27 different institutions with I-125
LDR monotherapy to 145 Gy (151). At 5 years, the biochemical failure-free survival

806
rates exceeded 90%, which was comparable with other published brachytherapy series
and with surgical or EBRT outcomes. Recently, a small Italian randomized trial
comparing RP with LDR brachytherapy for low-risk patients showed no differences in 5-
year bRFS rates between these two treatment modalities (152). Brachytherapy patients
were noted to have persistent increased genitourinary irritative side effects, but superior
urinary continence and erectile function compared with RP patients. RTOG study 0019
examined combined EBRT with LDR brachytherapy boost for patients with intermediate
risk features treated at over 20 different institutions (153). Treatment was delivered
with combined conventionally fractionated 3D conformal EBRT to 45 Gy with LDR
brachytherapy boost 2 to 6 weeks later to 108 Gy. At 4 years, biochemical recurrence
rates were 14% to 19%, comparable with results achieved with dose-escalated EBRT.
However, incidence of grade 3 or higher genitourinary or gastrointestinal toxicity was
15%, higher than that observed in contemporary studies of patients treated with
brachytherapy or EBRT alone. RTOG study 0321 examined combined EBRT with HDR
brachytherapy boost for patients with a slightly higher intermediate risk group of
patients (135). Treatment was delivered with EBRT to 45 Gy and two 9.5 Gy HDR boost
fractions (total 19 Gy boost) within an overall treatment time of <8 weeks. At 29
months, the estimated rate of grade 3 through 5 genitourinary and gastrointestinal
adverse events was 2.4%, demonstrating the feasibility of EBRT/HDR treatment in the
multi-institutional setting and an acceptable level of adverse events. Finally, a
prospective (but not randomized) study for intermediate to high-risk patients utilized
∼9 months ADT with either 76 Gy EBRT as compared to 45 Gy EBRT with 18 Gy HDR
boost given in two fractions and demonstrated a small but not statistically significant
difference in 5-year bRFS between treatment arms, but lower rates of late grade 2 rectal
toxicity in the HDR-treated patients (13% vs. 3%, p < 0.005) (154).

CONCLUSION
Significant advances have been made in the treatment of prostate cancer with RT over
the last 10 years that have resulted in improvements in disease control with decreased
risks of toxicity and series adverse impacts upon long-term patient quality of life.
However, these advances have depended upon closer detail to the process of planning
and delivery of RT to the prostate. The optimal selection of radiation modalities either
alone or in combination and the timing and duration of ADT in this setting remain to be
established. Nevertheless, the results to data suggest that RT is an attractive and viable
treatment option for men with prostate cancer.

KEY POINTS
• Prostate cancer is the most common noncutaneous malignancy in men in the United States
and is the second most common cause of cancer-related deaths in men.
• Clinical T stage, Gleason grade, and pretreatment PSA are the most important factors used
for risk stratification.
• Definitive treatment involves treatment of the entire prostate gland.
• While the prostate gland is always in the target volume, a decision must be made as to
whether the seminal vesicles and pelvic lymph nodes are included.

807
• There are many options for image guidance, including CBCT, ultrasound localization
system, or implanted fiducials.
• Postprostatectomy target volume delineation is subject to significant variation but the
vesicourethral anastomosis (VUA), periurethral, and perivesicular tissues should all be treated
as these are the most common sites of recurrence following RP.
• The use of IGRT in the postoperative setting is not as clearly established as that in the
definitive setting.
• The prostate gland itself, with minimal margin, is the target for radioisotopic implant.

QUESTIONS
1. NCCN guidelines recommend pelvic imaging with CT or MRI in clinically
localized prostate cancer when the probability of lymph node involvement is
greater than:
A. 5%
B. 10%
C. 15%
D. 20%
2. A bone scan is recommended in which of the following scenarios?
A. T1c and PSA 15
B. Gleason 4+3
C. T2b
D. PSA 25
3. What are the usual prescription doses for prostate brachytherapy using I-125
and Pd-103, respectively?
A. 125 Gy and 145 Gy
B. 110 Gy and 90 Gy
C. 145 Gy and 125 Gy
D. 125 Gy and 110 Gy
4. Which radioisotope is used in HDR brachytherapy?
A. I-125
B. Pd-103
C. Cs-131
D. Ir-192
5. RTOG pelvic nodal consensus CTV contours for high-risk prostate cancer include
which lymph nodes?
A. Presacral, distal common iliac, internal and external iliac, obturator
B. Para-aortic, presacral, distal common iliac, internal iliac, obturator
C. Presacral, distal common iliac, internal iliac

808
D. Para-aortic, presacral, distal common iliac, internal and external iliac

ANSWERS
1. B
2. D
3. C
4. D
5. A

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specific antigen doubling time as surrogates for prostate cancer-specific mortality:
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150. D’Amico AV, Moul JW, Carroll PR, et al. Surrogate end point for prostate cancer-
specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer
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ultrasound-guided radioactive implantation of the prostate for definitive
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26B Genitourinary
Cancer
Cancers: Bladder

Julian Johnson and Albert Chang

INTRODUCTION
Bladder cancers are fairly common cancers of the urinary tract, affecting 70,000 adults
in the United States each year. It is the fourth most common tumor in men and the
ninth most common cancer in women (1). The majority of bladder cancers in the United
States are transitional cell carcinomas (TCCs) while the majority in the developing
world are squamous cell carcinomas. Curable bladder cancer can be conceptualized in
several categories: those that require superficial therapy, those with more advanced
disease who require more aggressive definitive therapy, and finally those who are
ineligible for bladder conservation but are curable. Radiotherapy plays a pivotal role in
bladder preservation and is commonly utilized in the postoperative setting.
Radiotherapy is not used for superficial bladder cancers. This chapter will focus on how
to identify which patients fall into which subgroup, how to deliver radiotherapy in the
group of patients who are eligible for bladder preservation, and finally postoperative
radiotherapy.

Risk Stratification
The most important assessment in the risk stratification of patients with bladder cancer
is the depth of invasion of the primary tumor. Once bladder cancer reaches the
muscularis propria the risk of locoregional spread is much higher and more aggressive
definitive therapy is required. The risk of lymph node spread for superficial tumors is
5% or less compared to 20% for tumors that have reached the muscularis propria and
20% to 40% for tumors that have invaded beyond the muscularis propria (2).
Thankfully, the majority of bladder cancers are limited to the mucosal surface (3). These
superficial tumors can be managed with transurethral resection of bladder tumor
followed by superficial therapy with intravesicular mitomycin C or bacilli Calmette–
Guerin (BCG). BCG is the preferred therapy for most superficial disease (Tis), papillary
tumors (Ta), and tumors confined to the mucosa (T1) of all grades (low and high).
Mitomycin C can be used for low grade, Ta tumors. Superficial tumors have a high
recurrence rate at 5 years; 50% or greater. Many of these recurrences will progress to
muscle invasion.
Unfortunately, half of all patients with muscle invasive disease will die of bladder
cancer in 5 years, regardless of therapy. But muscle invasive TCC of the bladder can be
curable. Identifying which therapies are options for these patients requires an
understanding of the diagnostic studies that yield proper staging and risk stratification.

Diagnostic Studies and Staging


The classic presentation of bladder cancer is painless gross or microscopic hematuria,
which occurs in up to 80% of cases. Urinary urgency, frequency, and dysuria without

819
hematuria may occur in up to 30% of patients. Initial urologic evaluation must include
urine cytology and cystoscopy with possible transurethral biopsy/TURBT during
cystoscopy. TURBT specimens should generally contain some muscle to properly
evaluate for muscle invasion. If muscle invasion is discovered at the time of TURBT, the
patient should have a computed tomography scan of the abdomen and pelvis to
evaluate for suspicious lymph nodes. Patients should also have the upper urinary tract
evaluated (NCCN guidelines version I.2016).
The standard staging system utilized is the tumor, nodal, and metastasis (TNM)
staging system of the American Joint Committee on Cancer (AJCC) (Table 26B.1) (4).
The system is based on sub-dividing patients into groups by the extent of local tumor
invasion and the presence or absence of nodal or distant metastases. In this system, T-
staging, based upon the depth of invasion of the primary tumor (T), conveys important
prognostic information. The most useful assessment is whether the tumor is organ-
confined (≤T2) or non–organ-confined (≥T3). However, the utility of available
methods for determining the degree of muscle invasiveness preoperatively is modest
with accuracy at most 70% even with the combination of cystoscopic evaluation and
TURBT when compared to pathologic examination following cystectomy. Determination
of the extent of muscle invasion at biopsy also requires adequate sampling of the
bladder wall muscle. In addition to depth of invasion, other factors to be determined at
the time of staging include the size and location of the lesion, the presence of CIS, the
histologic type, and the degree of differentiation. The majority (90%) of bladder cancers
in the United States are transitional cell malignancies, and for these by consensus
definition, the degree of differentiation is limited to low-grade and high-grade. With
rare exception, muscle-invasive (T2 or greater) urothelial cancer is high-grade. Given
the high incidence of multicentric disease examination of specimens taken from
clinically uninvolved areas of the bladder is also recommended. (See Table 26B.1 for
current AJCC staging system.)
TABLE 26B.1 2010 American Joint Committee on Cancer (AJCC) TNM Staging System for
Bladder Cancer

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Treatment Options
As mentioned above, bladder cancer is divided into superficial, muscle invasive, and
more advanced disease. Superficial cancers do not require surgery, systemic
chemotherapy, or radiotherapy. Bladder conserving surgery using TURBT alone may be
appropriate treatment for selected early stage patients (5), particularly for patients who
are poor candidates for aggressive interventions. TURBT is also a critical component of
multimodality treatment strategies for more advanced disease, and the completeness of
resection is an important predictor of local control and survival (6). Even for
noninvasive disease, recurrence after TURBT alone is common, particularly for high-
grade lesions (7). Recurrence rates can be decreased by the use of intravesical BCG,
resulting in 70% to 80% 5-year survival for T1 tumors (8,9). With progression from T1
to muscle-invasive disease, radical cystectomy has been the standard recommendation;
however, some would argue that at this point, organ-preserving therapy with radiation
and chemotherapy may also be an option (10,11).

821
Muscle invasive cancer can be treated with cystectomy with or without
chemotherapy/radiotherapy or with bladder preservation with TURBT followed by
chemoradiation. No clinical trial has directly compared cystectomy to bladder
preservation, but the data seems to indicate that overall survival rates are comparable
(2,12–16). Generally patients may proceed with bladder preservation based on patient
or clinician choice if they are eligible. Patients who have diffuse disease, invasion of
adjacent structures (T4 disease), hydronephrosis, diffuse carcinoma in situ, inadequate
TURBT, poor bladder function, or inability to tolerate chemotherapy are ineligible for
bladder preservation with TURBT and chemoradiation.

Nonbladder Sparing Treatment Approaches for Muscle Invasive Disease


Five-year overall survival estimates in modern radical cystectomy series are
approximately 50%. Radical cystectomy includes removal of the bladder, prostate,
seminal vesicles, and proximal urethra in males. In females the bladder, urethra, uterus,
fallopian tubes, ovaries, and anterior vaginal wall are removed. Radical cystectomy may
be followed by various reconstruction options, which is beyond the scope of this
chapter.
Local control rates with radical cystectomy are high (17). However, the risk of pelvic
relapse may approach 30% in patients who are found to have extravesicular extension
(T3b) or positive nodes and may approach 70% in patients with positive margins
(18,19). These high locoregional recurrence rates generated interest in chemotherapy
and radiotherapy in the adjuvant or neoadjuvant setting.
An approximately 5% overall survival benefit has been observed when neoadjuvant
chemotherapy is utilized prior to radical cystectomy for patients with muscle invasive
bladder cancer (13,20,21). Initially MVAC was the chemotherapy of choice in the
neoadjuvant setting. However, gemcitabine and cisplatin has been shown to be equally
effective and less toxic (22). It is worth noting that more than half of patients will have
notable downstaging when neoadjuvant chemotherapy is utilized. More than one
quarter may have a complete response. Responders to chemotherapy enjoy a higher
overall survival, but they still require definitive therapy (cystectomy or
chemoradiation). Adjuvant chemotherapy has also demonstrated disease free and
overall survival benefits in several studies (23), but neoadjuvant chemotherapy is
favored because responders may be eligible for bladder-sparing approaches.
An intergroup randomized trial showed that patients who had preoperative
radiotherapy had a 5-year overall survival of 53% and the surgery alone group had an
overall survival of 43%. This difference was not statistically significant (24). A
subsequent meta-analysis of five randomized trials did not show a benefit to
preoperative radiotherapy compared to cystectomy alone (25). Overall, preoperative
radiotherapy is not commonly utilized because irradiated bowel is less suitable for ileal
conduit reconstructions and the data behind neoadjuvant chemotherapy is stronger.
Interest in postoperative radiotherapy stems from the high rates of local recurrence in
the setting of T3b, T4, or positive margins. The local recurrence rates in these situations
are at least 30% (19,26). Postoperative radiotherapy is generally not indicated for node
positive disease because at that point the primary concern is distant, not local
recurrence. It is worth noting that postoperative radiotherapy to the pelvis after
cystectomy is likely to cause more bowel toxicity since the organs of the pelvis are no
longer displacing the small bowel from the true pelvis.

Bladder-Sparing Approaches for Muscle Invasive Disease


This section will focus on selective bladder-sparing techniques. There are two

822
subcategories of this approach: (1) patients who are medically inoperable and (2)
patients who are medically operable but would like to preserve their bladder rather than
have radical en bloc removal of the bladder and prostate or uterus and ovaries. Overall
functional outcomes after selective bladder preservation are excellent. A recent analysis
of late toxicity for 157 patients treated on 4 RTOG protocols revealed that there were
no grade 4 toxicities or treatment-related deaths. Further, only 7% of patients
experienced late grade 3 or greater pelvic toxicity (6% GU and 2% GI), and the
toxicities resolved in all but one patient. Overall quality of life after combined modality
therapy is excellent for the majority of patients with only ∼30% requiring a cystectomy
(27). In addition, for those with a retained bladder, >75% are able to retain normal
urinary function by urodynamic studies, and >85% with no bothersome urinary side
effects (28).
The history of bladder preservation strategies began as early as the 1980s,
investigators attempted to preserve the bladder. Definitive radiotherapy series
demonstrated that half of patients may be recurrence-free at 5 years, but overall
survival was notably lower than cystectomy series; only 20% to 40% (29–34). When
investigators at the University of Paris noted a very high complete pathologic response
rate following combined maximal TURBT and neoadjuvant chemoradiotherapy
(5FU/cisplatin), they attempted to elucidate what factors would allow patients to avoid
cystectomy altogether (35).
Investigators at the University of Paris, University of Erlangen (Germany), and
Massachusetts General Hospital each developed bladder preservation strategies that
involved TURBT, chemoradiation, and restaging cystoscopy at some point mid-way to
two-thirds of the way through chemoradiation to assess response. Nonresponders were
sent for cystectomy. Since then, there have been multiple RTOG trials published on
selective bladder preservation (Table 26B.3). The current treatment paradigm involves
an initial maximal TURBT, concurrent cisplatin-based chemoradiotherapy to the entire
pelvis up to 40 to 45 Gy with a cystoscopy 3 to 4 weeks later with biopsy. If the tumor
has decreased to ≤T1, there are two options. The first of which is to boost the entire
bladder with an additional 8 Gy followed by boosting the tumor only with an additional
12 Gy. The second option is to boost the entire bladder with an additional 12 Gy. Target
volumes and fields will be described in a subsequent section.
TABLE 26B.2 Approximate 5-Year Relapse-Free and Overall Survival After Radical
Cystectomy for Bladder Cancer by Stage (5)

Overall, contemporary series show equivalent 5-year overall survival when cystectomy
is compared to selective bladder preservation (TURBT + chemoradiation);

823
approximately 50% (Tables 26B.2 and 26B.3). Again, selective bladder preservation and
radical cystectomy have never been directly compared in a randomized trial.

Palliative Radiotherapy
Patients with advanced bladder tumors who are not eligible for cystectomy will often
have metastatic disease. These patients may be managed with chemotherapy and
reassessed for the appropriateness of concurrent chemoradiation. A randomized trial
conducted in the United Kingdom randomized patients with advanced symptomatic
bladder primaries to 35 Gy in 10 fractions or 21 Gy in 3 fractions. Sixty-eight percent
of patients had symptomatic improvement and there was no difference between the two
arms (36).
TABLE 26B.3 Radiation Therapy Oncology Group (RTOG) Protocols for Invasive Bladder
Cancer (1985–2009) (28) (42)

Treatment Planning Technique


The traditional means of treating bladder cancer with external beam radiotherapy is a
four-field box. There are four separate fields: (1) the whole pelvic field, (2) the bladder
field, and (3) the final tumor boost. If selective bladder preservation is the goal, the
treatment break will take place after the whole pelvic treatment. If the patient is
medically inoperable, the patient will not have a treatment break.

SIMULATION
Whole Pelvic Field
The whole pelvic field is typically treated with high-energy photons (6 to 15 MV) and a
3-dimensional (3D) conformal planning technique. The whole pelvic field in bladder
cancer radiotherapy targets the external and internal iliac lymph nodes, the bladder,
and the obturator lymph nodes, and provides a margin around the bladder and
prostate. The common iliacs are not targeted because irradiation of bowel must be
limited and because the highest risk of nodal disease is in the external and internal iliac
lymph node chains. Therefore, the superior border of all fields in the four-field box is at
the mid-sacroiliac joint (approximately S2–S3 vertebral bodies). The inferior border of
all four fields should adequately cover the prostate or in women the proximal 2 cm of
urethra. In women, the inferior border should not be so low that the vulva is irradiated

824
to a high dose. Therefore, the inferior border is at the bottom of the obturator foramen
or 2 cm below the tumor, whichever is lower. The posterior border of the lateral fields is
2 cm posterior to the bladder and internal iliac lymph nodes. Up to half of the rectum
should be blocked. The anterior border is 2 cm anterior to the external iliac lymph
nodes and bladder. The lateral border of the anterior and posterior fields should extend
1.5 to 2 cm beyond the pelvic inlet. The femoral heads should be blocked to keep the
total dose below 40 to 50 Gy. During the treatment of the pelvic field, patients can be
treated with a full bladder to displace small bowel from the field. Point doses to the
bowel should remain below 50 Gy. The volume of bowel receiving 45 Gy should be
limited to less than 200 cc (Fig. 26B.1A,B).

FIGURE 26B.1 Whole pelvic fields for bladder cancer. A: Small/mini-pelvis field (45 Gy): superior border is
S2/S3; inferior border is bottom of the obturator foramen. The border is 1/5 to 2.0 cm lateral to the medial
aspect of the pelvic bone. Blocks can be used for the femoral heads. The lateral beams have the same superior and
inferior borders as the AP/PA beams. The anterior field border is 1 cm anterior to the bladder or 1 cm anterior
to the pubic symphysis, whichever is more anterior. The posterior border is 2.5 cm posterior to the bladder or
any visible tumor. The whole bladder field (54 Gy) is the bladder with a 2-cm block margin. The tumor boost
field (64 Gy) is a 2-cm expansion on the primary tumor. B: Bladder.

Subsequent Boost Fields: Bladder Only or Bladder Followed by Tumor Only


Patients undergoing selective bladder preservation will have a treatment break after
initial treatment to the pelvic fields. The patient can be simulated with an empty
bladder during treatment of the bladder and/or tumor fields. Patients may have
significant irritative voiding symptoms and urinary frequency after initial treatment to
the pelvis, which may make treatment with a full bladder difficult. If a third, tumor-
only field is treated, it should be tumor only with a 2-cm margin around the tumor.
Coning down from the bladder to the tumor is advantageous because it may allow in
minimizing radiation dose to normal bladder, which may impact subsequent bladder
function. However, it should only be done if there is sufficient confidence that the
original tumor will not be missed. Keep in mind that the dose of the final treatment will
be 60 to 65 Gy, which is the approximate tolerance for the whole bladder. Some
radiation oncologists advocate attempting to treat tumor-only boost fields with a full
bladder to further minimize the amount of normal bladder mucosa irradiated. An

825
example is rectal constraint V55 Gy <50%.

Postoperative Radiotherapy
Postoperative radiotherapy may be indicated for pathologic stage T3 or for positive
margins. Consider irradiating the cystectomy bed, external iliac, internal iliac, common
iliac, obturator, and presacral lymph node chains for patients with positive margins. For
patients with negative margins, consider omitting the cystectomy bed and presacral
lymph nodes as the risk of failure there is low with negative margins (26).

Follow-up
Patients treated for muscle-invasive disease (stage T2 or greater) should be followed
with urine cytology and cystoscopy every 3 to 6 months for 2 years, with imaging of the
chest, upper tract, abdomen, and pelvis. If the patient has undergone cystectomy, urine
cytology is still warranted to assess for abnormal cells from the upper tract or ureters.

Prognosis
Survival from bladder cancer is largely determined by distant metastasis; therefore,
ongoing prospective trials are focusing on incorporating novel combinations of cytotoxic
chemotherapy and targeted agents. Radical cystectomy remains the standard treatment
for muscle-invasive bladder cancer. It provides excellent rates of local control, and a 5-
year survival that ranges from 30% to 90% depending on the extent of disease and risk
for distant metastasis (Table 26B.2). Multimodality treatment using TURBT,
chemotherapy, and radiotherapy provides high rates of complete disease response, and
survival that is comparable to radical cystectomy (Table 26B.3). Furthermore, 60% to
70% of patients treated with multimodality, bladder-preserving treatment strategies are
able to retain their native bladder, offering the potential of superior long-term bladder
function and patient quality of life.

KEY POINTS
• Bladder cancer is one of the most common cancers in adults in the United States: it is the
fourth most common in men and the ninth most common in women.
• Most bladder cancers are superficial (Tis, Ta, T1) and require superficial therapy only with
maximal TURBT and intravesicular therapy (MMC or BCG).
• One of the most important distinctions from a radiation oncologist’s perspective is whether a
patient has muscle invasive (≥T2) disease or not. Such patients should be treated with
chemoradiation or cystectomy (unless metastatic).
• The factors that exclude medically operable patients from attempted bladder preservation
include diffuse disease, inability to perform maximal TURBT, T4 disease, hydronephrosis,
inability to tolerate chemotherapy, and metastatic disease.
• Selective bladder preservation refers to a strategy in which patients with a good or complete
response noted on cystoscopy after 40 to 50 Gy of chemoradiation to the whole pelvis
continue radiotherapy for an additional 10 to 25 Gy to the bladder only. Nonresponders are
referred for radical cystectomy. Medically inoperable patients do not require a treatment

826
break since there is no cystectomy salvage option.
• Complete response rates after TURBT and chemoradiation are 70% to 80%.
• There are no trials that directly compare cystectomy to chemoradiation. A 5-year overall
survival for patients that are eligible for bladder preservation is approximately 50%, which is
comparable to patients who undergo cystectomy.
• Eighty percent of the patients who survive 5 years will have an intact bladder. Most patients
report satisfactory bladder function.
• Example dose constraints: rectum V55 Gy <50%, bowel V45 <200 cc, Femoral head Dmax
<50 Gy.

QUESTIONS
1. What is the next most appropriate management for a patient who has had a
cystoscopy with biopsies revealing an incompletely resected muscle invasive
bladder carcinoma in the background of diffuse carcinoma in situ?
A. Repeat TURBT
B. Radical cystectomy
C. Taxane-based chemotherapy and radiation
D. Induction chemotherapy followed by concurrent chemotherapy and radiation
2. What percentage of patients who survive selective bladder preservation strategies
with TURBT and chemoradiation will have an intact bladder? What is the 5-year
overall survival?
A. 15%
B. 25%
C. 60%
D. 80%
3. The initial pelvic radiotherapy field for a bladder cancer being treated with
bladder-sparing chemoradiation is designed to include which of the following?
A. Inguinal lymph nodes, obturator lymph nodes, and prostate in men.
B. Obturator lymph nodes, proximal 2 cm of the female urethra, and common
iliac lymph nodes.
C. Prostate, internal iliac lymph nodes, and external iliac lymph nodes.
D. External iliac lymph nodes, internal iliac lymph nodes, and common iliac
lymph nodes.
4. What clinical stage is a patient with a large tumor with extension into the
perivesicular tissues without invasion of adjacent organs who also has three
positive lymph nodes in the obturator and internal iliac lymph nodes?
A. T2bN2
B. T3aN2
C. T3bN3

827
D. T4aN1a
5. Which of the following is the most appropriate next step in management for a
patient who has had a TURBT revealing a high-grade papillary urothelial
carcinoma without muscle invasion?
A. Observation
B. CT of the abdomen to look for nodal disease
C. Intravesicular mitomycin C
D. Intravesicular BCG

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35. Housset M, Maulard C, Chretien Y, et al. Combined radiation and chemotherapy
for invasive transitional-cell carcinoma of the bladder: a prospective study. J Clin
Oncol. 1993;11(11):2150–2157.
36. Duchesne GM, Bolger JJ, Griffiths GO, et al. A randomized trial of
hypofractionated schedules of palliative radiotherapy in the management of
bladder carcinoma: results of medical research council trial BA09. Int J Radiat Oncol
Biol Phys. 2000;47(2):379–388.

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26C Cancers of
Tract: Testis
the Genitourinary

Julian Johnson and Albert Chang

INTRODUCTION
Testicular cancer is the most common malignancy in men between the ages of 15 and 35
years (1,2). Testicular cancer only accounts for approximately 1% of all malignancies in
adults and <0.2% of all deaths. Disturbingly, between 1973 and 2003 the incidence of
germ cell tumors increased 61% in the United States.
The most established risk factor for testicular cancer is a history of cryptorchidism,
which increases the risk of testicular cancer five times (3,4). Only 10% of patients with
testicular cancer will have a history of cryptorchidism. Orchiopexy lowers the risk.
Interestingly, cryptorchidism increases the risk of testicular cancer in the contralateral
normally descended testis. Patients with a first-degree relative are also at higher risk for
testicular cancer (5). Testicular cancer is 5.4 times more common in white men
compared to black men.
Testicular cancers are divided into seminomatous and nonseminomatous germ cell
tumors (NSGCT). The purpose of this chapter is to describe the approach to stage I and
stage II seminomas. NSGCT and later stage seminomas are treated with chemotherapy
alone. NSGCT are considered more dangerous than seminomas and at one time were
responsible for more than 10% of all cancer deaths in men aged 25 to 34 years (1).
Today, NSGCTs are highly curable with platinum-based multiagent chemotherapy alone;
therefore, radiotherapy plays a minor role (6). Radiotherapy is much more important in
the treatment of seminoma. Some early stage seminomas have a prognosis so favorable
that they may be treated with transinguinal orchiectomy alone. Even patients who
require treatment can enjoy a long life after treatment, increasing the focus on
minimizing long-term sequelae of treatment (7).

DIAGNOSIS
The most common presentation is a painless testicular mass (3). Up to half of patients
will actually have pain in the testicle at diagnosis. A detailed history and physical
examination should be obtained, querying for history of cryptorchidism, and prior
inguinal or scrotal surgery. A physical examination including testicular and abdominal
examination should be undertaken. The normal pattern of nodal drainage leads directly
from the testis to the para-aortic lymph nodes. In patients with a history of inguinal or
scrotal surgery, the risk of aberrant drainage to the inguinal nodes may be increased, so
this area should be examined. Transillumination of the testicle may distinguish between
solid and cystic swelling of the scrotum. All patients should be referred for a testicular
ultrasound. The characteristic appearance of a testicular cancer is a hypoechoic mass.
Patients with a suspected testicular cancer should undergo computed tomography
scan of the abdomen to identify liver or infradiaphragmatic lymph node metastases.
Chest imaging should be obtained to exclude pulmonary metastases.

831
Laboratory studies should include completed blood count, serum chemistry, and liver
function studies. Serum lactate dehydrogenase, α-fetoprotein (AFP), and serum β-human
chorionic gonadotropin (β-HCG) titers are prognostic and should be obtained. These
serum markers also aid the clinician in distinguishing between pure seminoma and
other germ cell tumors and are very useful in monitoring treatment response. AFP or β-
HCG levels may be elevated in up to 90% of nonseminomatous germ cell tumors. A
modest elevation of β-HCG may be found in 15% to 20% of patients with pure
seminoma, whereas an elevated AFP raises the suspicion of mixed tumor. The latter
should be treated as nonseminomatous disease even if histologic evaluation does not
support this finding. Elevation of these markers after treatment raises concern for
residual or recurrent disease.

Treatment Options
Since more than half of all solid swellings of the testis are malignant, all patients with
suspicious solid testicular masses should undergo radical inguinal orchiectomy to
establish diagnosis. There should be no violation of the scrotum nor should the mass
simply be biopsied. Patients can subsequently be managed based on their stage of
disease. The American Joint Commission on Cancer staging system incorporates primary
tumor, size of regional lymph nodes, presence or absence of distant metastases, and
tiered levels of serum LDH, α-fetoprotein, and β-HCG (Table 26C.1) (8). Alternative
staging systems exist, including the Royal Marsden Staging, which divides patients into
stage I (confined to testis), IIA (<2-cm lymph nodes), IIB (2- to 5-cm lymph nodes), IIC
(>5- to 10-cm lymph nodes), IID (>10-cm lymph nodes), stage II (nodes above and/or
below the diaphragm), and stage IV (extralymphatic metastases). There is also an
International Germ Cell Cancer Collaborative Group (IGCCG) classification, which
divides tumors into good prognosis (no nonpulmonary visceral metastases),
intermediate prognosis (nonpulmonary visceral metastases), and poor prognosis (9).
TABLE 26C.1 2010 American Joint Committee on Cancer (AJCC) TNM Staging System for
Testicular Cancer

832
Stage I Seminoma
Patients with stage I seminoma enjoy a variety of options including active surveillance,

833
radiotherapy, and single-agent chemotherapy.

Observation/Active Surveillance
Overall, several studies have shown that early-stage patients who are observed after
inguinal orchiectomy have a 15% to 25% risk of relapse at 5 years (10–15).
Withholding radiotherapy from these patients is advantageous because most of these
patients would not relapse and relapses are salvaged relatively easily (16). Observation
protocols involve computed tomography scans of the abdomen and pelvis with chest
radiographs every 4 months for 2 years, then every 6 months up to 10 years after
diagnosis. Serum markers should be collected every 4 months for 2 years. The effect of
multiple computed tomography scans in this population has not been studied, and the
theoretical increase in the risk of secondary malignancy should be discussed.
A study published by Kaiser retrospectively evaluated 502 patients with stage I
seminoma who were treated with active surveillance, chemotherapy, or radiotherapy
after orchiectomy. Recurrence-free survival at 5 years was 97.2% to 98.3% in the
radiotherapy and chemotherapy groups compared with 89.2% in the group of patients
who were observed. The salvage treatment of relapsed seminoma is quite effective,
resulting in no difference in overall survival or cause-specific survival between groups
(17). A study on a much larger group of patients (n = 6,764) in the Surveillance,
Epidemiology, and End Results database demonstrated that radiotherapy was associated
with an improved cause-specific survival at 20 years with a hazard ratio of 0.37 (18).
At 20 years, the difference in cause-specific survival was statistically significant, but
quite small (cause-specific survival was 98.7% vs. 99.2%). The avoidance of medical
expenses, time off from work, decreased sperm count, radiotherapy-associated fatigue,
and increased risk of second malignancy is attractive to patients and oncologists. In
fact, between 1998 and 2011, the rates of observation after orchiectomy increased from
approximately 24% to 54% (19). Interestingly, this same US study found that
observation was less common at community hospitals and more commonly offered to
ethnic minorities. A subset of patients with stage I seminoma may be at higher risk of
relapse, including those with larger tumors (>4 cm) and rete testis invasion (20). A
large group of researchers from Spain has published a nomogram that incorporates
tumor size as a continuous variable and presence or absence of rete testis invasion (21).

Radiotherapy
When patients are unsuitable for observation due to tumor factors (large tumors or
tumors with rete testis invasion) or patient factors (patient choice, or inability to follow
up with surveillance protocol), patients should be offered adjuvant treatment with
chemotherapy or radiotherapy.

Chemotherapy
The rates of chemotherapy administration increased from 1.5% to 16% while the
utilization of adjuvant radiotherapy decreased from 71% to 29% (19). A randomized
trial in the United Kingdom compared radiotherapy to single-agent carboplatin in 1,447
patients with stage I seminoma. At 5 years, carboplatin was not inferior to adjuvant
radiotherapy for stage I seminomas treated with orchiectomy with recurrence free
survival rates ∼95%. The number of contralateral germ cell tumors were also lower in
the patients who received carboplatin compared to radiotherapy (2 vs. 15) (22). The
most common sites of relapse after radiotherapy were outside of the radiation field
(supradiaphragmatic or inguinal), whereas patients treated with carboplatin most
commonly relapsed in the para-aortic nodes.

834
In summary, stage I seminoma has a very good prognosis. Some patients are at such
low risk of relapse that observation is the optimal strategy. Relapses have good salvage
rates, which makes observation an even more attractive option. For those patients who
require adjuvant treatment to prevent relapse, either single-agent chemotherapy or
adjuvant para-aortic radiotherapy are options. With either treatment, relapse rates are
approximately 5% at 5 years. Cause-specific survival for stage I seminoma remains
>90% for all patients.
Of note, chemotherapy is preferred in patients with congenital horseshoe kidney.
Horseshoe kidney is associated with aberrant lymphatic drainage, which makes
traditional para-aortic and dog-leg fields possibly less efficacious. Furthermore, the
presence of midline renal tissue would predispose the patient to high rates of radiation-
induced nephritis.

Stage II Seminoma
Stage II seminoma is characterized by the presence of regional infradiaphragmatic
lymph node positivity. Biopsy confirmation of lymph node positivity is generally not
considered necessary. Seminoma is very sensitive to chemotherapy and radiation, so
lymph node dissection is generally not part of the treatment for these patients. All
patients with positive lymph nodes require inguinal orchiectomy followed by adjuvant
treatment with chemotherapy or radiotherapy.
Patients referred for radiotherapy should be treated with 30 Gy to the para-aortic and
ipsilateral iliac lymph nodes (dog-leg field) followed by a boost to enlarged lymph
nodes. Nodes less than 2 cm should be boosted to 34 Gy and nodes of 2 to 5 cm should
be boosted to 36 Gy or more.

Stage II with Bulky (>5 cm) Lymph Nodes


Patients with lymph nodes greater than 5 cm should not be managed with radiotherapy.
Bulky lymph nodes portend a high risk of distant relapse (23); therefore, the standard
of care for these patients is platinum-based, multiagent systemic chemotherapy. Even in
the presence of bulky lymph nodes, cure rates are nearly 90% (24). The management of
relapsed disease is similar to the management of bulky disease in that platinum-based
multiagent chemotherapy is the preferred strategy.
Following chemotherapy for bulky node positive disease, patients should have follow-
up imaging until retroperitoneal masses resolve. The data indicates that consolidative
radiotherapy to residual masses does not decrease rates of relapse (25,26). A surgical
series from Memorial Sloan-Kettering Cancer Center indicates that, in 55 patients with
residual masses after chemotherapy who underwent retroperitoneal lymph node
dissection, no patient with a residual mass less than 3 cm had viable tumor. Therefore,
patients with residual masses less than 3 cm are typically observed.

Treatment Planning
Planning radiotherapy for seminoma requires knowledge of the typical patterns of
disease spread. The right and left testicles differ slightly in their lymphatic drainage.
The right testicular lymphatic trunks terminate in the sentinel nodes along the inferior
vena cava and common iliac vein. The left testicular lymphatic trunks travel along the
spermatic vein to drain into the lateral aortic nodes at the left renal vein pedicle. Right
testicular lymphatics may cross over directly to the left PA nodes, but left testicular
lymphatics generally cross to the right only after extensive involvement of the first
station nodes. Tumor may spread in a retrograde fashion to nodes surrounding the vena

835
cava and aorta. Further extension may occur via the thoracic duct to the left
supraclavicular region or by the transdiaphragmatic lymphatics to the mediastinum.
Although the primary drainage is to the retroperitoneal area, some lymphatic channels
may also drain to the iliac lymph nodes. Normal lymphatic drainage may be altered if
the patient has had an orchiopexy, herniorrhaphy, or other surgical procedures in the
pelvis or inguinal region. Early tumor involvement of the epididymis increases the risk
of external iliac nodal involvement.
Most published data on radiotherapy for testicular cancer utilizes opposed
anteroposterior fields with megavoltage photons.
The most common site of lymph node metastasis is the para-aortic lymph nodes
(14,27). Therefore, traditional radiotherapy fields have encompassed the PA nodes and
ipsilateral pelvic nodes (28,29). The superior border is traditionally at the T11/T12
vertebral bodies, while the inferior border was the inguinal ligament (the traditional
“dog-leg” or “hockey-stick” field). Under usual circumstances, pelvic nodal involvement
occurs in only 2% to 3% of patients. A British trial published a comparison of the para-
aortic field to the traditional dog-leg field in 478 men with stage I seminoma. The total
dose was 30 Gy in 15 fractions. Acute toxicity was less common and less severe in the
patients treated with para-aortic radiation only. Sperm counts were also significantly
higher in men on the para-aortic radiotherapy arm. There was no difference in relapse
rates between patients treated with para-aortic compared to combined para-aortic and
dog-leg fields (30). As a result, patients with stage I seminoma who are treated with
adjuvant radiotherapy are often treated with para-aortic fields only (30). In stage II
patients, the PA and ipsilateral pelvic nodes should be treated, and if the PA disease is
bulky, consideration may be given to including the contralateral pelvic nodes. Although
in the past inguinal nodes and the orchiectomy incision have been treated, more recent
information indicates that this may be unnecessary, even if the inguinal area has been
violated by surgery. Surveillance studies have shown an extremely low risk of relapse at
these sites (31); therefore, adding the hemiscrotum and inguinal nodal region to the
treatment portal is normally not required and should be avoided if possible because of
the resulting significant dose to the remaining testicle. Patients with a history of
inguinal or pelvic surgery were also thought to be at risk for altered lymphatic
drainage, and it has been recommended that the treatment fields be altered to include
the pelvic nodes (32). However, several authors challenge this practice since recurrence
rates in surveillance studies are extremely low (29,33). The contralateral, remaining
testis should be placed in a scrotal shield to minimize radiation and prevent
azoospermia.
Intensity-modulated radiotherapy can be used to irradiate the at-risk areas, but the
combination of multiple beams vastly increases the amount of tissue that receives low
doses of radiation. The effect of such a large volume irradiated to a low dose is very
important to consider in this group of young patients. Generally anteroposterior
opposed fields are the preferred means to irradiate the lymph nodes.

RADIATION TREATMENT FIELDS


Para-aortic Fields for Stage I
In patients with no history of pelvic or scrotal surgery and stage I disease, the para-
aortic lymph node region may be treated with equally weighted AP/PA fields. The fields
should target the retroperitoneal lymph nodes but not necessarily the ipsilateral renal
hilar nodes. Preferably, one should contour the aorta and inferior vena cava from the

836
bottom of the T11 vertebrae to the bottom of L5.

FIGURE 26C.1 A,B: Example of filed arrangement based on bony landmarks. Left: AP Para-aortic field. The
superior border is T11, the inferior border is L5. The spinous processes of the vertebral bodies are covered.
Right: AP Dog-leg field used for stage II seminoma. The common and external iliac vessels are treated down to
the upper border of the acetabulum. If gross nodes are present, nodes should be identified on CT based
planning and treated with a 0.8-cm GTV to TV expansion.

The superior border should be placed at the bottom of the T11 vertebral body. The
inferior border will be placed at the bottom of the L5 vertebral body. The lateral borders
should encompass the tips of the transverse processes of the vertebrae and are
approximately 10 cm wide. The para-aortic field is depicted in the left panel of Figure
26C.1.
Dog-leg Fields for Stage IIA–IIB and patients who have undergone ipsilateral
pelvic surgery (i.e., inguinal herniorrhaphy or orchiopexy).
In patients with a history of ipsilateral pelvic surgery or stage II disease, the dog-leg
field should encompass the retroperitoneal lymph nodes, and the ipsilateral common,
external, and proximal iliac lymph nodes down to the top of the acetabulum. For
patients with ipsilateral pelvic surgery, the ipsilateral inguinal nodes and the inguinal
scar should also be targeted. Preferably, the aorta and the inferior vena cava should be
contoured from the bottom of T11 and further inferiorly to the ipsilateral iliac arteries
and veins up to the top of the acetabulum.
The superior border should be placed at the bottom of the T11 vertebral body. The
inferior border should be placed at the top of the acetabulum. The medial border for the
lower aspect of the modified dog-leg field extends from the contralateral transverse
process of the fifth vertebrae to the medial border of the ipsilateral obturator foramen.
The lateral border of the lower aspect of the modified dog-leg field is delineated by a
line from the top of the ipsilateral transverse process of the fifth vertebrae to the
superolateral border of the ipsilateral acetabulum. The dog-leg field is depicted in the
right panel of Figure 26C.1.

837
Dosage and Fractionation

Dosage for Stage I


In addition to field size reduction, randomized data supports reducing the dose of
radiotherapy from 30 to 20 Gy. The MRC TE 18 trial randomized 625 patients to 20 Gy
in 10 fractions or 30 Gy in 15 fractions. At 2 years, the relapse rate in both arms was
3% to 4%. There was no difference in relapse rates at longer follow-up (34). There was
only one death from seminoma in the study. There was significantly less acute fatigue in
the 20 Gy arm, but this difference disappeared by the twelfth week (35). At Princess
Margaret Hospital, 25 Gy in 1.25 Gy daily fractions has been used for more than two
decades without an in-field recurrence (10).

Dosage for Stage II


Stage II seminomas treated with radiotherapy should receive 20 to 30 Gy to the entire
para-aortic and dog-leg field with a 4 to 10 Gy boost to enlarged lymph nodes, which
can be delivered concurrently or sequentially. For example, frequent fractionation
schemes would involve 20 Gy in 1.25 Gy daily fractions while the enlarged lymph nodes
receive 30 Gy in 1.875 Gy daily fractions. Alternatively, the entire field can receive 30
Gy in 2 Gy fractions followed by a 4 to 6 Gy boost to the enlarged lymph nodes.

Prognosis
Successful treatment of germ cell tumors offers the potential for many years of
productive life following treatment. Treatment results vary significantly with tumor
histology and disease stage (Table 26C.2). Pure seminoma, even when metastatic to
retroperitoneal nodes, can be cured in the majority of patients. Stage I seminoma is
associated with a 15% to 20% risk of relapse when treated with orchiectomy alone;
however, virtually all recurrences can be successfully salvaged, and disease-specific
survival approaches 100% (14,27,36). For stage I disease treated with inguinal
orchiectomy and infradiaphragmatic radiation approaches, relapse rates are
approximately 3% to 4% (28–30,33,35,37–45). Virtually all recurrences will be outside
the irradiated area, and again, nearly all recurrences are successfully salvaged, most by
systemic chemotherapy.
TABLE 26C.2 Outcome Following Primary Radiation Therapy for Early Stage Seminoma and
Chemotherapy for Bulky or Advanced Stage Seminoma

838
Relapse rates for stage II patients depend on the bulk of disease and are higher than
for stage I disease but are still only in the range of 5% to 15%. Nonetheless, due to
excellent salvage options, postorchiectomy radiotherapy results in disease-specific
survival rates above 90% (46–48). Patients with bulky disease treated with cisplatin-
based chemotherapy still have excellent survival rates, with long-term survival possible
even in advanced metastatic disease (49,50).
Because of the success in treating testicular cancer, increased attention is paid to the
long-term sequelae resulting from treatment, particularly impaired fertility, secondary
malignancies, and cardiac disease. Men with seminoma commonly have impaired
spermatogenesis at baseline; however, use of proper radiotherapy techniques is critical
to minimize dose to the remaining testicle and preserve fertility. Second malignancies
are increasingly recognized as a significant problem after radiotherapy and/or
chemotherapy for testicular cancer, perhaps occurring in close to 20% of patients
treated for testicular cancer (51). Current trends toward increased use of surveillance in
selected patients and avoidance of mediastinal irradiation should decrease the rates of
these serious late effects. In addition, the adoption of smaller volumes and lower doses
of RT is predicted to significantly reduce the risk of second malignancy following RT
without compromising long-term survival (52).
The relatively indolent course, predictable patterns of early progression, and marked
sensitivity to both radiation and chemotherapy make seminoma one of the most curable
malignancies. Testicular germ cell tumors have become a model for curable cancer, with
cure being the goal of treatment while optimizing the risks of late effects even in
advanced disease. Clinical outcome and survival for nonseminomatous disease is
slightly less than that expected for seminoma, but with cisplatin-based treatment, it is
still quite good.

KEY POINTS
• Testicular cancer is the most common cancer in males of age 15 to 35 years. It is more

839
common in caucasian males.
• Testicular cancer is divided into nonseminomatous germ cell tumors (NSGCTs) and
seminomas. Seminomas almost never have a positive alpha-fetoprotein (α-FP or AFP).
• Radiotherapy is most important as adjuvant treatment for early stage I and II seminomas.
• Stage I seminomas require radical inguinal orchiectomy followed by observation, para-aortic
radiotherapy, or single-agent chemotherapy.
• Primary tumors >4 cm and tumors with rete testis invasion may not be appropriate for
observation. Stage II seminomas with regional lymph nodes ≤5 cm require adjuvant para-
aortic and pelvic radiotherapy or chemotherapy and are not eligible for observation.
• Lymph nodes larger than 5 cm are associated with a high risk of distant metastases. These
patients should be treated with inguinal orchiectomy and adjuvant multiagent systemic
chemotherapy without radiotherapy.
• Following multiagent chemotherapy, residual disease measuring less than 3 cm in size may be
observed.
• At 5 years, overall survival for stage I, stage II, and stage III seminoma is 100%, 97%, and
85%, respectively.
• For stage I seminoma, treat with 20 Gy in 2 Gy fractions. For stage II seminomas, treat the
entire field to 20 to 30 Gy, followed by a boost to a higher dose for positive nodes of 4 to 6
Gy. Alternative fractionation schemes can also be used.

QUESTIONS
1. A 20-year-old man presents with a painless unilateral swelling. Inguinal
orchiectomy reveals a 1-cm seminoma without rete testis invasion. CT of the
abdomen demonstrates several 2-cm lymph nodes in the para-aortic chain. There
are no visceral metastases noted and no lymph nodes above the diaphragm.
Which of the following is the best course of management? The patient wishes to
conceive with his fiancée in the near future, so he is concerned about fertility.
A. Observation with CT scans of the chest, abdomen, and pelvis every 4 months.
B. Single-agent carboplatin with follow-up imaging to monitor for resolution of
positive nodes.
C. Retroperitoneal lymph node dissection to prevent radiation toxicity and
chemotoxicity to the remaining testis.
D. Radiotherapy to the para-aortic and pelvic lymph nodes.
2. A 40-year-old man who has a 4-cm pure seminoma with rete testis invasion and
several enlarged para-aortic lymph nodes undergoes a computed tomography
scan (a priori, his computed tomography scan reveals 1.5-cm residual disease 2
months after chemotherapy). Which of the following is the most appropriate
management option?
A. Retroperitoneal lymph node dissection if the disease is PET positive

840
B. Observation
C. Consolidative radiotherapy to the residual disease with a 1 cm margin
D. Two additional cycles of chemotherapy followed by
3. What is the risk of nodal relapse for patients with stage I seminoma who opt for
observation after a radical inguinal orchiectomy?
A. <5%
B. 15%
C. 40%
D. 80%
4. Which of the following is true regarding studies comparing 20 versus 30 Gy
adjuvant radiotherapy for patients treated with inguinal orchiectomy?
A. Patients who underwent radiotherapy with 30 Gy had a higher risk of late
side effects, including fatigue.
B. Patients who underwent radiotherapy with 30 Gy had a lower risk of pelvic
relapse compared to patients treated with 20 Gy.
C. Patients were treated with para-aortic radiotherapy only in both arms.
D. The relapse rate at 2 years exceeded 5% in the 20 Gy arm.
5. What is the Royal Marsden staging classification for a 3 cm seminoma with rete
testis invasion and a beta-HCG level of 6000?
A. Stage I
B. Stage IB
C. Stage III
D. Stage IS

ANSWERS
1. D
2. B
3. B
4. B
5. A

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adjuvant treatment of stage I testicular seminoma: a report on medical research
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radiotherapy for stage II seminoma. Am J Clin Oncol. 1997;20(2):196–201.
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2008;70(3):853–858.

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27 The Lymphomas

John P. Plastaras, Stefan Both, Amit Maity, and Eli Glatstein

INTRODUCTION
The role of radiotherapy in the treatment of lymphomas has evolved significantly in
recent decades. Once a mainstay of curative treatment for lymphoma, the role of
radiation had become complementary to multiagent chemotherapy for the majority of
patients diagnosed with lymphoma. Many of the studies have been aimed at reducing
radiation doses and volumes treated. In addition, many studies have also investigated
how to eliminate radiation altogether by appropriate use of risk stratification and/or
response to treatment. Modern radiotherapy for lymphoma is thus aimed at maintaining
efficacy while limiting toxicity as much as possible.
The lymphomas are broadly divided between Hodgkin lymphomas (HLs) and non-
Hodgkin lymphomas (NHLs). The WHO has classified 83 subtypes of lymphoma, largely
based on the implementation of immunotyping, with recognition of borderline
categories and entities associated with certain age groups (1). HLs are broadly divided
based on histologic subtype into (1) classic HL (nodular sclerosing, mixed cellularity,
lymphocyte rich, and lymphocyte depleted); and (2) nonclassic HL (nodular lymphocyte
predominant).
NHLs are divided into B-cell and T-cell/NK-cell categories. Treatment approaches
depend not only on histologic subtype, but also on the stage, patient factors, and
predicted clinical behavior. In practice, clinicians often categorize lymphomas as
indolent, aggressive, or highly aggressive, but true aggressiveness may not always track
precisely with pathologic subclassification. This behavior can range broadly from
indolent lymphomas that can take decades to become clinically significant to highly
aggressive lymphomas that can progress within weeks. For diffuse large B-cell
lymphoma (DLBCL), the most commonly diagnosed NHL, subclassification using genetic
profiling is frequently used to divide lymphomas into germinal center B-cell-like and
activated B-cell-like (2). In addition, alterations in c-MYC paired with Bcl-2 or Bcl-6,
resulting in so-called “double-hit lymphomas,” are associated with particularly poor
responses to standard therapy (3). Regardless, observation of the actual clinical course
is a still key factor in making treatment decisions. Although radiation alone is
sometimes used, such as for limited-stage, low-grade follicular lymphomas and
extranodal marginal zone lymphomas, most lymphomas will be treated with
chemotherapy first. Radiotherapy timing, volume treated, and dose are highly
dependent on the type, effectiveness, and response to chemotherapy. When patients are
treated with radiation alone, relapses tend to occur outside of the radiotherapy fields.
When patients are treated with chemotherapy alone, relapses tend to occur at sites of
prior disease. Combining radiation and chemotherapy allows for an opportunity to
truncate both modalities, which minimizes toxicities that are primarily dose dependent
—without sacrificing cure. Therefore, initial multidisciplinary integration is a key for
effectively and safely treating patients with lymphoma.

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STAGING AND PROGNOSIS
The staging system most commonly used for HL and NHL has been the Ann Arbor
Staging System; however, the Lugano Classification, based on an international working
group that met in 2011, has refined the approach to staging, especially with respect to
the use of 18F-FDG PET/CT (4). For nodal lymphomas, patients are grouped into three
general categories based on general treatment approaches: (1) limited stage, (2) stage II
bulky, or (3) advanced stage (Table 27.1). The definition of “bulky” has been modified
based on histology with a recommendation to designate the longest measurement by CT
scan, omitting the term “X.” For HL, a single nodal mass of 10 cm or greater than a
third of the transthoracic diameter by CT is considered bulky, but an upright chest x-ray
is no longer required to determine bulk. For NHL, 6 cm may be used for follicular
lymphoma and 6 to 10 cm for DLBCL. The designation of A or B is based on the
presence of “B” symptoms, which are unexplained fevers, night sweats, and
unexplained weight loss of >10% over a 6-month period. In the revised Lugano
Classification, B symptoms are now only assigned to HL patients since B symptoms do
not appear to affect prognosis in NHL. The wisdom of that decision remains to be seen.
For limited stage HL, prognosis and intensity of treatment is based on factors that
divide patients into favorable or unfavorable risk categories. If a patient has any one of
the risk factors, they are considered unfavorable. The factors that have been used have
varied slightly according to each cooperative group that have run important clinical
trials in HL (Table 27.2). For advanced stage patients, the International Prognostic
Score (IPS) can be used to predict prognosis, with higher scores portending worse
progression-free survival (5). One point is assigned for each of the seven factors: male
sex, age ≥45 years, stage IV, hemoglobin <105 g/L, WBC count ≥15 × 109/L,
lymphocyte count <0.6 × 109/L or <8% of differential albumin <40 g/L. Although
the IPS can predict the chance of relapse and has been used to define high-risk patients
in clinical trials, it has not been frequently used to justify the use of consolidative
radiation.
TABLE 27.1 Revised Staging System for Primary Nodal Lymphomas from the Lugano
Classification (4)

For NHL, there are scoring systems based on clinical factors that can predict
outcomes. For DLBCL, the International Prognostic Index (IPI) uses a point system
similar to the IPS with a point assigned for each negative prognostic factor (elevated
LDH, age >60 years, ECOG performance status >1, Stage III/IV, >1 extranodal sites)
(6). The original IPI was developed before the introduction of rituximab, but the same

846
factors in the rituximab era, the “R-IPI,” identifies prognostic groups with 4-year
progression-free survival ranges of 53%, 80%, and 94% for the three risk groups (7).
Separate IPI scoring systems have been developed for follicular lymphoma and mantle
cell lymphoma to account for the different prognoses of these NHL subtypes.
TABLE 27.2 Factors for Limited-Stage, Unfavorable-Risk Disease

In HL, one of the most powerful and consistent predictors of outcome is interim PET
scans performed part-way through chemotherapy (8–10). However, the value of interim
PET scanning in DLBCL appears less consistent, showing a correlation in some studies
(11–14), but not in others (15–17). When radiotherapy was consistently added to
chemotherapy, a positive interim PET scan did not predict for relapse (18). In a
separate study, an interim positive PET scan was associated with relapse only in
patients treated with chemotherapy alone, but not in those treated with combined
modality therapy (19).

INDICATIONS FOR TREATMENT


In the treatment of lymphomas, the radiation technique depends on the clinical context
and indications for treatment. It is important to determine first and foremost whether
the intent of treatment is curative or palliative. Unlike most solid cancers where “Stage
IV” is nearly synonymous with incurable, advanced stage lymphomas, it can frequently
be cured by chemotherapy with or without radiation. “Consolidative” radiation is the
term used for radiation given after a complete response following chemotherapy as a
strategy to sterilize potential sites of relapse. This can be part of initial therapy or for
relapsed or refractory lymphoma. Although the chances of cure are certainly less in the
relapsed/refractory circumstance, more aggressive treatments including high-dose
chemotherapy with autologous stem cell rescue can often still result in cure. When
radiation alone is used for cure, this is termed “definitive” radiation. Finally, when
radiation is used purely to relieve symptoms without an attempt to alter survival, this is
termed “palliative.” In the palliative setting, there is not an expectation to permanently
prevent sites of lymphoma growing again, and therefore the volumes and doses are
more limited. Due to the radiosensitivity of most lymphomas, even extraordinarily low
doses of radiation can often accomplish goals of symptom control.

Combined Modality for Hodgkin Lymphoma


Combined modality therapy is a standard for limited stage HL in both favorable and
unfavorable risk patients. There are many who prefer a chemotherapy-only approach
for limited stage patients. NCCN Guidelines and ACR Appropriateness Criteria for HL
are frequently updated and reflect the ongoing debate between these approaches with a
focus on matching the right intensity of treatment for each patient. One approach to

847
determining the intensity of treatment is based on prognostic factors at the time of
diagnosis (Table 27.2). The German Hodgkin Study Group trials HD10 and HD11 trials
both studied combined modality approaches with an aim to find the correct intensity of
treatment using a 2 by 2 randomization. In the HD10 trial of favorable risk patients,
chemotherapy intensity was studied, ABVD × 2 versus ABVD × 4, along with involved
field radiotherapy (IFRT) to 20 Gy versus 30 Gy (20). Reduced intensity therapy with
ABVD × 2 and 20 Gy had equivalent freedom from failure compared to the other arms,
and has thus emerged as a standard of care for favorable risk patients. The HD11 trial
studied unfavorable risk patients, who were randomized between ABVD × 4 versus
BEACOPP (standard) and 20 Gy versus 30 Gy (21). In this study, ABVD × 4 was much
less toxic than BEACOPP (standard), but had similar efficacy. Although there was no
difference between 20 and 30 Gy when combined with BEACOPP (standard), there were
more relapses when 20 Gy was used with the less intense ABVD regimen compared to 30
Gy. Thus, ABVD × 4 and 30 Gy remained a standard for unfavorable risk patients
following the results of that trial. An alternate approach to using only prognostic
factors is to use response-adapted treatments, which we prefer. Although there has been
a lot of enthusiasm for using PET/CT during or after all chemotherapy to drive
radiotherapy decisions, there are data to question this approach. The EORTC/LYSA/FIL
H10 trial found that omitting radiation based on interim PET scans lead to an increased
risk of relapse (22). In fact, the PET-response adapted arms had to be closed early in
both the favorable and unfavorable risk portions of this trial. The RAPID UK trial
reported results from a trial in which patients with early stage HL without bulky
mediastinal disease who had a negative PET scan after three cycles of ABVD were
randomized to observation or consolidative radiation (23). Although these results have
been interpreted in different ways, based on their predetermined statistical goals, the
authors were unable to show a noninferiority of the no radiation arm versus the
radiation arm.
The role of radiotherapy in advanced stage HL is very selective. It is usually reserved
for large volume residual disease after chemotherapy (24). The decision to use radiation
in advanced stage patients also depends on the intensity of the chemotherapy. For
example, the HD15 trial, which studied different schedules of the relatively intense
BEACOPP regimen, only gave radiation to PET-positive residual mass that were 2.5 cm
or larger (25). The use of radiotherapy in advanced stage HL remains controversial, but
ongoing clinical trials may help clarify the role more precisely.

Combined Modality for Non-Hodgkin Lymphoma


Probably the most common role for combined modality therapy is for limited stage
DLBCL. Two randomized trials performed prior to the introduction of rituximab have
demonstrated value for the addition of radiation to multiagent chemotherapy. The
ECOG 1484 study evaluated the role of adding radiation to complete responders after
eight cycles of CHOP chemotherapy (26). In this setting, radiation improved disease-free
survival but not overall survival. The SWOG 8736 study showed that radiation
combined with limited chemotherapy (CHOP × 3) had improved progression-free and
overall survival to eight cycles of CHOP (27). Although a subsequent report with longer
follow-up showed that significant differences diminished over time, limited
chemotherapy with radiation is still considered a standard of care for carefully selected
patients. However, there have been several other studies that have not shown a benefit
for radiation in the prerituximab era (28,29). Retrospective data and results from a
nonrandomized prospective study (RICOVER-60) have suggested that patients who get

848
radiation, especially for initially bulky DLBCL, have superior outcomes (30–32).

Radiation Alone
Although radiation alone has been used in the past with curative intent for both HL and
NHL, the use of combination chemotherapy has been shown to be more effective for
classic HL and aggressive NHL histologies. However, radiation alone is still used to cure
limited stage nonclassic HL (nodular lymphocyte predominant) and limited stage low-
grade NHL. Radiation alone for low-grade, limited stage follicular lymphoma results in a
sizable minority of patients with long-term disease control (33). Limited stage
extranodal marginal zone (MALT) lymphomas of the stomach, thyroid, lung, salivary
glands, and orbit, can all be effectively controlled with doses ranging from 24 to 30 Gy
(34,35). Primary cutaneous B cell lymphomas of the skin can be frequently controlled
with low doses under 12 Gy (36). Radiation alone is also commonly used in the
palliative setting. Very low dose (2 Gy × 2) is effective in low-grade histologies (37),
but can result in meaningful palliative responses, even in some aggressive histologies
(38). Although such low doses are effective for palliation, especially in patients with
multiple sites of involvement, higher doses are still recommended for the curative
setting (39).

Relapsed/Refractory Setting
With the trend of chemotherapy alone being used for initial therapy, there has been an
increased fraction of patients referred only after chemotherapy has failed. There is still
hope for cure in patients who have persistent disease after initial standard therapy or
when lymphoma relapses after first remission. For both HL and NHL, high-dose
chemotherapy with stem cell rescue can result in cure. There remains uncertainty just
exactly how good this strategy is because most analyses fail to look at the intention to
treat with transplant as opposed to those who actually receive the autologous
transplant. When radiotherapy can be incorporated with salvage therapy, there appear
to be improved outcomes (40,41). For patients who relapse after high-dose
chemotherapy with stem cell rescue, radiation can help lead to long-term survival in
some patients, particularly if all sites of relapse are radiated (42). The optimal sequence
of when radiation should be used in salvage regimens is not known, but there does
appear to be value of adding radiation when possible.

RADIATION THERAPY TECHNIQUES


History of Field Design
The history of the treatment of lymphoma paralleled the early history of radiotherapy
itself. While curative treatment for HL was being developed, we also saw the
introduction of the linear accelerator by Henry Kaplan, the concept of treating
microscopic disease in the hopes of cures, and the use of customized blocks to shape
fields to minimize toxicity. Originally, radiation fields were designed using 2-
dimensional (2D) planning, based on anatomical landmarks visible on plain x-ray film
or fluoroscopy. When radiation was used as the primary modality for cure, very large
treatment volumes were employed, with the attempt to treat all nodal tissue. As
effective multiagent chemotherapy was developed, trials demonstrated that fields could
be reduced from total nodal radiation, subtotal nodal irradiation, extended field,
mantle, inverted-Y, and then IFRT (Figs. 27.1 and 27.2). The 2D definitions for IFRT

849
were canonized in a 2002 review by Drs. Yahalom and Mauch (43). For some time, IFRT
was incorporated in a standard manner into combined modality lymphoma trials
(20,21,27). Most of these 2D fields used anterior–posterior/posterior–anterior (AP/PA)
field arrangements. As 3-dimensional (3D) planned conformal radiation therapy and
intensity modulated radiation therapy (IMRT) became standard in other disease sites,
their application in lymphoma appeared (44,45). The application and comparison of
volumetric treatment-planning techniques obviously required delineation of treatment
volumes, which was more conceivable in the IFRT era (46,47). Different groups varied
on exactly how to contour the target volumes based on the IFRT concept, but having
specific targets enabled technique development to keep dose to organs-at-risk (OAR)
below predefined limits (48). Concurrently, with the advent of volumetric planning for
lymphoma, some centers adopted even more limited radiation volumes, using an
“involved node radiotherapy” (INRT) concept. The INRT concept involves treating only
the areas of previously abnormal disease with margin, but not attempting to treat any
elective nodal volumes. Single-institution and pooled results have shown that the risk of
failure in regions that would have been treated using IFRT was rare (49). The EORTC–
GELA group adopted INRT for their next study and described how to define these
volumes (50,51). Central to the precise definition of these limited radiation volumes was
the use of PET/CT in the treatment planning position to ensure accuracy; however, this
is difficult to achieve in practice outside of a clinical trial. Smaller target volumes
inevitably result in lower dose to OARs, in particular heart, lung, breast, and thyroid
(52). In addition, compared to IFRT, INRT is predicted to have a lower risk of secondary
cancers (53). In practice, it is rare to have the opportunity to simulate the patient prior
to starting chemotherapy. Most routine diagnostic PET/CT scans are not performed in
optimal radiotherapy positions, so rigid fusions with prechemotherapy scans are flawed.
However, the impact of positioning may be helped with the advent of deformable image
fusion.

850
Figure 27.1 Historic very large radiation fields used in the treatment of lymphoma based on 2D landmarks. A:
Total nodal irradiation (TNI). B: Subtotal nodal lymph node irradiation (STLNI). (Reproduced from Hill-
Kayser CE, Plastaras JP, Tochner Z, et al. (95))

Figure 27.2 Historic limited radiation fields for mediastinal lymphoma based on 2D landmarks. A: The classic
mantle field consisted of treatment to the bilateral neck, supraclavicular regions, axillae, hilae, mediastinum, and
pericardial nodes. B: The “Modified mantle” that blocks the axillary regions reduces breast cancer risk (96) and
pulmonary toxicity. C: IFRT for mediastinal lymphoma based on Yahalom and Mauch (43) blocks the high
neck and reduces dose to the carotid arteries, salivary glands, and dentition. (Reproduced from Hill-Kayser CE,
Plastaras JP, Tochner Z, et al. (95))

Involved Site Radiotherapy


In order to take into account the reality of poor fusions, the concept of “involved site

851
radiotherapy” (ISRT) has been advocated by the International Lymphoma Radiation
Oncology Group for HL and NHL (ILROG) (54,55). Essentially, the concept entails using
volume-based radiotherapy techniques according to the International Commission on
Radiation Units and Measurements (ICRU) without any elective nodal radiation.
Volumes are expanded liberally to account for inaccuracies in fusion and uncertainty
when trying to surmise how lymphomas shrink during chemotherapy. When lymphomas
shrink during chemotherapy, the postchemotherapy volume is used to define the clinical
target volume radially, but the prechemotherapy volume is used superior-inferiorly.
Omission of elective nodal groups is only advocated in the setting of effective
chemotherapy.

Extranodal Lymphomas
Extranodal lymphomas pose a particular challenge when determining the radiation
volumes. The ILROG has published guidelines for a variety of extranodal sites (56).
According to ILROG guidelines, if an orbital lymphoma only involves the conjunctiva or
eyelid, the entire conjunctival reflection to the fornices is usually treated, but not the
entire orbit. However, if the lymphoma involves the retrobulbar region, lacrimal gland,
or is a deep conjunctival lesion, the entire orbit is usually treated. A small but poignant
series demonstrated that partial orbital radiation leads to a high ipsilateral relapse rate
(57). Thus, lower doses of radiation are advocated to decrease toxicity rather than
geometric attempts to avoid periorbital OARs. Other challenging locations are the
nasal/paranasal sinuses. Extranodal NK/T cell lymphomas, nasal type are a particular
subtype of NHL that requires special attention. For limited stage extranodal NK/T cell
lymphomas, primary radiotherapy, with or without concurrent chemotherapy to high
doses (> or = 50 Gy), can result in cure. For aggressive NHL of the sinuses, the large
majority of which turn out to be DLBCL, induction chemotherapy with R-CHOP is
commonly employed. The consolidative radiation volume should include the entirety of
the affected sinus and any sinuses that are breached, but uninvolved sinuses need not
be included in the CTV in the era of modern imaging and combined modality therapy
(56).
Cutaneous lymphomas also pose challenges in determining the appropriate radiation
volume, technique, and dose. First and foremost, an understanding of the
dermatopathology is key to determining the appropriate treatment. The ILROG has
published general guidelines for treatment of cutaneous lymphomas (58). When limited
to a localized distribution, certain lymphomas such as primary cutaneous follicle center
lymphoma, primary cutaneous marginal zone lymphoma, and primary cutaneous
anaplastic large-cell lymphoma can be cured with radiotherapy alone using a margin of
1 to 1.5 cm for CTV. Primary cutaneous diffuse large B-cell lymphoma, leg-type has a
somewhat worse prognosis and is generally treated with combined modality therapy (R-
CHOP) followed by radiation with 1- to 2-cm expansion to CTV. Cutaneous T-cell
lymphoma (mycosis fungoides) can be treated with radiation depending on the
situation. If diffuse control is required when topicals and other systemic therapies fail,
total skin electron therapy may be a durable palliative treatment, particularly when
intractable pruritus is present. Implementation of total skin electron therapy requires
special commissioning, treatment stands to allow the patient to adopt various positions,
and close attention from physicists to ensure homogenous and tolerable treatment (59).
For focal palliation of CTCL, limited en face electron fields can be used, but somewhat
higher doses than the 4 Gy used for low-grade B cell lymphomas are required for a
reliable response. Compared to a 30% response rate for 4 Gy (2 Gy × 2), 8 Gy (4 Gy ×

852
2) results in a response rate of over 90% (60).

Simulation Techniques
In planning lymphoma cases, patient positioning and immobilization depend on the site
of treatment. For head and neck and mediastinal lymphomas, thermoplastic masks can
allow for limited PTV expansions by reducing interfraction setup errors. In certain
situations, five-point thermoplastic masks can be used to restrict rigidly the relationship
between the neck, clavicles, and mediastinal structures (Fig. 27.3). The position of the
arms depends on the treatment volume as well as the technique. While arms up may
better reproduce the prechemotherapy PET/CT allowing better image fusion, it limits
the potential use of lateral beam angles to approach the neck and/or Waldeyer ring.
Arms down may limit certain lateral beam angles for thoracic volumes. The position of
the arms does alter the position of axillary nodes, which should be considered if they
need to be treated. Ultimately, the decision to treat arms up, down, or akimbo is patient-
and technique-specific. Putting female patients on an incline board can move the breasts
and heart away from the upper mediastinum, potentially decreasing dose to the
structures (61). For inguinal lymphomas, “frog-leg” positions can alleviate skin folds as
a measure to reduce skin toxicity. In addition, these positions allow for more freedom to
move the penis/scrotum away from intended fields or to use a “clamshell” to reduce
dose to the testicles. Ideally, CT-compatible mock clamshells can be used to position
optimally the patient when testicular shielding is desired (Fig. 27.4).

Figure 27.3 Thermoplastic immobilization mask. For optimal stabilization of the cervical and thoracic spine
with respect to clavicle position, a five-point mask that encompasses the shoulders can be used. If breath-hold
devices are used, holes need to be made to accommodate these devices.

In addition to fusion with PET/CT scans, intravenous contrast-enhanced CT scans can


be very helpful in delineating nodes. Small PET-negative nodes that are present on
prechemotherapy scans that disappear are highly suspicious for involvement by
lymphoma, but are difficult to discern without contrast (50). When using the ISRT
paradigm, exclusion of normal structures is greatly aided by intravenous contrast,
especially around the heart and great vessels (54,55). If cardiac substructures are to be
preferentially avoided using ultra-conformal techniques, then contrast is also a must
(62). Oral contrast is appropriate for certain abdominal lymphomas, particularly those
in the mesentery. Barium can be used, but it can cause some small errors in photon

853
dose-distributions if the Hounsfield units are not overridden to water-equivalent prior to
planning. If proton therapy is used, any structures with contrast must be overridden
due to profound effects on the dose distribution, or noncontrast and contrast scans
should be acquired at the time of simulation. Alternative low attenuation oral contrast
agents, such as VoLumen or milk (63), with low Hounsfield units, can reduce this issue,
but delineating bowel using “negative contrast agents” can be challenging when bowel
is intimately involved with tumor (Figs. 27.5A and 27.5B). The addition of intravenous
contrast to negative contrast agents improves the ability to distinguish bowel as the
bowel wall is enhanced (Figs. 27.5C and 27.5D).

Figure 27.4 CT-compatible testicular shield. The high-density “clamshell” used during treatment creates artifact
that compromises CT-based radiation contouring and planning. A mock testicular shield made from CT-
compatible material is shown in axial cross-section that allows for accurate body positioning.

Figure 27.5 High-density and low-density oral contrast agents with or without intravenous contrast in CT

854
simulation of abdomen and pelvis. A: High-density barium oral contrast with intravenous contrast in the pelvis.
Contrast shows clear delineation of small bowel and blood vessels, which may need to be overridden during
radiotherapy planning. B: Low-density oral contrast, VoLumen without intravenous contrast in the pelvis.
Delineation of bowel and vessel is more difficult. C: VoLumen without intravenous contrast in the abdomen. D:
VoLumen with intravenous contrast in the abdomen shows small bowel more clearly with enhancement of the
bowel wall.

Motion Management
With the advent of highly conformal radiation for lymphoma, close attention to motion
becomes increasingly relevant. In the mediastinum, where respiratory motion
predominates, gated 4-dimensinal (4D) CT scans can be acquired to ascertain actual
target movement. The ISRT guidelines call for use of volumes as described by the
International Commission on Radiation Units and Measurements (ICRU) Report 83
(GTV, CTV, PTV) and Report 62, which delineate the internal target volume (ITV)
(54,55). Large anterior mediastinal masses, even those remaining after chemotherapy,
tend to “pancake out” laterally when patients are supine compared to when upright.
These large masses can move significantly during the breathing cycles, as shown in
Figure 27.6. During the exhale phase, mediastinal masses can extend laterally, which
can lead to increased dose to the lungs and breast tissues, especially when AP/PA field
arrangements are used. During the inhale phase, masses elongate cranio-caudally, but
show a more narrow profile laterally. This narrowing of the mediastinum can be
accentuated with deep (maximum or near maximum) inspiratory breath hold (Fig.
27.7).

Figure 27.6 Effect of respiration on lateral dimensions of mediastinal lymphomas. Fused CT images of axial
slices in maximal inspiration (more narrow) and maximal expiration (wider) from a planning 4D CT scan of a
patient with a residual mass after chemotherapy for Hodgkin lymphoma.

Breath-hold techniques have been explored in treatment planning for lymphoma


(64–68). A Phase II study of deep inspiration breath hold (DIBH) was conducted where
free-breathing and DIBH PET/CT scans were acquired in the treatment position prior to
initiation of chemotherapy as well as postchemotherapy scans. Of the 22 eligible
patients, 19 were preferentially treated with DIBH based on more favorable lung, heart,
and breast dosimetry (66). In this study, which used the RPM system with video/goggle
guidance, they found that the DIBH on average could decrease the mean dose and V20
of the heart and lung without an effect on female breast dose. An alternate approach,

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using moderate DIBH with active breathing control, also decreased mean lung and heart
doses, but actually showed increased dose to the breasts (67). DIBH can reduce heart
and lung doses beyond what can be achieved by IMRT alone (64,65). In practice, the
use of DIBH is more practical for lymphoma patients than lung cancer patients as they
are usually healthy enough to participate in the rigorous demands of this technique
(66).

Figure 27.7 Effect of deep inspiratory breath hold on mediastinal width. Axial CT slices of a patient with
residual anterior mediastinal lymphoma imaged at the level of the carina using either free-breathing (A) or at
deep inspiratory breath-hold (B).

On-Board Imaging
The use of daily IGRT for lymphoma patients can help minimize PTV expansions
required. Alignment to bony anatomy with orthogonal kilovoltage on-board imaging
may be satisfactory for the majority of cases, especially when optimized immobilization
devices are employed. Volumetric daily imaging, such as cone beam CT (CBCT) or CT-
on-rails, can be employed for confirmation of DIBH position and when using highly
conformal techniques, such as IMRT or volumetric modulated arc therapy (VMAT) (69).
Spatial resolution of soft tissue in the abdomen is challenging with CBCT, with only
moderate interobserver correlation for gastric MALT lymphomas (70). When using
proton therapy, variations in patient positioning can result in alterations in the dose
distribution, so particular care is required for highly accurate and reproducible setup.
Close attention is paid to the position of the clavicles, which are notoriously prone to
motion that is independent of the thoracic spine. Until volumetric on-board imaging is
routinely available on proton therapy equipment, verification of off-line 4D CT scans
can help assess whether radiotherapy is robustly delivered.

Radiotherapy Planning Techniques


When ICRU standardized target volumes are used for lymphoma radiation, comparative
radiation planning can help determine the best method for OAR-sparing with good
coverage. Three-dimensional CRT plans using customized beam arrangements other
than AP/PA can selectively spare OARs. For example, anterior mediastinal masses that
drape anteriorly over the upper portion of the heart can be approached with inferior
oblique fields to minimize dose to the heart (Fig. 27.8). IMRT can be used to spare
particular OARs, but this is usually at the expense of larger volumes of lung and/or
breast receiving low doses, obviously an issue for some patients. Using involved field
concept volumes, early work with IMRT in mediastinal lymphomas demonstrated the
ability to lower mean lung (44) or heart (47) doses with IMRT compared to 3D CRT.
Dose-painted IMRT can be used to boost particular regions of elevated risk (44). As in

856
other thoracic sites, beam angles can substantially drive the quality of IMRT plans for
mediastinal lymphomas. Equally spaced coaxial IMRT beam angles are likely to result in
high volumes of lung and breast tissue treated with low–moderate doses compared to
limited beams, such as the “butterfly” technique (69). VMAT plans for mediastinal
lymphomas that concentrically treat patients (68,71) will deliver excessive dose to lung
and breast compared to optimized limited arcs (72). When concentric beam angles/arcs
are employed in the chest, dosimetric studies have suggested that IMRT/VMAT will
increase the risk of second cancers, especially in female patients (53). Beam angle
selection can limit, but not eliminate this risk (69). Unlike the chest, concentrically
delivered VMAT has an appealing dose-distribution for mesenteric lymphomas.
Although whole abdomen radiation for mesenteric sites has fallen out of favor, VMAT
plans deliver a modest dose bath to the mesenteric tissues surrounding residual
abdominal lymphomas.

Figure 27.8 Use of noncoaxial 3D conformal beam arrangements to limit dose to the heart. For this patient with
an anterior mediastinal mass that lay anterior to the heart, delineation of the ITV (orange) and PTV (green)
allows targeting with an off-axis field (anterior-inferior oblique) that decreases dose to the heart compared to a
traditional AP/PA beam arrangement.

Critical to successful implementation of IMRT/VMAT inverse planning is the


formulation of the target coverage goals and OAR dose constraints that reflect a balance
relative to important OARs. Typically for mediastinal lymphomas, the balance between
lung, heart, and breast dose depends on the patient and their personal and family
medical history. The spinal cord becomes increasingly important in the case of
reirradiation. Pulmonary toxicity can manifest either as subacute radiation pneumonitis
or late pulmonary fibrosis. Radiation pneumonitis is relatively uncommon, with rates
ranging from 3% to 10% undergoing initial treatment (73–76). Pneumonitis is more
common (25% to 35%) when radiation is combined with autologous stem cell transplant
in the relapsed/refractory setting (73,75). Lung dosimetric parameters are strong
predictors of risk, with MLD over 13.5 to 14 Gy and V20 of over 30% to 36%
predicting for higher rates (73,75,76). Pinnix et al. (73) specifically studied patients
treated with IMRT, and found that V5 over 55% was the strongest dosimetric predictor
with this technique. The heart dose/volume constraints are particularly important

857
because of the high incidence of cardiac disease noted in survivors of HL. In a large
study from the Netherlands Cancer Institute examining cardiovascular risk in over
2,500 patients treated for HL with a median follow-up of 20 years, patients treated
before the age of 25 were found to have cumulative incidences at age 60 or older of
20%, 31%, and 11%, respectively, for coronary heart disease (CHD), valvular heart
disease (VHD), and heart failure (HF) as first events. The hazard ratios for CHD, VHD,
and HF were 2.7, 6.6, and 2.7, respectively for those who received mediastinal RT
compared to those who did not. Likewise, the Harvard group reported a 20-year risk of
cardiac events of 16% with a median follow-up of 14.7 years in patients who received
mediastinal RT for HL (77).
Of course, given their long follow-up, these studies examining 20-year risk of cardiac
disease included many patients treated with relatively high doses of radiation with large
outdated mantle fields in which much of the heart would have been irradiated. With a
trend in radiotherapy practice over the last 2 decades toward lower doses and smaller
fields, one would expect that the incidence of future cardiac events for patients
receiving current state-of-the-art radiation will be much lower. Using a dosimetric risk-
modeling approach, Maraldo et al. (78) predicted a substantially lower risk in cardiac
disease risk in patients INRT compared to mantle fields. One large study of pediatric
patients treated on German-Austrian DAL-HD trials between the years 1978 and 1995
showed that lower doses were less cardiotoxic, with the cumulative incidence of cardiac
disease after 25 years highest in those who received 36 Gy (21%), decreasing to 10%,
6%, 5%, and 3% in groups that received 30, 25, 20, or 0 Gy respectively (79).
Dose constraints vary by institution, but Cella et al. (80) have proposed the
constraints listed in Table 27.3 based on published literature. In practice, delineation of
cardiac substructures may be tedious, but may help preferentially spare regions when
highly conformal radiation is used. A methodologically controversial study in breast
cancer patients and phantoms claimed that each increase of the mean heart dose of 100
cGy increased the rates of major coronary events by 7.4% (81). Based on this, some use
aggressive limitations on the mean heart dose, such as 4 or 5 Gy, in the hopes of
reducing coronary events.
TABLE 27.3 Organs-at-Risk Target Planning Parameters for Mediastinal Lymphomas as
Suggested by Cella et al. (80)

Similarly, there is not a consensus on a dose parameter for breast tissue in order to
reduce the risk of breast cancer. Travis et al. (82) found an increased risk of breast

858
cancer in all radiation dose categories of 4 Gy or more in young patients. This study
found that risk increased with increasing dose to the location in the breast in which the
subsequent tumor developed, with up to an 8-fold increased risk for doses >40 Gy. A
similar conclusion regarding a dose response for breast cancer was reached by Van
Leewen et al. (83). The model that appears to best fit these clinically observed rates of
breast cancer was developed by Sachs and Brenner and takes into account cellular
repopulation by proliferation that takes place during fractionated radiotherapy (84).
Using this model, Hodgson et al. (85) estimated the risk of breast cancer in patients
treated with radiation and predicted that 35 Gy IFRT would reduce the 20-year excess
relative risk of breast by 63% compared with 35 Gy mantle RT and that low-dose (20
Gy) IFRT would reduce the risk by 77%. There are actual patient data supporting these
theoretical predictions with one study from the Netherlands showing that women with
HL treated with mediastinal irradiation (without axillae) had a substantially lower risk
of developing breast cancer than those treated with mantle field irradiation that would
have included the bilateral axillae (86). Based on these data and given that even very
low doses of radiation may result in second cancers, the ALARA (as low as reasonably
achievable) principle is generally followed along with using the smallest volume of
breast tissue that is feasible when doing treatment planning in females receiving
mediastinal irradiation.

Figure 27.9 Comparison of pencil beam scanned PBT plan with IMRT in mediastinal lymphoma and bilateral
hilar involvement. Axial CT-slice with dose color wash at the level of the hilae with the ITV contoured (orange).
A: IMRT; B: Pencil beam scanned proton therapy using posterior-oblique fields, painted twice.

Proton beam therapy (PBT) for lymphomas is a modality, which delivers a low
integral dose and has the potential to lower dose to specific OARs. For example, even a
single posterior proton field can treat female mediastinal HL patients with the beam
stopping at the chest wall with virtually no breast exposure (Fig. 27.9). This beam-
stopping depth-dose characteristic of PBT is governed by the Bragg peak. Although
having virtually no exit dose can result in dosimetrically superior plans as shown in a
treatment planning system, the depth of penetration depends entirely on what tissue
has been traversed by the beam. The sensitivity of proton deposition to uncertainties,
and in particular to the range and setup, increases the potential for error in actual
delivery and needs to be accounted for carefully. Several dosimetric studies comparing
PBT to conventional 3D conformal photon therapy in patients with mediastinal
lymphomas have demonstrated significantly reduced radiation dose to breast, lung,
heart, and total body (87–90). One study evaluating young women with HL
demonstrated a reduction in unnecessary breast dose by as much as 80% with PBT (88).
A comparative dosimetric study evaluated dose to the heart, lungs, and breasts, and
modeled risks of cardiovascular disease, lung cancer, breast cancer, and the
corresponding life years lost between 3D CRT, VMAT, and PBT (71). They found that
pencil-beam scanned (PBS) proton therapy was estimated to have the lowest life years

859
lost due to predicted treatment-related mortality. In addition, the National
Comprehensive Cancer Network (NCCN) guidelines for HL version 2.2015 stated that
therapy with either photons or protons is acceptable as significant dose reduction to
organs at risk (e.g., lung, heart, and breasts) can be achieved with proton beam
radiotherapy which can reduce the risk of late effects (91). Because ISRT volumes are
based on the unique distributions of lymphomas, PBT beam arrangements need to be
customized to the individual patient. A young woman with axillary disease and upper
mediastinal disease may be best treated with posterior beams, whereas a young man
with an anterior mediastinal mass that drapes over the heart may be best treated with
anterior beams. In general, AP/PA proton beam arrangements are avoided since they do
not exploit the beam stopping advantage of protons. One small study that used AP/PA
proton beams did not detect much of an advantage over photons, which emphasizes the
importance of careful beam selection (92). Both double-scatter (DS) and PBS proton
therapy may be used for lymphoma, and each has its advantages and disadvantages. DS
PBT is less conformal than PBS, especially in the proximal edge of the target volume.
However, due to the necessity of using physical compensators with DS, conformality
distal to the target degrades with DS when the depth of the target changes drastically
over a short distance. This transition typically occurs from the upper mediastinum to
the lower mediastinum when there is disease anterior to the heart. This issue can be
mitigated by splitting fields into upper and lower fields that use different compensators
and half-beam blocking, but this can be cumbersome. PBS PBT offers high 3D dose
conformality and can handle sharply changing target volumes even using a single large
field. The conformality of PBS PBT depends in part by the size of the spot, which is
defined as “sigma.” PBS PBT has been shown to be dosimetrically superior to DS PBT,
IMRT, and 3D CRT with respect to mean heart and lung dose (93). However, PBS is not
a continuous beam and delivers the dose to the target spot-by-spot, layer-by-layer with
technical specifications that vary. Therefore, the dose distribution is more sensitive to
the interplay effect generated by the beam delivery in conjunction with respiratory-
induced target motion. Plan robustness of PBS plans has been confirmed through
exhaustive modeling studies on 4D CT scans taken through a course of radiation (94).
Robustness of target coverage relative to respiratory motion can be improved by
techniques such as dose “repainting,” use of larger spot sizes, active respiratory motion
management, or tracking of the target volume. Lastly, fractionation itself can help
smear out interplay problems. A rule of thumb to maintain robust ITV coverage is to use
a spot with sigma about twice as large as the degree of motion perpendicular to the
beam direction and a single repainting of PBS PBT (94). Although active motion
management techniques (e.g., breath hold) are compatible with PBS PBT, the longer
time for delivery can make it less practical than for DS PBT. Compared to IMRT, both
DS and PBS PBT tend to be less conformal in the high-dose region around the target
volume. The relationship between the target and a sensitive OAR, such as the left
anterior descending coronary artery, will affect which modality dosimetrically is best
for an individual patient.

Individualized Patient Care


For lymphomas, there are multiple ways to achieve cure, which can involve all
chemotherapy, all radiation therapy, or combined modality approaches. Patient
preference, proximity to facilities, co-morbidities, family history, tolerance of
chemotherapy, and PET-based responses can all inform treatment decisions.
Multidisciplinary clinics can help select which patients will benefit from radiotherapy,

860
which is still a powerful tool in the treatment of lymphoma.

ACKNOWLEDGMENTS
The authors would like to thank Angela Natale for help in figure preparation.

KEY POINTS
• Radiation therapy for lymphomas has evolved significantly with lower doses and smaller fields
when effective chemotherapy has been delivered.
• Radiation therapy planning requires target volume definition based on careful review of
prechemotherapy PET/CT scans and postchemotherapy scans to allow volumetric radiation
planning.
• When treatment planning volumes are specifically defined, highly conformal radiation
techniques such as IMRT, VMAT, and proton therapy can be employed to optimize target
coverage and OAR avoidance.
• Although PET/CT responses can help define lymphoma patients with good prognosis,
combined modality therapy results in the highest disease-free survival which should be
balanced with the predicted risk of significant treatment-related toxicity.

QUESTIONS
1. What are the average dosimetric differences between deep breath hold and free
breathing techniques for mediastinal lymphomas?
A. Deep breath hold decreases dose to spinal cord
B. Deep breath hold decreases dose to lungs and heart
C. Deep breath hold decreases dose to female breasts
D. Deep breath hold decreases the PTV margin required for setup error
2. When treating lymphoma patients with an involved site radiotherapy (ISRT)
paradigm, how are previously non-involved lymph node regions incorporated
into target volumes?
A. Previously non-involved regions are omitted when chemotherapy was
effective
B. Previously non-involved regions are omitted even when chemotherapy was
ineffective
C. Previously non-involved regions are treated to a lower dose when
chemotherapy was effective
D. Previously non-involved regions are treated to the full dose unless there is
overlap with OARs
3. What are the average dosimetric differences between AP–PA beam arrangements
and IMRT when treating mediastinal lymphomas?

861
A. IMRT lowers mean heart dose and lung V5
B. IMRT increases mean heart dose and lung V5
C. IMRT lowers mean heart dose and increases lung V5
D. IMRT increases mean heart dose and lowers lung V5
4. The risk of radiation pneumonitis in lymphoma patients is most dependent on
which factor?
A. Cumulative dose of bleomycin
B. History of smoking
C. History of allergic reaction to antibody therapy
D. Mean lung dose over 13.5 Gy
E. Radiotherapy given in newly diagnosed setting
5. Radiotherapy treatment planning using INRT or ISRT focuses on what
parameters for field design and daily alignment?
A. Customized radiation plans based on pre- and postchemotherapy volumes
and daily positioning based on structures with a fixed relationship to the
target volumes
B. Templated blocks with borders based on patient size positioned daily based on
surface anatomy
C. Customized blocks with borders based on easy-to-identify bony anatomy and
positioned daily based on surface anatomy
D. Customized blocks with borders based on easy-to-identify bony anatomy and
positioned daily based on bony anatomy

ANSWERS
1. B
2. A
3. C
4. D
5. A

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28 Cancers of the Head and Neck

Yolanda I. Garces, Charles Mayo, Christopher Beltran, and Robert L.


Foote

INTRODUCTION
Head and neck (H&N) cancer is a complex disease site to master because there are many
factors that one has to consider. First, this group of malignancies encompasses more
than just one disease site. H&N cancers include a wide variety of primary sites from the
orbit, ear, and scalp cranially to the thyroid gland caudally. Further, H&N cancer
physicians need to be proficient in the treatment of a wide variety of histologic
subtypes, from the common squamous cell carcinomas to the rare sarcomas. This review
will focus on the more common adult squamous cell carcinomas of the H&N as well as
thyroid cancers given their increasing incidence; it will not include rare diseases. In
addition, a solid understanding of H&N anatomy as well as the patterns of cancer
spread, both local as well as nodal, are critical to the development of optimal treatment
plans and strong decision making. Finally, a well-integrated multidisciplinary team is
also critical for treatment success.

INCIDENCE AND EPIDEMIOLOGY


An estimated 60,000 US citizens will be afflicted with H&N cancer in 2015. Another
62,500 will be diagnosed with thyroid cancer. The incidence of cancer overall is
declining; which is predominantly due to increased cancer screening and smoking
cessation in recent decades. However, the incidence is increasing for human papilloma
virus (HPV)-related oropharyngeal cancer and thyroid cancer (1). Alarmingly, the 5-
year relative survival rates for larynx cancer have declined from 66% to 63% when
comparing the 1975–1977 to the 2004–2010 cohorts making larynx cancer one of the
two cancers where there has been a statistically significant decline in 5-year survival;
the other being cancer of the uterine corpus. Conversely, the vast majority of other
cancers are now associated with a higher likelihood of 5-year survival (1).
The main risk factor for H&N cancer remains current or past tobacco use. Concurrent
alcohol use significantly augments the risk (2). H&N cancer patients have often
decreased or already quit smoking by the time they are seen by their healthcare team
(3). However, relapse back to smoking remains high. Strong recommendations for
quitting and remaining quit are essential to help improve treatment outcomes, and most
healthcare providers are good at asking and providing this advice. However, beyond
asking and advising (4), it is essential that cancer centers develop mechanisms to assist
with behavioral counseling, providing appropriate cessation medications as well as
tobacco cessation follow-up with patients to optimize outcomes (5). It is well known that
smoking cessation can reduce the risk of second primary cancers (6). The epidemic of
HPV-related oropharynx cancers among younger, relatively healthy individuals who
never smoked is changing the perception of H&N cancer patients and survivors.
The causal relationship between HPV and oropharynx cancers was first described in
2000 (7). The incidence of HPV-related cancers is increasing in the United States and

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worldwide. HPV-related oropharynx cancers are occurring predominantly in never
smoking younger men who are less than 60 years old (8). These cancers are
predominantly located in the tonsil, tongue base, or pharyngeal wall. It is felt that
changes in sex behaviors in developed countries have led to this increase. Men also have
higher rates of HPV prevalence than do women (9). Interestingly, patients who have
HPV-related tumors and are either never smokers or smoked less than 10 pack-years in
their lifetime have a better prognosis (10). Clinical trials are being conducted to exploit
this benefit and to reduce morbidity of treatment.

TREATMENT
General Principles
The treatment of H&N cancer with radiotherapy is typically complex and utilizes
intensity-modulated radiation therapy (IMRT) for the majority of patients. IMRT is
typically delivered with volumetric-modulated arc therapy (VMAT) as discussed in the
treatment section below. The only general exception is for patients with early-stage
larynx cancer, where we generally still utilize 3D-conformal fields in which the
outcomes are excellent and the risk of long-term complications is low due to the small
field size (see Fig. 28.1A) (11). The field arrangement for an early-stage larynx patient
typically is opposed laterals that enter “above” or “cranial to” the shoulders. One
centimeter of bolus material is placed over the skin overlying the anterior commissure
region for patients who have anterior commissure involvement and a “thin” neck with
less than 1 cm of subcutaneous tissue between the skin and the anterior thyroid
cartilage. Wedges with the heels placed anteriorly are utilized to keep the dose uniform
throughout the target volume (see Fig. 28.1B). However, it is fairly common for centers
to utilize field-in-field techniques or dynamic wedges rather than physical wedges. The
dose of radiation for invasive cancers typically ranges from 225 to 200 cGy per day to a
total dose of 6,300 to 7,000 cGy, respectively. For some T2 larynx cancers utilizing a
BID fractionation of 120 cGy with at least a 6-hour interval between fractions to a total
dose of 7,920 cGy provides increased local control (12). There are dosimetric studies as
well as early retrospective clinical data that are evaluating carotid artery sparing
techniques to minimize possible long-term complications from definitive treatments
including carotid stenosis and stroke (13,14).

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Figure 28.1 A: Early larynx (cT1N0) cancer treatment field. B: Early larynx (cT1N0) cancer isodoses.

The vast majority of H&N patients are being treated with IMRT in the last decade
with comparative effectiveness research showing that the primary reason for this being
an improvement in xerostomia for patients who receive IMRT and are able to undergo
parotid sparing techniques (15). These patients require a multidisciplinary team to best
identify the most appropriate treatment options. Therefore, this section will focus on
general treatment principles for optimal H&N treatment and then review unique issues
as they relate to H&N cancers including the following: target volumes and normal organ
contouring, planning challenges for dosimetrists and physicists, image-guided and
adaptive radiation therapy, and finally novel radiation therapy techniques like
intensity-modulated particle therapy.

General Treatment Recommendations


It is beyond the scope of this chapter to discuss which primary treatment option
(surgery vs. radiation therapy) is best for patients, and it will focus primarily on
definitive treatments for the majority of patients and discuss postoperative challenges
for H&N cancer (squamous cell carcinomas and well-differentiated thyroid carcinoma)
patients as well. Treatment volumes for both the primary (16,17) and nodes (18) are
summarized by disease site for the uninvolved neck to the N3 neck in Tables 28.1 and
28.2. The primary and nodal tumor volume (gross tumor volume: GTVp, GTVn) is
determined by radiologic imaging which could include CT simulation with or without IV
contrast, contrast-enhanced CT, PET/CT, or MRI as well as a good clinical examination
including nasopharyngolaryngoscopy. It is also beyond the scope of this chapter to
discuss the various dose options for each disease site and/or clinical scenario. The
typical doses of 7,000 cGy, 6,300 cGy, and 5,600 cGy in 35 fractions for high-,
intermediate-, and low-risk target volumes for definitive cases are displayed in Table
28.2. Similarly, postoperative radiation doses are 6,000 cGy and 5,400 cGy in 30
fractions for the high- and low-risk target volumes.
For postoperative patients, chemotherapy is added to radiation therapy primarily for

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fit patients with high-risk features of extracapsular extension and/or positive margins
(19). Chemotherapy is typically cisplatin-based, but there are ongoing clinical trials
investigating various chemotherapy regimens for high-risk patients including docetaxol
and cetuximab (Radiation Therapy Oncology Group (RTOG) 1216, ClinicalTrial.gov
Identifier NCT01810913). Of note, this trial includes patients with high-risk non–HPV-
related oropharynx cancers. There is an intermediate-risk group of patients who should
consider radiation therapy alone or participation in a clinical trial that is looking at the
addition of cetuximab (RTOG 0920, ClinicalTrial.gov Identifier NCT00956007). The
patients eligible for this clinical trial have the following risk factors: perineural or
lymphovascular invasion, a single lymph node greater than 3 cm or ≥2 lymph nodes
(all less than 6 cm) with no extracapsular extension, close margins (within 5 mm), a T3
or T4 primary tumor of the oral cavity, oropharynx, or larynx, or a T2 oral cavity
cancer with >5-mm depth of invasion. It is essential that all patients are seen promptly
after surgery as the complexity of treatment planning and the social factors associated
with H&N cancer patients can make a long and possibly toxic treatment challenging for
patients. Ideally, the entire “package” of treatment from surgery to the completion of
radiation therapy is delivered within 11 weeks from the date of surgery (20).
TABLE 28.1 Primary Tumor Site and Gross Tumor Volume (GTVp) Delineations

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TABLE 28.2 Target Volumes by Dose and Disease Site for the N0 through N3 Neck

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875
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877
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Treatment volumes in the postoperative setting do differ slightly from definitive cases
as one needs to consider the surgery performed and invasion of the tumor into adjacent
sites for the primary and nodal disease clinical target volume (CTV). Typically, no GTV
is identified on the planning study since the primary tumor and involved nodes have
been completely resected with negative margins. A pre-op GTV can be added as a guide,
but this volume is not used for CTV or planning target volume (PTV) expansions. The
nodal levels and volumes tend to be as described by the International Multi-Cooperative
Group Consensus 2013 Neck Node Guideline (18). A simultaneous integrated boost (SIB)
to 66 Gy in 30 fractions to the site of a positive margin is included in the treatment
plan and is designed with the aid of surgical clips and/or a thorough review of the
operative note, pathology report, preoperative imaging, and communication with the
surgeon.
No data exist to support different volumes or expansions for patients with HPV-
related disease with or without extracapsular extension; however, there is great interest
in decreasing the dose or intensity of the radiation treatments for patients with
favorable prognosis who have undergone resection. There are several studies looking at
dose de-escalation in the setting or primary radiation therapy including the following
ClinicalTrials.gov Identifiers—NCT02254278, NCT01706939, NCT01088802,
NCT01302834, NCT02258659, NCT01663259, and NCT02159703. Three additional
studies in the postoperative setting will be highlighted as follows: First, the Eastern
Cooperative Oncology Group (ECOG) is conducting a randomized phase II trial of
transoral surgery followed by low-dose or standard-dose radiation therapy in HPV-
related stage III to IVA patients who are intermediate risk (ECOG E3311 trial,
ClinicalTrials.gov Identifier NCT01898494). Second, Washington University is
conducting a three-institution trial called ADEPT which is looking at adjuvant dose de-
escalation for extracapsular spread among p16 positive patients who have undergone
transoral resection (ADEPT trial, ClinicalTrials.gov Identifier NCT01687413). Finally,
Mayo Clinic is conducting a single institution trial which is offering patients twice-daily
adjuvant hyperfractionated radiation therapy to 3,000 or 3,600 cGy in 150 cGy
fractions over 2 weeks in combination with docetaxol for patients with or without
extracapsular nodal extension, respectively (MC1273, ClinicalTrials.gov Identifier
NCT01932697). All these trials are ongoing and will likely inform future treatment
options for this growing and favorable subgroup of patients.
Thyroid cancer patients can also be treated in the adjuvant setting. However, the role
of adjuvant radiation therapy remains somewhat controversial for the well-
differentiated thyroid cancers, given the lack of randomized trials. There are several
retrospective series that support its use (21–23). Because of this lack of evidence, the
national guidelines, including those of the American Thyroid Association and the

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National Comprehensive Cancer Network, recommend that radiation therapy be
discussed in those who have gross residual disease that is unresectable, not radioiodine
avid, and is threatening vital structures among those patients with papillary, follicular,
and Hurthle cell cancers (24,25). They also recommend adjuvant radiation for those
patients with medullary cancers who have gross extrathyroidal extension and a positive
margin or have medium- to high-volume extranodal extension (26). Radiation therapy
can help decrease the risk of local recurrence and may improve survival; studies
support the use of IMRT (27). Because of the associated acute side effects, many
providers are reluctant to refer their patients for radiation therapy and few centers
have expertise in this setting.
Anaplastic thyroid cancer (ATC) represents a rare form of thyroid cancer that does
require intensive treatments if found when still locally and regionally confined. Success
with aggressive surgery, radiation therapy, and chemotherapy (28–30) has led to the
ongoing RTOG trial evaluating paclitaxel and pazopanib with radiation therapy (RTOG
0912, ClinicalTrials.gov Identifier NCT 01236547). The American Thyroid Association
published their guideline for the management of ATC in 2012 and advocates for an
aggressive approach for patients with stage IVA or IVB resectable and select stage IVB
unresectable patients (26). Again, IMRT is an important component of treatment for
these patients and clinical experience is valuable. See Figure 28.2 for a case example.

Figure 28.2 Anaplastic thyroid case example. A 60-year-old female presented with localized stage IVA (pT4 a
N1 a M0) anaplastic thyroid carcinoma in 2012. At the time of her total thyroidectomy and central
compartment node dissection, she was found to have anaplastic thyroid carcinoma arising from an encapsulated
follicular variant of papillary thyroid carcinoma within the right lobe of her thyroid gland (3.4 × 2.8 × 2.5 cm
mass). She had extrathyroidal extension as well as a focally positive margin. She had one out of two lymph nodes
in the central compartment involved with anaplastic thyroid carcinoma. She had four right central neck
compartment lymph nodes and one Delphian lymph node that were negative for carcinoma. She had no evidence
of distant disease. She was then treated on RTOG 0912 with definitive radiation (6,600 cGy and 5,940 cGy in
33 fractions delivered to her high- and low-risk regions, respectively). See the color wash figures in the axial,
coronal, and sagittal planes. The DVH curves shown in the upper-right panel show the spinal cord (yellow curve)
and right and left parotid glands (blue and brown curves, respectively). The patient has done well with no
evidence of local-regional disease recurrence, but did develop biopsy-proven metastatic disease in her lungs and
left lower extremity (adductor muscles, lymph nodes, and skin) in May 2014 which has been treated with

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stereotactic body radiation therapy, cryoablation, and surgery. She remains PS 0 and has not received systemic
chemotherapy as of July 2015.

Organs at Risk Contouring and Dose Constraints


Contouring the organs at risk (OARs) for H&N cancer patients can be very involved and
time consuming. Oftentimes, contouring 20 to 30 OARs as well as 3 to 9 target volumes
(GTV, CTV and/or PTVs) is required. These GTVs and CTVs can be in close proximity to
radiosensitive structures (e.g., spinal cord, brachial plexus, optic structures, and
salivary glands) great care must be taken in contouring and planning as these structures
are likely adjacent to steep dose gradients. Often a specified margin is placed on these
OARs to develop a planning organ at risk volume (PRV). CTV expansions do not include
bone, air, or adjacent organs unless they are involved. Further, PTV expansions of 5 mm
are utilized for patients undergoing cone beam CT scan (CBCT) for patient setup based
on studies of our immobilization system (31), and 2 to 3 mm for Brainlab ExacTrac.
There are excellent atlases as well as anatomy books that can help with contouring of
the organs (32–36) as well as targets (16,18). The current dose constraints that are
utilized for H&N cancer planning at Mayo Clinic are outlined in Table 28.3.
TABLE 28.3 Mayo Clinic H&N Cancer Normal Tissue Dose Constraints for Standard
Fractionation Adjuvant or Definitive Radiation Therapy

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Dosimetric Considerations
Clearly defined nomenclature is critical to understanding dose constraints and goals of
treatment planning. Dosimetrists understand that good plans are often a trade-off
between target coverage and protection of normal structures. Figure 28.3 illustrates the
nomenclature used in Tables 28.3 and 28.4 for defining dose volume histogram (DVH)
metrics. Planning priorities are requested where the physician requests a priority of 1,
2, 3, or “report” after careful contouring and discussion with the patient in terms of
goals of therapy and the risks from the treatment. These priorities are designed to
balance the doses to the targets and to the critical normal structures like the salivary
glands, spinal cord, and optic structures. Finally, a treatment plan is a combination of
evaluation of the isodose curves and DVH metrics while taking into account target
coverage and what was achievable on OARs. One can also “report” doses to structures
that might not have strict or well-understood dose constraints like the thyroid gland,
mastoids, or the semicircular canals. The normal tissue constraints utilized come from a
combination of clinical experience, the Quantitative Analyses of Normal Tissue Effect in
the Clinic (QUANTEC) supplement, and prior and ongoing RTOG studies (37). See Table
28.3.

Figure 28.3 Dose versus volume nomenclature.

Table 28.4 describes the end point dictionary utilized for this clear nomenclature.
Both absolute and relative values for dose and volume are used according to the issue
addressed by the constraint. The nomenclature defines both input and output units.
Output units are enclosed in square brackets. Limits on high doses are typically given a
higher priority for the minimum dose to the hottest 0.03 cc subvolume of structure
(D0.03 cc[Gy]) than for the maximum dose to any single pixel in the structure
(Max[Gy]). Similarly, keeping a subvolume of a structure less than 0.1 cc receiving 54
Gy or more, for example in the optic nerve (V54 Gy <0.1 cc), is also more valuable
than the Max[Gy] dose. In addition to monitoring volumes receiving a specified dose or
more (e.g., PTV:V95%[%], percentage of PTV volume receiving 95% of the prescribed

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dose or more), we track the volume of target that is underdosed. For example
CTV:CV95%[cc] is the absolute volume of CTV that received 95% of the prescribed dose
or less.
TABLE 28.4 End Point Dictionary

Physics Challenges
Treatment planning is a negotiation with what is possible. It is typically not possible to
meet all constraints for target coverage and for normal tissue sparing, since these
structures are often adjacent or overlapping. Planning optimization can be made more
efficient, quickly achieving treatment plans that reflect overall planning objectives,
through use of dose sculpting structures in addition to constraints on normal and target
tissues alone.
For targets, a planning volume or “IMRT_PTV” is created for each PTV dose level
(e.g., IMRT_PTV5400, IMRT_PTV6300, IMRT_PTV7000) to reflect physician preferences
for dose compromises to coverage of the PTV to spare OARs. Each volume is cropped
away from the body surface by 3 mm to reduce skin dose. High dose volumes are
subtracted out of lower dose volumes with a 1-mm margin. If these structures overlap
normal structures that are to be spared with a higher priority than the target (e.g.
brainstem, optic nerve, or brachial plexus), they are cropped out of the planning volume
with a 1- to 3-mm margin. A dose limiting annulus (DLA) is created for each IMRT_PTV
to use in the optimizer to drive the prescribed isodoses to conform to the PTV. Figure
28.4 illustrates creation of the DLAs, as 1- to 2-cm thick shells around their respective
IMRT_PTV with 1-mm gap.

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Figure 28.4 High- and low-dose limiting annulus (DLA).

Buffer structures are created around critical normal structures control dose gradients.
Figure 28.5 illustrates a buffer around the spinal cord and brainstem. The beam
arrangement includes three VMAT arc beams. Collimator angles are ±30 degrees and
90 degrees, with X jaws ≤22 cm. During optimization:

• Max and Min doses are set on IMRT PTVs; PTVs are used for plan evaluation only
• Max dose are set on DLAs corresponding to IMRT_PTV min doses, to drive conformality
• Set max dose to cord ∼4,000 cGy as needed. During optimization, push down volume
at matching dose (e.g., V40 Gy[%] in buffer to soften the dose gradient near the cord
and push the 4,000 cGy line away from the cord/brainstem)
• Push low- and intermediate-dose levels to lower parotid mean doses
• Push high/intermediate dose out of brain
• Push low- and intermediate-dose level on larynx, esophagus, and constrictors as
needed.
• Monitor DVH prescription constraints and add other constraints as needed.

Figure 28.6 illustrates a dose distribution resulting from the use of this approach. The
dose distribution shows the 7,000 cGy (yellow isodose line) covering the PTV_7000
while the 5,940 cGy (blue isodose line) covers the PTV_5940. Treatment plans are
typically produced within 1 to 2 hours by skilled planners. Prior to treatment, the plans
are delivered to a phantom (or other devices) to ensure accurate delivery of plan to a
patient.

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Figure 28.5 Cord/brainstem buffer.

IMRT quality assurance (QA) measurements are carried out for each plan prior to
treatment, to demonstrate the system produces the expected absolute dose and dose
distribution within acceptable limits. There is a broad range of devices used in clinical
practice to carry out IMRT QA. Typically the dose distribution is measured in one or
more flat planes or in a curved plane embedded in a phantom. Typically, measurements
are carried out with the beams irradiating the array at the treatment angles or a single
angle. Measured doses are compared to doses predicted by the treatment planning
system for the measurement plane, examining dose profiles, the fraction of
measurement points passing a gamma test, or both. Measurement devices typically use
diode or ionization chamber arrays, and radiochromic or radiographic film. Some
devices additionally use a single point ionization chamber for assessment of absolute
dose. For planar devices, the user may select a measurement plane that specifically
checks dose gradients near to critical structures, for example, a sagittal plane to check
regions near the cord, brainstem, and larynx.

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Figure 28.6 Dose distribution.

IMRT and VMAT utilize dynamic modification of several parameters (multileaf


collimator, collimator, dose rate, gantry angle, etc.) during irradiation. Disagreement of
measured and predicted doses may result from improper behavior of these components.
In addition, other factors contribute to disagreement. Positioning errors (1 to 2 mm) are
common. In addition, steep dose gradients perpendicular to the measurement planes
can result in substantial differences in measured dose as a result of small (≤1 mm)
errors in positioning of the device with respect to the gradient.
Response of measurement devices may vary with angle of irradiation. If the couch is
not included in the verification plan then attenuation may result in systematic errors.
Calibration of the devices may vary over time. Random, spatially varying errors in the
dose response of the detector range from 0.5% to 5%, depending on the type of detector
used.

Treatment Delivery Including IGRT and ART


The delivery of radiation therapy is a key component to successful treatment. A plan
has to do more than “look good on paper”; it must be deliverable. If a patient is unable
to lay still due to a difficult setup or an uncomfortable immobilization device, the
treatment might not be successful. Great care is taken in simulation for this reason. Our
institutional practice for H&N cancer is to perform two simulations. At the first
simulation, the 3- or 5-point thermoplastic mask (ORFIT Industries, Jericho, NY) with
either a bite block (Precise Bite, CIVCO Medical Solutions, Coralville, IA), mandibular
fluoride carrier or maxillary and mandibular fluoride carriers, oral sponges and/or
customized oral stents, as appropriate, is fabricated. A standard H&N rest is customized
using a Klarity mold (Klarity Medical Products, Newark, OH). The arms are at the
patient sides with the hands holding a ring over the abdomen. The chin is extended for
all cases with the exception of nasal cavity and paranasal sinus cancers. The patient

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then returns after a minimum of 2 hours for the CT simulation, which may be done with
IV contrast. This allows the mask to cure and more closely replicates setting the patient
up for treatment each day. This has minimized our need for re-simulation due to patient
factors like the mask feeling too tight or the interfraction flexion of the head, neck, and
shoulders changing from simulation to treatment. To avoid dose errors and enhanced
skin dose resulting from scatter, immobilization devices should be minimally
attenuating, and not introduce significant dose errors if the immobilization system is
mistakenly omitted from the treatment plan. The delivery of radiation therapy is image
guided as discussed below. We do not routinely utilize ART, but do consider it on a case-
by-case basis as discussed below.
IGRT is an evolving area due to improved computing capabilities and advances in
technology. For example, CBCTs can be obtained in treatment position on the linear
accelerator and a match with 6 degrees of freedom (6-DOF) can be obtained in just 1 to
2 minutes. Our institutional experience has shown this to be more accurate than 3-DOF
and has been rapidly adopted as our standard (31). We continue to use Brainlab
ExacTrac (BrainLab, Feldkirchen, Germany) for small-field nasal cavity and paranasal
sinus cases. On board daily imaging (OBI) is also a quite reasonable approach for
aligning the bony anatomy; but very little soft tissue anatomy can be visualized and/or
utilized. For large fields, we perform OBI to align the patient prior to CBCTs. If tumor
size or shape changes or other systematic changes occur (weight loss or change in size,
shape and/or location of OARs) then no IGRT technique can account for this and one
might need to adapt or change the original treatment plan.
ART is evolving into its own field as well. We counsel patients not to swallow during
simulation and radiation therapy. If the patient has had significant tumor shrinkage or
weight loss, the original plan may no longer be covering the intended treatment volume
(38). Alternatively, the OARs might be receiving more dose than intended. For example,
it has been described that the parotid can shift medially into the high dose volumes and
receive more dose than intended, which would abolish the primary reason for IMRT
(39). Knowing when and how to replan a patient is still an area of active research and
no standard has been developed. How to accumulate the doses across the targets and
OARs is a challenge. We often do not know when the volume change occurred. We do
not precisely know how much dose the target or OARs have received. We do not know if
it will make a clinically meaningful difference in outcomes to replan (40,41). How this
time- and labor-intensive replanning can be incorporated into a safe, efficient, and cost-
effective workflow is yet to be determined. Many questions remain to be answered. The
radiation oncology community is poised to answer these questions to improve outcomes
of radiation therapy.

NOVEL RADIATION THERAPY AND THE FUTURE OF H&N


CANCER TREATMENTS
In the last few years, charged particle radiation therapy has become an accepted and,
some would argue, the preferred treatment for appropriately selected H&N cancers. This
has been made possible by the advent of spot scanning proton and carbon ion radiation
therapy, and thereby intensity-modulated charged particle therapy (IMCPT). Intensity-
modulated proton therapy (IMPT), in particular multi-field optimized (MFO) IMPT,
allows the sculpting of the radiation dose around critical structures near the target area
and good conformality to the target (42). Figure 28.7 compares an IMRT plan to an
MFO-IMPT plan for a H&N cancer treated primarily with radiation therapy including
bilateral cervical lymph nodes. The conformality of the 7,000 cGy(RBE) dose level to the

888
target is very similar, but there is a distinct difference in the doses below 5,000
cGy(RBE), with a clear advantage to the proton plan.
The advantage of proton therapy, and in particular MFO-IMPT, does not come
without a cost. There are three key points that are of particular importance in H&N
IMPT.
First is the robustness of the plan to positional and range errors. In conventional
IMRT planning, a PTV structure is created by adding an appropriate margin to the CTV.
The dose to the PTV is, in general, an adequate surrogate of the CTV when positional
uncertainties are considered. In proton therapy, the PTV concept no longer holds and
this is especially true for H&N cancer treatments due to the large anatomical
heterogeneities, that is many bone-air-tissue interfaces. Some institutions have therefore
dropped the PTV nomenclature and instead use optimization target volumes (OTVs) and
directly evaluate the CTV (and critical structures) under positional and range errors. It
is possible that two IMPT plans give very similar dose distributions, but under
robustness conditions one plan is severely degraded while the other only has minor
perturbations. When evaluating robustness, it is important that the CTV does not
encompass an air cavity as it is difficult to robustly cover air.
They second key point is anatomical changes during the course of therapy. It is
important for a new center treating H&N cancer patients with IMPT to obtain a weekly
CT scan in the treatment position and recast the plan on the new CT. Not only would
target coverage be compromised if the volumes change, but a critical structure that was
previously being spared may now be receiving very high doses. These changes may have
been insignificant in an IMRT plan, but have the potential to be devastating in the
proton setting.
The last key point is to understand the limitation of the immobilization system that is
being used and properly work around those limitations. For example, how does the neck
flexion change on a daily basis; are the shoulders in a reproducible position; or does the
chin/mandible position change throughout the course of treatment. Minimizing these
issues is the first step, but also field arrangements can be chosen that would reduce the
impact of these uncertainties.

Figure 28.7 Comparison of IMRT (left) and IMPT (right) 7,000 cGy(RBE) plan for a definitive bilateral

889
H&N cancer patient. Note the distinct difference in the doses below 5,000 cGy (RBE).

Finally, in this era of targeted agents and immunotherapies, the future of H&N cancer
treatments is bright. Cetuximab added to radiation therapy was a success (43). HPV-
related malignancies likely have a better prognosis in never smokers and the different
molecular mechanisms that underlie this difference could be further exploited.
Similarly, the non–HPV-related malignancies might also have different molecular
signatures that could be targeted (44,45). Various immunotherapies are being explored
for H&N cancers including the following: monoclonal antibody therapies, cytokine
therapies, cancer vaccines, adoptive T-cell immunotherapies, and immunologic targeting
of stem cells (46). Continued understanding and exploration of these molecular
mechanisms and immune responses will play a crucial role in the future of H&N cancer
radiation therapy.

ACKNOWLEDGMENTS
We would like to acknowledge Marlene Huston for assistance with manuscript preparation.

KEY POINTS
• H&N cancer represents a diverse collection of tumor sites and histologies. In addition to a
highly functional multidisciplinary team, mastery of anatomy, patterns of spread, and tumor
recurrence are needed to optimize patient outcomes.
• Careful treatment simulation, planning, and delivery are essential for treatment success.
• Proton beam therapy, in particular IMPT, and carbon ion therapy are emerging technologies
which can further reduce dose to normal tissues and increase dose to target volumes.

QUESTIONS
1. According to SEER data, the incidence of which type of H&N cancer is increasing
when comparing a 1970 cohort to a 2000 cohort of patients?
A. Larynx cancer
B. HPV-related oropharyngeal cancer
C. Oral cavity cancer
D. Hypopharynx cancer
2. Which of the following is the most appropriate adjustment of CTV expansion in a
46-year-old never smoking male with an HPV-related base of tongue cancer,
given the favorable prognosis?
A. Decrease
B. None
C. Increase
3. Which of the following volumes is not used in proton beam therapy treatment
planning?

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A. GTV
B. CTV
C. PTV
D. OTV

ANSWERS
1. B The incidence is increasing for HPV-related oropharyngeal cancers.
2. B There are ongoing studies looking at various aspects of dose de-escalation
to reduce toxicity, but none are decreasing the margins.
3. C PTV is not used in proton beam therapy treatment planning due to range
uncertainties and beam path tissue inhomogeneity.

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29 Cancers of the Skin, Including Mycosis
Fungoides

Aditya N. Halthore, Kenneth R. Stevens Jr., James C. L. Chow, Zhe (Jay) Chen,
Alexander Sun, and Jonathan P. S. Knisely

INTRODUCTION
The superiority of and justification for radiotherapy for cancers of the skin derives from
its ability to cure while preserving normal tissues, thereby achieving both aesthetic and
functional outcomes. To achieve such an outcome, radiation therapy planning and
implementation must be tailored to the anatomic site and specific tumor characteristics,
any previous treatment, along with some consideration of the patient’s age and
performance status.
Contemporary radiotherapy treatment for skin cancer can be delivered with
superficial or orthovoltage radiotherapy, electron beam therapy, or with isotope or
electronic brachytherapy. Not all centers will have every radiation treatment modality
that may be potentially useful for a given clinical indication. Therefore, critical and
careful use of the available treatment modalities is mandatory to assure that optimal
treatment results will be achieved. Indeed, good judgment may indicate that certain
patients should be referred to alternate centers where specialized equipment or
techniques and the expertise to employ them deftly may be available.
Treatment planning and implementation are usually straightforward, because the
cancer can be directly visualized, palpated, and observed directly during each treatment
setup. The treatment volume is frequently little more than a superficial thin slab
requiring a single direct beam collimated by a simple field-defining device placed on or
near the skin. However, anatomical complexities and the need for individualization of
treatment may make these cases among the most complex encountered by many centers.
The steps in planning irradiation for skin cancer are as follows:

1. Define the extent and size of the cancer (staging).


2. Determine what radiotherapy treatment technique may best address the disease that
needs to be treated.
3. Prescribe the treatment, including beam type, energy, daily fraction size, and total
dose, including, when appropriate, specification of patient immobilization devices,
beam filters, bolus, attenuator, and shielding devices.
4. Design and create any necessary field-defining device, accounting for margins.
5. Design and create device for blocking exit beam when appropriate.
6. Supervise and approve initial irradiation setup.
7. Document setup with photographs of the gross lesion, lesion with shields in place,
and with both machine and shields in place.

GENERAL PRINCIPLES
Staging and Target Volume Determination

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It is generally accepted that cancer staging assists in selection of therapies and provides
prognostic information. In addition, for skin cancer, accurate staging can assist with
radiotherapy treatment planning, augmenting its importance. The Union for
International Cancer Control and the American Joint Commission on Cancer have
published staging systems for squamous and basal cell carcinomas, Merkel cell
carcinoma, melanoma, and cutaneous T-cell lymphoma (1).
There are anatomic and histopathologic high-risk features for staging of basal and
squamous cancers that can be of value in assessing patients for possible
radiotherapeutic treatment. For example, in differentiating between T1 and T2 tumors,
high-risk histopathologic features should be assessed, including differentiation,
thickness and depth of invasion, and whether perineural infiltration is seen. Also
important is anatomic location, with tumors arising on the ear or lip deemed to be high-
risk features.
There is also a designated TNM staging system for carcinomas of the eyelid that
reflects the unique anatomic features and importance of the eyelid and ocular adnexae
in protecting the eye. Knowledge of these staging systems can assist with advocating for
patients receiving appropriate radiation therapy and in optimizing radiotherapy
treatment parameters for these patients.
Despite the fact that skin cancers can be visualized and palpated before planning
treatment and on each day at treatment setup, geographic miss is the most common
cause of failure. Most of these cancers arise on the face or neck, are detected early,
grow slowly, and present with a small tumor volume. The gross dimensions are usually
readily determined by visual examination with adequate lighting to aid inspection for
edema and by palpation to determine the extent of induration and fixation. Visual
magnification is often useful to define the peripheral-most margin of the gross tumor.
Occult extension of cancer beyond the gross margins is generally limited to a few
millimeters, but this varies.
In certain circumstances, special imaging may be extraordinarily valuable in assuring
the high-dose volume completely covers the skin cancer. This may be useful for cancers
with clinically indistinct margins or high histologic grade, for sclerosing basal cell
carcinomas, and for those cancers classified as recurrences following surgery or
irradiation. Patients with signs or symptoms of perineural involvement or regional
nodal metastases, fixity to bone, as well as lesions greater than 5 cm in diameter may
also benefit from specialized imaging.
It should be remembered that basal cell carcinomas arising on skin closely overlying
bone may spread along the periosteum. Tumors in the medial canthal region, overlying
the cranial vault, the malar eminences, and the upper half of the nose are examples of
such sites. Tumors arising at or near periauricular and nasomalar embryonic fusion
planes may have occult deep extension, also meriting careful radiologic workup to
accurately determine the target volume extent. These diagnostic evaluations are
fortunately not required for the majority of skin carcinomas.
The deep margin of the tumor should be encompassed by at least the 90% isodose
surface. Field margins for <2 cm primary tumors should be 1 to 1.5 cm; for tumors >2
cm, field margins should be 1.5 to 2 cm (2). Caution should be exercised in planning
and treating skin cancers over the calvarium to minimize, when feasible, dose to cortical
brain. The use of CT scan-based treatment planning for small skin lesions may introduce
more errors than if a simpler technique of using a transparency to determine the field
size and shape is used. However, for larger, more complex lesions that are deeply
invading and are in contiguity to critical structures, CT simulation, with appropriate
use of multimodal image fusion has improved the ability to accurately plan treatments

896
that will achieve tumor control and normal-tissue sparing.

RADIATION DELIVERY MODALITIES


Commissioning and Calibration
For all radiotherapy equipment, careful commissioning, calibration, and appropriately
detailed and frequent quality assurance are mandatory to avoid underdosing or
overdosing patients. Measurement and review of each treatment machine’s central axis
percent depth dose and cross-sectional isodose curves, based on the type of radiation,
energy, and field size should be routine. A lack of familiarity with routine,
manufacturer-specified usage guidelines, and therapeutic directives that are developed
for the safe use of the equipment is neither in the best interest of the patient nor of the
responsible physician, physicists, and therapy staff.

Superficial and Orthovoltage Therapy


Superficial and orthovoltage therapy refer to using low-energy photon beams in the
range of 50 to 150 kVp for surface lesions and 150 to 500 kVp for lesions deep to the
skin. Although Grenz ray (<20 kVp) and contact therapy (40 to 50 kVp) are no longer
used for invasive skin cancer due to their low penetration depth, superficial and
orthovoltage therapy are still popular because of their simple and effective treatment
administration. Superficial and orthovoltage therapy employ kilovoltage (kV) x-ray
treatment units that are less complicated and easier to set up than electron therapy
delivered from a linear accelerator. Since kV photon beams are used to treat superficial
skin carcinomas and keloids at the skin surface, 3-dimensional (3D) treatment planning
with image modalities such as computed tomography or magnetic resonance is required
only when the extent of deep tumor infiltration and invasion needs to be assessed and
accounted for.
Skin irradiation with superficial or orthovoltage therapy therefore commonly only
needs a clinical markup followed by a beam-on time or monitor unit calculation at the
first treatment fraction. Regarding dosimetric characteristics, though electron beams
have a sharper falloff of depth dose to spare critical tissue deeper than the lesion, small
field, low-energy photon beams have a sharper penumbra and superior flatness, and are
therefore more suitable to treat small lesions. However, low-energy photon beams will
deliver a higher dose to bone than to soft tissues at the same depth (3).

Superficial and Orthovoltage Treatment Units


Nowadays, most kV x-ray treatment units can produce low-energy photon beams in both
the superficial and orthovoltage range. Superficial therapy is commonly delivered with
circular collimators between 2 and 10 cm in diameter at a source-to-surface distance
(SSD) of 20 cm and orthovoltage therapy at an SSD of 50 cm with square applicators
ranging from 4 × 4 cm2 to 10 × 10 cm2. Some square applicators are closed at the
bottom using a piece of flat polymethyl methacrylate plate. Such closed applicators help
to maintain a nonvaried treatment distance from the patient’s skin.
A typical kV x-ray unit (Fig. 29.1) contains a standalone transformer, control console,
treatment couch, and a floor-mounted tube stand, and comes with the aforementioned
circular and square collimators. The treatment head of the unit contains the x-ray tube,
primary collimator, filter, transmission ionization chamber, and the applicator (Fig.
29.2). The filters, made of copper or aluminum, remove low-energy photons and are

897
designed and specified for different photon beam energies, applicators, and specific
(e.g., 20 and 50 cm) SSDs. More recent treatment unit models have an internal
transmission ionization chamber linked to the control console. The application of
monitor units instead of beam-on time avoids error due to the shutter effect in dose
delivery.

Figure 29.1 An example of a modern orthovoltage x-ray unit.

Relative Exposure and Backscatter Factors


In superficial and orthovoltage therapy of skin cancer, the irradiated area may be
tailored by a lead cutout placed on the skin in conjunction with an appropriately sized
circular or square applicator. The collimator selected should be approximately 1 cm
larger (circumferentially) than the maximal size of the cutout, and the lead should, of
course, be large enough that any inadvertent patient motion after a given day’s setup
has been achieved will not result in unwanted exposure of normal tissue.
In calculating the monitor units from the daily prescription dose, relative exposure
and backscatter factors (BSFs) are selected based on variations in applicator and cutout
size for the treatment. Relative exposure factor is the dose ratio of an applicator to a
reference applicator measured using the same SSD. The reference circular applicator
has a diameter of 5 cm while the reference square applicator has a dimension of 10 ×
10 cm2. Since absolute dose calibrations are carried out using the reference circular and
square applicators, the relative exposure factor reflects the change in dose dependent
on applicator selection. The relative exposure factor varies with the applicator size and
photon beam energy, and increases as applicator size increases.

898
Figure 29.2 Circular collimators and square applicators of varying sizes for the orthovoltage unit shown in Figure
29.1 are shown.

BSF is a ratio of the dose at the depth of maximum dose in water to that in air
without water. A special case of the tissue–air ratio is when the depth of the ratio is
equal to the depth of maximum dose. When the applicator type and size are selected for
skin therapy with lesion depth equaling zero, the BSF for the corresponding applicator
reflects the percentage change in dose between the surface of the skin compared to the
dose in air. BSF is normally larger than 1 due to the contribution of electron backscatter
in water, and the factor depends on the field size and photon beam energy. For skin
irradiation, since the lesion is outlined by a cutout made of lead, the BSF is a function of
the field size (cutout) covering the lesion with a margin. In monitor unit calculations,
BSF varies with the field size and photon beam energy delivered through the applicator.

Stand-In/Off and Attenuator Correction


For skin lesions close to the bridge or tip of the nose, the irradiated area may be curved
toward (in) or away (off) from the applicator. The SSD is therefore decreased or
increased and a correction is needed in the monitor unit calculation based on the
inverse square/cube law. From dosimetric measurements, the output of a treatment unit
is known to vary as a function of the inverse square of the distance for the open
applicator, and inverse cube of the distance for the closed applicator. The
radiotherapist measures the stand-in or -off distance in the clinical markup. In the
stand-in case (e.g., tip of nose), the lesion is curved in from the bottom of the
applicator. As the SSD is decreased, a correction is needed to reduce the monitor units.
Similarly, more monitor units are needed when the lesion is curved off from the bottom
of the applicator, leading to a larger SSD in the stand-off case (e.g., bridge of nose).
When the lesion is at the bridge or tip of nose, an attenuator may be used to correct
the dose distribution due to the surface curvature. For superficial or orthovoltage
energies, the nose bridge or tip attenuator is made of a stack of either aluminum or
copper foils, with thickness of each foil equaling 0.5 mm. Each attenuator contains five
layers of aluminum/copper foil, each cut to progressively smaller or larger areas to
compensate for the dose variation from the differences in SSD and oblique beam entry
as a result of the skin surface curvature (Fig. 29.3). The attenuator for the tip of the
nose is therefore shaped like a ziggurat, while that for the bridge of nose is shaped
similarly, like a terraced mountain ridge.

899
Figure 29.3 Cross-sectional schematic of an attenuator (compensator) used for 100 kV therapy for bridge of
nose cancers. Attenuators are best suited for kV x-ray therapy and should be avoided in electron therapy where
unwanted scatter may enlarge the field.

Monitor Unit Calculation


The monitor units required for superficial or orthovoltage therapy are calculated by the
following equation:

Absolute dose calibration to deliver 1 cGy per monitor unit is done using the reference
applicator with a specific SSD. The BSF depends on the field size and photon beam
energy while the relative output factor depends on the size of applicator. An
attenuation factor is used in the calculation to reflect the beam attenuation when a
compensator is used in treatment. The attenuation factor used is smaller than one.
Percentage depth dose (PDD) is needed when the lesion is at a depth from the patient’s
surface. When the lesion depth is set to zero, the value of PDD is equal to 100 in the
above equation. The stand-off correction needs a measurement of the stand-in or -off
distance in the clinical markup and then the application of the inverse square/cube law.
For monitor unit calculation, tables of BSF, relative output factor, attenuation factor
and PDD are all incorporated. The calculation is carried out by two radiotherapists
individually with the result further approved by a medical physicist.

Electron Beam Therapy


Electron beam therapy, delivered with a linear accelerator, has become increasingly
commonly used to treat superficial skin cancers, in part because of some of the
dosimetric advantages of charged particle therapy, and in part because many
radiotherapy departments no longer have access to superficial and orthovoltage therapy
units, as older units have broken down and have not been replaced.
Static electron beam fields are easily employed for lesions on relatively smooth

900
surfaces where the beam may enter orthogonal to the skin surface. A single direct
electron field is employed at a nominal SSD of 100 cm, and provides control rates for
appropriately selected lesions that do not differ from those achieved with x-ray therapy.
Electron beam therapy can provide relatively uniform dose from the surface to a defined
depth (up to ∼5 to 6 cm) and dose rapidly falls off to near zero thereafter. This can be
a major advantage in sparing tissues deep to the cancer, particularly if large fields need
to be irradiated.
The dose specification for treatment is commonly given at a depth that lies at, or
beyond, the distal margin of the disease; the energy chosen for the treatment depends
on the depth of the lesion to be treated. The relative biologic effectiveness (RBE) of
electrons in cancer treatment is 10% to 20% less than that of superficial or orthovoltage
x-rays. This can be simply addressed by prescribing electron beam therapy to the 90%
isodose surface (as opposed to Dmax). The therapeutic range is defined as the depth of
the 90% isodose curve, and is, in centimeters, roughly calculated as one-fourth of the
electron energy in MeV. The therapeutic range of available electron beam energies must
be considered (together with the thickness of bolus required to bring the skin dose up to
full dose) when considering what energy (and bolus thickness) to specify in prescribing
treatment. The therapeutic range of the electron energy chosen should reach the deep
edge of the planning target volume.
Because the dose falls off so rapidly for electron beam therapy (Fig. 29.4), the guiding
principle is to select the next-higher electron energy if there is concern that the 90%
isodose surface is not covering the deep edge of the planning target volume. The
approximate range of the depth of the 90% isodose line for electron beam energies is
shown in Table 29.1. The depth and shape of the isodose lines should be determined for
each treatment machine at various energies and field sizes.

Figure 29.4 Isodose curves for 6-, 9-, and 12-MeV electrons, 8 × 8-cm field, showing greater skin sparing for
lower-energy electron beams.

TABLE 29.1 Range of Depth of 90% Isodose Lines of Electron Beams

901
Electron beam depth doses have extremely important changes that are dependent on
both field size and on treatment energy. The loss of lateral electronic equilibrium in
smaller electron beam fields can significantly affect central axis dose, and this will lead
to the 90% isodose surface shifting to a shallower depth and an increased level of dose
deposition in the skin (4). It is very important to check and double-check small electron
field output factors. Microchambers, thermoluminescent dosimeters (TLDs), or film
dosimetry should be used to confirm the proper output factor. The output factor for
radiation fields of 2 to 3 cm in diameter are ∼0.90 cGy/MU at 100 cm (SSD).
Significant dosage errors can occur if the output factor is not correct. Output factors
that are significantly greater or less than 0.90 should be critically reviewed and double-
checked.
For oblique beam entry, the effects on dose deposition can be quite complex.
Increasing degrees of obliquity beyond ∼20 degrees are associated with a shallower
Dmax and significant changes to the depth–dose curves (4). Equations to permit
calculation of point doses for oblique beam entry on irregular surfaces have been
developed; Monte Carlo techniques can also be used to better understand the effects of
beam obliquity and irregular surface contours (4–6). Misunderstanding and neglecting
the effect of beam obliquity when calculating dose per MU for an oblique electron beam
with an irregular field would lead to a significant dosimetric deviation.
Several additional particular characteristics of electron beam isodose curves that
should be remembered when considering electron beam therapy include the lateral
bulging of lower isodose curves that arises from larger scattering angles of the electrons
in tissue as they lose energy, the lateral constriction of the higher isodose curves
(greater than 80%) at energies >15 MeV, and the fact that electron beams <12 MeV
are associated with skin sparing, which requires the use of bolus material to raise the
skin dose to acceptably high levels (Table 29.1 and Fig. 29.4). This added thickness
must, of course, be included in beam selection and in depth dose calculation.
Bolus is frequently applied directly to the skin in electron beam therapy to increase
the surface dose to near 100% and to limit the dose delivered to deep tissues beyond the
planning target volume. Superflab (Mick Radio-Nuclear Instruments, Mt. Vernon, NY) is
a well-regarded bolus material, because it is nearly tissue equivalent, transparent, and
easy to shape. It is available in 3-, 5-, and 10-mm thickness. This bolus, of course, blurs
or masks the outline of the treatment field. For this reason, it is helpful during the
treatment setup to align the patient and machine as for irradiation but with a gap to
permit bolus placement. The correctness of the position of the treatment field should be

902
visually confirmed. The bolus is then slipped into place. The minimum thickness of
bolus to achieve maximum dose at the surface varies with the energy of the electron
beam (Table 29.1). Although 5- and 10-mm thick boluses are commonly used for 6 and
9 MeV electrons, based on the percent depth-dose data, an 8-mm thick bolus (e.g., a
combination of 5- and 3-mm thickness) may be more appropriate. Bolus can also flatten
out irregular surfaces and reduce the effects of beam obliquity. CT treatment planning
may permit the construction of a customized 3D wax bolus that achieves the goals of
decreasing beam obliquity, decreasing dose to tissues deep to the target, and bringing
the surface dose to an adequately high level.

Field Defining Devices, Field Shaping, and Protection from Exit Beam
For superficial and orthovoltage photon therapy, an applicator cone and a lead shield
of a few millimeter thickness are adequate to protect the skin adjacent to the
radiotherapy portal. Field shaping for electron beam therapy is considerably different
from photon therapy. Electron applicators are always used to decrease the penumbra
from electron scattering in the linac head and in air, and additional customized lead or
Cerrobend field shaping devices may be placed on the applicator, as close as possible to
the patient. To decrease the dose to the patient to below 5% beneath lead shielding, it
needs to be approximately one-tenth as thick as the practical range (Rp) of the electron
beam being used (Table 29.2). A rule of thumb for estimating the thickness of shielding
of lead in millimeter to decrease the dose to below 5% is the energy of the beam in
MeV/2.
When shielding is placed upon the patient surface, as opposed to being mounted on
the applicator, it must be constructed of multiple layers of thin lead, thick lead cut with
a saw, or molded from Cerrobend. With such a surface shield, a zone of increased dose
develops just deep to the edge of the cutout. The magnitude of this dose increases with
beam energy. At lower energies this effect is commonly disregarded. Concern for this
effect, the need for bolus, and the ease of block construction encourage the practice of
fixing the field-defining device for the electron beam on the end of an electron cone
several centimeters from the skin.
TABLE 29.2 Minimum Cerrobend Thickness to Block 95% of Electron Treatment Beam (10 ×
10 cm Field Size)

903
A sequence of steps for fabricating customized shielding for photon or electron beam
therapy of skin cancer may be adapted from these recommendations:
1. Overlay the skin surface with a clear plastic sheet that readily conforms to
undulations of the surface.
2. Trace the field outline on the plastic.
3. Overlay the lead with the plastic. Then, with the point of a knife or awl, punch the
outline through the plastic onto the surface of the lead. Another technique is to draw
the field outline on the skin with a ballpoint pen. Overlay clear adhesive tape on the
skin. The tape will pick up the ink outline. Place the clear adhesive tape with outline
on lead sheet and proceed with the next step.
Cut out the lead sheet target field outline with a knife and smooth the edges of the
cutout. Adhesive tape placed over the cutout’s edges will prevent any sharp edges from
causing problems when the lead is shaped to the patient’s contour. Thin lead can be
shaped with the fingers. For thicker lead or for shaping sharply undulating surfaces,
such as the medial canthus, the lead can be pressed or hammered lightly to conform to
a facial or other plaster cast created specifically for this purpose. The hammering must
not appreciably thin the lead.
Wrapping the patient’s custom tailored shielding lead with low-density polyethylene
cling film will prevent heavy metal exposure to the patient’s skin. Disposable gloves
used for protection from exposure to pathogens in patient care may also be used to
prevent lead exposure, but because visibility of the shielding device is compromised, this
protection may be better used only for exit beam shielding.
The protection of normal tissues from exit beam irradiation is important to consider.
A thin layer of lead will protect tissues distal to the target from further direct
irradiation. Because of the potential for electron backscattering from the high-Z material
of the shielding, a 3-mm layer of wax, which will absorb any backscattered electrons, is
often used to cover a 1-mm lead shield. This wax will also protect the patient from
exposure to the heavy metals used to fabricate the internal shielding. Such a device will
adequately protect for energies up to 12 MeV. The final thickness of the shielding may
lead to difficulty with internal shielding placement or decreased patient tolerance of the
shielding during therapy. Care should be taken when using internal eye shields—those
made for photon therapy are inadequate for electron beam therapy—the transmitted
and scattered dose will be high enough to produce cataracts (7,8).

Electron Arc Therapy


For treating large superficial lesions on a curved surface such as the chest wall, electron
arc therapy is an option. Electron arc therapy uses an electron field rotating around the
isocenter to provide a homogeneous dose distribution to the target. The prediction of
dose distribution is complex as it is related to the beam energy, field size, SSD, patient
curvature, and depth of the isocenter. Since the source-to-axis setup technique is used,
an electron applicator provided by the manufacturer for the SSD setup is not needed.
The electron field for electron arc therapy is defined by using a custom-made applicator
with a rectangular cutout. Electron arc therapy has been found to be efficient to treat
large superficial lesions of the nasal cavity; postmastectomy chest wall; and
reconstructed breast, torso, and limbs, which are difficult to irradiate with a static
electron or kV x-ray field. In this section, the electron beam setup, dosimetry, and
monitor unit calculations are discussed.

904
Electron Beam Geometry and Setup
Since source-to-axis distance setup is used in electron arc therapy, the distance between
the cutout and isocenter should be large enough to include the patient’s body. Normally,
a distance of 35 cm is used with the applicator height equal to about 15 cm. The cutout
is usually made to produce a rectangular field, for example, with physical size equal to
2.6 × 21 cm2, and is inserted at the bottom of a custom-made applicator. This
applicator is attached to the block tray holder on the treatment head of the linear
accelerator. Dosimetry calibration and measurement are carried out using cubic and
cylindrical solid water phantoms with the accelerator gantry rotating to produce an
electron arc.

Monitor Unit Calculation


The monitor unit for electron arc therapy is calculated by the equation:

The dwell factor is defined as (9):

This factor accounts for the dosimetric variation when the static electron beam
changes to rotating status in the arc therapy. The relative output factor is defined as the
dose ratio of the electron arc cutout to the reference 10 × 10 cm2 cutout. Measurement
of the relative output factor is performed at SSD equal to 100 cm and at a depth of
reference (e.g., 2 cm for the 9 MeV electron beam) in water. This factor corrects the
single-beam dose from the absolute calibration to electron arc. The inverse square law
factor is used to correct the monitor unit with a variation of SSD that differs from 100
cm in the electron arc delivery. For monitor unit calculation in electron arc therapy, the
dwell factor, relative output factor, and inverse square law factor can be determined by
measurements or Monte Carlo simulations (9).

Electronic and Radioisotope Brachytherapy


There has been recent interest in using low-energy photons in new electronic and
radioisotope brachytherapy devices and techniques. Remote afterloading high-dose rate
(HDR) brachytherapy devices were initially used in locally irradiating intracavitary
locations such as gynecologic malignancies and breast operative sites (10). Their use
subsequently expanded to include irradiation of small superficial cancers, including
skin cancer such as Kaposi sarcoma (11). The specialized Leipzig and Valencia
applicators were developed by investigators in Germany and Spain to facilitate
brachytherapy of superficial (e.g., cutaneous) tumor sites with these radiation sources.
HDR surface brachytherapy places an iridium-192 source in close proximity to the

905
target lesion using a computer-controlled remote afterloader that houses a radioactive
source that may be precisely delivered using specialized catheters or applicators. The
choice of applicator is commonly dependent on the size and depth of the target. Small,
superficial tumors (up to 2.5 cm in diameter and 0.5 cm in thickness) may be readily
treated using vendor-specific Leipzig or Valencia skin applicators, and applicators of
even greater diameter are commercially available; the risk of a poor cosmetic outcome
may be unacceptably high for hypofractionated regimens delivered to larger volumes
(12). Prefabricated silicone rubber sheets with parallel catheter channels that permit a
known distance between the catheters and the skin surface may be used for more
extensive skin lesions on uncovered body parts with infiltration depth less than 1 cm,
and in addition, special, customized applicators may be prepared for complex
geometries (13).
The dosimetry of some specialized applicators may be nonuniform because of the
nonisotropic radiation dose distribution of the HDR source and because of special
geometric considerations as the radiation is delivered to curved surfaces. Care is
warranted in assuring acceptable dosimetry for nonstandard settings; dose delivered
cannot be recovered.
The development of kV radiation sources that mimic the functionality of the remote
afterloading HDR brachytherapy devices has been followed by vendor adaptation of the
Leipzig and Valencia applicators. These devices may be useful in treating small
superficial skin cancers that will fit well within the applicator selected and have a
thickness of less than 3 or 4 mm. Circular treatment cones of a range of sizes up to 50
mm in diameter may be used. The Valencia applicator has a flattening filter, so
although the dose rate is lower than for the Leipzig applicator, the flattening filter does
achieve its goal of greater dose uniformity through the target volume (14). The
target/source to skin distance is 2 to 3 cm, resulting in a rapid decrease in radiation
dose with increasing depth from the cone applicator and skin surface. The percent
depth doses for a 50 keV beam at these treatment distances are approximately 58% to
66% at 4 mm depth, and 51% to 60% at 5 mm depth. Some treatment cones use a step
filter to provide a flatter isodose curve.
Not unexpectedly, these relatively novel radiotherapy devices harbor the potential for
misadministration and misunderstanding of directives, but the process is amenable to
standardization (15). There is limited clinical information regarding the efficacy of
these devices for treatment of skin cancers at this time, but a significant number of
patients have been reported from Leipzig, where a complete response rate of 91% for
over 500 patients with a variety of conditions was observed (16). The Valencia group
has reported a much smaller series of patients with nonmelanoma skin cancer and
report 98% local control at 4 years (17).
There is, as yet, too little reported experience with electronic brachytherapy to merit
more than a mention here (10,18). Several vendors have begun to market these devices,
not only to radiation oncologists, but to dermatologists as well. It may be hoped that
with appropriate case selection and careful attention to treatment-related parameters,
successful treatments will be reported in an adequately detailed fashion to permit
determination of this approach’s suitability for continued use in treating skin cancer.
Figure 29.5 shows an electronic brachytherapy applicator and a treatment setup.

Selected Aspects of Treatment Setup


Because the lateral radiation margins are often narrow, the importance of effective
patient immobilization and precision in cutout positioning cannot be overemphasized.

906
Immobilization techniques used for irradiating head and neck cancers are used for skin
cancers of the face and neck. The surface of the treatment field should be as nearly
perpendicular to the treatment beam axis as is practical. With an orthovoltage photon
beam, dose inhomogeneities because of irregular surface contours can usually be
diminished to acceptable levels by increasing the SSD. Lead cutout positioning and
fixation are facilitated if the shield conforms closely to the contours of the region and
the tape fixes the cutout to the patient. When the cutout can be fixed to the skin, the
treatment beam breadth should exceed that of the cutout area by about 1 cm,
minimizing the effect of patient movement. Of course, the width of the lead must exceed
that of the treatment beam. Frequent clinical physician visualization of the treatment
setup is very important to confirm that the treatment field is properly aligned relative to
the tumor.

Figure 29.5 An example of electronic brachytherapy using an Esteya applicator. A template (specific for each
applicator size) is placed on the patient’s lesion and the external diameter of the applicator is drawn on the
patient using the template’s open areas. The arm of the device with the specific applicator is then placed in
contact with the patient’s skin surface. (Adapted from Pons-Llanas O, Ballester-Sánchez R, Celada-Álvarez FJ,
et al. Clinical implementation of a new electronic brachytherapy system for skin brachytherapy. J. Contemp
Brachytherapy. 2015;6:417–423.)

907
Fractionation Schedules
The National Comprehensive Cancer Network (NCCN) has published recommended dose-
fractionation schedules for curative treatment of skin cancers with orthovoltage, and
have included recommendations for prescription modifications for electron beam
treatment (2). The dose-fractionation recommendations are the same for both squamous
and basal cell carcinomas. There are recommendations for treatment of nodal metastatic
disease included in the recommendations for squamous cell skin carcinoma. Additional
orthovoltage radiotherapy prescriptions with dose-fractionation schedules are shown in
Tables 29.3 and 29.4. As stated above, because of a difference in the RBE between
photons and electrons, the prescription for electrons should be to the 90% isodose
surface to ensure an adequate dose to the tumor.
The NCCN has also published recommendations for postsurgical radiation therapy
management of Merkel cell carcinoma (19). For melanoma, the NCCN has not published
recommendations on dose fractionation, though they have published recommendations
on the use of radiation as an adjunct to surgical management and for palliative
treatments (20).
Clinical judgment and experience are necessary to give the appropriate radiation
dose. The total radiation dose ultimately delivered may vary from the planned
prescribed dose. The lesion at the completion of treatment should show evidence of
significant regression, and a moist reaction and surface crusting may be present. It is
important for the radiation oncologist to closely observe the reaction of the surface of
the tumor and the surface of the surrounding normal skin, particularly toward the end
of the planned time of completion of the irradiation. The desired radiation response
may require a break in the treatments, and an up- or down-titration in the number of
planned treatments and the ultimate total radiation dose, to achieve the desired result
of tumor control without normal tissue necrosis.

Cutaneous Basal and Squamous Cell Carcinomas


Basal and squamous cell carcinomas of the skin are most commonly diagnosed in
patients over the age of 50, are related to earlier sun exposure, and are often optimally
treated with radiation therapy. Many patients with small tumors are not referred for
consultative opinions, and patients referred for radiation are often those that have
neglected skin cancers that are too locally advanced to be considered for attempts at
radical resection or are recurrent after multiple ineffective local procedures by other
caregivers.
Basal cell carcinomas appear to arise in embryonic fusion plate regions with a higher
frequency than elsewhere on the face (21). Both basal and squamous skin cancers have
a linkage to a sun exposure history. One important difference between basal and
squamous cancers is that basal cell carcinomas, though locally invasive and destructive,
metastasize extremely rarely, so that looking for metastatic disease is not generally
appropriate, though imaging to assist with local radiotherapy portal design is often
valuable. For squamous cell carcinomas, appropriate management with surgery,
radiation, or both of the primary site and of any regional nodal metastases is critical to
a good outcome.
TABLE 29.3 Recommended Orthovoltage Dose and Fractionation Schedule

908
For small basal and squamous cell carcinomas of the skin, good results have been
published for superficial and orthovoltage photon therapy and electron beam therapy.
Field margins for <2 cm primary tumors should be 1 to 1.5 cm; for tumors >2 cm,
field margins should be 1.5 to 2 cm (2). In practice, 1-cm lateral margins for photon
fields applied to lesions ≤2 cm in diameter produce control rates greater than 90%,
and it is conceivable that higher local control rates can be achieved through meticulous
attention to planning and delivering treatment. A review of isodose curves reveals that
lateral margins for fields irradiated with electron beams should be wider compared to
orthovoltage beams for similar-sized cancers, but these margins have been less well
defined. If a lesion is <2 cm in diameter and a 1-cm margin is to be given a minimum
of 90% of Dmax, the lateral margin for the electron beam field needs to be almost 1.5
cm. This requirement for a larger electron beam field size can be a major disadvantage
in treating lesions of the eyelids and canthi. Generous lateral margins of 2 cm or more
should be strongly considered for larger lesions (7 to 8 cm diameter), infiltrating
lesions, and lesions at high risk for occult extension.
TABLE 29.4 Recommended Orthovoltage Dose and Fractionation Schedule

909
The deep margin of the cancer should always be well-included within the planning
target volume; this may preclude use of electronic brachytherapy or isotope
brachytherapy treatment of some tumors because of the shallow depth-dose
characteristics of these low-energy sources and the limited applicator sizes.
Perineural invasion occurs in 2% to 6% of cutaneous basal and squamous cell
carcinomas of the head and neck and is associated with midface location, recurrent
tumors, high histologic grade, and increasing tumor size (22). The cranial nerves most
commonly involved are named branches of the trigeminal and facial nerves. Cranial
nerve involvement may portend a worse prognosis, with tumor extension and
recurrence along the cranial nerves and metastases to adjacent lymph nodes often also
seen. Surgical resection should be considered for the primary if the tumor is considered
to be resectable, but the risk of perineural spread beyond the excision margin should
lower the threshold for definitive adjuvant irradiation. It can sometimes be difficult to
know whether treatment portals should include both the distribution of the trigeminal
and facial nerves, but careful consideration of the location of the primary lesion and
clinical symptomatology may help refine radiotherapy portal design.
University of Florida investigators recommend elective regional irradiation of first-
echelon lymph nodes for patients with clinical (symptomatic) perineural invasion and
for those with squamous cell carcinoma with microscopic perineural invasion. Patients
with involvement of named branches of cranial nerves should have radiation volumes
that include the involved cranial nerve to the base of the skull (22,23). Planning for
these volumes requires careful clinical examination, detailed CT and MRI imaging, and
conformal radiation treatment planning and delivery, for which intensity-modulated
techniques may permit normal tissue sparing to a greater degree than 3D conformal
techniques.
University of Michigan investigators have detailed the pathways of recurrent tumor
for skin squamous cell carcinomas involving the trigeminal and facial cranial nerves
(24). They identified the auriculotemporal nerve and the greater superficial petrosal
nerves as the pathways of tumor spreading between those nerves. They recommend that
for tumors involving cranial nerve VII, the auriculotemporal nerve and V3 are at risk;
and for tumors involving V2, the greater superficial petrosal and cranial nerve VII are
at risk. They advocate that these at-risk volumes should be included in the planning

910
target volume when these nerves are involved.

Cutaneous Melanoma

Radiotherapy Indications
Surgical resection is the most common treatment of cutaneous melanoma; primary
irradiation is rarely used in the treatment of primary melanoma, but there are well-
defined roles for radiation in the locoregional management of melanoma (25,26).
Lentigo maligna, also known as melanoma in situ (Clark Level 1, Stage 0 melanoma)
or Hutchinson melanotic freckle is very well treated by primary irradiation (25,27).
Margins of 5 mm are recommended for surgical management, but an Australian report
on in vivo confocal microscopy described subclinical tumor extending beyond 5 mm
from the lesion in most patients (28). The ability of radiotherapy fields to be extended
to cover larger margins is an advantage for this condition, where skin flaps or skin
grafts may be required to obtain adequate wound closures, and facial cosmesis may be
compromised permanently.
For resected melanomas of the head and neck, where anatomical constraints on
radical resection exist and ideal surgical margins are difficult to obtain, adjuvant
irradiation decreases locoregional recurrences. The NCCN recommends adjuvant
treatment of the primary tumor site with radiation for selected patients with factors
including, but not limited to, deep desmoplastic melanoma with narrow margins,
extensive neurotropism, or locally recurrent disease. A wide range of radiation
dose/fractionation schedules is effective, but hypofractionated regimens may increase
the risk for long-term complications.
Radiotherapy to regional nodal basins (48 Gy in 20 fractions) or observation after
therapeutic nodal dissection significantly decreases locoregional recurrence, though
survival is not affected (29). Adjuvant radiotherapy’s benefits must be weighed against
the increased probability of long-term skin and regional toxicities and potential reduced
quality of life.

Radiation Therapy Technique


An adjuvant radiotherapy technique was developed at the University of Texas, M.D.
Anderson Cancer Center that covered the primary site, nodal operative site, and
regional lymph nodes using shaped electron beams of 9 to 16 MeV to deliver 30 Gy in
five fractions (6 Gy per fraction) over 2.5 weeks, Monday and Thursday, or Tuesday
and Friday. Dose is calculated at Dmax. The central nervous system (brain and spinal
cord) must be spared and should be treated to a maximum of 24 Gy in four fractions
(30,31). This radiotherapy technique has also been extended to treat metastatic nodal
disease of the axilla and inguinal regions. IMRT may be used to cover some of these
same volumes as effectively with the use of bolus to assure adequate skin dose.

Merkel Cell Carcinoma


Merkel cell carcinoma is a rare cutaneous malignancy with a roughly 25% mortality
rate and a high propensity of regional and distant tumor spread. There is no class I data
evaluating radiotherapy’s role in the management of this disease. The published
literature appears to show an improvement in locoregional control when radiotherapy is
added to management of the primary site and nodal beds, particularly when surgical
margins are compromised (32–39).
Because of the high incidence of nodal metastases, the regional lymphatics should be

911
electively treated with surgery and/or radiation in all patients with apparently localized
disease, The addition of radiation to surgically managed regional nodes, even if sentinel
nodes are negative, appears to be of value (40,41). If nodal disease is found at surgery,
postoperative irradiation should be given. The radiation doses are similar for squamous
cell carcinomas of the head and neck: primary tumor—negative margins, 60 Gy in 30
fractions over 6 weeks; microscopically positive margins, 66 Gy in 33 fractions over 6
1/2 weeks; gross disease, 70 Gy in 35 fractions over 7 weeks. Elective irradiation of
subclinical disease in a nonresected neck would be 50 Gy in 25 fractions over 5 weeks.
Radiation fields should be generous (3 cm margins) around the primary site because of
the propensity of cutaneous in-transit tumor spread. The location of the primary site in
relation to regional nodal basins may preclude including these nodal stations in the
same radiotherapy portals. It has been stated, “For some patients, you can’t treat a
radiation field big enough.”

Mycosis Fungoides
Mycosis fungoides (MF) is a low-grade, non-Hodgkin T-cell lymphoma that develops
primarily in the skin. It can also involve lymph nodes, blood, and visceral organs in
patients with advanced cutaneous disease (42). MF primarily affects adults over the age
of 40, with approximately 1,400 new cases per year in the United States (43).
Approximately 50% of all cutaneous T-cell lymphoma (CTCL) cases are MF.
MF may start as a scaly, red rash in areas that usually are not exposed to the sun
(premycotic phase) and progress to patch phase (with thin, reddened, eczema-like rash),
plaque phase (with small raised bumps or hardened lesions on the skin), and tumor
phase (with tumors formed on the skin). Patients present with tumors or erythroderma
(with patches and/or plaques covering greater than 80% body surface area) are at high
risk for extracutaneous dissemination to lymph nodes, viscera, and blood.
Early-stage MF consists of patches and/or plaques on the skin with no (stage IA & IB)
or limited (stage IIA) lymph node involvement and no visceral involvement. Patients
present with advanced skin lesions (e.g., tumors, generalized erythroderma) or
extracutaneous disease are classified as having advanced stage MF (stages IIB to IV) (1).

Radiation Therapy Indications


Early stage MF is typically managed with skin-directed therapies, which include topical
corticosteroids, topical chemotherapy (nitrogen mustard or carmustine), phototherapy
(psoralen plus ultraviolet A (PUVA), ultraviolet B (UVB)), and radiation therapy, among
others. To achieve and maintain long-term disease control, serial administration of skin-
directed therapies may be necessary. For patients with disease limited to the skin, skin-
directed therapy alone can usually produce high rates of remission and even cure (43).
Systemic therapy may be used after skin-directed therapies fail to control the disease.
For patients with advanced stage disease, systemic therapy is used either alone or in
combination with skin-directed therapies.
MF are extremely sensitive to ionizing radiation. As such, radiation therapy in the
form of localized or total-skin irradiation provides one of the most effective treatments
for MF (42). For patients with unilesional or localized MF (involving less than 10% of
body surface area), local radiation is typically used with efficient disease clearance. For
patients with extended or advanced diseases, total-skin electron therapy (TSET) is used
in either primary or adjuvant settings. TSET monotherapy provides rapid and effective
palliation, with complete response rates of 95% for T1, 90% for T2, 60% for T3, and
75% for T4 disease (44). For stage IA disease, TSET monotherapy produces a 10-year

912
relapse-free survival of approximately 50% (44). For patients with more advanced
disease, TSET monotherapy is rarely curative; it is often administered to induce
cutaneous remission followed by adjuvant systemic and/or topical therapy to prolong
remission. Some patients may be candidates for a second course of total-skin electron
irradiation for recurrent MF (42,44).

Radiation Treatment Techniques


Key factors to consider in radiation treatment planning for MF include the spatial
extent of the lesions (i.e., the depth into the skin and lateral spread over the skin
surface), the dose required to control the lesions, and the radiation impact on normal
tissue and critical structures. The lesion depth into the skin dictates the type and the
energy of radiation to be used. Because the primary targets of MF are mostly superficial,
radiation modalities that can concentrate dose to only the desired skin layers are ideal.
For this reason, electron beams are preferred over photons. Electron beams stop at a
finite penetration depth in tissue. The penetration depth can be controlled by tuning the
electron energy, enabling confinement of radiation dose to a desired skin layer with
little radiation damage to deeper normal tissues. The spread of the lesions over the skin
surface determines the size of radiation fields and, potentially, the treatment technique.
For example, when total-skin irradiation is required, only electron beams can be used
because the whole-body dose from a photon-based technique would be totally
unacceptable. Treatment planning considerations for localized and total-skin irradiation
are discussed further below.

Local Radiation Therapy. Local irradiation is highly effective for MF with individual
lesions or with limited skin involvement. Orthovoltage x-rays (e.g., 120 kVp) and
electron beams have both been used in the treatment of localized MF lesions. While low-
energy x-rays deposit maximum dose at the skin surface, it is inherently more
penetrating compared to electron beams. Unwanted irradiation of normal tissues along
the beam path is unavoidable. Nonetheless, because an orthovoltage unit is relatively
simple to maneuver for complicated setups, it is still being used in some institutions for
localized MF tumors with deep disease infiltrations and/or for boost irradiation of skin
areas that are underdosed from a total-skin electron treatment, such as the perineum
and soles of feet.
Treatment planning considerations for local radiation therapy using electrons (or
orthovoltage x-rays) are similar to those discussed in the earlier sections of this chapter
for other superficial lesions. Radiation field aperture is typically designed with a
peripheral margin up to 2 cm, although the exact size/shape is often influenced by the
location of the lesions and their proximity to sensitive normal tissues. Beam energy is
dictated by the desired treatment depth. Because the energy of available electron beams
is limited, custom bolus may be used to ensure adequate dose to skin surface and/or to
control the treatment depth.
A total treatment dose of 15 to 25 Gy delivered over 1 to 3 weeks is usually effective
in long-term control of local diseases. Total dose ranging from 8 to 30 Gy has been
reported in trials (45,46). Complete responses were observed in greater than 90% of
cases for those lesions receiving over 3 Gy and lesions typically disappeared by 2 to 3
weeks (45). In a single center retrospective study, a single fraction dose of 4 to 9 Gy
produced a complete response in 255 of 270 individual lesions (94%) (47). While
radiation treatment is highly effective in local control, new lesions can develop outside
of the treated field. Skin-directed maintenance therapy such as topical nitrogen mustard
or topical corticosteroids may be used after local radiation therapy. If indicated, it is

913
also appropriate to administer local radiation therapy either before or following a
course of total-skin electron treatment. Treatment related toxicity from local radiation
therapy is dependent upon the dose of radiation used and the location of the lesion.
Typical side effects include erythema and hair loss.

Figure 29.6 Illustration of a dual-field beam TSET setup currently used at Yale University. Note the beam axis
for the dual-field coincides with the central axis of a horizontally directed beam. (Adapted from Chen Z,
Agostinelli AG, Wilson LD, et al. Matching the dosimetry characteristics of a dual-field Stanford technique to
a customized single-field Stanford technique for total skin electron therapy. Int J Radiat Oncol Biol Phys. 2004;
59:872–885.)

Total-Skin Electron Therapy. For patients with extended or advanced MF, TSET is the
most effective single agent treatment (44). The dosimetric goal of TSET is to deliver
sufficient dose to the superficial layers (up to about 5 mm below the skin surface) of the
entire body with minimum or no dose to the normal tissues inside (42,48). Technical
challenges in fulfilling this dosimetric goal arise primarily from the unusual target
volume which wraps around the body amid ever-changing curvatures and unavoidable
self-shielding among the body structures. In addition, bremsstrahlung x-rays produced
from the interactions of the electron beam with the materials in its beam path must be
kept low to prevent serious radiation toxicity arising from whole-body exposure to these
contaminating x-rays (42,49).
Modern TSET techniques are all based on linear accelerator-based electron beams. The
basic geometry involves a horizontally directed electron beam with the patient standing
at a distance of 3 to 7 m away from the radiation source. By positioning the patient at
an extended distance, a large electron beam is created at the location of the patient. At
an SSD of 7 m, a 3-mm diameter electron pencil beam can broaden into an electron
beam of about 180 cm in diameter due to electron scattering through the air (50). At
shorter SSD (e.g., 3 to 4 m), a composite dual-field beam is typically used, which
consists of two horizontally directed beams with one angled toward patient’s head and
the other toward patient’s feet (51), resulting in an effective uniform beam covering
patient from head to toe (Fig. 29.6). The use of dual-field beam is due primarily to the
limitations imposed by accelerator design and the extended SSD available in the

914
accelerator room.
The first linear accelerator-based method reported by Stanford University used a dual-
field beam with the patient irradiated in two treatment positions: one facing the beam
source and the other with the back toward the source (51). This is equivalent to a two-
field AP-PA treatment. Following basic treatment planning principles, the lateral dose
uniformity can be improved by increasing the number of treatment positions, that is, the
number of equivalent fields spaced equally around the patient (52). Stanford ultimately
settled on a six-field technique in which patients stand in six different orientations with
respect to the dual-field beam: anteroposterior, posteroanterior, right and left anterior
oblique, and right and left posterior oblique (52).

Figure 29.7 Illustration of the six treatment positions used in the Stanford total-skin electron therapy.
(Reprinted from Smith BD, Wilson LD. Cutaneous lymphomas. Semin Radiat Oncol. 2007;17:158–168.)

The Stanford six-field technique has been adopted by most institutions as the
standard TSET technique. The technique can be implemented with either a single-field
or a composite dual-field beam (50). Figure 29.6 depicts a dual-field beam setup
currently used in the Yale TSET program. With a patient standing at 3.8 m from the
radiation source and a 3.2 mm Lexan attenuate/scatter screen placed in front of the
patient, the dual-field beam is made up of two fields with the accelerator head rotated
17.5 degrees above and below the horizontal direction toward the patient. The Lexan
screen is used to attenuate and scatter the 6 MeV incident electrons produced from a
Varian 21EX linear accelerator using the high dose rate total skin electron (HDTSe)

915
mode. The mean energy of the electrons reaching patient’s skin surface is approximately
3.9 MeV. For total-skin treatment, the patient is irradiated in six specific treatment
positions to maximize skin unfolding and lateral dose uniformity (Fig. 29.7).
Traditionally, the treatment of all six positions is delivered over the course of a 2-day
treatment cycle. On day 1, the anteroposterior, right posterior oblique, and left
posterior oblique positions are treated. On day 2, the posteroanterior, right anterior
oblique, and left anterior oblique positions are treated. Figure 29.8 compares the depth-
dose curves of a complete treatment cycle (all six positions) to a single position (e.g.,
anteroposterior) at the level of beam axis. Due to the obliquity of incident electrons from
the neighboring irradiation positions, the depth dose curve of a complete treatment
cycle is shifted toward the skin surface, with the dose maximum at 1 mm, the 80%
isodose line at 6 mm, and the 20% isodose line at 12 mm (50). Figure 29.9
demonstrates a relatively uniform dose delivered by this setup to the entire skin surface
with minimum dose to the deeper tissues inside the body. The total x-ray contamination
was 1.2% of the skin dose, well within the acceptable limit (53).

Figure 29.8 Comparison of percent depth dose curves for a single position irradiation and a six-position
treatment. (Adapted from Chen Z, Agostinelli AG, Wilson LD, et al. Matching the dosimetry characteristics of
a dual-field Stanford technique to a customized single-field Stanford technique for total skin electron therapy.
Int J Radiat Oncol Biol Phys. 2004;59:872–885.)

Figure 29.9 A representation of single position and six position treatment setups. The six position treatment
setup can deliver a relatively uniform dose to the surface while minimizing delivery of dose to deep tissues.

916
TABLE 29.5 Standard TSET Treatment Protocol at Yale-New Haven Hospital (50)

For standard TSET treatment (Table 29.5), the effective dose delivered over the 2-day
treatment cycle is typically 2 Gy to the skin surface. Patient receives treatment 4 days
(2 cycles) per week, with a total dose of 36 Gy delivered over 9 weeks. A 1-week break
may be given after a dose of 18 Gy has been delivered to provide relief from the
generalized skin erythema associated with treatment. Although the six treatment

917
positions are designed to maximize skin unfolding and minimize self-shielding, overdose
may occur to certain structures such as hands and ankles due to high convexity and
radiation exposure from more than three positions. Under dose could also occur to areas
such as the top of the scalp, the perineum, the underside of the breasts, panniculus
folds, and the soles of the feet due to self-shielding. Customized shielding and
supplemental irradiation are used to bring the dose to these areas close to the desired
value. In addition, some critical structures (such as the lens of the eyes) and
radiosensitive structures (such as the nail beds and lips) may need additional shielding
to prevent unnecessary radiation injury. Detailed dosimetric measurements are typically
required to determine the most appropriate shielding regimen or supplemental
treatment for a particular treatment arrangement and patient geometry.
Table 29.5 lists the nominal shielding and supplemental treatment regimen used at
Yale-New Haven Hospital (50). Individualized adjustments are made by the radiation
oncologist based on the conditions of specific patients and clinical judgment. The eyes
and lens are shielded with a combination of internal and external eye shields. Because
of the increased backscatter dose from the internal shield to the eyelid, using internal
eye shield throughout the treatment course would have overdosed the eyelid. External
eye shields made of lead sheets or Cerrobend block casted in swimming goggles are used
to keep eyelids from over exposure. It is appropriate to start treatment with internal eye
shields and switch to external eye shields during the later portion of the treatment
course, or use internal and external shields in alternating treatment cycles. To prevent
severe reaction to the fingers, hands, lips, and feet, lead-lined mitts, lead-sheet based
shields, and blocks to protect the feet can be used to reduce the dose to these areas.
Both electron beam and orthovoltage x-rays can be used for supplemental treatment
to underdosed areas. One can use 120 kVp, HVL 4.2 mm Al, x-rays to deliver patch
treatments to the soles of feet (14 Gy, 14 fractions, treatment days 1 to 7 and 30 to 36)
and perineum (18 Gy, 18 fractions, treatment days 1 to 9 and 28 to 36). The scalp dose
can be supplemented with either orthovoltage patches (6 to 20 Gy over 1 to 3 weeks) or
with an electron reflector mounted above the patient’s head (50). Other areas of
potential underdosing include the ventral penis, the upper medial thighs,
inframammary folds, folds under any pannus, and the lateral and flatter regions of the
face and trunk. Supplemental patch fields, as guided by in vivo dosimetry or clinical
suspicion, are appropriate for these regions to ensure that the surface dose is at least
50% of the prescribed TSET dose (44). When determining the total dose given in patch
treatments, doses to areas such as the feet and perineum may be reduced as clinically
indicated to enhance patient tolerance, provided such areas are uninvolved (44). For
tumors having a thickness greater than 6 mm, for example, for patients with bleeding,
weeping, or painful tumors at presentation, an initial or concurrent boost of 10 Gy in
five fractions using either 6 to 16 MeV electrons or orthovoltage photons has been
effective (44). Asymptomatic plaques and tumors that persist at the end of treatment
may receive a similar boost to ensure adequate dose delivery at depth.
TSET has been proven to be an effective treatment modality for MF (42,44). The
typical response to radiation is a gradual decrease in the size and symptoms that can
start within a few days of starting the treatments. Even large tumors or deeply ulcerated
tumors will eventually resolve and be replaced with normal skin. Nonetheless, total-skin
electron irradiation is a very specialized radiation treatment technique, which requires
knowledge and use of proper positioning of the patient’s trunk and extremities to
optimally expose all skin surfaces to the electron beam. Significant medical physics
effort is required to set up and maintain such a technique. A team of experienced
radiation oncology physicians, medical physicists, medical dosimetrists, and radiation

918
therapists must be in place to properly plan and deliver the optimal TSET. For these
reasons, TSET is not readily available in all radiation therapy departments.
For those centers planning to establish such a treatment technique, European
Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma
Project Group has developed guidelines for total-skin electron radiation in the
management of MF (53). These guidelines include recommendations on optimal
treatment distance (between 3 and 8 m); ideal beam uniformity (within 10% across
clinically useful vertical and lateral dimensions); acceptable photon contamination at
the level of the bone marrow (must be <0.7 Gy for a full course of treatment to avoid
hematologic sequelae); desired therapeutic treatment depth (80% isodose surface should
be at least 4 mm below the skin surface); primary treatment dose (at least 26 Gy to a
depth of 4 mm in truncal skin, ∼31 to 36 Gy to the skin surface); and the utilization of
supplemental patch treatments to underdosed skin surfaces (perineum, soles of feet,
scalp, and behind pendulous tissue). The guidelines recommend a minimum dose of 26
Gy at a depth of 4 mm for all skin surfaces. However, caution should be exercised in
giving >20 Gy to the soles of the feet because of the limited tolerance of the skin of the
sole. The references included in the end of this chapter may serve as a starting point for
those intended to embark on this endeavor.

CLINICAL CONSIDERATIONS
Examples of Treated Patients
Case 1: Squamous cell carcinoma of lip (Figs. 29.10–29.14)
An 87-year-old woman had a destructive squamous cell carcinoma of the right side of
her upper lip. Because of her age and difficulty in arranging transportation, she was
treated with 300 cGy/day to the 90% line in three fractions per week, with 6 MeV
electrons, with 5 mm of gel bolus over the lip and a lead shield between the upper lip
and the upper alveolar ridge. Following eight fractions, she was given a 13-day break
because of an intense radiation reaction on the surface of the tumor and the
surrounding skin, and then she returned for an additional eight fractions. Her tumor
was subsequently totally controlled with good cosmetic result with a total dose of 4,800
cGy in 16 fractions over 42 elapsed days.

919
Figure 29.10 An 87-year-old woman with squamous cell carcinoma of right side of upper lip. Prior to
irradiation.

Case 2: Squamous cell carcinoma of the left ala nasi (Figs. 29.15–29.18)
This 79-year-old man had a very large ulcerated 4 × 4 × 3.5-cm squamous
carcinoma that involved and distorted the left ala nasi blocking the left nostril (Fig.
29.15). The treatment planning CT scan and the radiation treatments were performed
with the patient immobilized in a thermoplastic mask (Fig. 29.16). The CT scan showed
the depth of the tumor involvement. He was initially treated with a combination of 12-
MeV electrons (70% weighting) and 16-MeV electrons (30% weighting). The shaped left
anterior oblique field (Cerrobend cutout in electron cone) included a 1-cm peripheral
margin. He received a total of 5,100 cGy to the 90% line in 17 fractions over 30 days,
treating 4 days/week. The final 1,800 cGy was given with a reduced field size and with
12-MeV electrons because the tumor depth had decreased by that time. No bolus was
used because the 90% isodose line (green line) of the 12- and 16-MeV electron beams
was at the tumor surface (Fig. 29.17). Excellent tumor control and cosmesis was
provided (Fig. 29.18).

920
Figure 29.11 At the time of fourth radiation treatment with 6-MeV electrons, 5-mm gel bolus on the skin,
black line is edge of radiation field as defined by Cerrobend cutout, treated at 300 cGy per day to 90% line,
three fractions per week. A lead shield enclosed in a folded glove is placed between the upper lip and the upper
alveolar ridge.

Figure 29.12 At 7 th radiation fraction, 2,100 cGy to the 90% isodose surface. Following the 8 th treatment
(2,400 cGy), a 13-day treatment break was needed because of the intense symptomatic radiation reaction over
the tumor surface.

921
Figure 29.13 At completion of radiation treatments, 4,800 cGy in 16 fractions, 3 fractions per week, over 42
elapsed days. Eight fractions followed by a 13-day break, followed by eight more fractions.

Cancer of the ala nasi commonly invades and destroys the underlying cartilage.
Laterally, the lesion may extend to the embryonic fusion planes of the nasolabial fold.
This permits deep infiltration. Although not used in this patient, exit beam shields of
lead, coated with paraffin, and then slipped into the left nostril or anterior to the upper
gum may be used. When the tumor is close to the orbits, extra eye shields are used.

Figure 29.14 Six weeks following completion of irradiation. No evidence of tumor. There is slight deformity of
the right side of the upper lip because of prior destruction from the tumor. Considering the original tumor
appearance, this is a very good functional and cosmetic result.

922
Figure 29.15 4 × 4 × 3.5 cm ulcerated and bleeding squamous cell carcinoma of left ala nasi, prior to treatment.

Figure 29.16 Photo taken at 3,000 cGy, original field is marked in black ink and reduced field is marked in red
ink; treatment continued to total of 4,800 cGy.

923
Figure 29.17 Isodose lines of treatment with combination of left anterior oblique 12 and 16 MeV electrons,
treatment prescription calculated to green 90% isodose surface, which surrounded tumor volume and also
included tumor surface. No bolus was used. Colors and percent isodose surfaces: red 105%, blue 100%, green
90%, yellow 80%, magenta 70%, light blue 60%, orange 50%, purple 30%, light yellow 20%.

Figure 29.18 Two months following the completion of radiation treatment, no visible tumor, slight skin
distortion, excellent cosmetic result considering initial tumor appearance.

Case 3: Basal cell carcinoma of the left medial canthus and bridge of nose with
extension into the left lower eyelid (Figs. 29.19 and 29.20).
Cancers near the eye may invade the bone or soft tissues of the orbit. When there is
any question of deep invasion, imaging studies through this level may provide useful
information. Such invasion was not present in this patient. Gross margins were
otherwise readily determined. The relatively small size of the treatment field, together
with the problems of dose distribution and use of a lead eye shield of appropriate
thickness for the electron beam, made the x-ray beam preferable (7,8,54,55). The
contour across the treatment field was irregular. (The bridge of the nose was ∼1.5 to 2
cm anterior to the canthus.) The resulting variation in surface dose was decreased by
increasing SSD of the x-ray beam to 50 cm rather than the usual 20 to 30 cm.

924
Figure 29.19 An internal (Gougelman) eye shield is in place in the anesthetized left eye. An external eye shield
covers the right eye.

Figure 29.20 A lead cutout and the eye shields are in place.

925
Figure 29.21 This 93-year-old woman with nodular squamous cell carcinoma was treated with 45 Gy in 10
fractions over 2 weeks using 250 kV photons.

A 200 keV x-ray beam of half-value layer (HVL) 1 mm copper at 50 cm SSD is


appropriate. The field diameter, allowing at least 1 cm of lateral margin around the
lesion, was 4.5 cm. A lead cutout of 1 mm thickness was constructed and shaped. Figure
29.19 shows that before it was taped in place, an eye shield of 2-mm-thick lead was
inserted on the surface of the anesthetized left eye and the closed right eye was covered
with an additional 1-mm-thick shield to block radiation that might be transmitted to the
right lens through the lead of the cutout. The lead cutout was then taped in place (Fig.
29.20). After each treatment, an eye patch is worn until sensation returns to the cornea.
Fractionation and total dose schedules, chosen to produce minimum fibrosis,
telangiectasia, and edema of eyelids and adjacent skin, were 54 Gy given in 27
fractions. Obviously, larger and more deeply infiltrating lesions require consideration of
electron beam techniques, some requiring 12 to 22 MeV electron beams (8). In such
patients, loss of vision or even of the eye may be unavoidable if the cancer is to be
cured.

Case 4: Nodular squamous cell carcinoma (Figs. 29.21 and 29.22)


This 93-year-old woman with a nodular squamous cell carcinoma overlying her malar
eminence (Fig. 29.21) was treated with 45 Gy in 10 fractions over 2 weeks using 250
kV photons with an orthovoltage unit and applicators akin to those shown in Figures
29.1 and 29.2. At age 100, at 7-year follow-up, the patient was alert and well and had
maintained a clinical complete remission with excellent cosmesis (Fig. 29.22).

926
Figure 29.22 At age 100, at 7-year follow-up, the patient was alert and well, with a sustained complete response
to treatment and an excellent cosmetic result.

Figure 29.23 Basal cell carcinoma, wrapping over the bridge of the nose, prior to irradiation.

927
Figure 29.24 Clinical setup photograph showing the use of an aluminum foil attenuator and customized lead
cutout shielding to protect normal tissues. The attenuator is placed to provide compensation for the missing
tissue on each side of the bridge of the nose.

Figure 29.25 Regression of the lesion with complete re-epithelialization is present at 3 months, time. This
treatment approach minimizes irradiation of tissues deep to the skin.

928
Figure 29.26 Gold eye shields for superficial or orthovoltage therapy can shield one or both eyelids. The spade-
shaped shields can be placed to have the ‘handle’ overlying either the upper or lower eyelid to help shield it from
the therapy beam, and the spherical shields can be placed below both eyelids.

Figure 29.27 This gentleman was treated with 50 Gy in 20 fractions over 4 weeks time using 100 kV x-rays for
a basal cell carcinoma of the right lower eyelid. An internal gold eye shield was placed below the lower eyelid to
protect the globe and upper eyelid.

Figure 29.28 Treatment setup that includes additional lead cutout shielding to help protect the patient from
incidental scattered irradiation.

929
Figure 29.29 An example of a multi-beam IMRT plan showing that reasonable whole scalp coverage is
achievable with acceptable sparing of intracranial contents. Multiple beams are arranged to tangentially irradiate
the scalp without unacceptable over- or under-lap. Dose-volume histogram is shown with whole brain (pink line)
receiving a low dose relative to scalp (red line). Fatigue may be observed in the elderly thus treated.

Case 5: Squamous cell carcinoma of the bridge of the nose (Figs. 29.23–29.25)
Figure 29.23 shows a gentleman with a basal cell carcinoma of the bridge of the nose
(delineated by dotted black line) and shows the difficulty that can be encountered with
complex surface changes. An aluminum foil attenuator (Figure 29.3) was used to
provide dose homogeneity at the surface and relevant superficial depths across the
curved contour of the nasal bridge (Figure 29.24). He was treated with 45 Gy in 10
fractions using 100 kV x-rays over 2 weeks’ time, and the cosmetic result at 3 months is
shown in Figure 29.25.

KEY POINTS
• Skin cancer is currently most often treated with surgery, but radiotherapy remains an
important therapeutic modality, especially for locations where R0 resections with acceptable
cosmetic outcomes are unlikely to be achieved.

• Not every skin cancer should be treated with the same approach. The selective use of
advanced imaging can help identify ostensibly normal areas that are involved with a recurrent
or deeply infiltrating tumor that might have been undertreated with a simple approach.

• Normal tissue protection is as important for skin cancer radiotherapy as it is for other tumor
sites. The selection of treatment techniques and the design and use of shielding, attenuators,
and bolus, as well as assuring that all are being appropriately used is incumbent on the
physician prescribing the treatment.

QUESTIONS
1. Which of these skin cancers is least likely to spread to regional nodes?
A. Lentigo maligna

930
B. Squamous cell carcinoma
C. Merkel cell carcinoma
D. Basal cell carcinoma
2. What is the appropriate radial margin to use when prescribing orthovoltage
irradiation for a 2.1-cm, moderately differentiated squamous cell carcinoma of
the skin of the shoulder that recurred after a community dermatologist
performed a shave excision?
A. 1.0 to 1.3 cm
B. <1.5 cm
C. >2.0 cm
D. 1.3 cm
E. 1.5 to 2.0 cm
3. What is the appropriate radial margin on the primary tumor site when treating a
surgically excised Merkel cell carcinoma, where the surgeon informs you that to
achieve closure, she could not achieve recommended margins of 1 to 2 cm? The
pathology report indicates that the primary tumor was 1.5 cm in diameter and
there was no evidence of nodal spread on the sentinel lymph node biopsy by
H&E staining.
A. 2 cm
B. 3 cm
C. 4 cm
D. 5 cm
4. How many millimeters of lead must be used to protect normal tissues from an 8
MeV electron beam?
A. 2.5 mm
B. 3 mm
C. 4 mm
D. 5 mm

ANSWERS
1. A. Although metastatic spread to regional nodes is often seen with
melanoma, squamous cell carcinoma, and Merkel cell carcinoma, it is also
seen, albeit very rarely, in patients with basal cell carcinoma. Lentigo
maligna is a noninvasive malignancy, and therefore has no risk of nodal
metastatic spread.
2. E. NCCN guidelines for radiotherapy margins for nonmelanoma skin cancer
indicate that for lesions <2 cm, a radial margin of 1 to 1.5 cm is
adequate. For lesions >2 cm, a margin of 1.5 to 2 cm is needed. If
electron beam therapy is being used, even larger margins are required
because of the wider penumbra, and the prescription should be written to
include bolus if the full dose would not be delivered to the skin surface
when an energy is chosen that will cover the deepest component of the
tumor by the 90% isodose surface.

931
3. D. Merkel cell carcinoma has a high propensity for occult involvement of
tissues beyond any clinically apparent disease. Surgical margins of 1 to 2
cm are therefore recommended in the NCCN guidelines, and the prompt
initiation of radiotherapy to the resection bed is well recognized to
decrease local recurrence rates. In fact, the risk of occult involvement of
draining lymphatics is significant enough that irradiation of nodal basins
is recommended by many, with in-transit skin also included in the
radiotherapy portals, if feasible, to further improve locoregional control.
The addition of radiotherapy to the primary site and regional nodal
volumes has not been shown with class I data to improve survival, but the
relative rarity of this disease may prevent such studies from being
performed.
4. C. The “rule of thumb” for calculating the thickness of lead-equivalent
shielding to protect normal tissues from incident electron beam therapy is
that the thickness in millimeters of lead required is one-half the incident
electron energy. This does not apply well for electron energies beyond
approximately 9 MeV.

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25. Oxenberg J, Kane JM 3rd. The role of radiation therapy in melanoma. Surg Clin
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29. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus
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287.

935
30 Breast Cancer

Yvonne M. Mowery, Sua Yoo, and Rachel C. Blitzblau

INTRODUCTION
Radiotherapy plays an essential role in the definitive management of in situ and
invasive breast carcinoma. This chapter reviews factors relevant to breast radiation
treatment planning, including breast and regional nodal anatomy, breast cancer
biology, and indications for adjuvant radiotherapy after breast-conserving surgery and
mastectomy. Patient positioning, treatment techniques, target volumes, and dose
fractionation are discussed for different clinical scenarios.

ANATOMY
The breast is positioned within the superficial fascia on the anterior chest wall (Fig.
30.1). It extends from the second rib superiorly to the inframammary fold, typically at
the sixth rib. Horizontally, the breast spans from the lateral sternal edge to the
midaxillary line. Breast tissue extending into the axilla is referred to as the axillary tail
of Spence. The pectoral fascia, serratus anterior, external oblique muscles, and upper
rectus sheath form the posterior border of the breast. The retromammary bursa consists
of loose areolar tissue located between the glandular breast elements and deep fascia of
the pectoralis major. This space allows for breast mobility along the chest wall.
Anteriorly, the breast is attached to the skin by fibrous connective tissue septa called
suspensory or Cooper ligaments. These ligaments insert perpendicularly to the
superficial fascia below the dermis and attach posteriorly to the deep fascia, providing
structural support without impairing mobility. Infiltration of these ligaments by
malignancy leads to skin retraction and dimpled appearance of the breast.
The breast consists of 15 to 20 lobes arranged radially around the nipple. Each lobe
contains 20 to 40 terminal ductal lobular units (TDLU), which represent the functional
unit of the breast. A TDLU contains clusters of tubuloalevolar glands or lobules that
drain into a terminal duct. Terminal ducts coalesce to form interlobular ducts, and
ducts from each lobe join to empty into a larger lactiferous duct. Typically 5 to 10 main
lactiferous ducts converge to open at the nipple. The glandular breast tissue with its
branching duct system is embedded in subcutaneous adipose tissue and surrounded by
supportive connective tissues, blood vessels, nerves, and lymphatics. The upper outer
quadrant contains the most glandular tissue and is the most common site of breast
carcinoma.

Blood Vessels
The internal mammary (IM) and lateral thoracic arteries provide the majority of the
breast blood supply (Fig. 30.2). The IM artery (internal thoracic artery) is a branch of
the subclavian artery and delivers blood to greater than 50% of the breast. It descends
vertically across intercostal spaces lateral to the sternum and branches into perforating
arteries that supply the medial and central breast. The lateral thoracic artery is a

936
branch of the axillary artery and primarily supplies the upper outer quadrant. The
pectoral branch of the thoracoacromial artery runs between the pectoralis major and
minor to supply the posterior breast. The subscapular artery and lateral branches of the
third to fifth posterior intercostal arteries provide minor contributions to the arterial
blood supply. Venous drainage is primarily through tributaries of the axillary vein and
perforating branches of the internal thoracic and posterior intercostal veins.

Lymphatic Drainage
A dense network of lymphatic vessels exists within the breast, and approximately 35%
of breast cancer patients have positive lymph nodes at presentation (1). The axilla is
most commonly involved, followed by the IM and supraclavicular regions, respectively.
The probability of drainage to the infraclavicular or interpectoral regions is <2% (2).
Lymphatic drainage patterns vary based on breast “quadrant” (upper outer, upper
inner, lower outer, lower inner, and central) (2–4). The dominant drainage site is the
axilla regardless of location; however, IM drainage is much more frequent for medial or
central breast lesions (5).
Axillary nodes are categorized into three levels based on their position relative to the
pectoralis minor muscle (Fig. 30.3). Level I contains axillary nodes situated lateral to
the pectoralis minor. Level II nodes lie posterior to the pectoralis minor and include the
interpectoral (Rotter) nodes situated between the pectoralis minor and major. Level III
(infraclavicular) nodes are located medial to the medial border of the pectoralis minor
and inferior to the clavicle. Supraclavicular lymph nodes lie within the supraclavicular
fossa, between the anterior scalene and sternocleidomastoid muscles. Adjacent nodes
above the cricoid cartilage are considered lower cervical nodes and categorized as
metastatic disease. Nodal involvement typically exhibits progressive, orderly spread
from level I to adjacent axillary levels, then to the supraclavicular region (6). Reported
rates of “skip metastases” range from 1.5% to 19.2% (7).

937
Figure 30.1 Mammary gland (coronal and sagittal sections). Reprinted with permission from Netter FH. Atlas of
Human Anatomy. 5th ed. Philadelphia, PA: Elsevier; 2010.

A complete axillary lymph node dissection is usually limited to surgical levels I and II,
which differ from radiologically defined axillary levels. A level I and II axillary
dissection removes all nodes below the axillary vein, extending medially behind the
pectoralis minor and laterally to the point where the axillary vein crosses the latissimus
dorsi tendon. In an effort to reduce surgical morbidity, surgeons typically do not
skeletonize the axillary vessels. In contrast, the NRG oncology breast contouring atlas
defines axillary level II as beginning where the axillary vessels cross the pectoralis
muscle laterally and extending until the vessels cross the medial border of the muscle.
This volume is typically superior to standard surgical fields.

938
IM nodes are situated in intercostal spaces within 3 cm of the sternal edge. Most of
these lymph nodes are located medial to the IM vessels within the first and second
intercostal spaces and lateral to the IM vessels within the third intercostal space (8).
Lymphatic drainage infrequently occurs to IM nodes only (<2%), but drainage from
∼20% of patients with early breast cancer flows to both axillary and IM nodes (4). In
the absence of grossly abnormal IM nodes, this nodal region is not typically dissected.

Figure 30.2 Normal anatomy of the breast, chest wall muscles, and vasculature (A) 1. Perforating branches from
internal mammary artery and vein; 2. Pectoral branches from thoracoacromial artery and vein; 3. External
mammary branch from lateral thoracic artery and vein; 4. Branches from subscapular and thoracodorsal arteries
and veins; 5. Lateral branches of third, fourth, and fifth intercostal arteries and veins; 6. Internal mammary
artery and veins; 7. Sternocostal head of pectoralis major muscle; 8. Clavicular head of pectoralis major muscle;
9. Axillary artery and vein; 10. Cephalic vein; 11. Axillary sheath; 12. Latissimus dorsi muscle; 13. Serratus
anterior muscle; 14. External abdominal oblique muscle. (B) 1. External abdominal oblique muscle; 2. Rectus
sheath; 3. Rectus abdominis muscle; 4. Internal intercostal muscle; 5. Transverse thoracic muscle; 6. Pectoralis
minor muscle; 7. Perforating branches from internal mammary artery and vein; 8. Internal mammary artery and
vein; 9. Cut edge of pectoralis major muscle; 10. Sternoclavicular branch of thoracoacromial artery and vein; 11.
Subclavius muscle and Halsted ligament; 12. External intercostal muscle; 13. Axillary vein; 14. Axillary artery;
15. Lateral cord of brachial plexus; 16. Lateral pectoral nerve (from the lateral cord); 17. Cephalic vein; 18.
Thoracoacromial vein; 19. Intercostobrachial nerve; 20. Lateral cutaneous nerves; 21. Lateral thoracic artery and
vein; 22. Scapular branches of lateral thoracic artery and vein; 23. Medial pectoral nerve (from medial cord); 24.
Ulnar nerve; 25. Pectoralis minor muscle; 26. Coracoclavicular ligament; 27. Coracoacromial ligament; 28. Cut
edge of deltoid muscle; 29. Acromial and humeral branches of thoracoacromial artery and vein; 30.
Musculocutaneous nerve; 31. Medial cutaneous nerve of arm; 32. Subscapularis muscle; 33. Lower subscapular
nerve; 34. Teres major muscle; 35. Long thoracic nerve; 36. Serratus anterior muscle; 37. Latissimus dorsi
muscle; 38. Latissimus dorsi muscle; 39. Thoracodorsal nerve; 40. Thoracodorsal artery and vein; 41. Scapular
circumflex artery and vein; 42. Branching of intercostobrachial nerve; 43. Teres major muscle; 44. Medial
cutaneous nerve of forearm; 45. Subscapular artery and vein; 46. Posterior humeral circumflex artery and vein;
47. Median nerve; 48. Coracobrachialis muscle; 49. Pectoralis major muscle; 50. Biceps brachii muscle, long
head; 51. Biceps brachii muscle, short head; 52. Brachial artery; 53. Basilic vein; 54. Pectoral branch of
thoracoacromial artery and vein. (From Osborne MP, Boolbol SK. Breast anatomy and development. In: Harris
JR, Lippmann ME, Morrow M, et al., eds. Diseases of the Breast. 5th ed. Philadelphia, PA: Wolters Kluwer;
2014.)

939
Figure 30.3 Lymphatic drainage of the breast showing lymph node groups and levels. 2. Substernal cross-
drainage to contralateral internal mammary lymphatic chain; 3. Subclavius muscle and Halsted ligament; 10.
Pectoralis minor muscle; 11, Axillary artery and vein. Internal mammary lymph nodes (A); apical lymph nodes
(B); interpectoral (Rotter) lymph nodes (C); axillary vein lymph nodes (D); central lymph nodes (E); scapular
lymph nodes (F); external mammary lymph nodes (G). Level I lymph nodes: lateral to lateral border of
pectoralis minor muscle; level II lymph nodes: behind pectoralis minor muscle; level III lymph nodes: medial to
medial border of pectoralis minor muscle. (From Burstein HJ, Harris JR, Morrow M. Malignant tumors of the
breast. In: DeVita VT, Lawrence, TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles &
Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.)

EPIDEMIOLOGY
Breast cancer is the most common malignancy among women, with an estimated
cumulative lifetime risk of approximately 12% in the United States. The American
Cancer Society estimates that 231,840 new cases of invasive breast cancer and 60,290
new cases of carcinoma in situ will be diagnosed among US women in 2015. An
additional 2,350 new cases are anticipated among US men. Breast cancer is the second
leading cause of cancer death among women. Female breast cancer deaths in the US are
expected to be approximately 40,290 in 2015 (9). While breast cancer incidence has
been relatively stable for the past decade, death rates have decreased by approximately
1.9% per year between 2002 and 2011 (10).
Greater than 90% of breast cancer cases are sporadic; however several risk factors are
associated with breast cancer development. Increasing age is a major risk factor, with
incidence rising sharply above age 40 and peaking at ages 75 to 79. This pattern is
reflected in recommendations to initiate screening mammography at age 40 or 50 for
women at normal risk for breast cancer (11–13). Longer duration of endogenous
estrogen exposure also appears to play a role. This hormonal effect likely accounts for
the association between breast cancer and nulliparity, early menarche, older age at first
pregnancy, and delayed menopause (14–16). Exogenous hormone exposure from
postmenopausal hormone replacement therapy has also been associated with increased
breast cancer risk (17,18). A small increase in relative risk has been demonstrated
among women currently or recently using oral contraceptives (19).
Ionizing radiation is a well-established environmental risk factor for breast cancer
development. A dose-dependent relationship exists between radiation exposure and
breast cancer, with greater risk with exposure at a younger age (20,21). Cumulative

940
breast cancer incidence ranges from 13% to 20% by age 40 to 45 among women who
received chest radiotherapy during childhood, adolescence, or young adulthood (22).
Increased breast cancer risk is noted as early as 8 years after therapeutic chest
irradiation, and the risk does not plateau with longer follow-up. Consequently, National
Comprehensive Cancer Network (NCCN) guidelines recommend early initiation of breast
cancer screening for women who have undergone thoracic irradiation between the ages
of 10 and 30. For women aged <25 years at the time of treatment, screening is
recommended starting 8 to 10 years after radiation. For women treated at age 25 to 30,
screening should begin 8 to 10 years after thoracic radiotherapy or at age 40,
whichever comes first (13).
Approximately 5% to 10% of breast cancers are hereditary (23). Most cases have been
linked to mutations in BRCA1 or BRCA2, which are two tumor suppressor genes
involved in maintaining chromosomal stability. Lifetime breast cancer risk is 28% to
84% among BRCA mutation carriers, with diagnosis often occurring at a younger age
compared to sporadic cases (24). BRCA mutation carriers also have an increased risk of
bilateral breast cancer and ovarian cancer, which can influence further workup and
treatment decisions (25). Genetic testing should be considered for breast cancer patients
meeting any of the following criteria: diagnosis at age ≤50, triple-negative breast
cancer, ≥2 breast cancer primaries, male, personal history of ovarian cancer, known
BRCA mutation within the family, or family history of breast and/or ovarian cancer
(26).

CLINICAL PRESENTATION AND HISTOLOGIC SUBTYPES


Breast cancer typically presents as an abnormality on screening mammogram or a
palpable breast mass. Less common presentations include bloody nipple discharge,
axillary adenopathy, and breast skin changes such as erythema, thickening, or peau
d’orange. The upper outer quadrant is the region most commonly involved by both in
situ and invasive carcinoma. Primary tumor location is not correlated with prognosis
(27). Axillary lymph node status is the most important predictor of disease-free and
overall survival in nonmetastatic breast cancer (28). Approximately 5% of patients in
the United States have distant disease upon presentation (29,30).
Noninvasive breast cancer, or carcinoma in situ (Tis), represents a proliferation of
abnormal cells that do not extend beyond ducts or lobules into surrounding stroma.
Rates of ductal in situ carcinoma (DCIS) diagnosis have increased dramatically with
rising use of screening mammography, and DCIS now represents approximately 20% of
breast cancers diagnosed by screening (31). DCIS most often presents as
microcalcifications on mammogram, and it is estimated that approximately 15% to 60%
of DCIS cases progress to invasive ductal carcinoma (IDC) without treatment (32). By
contrast, lobular carcinoma in situ (LCIS) is typically an incidental pathologic finding.
LCIS is associated with increased breast cancer risk in the ipsilateral and contralateral
breast, however there is controversy regarding whether it represents a precursor lesion
for breast cancer (33).
IDC is the most common invasive histologic subtype, followed by invasive lobular
carcinoma (ILC). Invasive carcinomas extend through the basement membrane to
directly infiltrate surrounding breast tissue, often resulting in a stellate or spiculated
appearance. This infiltration provides access to lymphatic and blood vessels, facilitating
spread to adjacent lymph nodes and distant hematogenous sites. Compared to IDC,
lobular carcinomas are more likely to be multifocal and diffusely infiltrative, resulting
in poorly defined margins on examination and imaging (34). Hormone receptor and

941
HER2 status have been increasingly recognized as prognostic factors in breast cancer
regardless of histologic subtype.
Inflammatory breast cancer (IBC) is an aggressive breast cancer subtype with a higher
propensity for lymphatic and distant spread compared to other invasive carcinomas.
IBC typically presents with rapid development of breast tenderness, warmth, erythema,
skin thickening, and/or peau d’orange appearance. Skin changes are secondary to
tumor emboli within dermal lymphatics. Due to this dermal lymphatic involvement,
most women with IBC have positive nodes and approximately one-third have metastatic
disease upon presentation. Neglected primary tumors may have a similar appearance to
IBC, however there is a longer interval between initial symptoms and development of
skin changes.

PATIENT SELECTION
Breast Conservation
Large randomized trials have established that breast conservation, consisting of partial
mastectomy followed by adjuvant radiotherapy, provides equivalent outcomes to
mastectomy in the treatment of early-stage invasive and in situ breast carcinoma
(35,36). The whole breast with or without regional lymph nodes is irradiated to
eradicate microscopic residual disease and minimize the risk of local recurrence. A large
meta-analysis has demonstrated improved breast cancer survival with adjuvant
radiotherapy after breast-conserving surgery (37).
Breast conservation candidates must be motivated to preserve their breasts and
should not have any contraindication to adjuvant radiotherapy. Contraindications to
breast conservation include widespread disease that cannot be incorporated in a local
excision, extensive suspicious microcalcifications, persistently positive margins, and
pregnancy at the time of radiotherapy. Collagen vascular disease (38), prior ipsilateral
breast irradiation, tumor size relative to breast size or location resulting in subobtimal
cosmetic results, and genetic predisposition to breast cancer may be relative
contraindications as well. Young patient age, in and of itself, is not a contraindication
to breast conservation, as excellent outcomes have been reported for these patients with
breast conservation as well (39). Large pendulous breasts are not a contraindication to
breast conservation, but may affect patient positioning considerations.

Postmastectomy
Locoregional postmastectomy radiotherapy is associated with significantly improved
outcomes for women with node-positive breast cancer. A recent meta-analysis of
randomized controlled trials by the Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG) showed relative risk reductions of 32% for locoregional recurrence and 20%
for breast cancer mortality among all node-positive women receiving radiotherapy after
mastectomy and axillary dissection (40). These results are driven largely by the large
British Columbia and Danish Breast Cancer Cooperative Group trials, which showed
improved overall survival with postmastectomy locoregional radiotherapy for node-
positive women (41–43). While guidelines universally endorse postmastectomy
radiotherapy for patients with four or more positive axillary nodes, recommendations
have been mixed for patients with one to three positive axillary nodes (44–48).
The EBCTCG meta-analysis did not show any improvement in locoregional control or
breast cancer mortality with postmastectomy radiotherapy for node-negative women

942
(40). However, several guidelines recommend at least consideration of postmastectomy
radiotherapy for patients with T3–T4 tumors or positive margins (44,46,47). Additional
factors such as lymphovascular invasion, high-grade histology, multicentric disease,
skin or nipple involvement, and young age or premenopausal status have also been
associated with postmastectomy recurrence and therefore may influence decisions
regarding adjuvant radiotherapy (49,50). Currently, NCCN guidelines recommend use
of the highest pre- or post-treatment stage to make decisions regarding PMRT in the
setting of neoadjuvant chemotherapy.

Omission of Radiotherapy
Consideration of omission of radiotherapy after breast-conserving surgery may be
appropriate for a highly selected patient group. One such population is women over the
age of 70 with small (<2 cm), estrogen receptor–positive, node-negative tumors. Ten-
year results of the CALGB 9343 trial showed that patients who received tamoxifen
alone, without adjuvant radiotherapy, had slightly higher rates of local recurrence (9%
vs. 2%), but with no difference in overall survival (51). Breast-conserving surgery
without adjuvant radiotherapy may also be appropriate for women with completely
resected, small DCIS that is low- or intermediate-grade (52). Similarly, the randomized
RTOG 9804 trial shows a statistically significant reduction in local recurrence risk for
small, completely resected DCIS, but with very low recurrence rates in both arms (53).

SIMULATION
Historically, simulation for breast radiation was performed on a conventional simulator
with asymmetric collimators and a breast tilt board (54). Currently, most treatment
centers in the United States utilize computed tomography- (CT) based treatment
planning.

Supine Intact Breast


The patient is placed in the supine position with arms up on a breast board, Vac-Lok, or
other immobilization device. A tilt should be applied to the immobilization device in
order to isolate breast tissue below the clavicle. The head is turned slightly to the
contralateral side if regional nodal irradiation is planned. The clinical boundaries of
breast are marked with radiopaque fiducial wire. The medial border is placed at midline
over the sternum, and the lateral border is placed at the midaxillary line. The superior
border is placed at the inferior aspect of the clavicular head, and the inferior border is
placed approximately 2 cm below the inframammary fold. For an intact breast,
adjustment of wires may be required to allow approximately 2-cm margin around
palpable breast tissue, particularly for large-breasted women. A fiducial wire is also
placed over the lumpectomy scar and any drain sites. If nodal volumes are to be
included, a catheter can be placed 3-cm lateral to the midline sternal catheter toward
the contralateral side to facilitate field design encompassing the IM nodes. Although
these catheters are placed as guides, target delineation is largely based on CT volumes
as discussed below.
A scout CT scan is obtained to verify patient positioning and setup. Axial 3-mm CT
slices are then acquired. The superior border of the CT scan should be at least 4 cm
above the superior border for breast-only treatment or above the angle of the mandible
if treating supraclavicular nodes. The inferior border should be at least 4 cm below the

943
inferior catheter. For breathhold technique (further discussion below), the inferior
border is lowered to encompass the tracking device on the patient’s abdomen. Axial CT
images are reviewed at the time of simulation to identify any needed positioning
changes.
A stable reference point is set at the middle of the breast in the longitudinal direction,
at the center of the patient in the lateral direction, and at the mid-chest level in the
vertical direction. This reference point is projected on the skin with the room lasers, and
alignment marks are made on the patient with marker and protected with clear stickers.
These can be subsequently used during positioning on the treatment table as a stable
point from which to shift to treatment isocenter. At some institutions, tattoos are used
to delineate alignment marks. An isocenter may also be selected at the time of
simulation.

Prone
Prone positioning can be considered for patients who will not receive nodal irradiation
(55). Improved dose homogeneity and decreased lung dose have been observed with this
technique (56,57). Effect on cardiac dose varies depending on patient anatomy (57,58).
Prone setup may be particularly beneficial for women with large breasts by facilitating
reduced separation (59).
The patient is initially placed in the supine position with arms up, and catheters are
placed to demarcate the clinical limits of breast tissue as described for supine
simulation. The patient is then positioned in the prone position on a prone breast board
with the ipsilateral breast suspended in the open area of the breast board with both
arms up. The contralateral breast is pulled away beneath the patient with the support of
the contralateral breast board plate. The head can be turned toward the treated side,
away from the treated side, or in a neutral position depending on prone breast board
style and patient comfort.
A scout CT scan is obtained to verify patient positioning and setup. Axial 3-mm CT
images are then obtained with similar superior and inferior borders as discussed for
supine positioning. Breathhold technique is not utilized in the prone position. A stable
reference point is set at the middle of the breast in the longitudinal direction, at the
center of the board in the lateral direction, and at the level of the contralateral breast
board plate. This reference point is marked on the patient skin. Indexing and leveling
marks are also made on the patient, primarily on the back and arms, to maximize
reproducibility on the treatment table. This is particularly important for prone position
due to greater interfraction setup variability compared to supine position (60).
Repeat simulation in the supine position is typically performed for tumor bed boost
planning. For certain tumor locations and/or large breasts, a lateral decubitus position
is preferable to supine positioning for en face treatment. In other cases, boost may be
best performed in the prone position, most commonly with minitangent fields. If
needed, repeat simulation should be performed near the end of whole breast irradiation
(WBI) to allow for any changes in tumor bed or seroma.

Postmastectomy
The patient is immobilized in the supine position with both arms above the head. The
mastectomy scar, drain sites, and clinical boundaries of breast tissue are marked with a
radiopaque wire as described for intact breast simulation. If intact, the contralateral
breast can be used to determine the appropriate location of the inferior, lateral, and

944
superior borders. The CT scan is then performed as described for breast conservation. A
stable reference point is set on the patient, and alignment marks are made as discussed
above.

Breathhold
The patient is simulated in the supine position as discussed above. Respiratory gating or
active breathing control can be used to monitor respiration. Respiratory gating utilizes a
reflective marker placed on the patient during simulation and treatment. Marker motion
with respiration is tracked by an infrared camera, and the respiratory pattern is
displayed as a waveform. The patient practices deep inspiration and breathhold a few
times. Gating thresholds are set at the amplitude level where the patient is able to
perform stable deep inspiration breathhold over 15 to 20 seconds. Axial CT images are
obtained during breathhold within this optimal breathhold threshold, as well as during
free breathing.

Figure 30.4 Cardiac sparing with (A) free breathing versus (B) breathhold for treatment of left-sided breast
cancer. Isodose curves are shown at the same level within the breast for a patient simulated in (A) free breathing
and (B) deep inspiratory breathhold.

Active breathing control is an alternative technique in which the patient breathes


through a mouthpiece that is connected to a breathing control device. This apparatus
has respiratory flow monitors and valves to control inspiration and expiration. The
valves are closed to immobilize breathing motion temporarily when the patient reaches
the optimal inspiratory phase of the respiratory cycle. A nose clip prevents air leakage
and facilitates accurate inspiratory volume measurement. Axial CT images are obtained
during this preselected respiratory phase, as well as during free breathing.
Deep inspiration breathhold facilitates reduced cardiac dose compared to free
breathing during treatment of left-sided breast cancer for many patients (61,62).
Breathhold and free breathing images are compared at the time of simulation to
determine which position provides better cardiac sparing (Fig. 30.4).

TREATMENT PLANNING: TARGET DELINEATION


Breast cancer was historically treated using clinical body landmarks. In the current era
of CT-based three-dimensional treatment planning, targets can be more precisely
delineated. CT images from simulation are exported from the CT acquisition software
and imported to the treatment planning software. Contours of normal structures,
including lungs, heart, and potentially other structures such as the spinal cord, brachial

945
plexus, and contralateral breast, are drawn on the acquired CT images. Target
structures, including the breast or chest wall are contoured. Regional lymph nodes
consisting of axillary levels I, II, and III, supraclavicular, and IM nodes are also
contoured in the setting of nodal treatment. In the intact breast setting, the lumpectomy
cavity is contoured including seroma, architectural distortion of the tissue, and any
surgical clips present in the breast.
Contouring is generally performed manually by the treating physician and planning
dosimetrist. However, automated contouring is increasingly possible with newer
treatment planning software (63). Studies show that even amongst experts, there is
significant interobserver variability in contouring of breast, chest wall, and regional
nodal targets (64). Published guidelines are available from NRG Oncology regarding
delineation of the breast, chest wall, and regional draining nodal basins (65). While
individual patient anatomy may not strictly conform to the example images in this atlas,
it provides a starting point for practitioners, and continues to be utilized in current
cooperative group protocols.

Breast Conservation
The desired target in the breast conservation setting is the entire ipsilateral breast. Care
must be taken to ensure adequate coverage of the tumor bed, particularly if this is
located to one edge of the breast tissue. Treatment of regional nodes may be appropriate
after breast conservation as well. Nodal irradiation has been universally considered to
be indicated in the setting of four or more involved axillary lymph nodes.
Comprehensive nodal irradiation is more controversial in the setting of one to three
positive lymph nodes. However, data recently reported from the MA20 and EORTC
22922 trials, in which patients with one to three positive nodes were randomized to
WBI with or without radiotherapy to lymph node targets, indicate at least a trend
toward survival benefit with the addition of nodal irradiation (66,67).
Additionally after publication of the ACOSOG Z0011 study showing noninferior
outcomes for patients who do not receive axillary dissection in the setting of one or two
positive sentinel lymph nodes, an increasing number of patients are not undergoing
axillary dissection after identification of a positive sentinel node (68,69). An analysis of
the radiotherapy treatment patterns on the ACOSOG Z0011 study showed that
approximately 15% of patients did receive a third field to the supraclavicular region.
Approximately 50% of patients received coverage of the lower axilla interpreted as high
tangents, regardless of treatment arm (70).
The EORTC 10981–22023 AMAROS trial showed equivalence of radiotherapy to
axillary dissection in controlling the axilla in the setting of positive sentinel lymph node
biopsy after breast conservation (67) with a significantly lower rate of lymphedema.
Therefore, it may be increasingly common to consider regional nodal radiotherapy
rather than axillary dissection in the setting of a small number of positive sentinel
nodes. In this context, it may be particularly important for the radiation oncologist to
consider inclusion of at least lower axillary levels in high tangent fields versus full
nodal irradiation with a third field depending on individual patient risk. Of note, if
axillary nodes were not dissected, the full axilla and supraclavicular nodes (rather than
a supraclavicular field alone without attention to the lower axilla) should be covered if
nodal treatment is desired.

Postmastectomy

946
The desired target volumes in the setting of postmastectomy radiotherapy include the
chest wall, axillary, supraclavicular, and IM lymph nodes. Though IM nodes were
included in the large randomized trials evaluating postmastectomy radiotherapy,
inclusion of IM nodes in the setting of PMRT remains controversial. Ten-year results
from one trial comparing outcomes for stage I and II breast cancer patients treated with
mastectomy and postoperative radiotherapy with or without treatment of the IM nodes
demonstrated no difference in overall survival (71). The recently reported MA20 and
EORTC 22922 trials evaluating inclusion of nodal treatment (or not), also included IM
coverage in addition to axillary and supraclavicular treatment. For many practitioners,
the decision regarding inclusion of IM nodes may be performed on an individual patient
basis to achieve a balance between local recurrence risk and morbidity of treatment. In
particular, consideration may be given to exclusion of IM nodes when treating left-sided
breast cancer, given concern for cardiotoxicity.

TREATMENT PLANNING: FIELD DESIGN


Tangent Fields for Intact Breast
Tangential fields are designed to encompass the entire breast as defined by the treating
physician (Fig. 30.5A–D). It is important to allow adequate clearance of breast tissue.
The entire contoured tumor bed should be included within the tangential fields with
adequate margin. The authors of this chapter recommend a margin of at least 2 cm
around the tumor bed within the tangential field to allow for variation in setup. The
isocenter is generally set along the chest wall, midway between the superior and inferior
aspects of the field. If treatment of only lower axillary levels is desired, without
inclusion of upper axillary or supraclavicular nodes, high tangents can be considered.
In this situation the upper level of the tangents is raised to ensure coverage of the
desired axillary levels, generally at least level I, possibly also level II depending on
individual patient risk. It is important to note that inclusion of levels I and II may be
best achieved by contouring these axillary levels to ensure appropriate coverage within
tangents.

Tangent Fields for Chest Wall


The entire ipsilateral chest wall target, as defined by the treating clinician, should be
included within the tangential fields (Fig. 30.5E–G). Fields may require modification to
ensure inclusion of the entire mastectomy scar and drain sites. When drain sites fall
significantly outside the tangents, an abutting electron field can be utilized to
supplement superficial dose in these areas.

Inclusion of Nodal Targets


Breast/chest wall and regional nodal treatment traditionally entails matching opposed
tangents to an anterior oblique supraclavicular field that is half-beam blocked inferiorly
(Fig. 30.5E–G). This can be accomplished with single isocenter or dual isocenter
methods. Couch rotation and collimator angulation can be used to match diverging field
edges and minimize normal tissue toxicity from overlap (46–49). The use of half-blocked
or over-rotated tangents minimizes tangent beam divergence into the lung.

947
Figure 30.5 Tangent, supraclavicular, and internal mammary field design. (A) Medial and lateral tangent fields
with field entry shapes displayed on skin rendering with patient in the supine position. (B) Isodose curves for the
same supine patient. The isocenter (yellow circle) is located within the patient at a point that is approximately
midway along the central axis. (C) Medial and lateral tangent fields are shown with field entry shapes displayed
on skin rendering with patient in the prone position. (D) Isodose curves for the same prone patient. The
isocenter (yellow circle) is located medial to the breast, outside the body. The tumor bed is in red. (E) Single
isocenter three-field beam arrangement. The shared isocenter is marked by a blue sphere. The internal mammary
nodes are included within partially wide tangents. (F) Dual isocenter three-field beam arrangement. The oblique
nodal field isocenter is marked by a blue sphere. The isocenter for the tangents is within the patient at the
location of the red dot. The internal mammary nodes are included within partially wide tangents. (G) Matched

948
electron beam arrangement. An electron field is matched medially to opposed tangents and superiorly to the
anterior oblique field to encompass the internal mammary nodes and lower inner chest wall.

Three-Field Single Isocenter


In this technique the single isocenter is set along the match line at the bottom of the
clavicular head (Fig. 30.5E). For the tangential fields, the superior jaw is set to zero at
the level of the isocenter and the inferior jaw is opened to the inferior marking wire to
encompass the entire chest wall target. The supraclavicular field is designed with an
inferior jaw set to zero at the level of the isocenter and the superior jaw is set to the
level of the bottom of the cricoid cartilage. The supraclavicular field is obliqued slightly
an anterior oblique field to avoid the spinal cord. The medial jaw edge is set to the
lateral vertebral bodies, and custom multi-leaf collimators (MLCs) can be used to shape
this field medially and laterally. The lateral field edge is set to cover desired axillary
levels and supraclavicular nodes, depending on the clinical situation and desired
axillary targets. While this technique has the advantage of simpler setup and imaging
on the treatment machine, one drawback is that the tangent field length is limited to 20
cm, and tools for modulating dose are often restricted further. The superior border of
the tangent, that is the match line, can be adjusted up or down to compensate for this.
However, lowering the match line can result in inadequate dose coverage for the
superior breast tissue area and increases in the ipsilateral lung dose.

Three-Field Dual Isocenter


With this technique, the supraclavicular field isocenter and borders are placed as
described for the single isocenter method. However, for tangential field design, an
isocenter is set along the chest wall approximately equal depth from medial and lateral
tangential fields and midway between the superior and inferior borders of the field (Fig.
30.5F). In order to create a nonoverlapping matching plane between the superior border
of the tangents and the inferior border of the half-beam blocked supraclavicular field,
table kick and collimation are utilized for the medial and lateral tangential fields.
Modern treatment planning software can often perform this automatically and it can
then be visually double-checked within the computer planning software. While this
technique requires more complicated setup and imaging on the treatment machine, it
allows the tangential fields to be greater than 20 cm. This may be required for patients
with larger habitus or breast size.

Internal Mammary Nodal Coverage


If the IM nodes are to be treated, multiple methods have been described to ensure
coverage. These include partially wide tangent fields (Fig. 30.5E–F), extended tangent
fields, and matching electron/photon fields (Fig. 30.5G). Dosimetric comparison studies
have determined that the partially wide tangent technique provides the optimal blend of
target coverage and normal tissue sparing (72–74). For patients requiring a matched
electron field, split electron fields using a lower energy below the third intercostal space
can help lower cardiac dose (75).

Supraclavicular/Axillary Field
The supraclavicular and desired axillary nodal levels are generally included in a single
anterior oblique photon field angled off the spinal cord. The starting angle is often 15

949
degrees, but this can be adjusted as needed based on patient anatomy. Historically dose
was prescribed to a depth of 3 cm. However, dose should be prescribed to adequately
encompass the contoured nodal volumes within the desired prescription dose using
modern CT-based treatment planning (Fig. 30.6A–B). Field borders are set based on
contoured nodal volumes, and custom MLCs can be utilized to avoid spinal cord
medially and the shoulder joint as appropriate laterally. Avoidance of skin flash
superiorly in the supraclavicular region can decrease acute skin reaction and may
preserve a strip of lymphatics within the skin to help minimize risk of upper extremity
lymphedema.

Posterior Axillary Field


If deeper axillary nodal volumes cannot be adequately encompassed within a minimum
dose of 4,500 cGy through a single anterior oblique supraclavicular/axillary field
without excessive hot spots, the dose to deeper axillary structures can be supplemented
with a posterior axillary field. This field is designed to oppose the
supraclavicular/axillary field. Conventional field borders are the clavicle superiorly and
the tangential match line inferiorly. The lateral and medial borders are based on patient
anatomy and contoured axillary nodal targets (Fig. 30.6C–E). The prescribed dose to
this field is low, typically in the range of 25 to 50 cGy per day to supplement the dose
from the anterior oblique supraclavicular field.
Alternatively, a full posterior oblique opposed field can be used to provide
supplemental coverage of the entire supraclavicular/axillary field (Fig. 30.6F–H). This
field is designed with a nondivergent medial border to avoid spinal cord dose. In this
setting, the dose is generally prescribed to a midpoint, and the anterior posterior field
weighting can be adjusted as desired based on patient anatomy, target coverage, and
placement of dose hot spots. In the setting of either type of posterior field utilization,
mixed beam energy, forward planned electronic compensation, or field-in-field
techniques may also be utilized to improve dose homogeneity.

Dose Modulation
The large variability in tissue thickness within the breast poses a challenge in achieving
a homogeneous dose distribution. Lack of scatter from lung tissue contributes to
insufficient coverage near the central chest wall region, leading to higher dose
elsewhere when a plan is normalized to provide adequate coverage near the chest wall.
Hot spots are typically greater in women with large breasts due to greater separation.
Traditionally, wedges have been utilized to improve dose homogeneity (76–79). Physical
wedges (typically 15, 30, 45, or 60 degrees) are placed along the desired plane with the
heel compensating for the thinnest area of breast tissue. Field size is limited within the
wedge plane, with maximum dimension depending on wedge angle. Alternatively,
dynamic wedges use collimator jaw movement while the beam is on to modulate dose.
This allows additional wedge angles, avoids manual wedge placement by the therapists,
and permits larger field size. Patient-customized physical compensators can also be
used, although construction of these devices is impractical due to the required labor and
time involved (80,81). Mixed beam energies represent another simple method of
improving dose homogeneity with standard tangential fields (82,83).

950
Figure 30.6 Supraclavicular and axillary nodal fields. (A) Digital reconstructed radiograph (DRR) of a nodal
field for a patient who has undergone a complete axillary dissection. The anterior oblique field has been shaped
to include only the undissected axilla and supraclavicular region. (B) DRR of a nodal field for a patient who has
not undergone an axillary dissection or for whom full axillary coverage is indicated. The field extends farther
laterally than is seen in panel A to encompass the entire axilla and supraclavicular region. (C–E) DRRs for a
right anterior oblique field (C) and partial posterior axillary boost beam (D) with an axial image (E) showing

951
both fields. (F–H) DRRs for a right anterior oblique field (F) and full opposed left posterior oblique field (G)
with an axial image (H) showing both fields. Axillary level I is yellow, II is green, III is brown, and
supraclavicular nodal region is red.

Several studies have shown reduced short-term toxicity and improved cosmesis with
intensity modulated radiation therapy (IMRT) compared to wedge-based tangential
whole breast radiotherapy (84–89). Improved cardiac dose sparing has been proposed
as an additional benefit (90–96). Breast IMRT studies have utilized various techniques
including “field-in-field” or multi-segmented 3D conformal radiotherapy, inverse and
forward planned techniques, and dynamic or segmental multileaf collimator modes.
Helical tomotherapy and volume modulated arc therapy (VMAT) have been introduced
as additional methods of dose modulation.
The American Society for Radiation Oncology (ASTRO) recently recommended against
routine usage of IMRT to deliver whole breast radiotherapy. This was one of five
recommendations released in 2013 for the Choosing Wisely campaign, identifying
treatment options that should be carefully considered to avoid overuse (97). Inverse
planned IMRT should be limited to specific breast cancer cases such as patients with
unusual anatomy, where this technique will more likely provide significant clinical
benefit (98–101).
Electronic tissue compensation (ECOMP) represents an alternative method of
modulating dose to achieve homogeneous dose distribution. ECOMP involves forward
planning to modify the fluence distribution manually within each tangential field to
improve dose homogeneity. Treatment planning software subsequently converts the
fluence maps to dynamic multileaf collimation sequences for treatment delivery. ECOMP
requires less planning time and utilizes fewer monitor units to deliver compared to
inverse planning IMRT, while providing similar target coverage and normal tissue
sparing (102,103).

Normal Tissue Dose Constraints


The primary organs at risk during breast and chest wall irradiation are the lungs and
heart. Dose to the opposite breast should also be minimized to reduce risk of radiation-
induced contralateral breast cancer. Lung dose has been correlated with radiation
pneumonitis, and V20 Gy ≤20% has been associated with significantly lower incidence
of radiation pneumonitis (104). However, achieving an ipsilateral lung V20 Gy ≤20%
can be difficult when IM nodes are targeted. Symptomatic radiation pneumonitis is rare
with ipsilateral lung V20 Gy <30% (105,106). Ipsilateral lung dose-volume constraints
of V20 Gy ≤20% and V20 Gy ≤30% are commonly accepted in breast treatment
planning (107).
Breast radiotherapy has been associated with cardiac mortality in numerous trials
predating the era of CT-based radiation treatment planning (108–110). More recent
studies indicate that radiotherapy-associated cardiac toxicity has decreased with the
advent of modern treatment planning techniques (111–113). Normal Tissue
Complication Probability models in the Quantitative Analyses of Normal Tissue Effects
in the Clinic (QUANTEC) guidelines estimate a <1% risk of cardiac mortality at 15
years with a cardiac V25 Gy <10% (114). A large population-based case-control study of
patients with prior radiotherapy for breast cancer showed a linear increase in major
coronary events of 7.4% per Gray mean radiation dose to the heart with no apparent
threshold (115). Shielding blocks or multileaf collimators should be used to minimize
radiation dose to the heart. Prone positioning, deep inspiratory breathhold, and dose

952
modulation techniques discussed above may also facilitate lower cardiac doses.

Treatment Imaging
The CT dataset is used to create digitally reconstructed radiographs (DRR) for
orthogonal setup films (AP and lateral) and beam’s eye view for each tangential
treatment field. Port films and kV on-board imaging are performed before delivering the
first treatment to confirm isocenter location and patient positioning. Imaging frequency
during the treatment course depends on numerous factors, including daily setup
variability, patient positioning, and utilization of respiratory gating. Free-breathing
treatment in supine position typically requires less frequent imaging than breathhold or
prone breast treatment. Supine treatment with respiratory gating requires port images
for the first few days to confirm patient breathhold level. Prone position typically
requires daily orthogonal setup imaging since the treatment area is difficult to visualize.

DOSE AND FRACTIONATION


Breast Conservation
WBI has historically delivered 45 to 50 Gy in 25 to 28 fractions at 1.8 to 2 Gy per
fraction. However, 10-year data from multiple large randomized trials have
demonstrated the noninferiority of hypofractionated whole breast radiotherapy (42.5
Gy in 16 fractions (116) or 40.05 Gy in 15 fractions (117)). The Canadian trial
included only node-negative patients and placed restrictions on breast size and
treatment hot spots (116). The UK START trials had broader inclusion criteria,
including approximately 25% node-positive patients (117).
Hypofractionated WBI should be strongly considered for appropriate patients, given
the high-quality evidence supporting its safety and efficacy. This was highlighted in one
of the ASTRO 2013 Choosing Wisely recommendations, stating not to initiate
radiotherapy in women aged 50 years or older with early-stage invasive breast cancer
without considering a hypofractionated treatment schedule (97). ASTRO has also
released guidelines on dose and fractionation schedules in patients appropriate for
hypofractionated radiotherapy (118). Prone positioning and advanced dose modulation
strategies may help improve dose homogeneity and increase the number of patients
appropriate for hypofractionation. More hypofractionated regimens are currently under
investigation, such as 28.5 or 30 Gy in five once-weekly fractions of 5.7 or 6 Gy (119).
If nodal targets are included in the treatment of the intact breast setting, treatment
planning and dose coverage are as described in the postmastectomy setting. The authors
are not currently using hypofractionated radiotherapy in the treatment of lymph nodes
on a routine basis, though it should be noted that this is more commonly used in other
countries (120,121). Patients with N1 disease were included on the UK START trials,
and a subset of patients received hypofractionated nodal irradiation. Additionally, the
original British Columbia postmastectomy radiotherapy trial utilized a hypofractionated
course (37.5 Gy in 16 fractions). This regimen was well-tolerated; however, no
fractionation randomization was included in this trial (43).

Postmastectomy
Standard prescribed dose to the chest wall and IM nodes is 45 to 50.4 Gy in 25 to 28
fractions. In most cases, chest wall bolus is utilized to ensure adequate dose to the skin
and superficial subcutaneous tissue. Significant heterogeneity exists in the accepted

953
bolus thickness and schedule (107). The authors’ preferred technique is 0.5–1 cm bolus
applied every other day. However, this is modified based on the clinical situation and
estimated patient risk. More frequent bolus schedules, including possibly daily bolus,
may be considered for the patients at highest risk, particularly those with IBC.

Tumor Bed Boost


Randomized controlled trials have demonstrated improved local tumor control with
additional radiotherapy to the tumor bed for patients with invasive breast cancer in the
setting of breast conservation (122–124). A greater absolute benefit was observed for
younger patients. There are no level one data evaluating boost for DCIS, but
practitioners often extrapolate from the invasive data and utilize a boost in these
patients. This is particularly true in the setting of close or positive margins and for
young patients, supported by one series that showed a benefit for boost in women
younger than 40 years of age (125). A tumor bed boost usually consists of 10 Gy to 16
Gy at 2 to 2.5 Gy per fraction delivered to the lumpectomy cavity, typically with 1.5- to
2.5-cm additional margin. Boosting to a total tumor bed dose greater than 60 Gy should
be considered in patients with positive margins.
Tumor bed boost is typically administered by en face electrons, with beam energy
chosen based on tumor depth. A normalization point can be set at D-max for the chosen
electron energy and dose prescribed to the desired isodose level. Alternatively, dose can
be prescribed to a specific depth. Photons may be necessary to provide adequate
coverage for deep tumors depending on patient anatomy. In this case, generally a 4- to
5-beam bouquet is used, often in a noncoplanar arrangement to minimize exit dose into
the lungs, heart, or contralateral breast. Brachytherapy can also be utilized to deliver
the boost dose, although this is rarely performed (123). Historically, the boost has been
administered sequentially after WBI; however, studies are ongoing to investigate
simultaneous integrated photon boost (126).

Mastectomy Scar Boost


A radiotherapy boost is commonly administered to the mastectomy scar in the
postmastectomy setting based on extrapolation of tumor bed boost data. While most
local recurrences after mastectomy occur at or near the scar (127), no randomized
controlled trials have examined whether additional radiotherapy provides any benefit.
One retrospective review has shown reduced local recurrence and improved survival in
patients with stage II–III breast cancer receiving a chest wall boost above 50.4 Gy
(128,129). Mastectomy scar boost typically consists of 10 Gy at 2 to 2.5 Gy per fraction
delivered by en face electrons to a margin of 2 to 3 cm around the scar. Additional dose
above 60 Gy may be considered in particularly high-risk settings such as IBC or other
skin involvement.

PARTIAL BREAST IRRADIATION


Accelerated partial breast irradiation (APBI) is an alternative to WBI for a subset of
patients with low-risk breast cancer. APBI targets the lumpectomy cavity with a small
margin of normal surrounding tissue. This limited treatment volume is based on studies
showing that most local recurrences occur in or near the tumor bed after breast-
conserving therapy (130–134). Irradiation of a smaller normal tissue volume allows
delivery of a higher dose per fraction and shorter total treatment course. This may offer

954
improved patient convenience and treatment accessibility, as well as decreased
healthcare system costs.

Patient Selection
Appropriate patient selection for use of partial breast irradiation is essential,
particularly given the absence of long-term results from randomized trials comparing
APBI with conventional WBI. Several groups have released selection guidelines,
highlighting a favorable-risk patient population with small tumors, negative margins,
and no lymph node involvement. APBI is typically not recommended for younger
women or patients with invasive lobular histology.

Treatment Planning
Several techniques can be utilized to deliver APBI, including brachytherapy,
intraoperative radiotherapy (IORT), and external-beam radiotherapy (EBRT). The
longest follow-up is available for brachytherapy, but the optimal APBI method has not
been determined (135). The NSABP B-39/RTOG 0413 trial randomizing patients to APBI
or WBI allowed use of multicatheter brachytherapy, MammoSite balloon catheter, or
three-dimensional conformal radiation therapy (3D-CRT) in the APBI treatment arm.
Simulation for treatment planning entails CT in the prone or supine position as
described previously for WBI. The lumpectomy cavity, including surgical clips and
postoperative changes, is outlined. Typical postoperative clinical target volume (CTV)
for EBRT-based APBI consists of the lumpectomy cavity expanded by 1 to 1.5 cm
(136–143). An additional 0.5 to 1 cm is generally added to generate the planning target
volume (PTV), accounting for setup variability and patient motion. The seroma cavity
with 1- to 2-cm margin is the recommended PTV for brachytherapy-based APBI (144).
Promising cosmetic and local control outcomes have been demonstrated with
brachytherapy-based APBI. The Budapest randomized controlled trial demonstrated
excellent local control and superior cosmesis with interstitial APBI compared to WBI at
10 years (145). Similar results have been shown in in small single-institution series and
the RTOG 95–17 phase II trial using multicatheter interstitial brachytherapy
(146–148). Implantation for interstitial brachytherapy is typically performed under
general anesthesia. The tumor bed is localized by CT or an Integrated Brachytherapy
Unit to visualize surgical clips, and catheters are inserted into the tumor bed and
surrounding tissue. Repeat CT or orthogonal x-ray imaging is performed to reconstruct
catheter placement for dosimetric planning. The most common interstitial catheter dose
regimens are 45 to 50 Gy over 4 days, 32 to 34 Gy in twice daily 4 Gy fractions over 4
to 5 days, and 36.4 Gy in twice daily 5.2 Gy fractions over 4 days (HDR) (145–147).
Intracavitary and hybrid brachytherapy techniques have recently gained favor due to
increased reproducibility and easier use compared to interstitial catheter placement.
Available devices, including MammoSite, Contura, SAVI, Axxent, and ClearPath, are
typically placed into the lumpectomy cavity at the time of surgery or postoperatively
under image guidance. A CT scan is performed to evaluate the quality of the implant,
including assessment of conformity to the cavity and distance to skin (ideally ≥7 mm).
Several dosimetric optimization methods have been described (149). Data from the
American Society of Breast Surgeons MammoSite registry show excellent cosmesis and
local control comparable to WBI in a highly selected patient population receiving 34 Gy
in 3.4 Gy fractions twice daily over 5 days (150).
IORT involves delivery of a single dose to the lumpectomy bed at the time of

955
resection. Two randomized controlled trials have shown slightly higher local recurrence
rates with IORT compared to external-beam WBI, though low in both arms (151,152).
The TARGIT technique delivers approximately 20 Gy to the tumor bed surface from a
point source of 50 kV x-rays within a spherical applicator (1.5- to 5-cm diameter,
selected to fit tumor bed dimensions) (151). Electron intraoperative radiation therapy
(ELIOT) uses a linear accelerator to deliver 21 Gy to the tumor bed intraoperatively with
3 to 12 MeV electrons (152).
Numerous EBRT techniques have been utilized to deliver APBI without requiring
specialized equipment or training. 3D-CRT entails using three to five noncoplanar
conformal fields with different wedge angles, while IMRT utilizes four to five coplanar
or noncoplanar fields with dynamic MLC movement. Beam orientations should be
selected to minimize dose to the critical normal structures. VMAT utilizes one or two
partial arcs with varying speed of gantry rotation, MLC movement, and dose rate.
Prescription dose is typically 3.85 Gy twice daily to 38.5 Gy administered within 1
week. Notably, several studies utilizing these widely available external-beam techniques
have demonstrated suboptimal cosmetic outcomes (136,141,143). Increased rates of
subcutaneous fibrosis and fair to poor cosmesis have been associated with large volumes
of breast tissue receiving relatively high dose (141,143). An analysis of patients treated
with 3D-CRT APBI showed high rates of excellent to good cosmesis when the ipsilateral
breast volume receiving more than 50% of the prescribed dose remained below 40%
(153).

KEY POINTS
• Nodal involvement is common in breast cancer, with axillary nodes most frequently involved
regardless of tumor location within the breast.

• Adjuvant whole breast irradiation is standard after breast-conserving surgery to reduce


locoregional recurrence risk and to improve survival. Postmastectomy radiotherapy is typically
recommended for patients with nodal involvement, particularly >3 positive lymph nodes.

• Prone positioning may facilitate improved dose homogeneity and reduced normal tissue dose
for certain patients, particularly in the setting of large, pendulous breasts.

• Contouring target volumes, including tumor bed and nodal regions (if indicated), facilitates
field design with CT-based three-dimensional treatment planning.

• Medial and lateral tangential fields are designed to encompass the entire breast or chest wall
with adequate margin to allow for setup variation.

• An anterior oblique field is utilized to cover the supraclavicular nodes and undissected axilla.
This field is matched inferiorly with opposed tangents using a single or dual isocenter
technique. IM nodal coverage may be achieved with partially wide tangents, extended
tangents, or matched electron fields.

• Wedges may be used to improve dose homogeneity within the breast. Newer dose
modulation methods include electronic compensation and “field-in-field” techniques.

956
• Cardiac dose should be minimized using multileaf collimators. Deep inspiratory breathhold
or prone position may also facilitate reduced cardiac dose.

• Standard whole breast radiotherapy fractionation is 45 to 50 Gy in 25 to 28 fractions.


Hypofractionated whole breast radiotherapy is also appropriate for many patients. Commonly
used dose regimens are 40.05 Gy in 15 fractions or 42.5 Gy in 16 fractions.

• Tumor bed boost is generally performed with en face electrons to treat the lumpectomy cavity
plus 1.5- to 2.5-cm margin.

• Accelerated partial breast irradiation is typically limited to older patients with small tumors
and no nodal involvement. Treatment modalities include brachytherapy, intraoperative
radiotherapy, and external-beam radiotherapy.

QUESTIONS
1. Which of the following is NOT a risk factor for development of breast cancer?
A. BRCA1 mutation
B. Young age
C. Radiation exposure
D. Early menarche
2. Which of the following is a potential benefit from treatment in breathhold?
A. Decreased radiation dose to heart
B. Decreased radiation dose to ipsilateral lung
C. Easier patient setup and shorter treatment time
D. Better axillary nodal coverage
3. Which of the following is a disadvantage of three-field single isocenter versus
three-field dual isocenter technique?
A. Increased contralateral lung dose
B. Supraclavicular nodal coverage omitted
C. More complicated setup
D. Tangent field size limited to 20 × 20 cm
4. All of the following are techniques used to cover internal mammary nodes
EXCEPT
A. Partially wide tangents
B. Three-field dual isocenter
C. Extended tangents
D. Matching photon and electron fields
5. Which of the following is a typical expansion on the lumpectomy cavity to
generate a clinical treatment volume (CTV) for tumor bed boost?

957
A. 0.5 cm
B. 1 cm
C. 2 cm
D. 3 cm

ANSWERS
1. B Breast cancer incidence rises with increasing age. Therefore, older age
rather than young age is a risk factor for developing breast cancer.
Additional risk factors include BRCA1 and BRCA2 mutations, radiation
exposure, early menarche, nulliparity, and late menopause.
2. A Deep inspiration breathhold often facilitates decreased cardiac dose when
treating left-sided breast cancer. Longer treatment time and more difficult
patient setup are required for respiratory gating with the breathhold
technique. Ipsilateral lung dose and nodal coverage are not significantly
affected by breathhold.
3. D Tangent field size is limited to 20 × 20 cm for three-field single isocenter
technique. Patient setup and imaging is simpler with a single isocenter
compared to dual isocenter. Both techniques include an anterior oblique
field for supraclavicular nodal coverage. Contralateral lung dose does not
differ between techniques.
4. B Three-field dual isocenter technique is utilized to cover supraclavicular
nodes and the undissected axilla. Partially wide tangents, extended
tangents, and matching photon/electron fields can be used to cover
internal mammary nodes.
5. C The tumor bed boost CTV typically includes the lumpectomy cavity with a
1.5- to 2.5-cm margin.

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117. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast
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118. Smith BD, Bentzen SM, Correa CR, et al. Fractionation for whole breast irradiation:
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119. FAST Trialists group, Agrawal RK, Alhasso A, et al. First results of the randomised
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conservative treatment of early breast cancer: results of a randomized clinical trial
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124. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on
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surgery in small breast carcinoma: long-term results of a randomized trial. Ann
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134. Clark RM, McCulloch PB, Levine MN, et al. Randomized clinical trial to assess the
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135. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation
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136. Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from
RAPID: a randomized trial of accelerated partial breast irradiation using three-
dimensional conformal external beam radiation therapy. J Clin Oncol.
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137. Shah C, Wilkinson JB, Lanni T, et al. Five-year outcomes and toxicities using 3-
dimensional conformal external beam radiation therapy to deliver accelerated
partial breast irradiation. Clin Breast Cancer. 2013;13(3):206–211.
138. Berrang TS, Olivotto I, Kim DH, et al. Three-year outcomes of a Canadian
multicenter study of accelerated partial breast irradiation using conformal
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139. Kim Y, Parda DS, Trombetta MG, et al. Dosimetric comparison of partial and whole
breast external beam irradiation in the treatment of early stage breast cancer. Med
Phys. 2007;34(12):4640–4648.
140. Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using
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141. Liss AL, Ben-David MA, Jagsi R, et al. Decline of cosmetic outcomes following
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86(5):854–859.
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146. Vicini FA, Antonucci JV, Wallace M, et al. Long-term efficacy and patterns of
failure after accelerated partial breast irradiation: a molecular assay-based clonality
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147. King TA, Bolton JS, Kuske RR, et al. Long-term results of wide-field brachytherapy
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148. Rabinovitch R, Winter K, Kuske R, et al. RTOG 95–17, a Phase II trial to evaluate
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applicator: a review of technique and outcomes. Brachytherapy. 2005;4(2):130–136.
150. Shah C, Badiyan S, Ben Wilkinson J, et al. Treatment efficacy with accelerated
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151. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative
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152. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus
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153. Mellon EA, Sreeraman R, Gebhardt BJ, et al. Impact of radiation treatment
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technique. Pract Radiat Oncol. 2014;4(3):e159–e66.

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31 Cancers of the Central Nervous System

Vinai Gondi, Wolfgang A. Tome, and Minesh P. Mehta

INTRODUCTION
The central nervous system (CNS) comprises the brain, the spinal cord, and their
coverings. Patients with benign lesions may live out their natural lifespan, whereas the
survival of those with malignant tumors is frequently measured in months to years. The
optimal radiation therapy treatment technique should maximize the therapeutic benefit
and minimize the potential toxicities, especially for long-term survivors.

EPIDEMIOLOGY
Primary Central Nervous System Tumors
Annually, an estimated 86,000 new cases of primary nonmalignant and malignant CNS
tumors are diagnosed in the United States with an estimated 13,000 deaths (1,2). The
incidence of all primary nonmalignant and malignant brain and CNS tumors is 21.42
cases per 100,000 person-years. In the United States, the rate is slightly higher in
females (23.26 per 100,000 person-years) than males (19.42 per 100,000 person-years)
(2). The incidence rates are higher in more developed countries than in less-developed
countries (3). The incidence rate of childhood primary nonmalignant and malignant
brain and CNS tumors is 5.42 cases per 100,000 person-years (2).
Most of the primary CNS tumors are located within the frontal, temporal, parietal,
and occipital lobes of the brain. Sixty-one percent of gliomas occur in the frontal,
temporal, parietal, and occipital lobes. Tumors in other locations in the cerebrum
account for another 5%. Of all tumors, 1%, 3%, and 4% are found in the ventricles,
cerebellum, and brainstem, respectively. The pituitary and craniopharyngeal duct
account for 16% of tumors. Tumors of the meninges represent 36% of all tumors (2).
The overall incidence of primary spinal cord and cauda equina tumors is
approximately 3% of all primary CNS tumors (4). Schwannomas and meningiomas
account for 61% of primary spinal tumors, with meningiomas being more frequent; both
types occur primarily in adults. The frequency of individual spinal cord tumors is quite
different from that of their histopathologic counterparts in the brain. Gliomas constitute
46% of primary intracranial tumors but only 23% of spinal tumors. The incidence ratios
of intracranial to intraspinal astrocytomas, ependymomas, and meningiomas are
approximately 10:1, 3:1, and 18:1, respectively (5). Finally, the incidence ratio of
intracranial to intraspinal tumors is higher up to four times in pediatric patients than in
adults.
Table 31.1 shows the current WHO pathologic classification system of common
primary CNS tumors (6). The most frequently reported histology is meningioma, which
accounts for over 36% of all tumors, followed closely by glioblastoma and astrocytoma
(2). The predominately benign nerve sheath tumors account for 8% of all tumors, of
which 54% are acoustic neuromas. Gliomas account for 28% of all primary brain and
CNS tumors and 80% of malignant tumors (2). The most common spinal cord

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intramedullary tumors are those that are derived from glial precursors (astrocytes,
ependymocytes, and oligodendrocytes) (7).

Tumors Metastatic to the Central Nervous System


Metastatic brain tumors are the most common intracranial neoplasms in adults and are
about 10 times more common than primary intracranial tumors. In two cohorts of
patients diagnosed with colorectal, lung, breast, or kidney carcinoma or melanoma,
brain metastases were diagnosed in 8.5% to 9.6% (8,9). The cumulative incidence was
estimated between 16% and 20% in patients with lung carcinoma, 7% in patients with
renal carcinoma, 7% in patients with melanoma, 5% in patients with breast carcinoma,
and 1% to 2% in patients with colorectal carcinoma.
With the exception of a primary paraspinal or neuraxis tumor, spinal cord tumors
occur most often in the setting of disseminated disease from a distant primary tumor
site. The spine is overall the most common site of bony metastases, with a reported
incidence of 40% in patients with cancer (10). Of those patients with spine metastases,
10% to 20% develop malignant spinal cord compression (MSCC), accounting for 14,100
to 28,200 cases annually (11–13). MSCC from epidural metastases occurs in 5% to 10%
of all patients with cancer and in up to 40% of patients with preexisting nonspinal bone
metastases (10,14–16). MSCC may involve the spinal cord at any level, and symptoms
depend on the location of the compression. The incidence of MSCC by vertebral levels is
10% to 16% cervical, 35% to 40% in T1 to 6, 44% to 55% in T7 to 12, and 20% in the
lumbar spine (17–19). In 10% to 38% of cases, metastatic lesions present initially at
multiple, noncontiguous levels (17,20,21).
TABLE 31.1 WHO Grades of CNS Tumors

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The histology of MSCC follows the incidence patterns of primary malignancies, with
the most common histologic diagnoses (i.e., breast, lung, and prostate) accounting for
approximately half of all cases (1,10). Approximately 25% of all patients with MSCC
have breast cancer, 15% have lung cancer, and 10% have prostate carcinomas. Overall,
5.5% of patients with breast cancer, 2.6% of patients with lung cancer, 7.2% of
patients with prostate cancer, and 0.8% of patients with colorectal cancer experience
an MSCC (12). Other commonly reported histologic diagnoses in adults include, in the
order of cumulative incidence, multiple myeloma, nasopharynx, renal cell, melanoma,
small cell lung, lymphoma, and cervix (10,12,22).

970
WORKUP AND STAGING
For both benign and malignant CNS tumors, magnetic resonance imaging (MRI) is the
gold standard for imaging (23). The preferred slice thickness of MRI is ≤5 mm with
≤2.5 mm slice sampling, although 1.25 mm slice thickness on newer MRI volumetric
sequences permits more detailed visualization. T1-weighted images with contrast
provide excellent visualization of contrast-enhancing tumors, such as meningiomas,
glioblastoma multiforme, and brain metastases. T2-weighted images generally
demonstrate areas of edema, and T1-weighted fluid-attenuated inversion recovery
(FLAIR) images better delineate infiltration by low- or high-grade gliomas. MRI
registration with the treatment-planning computed tomography (CT) scan is therefore
essential for target delineation. Additional imaging studies can reflect the biologic
characteristics of CNS tumors, such as tumor metabolism, proliferation, oxygenation,
blood flow, and the function of surrounding normal brain; these include MRI
spectroscopy, fMRI, PET scans, and single photon emission tomography (SPECT) scans
(24–26). After radiation therapy, PET scans and MRI spectroscopy assist in
differentiating active tumor versus radionecrosis.
MRI of the entire neural axis along with cerebrospinal fluid (CSF) cytology is required
for staging of tumors with a high propensity for spread within the CNS by involvement
of the CSF, leptomeninges, or spinal cord. These tumors include medulloblastomas,
primitive neuroectodermal tumors (PNETs), anaplastic ependymomas, choroid plexus
carcinomas, pineoblastomas, germ cell tumors, and lymphomas.
In patients who present for urgent symptom management, CT scan can be obtained
rapidly, providing information on ventricular obstruction, hemorrhage, or edema.
Owing to the risk of herniation and death, lumbar puncture should be avoided, if at all
possible, until the intracranial pressure has normalized. The most important modality in
the workup of suspected MSCC is gadolinium-enhanced MRI of the entire spinal axis. In
the initial evaluation of a patient with suspected metastatic spinal cord compression, it
is critical to image the entire spine, as 25% of these patients have spinal cord
compression verified at multiple levels by MRI, and approximately two-thirds of these
have involvement of different regions of the spine (27). In addition, a sensory level
present on patient evaluation may be two or more levels different from the actual lesion
on MRI in 28% of patients, and four or more levels distant in 21% of patients (27).

GENERAL MANAGEMENT
Multimodality therapy for CNS tumors may consist of medical therapy, surgical
resection, radiation therapy, or some combination of the above.

Medical Therapy
Medical treatment generally consists of steroids with or without mannitol (28). Patients
who present with emergent symptoms are typically treated with dexamethasone.
Response to therapy is usually noted within 12 to 18 hours of administration with over
80% of patients showing dramatic improvement by 3 to 4 days after initiation of
therapy (29,30). A common regimen in patients receiving radiation therapy is high dose
dexamethasone (10 to 25 mg IV or po) followed by maintenance on oral steroids (4 to 6
mg three or four times a day), with tapering initiated upon stabilization of symptoms
and initiation of therapy, usually over 1 to 2 months (28,31,32). In the setting of MSCC
from solid tumors, dexamethasone has been shown to improve rates of surviving with

971
intact gait function (33,34). Side effects of intermediate to long-term steroid use may
include hyperglycemia, insomnia, emotional lability, thrush, gastric irritation,
ulceration and possibly perforation, proximal muscle wasting, weight gain and
adiposity (moon facies, buffalo hump, and centripetal obesity), osteoporotic
compression fractures, arthralgias with withdrawal, and aseptic necrosis of the hip
joints (35). Some of these side effects persist even after steroid withdrawal. Owing to
the incidence of steroid-induced complications with dosing longer than 21 days in
duration, higher doses and longer tapering schedules should be based on the physician’s
assessment of symptom severity and response (34,36,37). Patients should be instructed
during tapering to note signs of worsening headaches and/or existing neurologic
deficits. They should be instructed to resume a higher steroid dose should such
symptoms occur and consult their physician. Asymptomatic patients generally do not
require corticosteroids and routine use of corticosteroids during radiation therapy in
asymptomatic patients should be avoided. Select patients with MSCC may not receive
steroids during treatment if they are at high risk of complications due to underlying
medical comorbidities, such as peptic ulcer disease, uncontrolled diabetes, or other
medical problems that may cause severe or life-threatening problems if exacerbated by
steroids (38). Dexamethasone and mannitol decrease peritumoral brain edema by
different mechanisms of action and mannitol is therefore often used in steroid-
refractory patients (39). A common regimen of mannitol is a 20% to 25% solution given
intravenously over 30 minutes dosed at 0.5 to 2.0 g/kg (40).
Stabilization of the patient in status epilepticus is critical (41). After securing the
airway and stabilizing the patient, seizure activity must be terminated as rapidly as
possible, especially as failure to control seizures can potentially lead to physical
injuries, airway compromise, secondary brain hypoxia/injury, or coma (40,41). Rapid
onset/short-acting benzodiazepines and phenytoin are commonly used. Recommended
initial regimens include 0.1 mg/kg at 2 mg/min of lorazepam or diazepam at 0.2 mg/kg
at 5 mg/min. Phenytoin infusion of 15 to 20 mg/kg at <50 mg/min in adults is
indicated for seizure activity refractory to benzodiazepines or after truncation of
seizures with diazepam (41). There is no clear evidence to support the prophylactic use
of anticonvulsants in patients diagnosed with a brain tumor in the absence of
documented seizures (42,43).

Surgical Therapy
Surgical resection and/or placement of a shunt are often required for emergent
management of brain tumors causing life-threatening hydrocephalus, mass effect, or
profound neurologic impairment. This may relieve symptoms enough for other
treatment modalities to be initiated. Symptoms are usually related to mass effect, so
resection or debulking are often the only logical choices if medical therapy fails to
provide improvement in neurologic symptoms. Rapid surgical decompression is the
treatment of choice for such problems when surgery can be safely performed based on
patient performance status or tumor location.
Two randomized trials comparing radiotherapy with or without surgical resection in
the management of a solitary brain metastasis have documented a survival advantage
with the addition of surgery over radiation alone (44,45). However, a third randomized
trial was negative (46). There is no level I evidence demonstrating any survival benefit
from operating on patients with multiple metastases. However, patients with severe
neurologic symptoms from one or more dominant metastases who are unresponsive to
medical therapy may benefit from a craniotomy. An improvement in the patient’s

972
performance status can then be followed by external-beam radiation therapy.
Many patients with spinal cord compression are not candidates for laminectomy and
are treated with steroids and radiation therapy. Most series in the literature show no
difference in outcomes when comparing laminectomy-treated patients to those managed
with radiation therapy alone (10,19,47,48). However, a randomized trial evaluating the
benefit of adding surgical decompression to the radiotherapeutic management of
symptomatic metastatic spinal cord compression showed that patients who underwent
decompressive surgery had a significantly improved median time of gait retention and
ability to regain gait function albeit without affecting overall survival (49). Therefore,
all patients presenting with MSCC of short duration should be evaluated by an
experienced spine surgeon for emergent decompression before initiating radiation
therapy.

GENERAL CONCEPTS OF RADIATION THERAPY


Multimodality Imaging for Simulation, Treatment Planning, and Dose Delivery
The success of modern radiation therapy, besides the introduction of new irradiation
technologies, can also partially be attributed to the development and availability of
various novel imaging techniques that help to (i) better delineate targets and regions of
avoidance, (ii) better understand the dosimetrically relevant composition of the tissue in
the path of the radiation, (iii) lower the setup uncertainty of the patient, (iv) verify the
location of the target during dose delivery, and (v) assess the location of the deposited
dose.
A high-resolution CT scan acquired at the time of treatment planning simulation
provides a 3-dimensional (3D) voxel grid of the patient. In each voxel, the CT software
calculates the linear attenuation coefficient of the matter contained in it. Based on this,
each voxel gets assigned a shade of gray (for visualization purposes of the tissue) and a
CT number, the Hounsfield Unit, which later is translated into physical density in the
treatment planning software (for dose calculation purposes). Since the CT modality has
poor soft tissue contrast, iodine-based contrast agents are often injected into the blood
to better visualize vessels or tumors. Images with sub-millimeter voxel dimensions can be
acquired with only a minute or two scanning time.
MRI is a complementary imaging modality to CT. Since it does not involve ionizing
radiation and has very good soft tissue contrast, it is one of the most widely used
imaging modalities in the management of CNS tumors. Its signal is based on relaxation
properties of proton spins in a strong external magnetic field. Based on the signal
strength of each voxel received during imaging, a shade of gray is assigned and the
image is reconstructed. Numerous sequences have been researched and developed to (i)
disturb the spin lattice of patients’ protons in the applied external magnetic field and
(ii) detect their relaxation properties.
The two most commonly known techniques are the T1- and T2-weighted sequences,
where T1 and T2 are the longitudinal and transverse relaxation times of proton spins,
respectively. Generally speaking, the shorter the voxel’s T1, the more signal it produces,
and it appears brighter on the scan. On the other hand, the longer the T2, the longer
the signal is acquired, making the signal-producing tissue brighter. Water in the bulk
phase (e.g., CSF) has long T1 and T2 relaxation times; therefore, it appears dark on T1-
weighted but bright on T2-weighted acquisitions. Gadolinium-based contrast agents,
which lower T1 relaxation times, are often utilized to enhance brain tumor appearance.
Because several tumors compromise the brain–blood barrier, they permit entrance of

973
contrast agents which lower the T1 time, making the tumor brighter on T1-weighted
images. Vasogenic edema associated with brain tumors appears bright on T2-weighted
images. Oftentimes extremely high spatial resolution is needed (e.g., for visualization of
cranial nerves), in which case the constructive interference steady state (CISS, also
called FIESTA) sequence is utilized. If visualization hyperintense abnormalities obscured
by CSF within ventricles is needed, a specialized MRI technique called FLAIR can be
utilized to dampen the signal from the CSF. Magnetic resonance spectroscopy (MRS)
measures the levels of various metabolites in body tissues. It can be tuned to recognize
tumor cellular metabolites. The level of these metabolites can be spatially overlaid with
MRI images allowing a better differentiation of tumor from normal tissue.
Diffusion tensor imaging enables visualization of neural fiber directions to examine
the connectivity of different regions in the brain. Conceptually, this could be used to
potentially avoid hot spots and high doses within critical fiber tracts. fMRI measures
signal changes in the brain that are due to changing neural activity. The measurement
is done through the mechanism called blood-oxygen-level dependent (BOLD) effect,
which is based on the fact that increased neural activity requires enhanced oxygen
levels. Deoxygenated hemoglobin attenuates the MRI signal, while in the oxygenated
state it enhances the signal, leading to a T2 signal increase related to the neural
activity.
After the desired MRI scans were acquired, they are co-registered with CT images in
the treatment planning software with the help of specially designed mutual information-
seeking algorithms combined with human input. This co-registration allows delineation
of the most pertinent regions of interest in the framework of the treatment planning CT.
After an acceptable treatment plan has been created using an appropriate treatment
planning system (TPS), the patient is positioned for using appropriate external
immobilization and three-point alignment, following which setup verification of the
relevant anatomy and/or fiducials is performed. The simplest modality for this is the
radiographic film. Port films are compared to digitally reconstructed radiographs from
the TPS and setup corrections are applied as necessary. Electronic devices such as
electronic portal imaging device (EPID) have substituted radiographic film with an
electronic screen. Conventionally, the megavoltage photon beam is used to obtain the
verification image. The Compton interaction responsible for image creation results in
very low tissue contrast, making it difficult to interpret the images. Recent technologic
advances have introduced in-room imaging with kilovoltage photon beams, in which the
portion of photoelectric interactions significantly increases, resulting in a very
substantial increase in tissue contrast and therefore image quality. X-ray sources and
imaging panels are mounted on modern linear accelerators, allowing them to acquire CT
type image sets, called cone beam CT. As a result, 3D information at the time of the
patient setup is compared with the 3D image sets on which the treatment plans have
been generated. Necessary shifts can be applied to best match the treatment planning
conditions.

Volume Definition
Treatment-planning volumes are based on reports 50 and 62 of the ICRU (50,51). Gross
tumor volume (GTV) represents grossly identifiable disease (50,51). For glioblastoma
multiforme, this includes T1-enhancing abnormality on MRI. For nonenhancing low-
grade glioma, this is usually T2-hyperintense or FLAIR abnormality on MRI, often better
visualized as FLAIR abnormality. The clinical target volume (CTV) includes the
subclinical microscopic tumor extent as well as resection cavity. For glioblastoma

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multiforme, two CTVs are delineated: (i) T2-hyperintense abnormality plus resection
cavity and 2-cm margin treated to 46 Gy and (ii) T1-enhancing abnormality plus
resection cavity and 2-cm margin treated to 60 Gy cumulative dose (50). Uniform
expansion may result in an excessively large volume with unnecessary dose to normal
surrounding tissues. The CTV is therefore reduced around natural barriers to tumor
growth, such as the skull, ventricles, and the falx. In addition, the CTV margin maybe
limited in areas near critical organs.
The planning target volume (PTV) is also referred to as the “dosimetric margin,”
which has two components (51). The internal margin accounts for variations in size,
shape, and position of the CTV in relation to anatomic reference points. In the CNS, this
is usually not a major component and is due mainly to physiologic variations, such as
the possible changes in the mass effect from cerebral edema that may increase or
decrease over the course of treatment. Setup margin is added to take into account
uncertainties in patient-to-beam positioning, although this may be reduced by utilizing
appropriate immobilization devices, Dosimetric margins as low as 3 to 5 mm are
acceptable with optimal immobilization devices. For treatment plans emphasizing
homogenous dose delivery, the maximum dose to PTV should be generally less than
110% of the prescription dose, and 95% of the target should receive at least the
prescription dose.

Organs at Risk
Organs at risk (OARs) are critical normal structures whose relative radiation sensitivity
and proximity to the CTV may significantly influence the prescribed dose and the
treatment-planning strategy. It is especially important to limit the risk of late toxicities
by respecting the dose tolerances of normal structures when long-term survival is
expected. The relationship between the planning organ at risk volume (PRV) and the
OAR is analogous to that of the PTV and the CTV (51). For each OAR, when part of the
organ or the whole organ is irradiated above the accepted tolerance level, the maximum
dose should be reported (50). The volume receiving more than the maximum allowable
dose should be evaluated using the corresponding dose–volume histogram (DVH).
Recent publications of Quantitative Analyses of Normal Tissue Effects in the Clinic
based on review of published series established recommended dose constraints for the
brain, brainstem, optic nerves/chiasm, cochlea, and spinal cord (Table 31.2).
The spinal cord and brainstem are the two most critical normal structures to be
considered in the CNS, given the devastating consequences that can arise from damage
to these structures. Damage to the spinal cord can result in pain, paresthesia, sensory
deficits, paralysis, Brown-Sequard syndrome, and bowel/bladder incontinence (52).
With conventional fractionation of 2 Gy per day for the full cord cross-section, alpha–
beta has been estimated to be as low as 0.87 Gy, suggesting a strong dose-per-fraction
response relationship. In addition, 50, 60, and 69 Gy have been estimated to be
associated with 0.2%, 6.0%, and 50% rates of myelopathy, respectively. In the case of
re-irradiation, a 25% increase in spinal cord tolerance 6 months after the initial course
of conventionally fractionated radiotherapy has been proposed (53).
Although damage to the brainstem can result in symptoms similar to those seen in the
spinal cord, the brainstem is also critical in providing motor and sensory innervation to
the head and neck via the cranial nerves, as well as the regulation of respiratory and
cardiac function. A maximal dose constraint of 54 Gy is generally considered to have a
minimal risk of causing severe neurologic effects, and small volumes (1 to 10 cc) may be
irradiated to as much as 59 Gy with a continued small risk of side effects (54).

975
Furthermore, series on dose-escalated radiotherapy for skull base tumors have
demonstrated that the ventral surface of the brainstem may be somewhat radioresistant,
with surface doses as high as 64 CGE and 53 CGE to the brainstem center resulting in
high rates of toxicity-free survival (55).
TABLE 31.2 Normal Tissue Tolerance of Intracranial Organs at Risk

Radiation induced optic neuropathy (RION) can result in profound and irreversible
visual loss approximately 10 to 20 months after treatment, with a median onset of 18
months after treatment and vascular damage representing one possible mechanism of
action (56). The alpha/beta ratio is estimated to be quite small, in some cases <0,
suggesting a very strong dose-per-fraction effect. With conventional fractionation, a
dose of 50 Gy is associated with a near-zero incidence of RION. This risk increases to
between 3% and 7% at doses of 55 to 60 Gy, and becomes more substantial with rates
of 7% to 20% reported for doses >60 Gy at traditional fraction sizes (57). The retina is
another radiosensitive vision structure, where radiation-induced retinopathy can mimic
the symptoms of diabetic retinopathy. The threshold dose radiation retinopathy is
estimated to be at 30 to 35 Gy, with lower doses associated with a near-zero risk of
retinopathy and >50 Gy associated with approximately a 5% chance of retinopathy.
Consequentially, most protocols set 45 Gy as the maximum dose constraint for the
retina (58).
The pathogenesis of radiotherapy-induced cognitive decline may at least partially
involve a neural stem cell compartment located in the subgranular zone of the
hippocampal dentate gyrus. Preclinical and clinical studies have demonstrated not just
the importance of this neural stem cell compartment on memory function, but also its
exquisite radiosensitivity (59). In RTOG 0933, a prospective clinical trial of whole-brain
radiotherapy for brain metastases, conformal avoidance of the hippocampal dentate
gyrus using intensity-modulated radiotherapy reduced the rate of memory decline, as
compared to historical controls (60). These findings provided the first direct clinical
evidence that the application of advanced radiotherapy techniques to minimize
hippocampal dose may prevent radiotherapy-induced cognitive decline. However, the
precise radiobiologic dose-tolerance of the hippocampal dentate gyrus remains unclear.
Exploratory analysis of patients enrolled on RTOG 0933 demonstrated that dose to
100% of the hippocampal dentate gyrus correlated with severity of memory decline,
suggesting that better memory preservation might be attainable with lower hippocampal
dose (60). In a prospective study of benign and low-grade tumor treated with photon
radiotherapy without hippocampal avoidance, >7.3 Gy in 2-Gy fractions to 40% of the
hippocampal dentate gyrus was associated with long-term impairment in list-learning
recall (61).
Temporal lobe injury (TLI) can be associated with such symptoms as dizziness,

976
memory impairment, disorientation, and personality changes or with more specific
symptoms such as temporal lobe epilepsy (62). Data from studies in nasopharyngeal
cancer patients has established 70 Gy as a threshold for an increased incidence of TLI
(63). Some authors treating skull base tumors have proposed a D2 cc of 74 Gy as an
absolute threshold dose (64).

Intensity-Modulated Radiation Therapy


Intensity-modulated radiation therapy (IMRT) is an advanced form of the 3D CRT.
While CRT delivers an irregularly shaped beam of uniform intensity, IMRT modulates
the intensity of the photon beam across the treated area by delivering multiple subfields
(segments), each of irregular shape and different photon intensities. There are three
major advantages of utilizing IMRT for CNS tumors: (i) shape dose around concave
PTVs (such as with some meningiomas); (ii) improve homogeneity of the delivered dose
to complex-shaped PTVs; (iii) permit simultaneous integrated dose delivery using two or
more PTV dose levels (such as for glioblastoma multiforme); and (iv) improve dose
homogeneity to target in the regions where large variations of external contours exist
(such as in case of posterior fossa lesions or spinal cord meningiomas).
These advantages of IMRT technique are achieved through inverse planning during
which dosimetric objectives are set for tumor coverage and for OAR avoidance. An
optimization algorithm is then employed to find the optimal photon fluence that meets
the predetermined dosimetric objectives. After the optimal photon fluence has been
found, another optimization algorithm is employed to determine the optimal way (i.e.,
the shape, the number, and the intensity of segments) to deliver the calculated fluence.
In order to fully utilize the power of IMRT, the irradiated tissue should be as static as
possible during delivery, the dosimetric objectives for planning should not be
unrealistic, and great care should be given to contour targets and OARs which include
lenses, eye globes, optic nerves, chiasm, brainstem, temporal lobes, pituitary gland,
inner ears, general brain parenchyma, and spinal cord.
Immobilization can help to reduce the necessary margins when creating PTVs.
Margins should be set based on a realistic assessment of setup uncertainties and the
quality of immobilization. During IMRT planning, unrealistic desired objectives could
lead to suboptimal plans. For instance, if aiming to cover the PTV with a homogeneous
dose of 60 Gy, while constraining the maximum dose to the adjacent, say 1 mm distant
chiasm, to 40 Gy, the software will substantially increase the needed monitor units and
generate a large number of very tiny area segments, which might not be deliverable due
to machine limitations. Good IMRT plans can achieve better than 5%/mm dose gradient
while still preserving good target dose uniformity.

Proton Therapy
Proton therapy is a form of particle therapy that is becoming increasingly available. Its
dosimetric advantages of sharper lateral penumbrae and finite distal range permit
greater sparing of organ at risk in close proximity to the tumor target. This becomes
particularly important in the treatment of radioresistant tumors in eloquent locations,
such as skull base chordoma and chondrosarcoma, where dose-escalation to 70 Gy or
higher in close proximity to brainstem, optic nerves, temporal lobes, and cochlea is
required for optimal local control. In addition, reduced integral dose, due to the finite
range of proton therapy and fewer proton beams needed to optimally treat the tumor
target, may have important implications in terms of secondary malignancy risk

977
reduction and adverse cognitive effects. In the setting of craniospinal irradiation,
proton therapy has been observed to have significant clinical benefits in terms of acute
toxicities, and is postulated to minimize the risk of multiple long-term toxicities. Trials
testing the potential benefits of proton therapy for novel CNS tumor indications remain
ongoing.

SIMULATION PROCEDURES
Positioning
When simulating CNS tumor patients, patient positioning becomes very important and
appropriate position devices should be used to aid in reproducibility and setup. The
head, neck, and body should be positioned such that the setup marks are in locatable
and reproducible positions. Marks on steeply sloping surfaces, ears, nose, lips, and chin
should be avoided whenever possible. In some settings, there is a benefit from
positioning the head on a pituitary head-board for posteriorly located tumors (e.g.,
occipital lobes or posterior fossa). For patients requiring craniospinal irradiation, it is
often useful to have the patient supine with the chin slightly extended such that the exit
of the PA spine field does not exit through the patient’s oral cavity. CT scan simulation,
3D treatment planning, and IMRT allow for different head and neck positions in most
situations as noncoplanar beams can be used to avoid entry and exit dose to OARs.

Immobilization
There exist a variety of commercially available head immobilization devices, most of
which use thermoplastic or other materials, such as expandable foam or plastic beads in
a vacuum bag. They are adaptable for flexion or extension when the patient is in the
supine position. Variability of setup should not be >2 or 3 mm with a thermoplastic
mask. To obtain more accurate and/or rigid head positioning and immobilization, a
modified stereotactic aquaplast mask with reinforcement strips may be used to help
insure reproducibility and setup.
Once the patient is placed in the appropriate positioning device, they are scanned,
typically using between 2 and 3 mm slice thicknesses. The clinician may need to decide
at the time of simulation where the isocenter should be placed. After completion of
treatment planning in virtual reality (see subsequent text), verification films should be
obtained before treatment; these may include orthogonal radiographs to verify the
isocenter, and films of any custom-shaped portal fields. Isocenter films (with or without
portal images) are usually obtained weekly to verify accuracy of the treatment setup.
Volumetric imaging capabilities now offer more detailed imaging verification of the
patient setup.
Generally, special custom immobilization devices are used for patients with spinal
cord tumors to ensure setup reproducibility, especially with craniospinal irradiation
patients since the match lines (areas where fields abut) are of importance. Regardless of
the immobilization device, it must fit the physical dimensions of the CT scan or MRI
scanner and be constructed of materials compatible with the imaging modality.

Simulation
In this chapter, the reader may assume that patients are simulated in the supine
position using 3D CT scan-based planning, unless otherwise stated. The primary body
planes are transverse, sagittal, and coronal, with body axes anterior, posterior, right,

978
left, superior, and inferior. Isocentric treatment machines rotate 360 degrees around a
transverse plane of the patient’s body, and treating in a coronal or sagittal plane
requires the treatment couch to be rotated.
For CT scan simulation involving the brain, the patient is placed in the positioning
device and scanned and the isocenter or reference markers are selected and marked on
the thermoplastic mask. For intracranial disease, a single-field or opposed-beam two-
field arrangements are usually not considered acceptable, as they deliver excessive dose
to normal tissues in the beam paths. The exception is a short course of palliative
radiation therapy to the whole brain or cervical spinal cord using an opposed lateral
beam arrangement. An optimum beam arrangement typically consists of multiple
noncoplanar beams. For tumors involving both hemispheres of the brain, the ideal beam
arrangement is six noncoplanar beams; two on the right and left sides of the patient
(entering anterior to shoulder and posterior to shoulder), and two superior obliques.
When applicable, the contralateral uninvolved hemisphere of the brain should be spared
as much as possible. In these cases, for patients with right-sided lesions, for example,
the contralateral beams should not be utilized, if possible. Beam exit through the
thyroid gland, eyes, lacrimal gland, and oral cavity should also be avoided as much as
possible.
Most lesions can be treated well with 6 to 10 MV photon beams. For more lateralized
tumors, it is ideal to not include contralateral beams if possible. Typically, a
homogenous dose distribution within the target volume is desirable, with not >5% to
10% inhomogeneity in the irradiated volume. When IMRT is used, a practical
timesaving approach uses the beam arrangement of an optimized noncoplanar 3D plan
as a starting point. This can significantly shorten the treatment-planning effort and
allows for greater freedom of optimization than a coplanar (i.e., 2-dimensional, 2D)
plan.

SPECIFIC EXAMPLES OF TREATMENT TECHNIQUES


Whole Brain Radiation Therapy
Whole brain radiation therapy evolved in the early days of radiation therapy when
precise anatomic definition of tumor was limited to plain radiography. Nonetheless, the
benefits were apparent. In the first randomized clinical trial in brain tumors in the
United States, 60 Gy whole brain radiotherapy increased survival in patients with
glioblastoma multiforme over steroids alone (65). With the advent of CT and MRI, more
focal radiation techniques for brain tumors became the standard. Still, there are
important clinical settings in which the brain and/or meninges are the target for which
whole brain radiation therapy is an essential component of therapy. These clinical
situations with examples are reviewed below.

Acute Leukemia
The CNS is a known sanctuary site from leukemic chemotherapy. After failures in the
CNS and eyes were noted, CNS penetrating therapy such as intrathecal drugs and
radiation therapy became an important component of treatment of leukemia (66). While
the doses of radiotherapy are low, in the 12 to 18 Gy range, the target remains the
entire brain, cranial meninges down to the level of C2, and the posterior retina and
optic nerves. An example of a C2-whole brain field for cranial prophylaxis is shown in
Figure 31.1A. Opposed lateral fields in an aquaplast mask with a 2- to 3-degree
posterior cant on the fields can help spare exit through the contralateral lens. The

979
anterior border is set at the fleshy canthus of the eye, which corresponds to the
anatomic equator of the eye. Radio-opaque markers placed on the fleshy canthus are
very helpful for conventional simulation. For a CT simulation, the anterior border is
placed at the posterior border of the lens, and the gantry angle is adjusted to make the
beam nondivergent across the posterior aspect of both lenses. It is very important to
note that the block be placed to ensure that the entire posterior globe be included in the
fields. At least a 1-cm margin should be included on the middle cranial and base of skull
meninges. One centimeter of flash should be provided over the convexity, and the soft
tissue of the posterior neck should be shielded with a minimum 1-cm margin on the
intracranial contents (Fig. 31.1A).

Figure 31.1 Sample whole brain radiotherapy fields illustrating blocking for C2-whole brain fields (A) that
would be appropriate for leukemic prophylaxis and whole brain fields with a scalp block (B) that would be
appropriate for whole brain radiotherapy of metastatic disease.

Brain Metastases
The radiation therapy oncology group (RTOG) conducted a number of trials in the early
1980s on whole brain radiotherapy for brain metastases (67). These established a
palliative benefit for whole brain radiation therapy. More recently, whole brain
radiotherapy with a stereotactic boost showed a survival and neurologic function
benefit in selected patients with brain metastases (68). Randomized trials of stereotactic
radiosurgery (SRS) and whole brain radiation versus SRS alone for 1 to 4 brain
metastases showed equivalent survival, but suggested a local control benefit to whole
brain radiotherapy (69,70).
Traditionally, an open flashing rectangular field with the inferior border collimated to
a line connecting the superior orbital rim with the mastoid tip was used. Increasingly,
CT simulation with MLC blocking techniques has become common, allowing relatively
easy target definition and blocking. The target in whole brain radiation is the brain
parenchyma. While posterior fossa metastases may have a higher association with
leptomeningeal spread, there is no evidence that including the cranial meninges
prevents this pattern of failure. Figure 31.1B illustrates a whole brain field that includes
the brain parenchyma with a 1-cm block margin. This typically blocks the lenses of the
eyes, but occasionally adjustment of the leaves over the lenses is necessary. The
advantage of including a “scalp block” is to avoid the tangent effect of the beam over
the vertex scalp that often leads to a characteristic “reverse mohawk” bald patch among
surviving patients. Inhomogeneities across the superior thinned parts of the head can
also be reduced with simple field-within-a-field techniques.

980
Whole brain radiation is now known to cause mild-to-moderate memory deficits as
early as 4 months after treatment (66). RTOG 0614 demonstrated a modest
improvement in overall neurocognition with the use of prophylactic memantine during
whole brain radiation for brain metastases. In addition, RTOG 0933 demonstrated that
use of intensity modulated radiotherapy during whole-brain radiotherapy to
conformally avoid the hippocampal dentate gyrus, where neural stem cells whose
neurogenic differentiation subserves memory function are believed to reside, was
associated with highly promising memory preservation results (59,60) (Fig. 31.2). Phase
III trials to confirm these promising phase II results are ongoing through NRG Oncology.
NRG CC001 is a phase III trial of whole-brain radiotherapy plus memantine with or
without hippocampal avoidance. NRG CC003 is a randomized phase II/III trial of
prophylactic cranial irradiation with or without hippocampal avoidance for small cell
lung cancer.

Craniospinal Irradiation
Certain neoplasms will require treatment to the entire craniospinal axis. This may
include medulloblastomas and PNETs, high-grade ependymomas, some germ cell
tumors, pineoblastomas, disseminated CNS lymphoma, and leptomeningeal
carcinomatosis or gliomatosis. Several positioning variations are used in clinical
practice often in an immobilization cast to ensure daily positional reproducibility (71).
Patients are ideally treated in the supine position with the neck extended to avoid
beams exiting the oral cavity. Conventional methods utilize field “feathering” to reduce
hot or cold spots caused by imperfect fields matching between cranial and spine fields.
This method feathered each junction on a weekly basis with the cranial fields’ inferior
border decreasing between 5 and 10 mm. The intracranial contents and upper one or
two segments of the cervical cord are treated through opposed lateral fields, usually
positioned so that the isocenter is at midline with the beam axes passing through the
lateral canthi to minimize divergence into the contralateral eye. The collimator and
couch are rotated to create a straight line through the inferior portion of the brain fields
that removes the possibility of overlap with the posterior spine field. This can be
visualized with the treatment planning systems simulation software (see subsequent
text). Customized blocks protect the normal head and neck tissues from the primary
radiation beam; as mentioned above, care must be taken not to underdose the cribriform
plate. Figure 31.3A represents a typical cranial field with blocks for the lenses and
collimator angled to match the divergence of the PA spine field. The inferior border of
the initial “short” field is placed around C2 to C3, leaving adequate room for
subsequent shifts in the match with the upper spine field, a technique commonly
referred to as “feathering the gap.”

981
Figure 31.2 Volumetric arc therapy plan for conformal avoidance of the hippocampus during whole brain
radiotherapy. This IMRT plan was generated using the partial-field dual-arc planning technique developed by
Shen et al. (75). The following isodose lines are shown 35 Gy (red), 33 Gy (orange), 30 Gy (green), 25 Gy
(blue), 16 Gy (purple), and 10 Gy (brown). This technique significantly spares the hippocampus with 100% of
the hippocampus receiving a dose of 8 Gy and a maximum hippocampal dose of less than 16 Gy.

982
Figure 31.3 A: Sample whole brain field with angled collimator for craniospinal radiotherapy of
medulloblastoma. B: Represents the prescription dose cloud for craniospinal radiation of medulloblastoma. Note
no loss of dose at the junction between brain and spine fields on account of a daily three-feathered junction
using the independent jaw. C: Illustrates the isodose cloud for an IMRT medulloblastoma posterior fossa boost
specifically avoiding the cochlea (shown in green). The optic pathway is shown in aqua and the primary tumor is
shown in pink.

Depending on length, the spine is treated through one or two posterior fields. It is
customary practice to maximize the field length of the upper spinal field (40 cm at 100
cm source–skin distance [SSD]) and minimize the length of the lower spinal field,
therefore simplifying planning for junction shifts (see in subsequent text). If 40 cm or
less of length covers the spine inclusive of the end of the thecal sac (typically near the
level of S3, this should be confirmed by MRI), a lower spine field is not necessary. All
fields’ central axes remain fixed; it is only the fields’ lengths that are changed.
Therefore, the caudal border of the lower PA spine field should be set inferior to S3 by a
length equal to the two-field shifts, and then blocked back to S3 using asymmetric
collimators.
Matching the upper border of the spine field to the lower border of the cranial field

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requires strict attention to accuracy, as overlap (i.e., overdosing) in the upper cervical
cord may have catastrophic outcomes for the patient. In one method, the collimator for
the lateral cranial fields is angled to match the divergence of the upper border of the
adjacent spinal field, and the treatment couch is angled so that the inferior border of
the cranial field is perpendicular to the superior edge of the spinal field (“exact-match”
technique). Both the rotation of the collimator and degree of couch rotation are
calculated and typically range from 9 to 11 degrees. The drawback to this technique is
that the couch rotation displaces the contralateral eye cephalad, so that it cannot be
blocked without blocking frontal brain tissue. This technique may also result in
underdosing of the temporal lobes and cribriform plate.
One method for craniospinal irradiation involves a 3D CT simulation of a patient in
the supine position in a wooden box that encompasses the entire spinal canal. The
patient’s cranium extends outside the end of the box to allow for positioning, utilizing
an aquaplast mask (see photo). This method, referred to as “simulated dynamic
feathering,” feathers the gap daily as opposed to conventional methods where the fields
are feathered after five fractions. The process is as follows:

Simulation
The patient is placed on the vac bag, which provides comfort. An aquaplast mask is
used to immobilize the cranium. The patient is aligned with the spine as straight as
possible and no rotation of the cranium before scanning. A scout is usually needed to
confirm that the patient is aligned and no adjustments are needed. An isocenter is
placed in the CT room for the cranium fields only and the mask is marked. The isocenter
is usually placed midline and will serve as a reference point for the spine field. Ideally,
the spine isocenter is placed such that the couch is moved as little as possible between
brain and spine fields. Generally, after the cranium fields are treated, the couch is
shifted in two directions: toward the gantry and raised to accommodate the extended
SSD of the PA spine field.

Treatment Planning
The cranial fields are designed as well as the spine field for the initial beams. Collimator
and couch are rotated to prevent the overlap between the brain and spine fields using
the treatment planning system. The planning system allows visualization of beam
divergence for all beams in the axial, sagittal, and coronal views. Once the initial fields
have been designed, they are copied and labeled accordingly (Shift#1, 2, etc.). The
cranial field’s inferior border is increased by 5 mm and the spine field’s superior border
is decreased to match the inferior border of the brain fields. A total of 1.5 cm shift is
used for this technique, which requires three shifts 5 mm each shift. It is important to
note that the spine field will not necessarily be 5 mm due to beam divergence as these
fields are generally treated at extended SSD’s (between 125 and 135 cm). The following
shifts are created using the same process. The number of beams can be as many as 12
treated on a daily basis using the dynamic method; therefore, patient comfort is
important as it contributes greatly to reproducibility. The number of shifts or junctions
is physician dependent.
Plan optimization usually involves a forward planned field in field technique for the
brain fields as well as for the spine field. However, it is possible to optimize the spine
fields using inverse planning to cool off hot spots. The rationale for inverse planning the
spine field is merely related to time. The control points needed for the spine field are
generally higher than that of the brain fields. Figure 31.3B shows the dose cloud for
such a craniospinal plan. Figure 31.3C shows the dose cloud for an IMRT-planned

984
posterior fossa boost, sparing cochlea. Documenting junction match requires placing
wires on the inferior border of brain fields before imaging the spine field for each
junction shift.

Partial Brain Radiation


The era of 3D CRT in the 1990s allowed substantial reduction of unnecessary radiation
to normal brain. The anatomic location of the brain atop the head also maximized the
benefits of noncoplanar beams, because vertex beam arrangements were available with a
simple rotation of the treatment couch. While the wedge requirements of noncoplanar
beam to produced homogeneous plans are more complicated, they are solvable (72). In
spite of this, the compensation requirements of such noncoplanar arrangements are
more easily handled with IMRT inverse planning. In addition, intensity modulation can
produce concave dose distributions around critical adjacent structures such as the optic
chiasm, brainstem, and cochlea and thus provide more adequate dose sparing. IMRT
also allows differential prescription of doses and simultaneously integrated boost plans
that has made IMRT routine for contemporary partial brain irradiation.

Low-Grade Glioma
Low-grade gliomas form a heterogeneous group of tumors that include the most
favorable pilocytic astrocytoma and the fibrillary astrocytomas with a less favorable
prognosis and propensity to progress to a higher grade histology. Doses are 45 to 54 Gy
in standard fractions with a typical 1 to 2 cm clinical margin on the radiographically
defined GTV. Higher radiation doses have been studied, but only resulted in increased
toxicity with no survival benefit.
A helpful quantitative tool to evaluate brain plans is the conformity index. Born from
radiosurgical planning, various conformity indices have been described. For an ideal
plan, conformity indices approach 1. From a practical point of view, the indices have
value in discriminating between generally acceptable treatment plans, since poorly
conformal plans and plans that do not cover the target are usually quite apparent to the
keen observer. The simplest conformity index can be defined as:
Conformity Index = Treatment Volume/Target Volume

When the entire body is contoured in the planning system, the treatment volume is
easily obtained from the DVH as the volume of the body receiving the prescription dose.
A conformity index <1.2 indicates a highly conformal plan and should be an important
and achievable planning goal.

High-Grade Glioma
Most high-grade gliomas are glioblastomas. Although temozolomide with radiation
prolongs median survival by about 2 months with a small number of 5-year survivors
(ref), most patients invariably recur, requiring salvage therapy. While hypofractionated
treatments and smaller treatment volumes are under investigation, the radiation
standard remains 45 to 50 Gy to a clinical target including all surrounding
postoperative flair signal plus a 2-cm margin along continuous white matter tracks
within the brain with a boost to a clinical target including the enhancing tumor or
postoperative cavity plus a 1- to 2-cm margin. It is important to adjust clinical targets
along known anatomic white matter tracks to avoid unnecessary irradiation of the
posterior fossa or contralateral brain, as both the tentorium and falx are effective

985
barriers to spread of glial tumors. The standard boost dose remains 60 Gy. While
radiotherapy dose-escalation demonstrated no survival benefit, these trials were
conducted prior to the widespread adoption of concurrent and adjuvant temozolomide.
The potential survival benefit of dose-escalation with concomitant and adjuvant
temozolomide remains the subject of an ongoing NRG oncology study.

Ependymoma
Ependymomas are uncommon primary glial CNS tumors that typically arise in the
posterior fossa and cauda equina. Ependymomas in the cauda equina are most often
low-grade myxopapillary type and carry a relatively favorable prognosis. Radiation
therapy is reserved for incompletely resected or recurrent tumors. Ependymomas
account for 5% to 10% of childhood intracranial tumors, but occur as well in adults.
Standard management involves complete surgical removal. Most authors agree that
posterior fossa ependymomas should receive postoperative radiotherapy, as recurrence
rates remain high even after complete surgical removal in this location. The addition of
radiotherapy for supratentorial ependymomas after complete surgical resection is
controversial, as this appears to be a more favorable subsite.

Meningiomas
Meningiomas are common CNS tumors, for which radiation therapy is a safe and
effective treatment approach. Radiotherapy for meningiomas can be challenging
because they often have irregular shapes and are located near critical structures. With
the advent of IMRT, fractionated stereotactic radiotherapy (FSRT), and SRS,
radiotherapeutic options in the management of meningiomas are now diverse. However,
regardless of the treatment modality, careful treatment planning is central, since
meningiomas are mostly benign tumors, and therefore the risk of serious late toxicities
needs to be minimized.
Fusion of a contrast-enhanced MRI with the planning CT scan provides the optimal
definition of the meningioma and adjacent OARs. For well-demarcated lesions, the GTV
and CTV are identical. Stereotactic positioning may be useful to reduce the margin for
PTV, which takes into account the error in tumor volume delineation, errors inherent to
image fusion, and for the variation in day-to-day setup. With invasive tumors, such as
those involving the sphenoid or cavernous sinuses, there is greater uncertainty, which
must be considered in determining the CTV.
The optimal beam arrangement is dictated by both the shape and location of the
lesion. With a large convexity lesion, for example, a potential arrangement may be three
coplanar beams angled at 120 degrees from one another (“Mercedes Star”), or a
cruciform arrangement of four coplanar beams. The couch and gantry are then rotated
so that each beam is shifted 10 degrees inferiorly with respect to the patient (Fig. 31.2).
These arrangements minimize the cross-sectional area of the lesion within the beam’s
eye view. Other suggestions for beam arrangements are presented in the subsequent
text, based on the region of the brain. The use of IMRT may be useful for concave-
shaped lesions. With superficially located lesions, 6-MV photons are typically utilized
owing to the short buildup depth; for more deeply situated tumors, such as cavernous
sinus lesions, higher energy beams may be considered.

Pituitary Tumors
Fusion of a contrast-enhanced MRI with a contrasted planning CT scan provides the
optimum definition of the suprasellar optic apparatus and the extensiveness of the

986
tumor. The GTV is the pituitary adenoma, including any of its extension into adjacent
anatomic regions. Generally, the entire content of the sella and, if appropriate,
extension into the sphenoid or cavernous sinuses are included in the CTV. With
appropriate immobilization devices, CTV expansion of 0.5 cm, that is, 1.0 to 1.5 cm
margin to block edge is adequate to create the PTV. Stereotactic positioning can reduce
the PTV, with margins of 7 mm giving excellent dose distribution with minimal dose to
surrounding tissues. OARs to be contoured include the optic globes, lenses, optic nerves,
optic chiasm, brainstem, and temporal lobes.
The traditional three-field approach using wedged opposed laterals and an anterior or
vertex beam superior to the eyes leads to unacceptably high doses to the temporal lobes.
IMRT may be useful to further improve dose distribution, especially for irregularly
shaped lesions. Beam energies of at least 6 MV should be used to spare surrounding
structures, most notably the temporal lobes. Ten-megavolt photons provide a good
balance between depth dose and penumbra width, although for stereotactic plans with
small margins, 6-MV photons may be more advantageous.

Spinal Tumors
The most favorable field arrangement will be determined by the location and adjacent
OARs, and it may be a single posteroanterior (PA) field, opposed-lateral fields, a PA field
with opposed laterals, opposed anterior–posterior (AP/PA) fields, or oblique wedge-pair
fields (73,74). In some circumstances, IMRT may be useful to spare esophagus, heart,
lung, kidney, and bowel, especially when higher doses need to be delivered. Some
metastatic lesions may be suitable for treatment in a single fraction with spinal
radiosurgery using appropriate immobilization and image guidance tools. In the cervical
region, an opposed-lateral beam approach minimizes the dose to the anterior neck.
When palliating a tumor in the cervicothoracic region, a split beam approach facilitates
the match with another treatment field. In this case, the central axis is placed just above
the shoulders and opposed-lateral beams are used to treat the upper spine, and a PA
field is used for the area of the spine below the central axis. Tumors in the thoracic
region can be treated with opposed lateral beams, a three-field approach using a PA
field and opposed lateral beams, a two-field approach using AP/PA beams, or a
posterior beam prescribed to an appropriate depth. When treating with a single
posterior beam, the depth prescription should take into account the dose to the spinal
cord to prevent accidental overdosing. In the lumbar region, AP/PA or PA fields reduce
the exposure to the kidneys. In the sacral region, opposed lateral beams with or without
a posterior beam or a four-field approach using AP/PA and opposed lateral beams may
be useful. Comparison of various treatment setups by means of DVHs is recommended.

ACKNOWLEDGMENTS
The authors would like to acknowledge the contributions of Lucien A Nedzi, Kevin S. Choe,
Arnold Pompos, Ezequiel Ramirez, Volker W. Stieber, Kevin P. McMullen, Allan DeGuzman,
and Edward G. Shaw to the writing of this chapter in the previous editions of this book.

KEY POINTS
• Multimodality therapy for CNS tumors may consist of medical therapy, surgical resection,
radiation therapy, or some combination of the above.

987
• The therapeutic ratio of radiation therapy for CNS tumors has improved due to the
introduction of new irradiation technologies, such as 3D CRT, IMRT, and proton therapy,
and the development and availability of advanced imaging techniques such as MRI that help
to better delineate targets and regions of avoidance.
• Modern radiation therapy for CNS tumors requires various novel imaging techniques that
help to better understand the dosimetrically relevant composition of the tissue in the path of
the radiation and verify the location of the target during dose delivery.

QUESTIONS
1. (T/F) In patients diagnosed with a brain tumor, prophylactic use of
anticonvulsants should be initiated irrespective of seizure history.
2. For radiotherapy planning of a resected high-grade glioma, the following MRI
sequence(s) should be obtained:
A. Preoperative T1-weighted sequence with contrast only
B. Postoperative T1-weighted sequence with contrast only
C. Preoperative T1-weighted sequence with contrast and preoperative T2/FLAIR
sequence only.
D. Postoperative T2/FLAIR sequence only
E. Pre- and postoperative T1-weighted sequences with contrast and pre- and
postoperative T2/FLAIR sequences only.
3. The following statements regarding radiobiologic tolerance of the brainstem and
spinal cord are true, except:
A. A maximal dose constraint of 54 Gy is generally considered to have a minimal
risk of causing severe neurologic effects.
B. 50 Gy at 2-Gy per fraction has been estimated to be associated with a 0.2%
rate of myelopathy.
C. Damage to the spinal cord can result in pain, paresthesia, sensory deficits,
paralysis, Brown-Sequard syndrome, and bowel/bladder incontinence.
D. Series on dose-escalated radiotherapy for skull base tumors have
demonstrated that the dorsal surface of the brainstem may be somewhat
radioresistant.
4. (T/F) A radiosensitive neural stem cell compartment located in the subgranular
zone of the hippocampal dentate gyrus may be central to radiotherapy-related
memory toxicity.
5. All of the following statements are true regarding craniospinal irradiation,
except:
A. The field length of the lower spine field should be maximized, where as the
field length of the upper spine field should be minimized.
B. Medulloblastoma is an example of a neoplasm requiring craniospinal
irradiation.
C. When treating craniospinal irradiation in the supine position, the neck should

988
be extended to avoid beams exiting the oral cavity.
D. In “exact-match” technique for matching the cranial fields to the upper spinal
field, the collimator for the lateral cranial fields is angled to match the
divergence of the upper border of the adjacent spinal field, and the treatment
couch is angled so that the inferior border of the cranial field is
perpendicular to the superior edge of the spinal field.

ANSWERS
1. False
2. E
3. D
4. True
5. A

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32 Pediatric Malignancies

Shannon M. MacDonald and Nancy J. Tarbell

INTRODUCTION
There are several special aspects to consider for radiation treatment planning for
children. Pediatric radiation oncology differs from other radiation subspecialties in that
it involves knowledge of all anatomic locations. Tolerances for organs at risk differ from
adults due to growth and development. There is also much greater variability in patient
size and their ability to cooperate. Pediatric malignancies are relatively rare. As a
pediatric oncology community, we rely more on the collective experience of our field
than most subspecialties. Forums and guidelines exist through Children’s Oncology
Group (COG) and the Pediatric Radiation Oncology Society (PROS). These websites help
to provide general radiation guidelines and also the ability to communicate with other
subspecialists in pediatric oncology, enabling pediatric oncologists to benefit from the
experience of others when faced with a difficult case. Given that approximately 80% of
pediatric cancer patients will go on to be long-term survivors, it is of paramount
importance that radiation treatment plans are devised with great care to ensure the best
possibility of local control with the lowest possible risk of long-term side effects (1).

Radiation Delivery for Children


Modern radiation planning and delivery for pediatrics take advantage of many of the
same technologic advances in imaging, planning software systems, and radiation
modalities used for the adult population. Nearly all treatments are planned using three-
dimensional (3D) imaging and cutting-edge modalities such as proton radiation,
brachytherapy, and intensity-modulated radiation, which are frequently used to provide
maximal normal tissue sparing. Advances in imaging have allowed for more precise
definition of structures and areas at risk and radiation guidelines over time have
allowed for smaller margins due to improved delineation of tumors and minimization of
setup error.

Immobilization
Immobilization is often a challenge for young children. They may be fearful of the
therapy or treatment room and/or lack the ability to understand the importance of
remaining still for treatment. For young children or those unable to tolerate treatment
without sedation, anesthesia is necessary. It is crucial for the pediatric radiation
oncology team to have a good working relationship with the pediatric anesthesia team
to ensure positioning is optimal for both teams and to provide safe and efficient
treatment. Children do not require deep sedation for radiation therapy as the purpose
of anesthesia is simply to keep the patient from moving, therefore the use of a conscious
sedative rather than full general anesthetic requiring intubation is preferred at most
institutions. Propofol is our institution’s preference due to ease of administration and
rapid recovery. Intravenous access is required for this type of sedation. A portacath is
the most common mode of access and many patients will have a portacath for

994
chemotherapy administration; some may have a Broviac catheter device that can also be
used. Children with a portacath can be accessed on Mondays prior to treatment and
have the access removed on Fridays following treatment. While positioning is optimized
for RT delivery, a good airway will supersede this for children under anesthesia. Most
children need only an oxygen mask, but a few will require a laryngeal mask airway
(LMA) or nasal trumpet to maintain a good airway. Prone positioning is the most
challenging for achieving and maintaining a good airway, but this is still possible for
the vast majority of patients. Older children can usually tolerate treatment without
sedation. Music may be helpful for soothing anxiety or providing distraction. For some
older children that have difficulty staying still, a low dose of a medication such as
Ativan may allow them to tolerate treatment without sedation. Select children that
cannot initially tolerate treatment do respond to coaching by nurses, child life
specialists, and even other pediatric patients going through a similar treatment. The
ability to avoid anesthesia allows for maintenance of a regular meal schedule, thereby
limiting impact on weight loss/gain and decreases the amount of time spent in the
radiation oncology department, permitting greater preservation of the child’s routine or
“normal” life. In addition, avoidance of anesthesia limits the strain on hospital
resources, including nursing and anesthesia staff while also reducing time on radiation
treatment machines and decreases the cost of a radiation course.
Some immobilization devices may be uncomfortable for children or difficult to use, as
most were manufactured for adults and later adapted for use in children.
Immobilization for the treatment of brain or head-and-neck tumors is usually
accomplished with a molded thermoplastic mask. Metallic markers can be placed on the
mask to help with localization. Some stereotactic treatments require a more rigid frame,
often with a bite block. These systems are sometimes only feasible for a single fraction
treatment and usually too difficult for children to tolerate without sedation. Treatment
to the trunk of the body or extremities will require the placement of tattoos and it is
very important to review with parents and children the placement and permanency of
these tattoos. Vac-loc bags, leg immobilizers, or custom-made immobilization devices are
used depending upon treatment site and patient anatomy. Respiratory gating or a four-
dimensional computed tomography (4D CT) to determine the margin needed to account
for respiratory motion is appropriate for some thoracic and abdominal locations. Image-
guided radiation therapy with daily kV quality images or cone-beam CT is generally
used to allow for a small setup margin and to improve accuracy. The dose of radiation
from setup imaging is small, but may need to be discussed with parents in the era of a
more heightened awareness of diagnostic radiation exposure for pediatric patients (2,3).

Three-Dimensional Treatment Planning


3D planning should be used for most, if not all, pediatric radiation treatment. Most
departments obtain a CT scan in the treatment position and fuse diagnostic magnetic
resonance imaging (MRI), CT and/or positron emission tomography (PET)/CT sequences
for treatment planning. Some radiation departments utilize MRI or PET/CT treatment
planning scanners. As our imaging techniques have improved, margins for error around
this volume can be made smaller, thereby allowing for full coverage of the tumor with
improved avoidance of the surrounding healthy tissues.

Intensity-Modulated Radiation Therapy


Intensity-modulated radiation therapy (IMRT) allows for the most conformal photon

995
plan with high-dose isodose lines closely surrounding the target volume. While IMRT
plans decrease high and moderate dose to nearby structures, these plans typically result
in the delivery of low-dose radiation to a larger volume of tissue outside of the target.
While this may be a little consequence in terms of function, second malignancy is a risk
for even low-dose radiation and is a greater concern for the pediatric population (4).
Despite this concern, recent data with reasonably long follow up indicate the risk of
second malignancy for pediatric patients treated with IMRT is still low (5).

Proton Radiation
Proton radiation is a form of particle radiation that allows for complete sparing of
tissue beyond the target volume for a given beam and often decreased dose proximal to
the target compared to photon radiation (6). Proton therapy decreases both high- and
low-dose regions outside of the target volume. Pediatric tumors are considered one of
the best indications for this type of treatment, given the importance of sparing
developing tissue from radiation. While clinical experience for protons is still limited
relative to photon experience, many publications have supported disease outcomes that
are comparable to favorable to photons and suggest that morbidity is less (7–12).
Protons are more costly than other external-beam radiation options. However, for
children, the avoidance of radiation to critical structures that would lead to costly
chronic medical conditions can render protons cost-effective and even cost-saving for
some patients (13,14).

PEDIATRIC DISEASE SITES/TREATMENT PLANNING


Embryonal Tumors of the CNS
Embryonal tumors are the most common malignant brain tumors in children. They are
highly malignant small round blue cell tumors that have a propensity to spread through
the cerebrospinal fluid (CSF). Subtypes of embryonal tumors include medulloblastoma,
supratentorial primitive neuroectodermal tumors (SPNETs), and atypical teratoid
rhabdoid tumors (ATRT). While treatment regimens differ, intensive treatment with
surgery, radiation, and chemotherapy is indicated for all embryonal tumor subtypes for
the best chance of disease control and survival.
Medulloblastoma is the most common embryonal tumor that is located in the
cerebellum, by definition. Workup includes MRI of the brain that characteristically
shows a mass in the cerebellum filling the fourth ventricle and causing obstructive
hydrocephalus. Maximal safe resection is recommended and additional workup includes
MRI of the spine (presurgical or 0 to 14 days after surgery) and a lumbar puncture to
obtain CSF (10 to 14 days after surgery; CSF should be obtained by LP and should not
be performed prior to surgery due to risk of herniation). At present, a risk stratification
system based on clinical factors divides patients into two risk groups, “high-risk” and
“standard-risk,” with standard-risk defined as children over the age of 3 with ≤1.5 cm2
of residual disease following surgery and no metastatic disease (grossly or in CSF) and
all others considered high-risk. In recent years, diffuse anaplastic histology has been
found to portend a poor prognosis and these patients should be considered for high-risk
therapy regimens (15). Molecular profiles will likely supersede current staging and
histologic risk stratification, but at present these profiles are used to dictate treatment
only in the setting of a clinical trial (16–18). Accepted radiation treatment for standard-
risk disease is 23.4 CSI followed by a whole posterior fossa or involved-field boost to 54

996
Gy. Lower CSI doses have and are being investigated for young children (<8 years old)
and for molecularly favorable profiles (19). Standard treatment for high-risk disease
includes CSI to 36 Gy followed by whole posterior fossa or involved-field boost to 54
Gy. Any sites of initial metastatic disease in the spine should receive 45 Gy and
metastatic lesions in the brain should receive at least 45 Gy, sometimes a higher dose
depending on location and the perceived risk-benefit ratio. Management for children
under the age of 3 is a bit more heterogeneous and generally consists of maximal safe
resection followed by chemotherapy, followed by delayed and usually localized
radiation therapy (20,21). In infants that present with disseminated or refractory
disease, low-dose CSI may be considered depending on patient age and parental wishes.
Disease-free survival for a patient with standard-risk disease treated with chemotherapy
and radiation exceeds 80% (15). Cure rates for high-risk disease are less favorable, but
fall between 50% and 70% (22). Children with standard-risk disease with anaplastic
histology have a disease-free survival in between these two groups of approximately
73% (15).
SPNETs are histologically similar to medulloblastoma but are located outside of the
cerebellum in any location of the supratentorial brain. Pineoblastomas are a subset of
SPNETs. The prognosis for patients with this disease is worse than medulloblastoma
even in the absence of dissemination. All patients with SPNETs are therefore considered
to have “high-risk” disease, regardless of whether or not the disease is metastatic at
diagnosis, and standard CSI doses for localized or metastatic disease is 36 Gy. A dose of
54 Gy is recommended to the tumor bed plus a margin of approximately 1 cm within
anatomical boundaries. For children under the age of 3, involved-field radiation to 50.4
to 54 Gy is generally recommended. Similar to medulloblastoma, management for
children under the age of 3 is maximal safe resection followed by chemotherapy,
followed by delayed, and usually localized, radiation therapy.
ATRT are rare malignancies that typically affect very young children. These tumors
look similar to medulloblastoma, but have a mutation that results in a deficiency of INI-
1 protein (23). The prognosis for ATRT is inferior to that for medulloblastoma and
SPNET; however, with more aggressive chemotherapy, 2-year progression free and
overall survival rates of 53% and 70%, respectively, can be achieved (24). The
treatment of ATRT includes maximal resection of primary disease, intense induction
chemotherapy including intrathecal chemotherapy, high-dose chemotherapy followed
by stem cell rescue (HDCSCR), and radiation therapy. For children under the age of 3,
localized radiation is recommended. For older children, CSI followed by additional
involved-field radiation is favored due to risk of dissemination and poor prognosis (25).
The COG protocol delivers involved-field RT for all children, regardless of age. Although
there are limited data on effective CSI dose, given the more aggressive nature of this
disease, 36 Gy is most standard for CSI. A dose of 50.4 to 54 Gy is recommended to the
involved-field.
Embryonal tumors are highly radiosensitive tumors. As a result, the technical quality
of radiation delivery significantly influences the risk of recurrence. Treatment planning,
especially CSI, must be planned with utmost care. The craniospinal volume includes the
entire brain and spine. Care should be taken to ensure coverage of the cribriform plate
and to give a margin of at least one vertebral body below the thecal sac, which is
typically located near S2, but can vary. Adequate margin lateral to the thecal sac is also
required. It is best to confirm the location of these regions with a neuroradiologist to
ensure coverage. Most CSI treatments are delivered with the patient in the prone
position, although supine CSI treatment is now being delivered in the supine position at
several institutions. There was some reluctance to deliver CSI in the supine position, as

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clinical verification that matched spinal fields is only possible in the prone position.
However, there is also a possibility that overconcern regarding field overlap could lead
to “colder” cold spots potentially increasing the risk of relapse. The spinal field is
typically too long to treat with just one field and typically two to three fields are
necessary. Fields are matched anterior to the spinal cord, which create a small area of
underdosing in the cord but avoids any areas of overlap or hot spots in the cord (Fig.
32.1). Care should be taken to minimize these areas of slight under- and overdosing and
fields should be “feathered” (match point varied during treatment) to minimize these
areas and decrease uncertainty. The use of IMRT and scanning proton techniques allow
for treatment without field matching of fields and because of the lack of exit dose
protons avoid exit dose to the thyroid, heart, lungs, abdominal organs, and ovaries (Fig.
32.2).
The posterior fossa volume extends from the tentorium superiorly to C1 inferiorly.
Laterally the posterior fossa volume includes the entire cerebellum and extends to the
bony occiput and anteriorly this volume includes the brainstem and lower midbrain (as
defined by COG guidelines). The involved-field volume GTV should include the tumor
bed (anything in contact with the initial tumor prior to surgery) and any residual gross
disease. Care should be taken to ensure coverage of anything touched by the initial
tumor and also to account for anatomical shifts following surgery. An expansion of 1 to
1.5 cm is typically used to form the CTV for the involved-field boost.

Ependymoma
Intracranial ependymomas are brain tumors that originate from ependymal cells lining
the ventricles or from ependymal cell rests located in the brain parenchyma. The
majority (approximately two-thirds) occur in the posterior fossa/fourth ventricle and
the remainder occur in the supratentorial brain (26). Diagnostic workup includes MRI
of the brain and spine and CSF sampling, though CSF is rarely positive when MRIs show
no evidence of metastatic disease (27). Intracranial ependymomas are defined as
classic/differentiated (WHO grade II) or anaplastic (WHO grade III) by histology.
Similar to medulloblastoma, we are learning more and more about the genetic profiles
for this disease and molecular characteristics may play a role treatment delivery on
future clinical trials (28). The initial treatment is complete surgical removal. Removal of
the entire tumor is critical for a favorable outcome and this has been demonstrated
clearly in both small and large series. For localized disease, the 3- to 5-year progression-
free survival rates range from 51% to 88% for gross total resection and from 0% to
54% for subtotal resection (7,29). If complete removal is achieved, radiation to the
tumor bed plus a margin is recommended. If resection is incomplete, a short course of
chemotherapy followed by a second-look surgery in attempt to achieve a gross total
resection prior to radiation is generally favored. Chemotherapy has not shown benefit
for this disease and cannot be used in place of RT; it is unclear if chemotherapy adds
benefit over surgery and radiation alone, but this is being investigated in a randomized
fashion on the current COG protocol, ACNS0831. Off protocol, maximal resection and
radiation is standard. Although there are concerns about radiating very young children,
localized radiation has been proven safe and effective for children as young as 12
months of age.

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Figure 32.1 Craniospinal irradiation requires spinal fields to be matched. Fields should be matched anterior to
spinal cord, which creates a small cold spot within the cord. To minimize this slightly underdosed area and to
minimize the uncertainty associated with matched fields, fields are “feathered” so that this match is moved to
different locations during treatment. This figure shows field feathering.

Figure 32.2 Proton radiation allows for complete sparing of all organs anterior to the vertebral body. This figure
shows a CSI plan for a young child. Note that the whole vertebral body is included to ensure even dosing and
avoid asymmetric growth.

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Treatment planning should start with a careful review of all images with a
neuroradiologist to determine any areas of residual disease and review all surfaces
contacted by initial tumor. Infratentorial ependymomas are notorious for extension
through the foramina of Luschka and Magendie. It is critical to determine original
tumor extension into these regions and treat these surfaces. Contouring the preoperative
volume to become familiar with both the anatomical location of the tumor as well as
ependymal and CNS structures in contact with the tumor may be useful. Care should be
taken to adjust this volume for anatomical shifts following surgery. The GTV should
include any surface contacted by the original tumor as well as any gross residual
disease. The CTV expansion should be approximately 5 mm with constraints for
anatomical boundaries. The recommended dose to this volume is 54 to 59.4 Gy in 30 to
33 fractions. The recently closed and current COG protocols (ACN0121 and ACNS0831,
respectively) prescribe a total dose to 59.4 Gy, but ACNS0831 requires that critical
structures (the spinal cord and optics) outside of the area of highest risk be blocked
after 54 Gy. It should be recognized that brainstem tolerance is considered 54 Gy and
that doses in excess of this may increase the risk of brainstem necrosis. Many do
however feel that the risk of local recurrence after radiation warrants this additional
risk. Children under the age of 18 months or with known brainstem injury should not
receive a total dose in excess of 54 Gy. Off protocol, our institution favors a dose of 54
Gy for patients of all ages that have undergone a gross total resection and have
infratentorial disease. Supratentorial tumors are also treated with maximal resection
followed by involved-field RT to 54 to 59.4 Gy. Again, care should be taken to define
GTV as any residual tumor and areas of the cerebrum in contact with presurgical tumor.
Due to shifts in the brain parenchyma, this is sometimes challenging and sulci/gyri of
the brain in contact with the initial tumor should be reviewed with a neuroradiologist.
Figure 32.3 shows an IMRT plan for a patient with an infratentorial ependymoma.
Supratentorial WHO grade II tumors that are completely resected may be observed
without radiation on protocol, but should receive RT off protocol. Limited data exist for
patients with metastatic ependymoma and outcomes are very poor. Most patients are
treated with CSI to 36 Gy followed by a localized boost to 54 to 59.4 Gy. For patients
with recurrence following radiation, reirradiation has been explored and may allow for
long-term survival for some patients, but, in general, this treatment is considered
palliative.

Low-Grade Astrocytoma
Though the most common pediatric brain tumor, low-grade gliomas can be cured with
surgery alone if they occur in a location amenable to surgery with acceptable morbidity,
and therefore, many do not require radiation. Tumors that occur in the hypothalamus,
thalamus, tectum, optics, and brainstem, often require radiation, as surgical morbidity
may be unacceptable in these locations. Histologic subtypes of pediatric low-grade
gliomas include pilocytic (WHO grade I) and diffuse (WHO grade II), with pilocytic
astrocytoma accounting for the majority of tumors in young children. Younger patients
are often treated with chemotherapy to delay radiation and for children with
neurofibromatosis chemotherapy alone may be sufficient and spontaneous regression is
possible. Packer et al. (30) reported a 68% 3-year progression-free survival rate for
children treated with carboplatin and vincristine. Additional chemotherapeutic agents
have since been studied and also shown efficacy, but second- and third-line regiments
tend to lead to less efficacious and less durable results. For most children with low-
grade glioma, chemotherapy typically delays progression, but radiation is usually still

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required for definitive treatment. When determining the appropriate therapy, one must
also consider the cumulative morbidity of multiple regimens and risks of functional loss
from progression of tumor. Data also indicate that young children are more likely to
respond and have a durable response than older children. Radiation provides durable
control with Merchant et al. (31,32) reporting 10-year progression-free survival rates of
74% for conformal focal radiation.

Figure 32.3 Intensity-modulated radiation therapy (IMRT) is one advanced technique used for the treatment of
pediatric malignancies. This figure shows beam arrangement and intensity modulation of fields for an
infratentorial ependymoma (A) and an axial image of plan and doses (B).

Because these tumors are not highly infiltrative, only a small volume expansion is
necessary around visible tumor. The GTV should include enhancing and nonenhancing
or cystic tumor plus a small margin of approximately 5 mm. A dose of 50.4 to 54 Gy is
recommended. If tumors contain a cystic component, it is important to monitor the
cystic component for changes during radiation therapy and adjust the plan as needed.
Although it is relatively rare for low-grade gliomas to disseminate, for these cases,
radiation volumes typically encompass the entire craniospinal axis to a dose of 36 Gy
followed by involved-field treatment to 45 to 54 Gy, depending on tumor location.
Pseudoprogression—enhancement and/or enlargement of tumor—may occur following
treatment, most frequently at 6 to 12 months following delivery of radiation. Care
should be taken to consider this in order to avoid unnecessary treatment or assume

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tumor progression or transformation to a more malignant process.

High-Grade Astrocytoma
High-grade gliomas of the supratentorial brain are seen much less frequently in the
pediatric population, than the adult population. Most high-grade gliomas are localized.
Maximal safe resection and radiation is standard. Chemotherapy has been studied, but
without great success and temozolamide seems less efficacious for children than adults,
perhaps due to the relatively low frequency of MGMT deletion for childhood tumors
(33). Despite this, at present, temozolamide is often used as a first-line chemotherapy
concurrent with RT and following RT due to absence of a more effective agent and the
still relatively poor prognosis of high-grade gliomas in children. Despite a less-favorable
prognosis compared with many other pediatric brain tumors, long-term survival is
attainable for some children, especially the very young, and some pediatric patients
with high-grade gliomas will be long-term survivors (34).
For treatment planning, one must be careful to include areas of contrast enhancement
and T2 fluid-attenuated inversion recovery signal abnormality for the initial GTV.
Again, review of all MRI sequences with pediatric neuroradiologist should be done. The
GTV plus a generous margin of approximately 1 to 2 cm is usually treated to 45 Gy. The
enhancing area plus a margin should receive a boost dose to bring this region to a dose
of 54 to 59.4 Gy. While anatomical boundaries such as bone and tentorium should be
respected when defining the CTV, these tumors often cross white matter tracts and it is
important to consider this when defining tumor margins to account for microscopic
spread of disease.

Diffuse Pontine Glioma


Diffuse infiltrating pontine gliomas (DIPG) are high-grade tumors that arise from the
pons. These tumors have a characteristic appearance on MRI of a nonenhancing T2
bright lesion that expands the pons. Biopsy is not necessary when this classic
radiographic appearance is evident; however, more recently and for clinical trials,
pathology is obtained for molecular profiling and sometimes drug selection (35).
Radiation is palliative but indicated to the tumor with a small margin to a dose of
approximately 54 Gy. Symptoms almost always improve promptly with treatment, but
sadly, duration of resolution or improvement of presenting symptoms is relatively short,
on the order of months. This disease is uniformly fatal and the median survival is
approximately 1 year. Dose escalations of radiation, altered fractionation, and
chemotherapy have all been explored and have failed to improve DFS or OS (36,37).
Molecular targets are currently under investigation for this tumor, but to date no
successful systemic agent has been defined.

Germinoma/Nongerminomatous Germ Cell Tumors


Pediatric intracranial germ cell tumors are rare and usually occur in adolescents. The
most common locations for these tumors are in the pineal gland and
infundibulum/suprasellar region. Rarely, they occur in other locations of the brain, with
the third most common location being the basal ganglia. When a GCT is suspected by
MRI findings, serum tumor markers, α-fetoprotein (AFP), and β human chorionic
gonadotropin (β-HCG) should be obtained. If a lumbar puncture can be safely
performed, CSF should be obtained for cytology and tumor markers. MRI of the spine is
also standard to rule out disseminated disease.

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“Pure” germinoma are highly curable tumors with DFS rates in excess of 90% for both
localized and disseminated disease. In the United States, chemotherapy followed by
reduced-dose radiation is usually recommended for children to reduce late side effects
of radiation. Two to four cycles of platinum-based therapy, usually carboplatin and
etoposide, are delivered. If a complete response is achieved, a dose of 21 Gy to the
whole ventricles followed by a boost to 30 to 40 Gy to the primary tumor region is
delivered. If a complete response is not achieved, a second-look surgery is recommended
(if this can be safely performed) to ensure that a nongerminomatous component is not
present and/or higher doses of radiation may be recommended. Some studies have
explored the use of chemotherapy followed by involved-field radiation to 30 to 40 Gy.
Early reports showed promising results, but higher rates of ventricular relapse were
later reported by Alapetite et al., resulting in a shift back to a larger low-dose volume,
whole ventricular RT, first followed by an involved-field boost (38,39). The current COG
protocol, ACNS1123, is investigating the use of pre-RT chemotherapy with four cycles
of carboplatin and etoposide followed by very low-dose whole ventricular radiation to
18 Gy and a boost to a total of 30 Gy to the primary tumor for localized pure
germinoma following a complete response to four cycles of carboplatin and etoposide.
The prognosis for nongerminomatous germ cell tumors is inferior to germinoma. The
standard chemotherapeutic regimen in the United States consists of six cycles of
alternating carboplatin/etoposide and ifosfamide/etoposide followed by radiation.
Patients that do not have a complete response to chemotherapy should undergo a
second-look surgery and those that have viable tumor remaining have been shown to
have an inferior prognosis. For these unfortunate patients, HDCSCR should be
considered (40). The last COG protocol, ACNS0122, delivered CSI to 36 Gy followed by
a boost to the tumor volume to 54 Gy after six cycles of chemotherapy. The results of
this trial have not yet been published in manuscript form, but 5-year event-free and
overall survival rates of 84% and 93%, respectively, have been reported (should be
published by time of proof). The current COG protocol, ACNS1123, examines a “middle
ground” radiation volume delivering 30.6 Gy to the whole ventricles followed by a dose
of 54 Gy to the involved field following six cycles of carboplatin/etoposide alternating
with ifosfamide/etoposide for patients with localized nongerminomatous germ cell
tumors who have a complete response to chemotherapy.
It is critical that the involved-field volume is determined at the time of planning CSI
or whole-ventricle treatment planning to ensure the CTV boost volume receives full
dose. The whole ventricular CTV should include the whole ventricles plus the CTV for
the boost volume. Germ cell tumors can involve the optic nerves and hypothalamus in
areas that are not part of classic CSI or whole-ventricle volumes and the CTV volume for
pineal gland tumors may extend outside of the whole-ventricle volume, especially for
infiltrating tumors. Guidelines to assist in contouring the whole ventricular volume, a
somewhat challenging and tedious volume, are available for the current germinoma
COG protocol (Fig. 32.4).

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Figure 32.4 The whole-ventricle volume is used for treatment of microscopic disease for germinomas. This
figure shows contours in axial, sagittal, and coronal views.

CRANIOPHARYNGIOMA
Craniopharyngioma is considered a “benign” tumor and highly curable. However, these
children can suffer great morbidity from tumor progression and/or treatment. The most
common type of craniopharyngiomas, adamantinomatous histology, is often difficult to
separate surgically from adjacent critical structures, preventing a curative complete
surgical resection. Treatment with biopsy and cyst decompression or minimal excision
followed by radiation is usually favored as a less morbid treatment. The standard GTV
for craniopharyngiomas includes both solid and cystic components. A small margin of 3
to 5 mm around the GTV should be given for the CTV volume. A dose of 50.4 to 54 Gy
at daily fractions of 1.8 Gy is recommended.
Given the high likelihood of survival, minimizing late morbidity is of paramount
importance, and modern modalities are recommended for treatment in an attempt to
decrease long-term morbidity. Intracavitary radiation may be used for the cystic
recurrence (41,42). Because of limited penetration, this treatment is not useful for
treatment of the solid component of craniopharyngioma.
For any tumors that have a cystic component, cyst growth or change in position may
occur during radiation therapy. Since the cystic portion of the tumor is also targeted in
treatment, it is crucial to make appropriate adjustments in the radiation plan during the
course of radiation. It is also important to recognize that dose to organs at risk may also
be altered by cystic change. CT or T2-weighted noncontrast MRI every 7 to 14 days or
daily cone-beam CT for cyst monitoring should be strongly considered.

Wilms Tumor and Other Renal Malignancies


Wilms tumor is the most common abdominal malignancy in children. These children
generally present with an abdominal mass, but are otherwise healthy. The North
American standard is to perform surgical resection as the initial treatment for
therapeutic treatment as well as for diagnosis, staging, and determination of subsequent
therapy. COG radiation therapy guidelines are based on both stage and pathology.

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Flank radiation is recommended for patients with stages I to III unfavorable histologies
(diffuse anaplasia, focal anaplasia, CCSK, CCSK—stages II and III) and for stage III FH.
The standard dose is 10.8 Gy in fractions of 1.8 Gy following complete removal of
tumor, but higher doses are recommended for recurrent disease, stage III DA, and
sometimes for children diagnosed at an older age. An additional 10.8 Gy is advised for
gross residual disease. Although 3D planning is useful for delineation of the tumor bed
and gross residual disease if present, guidelines are still based in large part on bony
landmarks. Respiratory motion should be considered and a 4D CT may be useful for
planning. Respiratory gating is not typically employed, but margins for respiratory
motion are added. The initial tumor should be reproduced on planning CT scan. Care
should be taken to include or evenly dose the entire vertebral body and to spare the
contralateral kidney and ovaries for females. AP/PA fields are typically used, but
oblique fields may be of benefit for contralateral renal sparing in some cases. Whole
abdominal radiation (WART) to a dose of 10.5 Gy at 1.5 Gy per fraction is
recommended for positive cytology, diffuse spillage, prior biopsy, or peritoneal seeding.
If feasible, RT should be started by postoperative day 9 if and no later than
postoperative day 14. Whole lung irradiation (WLI) to 10.5 Gy is recommended for
patients with pulmonary metastases that do not resolve following chemotherapy and for
patients with pulmonary metastases at diagnosis with loss of heterozygosity for 1p16q.
Brain, liver, and bone irradiation is indicated when metastases are present.

Neuroblastoma
Neuroblastoma is the most common solid non-CNS malignancy. Neuroblastoma occurs in
very young children and usually originates from the adrenal gland or paraspinal
ganglia. Children often present with an abdominal mass but in contrast to Wilms tumor,
the other common abdominal malignancy in children, these children are typically very
ill due to systemic involvement. Radiation therapy is not used for favorable disease and
is recommended mainly for patients with high-risk disease or rarely for children with
intermediate-risk disease refractory to chemotherapy. At present, children with high-risk
disease are treated with chemotherapy, HDCSCR, immunotherapy, and usually surgery
and radiation for local control (43). Many children with high-risk disease have primary
tumors that cannot be resected at diagnosis and surgery is performed after five or six
cycles of systemic therapy. The standard dose of RT recommended to the post-
chemotherapy presurgical volume in 21.6 Gy. This volume should include a tumor bed
(GTV) that encompasses all areas touched by this disease but accounts for shifts in
organs following surgical resection. For children with residual disease following
surgery, a total dose of 36 Gy is recommended to areas of gross disease. Advanced
radiation techniques such as IMRT, intraoperative radiation, and proton radiation
should be considered to minimize dose to the kidneys, liver, lung, developing bone, and
other normal structures (44). Although the dose of radiation is relatively low compared
with other disease sites, children are usually very young and volumes may be quite
large. Figure 32.5A demonstrates various treatment techniques for a child with high-risk
neuroblastoma with proton therapy for a fully-grown child. Note the gradient seen over
the vertebral body. For a growing child, contours or plan should be devised so that the
entire vertebral body receives a relatively homogeneous dose. Figure 32.5B shows a
proton planning volume that includes the vertebral body to ensure homogeneous dose
delivery. Radiation therapy to a dose of 21.6 Gy is also advised for any metastatic sites
persistent following induction chemotherapy. Metastatic sites requiring RT are typically
present in the bone. Figure 32.6 shows a bony metastatic site treated with protons. Note

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the low dose achieved to both the pelvis and femoral head growth plates. This would
not be possible with an alternative modality. In the setting of multiple metastatic sites
still positive after induction chemotherapy, consideration must be given to the amount
of tissue to be irradiated, and typically children are re-evaluated after further
chemotherapy and an attempt is made to limit the number of metastatic sites receiving
radiation to three to five. Additional indications for radiation for neuroblastoma are in
an emergent setting and include radiation to the liver for liver metastases in infants to
relieve respiratory distress after other measures have failed, and radiation for spinal
cord compression if surgical decompression is not feasible. A dose of 1.5 Gy for three
fractions is recommended to a portion of the liver and is generally promptly effective.
Care should be taken to shield the ovaries for females. For spinal cord compression, a
decision should be made regarding dose based on additional risk factors and plans for
subsequent radiation.

Figure 32.5 Proton plan for neuroblastoma. Part A shows a plan for a fully grown 17-year-old child with no
effort made to include the whole vertebral body. Part B shows a plan for a young child which intentionally
includes the whole vertebral body. It is important to be aware of even doses to the vertebral bodies/bone. When
using advanced techniques, it may be necessary to adjust contours in order to facilitate homogeneous dosing.

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Figure 32.6 Treatment of a bone metastasis for a child with neuroblastoma with proton radiation. Protons allow
for excellent sparing of nearby growth plates.

Hodgkin Disease
Hodgkin disease is a highly curable lymphoma often cured with chemotherapy alone,
but sometimes requiring radiation. At present, most patients are treated with risk-
adapted therapy dictating amount of chemotherapy and/or radiation therapy based on
response to chemotherapy (45). The radiation treatment of this disease has evolved over
many decades from large volume-extended-field radiation to involved-field radiation
and now to involved-site or involved-node radiation therapy (46). Defining these nodal
areas require the use of both pre- and post-chemotherapy imaging. Ideally a PET-CT in
the treatment position at the time of diagnosis should be obtained, but often this is not
feasible to obtain. Information regarding the initial nodal disease and use of fusion if
position allows should be performed. The location of nodal disease should be carefully
reviewed with radiology to assist in design of the GTV and CTV. Motion should be
accounted for by use of a 4D CT and/or additional margin for motion. Most pediatric
patients are treated if they present with initial bulky disease or do not achieve a rapid
early response. The most commonly used dose is 21 Gy at 1.5 Gy per fraction. Given the
very high cure rates seen in this disease, extreme care must be taken to avoid long-term
morbidity from this disease and cooperative trial groups continue to determine how to
minimize radiation dose and volume for this disease (47,48).

Leukemia
In spite of the frequency of leukemia in children, with modern chemotherapy radiation
is seldom necessary. For acute lymphocytic leukemia (ALL), radiation is employed in the
setting of high-risk disease, refractory disease, or at relapse. For patients with T-cell
ALL, current guidelines indicate radiation for patients with the following high-risk
features: WBC >50 × 109, CNS3 disease (>5 WBC/l or blasts in the CSF), Ph + ALL,
or other high-risk disease that are “slow responders” with poor response to induction
chemotherapy. Cranial radiation to a dose of 12 to 18 Gy, more often 12 Gy, at 1.5 Gy
per fraction is the recommended CNS dose for this disease. Testicular radiation is other
site for which radiation may be necessary, but it is now used only in the setting of

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refractory or recurrent disease. The recommended dose for testicular radiation for
leukemia is 20 to 24 Gy (49).

Rhabdomyosarcoma
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Two main
histologies exist, embryonal and alveolar and these tumors may occur in any location of
the body. Currently, the COG studies stratify patients into three risk groups (low,
intermediate, and high) on the basis of site, stage, histology, and group, but TNM
staging is also used. Risk stratification is highly complex, but in general risk groups
include: (1) low-risk: embryonal nonmetastatic favorable sites and embryonal group 1 or
2 unfavorable sites, (2) intermediate-risk: embryonal group III unfavorable sites and
nonmetastatic alveolar RMS at any site, (3) high-risk: metastatic disease.
The Intergroup Rhabdomyosarcoma Studies (IRS) enabled marked improvement in
therapy and outcomes for this disease over the past several decades (50). At present,
combined modality risk-stratified therapy is used for children with rhabdomyosarcoma,
and this represents another disease site that requires multidisciplinary discussion
regarding best management. Radiation treatment depends on several prognostic factors
and feasibility of surgery with organ preservation. Surgery is performed upfront for
resectable tumors and may be attempted following chemotherapy if tumors become
resectable usually with the goal of decreasing radiation dose and sometimes volume.
Contemporary treatment and the existing COG rhabdomyosarcoma trials require 3D
treatment planning to allow for full visualization of areas at risk and target volumes.
Radiation is omitted only for patients with completely resected favorable histology
disease. Following surgical resection, 36 Gy is recommended for microscopic disease
and nodal disease is treated to a dose of 41.4 Gy. Patients with gross disease receive a
dose of 50.4 Gy. Target volumes delineate pre-chemotherapy volume as the gross tumor
volume. A margin of 1 cm around this volume respecting anatomical boundaries is
recommended to encompass microscopic disease.

Ewing Sarcoma
Ewing sarcoma follows rhabdomyosarcoma in its frequency in the pediatric population.
When complete surgical resection can be achieved without unacceptable morbidity, this
is the preferred treatment and radiation is not required. Radiation therapy is indicated
for inoperable or either partially resected tumors. Radiation dose to 50.4 to 55.8 Gy to
the involved area of bone with a margin for microscopic disease is standard. The initial
extent of disease should be treated to a dose of approximately 45 Gy adjusting for the
shifting of organs or tissues after regression of the soft tissue portion of the tumor
following chemotherapy, but not the bony component of tumor. A margin of
approximately 1.5 cm should be used around this volume to form the CTV. Gross
disease at the time of treatment along with initially involved bone with a margin of
approximately 1.5 cm should receive an additional dose of 10.8 Gy to total 55.8 Gy
with the exception of tumors located in the vertebral body, which may receive a total
dose of 45 to 55.8 Gy depending on location and ability to avoid the spinal cord due to
spinal cord tolerance.

Retinoblastoma
Retinoblastoma is a rare disease almost always diagnosed in infants or children under
the age of 3. Approximately 60% of patients will have a nonhereditary and unilateral

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form of this disease and the remainder of patients will have the hereditary form of
retinoblastoma with a high propensity for bilateral disease and subsequent
malignancies, some radiation induced and some that occur in children that have not
received radiation (51). Radiation is largely avoided because of the fear of radiation-
induced malignancies and because of the young age of these patients, and bony growth
abnormalities that will occur in the irradiated bone following RT. Radiation is generally
reserved for disease refractory to alternative therapies (cryotherapy, laser therapy,
intra-arterial chemotherapy, intravitreal chemotherapy, and systemic chemotherapy) in
an eye with useful vision while enucleation is advised if it is thought that there is no
meaningful visual potential. The most common indication for treatment of the intact eye
is vitreous seeding. Postoperative radiation is delivered for advanced disease following
enucleation. A dose of 45 Gy is standard for all indications. Treatment of the entire
retina is most standard. For very localized tumors, the area of the involved retina may
be considered if alternative options exist for anterior retinal tumor occurrence (i.e.,
cryotherapy or laser therapy). In the postoperative setting, the orbit and up to the optic
chiasm is necessary in cases of frank orbital disease and high-risk pathology features
(trans-scleral extension or tumor involvement of the cut end of the optic nerve). Plaque
brachytherapy may be an option for unifocal tumors that are located in the peripheral
retina. Radiation does provide an excellent chance at durable control of disease, but
carries risks of facial hypoplasia and radiation-induced malignancies. Proton radiation
is an excellent option for this disease to reduce exposure of tissue at risk for a radiation-
induced malignancy and to avoid severe bony growth abnormalities (9,11). Referral to a
proton center with expertise in retinoblastoma should be considered. Figure 32.7 shows
a treatment setup utilizing an eye cup to ensure eye immobilization in addition to an
aquaplast face mask to ensure immobilization of the head. A cup similar to a contact
lens with a metal post is placed on the eye following sedation. A small amount of
suction allows for the eye to be positioned. The metallic post can be imaged with kV x-
rays for daily setup. Figure 32.8 shows a proton plan.

Figure 32.7 Retinoblastoma treatment. A suction eye cup is used to provide reproducible eye positioning for a
child under anesthesia.

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Figure 32.8 Retinoblastoma plan with protons. Protons provide excellent sparing of tissues outside of the target
area.

CONCLUSIONS
The field of radiation oncology is evolving rapidly both technologically and biologically,
and we see much improved cancer outcomes and survival rates than we did just a few
decades ago. As malignancies become more curable and life expectancies following the
diagnosis of cancer become prolonged, the impact of our treatments on quality of life or
even secondary risks of life-threatening complications become more apparent. We have
learned a great deal from our childhood cancer survivors. In no other subset of patients
are the late effects of treatment more apparent. Though we debate the absolute benefit
of these technologic advances in adults, there has been little argument against using
more expensive technology for our children in order to protect healthy tissues from the
adverse effects of radiation. As we continue to learn from our experience with childhood
malignancies and advance with biologic treatments, radiation treatments will without
doubt evolve and change with continued goals of providing curative treatment while
minimizing side effects and allowing our patients to experience a good quality of life
following the diagnosis of cancer. We hope that future treatments will include lower-
dose and smaller-volume radiation treatments combined with less toxic biologic agents.
In the meantime, we should continue to provide the most targeted treatment possible by
delineating proper target volumes and using the appropriate technology to deliver
radiation with the optimal therapeutic ratio.

KEY POINTS
• Highly conformal therapy is indicated in the treatment of pediatric tumors, given the
importance of sparing developing tissue from radiation. Advance modalities, such as proton
therapy, should be considered.
• Embryonal tumors of the CNS are the most common malignant brain tumors in children.
They are highly malignant but include very curable tumors such as medulloblastoma.
Currently, to achieve high cure rates, surgery, chemotherapy, and radiation therapy are all part

1010
of standard treatment for embryonal tumors.
• Wilms tumor and neuroblastoma are common tumors in children, often presenting with an
abdominal mass.
• Radiation for Hodgkin lymphoma has evolved over time. Children are now treated with risk-
adapted involved involved-site or involved-node radiation therapy to relatively low doses (21
Gy).
• Rhabdomyosarcoma and Ewing sarcoma are the most frequently encountered sarcomas in the
pediatric population.
• Childhood tumors generally have high cure rates and thus great care should be taken in the
planning and treatment to decrease the morbidity of treatment.

QUESTIONS
1. Approximately what percentage of pediatric cancer patients will be long-term
survivors?
A. <20%
B. 20% to 50%
C. 50% to 70%
D. >70%
2. Which of the following are true about medulloblastoma?
A. Medulloblastoma is the most common embryonal tumor
B. Tumors arise in the posterior fossa
C. Chemotherapy plus radiation are used for children over 3 years of age
D. All of the above
3. All of the following are true about ependymoma EXCEPT:
A. Standard treatment includes craniospinal radiation therapy
B. Infratentorial ependymomas often extend through the foramina of Luschka
C. The recommended dose of involved-field radiation is currently 54 to 59.4 Gy
D. Gross total resection is an important prognostic factor
4. Which of the following is NOT true regarding pediatric low-grade gliomas?
A. They can sometimes be cured with surgery alone
B. Young patients are often treated with chemotherapy to delay radiation
therapy
C. When using radiation therapy to treat low-grade gliomas, a large margin is
needed around the visible tumor
D. Radiation often provides durable control rates for this tumor
5. Localized CNS germinoma are highly curable with therapy that includes:
A. Two to four cycles of platinum-based therapy
B. Whole-ventricle RT plus a cone down to the primary tumor site

1011
C. Dose of RT that is typically reduced after a complete response to
chemotherapy
D. All of the above

ANSWERS
1. D
2. D
3. A
4. C
5. D

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33 Cancers of the Thorax/Lung

Gregory M. M. Videtic, Rupesh Kotecha, Neil M. Woody, and Kevin L.


Stephans

INTRODUCTION
The chest is home to a range of pathologic processes because of the number and variety
of structures it harbors. This chapter is focused on the principles and practice of chest
irradiation for primary neoplasms such as lung cancer, malignant pleural mesothelioma,
and thymoma. Other thoracic malignancies such as esophageal cancer, primary
lymphomas and sarcomas are dealt with elsewhere in this textbook. Radiotherapy (RT)
plays a fundamental role in the management of thoracic tumors and in doing so
encompasses all the facets of oncologic care, from cure to palliation. This chapter will
review the components of RT as they apply to the chest: the procedures and processes
required for its planning and delivery, focusing on relevant issues, including simulation,
target definition, dose and fractionation, dosimetric planning, tolerance of normal
structures, and tumor- and site-specific treatment techniques, for example, to the
pleural cavity after resection of mesothelioma. Specialty topics in RT including the use
of stereotactic body radiation therapy (SBRT) and proton therapy will be addressed.

ANATOMY
Many of the normal structures in the thorax are very sensitive to irradiation. It is
incumbent on specialists in radiation medicine therefore to understand the normal
anatomy of the chest in order predict the acute and late manifestations of RT on its
organs and tissues. The thorax contains the heart, lungs, and other vital structures
within a skeletal framework that also protects some of the abdominal organs (1). The
mediastinum occupies the central space of the thorax and is defined as the interval
between the two pleural sacs. It is commonly divided into a superior mediastinum,
above the level of the pericardium, and three lower divisions: anterior, middle, and
posterior. The anterior mediastinum lies between the sternum and pericardium and
most importantly contains the thymus. The middle mediastinum contains the
pericardium, heart, and the main bronchi and other structures of the roots of the lungs.
The posterior mediastinum, behind the pericardium, contains the esophagus and
thoracic aorta. The superior mediastinum contains portions of the thymus, great vessels
related to the heart, the trachea, the esophagus, and occasionally aberrant thyroid
tissue. The two lungs and their pleural sacs are situated in the thoracic cavity. The
pleura is a thin serous membrane adherent to various structures. Where it lines the
thoracic wall and diaphragm, it is known as the parietal pleura, and when it is reflected
onto the lung, it is called the visceral pleura. The latter covers the whole surface of the
lung parenchyma and track deeply into its fissures. The bronchi and pulmonary vessels,
which extend from the trachea and heart, respectively, collectively form the root of the
lung. The part of the medial surface where these structures enter the lung is known as
the hilus. The trachea extends from the inferior end of the larynx to its point of
bifurcation at a level between the 5th and 7th vertebrae dividing into right and left

1016
main bronchi. The esophagus extends from the lower end of the pharynx to the cardiac
opening of the stomach. The heart is situated in the middle mediastinum and is enclosed
in a fibroserous sac termed the pericardium.

DIAGNOSTIC WORKUP AND STAGING


A patient presenting with a suspected chest malignancy requires a thorough history and
physical examination as well as selected diagnostic tests in order to confirm
malignancy, identify the histologic tumor type, determine the disease stage, all in order
to direct treatment and management decisions. There are no cancer-specific laboratory
studies to gauge the presence of the majority of thoracic tumors but certain tests
including complete blood count, serum electrolytes, and liver function tests may point
to paraneoplastic syndromes, the presence of metastatic disease, or cancer-associated
phenomena such as malnutrition. Routine radiologic examinations include chest x-rays
and computed tomography (CT). CT studies are valuable at identifying tumor location
and size and at staging disease but have limitations with respect to recognizing
mediastinal nodal disease or metastatic disease. 2-deoxy-2[F-18]fluoro-D-glucose
positron emission tomography [FDG-PET] scanning is now considered standard in the
staging workup of thoracic tumors. It can help distinguish inflammatory from
neoplastic disease, it is more sensitive than CT at recognizing metastatic disease in
regional lymph nodes (LNs), and it is more accurate in determining the clinical stage of
the patient: for example, in lung cancer, up to 25% of patients judged potentially
curable were found on PET to have incurable advanced disease (2,3). Brain imaging is
frequently utilized for staging, especially for certain diagnoses, for example, small cell
lung cancer (SCLC), when there is a large burden of intrathoracic disease or in patients
who present with neurologic symptoms. Magnetic resonance imaging (MRI) is
considered more sensitive than CT at detecting frank and occult metastatic disease.
Pulmonary function tests (such as spirometry and diffusing capacity of the lung for
carbon monoxide [DLCO]) are not staging tools but are used to predict a patient’s
tolerance to different treatment modalities such as surgery or RT.
A range of diagnostic procedures may be employed in characterizing a thoracic tumor
(4). These include sputum cytology, percutaneous fine-needle aspiration (FNA),
bronchoscopy, mediastinosocopy, thoracentesis, endobronchial ultrasound-guided
(EBUS) FNA, thoracoscopy, and rarely, exploratory thoracotomy. The goal in choosing
any of these procedures is to effectively and safely obtain tissues for histologic
characterization, accurately map out extent of disease in the chest (e.g.,
mediastinoscopy or EBUS sampling of mediastinal LNs) and to appropriately complete
the staging.
The extent, or more formally the “stage,” of cancer at the time of diagnosis is the key
factor that defines prognosis and is a critical element in determining appropriate
treatment. The most widely accepted and clinically validated staging system is the
tumor node metastasis (TNM) system maintained collaboratively by the American Joint
Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC)
(5). The TNM system classifies cancers by the size and extent of the primary tumor (T),
the degree of involvement of regional lymph node (N), and the presence or absence of
distant metastases (M), and more recently, supplemented by carefully selected
nonanatomic prognostic factors for certain cancers (e.g., tumor grade, histology).
Detailed lymph node maps have been published in order to facilitate consistent and
appropriate labeling of regional thoracic (LNs). The International Association for the
Study of Lung Cancer (IASLC) lymph node map is now the recommended means of

1017
describing regional lymph node involvement for lung cancers (6). The seventh edition of
the TNM system is currently the accepted standard for staging patients diagnosed on or
after January 1, 2010 (7).

RT PRINCIPLES FOR THORACIC MALIGNANCIES


Introduction
There are general principles for planning thoracic RT that are valid across a range of
malignancies since it is the normal anatomy of the thorax which imposes the most
important constraints on the safe delivery of RT. These common principles when
considering planning chest RT include the approaches to simulation, target delineation,
motion control, definition of normal tissues and organs at risk (OARs), dose constraints,
dose limiting structures, and beam setups.
Specific thoracic RT dose prescriptions are determined by the tumor types being
treated and by the particular indications for treatment, including preoperative,
postoperative, definitive [both conventional and stereotactic], prophylactic, and
palliative therapies. The primary rationale for preoperative (also known as induction or
neoadjuvant) therapy is to facilitate complete surgical resection of disease, and yield a
negative-margin (R0) resection. In addition, preoperative RT may “downsize” a tumor to
alter the form of surgical resection required, for example, change the operation from a
pneumonectomy to lobectomy. It may also alter patterns of locoregional failure by
sterilizing micro-metastatic disease in regional lymph node chains and potentially affect
overall survival. Preoperative RT is typically well tolerated by most patients since their
patient performance and medical status are usually intact.
Postoperative RT is administered to patients showing high-risk features for
locoregional recurrence after surgical resection, that is, positive margins at the resection
line (R1), gross residual disease (R2), or regional lymph node involvement. Given that
patient status is often compromised after surgery, completing a planned course of
postoperative RT is often challenging due to patient intolerance of side effects.
The rationale for definitive RT is to provide optimal intrathoracic control of disease
by ablating visible tumor and eradicating micro-metastatic disease. Because of the
constraints imposed by normal thoracic structures on RT delivery, the potential doses
for optimal gross tumor control by conventional RT are often not achievable in the
chest. This has led to the pursuits of other means of dose optimization for thoracic RT
such as stereotactic delivery, integrating RT with chemotherapy (CHT), use of altered
RT dose schedules (e.g., hyperfractionation), and use of radiation protectants.
The most common indication for thoracic RT is in the palliation of local symptoms
attributable to advanced or metastatic disease. Since the primary goal of palliation is
symptom relief, thoracic RT schedules in this setting tend to be short, and favor large
doses per fraction with modest total doses, since late effects are not a critical
consideration in patients with a limited life expectancy.
Regarding upfront prophylactic therapy, the primary site where this is indicated
when dealing with thoracic malignancies is the brain. Since SCLC has a propensity for
micro-metastatic spread to that organ, prophylactic cranial irradiation (PCI) is routinely
used with that diagnosis. PCI typically involves lower total RT doses and short
treatment schedules.

Technical Factors

1018
Simulation
RT simulation for thoracic malignancies is performed using a CT scan for delineation of
the target volumes and the OARs. In general, patients are setup in the supine position
with their arms above their head. In special scenarios, such as for patients with superior
sulcus or Pancoast tumors, simulation can be performed in the akimbo position. For
mesothelioma patients receiving adjuvant radiation therapy after extrapleural
pneumonectomy (EPP), the incision and drainage sites should be marked with
radiopaque material and bolus should be applied over these sites and the chest wall at
the time of simulation.

Localization
A volumetric CT scan should be acquired with a 3-mm slice thickness from the second or
third cervical vertebrae to the third or fourth lumbar vertebrae to ensure adequate
margin around the lungs for generation of digitally reconstructed radiographs,
dosimetry calculations, and planning using noncoplanar fields (8). The liver should be
included in the simulation CT scan. Oral contrast can assist with delineation of the
esophagus. Intravenous contrast (IV) can be administered to assist with identification of
the major blood vessels, which is especially important for patients with centrally located
tumors and mediastinal LNs (9,10). Alternatively, if a patient underwent a diagnostic
CT scan of the chest with IV contrast, this can be co-registered to a noncontrast
simulation CT scan. For patients with early-stage lung cancer undergoing SBRT, the
isocenter should be placed in the center of the primary tumor volume. For patients
undergoing treatment to a primary tumor and regional LNs, the isocenter should be
placed in the center of the mediastinum near the carina. After placement of the
isocenter and acquisition of a verification scan, external marks are placed on the patient
or immobilization device to ensure accurate setup for treatment delivery.

Immobilization
Numerous immobilization devices are commercially available including a simple thorax
board, alpha cradle, vacuum-lock bag, and thermoplastic mold. Patients should be
positioned in a reproducible manner that is comfortable enough to reduce intrafraction
movement but reproducible enough to minimize interfraction set-up errors. Patients
undergoing SBRT can also be immobilized using a stereotactic frame.

Motion Management
For patients undergoing treatment to thoracic sites, the effect of respiratory motion on
target movement must be accounted for at simulation, treatment planning, and
treatment delivery (11,12). At the time of simulation, the motion of the primary tumor
should be characterized and quantified. For the initial simulation scan, patients should
be instructed to breathe at a normal pace. Motion management strategies are
recommended for patients in whom the target motion exceeds 5 mm in any direction
and include use of a four-dimensional CT (4DCT) scan, physical restriction of motion,
breath-hold techniques, and respiratory gating. A 4DCT scan can generate volumetric
datasets representing the various phases of the respiratory cycle (13). During
acquisition of the 4DCT, imaging data is stored relative to a respiratory phase or
amplitude either by use of an external motion detector, infrared-based respiratory
position monitor device, or a belt wrapped around the patient’s waist (14). The 4DCT
scan can reconstruct either 10 individual phase CT scans or a reduced number of scans
representing specific phases of respiration (e.g., 25%, 50%, 75%, 100%) which can be
viewed in a motion display (15). The 4DCT image dataset can also reconstruct a

1019
maximum intensity projection (MIP) to provide a rapid and reliable estimate of the
maximum motion of the tumor through the respiratory cycle (16). For accurate
dosimetry analysis and dose calculation, an average intensity dataset should be
generated from the 4DCT (17). Physical restriction of tumor motion is most commonly
performed with application of an abdominal belt or hoop (18). Breathhold is performed
with an active breathing control device to monitor the patient’s inspiratory and
expiratory breathing patterns (19). A respiratory gating technique uses external patient
signals (such as the movement of the chest wall) or fiducials to determine the RT
delivery time. During the course of treatment, the patient breathes at a normal pace, but
the treatment machine delivers the radiation treatment only during a specific interval
based on the position of the external signals (14).

Target Definition and Normal Structures

Target Volumes
The International Commission on Radiation Units (ICRU) Report No. 50 outlines the
definitions for treatment volumes in radiation therapy planning (20). For patients with
thoracic malignancies, the gross tumor volume (GTV) includes the primary tumor
volume and the involved regional LNs. Regional LNs are included in the GTV if they are
metabolically active on PET-CT (SUV = 1.5 × mean intensity of 1 cc of the aorta
volume or SUV >3), ≥1 cm in short axis on CT scan, or found to be pathologically
involved on bronchoscopy or mediastinoscopy. Regional hilar or mediastinal LNs should
also be included if there is serial growth documented on diagnostic CT scans, two or
more nodes are visualized in a high-risk nodal station, or if nodes are visualized at the
first echelon drainage or within 1 cm of the primary tumor. The primary tumor volume
should be contoured on the lung window settings (21). For tumors abutting the chest
wall or mediastinum, the edge of the primary tumor can be modified using mediastinal
window settings. Involved hilar and mediastinal LNs should be contoured using the
mediastinal window setting. The primary tumor volume can be disjointed from the
regional LNs and lymph node contours can be noncontiguous.
For patients with thoracic malignancies, internal margins (IMs) and target volumes
have to be considered and are defined in ICRU Report No. 62 (22). The IM accounts for
variations in size, shape, and position of the targets relative to the movements of
respiration and is used to generate an internal target volume (ITV). When using a 4DCT
scan, there are numerous approaches to reconstructing the image data for determining
the ITV. Ezhil et al. evaluated the generation of the ITV using four different methods:
(1) combining the GTV contours from each of the ten respiratory phases, (2) combining
the GTV contours from two extreme respiratory phases (0% and 50%), (3) defining the
GTV contour using the MIP, and (4) defining the GTV contour using the MIP with
modification based on visual verification of contours on individual respiratory phases
(23). Based on this comparison, methods 2 and 3 underestimated the ITV, and the use
of MIP with modification based on visual verification was recommended. There are
alternative methods of generating an ITV without use of 4DCT. For example, the targets
can be contoured on end of tidal volume inhale and exhale scans to create a composite
structure to capture any possible tumor motion (24,25). Alternatively, “slow” CT
techniques (slice thickness 4 mm, index 3 mm, revolution time 4 s/slice) can be used to
better capture potential tumor movement (26). For patients being simulated with an
active breathing control device, at least two confirmatory scans should be acquired to
verify the position of the target during subsequent breathholds and these scans are used
to generate the ITV.

1020
The clinical target volume (CTV) includes the GTV and adds a margin for coverage of
areas at risk for subclinical microscopic disease. For patients undergoing SBRT, the CTV
representation is equivalent to the GTV. For patients undergoing RT for locally
advanced nonsmall cell lung cancer (NSCLC), the CTV is created from a 0.5- to 1-cm
expansion around the GTV or ITV. Data to support these RT expansions arises from a
study by Giraud et al., who examined pathologic specimens from 70 patients with
NSCLC (27). They determined that the mean microscopic extension was 2.69 and 1.48
mm for adenocarcinoma and squamous cell carcinoma cases, respectively. Moreover, to
account for 95% of microscopic disease extension, a margin of 8 mm for
adenocarcinoma and 6 mm for squamous cell carcinoma histologies was required.
Similarly, pathologic studies have also shown that the extent of microscopic nodal
extracapsular extension is 0.7 and ≤3 mm in 95% of nodes (28). For patients with
SCLC, the CTV includes the ipsilateral hilar LNs (lymph node station 10), if not already
included in the GTV.
The planning target volume (PTV) includes the CTV and provides a margin for motion
of the target and setup reproducibility between fraction delivery. With regard to
internal motion, there should be at least a 1-cm expansion in the superior–inferior
dimension and a 0.5-cm expansion in the axial dimension. In the free-breathing (non-
ITV) setting, an additional setup margin of at least 0.5 cm should be added to create the
final PTV.

Organs at Risk
As important as it is to accurately identify and contour the tumor volume, defining the
OARs is equally important in creating an RT treatment plan. OARs should be outlined
on all CT slices in which the structures exist and are in the field of irradiation (29). The
lungs should be individually contoured as right and left lung structures and then
combined into a composite structure for dosimetry evaluation. The lung contours should
represent the inflated lung volume and exclude the proximal bronchial tree, areas of
atelectasis, scarring, pleural fluid, or large vessels. Considerable variability exists
regarding the subtraction of the GTV, CTV, or PTV from the composite lung volume with
no prospective evidence to support one particular method over another. SBRT protocols
have used the proximal bronchial tree to differentiate central lung tumors (within 2 cm)
from peripheral tumors. The proximal bronchial tree is composed of the distal 2 cm of
the trachea, carina, right and left mainstem bronchi, right and left upper lobe bronchi,
right middle lobe bronchus, left lingular bronchus, and the right and left lower lobe
bronchi. These structures should be contoured using mediastinal window settings with
inclusion of the outer wall of the airway.
The heart contour should include the pericardial sac extending from the superior
aspect, defined as either the ascending arch of the aorta or the inferior aspect of
the pulmonary artery passing midline, to the apex of the heart using mediastinal
window settings. The esophagus should be contoured with inclusion of the outer edge of
the muscular wall and adventitia from the inferior edge of the cricoid cartilage to the
gastroesophageal junction on mediastinal window settings. Of note, although oral
contrast can be used for easier identification of the esophagus, this may distort the true
dimensions of the structure. The spinal cord should be outlined on each slice as either
the true spinal cord or the extent of the bony canal from the same cranial level as the
esophagus contour (cricoid cartilage) to the bottom of the second lumbar vertebra. For
patients with superior sulcus tumors, apical tumors, or supraclavicular nodal
metastases, the brachial plexus should be contoured. The brachial plexus is located
posterior to the subclavian vessels between the anterior and middle scalene muscles

1021
from the interspace between the fourth and the fifth cervical vertebra to the interspace
between the first and the second thoracic vertebra. For patients with tumors abutting
the chest wall, the ribs and chest wall can be contoured by applying a 2-cm expansion
in the lateral, anterior, and posterior dimensions from the lung contours within 3 cm of
the PTV. This should include the intercostal muscles but exclude other muscles or the
skin. For patients with lower lobe tumors, consideration should be given to contouring
the liver and kidneys, each individually and then combined into a composite whole
kidney structure. For patients with implanted devices in the thorax, such as pacemakers
and defibrillators, the devices should be contoured separately. Dose–volume histograms
are created to evaluate the radiation exposure to the OARs. In general, the tolerance of
each of the normal organs depends on the dose per fraction received and the total dose
prescribed to the target, but the dose received to normal structures should be
minimized. Examples of suggested constraints for conventionally fractionated RT
treatments for thoracic malignancies are outlined in Table 33.1.
TABLE 33.1 Suggested Normal Tissue Dose Constraints for Conventionally Fractionated
External-Beam Radiotherapy (30)

Integration of PET-CT into Treatment Planning


FDG-PET has not only enhanced the accuracy of staging patients with lung cancer, but
is also useful in delineation of the primary tumor target, distinction between atelectasis
and tumor, evaluation of mediastinum, and detection of distant metastatic disease (31).
PET remains investigational for delineation of tumor volumes in patients who previously
received CHT, RT dose escalation, or other forms of response-adapted therapy.
PET-CT is useful in delineating the primary tumor extent, as the size and dimensions
of the primary tumor measured on PET-CT correlate well with pathologic examination
(32). There are numerous methods of utilizing PET in contouring, including use of the
absolute standardized uptake value (SUV) (typically 2.5) (33), a percentage of the
maximum SUV, a fixed percent intensity level of the maximum activity in the primary
tumor (typically 40% to 55%) (34), or an SUV intensity three-standard deviations above
the background level. The use of PET-CT for delineation of the primary tumor volume
also reduces variability in target contouring between providers (35). Compared to CT
scans, however, FDG-PET tumor volumes can be larger than CT volumes since the slower

1022
acquisition time of the PET scan captures the integral movement of the primary tumor
through respiration (36). Therefore, the PET volume may correlate more closely with the
ITV volume than the CT-derived GTV (37). It is important to note that FDG-PET may
increase the GTV contour in cases where the adjacent tissue appears morphologically
normal but has metabolic activity concerning for disease extension. At the same time,
FDG-PET may be used to reduce the CT-derived tumor volume when the tumor is
directly adjacent to a structure and no clear plane of separation is visualized. This is
useful in cases of atelectasis or for tumors abutting the chest wall (see Fig. 33.1) (38).
PET/CT is especially useful in evaluation of the mediastinum, where it has a higher
sensitivity (84%) and specificity (89%) than CT scans (57% and 82%, respectively) or
endoscopic ultrasound (78% and 71%, respectively) (39). In fact, when integrating
FDG-PET findings into radiation therapy treatment planning, significant changes to
target volume contours have been reported in 21% to 100% of cases, primarily due to
the addition of mediastinal lymph node targets (40). At the same time, given the high
negative predictive value of FDG-PET, nodal regions without significant SUV uptake can
be omitted from RT volumes.
A PET-CT scan is typically obtained during staging. This scan can be used in planning
if it can be co-registered to the simulation CT scan. Differences in patient set-up for
acquisition of each scan and these differences must be accounted for when co-
registering diagnostic to treatment planning studies. Alternatively, PET-CT scans may be
obtained in the treatment position on a firm flat-top couch with the same
immobilization device used for radiation therapy planning to minimize co-registration
errors (41). In either setting, consistent FDG-PET window and color settings should be
utilized.

Figure 33.1 FDG-PET improves staging accuracy for nonsmall cell lung cancer. FDG-PET differentiates
tumor from collapsed lung (A and B), and detects CT undetected node (arrow in C and D). Blue, CT lesion;
red, PET hypermetabolic lesion.

There are certain caveats to be aware of when interpreting FDG-PET images. False-

1023
positive findings can be seen in patients with inflammatory conditions, whereas false-
negative readings may be obtained either when LNs are below the size threshold for
detection (typically <1 cm) or are too close to the primary tumor volume (42).
Moreover, in patients who recently received CHT, the residual malignant cells may
decrease their glucose uptake, resulting in false-negative findings (40).

Elective Nodal Irradiation


Prior to the introduction of the CT scan into RT planning, lung cancer volumes were
based on anatomic landmarks and encompassed the definable lung tumor on CXR, any
clinically involved LNs, and the regional nodes considered at risk. This approach of
covering all the mediastinal LNs, independent of confirmed metastatic involvement, is
now termed elective nodal irradiation (ENI). The treatment of clinically uninvolved
nodal groups by ENI is now controversial. In the current CT-based era, the concern with
ENI is that it overexposes normal structures to treat presumptive at-risk sites of disease.
Furthermore, in generating the large fields required for ENI, the total dose potentially
deliverable to the tumor is limited by the dose to normal tissues. Non–ENI-based
approaches to RT planning have become an active area of interest in lung cancer. The
specifics on ENI will be addressed in each relevant tumor section (NSCLC, SCLC).

Treatment Planning

Dose
A range of dose/fractionation schedules is employed routinely in thoracic RT.
Guidelines have been developed for selection of dose and fractionation in SCLC (43),
definitive management of NSCLC (44–46), postoperative RT, (47), and palliation/poor
performance status (48,49). This section includes general dose and fractionation
information for thoracic RT. Guidelines for specific disease sites and specific techniques
(e.g., SBRT) are located in their respective sections.

Standard Fractionation. Standard fractionation using doses of 1.8 to 2 Gy per fraction


has an established role in preoperative, definitive, and postoperative RT in the chest.
Doses of 45 to 50 Gy in the preoperative setting are standard (50,51). In the definitive
setting, doses of 60 to 70 Gy are standard depending on the clinical setting (52,53). In
the postoperative setting, doses of 50 to 60 Gy in 1.8 to 2 Gy fractions are routine
(47,54,55). Generally the postoperative bed is treated to a dose of 50 Gy with a focal
boost to a dose of 60 Gy to areas of extracapsular extension or resected bulky nodes. For
areas of gross disease total doses of 66 to 70 Gy can be considered if normal tissue
constraints can be met.

Hyperfractionation and Hypofractionation. Hyperfractionation is utilized in


definitive thoracic RT. Hyperfractionation to a total dose of 69.6 Gy in 1.2-Gy fractions
given BID (twice-daily) with an interfraction interval of ≥6 hours has been employed in
NSCLC and may be superior to standard fractionation when concurrent CHT is not used
(56,57). Accelerated hyperfractionation to total dose of 45 to 54 Gy given BID is routine
in SCLC (58,59). In NSCLC, continuous hyperfractionated accelerated RT (CHART) to a
dose of 54 Gy in 36 fractions given at 1.5 Gy TID (thrice-daily) has been shown to be
superior compared to standard once-daily fractionation in the absence of CHT (60–62).
Accelerated hypofractionation may also provide advantages, for example, 40 to 45 Gy
in 15 fractions are associated with comparable responses to standard fractionation

1024
(63,64). Other hypofractionated regimens including split-course regimens are also
feasible and efficacious (65). A meta-analysis of clinical trials has suggested a 2.5%
overall survival benefit at 5 years for the use of altered fractionation (66).

Palliation. The primary role of thoracic RT in metastatic lung cancer is the palliation of
symptoms prior to the initiation of systemic CHT, or in patients who are unable to
receive systemic therapy at all. In the United States, 30 Gy in 10 fractions is commonly
utilized. However, multiple prospective randomized trials of different
dose/fractionation schedules have shown that thoracic symptoms can be treated safely
and effectively with 1- or 2-fraction (e.g., 17 Gy at 8.5 Gy per fraction 1 week apart)
schedules, with no overall benefit to higher RT doses for symptom relief. Selected
patients with good performance status may see modest survival benefits from higher-
dose palliative regimens (30 Gy/10 fraction equivalent or higher) but at the expense of
moderately higher esophageal toxicity (49). Although these randomized clinical trials of
palliative RT for lung cancer have been conducted in patients with NSCLC, the
treatment approaches and results from such studies are readily applicable to the patient
with symptoms related to SCLC (67).

Technical Factors

Beam Energy
Appropriate beam energy is critical in the treatment planning of thoracic RT. A 6 MV
photon beam energy is generally the preferred choice to provide optimal PTV coverage,
particularly near lung tissue density interfaces. With higher-energy beams, high-energy
secondary electrons travel resulting in dose loss in the boundary region (68–70). This
effect may not always be well represented in computerized treatment planning with
heterogeneity calculation (71). In addition, higher-energy beam neutron contamination
is also introduced. Despite these limitations, higher-energy beams no higher than 10 MV
may be occasionally helpful to provide improved dose homogeneity particularly in
AP/PA arrangements where tissue density is more consistent.

Heterogeneity
The chest is unique relative to other body sites as the lungs have significantly less
electron density and thus significantly less attenuation of an RT beam occurs than in
other surrounding tissues. These differences have the effect of changing the dose
distribution substantially if the heterogeneity of tissue densities is not considered.
Traditional thoracic RT was performed without heterogeneity correction but as these
corrections are now available in modern computer treatment planning systems they are
considered routine practice. Several algorithms for heterogeneity correction are
presently available although convolution/superposition algorithms (C/S) are most
common. Corrections with pencil beam algorithms which were historically used have
been shown to have reduced accuracy relative to other options (72). Caution should be
used when switching between homogeneous planning and accounting for heterogeneity
(see Fig. 33.2). Conversion factors have been suggested to adjust RT prescription dose
but these conversions may be different between algorithms within a type and between
types (72,73). Monte Carlo algorithms which are increasingly becoming available in
commercial planning systems may be particularly distinct from prior algorithms (74). It
is notable that when heterogeneity corrections are applied, PTV surface dose decreases
due to increased range of secondary electrons. This effect can be particularly
pronounced with high-energy beams (68,75).

1025
Intensity-Modulated RT
Since its initial development in the 1980s, 3D conformal RT (3D-CRT) has long been a
standard technique for dose delivery in lung cancer. This technique, while powerful,
may not provide optimal sparing of nearby normal tissues. Several dosimetric studies
have suggested that intensity-modulated radiation therapy (IMRT) can result in
statistically significant improvements in dose distributions (76–78). Retrospective data
by Li et al. comparing 3D-CRT to IMRT did show reduction in locoregional failure and
improvement in overall survival with IMRT without improvement in the distant
metastatic rate. Unfortunately, prospective comparisons have not been performed and
are unlikely to be forthcoming to validate the results of this retrospective comparison.
Based on available data, controversy remains regarding the routine use of IMRT,
particularly for lung cancer (79,80). First, some postulate that the mediastinal coverage
to high dose with 3D-CRT may be aiding in controlling microscopic mediastinal spread.
The higher conformality with IMRT could potentially reduce this incidental coverage.
Second, IMRT is associated with a lower V20 and mean lung dose but is also associated
with a higher low dose (V5) and the effect of this low dose cloud on lung toxicity has
not been well elucidated (78,80). Finally, there is a concern of motion interplay effect
where tumor motion and MLC leaf motion could interact to perturb the expected dose
distribution. However, studies have suggested this effect is likely to be small (81,82).
Despite these concerns, sufficient experience exists to suggest that IMRT may be safely
and effectively employed in thoracic malignancies and may be particularly appropriate
when normal tissue constraints cannot be met with 3D-CRT. While a clear role for IMRT
in all patients has not been observed, IMRT may be beneficial to achieve dose escalation
although the optimal strategy for such dose escalation has not been determined (83).

1026
Figure 33.2 Tissue heterogeneity correction in lung cancer planning. A: Impact of heterogeneity correction on
planning target volume (PTV) coverage in a patient with a tumor in the right lower lobe. This figure shows a
remarkable underdosage of PTV in a plan generated by the traditional homogeneous prescription method with
heterogeneity corrections (right panel) and the current heterogeneity-corrected prescription method (left panel) in
the (a) sagittal and (b) coronal planes. Isodose lines are color-coded as follows: red, 76.Gy; orange, 66 Gy
(prescribed dose); yellow, 60 Gy; green, 20 Gy. B: Impact of calculation algorithm on isodose distribution a lung
treatment plan (two fields, 15-MV photons show isodose lines calculated with Monte Carlo (MC, solid line) and
an equivalent path-length–based algorithm (EPL, dashed line). Figure 33.2B (left panel) shows that MC and
EPL have almost same isodose distribution when heterogeneity correction is not turned on (i.e., the lung tissue is
treated homogeneously), while Figure 33.2B (right panel) depicts remarkable overestimation of 95% isodose

1027
surface of the EPL-based dose computation comparing to that of MC calculation. (Courtesy of Indrin Chetty,
Henry Ford Hospital, Detroit, Michigan.)

SPECIAL TOPICS IN RT DELIVERY


Stereotactic Body Radiation Therapy
SBRT is a radiation technique that allows for the precise delivery of large fractions of
radiation by multiple beams guided by a set of coordinates relating to the direct position
of the tumor rather than external marks or anatomical structures. Given the high
hypofractionated radiation doses and small treatment margins involved SBRT requires
both careful definition of target and nontarget structures, as well as precise
management of target motion and treatment set-up (84).

Indications
While medically inoperable stage I NSCLC remains the primary indication, SBRT is also
utilized in the treatment of lung oligometastases (85), thoracic re-irradiation (86–93),
poor-risk stage I SCLC (94,95), and is under investigation for operable stage I NSCLC
(96,97) as well as potentially as a boost to conventionally fractionated radiation in
locally advanced NSCLC (98,99).

Treatment Planning
SBRT requires careful immobilization of the patient followed by management of target
motion so that it is limited to <5 to 10 mm. This may be accomplished by abdominal
compression, respiratory gating using either controlled breathhold or external
surrogates, or tumor tracking/respiratory modeling. Tumor motion should be assessed
by either fluoroscopy or 4DCT imaging at simulation, and verified by cone-beam CT
(CBCT) or other imaging during treatment.
In lung SBRT, a PTV can be created from a fixed expansion (1 cm superior–inferior, 5
mm axially) off the contoured GTV (100). Alternatively it may be derived from the
union of multi-phasic CT GTVs (free-breathing, inhale, exhale) or 4DCT images into an
ITV, which is then expanded uniformly by 5 mm yielding the PTV (84). Expansion of
the 4DCT ITV typically results in a smaller PTV, and likely more consistently represents
the actual tumor motion as well as center of mass (101).
Beam arrangements may consist of six or more noncoplanar open beams, IMRT
beams, noncoplanar volumetric arcs (typically at least 3 arcs each offset by 30 to
40 degrees), intensity-modulated arc therapy, or alternatively particle-based therapy.
The use of IMRT in the treatment of small moving lung targets is controversial due to
concerns of potential underdosing, though IMRT is allowed by recent protocols such as
Radiation Therapy Oncology Group (RTOG) 0813 and reported outcomes with IMRT
have been on par with other techniques (102). Planning should utilize collapsed cone
convolution or Monte Carlo algorithms, as there is a suggestion that pencil beam
algorithms may compromise tumor control due to potential for more variable
underdosing (103). Planning should focus on maximizing conformality and rapid dose
fall-off. Heterogeneity is acceptable and may be desirable for purposes of faster fall-off
provided critical serial structures are not overexposed. Per its protocol design, RTOG
0236 utilized homogeneous treatment planning prescribing 60 Gy in 3 fractions (see
Fig. 33.3). This has been estimated to correlate with a heterogeneity corrected
prescription of 54 Gy in 3 fractions (74), however, care should be taken in interpreting
this as the correction is based on estimates of attaining 95% coverage of the PTV

1028
periphery whereas other parameters such as mean dose to the GTV, ITV, and PTV may
vary considerably, furthermore this correction is also sensitive to tumor size and
location (104).

Dose
SBRT prescriptions can range from 30 to 60 Gy in 1 to 8 fractions. Early series
established a correlation with delivery of biologically equivalent dose (BED) of at least
100 to 105 Gy10 to improved LC (105,106), and reported excellent safety and tumor
control regardless of tumor location. In the United States, clinical practice favors the
results of the Indiana University phase I dose-escalation studies which ultimately
formed the basis for RTOG 0236 (107). In the phase II setting, these researchers found
this dose was associated with a grade 3 or higher toxicity rate exceeding 50% in
patients whose tumor fell within 2 cm of the proximal bronchial tree, which they termed
“central” tumors (108). While this has caused concern regarding the safety of treating
“central” tumors it is noted that Japanese series utilizing a lower dose per fraction (10
to 12 Gy) did not report variability of toxicity by location (105,109,110). Subsequent
publications from the Netherlands validated 60 Gy in 8 fractions even for very large
central tumors (111), and several United States retrospective series similarly
demonstrated the safety of SBRT for central lung lesions with fraction sizes of up to 10
Gy/fraction (112,113). Recently RTOG 0813, a dose-escalation for SBRT of central lung
tumors escalating dose from 50 up to 60 Gy in 5 fractions was completed reaching the
highest dose level without interruption (84).
Normal tissue constraints are still evolving with increased SBRT experience. Early
experiences used few normal tissue constraints focusing purely on conformality. More
recently constraints have emerged from early experience (113,114), though still need to
be validated in larger settings. Normal tissue constraints should be based on appropriate
protocols for the target being treated such as RTOG 0236, 0813, 0915, or large
institutional experiences (see Table 33.2).

1029
Figure 33.3 Representative dose distribution for a lung SBRT plan. The patient is a 75-year-old male with
medically inoperable adenocarcinoma of the right upper lobe, T1aN0M0, stage IA, treated with 60 Gy in 3
fractions (per RTOG 0236) delivered by dynamic arcs. Motion management was by abdominal compression.
Image guidance was by an infrared-based x-ray positioning system. Overall treatment time was 8 days. PTV =
GTV + 1 cm superior/inferior and 0.5-cm radial expansion. Green color fill is the GTV, yellow color filled-ring
represents a 2-cm planning structure to limit dose spillage, light blue line is 30 Gy, yellow line is 60 Gy.

Treatment Delivery
Image guidance during treatment initially consisted of bony registration followed by
port films, though modern approaches typically rely on CBCT. Free-breathing CT may
not represent the true tumor center of mass due to respiratory motion, and a pitfall can
be created by matching free-breathing CT to CBCT tumor at time of treatment,
potentially introducing systematic error that occasionally exceeds the PTV expansion
(101). One should either use the average CT as the reference for matching, or otherwise
localize only to bony anatomy if using a free-breathing image while verifying that the
CBCT tumor falls within the ITV.

Outcomes

1030
Local control (LC) of the index lesion after lung SBRT is typically defined as the absence
of tumor progression within 1 cm of the primary tumor site (100), and has historically
ranged from 90% to 98% (97,100,105,109,110,117–119), consistent with prospective
surgical series showing a locoregional failure rate of 5% to 7% for lobectomy, and 8%
to 17% for sub-lobar resection (120,121). A pooled meta-analysis of 40 SBRT studies
totaling 4,850 patients and 23 surgical studies (lobar or sub-lobar resection, 7,071
patients in total) likewise suggests no significant differences in LC (119). SBRT is well
tolerated even in the medically inoperable population. Pulmonary function is well
conserved with generally <3% risk of radiation pneumonitis, and even patients with
extremely compromised pulmonary function exhibiting OS outcomes at or above the
mean (122–124), suggesting there is no lower limit to pulmonary function for SBRT
provided patients are medically stable. Neuropathic pain and rib fractures may occur
with 10% to 15% of treatments of targets abutting the chest wall, though symptoms are
generally modest and potentially less common than in surgical series (125,126). Skin
ulcers (127), brachial plexopathy (128), and bronchial (129) or esophageal fistulas
(130) have been reported, though they are extremely uncommon and risk is modifiable
during the planning process when identified.
TABLE 33.2 Suggested Normal Tissue Dose Constraints for Lung SBRT Based on a Range of
Dose/Fractionation Schedules (115,116)

Endobronchial Brachytherapy
Endobronchial brachytherapy is a useful method of achieving palliation in a patient
with recurrent centrally located obstructing tumor and who has had previous definitive
RT. In most reports rates of relief from hemoptysis and obstructive symptoms are high,
while cough is less frequently improved (48,131–133). A range of dose regimens have

1031
been used, with most using weekly dosing such as 7 Gy × 3. Potential complications
include pneumothorax from the endobronchial catheter, as well as 5% to 10% risk of
high-grade hemoptysis due to the combination of cumulative treatment dose and
recurrence of resistant central disease. Mesh-based brachytherapy sewn to the surgical
staple line has also been investigated in conjunction with sub-lobar resection of early-
stage NSCLC, but was associated with increased risk of complications without improving
recurrence rates (121).

Protons
There is currently a growing interest in the applications of particle therapies, and in
particular protons, to the management of thoracic tumors due to contemporary
advances in the manufacturing, price profile, and availability of dedicated clinically
oriented proton-generating accelerators. What has made proton-based therapy
theoretically attractive for treatment of tumors as compared to x-ray based therapies is
that, in contrast to photons and electrons that deposit most of their energy near the
patient surface and deliver lower doses of RT at the depth of the primary lung tumor or
sites of nodal metastases, the physical properties of proton therapy allow energy to be
deposited at a specific depth that is known as the Bragg peak. After this depth, protons
are able to achieve a rapid energy fall-off, allowing normal tissues beyond the tumor
depth to receive little or no irradiation dose. Therefore, normal tissues on the distal side
of the target volume can be more or less spared, compared with photon beams where
there will always be an exit dose through the patient. With the current increased
availability of proton centers, some clinicians suggest that for chest tumors (e.g., lung
cancer), proton therapy may have a particularly strong rationale. In this setting, the
prime driver for considering protons is the purported advantages it would provide in
normal tissue sparing as opposed to an intrinsic improvement in cancer control. Given
its range of highly sensitive structures, the thorax would seem an appropriate setting
for testing protons’ clinical impact. By manipulating the physical properties of the
Bragg peak, proton therapy could preferentially reduce dose to normal critical
structures such as the lungs, esophagus, heart, brachial plexus, and spinal cord, all of
which may ultimately be able to lead to a reduction in acute and late toxicities from the
treatment and influence morbidity and mortality. If there is the potential for decreased
toxicities, some clinicians also suggest that proton therapy may also facilitate RT dose
escalation with the goal of improved local tumor control, which potentially could
influence overall survival (134,135). There are specific RT-related challenges in the use
of proton beams in the chest. Protons are significantly more sensitive compared to
photon beams to a variety of uncertainties such as respiratory motion, changes in
patient positioning, and tumor shrinkage. This creates more technical challenges in
planning and delivery of RT. This added complexity could introduce more challenges in
delivering RT (e.g., interruptions due to re-planning; set-up errors) and makes its use
limited to large treatment centers (136). At present, the use of protons for thoracic
cancers remains investigational. For example, an ongoing clinical research trial [RTOG
1308] is a randomized phase III trial of proton versus photon chemoradiotherapy in
locally advanced lung NSCLC with a primary endpoint of overall survival (135).

LUNG CANCER
Introduction
In 2014, an estimated 221,200 new cases of lung cancer were diagnosed in the United

1032
States, with an estimate of 159,260 lung cancer-related deaths (137). NSCLC represents
about 75% to 85% of lung cancer diagnosis (137), while SCLC make up approximately
10% to 15% (138). Although the use of the TNM staging system is standard for NSCLC,
SCLC has traditionally been classified as either limited (LSCLC) or extensive stage
(ESCLC), with disease confined to a hemithorax considered limited and all other
presentations considered extensive. The AJCC now recommends that TNM staging be
normative for SCLC (5). The primary risk factor for lung cancer is a history of smoking.
Risk may increase by contributions from exposure asbestos and other industrial
irritants. Successful promotion of smoking cessation is largely credited with recent
decreases in the incidence and mortality rates of lung cancer, particularly in men (139).

NSCLC
Stage I
Stage I NSCLC comprises only 10% to 15% of all lung cancer diagnoses. The standard
of care for stage I disease is surgical lobectomy, which results in excellent LC (95%) and
overall survival, ranging from 60% to 80% (120). Given the risk factors associated with
NSCLC, however, many patients cannot tolerate surgical resection. These patients
historically fare poorly with observation (140), and were treated with either 3D-CRT to
doses ranging from 60 to 74 Gy in conventional fractionation, though as high as 100
Gy has been investigated (141–143). Recent advances in technology such as SBRT are
now achieving LC rates in the medically inoperable population approaching those of
surgical resection (100,105,119), along with excellent LC and overall survival in limited
use in the operable population (96,97). The reader is referred to the section on SBRT for
further details. More hypofractionated courses in conventional RT such as 60 Gy in 15
fractions have been recently described as both safe and effective (144).

Stage II
Stage II NSCLC is even less common than stage I (137), and almost universally treated
surgically as the need for nodal coverage typically prevents radiation doses from
reaching levels which would attain equivalent LC (51,142,145). Patients unable to
tolerate surgical resection can be treated with concurrent or sequential
chemoradiotherapy, or RT alone if unable to tolerate the additional of CHT. Similar
dose and targeting strategies as those discussed below for stage III disease apply here as
well.

Stage III

Preoperative RT
Stage III is the most challenging NSCLC presentation due to its tumor and nodal
heterogeneity. A decision point in the management of many stage III patients is the role,
if any, of surgery in combination with CHT and RT (known collectively as trimodality
therapy when all three are employed together). Much like stage II disease, the LC
achieved with definitive chemoradiotherapy does not reach the levels attained by the
addition of surgical resection due to limitations of normal tissue toxicity on radiation
dose for fields, including significant portions of the mediastinum (142,145). However,
the predominant cause of mortality in lung cancer is distant metastatic failure, hence
bringing into question the role of any local therapy. Two randomized trials in this

1033
patient population have compared definitive chemoradiotherapy to induction
chemoradiotherapy followed by surgical resection. The Intergroup 0139 study
randomized 396 patients with technically resectable surgically staged IIIA (N2) NSCLC
to either (1) definitive RT to 61 Gy concurrent with 2 cycles of CHT or (2) the same
CHT concurrent with RT to 45 Gy followed by resection. There was no benefit to overall
survival afforded by the surgery despite progression free survival being improved (146).
A second randomized study, EORTC 08941, showed no difference in either of these
survival endpoints for trimodality therapy compared to chemoradiotherapy (147).
For those who receive trimodality therapy the most common induction regimen is 45
Gy in 25 fractions with concurrent CHT (148). Recent phase II trials are exploring the
safety, efficacy and outcomes for dose escalated RT (60 Gy/30 fractions) in this setting
(149,150).

Definitive RT
The standard of care for nonoperative treatment of stage III NSCLC is concurrent CHT
and RT given as 60 Gy in 30 fractions (see Figure 33.4) based on the most current
phase III randomized study showing no advantage, and potentially some detriment, to
dose escalation beyond 60 Gy in 30 fractions (83). RTOG 0617 randomly assigned 544
patients to receive either 60 Gy in 30 fractions or 74 Gy in 37 fractions, with or without
the addition of cetuximab to standard CHT. There was an unexpected overall survival
detriment to high-dose radiation, and notably also a decrease in LC. The addition of
cetuximab likewise increased toxicity without benefit to overall survival. Finally, altered
fractionation does not appear to have significant benefit in the setting of concurrent
CHT (151). For patients who cannot tolerate concurrent CHT with RT, sequential
therapy is recommended. When delivering sequential therapy or RT alone there may be
a benefit to dose escalation (152–154).
In the definitive setting, ENI is not recommended (44,155,156). While local failure
inside the high-dose volume is a significant contributor to treatment failure, recurrence
in omitted potential elective nodal regions has been low in both retrospective and
prospective series (145,155,157).

Figure 33.4 Representative coronal CT image from the treatment plan of a 77-year-old male with

1034
adenocarcinoma of the right upper lobe of the lung with biopsy-proven involvement of only lymph node station
[4R], T2bN2M0, stage IIIA. The final target (thick red line) represents a non-ENI approach with 4DCT
simulation and PET-fusion at the time of planning. Total dose delivered was 60 Gy in 30 fractions with 10-
MV photons via a three-field approach prescribed to the 99% isodose line with daily CBCT for image guidance.

Early randomized trials examined the role of PCI in both NSCLC and SCLC and did
find that rates of brain metastasis were reduced in both diseases, however unlike in
SCLC where PCI improved survival (158), a modern randomized study in NSCLC
showed no benefit despite some reduction in the frequency of future brain metastasis
(159).

Postoperative RT
While four randomized trials have confirmed a survival advantage for the addition of
adjuvant CHT for resected stages II to III NSCLC (160–164), adjuvant radiation has a
more limited range of indications. In N2+ disease the Lung Cancer Study Group
(included in postoperative radiation [PORT] meta-analysis) demonstrated improved LC
for PORT without a survival detriment (165,166). A sub-set analysis of a randomized
adjuvant CHT study (167, and reviews of the surveillance, epidemiology, and end
results (SEER), and National Cancer Database also suggest the potential for a survival
advantage when modern techniques and smaller fields are utilized in the setting of
resected stage III NSCLC (168,169).
PORT is typically delivered sequentially after completion of CHT, however in the
setting of positive margins concurrent delivery is an alternative (55). The target volume
for PORT is the bronchial stump and hilum, as well as known clinically and
pathologically involved mediastinal nodal stations. Intervening nodal stations may be
covered as well. Recommended dose is 50 Gy in 25 fractions for patients with negative
margins. Dose should be increased to 54 to 60 Gy in 27 to 30 fractions for close or
positive margins.

Stage IV
The primary role of radiation in metastatic NSCLC is the palliation of symptoms prior to
the initiation of systemic CHT, or in patients who are unable to receive systemic therapy
at all. The reader is referred to the section on palliative dose schedules in the section
“Treatment Planning” above.

SCLC
Limited Disease

Thoracic RT

Dose/Fractionation. The current standard of care in the United States for the dose and
fractionation of thoracic RT in LSCLC is 45 Gy given as twice-daily (BID) fractions of
1.5 Gy for a total of 30 fractions over 3 weeks based on the result of the most current
randomized phase III study (Intergroup 0096) (58). Two current randomized studies
are addressing the question of dose-escalated thoracic RT and its impact on overall
survival. CONVERT (Concurrent ONce-daily VErsus twice-daily RT) is a European phase
III trial in which patients were randomized to either 45 Gy/1.5 Gy BID in 30 fractions
or to 66 Gy in 33 once-daily fractions, both starting with the second cycle of CHT. The

1035
trial completed accrual in 2013 and results are pending. In North America, CALGB
30610/RTOG 0538 is an ongoing phase III trial in which patients were to be
randomized to one of two experimental arms: either 70 Gy/2 Gy once-daily over 7
weeks or 61.2 Gy/1.8 Gy once-daily over 16 days followed by 1.8 Gy twice-daily for 9
days; versus the standard comparator arm of 45 Gy/1.5 Gy BID. In 2013 after planned
interim analysis, and without differences between the arms, the 61.2 Gy arm was
dropped from the study in order to facilitate accrual but not because of any statistically
significant differences in events between the arms.

Timing/Sequencing/Duration. In fit patients, thoracic RT should be administered with


the start of CHT, rather than after greater than 2 cycles of CHT, since its early initiation
is associated with improved survival as shown in a range of randomized trials and three
major meta-analyses (170–172). Within the concept of “time-to-treatment” start, overall
treatment duration may in fact be the most important factor associated with LC and
overall survival in LSCLC (170). De Ruysscher et al. have promoted the concept of SER,
an acronym for the “Start of any treatment until the End of RT,” in the treatment of
LSCLC. Their analysis suggests the SER is the most important predictor with respect to
outcomes. The biologic rationale for this observation is that shortening the overall time
of RT delivery (i.e., acceleration) reduces the potential for triggering accelerated
repopulation in SCLC stem cells which could lead to resistant cells.

Treatment Volume. In 1987, a randomized clinical trial addressing the specific


question of treatment volume in SCLC was published by the Southwest Oncology Group
(SWOG) (173). Patients were randomized to a pre-CHT versus a post-CHT target
designed at the time of RT planning and the study showed that the RT target can be
restricted to the residual visible tumor (post-CHT target) without increasing the risk of
local failure.
With respect to current controversies of non-ENI target design, there has been a
prospective study from van Loon et al. (174), which showed that omission of ENI by
PET-based selective nodal irradiation in LSCLC resulted in a 3% rate of out-of-target
nodal failures. A recent report from the International Atomic Energy Agency (IAEA) on
ENI in SCLC still suggests caution in restricting target coverage in the absence of high
level evidence (175).

Extensive Disease

Thoracic RT
In incurable ESCLC, the role of thoracic RT is conventionally for relief and palliation of
local symptoms. In 1999, a novel role for thoracic RT in advanced stage SCLC patients
was published by Jeremic et al. (59). In this phase III study, ESCLC patients who had
received induction CHT and had shown response were randomized to either accelerated
hyperfractionated thoracic RT (50.4 Gy/36 BID fractions over 18 days) and concurrent
low-dose daily CHT or to CHT alone. The 5-year survival rate for those receiving the
thoracic RT compared to those not receiving it was 9.1% versus 3.7%, respectively, and
was statistically significant. These results did not prompt widespread introduction of
thoracic RT in the case of ESCLC patients. Recently Slotman et al. (176) reported the
results a phase III trial looking at the survival of ESCLC patients receiving thoracic RT
along with PCI compared to PCI only for those who respond after the completion of 4 to
6 cycles of CHT. Thoracic RT consisted of 30 Gy in 10 fractions. Overall survival at 1
year was not significantly different between groups: 33% for the thoracic RT group

1036
versus 28% for the control group. In North America RTOG 0937 is an ongoing
randomized phase II study comparing PCI alone to PCI and consolidative RT to the
chest and to limited numbers of partially responding distant metastases (177). The
trial’s primary end-point is to determine 1-year overall and median survival rates in
each arm.

PCI in LSCLC and ESCLC

Indications
PCI is considered standard of care for LSCLC patients. In 1999, Auperin et al. published
a meta-analysis of completed randomized trials of PCI in SCLC (158) and reported that
it yields a 25.3% decreased incidence of brain metastases at 3 years with absolute
improvements in overall and disease-free survivals in the PCI group by 5.4% and 8.8%,
respectively, compared to patients not receiving PCI. In 2007, the EORTC reported the
results of a phase III trial in which ESCLC patients were randomized to PCI or
observation after CHT (178). At 1 year, the PCI patients were found to have a
significantly lower rate of symptomatic brain metastases but, more strikingly, improved
1-year (27% vs. 13%) survivals compared to the patients in the no-PCI arm. This
finding has led to the recommendation that PCI be offered to any ESCLC patient who
shows a response to CHT.

Dose and Toxicity in PCI


The total doses used in PCI are modest. A dose of 25 Gy in 10 fractions delivered by
opposed lateral fields remains the standard of care in LSCLC based on phase III data
showing no benefits to dose escalation (179). Doses in ESCLC are more variable. PCI-
related neurocognitive toxicities appear self-limited and dose-dependent (180). That
said, in efforts to maximally reduce any neurocognitive toxicities in LSCLC patients
there are currently proposals for trials to reduce toxicity in PCI. The approach in these
trials has been extrapolated from similar studies but looking at the effect of whole brain
RT in patients with frank brain metastases For example, RTOG 0933 was a
nonrandomized phase II trial using IMRT to deliver hippocampal-avoidance whole brain
RT (HA-WBRT) (181). The hippocampus is felt to be critical in maintaining short-term
memory. The RTOG has proposed a trial that involves randomizing SCLC patients to
standard PCI versus PCI with hippocampal-avoidance.

MESOTHELIOMA
Introduction
Malignant pleural mesothelioma (MPM) is an uncommon tumor strongly associated with
asbestos exposure. MPM is staged according to the AJCC staging system (182).
Medically fit potentially resectable patients are treated surgically with extra-pleural
pneumonectomy (EPP) or with pleurectomy and decortication (P/D). Controversy exists
regarding the optimal surgical approach but combined modality treatment can have
good outcomes in favorable patients (183–186). Studies suggest that any surgical
resection is preferable to RT alone from an LC standpoint (187). Patients who are
unresectable are treated palliatively with CHT and RT as needed (188).

Indications

1037
There have been two conventional indications for RT for MPM: (1) as adjuvant therapy
following definitive surgical resection with EPP, or (2) for palliation of symptoms. Also,
IMRT-based consolidation treatment after P/D is increasingly used, and definitive RT
can also be employed in very selected clinical scenarios (187,189–191). RT prophylaxis
to drain or biopsy sites is a controversial indication due to conflicting results from a
small number of randomized trials, with the most current suggesting rates of surgical
track recurrences are not improved by its addition (192,193).

Simulation
For mesothelioma it is crucial to encompass the entire extent of the pleural surface
within the CT simulation scan. Particular attention to the lower border of the scan is
critical as the diaphragm can extend as low as the third lumbar vertebra (L3) and this
recess is a common site of failure (194). All scars and drain sites should be identified
with radiopaque wire. Clinicians should consider application of bolus to drain sites or
areas of chest wall invasion. After P/D, the standard principles of thoracic RT should be
followed.

Target Volume
After EPP, the CTV for adjuvant RT is defined as the entire resected pleural surfaces
(chest wall, pericardium, diaphragmatic crural insertions, any reconstructed
diaphragm, ipsilateral hilum, and mediastinal boundary). Surgical clips can aid in the
delineation of the medial aspect of the diaphragm, inferior diaphragmatic insertion, and
sterno-pericardial recess in particular. IMRT studies have suggested this sterno-
pericardial recess is a particular site of recurrence (187). A boost to the ipsilateral
mediastinum can be applied in the setting of resected N2 disease. Sites of positive
margins need to be defined as feasible for a boost volume. CTV to PTV expansion with
rigid immobilization is typically 5 mm to 10 mm. An example of the resulting PTV is
showing in Figure 33.5. After P/D, the CTV includes the rind of residual pleura (if
present) and the chest wall of the entire hemithorax including the insertion of the
diaphragm. This CTV is typically expanded by 8 mm to form the PTV for planning
(190).

Dose/Fractionation
In the adjuvant setting, 54 Gy at 2 Gy per fraction is standard following R0 resection
(see Figure 33.5). In cases of positive margin or pathologically involved mediastinal
nodes, a boost to a total dose of 60 Gy in 2-Gy fractions is recommended (194,195).
Following P/D or as definitive RT, doses of 45 to 50.4 Gy have been employed with
acceptable toxicity and control (190). For palliative treatment, minimal doses of 40 Gy
and at least 4 Gy per fraction appear to be associated with improved symptom control,
compared to conventional palliative schedules, such as 30 Gy in 10 fractions
(196–198).

Treatment Planning
Adjuvant RT following EPP was historically performed with AP/PA fields and electrons
to supplement dose in key areas (194). IMRT is now recommended in this setting as it
allows for better sparing of normal tissues and outcomes do not appear to be inferior to
conventional field arrangements (199). Rates of severe pulmonary toxicity with IMRT,

1038
however, may be higher than expected due to the delivery approach selected
(195,200,201). To minimize the risk of pulmonary toxicity, dosimetrists need to avoid
beam entry through the remaining lung and to restrict the mean lung dose of that lung
to 10 Gy or less, with ≤8.5 Gy preferred. Following P/D, only an IMRT approach is
indicated, with emphasis on mean lung and spinal cord tolerances in planning
(187,190,191).

THYMOMA
Indications
Thymomas represent the most common tumor in the anterior mediastinum (202,203).
Most patients present with localized disease and surgical resection provide histologic
conformation of the diagnosis and is often curative as a single modality. In addition to
the completeness of surgical resection, the Masaoka stage and specific histologic
classification of the tumor are important prognostic factors (204–206). Adjuvant
therapy is the most common RT indication and is recommended for patients who
present with stages III to IVa. Definitive RT is offered to the occasional patient who is
medically inoperable or who has tumors which are surgically unresectable. Patients with
Masaoka stage I thymomas (macroscopically and microscopically encapsulated) should
undergo surgical resection alone. Local recurrences are rare (<5%) and patients may be
salvaged with repeat excision (207). There is no role for postoperative RT for these
patients. Likewise, for Masaoka stage II disease (microscopic transcapsular invasion or
macroscopic invasion into surrounding fatty tissue with or without adherence to the
mediastinal pleura or pericardium), contemporary studies have failed to demonstrate an
LC benefit to adjuvant RT. Adjuvant RT is recommended for patients with stage III
thymomas (macroscopic invasion into nearby organs such as the pericardium, great
vessels, or lung) since only 50% of patients undergo complete surgical resection and the
local recurrence remains considerable even in this setting (208–211). Thymic
carcinomas are considerably rarer than thymomas, and patients often present with
locally advanced disease (207). Patients often undergo multimodality treatment
including upfront surgical resection with adjuvant CHT and RT (212,213). Adjuvant RT
may provide a locoregional control and possible survival benefit in patients with
resected thymic carcinomas, although data from different retrospective reviews are
conflicting (207,214).

1039
Figure 33.5 A: Representative axial, coronal, and sagittal images from the treatment plan and (B) the DVH for a
40-year-old male with right thoracic epithelioid mesothelioma treated with 3 cycles induction chemotherapy,
then a right extrapleural pneumonectomy followed by adjuvant right pleural space IMRT-based radiotherapy
(54 Gy in 27 fractions). The mean lung dose is 7.99 Gy.

Postoperative RT
A dose of 45 to 50 Gy is recommended for adjuvant RT in the setting of a negative or
close-margin resection. For patients with a microscopically involved resection margin, a
dose of 54 to 60 Gy is recommended (see Figure 33.6). A dose of 60 to 70 Gy is
recommended for patients with gross residual disease. Patients undergoing adjuvant RT
for a resected thymic carcinoma typically receive 60 Gy after complete surgical

1040
resection. The postoperative CTV should be referenced off of the available presurgical
imaging and incorporate relevant operative findings. In other words, the CTV should
include the visible surgical clips in the tumor bed, reflect the tumor bed as derived from
the preoperative extent of disease, and include other areas at risk for subclinical
microscopic disease. In patients with a positive resection margin, the radiation
oncologist should discuss the findings with the surgeon and pathologist to ensure
adequate coverage of the at-risk regions. Typically, a 0.5 cm to 1-cm margin is added to
the CTV (or ITV) to generate the PTV.

Preoperative RT
Typically, a dose of 45 to 50 Gy is recommended in the preoperative setting, delivered
in conventional fraction sizes of 1.8 to 2.0 Gy/fraction. ENI is not warranted in patients
with thymomas (215). The GTV consists of the visible tumor volume, generated from all
available studies including CT scans and FDG-PET scans. A CTV can be generated with a
0.5- to 1-cm margin to account for extension of microscopic disease. If a 4DCT scan is
acquired at the time of simulation, an ITV can be generated (see general principles
section). Typically, a 0.5- to 1-cm margin is added to the CTV (or ITV) to generate the
PTV.

Figure 33.6 Representative axial CT image from the treatment plan of a 63-year-old female with resected
Masaoka stage III thymoma with lung invasion, WHO type B2 with focal B3, who received adjuvant RT to a
dose of 60 Gy in 30 fractions delivered with 10 MV photons via a five-field 3D coplanar field setup. The CTV
is represented by the shaded red volume and representative isodose lines and their corresponding doses are
provided.

Treatment Planning
Patients should be treated with 3D-CRT or IMRT planning techniques to maximize the
conformality of the treatment volume and minimize the dose to the surrounding
thoracic structures (210). A radiation beam arrangement should be chosen based on
patient anatomy, extent of the RT target volume, and proximity to OARs. Classic field

1041
set-ups include: anterior/posterior fields with anterior weighting or a wedged-pair field.

KEY POINTS
• The treatment of thoracic malignancies with RT is very challenging because of the limitations
in safe delivery of dose imposed by the range of highly sensitive normal structures in the
thorax.
• Lung cancer is the most common thoracic malignancy and also kills more cancer patients than
any other because the majority of patients are essentially incurable at presentation.
Improvements in RT dose and delivery are currently very limited in terms of modifying the
natural history of this cancer and palliative therapy is the most common RT indication.
• Technologic and planning improvements in RT delivery, such as IMRT, motion
management, 4DCT, and the use of DVHs, have enhanced our understanding of the benefits
and side effect potential of treatment to the chest.
• SBRT has created a new paradigm of RT care by offering medically inoperable lung cancer
patients with early-stage disease the possibility of safe and effective cure.
• Ongoing refinements in RT delivery, such as particle therapies, are geared toward
minimizing toxicity in potentially curable patients.

QUESTIONS
1. When discussing the concept of heterogeneity in the planning and delivery and
radiotherapy for lung cancer, one is referring to:
A. The number of different organs in the thorax
B. The range of beams >10 MV that must be used in planning
C. The variable PTV margin used for different cancers.
D. The idea that the electron density of the lung needs to be taken into account
to correctly predict dose delivered.
2. Lung SBRT is used in medically inoperable early-stage lung cancer patients.
When considering the requirements for SBRT delivery, the physician must:
A. Employ a means of managing the tumor motion
B. Deliver the therapy over a minimum of 3 weeks
C. Ensure that no tumors near the tracheobronchial tree are treated with this
approach
D. Always use protons for normal tissue sparing
3. The following terms and concepts are all associated with a 4DCT simulation of a
thoracic malignancy, except:
A. Time
B. Tumor size
C. Internal target volume

1042
D. Breathing cycle
4. Radiotherapy dose escalation in the treatment of stage III non-small lung cancer
has been studied in randomized studies and has been shown to:
A. Be only effective in small cell lung cancer
B. Be only effective with the drug cetuximab
C. Ineffective because doses greater than 60 Gy have poorer overall survival
D. Ineffective because doses greater than 60 Gy have increased esophageal
toxicity
5. Elective nodal irradiation (ENI) is no longer recommended in the management of
lung cancers. The reason is:
A. It limits the amount of radiotherapy that can be delivered to the ITV
B. It was carried out before heterogeneity corrections were used in dose
calculations
C. PET-based planning suggests low failure rates in lymph nodes not included in
the target
D. DVHs measure lung toxicity better for 3D than 2D plans

ANSWERS
1. D
2. A
3. B 4DCT relates to time and image collection and has nothing to do with the
tumor size. 4DCT allows characterization of motion, hence it has a
relationship in helping to define the ITV.
4. C RTOG 0617, which randomized patients to 60 Gy versus 74 Gy showed a
decrement in survival in the dose-escalated (high dose, 74 Gy) arm.
5. C PET permits better determination of at-risk/involved lymph nodes when
designing the GTV and phase II data suggest no elevated failure rates in
nontargeted nodes with PET-based planning.

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1997;113:55–63.

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34 Soft Tissue and Bone Sarcomas

Yen-Lin Chen and Thomas F. DeLaney

INTRODUCTION
Sarcomas are rare malignant tumors of mesenchymal cell origin that can arise from
connective tissues throughout the body, including bone, soft tissue, and the peripheral
nervous system (1). In 2015, the estimated number of new soft tissue sarcoma diagnoses
in the United States is 11,930 and the number of new bone sarcoma diagnoses is 2,970,
accounting for <1% of all malignancies. The age distribution of sarcoma is bimodal in
nature with a peak at young age (in the top 5 most common causes of cancer death ages
<20 and 20 to 39) and a peak after 60 years of age (2). Soft tissue sarcomas can arise
in any portion of the body: 46% lower extremities, 18% trunk/body wall, 13% upper
extremities, 13% retroperitoneum, and 9% head and neck (3).
Because of the rarity of bone and soft tissue sarcomas, clinical outcomes have been
shown to be better when patients are evaluated and managed by centers with
multidisciplinary expertise in the treatment of sarcomas including orthopedic surgery,
surgical oncology, radiation oncology, medical/pediatric oncology, radiology, and
pathology. A South Sweden Health Care Region study, for example, showed that in 375
patients with soft tissue sarcoma, patients not referred at any time to a tumor center
had 2.4-fold higher local recurrence rates, and those referred only after definitive
surgery had 1.3-fold higher local recurrence rates (4). Other studies suggest that
multidisciplinary management of both bone and soft tissue sarcomas, especially at high-
volume academic centers, helps overcome specialty bias and facilitates better adherence
to guidelines for sarcoma management (5–10) while lack of access to centers of
expertise can increase mortality from sarcoma (11).
Radiation therapy (RT) plays a central role in the management of soft tissue sarcomas
in most anatomic sites, both for improving local control as well as preserving limb or
organ function, and in challenging bone sarcoma sites such as head and neck, spine,
and pelvis. This chapter will go into three major subcategories of sarcomas that pose
unique considerations from the standpoint of radiation planning: truncal and extremity
soft tissue sarcoma, retroperitoneal sarcoma, and bone sarcomas. Ablative treatments
for oligometastatic sarcoma are increasingly used and will also be discussed.

TRUNCAL AND EXTREMITY SOFT TISSUE SARCOMA


Natural History
Truncal and extremity soft tissue sarcomas present most commonly as a painless mass;
rarely there is pain, edema, or paresthesia. Due to the rarity of these tumors, delay in
diagnosis can be significant. Rapid appearance or growth of a preexisting lump may be
symptoms that would typically be alarming for possible malignancy.
Within a normal extremity, the muscles are separated into compartments by major
intermuscular septae. Between the muscles within the same compartment, muscles are
separated by minor septae. Sarcomas tend to grow longitudinally along the axis of the

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compartment and radially within the confines of the major fascial barrier of the
compartment rather than cross into neighboring compartment until quite late in their
natural history. Radially the tumor compresses the surrounding muscles and tissue and
results in zones with a mixture of sarcoma cells, atrophic muscles, and edema, a
“pseudocapsule” that can be appreciated during resection. Between the muscles within
a compartment, the sarcoma can permeate the minor intermuscular septae for a
distance away from the gross tumor. The minor septae and pseudocapsule, however, are
not true barriers to microscopic spread, and removal along the pseudocapsule is likely
to leave microscopic disease behind. Therefore, the minimal resection margin for
resection alone for a sarcoma is considered to be the major compartmental fascia,
interosseous membrane (tibia–fibula, ulna–radius), peritoneum, perineurium, or
adventitia of an organ, or at least a centimeter beyond the mass into surrounding fat.
Soft tissue sarcomas of the trunk and extremities rarely metastasize to lymph nodes
with the exception of a few histologic subtypes: clear cell sarcoma, angiosarcoma,
rhabdomyosarcoma, epithelioid sarcoma, and synovial sarcoma. Sentinel lymph node
mapping is quite controversial for these histologies. Generally, unless lymph nodes are
clinically involved or pathologically show high-risk features (extracapsular extension,
multiple lymph nodes, or lymph nodes greater than 3 cm), elective nodal RT to lymph
nodes is rarely used. PET may be useful in these lymphotropic sarcomas.

Figure 34.1 MRI images showing a T2bN0M0 grade 3 lower extremity soft tissue sarcoma (top left coronal, top
right axial). The tumor involves the medial compartment of the upper thigh and abuts the deep femoral artery
and vein and approaches but does not invade the femur. Note the extensive peritumoral edema on the sagittal
images (two lower panels).

Most sarcomas metastasize to the lungs. Myxoid liposarcoma and clear cell sarcoma
can have unusual sites of spread, including bone marrow, spine, and soft tissue.
Therefore, magnetic resonance imaging (MRI) imaging for bone metastases may be
useful (12). Brain metastases are overall rare and tend to be a late event in patients
with lung metastases or wide spread systemic disease.

Diagnosis and Staging


When a soft tissue sarcoma is suspected, anatomic imaging prior to biopsy or resection
is recommended. MRI is the preferred modality to image soft tissue sarcomas of the
trunk and extremities because of superior tissue definition of tumor from individual
muscles (13,14). Figure 34.1 shows an MRI of a T2b high-grade sarcoma involving the
medial compartment of the upper thigh.
Definitive diagnosis of a truncal or extremity sarcoma is best established by a core
biopsy with low complication rate and high accuracy (15,16). Incisional biopsy is
sometimes done if a histologic diagnosis cannot be made on the core biopsy sample. If

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necessary, the incision used to biopsy a sarcoma needs to be carefully placed directly
over the tumor and longitudinally over the limb. Transverse incisions or incision or
biopsy tracks through unaffected compartments can violate compartments otherwise not
likely to be involved by direct tumor extension: sarcoma cells can seed these areas and
unnecessarily increase the radiation target volume and surgical procedure. Excisional
biopsy is also rarely recommended without an attempt at core biopsy. Because the entire
incision or excisional scar as well as associate ecchymoses must be removed entirely,
doing so may result in loss of major neurovascular supply, loss of major muscles
necessary for the function of the limb, or skin/soft tissue defects too large to reconstruct
satisfactorily. Therefore, the biopsy approach may dramatically affect the treatment
approach and outcomes for patients with STS and is best undertaken at a sarcoma
treatment center. The Musculoskeletal Tumor Society evaluated 329 biopsies of primary
soft tissue sarcomas in 1982 and 597 cases in 1992 and found that when biopsy was
done in a referring institution instead of a sarcoma treatment center, the rate of errors,
complications, need for a more complicated resection, increased disability, loss of
function, local recurrence, or death were two to twelve times higher (17,18). For
patients receiving RT, details of the biopsy technique can significantly affect target
definition and radiation planning: although uninvolved skin should be avoided, it is
important to adequately dose (avoid bolus) for an initially unplanned
incision/excisional biopsy track must be adequately dosed to the surface at areas at high
risk of having tumor cell contamination.
Once a biopsy has been obtained, key findings on pathology include the histologic
subtype and grading. There are over 100 different histologic subtypes of soft sarcomas,
named based on the presumed normal tissue of origin that the tumor most closely
resembles (1). The most common soft tissue sarcomas include GI stromal tumors (19),
undifferentiated or unclassified soft tissue sarcoma (previously named malignant
fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, and malignant
peripheral nerve sheath tumor (MPNST). Some sarcomas are identified through unique
chromosome translocations: Ewing sarcoma, desmoplastic small round cell tumor,
myxoid and round cell liposarcoma, synovial sarcoma, alveolar soft part sarcoma, clear
cell sarcoma, extraskeletal myxoid chondrosarcoma, and dermatofibrosarcoma
protuberans, among others. While most of the soft tissue sarcomas behave similarly,
there are some notable exceptions in local aggressiveness and patterns of spread.
Differentiating between the various subtypes of sarcoma is important for prognosis and
individualization of treatment. For example, superficial myxofibrosarcoma is much more
infiltrative than other soft tissue sarcomas, particularly in the subcutaneous tissue, and
may be challenging to visualize and predict the distance of microscopic spread, even on
MRI (20). As a result, definition of clinical target volume (CTV) for preoperative
radiation treatment planning may be difficult, and surgical margins may be difficult to
clear. Hence, staged surgery to clear margins followed by postoperative RT may be a
more rational strategy for superficial myxofibrosarcoma (20–23) than preoperative RT.
Angiosarcoma of the skin, often associated with prior RT, can be multicentric in
presentation with great propensity for dermal, lymph node, and distant metastases and
pose challenges in both radiation treatment target design and dose. Epithelioid and
synovial sarcoma can have discontinuous spread (24–27).
Histologic grade of sarcoma is generally done using the French Federation of Cancer
Centers (FNCLCC) Sarcoma Group system into grades 1, 2, and 3 (1). For soft tissue
sarcomas, distant metastasis is best predicted by grade (28–31) and size (32). Staging
studies for soft tissue sarcomas include chest x-ray or chest CT (the latter for primary
tumor >5 cm, deep tumors, intermediate/high grade). Abdominal CT is recommended

1059
for myxoid liposarcoma because of risk of extrapulmonary spread. At present, there are
no conclusive studies on the use of PET for primary STS imaging or staging (33,34).
Tables 34.1 and 34.2 show the AJCC seventh edition staging system for soft tissue
sarcomas.
TABLE 34.1 American Joint Committee on Cancer Staging TNM Classification for Soft-
Tissue Sarcomas

Treatment Options and Prognosis

Amputation versus Limb Salvage


The primary goals of treatment for truncal and extremity soft tissue sarcoma are
survival free of disease and preservation of extremities, organs, mobility, and function.
A seminal prospective trial at the NCI in the 1970s randomized 43 patients with high-
grade soft tissue sarcoma to limb salvage surgery with postoperative RT (5,000 rads to
the entire anatomic area at risk and 6,000 to 7,000 rads to the tumor bed) versus
amputation, both arms with chemotherapy. At 5 years, the investigators found no
statistical difference in local recurrence (4 vs. none P2 = 0.06), disease-free survival

1060
(DFS) (71% vs. 78% at 5 years P2 = 0.75) or overall survival (83% vs. 88% P2 = 0.99)
between the limb salvage group or the amputation group, respectively (35). This trial
demonstrated that limb salvage was a viable option for extremity STS.
TABLE 34.2 American Joint Committee on Cancer Staging Classification for Soft-Tissue
Sarcomas—Stage Groupings

Whereas primary amputation may still be indicated for advanced sarcomas for which
a functional limb after limb-conserving therapy is not feasible (e.g., severe peripheral
vascular disease, diabetes, other comorbidities, involvement of a major nerve plexus or
artery, involvement of multiple compartments, or near-circumferential subcutaneous
involvement for which reconstruction may not be possible, among others), in the
majority of cases limb-conserving therapy is preferred. For limb salvage, primary tumors
are widely excised, ideally en bloc without tumor cut-through and with a cuff of normal
tissue around the tumor. The generally recommended margin for STS is at least 1 cm.
Resections that are done through the pseudocapsule or otherwise intralesional,
piecemeal, or subtotal in nature are suboptimal and are associated with higher local
failure. Local control can vary as much as 47% versus 87% in patients with and
without tumor violation (36).
However, for deep tumors near neurovascular structures, bones, or other critical
structures, acceptable margins may be much smaller (1 to 2 mm) if the specimen is
removed with the involved natural anatomic barriers such as fascia of the compartment.
Soft tissue sarcomas generally do not cross compartmental fascia or periosteum with the
exception of extremely advanced cases or where violation of the barrier has occurred
through biopsy or prior procedures. Major nerves are usually preserved if possible, with
nerve sheath as a margin. The exception is in neurogenic tumors such as MPNST where
it may be necessary to resect the involved nerve to minimize risk of leaving macroscopic
or diffuse microscopic disease. Margins along abutting bone can be cleared by stripping
the involved periosteum. Generally periosteal stripping should be limited to tumors
directly abutting the periosteum, especially in weight-bearing bones such as the femur,
because of dose-related pathologic fracture. If periosteal stripping is necessary for

1061
tumors directly abutting bone and stripping is required, some surgeons may recommend
prophylactic fixation. There is also a clear dose effect with radiation and fractures after
limb-sparing resection and RT (37–40). Major arteries involved sometimes may be
resected for better surgical margin and reconstructed, whereas veins generally are not.
Surgical wounds may be closed primarily or require rotational or free tissue flaps; the
use of flap reconstruction does not appear to adversely affect postoperative function or
health status outcomes (41,42). A multidisciplinary discussion of the anticipated
surgical approach, including stripping of periosteum, vascular resection, reconstruction
options, and potential margins of concern can help inform radiation planning, both in
the preoperative and postoperative settings.

Importance of Radiation Therapy in Limb Conserving Therapy


Following promising single institutional experiences combining RT with conservative
surgery in sarcomas (43), an NCI study randomized 141 patients after limb salvage
surgery for STS to RT plus chemotherapy versus chemotherapy alone without RT. At 9.6
years of follow-up, there was a highly significant decrease in local recurrence rate with
RT (one LR) versus without RT (17 LR, P2 = 0.0001). The impact of RT on LR was
significant in both high-grade and low-grade sarcomas, though there was no difference
in distant metastasis or OS (44).
A trial of adjuvant brachytherapy (BRT) versus no BRT after complete excision of
extremity or trunk sarcoma using iridium-192 implant to 42 to 45 Gy over 4 to 5 days
found 5-year local control rate of 82% versus 69% (P = 0.04). Within the high-grade
sarcoma patients, local control was 89% (BRT) versus 66% (no BRT) (P = 0.0025). In
contrast to the NCI trial, BRT did not affect local control for low-grade sarcomas (P =
0.49). As in the other studies, use of adjuvant RT did not impact distant metastasis or
disease-specific survival (30). Neither this nor the NCI trial comparing limb-conserving
surgery with or without RT was powered to detect a survival difference (30,44).
However, analysis of 2,606 soft tissue sarcoma in the Surveillance, Epidemiology, and
End Results (SEER) database found on multivariate analysis that RT was associated with
20% and 30% survival advantage for the matched and unmatched cohorts (P ≤ 0.02)
(42,45). Other studies suggest that local recurrence can be directly associated with
worse survival (Gronchi et al., 2009).
The most consistent prognostic factor for local recurrence is a positive or uncertain
surgical margins (28). In patients who initially undergo a nononcologic resection or an
R1 resection, as high as 35% to 67% of these patients may have residual sarcoma and
benefit from re-resection for local control even with the routine use of adjuvant RT
(46–50). RT may be given preoperatively or postoperatively in conjunction with re-
resection to yield high local control rates.
However, in some patients, re-resection after an initially unplanned excision may not
be feasible due to medical or functional considerations; in these patients, RT to median
doses of 66 Gy has been shown to have a reasonably high 10-year local control rate of
86% (51). It appears that if the margin cannot be cleared, higher RT dose may help
improve local control. A large series of 154 STS patients, for example, found that high
doses >64 Gy appear to improve local control rate to 85% versus 66.1% with doses
≤64 Gy (P < 0.04) (52).

Surgery Only for STS


There is likely a subset of patients with STS who may not require RT. Large population-

1062
based studies and single institution studies suggest that there may be some patients, for
example, those with T1 or low-grade tumors, who may not benefit from adjuvant RT
(53–56). In a prospective trial of selected patients with T1 STS, 84% of patients were
able to have R0 resection and were treated with surgery alone with isolated local
recurrence of 10.6% at 10 years (55). In a series of 74 patients treated with function-
sparing surgery without RT, 10-year local control rate was 93%: those with margins <1
cm had 87% LC compared with 100% for those with margins ≥1 cm (P = 0.04), rates
comparable to that reported with RT (56). Memorial Sloan Kettering Cancer Center
developed a nomogram based on 684 patients with extremity sarcoma treated with
limb-sparing surgery alone that includes age, size, margin status, grade, and histology
as five independent predictors of recurrence (53). In practice, surgical excision alone is
reserved for cases with low-grade, superficial tumors ≤5 cm in size, high-grade tumors
that are entirely intramuscular for which widely negative margins can be achieved.

Radiation Only for STS


For patients who cannot undergo surgery or for whom limb salvage is not feasible but
amputation is unacceptable, RT alone may be an option. A study of 112 patients treated
with RT to a median dose of 64 Gy for gross unresected disease found 5-year local
control of 45%. The LC differed based on size: LC was 51% for tumors <5 cm, 45% for
tumors 5 to 10 cm, and only 9% for tumors greater than 10 cm. Doses greater than 63
Gy were associated with better LC but doses >68 Gy were associated with higher
complication rates (27% vs. less than 8% for dose <68 Gy) (57).

Sequencing of Radiation Therapy: Preoperative versus Postoperative Radiation


Therapy
There are theoretical advantages and disadvantages to preoperative versus
postoperative RT: preoperative RT allows for clear tumor definition and areas at risk,
potential reduction of seeding, sterilizes the tumor, and allows for more conservative
surgical margins whereas postoperative RT allows for evaluation of the entire tumor
and surgical margins and potentially may allow omission of RT in selected cases. A
number of retrospective studies of preoperative or postoperative RT for STS have shown
comparable outcomes. There was higher late RT-related complications with
postoperative RT. Higher wound complication rates are seen with preoperative RT
(ranging from 27% to 37%) than with postoperative RT (ranging from 8% to 29.3%)
(43,58–61).
The only phase III randomized clinical trial to compare preoperative RT versus
postoperative RT was conducted by NCI Canada (CAN-NCIC-SR2). One hundred and
ninety patients with extremity STS, mostly intermediate or high grade, were randomized
to preoperative RT with 50 Gy (with postoperative boost of 16 to 20 Gy if positive
margins) versus postoperative RT to 50 Gy covering an initial large field covering the
incision plus a 16 to 20 Gy cone down to the tumor bed. The tumor volumes were 5 cm
proximal and distal to the tissues at risk followed by reduction to 2 cm around the
initial tumor bed. The primary end point was acute wound healing complications
defined as wound healing requiring deep packing, prolonged wound dressings,
secondary surgery, or hospital admission within 120 days of resection. A planned
interim analysis found highly significantly more acute wound healing complications
with preoperative RT (35%) versus postoperative RT (17%), and the study was
terminated early (62), however, a long-term follow-up found a statistically

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nonsignificant trend toward greater rates of fibrosis (48.2% vs. 31.5%), joint stiffness
(23.25% vs. 17.8%), and edema (23.2% vs. 15.5%). These predicted for lower
functional scores as measured by the Musculoskeletal Tumor Rating Scale (MSTS) and
the Toronto Extremity Salvage Score (TESS) (P < 0.01). Field size was greater with
postoperative RT versus preoperative RT and was the only significant predictor of
fibrosis and joint stiffness and a trend for edema (P = 0.002, P = 0.006, and P =
0.06, respectively) (63). Because of the reduction of late effects as well as other
potential advantages of preoperative RT (decreasing the necessary surgical margin and
reduce seeding), preoperative RT is generally preferred for most intermediate to high-
grade truncal or extremity STS.
There are some exceptions to this preference: patients with infiltrative subcutaneous
myxofibrosarcoma where defining the margins and appropriate preoperative target
volume may be challenging, surgery first may help define the margins for postoperative
RT. Patients who are obese, diabetic, or whose subcutaneous tissue may not be spared
and likely at higher risk of acute wound healing problems may be better served with
postoperative RT after complete healing (64).

Treatment Planning
Radiation treatment planning for truncal and soft tissue sarcoma requires a careful
consideration and understanding of the patient’s comorbidities, natural history of the
sarcoma subtype, available diagnostic imaging, any anticipated reconstruction and
normal structures and potential impact on limb function. Because sarcomas can involve
many different anatomic compartments of the limb, immobilization is the most
important first step in treatment planning.
Good immobilization is necessary to reproducibly position the affect limb. A variety of
devices may be used to achieve this ranging from standard plastic supports with Velcro
straps, to individually formed casts from polyurethane foam (Niewald et al., 1990),
thermoplastic shell, vacuum pillow on adaptable baseplates (65,66), or other variations
thereof (67). Immobilization across movable joints adjacent to the involved portion of
the extremity can eliminate one of the largest variables in positioning. Whenever
possible, the immobilization should minimize soft tissue distortion of the affected
portion of the limb. For proximal medial thigh lesions, frog-leg position and scrotal sling
can help reduce skin folds and dose to the scrotum/perineum; in some cases the
ipsilateral leg benefits from the frog-leg positioning while in other cases the
contralateral leg benefits. One should consider potential beam arrangements at the time
of the immobilization so that the desired dose can be delivered as conformally as
possible to the target and the uninvolved limb can be positioned to avoid exit dose or
clearance problems with the gantry head. For the sarcomas that occupy the near
entirety of an anterior or posterior compartment, for example, elevation of the
contralateral leg may allow for straight-forward opposed lateral beams, whereas those
in the medial/lateral compartments or only a small portion of the cross section of the
limb can benefit from anterior, posterior, obliques, or other angles that would be better
conform the dose and therefore the contralateral leg may be best left in the neutral
position. Each case must be individualized to optimize treatment planning options.
Figure 34.3 shows the treatment set-up and an intensity-modulated radiation therapy
(IMRT) plan for a medial thigh sarcoma. Figures 34.4 to 34.6 show the preoperative
treatment set-up and plan for a high-grade calf synovial sarcoma (Fig. 34.4), the set-up
digitally reconstructed radiograph (DRR), and postoperative boost (Fig. 34.6). Figure
34.12 shows an IMRT plan for a synovial sarcoma involving a long length in the medial

1064
aspect of a foot where the dose shaping allowed maximal avoidance of high dose to the
weight-bearing bones of the foot.

Figure 34.2 High-grade thigh sarcoma after preoperative chemoRT showing extensive internal necrosis.

Figure 34.3 A: Treatment set-up for T2bN0M0 proximal lower extremity high-grade sarcoma. Custom
accuform cushion, thermoplast food mold, and foot plate allow for reproducible immobilization of the right leg
for daily treatment. B: Shows IMRT plan for T2BN0M0 grade 3 lower extremity sarcoma involving the medial
compartment of the proximal thigh. Prescribed dose (in orange) covers the CTV, which is limited to the affected
compartmental fascia and the periosteum of the adjacent femur. Dose to the femur is limited to the affected
side. Dose to uninvolved soft tissue is minimized and a strip of soft tissue and skin laterally (at least 3 cm) is kept
free of dose.

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1066
Figure 34.4 Custom immobilization and set up (A and B) for a T2BN0M0 grade 3 pleomorphic sarcoma of the
right calf treated with preoperative radiation treatment. C, D and E: show the axial, sagittal, and coronal images
of GTV (solid red) and CTV (shaded magenta) and dose distribution from a 3D conformal photon plan. Note
that the CTV is confined to the fascia and the tibia rather than extending uniformly to the skin or the fibia to
allow for dose drop off at the uninvolved subcutaneous tissue laterally and the pretibial soft tissue anteriorly. F:
shows the dose volume histogram with L knee dose V50 < 50%. (continued)

For the upper extremity, the patient can lie prone or supine with the arm elevated or
akimbo away from the trunk with the patient positioned toward the contralateral edge
of the table to reduce risk of gantry interference. Supination or pronation of the forearm
may affect the tumor’s position within the forearm and optimal beam arrangements. For
the hand and fingers, custom bolus may be built into the immobilization if dose build-up
is desired because it may otherwise be difficult to add bolus after the planning without
affecting treatment set-up. Figures 34.7 and 34.8 show the MRI, immobilization, and
IMRT plan for a high-grade sarcoma involving the deltoid muscle at the humeral

1067
head/shoulder joint. Figure 34.11 shows a high-grade sarcoma involving the second
metacarpal and the custom immobilization with built-in bolus dorsal to the lesion, and a
3D conformal plan to allow some superficial sparing while achieving adequate dose to
the dorsal aspect of the lesion.
The use of bolus, especially for preoperative RT, is limited to cases where skin or
superficial spread may be of concern (e.g., angiosarcoma of the skin). Generally even for
CTV close to but not involving superficial subcutaneous tissue or skin, it is not necessary
to bring full dose to cover the planning target volume (PTV) expansion to the skin.
When treating any patient who has had initial incision or excision of the tumor,
marking the surgical scar and drain sites with radio-opaque wires is important for
target definition. These areas are potential sites of contamination and should be
included in the initial 50 Gy of the target.
CT-based simulation is preferred in most cases to allow for 3D conformal therapy.
When CT-based simulation with conformal blocking was introduced in sarcoma, it was
found to reduce volume of tissue receiving target dose by greater than 20% in four of
five patients with thigh sarcomas compared with 2D (68,69). Nowadays, CT simulation
also allows for fusion with MRI for better target definition.

Target Volume Definition


Based on the natural patterns of growth of sarcoma, traditional margins have included
as much as 5- to 10-cm longitudinal margin (reflecting the greater risk of microscopic
spread of sarcomas along the axis of the involved compartment) and 2 to 3 cm of radial
margin (reflecting a 1-cm margin generally considered to be the optimal surgical margin
plus a margin to account for target uncertainty in the era before MRI, daily set-up
uncertainty, and beam penumbra). The National Cancer Institute (NCI) Canada
randomized trial of preop versus postop RT utilized 5-cm longitudinal margins and 2-
cm radial margins for the first 50 Gy and 2 cm around the tumor bed for the boost (62).
The local control was high with these margins.

Figure 34.5 Orthogonal daily imaging with KV imaging.

However, the advent of MRI generated great interest in refining these margins. When

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satellite tumor cells in resected high-grade sarcoma specimens were correlated with MRI
signals, it was found that T2 MRI peritumoral signal abnormalities ranged from 0 to 7.1
cm beyond the gross tumor, T1 contrast enhancement abnormalities ranged from 0 to
5.3 cm, but sarcoma cells could be identified beyond the gross tumor in 10/15 cases: of
those, 6 cases had cells within 1 cm of the gross tumor but 4 cases had cells >1 cm and
up to maximum of 4 cm from the gross tumor. The presence of microscopic spread did
not correlate with tumor size or MRI peritumoral changes (70). A recent review of
patients treated preoperatively with CT- and MRI-planned RT used post gadolinium
contrast enhancement T1 MRI images to define the gross target volume (GTV). The GTV
was expanded with 1 to 1.5 cm radially and 3.5 cm longitudinally to form the CTV
respecting fascial barriers. PTV expansion was 5 to 7 mm and prescribed at least 95% of
the dose. At 5 years of follow-up, local control was 88.5%. Of the three patients who
had local failure as first relapse all had positive margins. Two additional patients (all
with margin <1 mm) had late local failure after distant metastasis. There were no local
failures with margins ≥1 mm. The authors concluded that with preoperative RT, these
margins seem to be appropriate for most patients (71). Because inter- and intraobserver
variability for gross tumor definition in sarcoma can be quite significant, peer review in
target definition for sarcoma is recommended (72).
RTOG 0630 evaluated the use of MRI fusion and image-guided radiation treatment
(IGRT) to further reduce both CTV and PTV. In this trial the GTV was defined by T1
contrast–enhanced MRI sequences, ideally with image fusion. The GTV was then
expanded 3 cm longitudinally for high-grade sarcomas and 2 cm longitudinally for low-
grade sarcomas or more to encompass suspicious peritumoral edema on MRI T2
sequences, but confined to the end of a compartment plus a 1-cm margin. The radial
expansion was 1.5 cm for high-grade tumors and 1 cm for low-grade sarcomas, confined
to intact fascial barrier or uninvolved bone or skin or subcutaneous tissue. IGRT using
either daily orthogonal imaging or CBCT was required for PTV of 0.5 cm; without IGRT,
a 1-cm PTV was required (73).
A companion study was made based on RTOG 0630 to assess the variability of
preoperative GTV and CTV target volume definition between radiation oncologist. It was
found that there was near perfect agreement in the GTV and CTV of a lower extremity
case among 10 sarcoma radiation oncologists but there was more variation in the CTV
definition for an upper extremity case (74). Another companion study found that there
was also good agreement in the definitive of suspicious edema using T2-weighted MRI
images of high-grade extremity sarcomas among sarcoma radiation oncologists (75).
Therefore, a consensus atlas for preop RT GTV and CTV target definition was developed
by the RTOG sarcoma radiation oncologists to guide target definition for this trial. The
key recommendations of the atlas included: MRI fusion be performed when possible
with CT planning to better delineate the GTV; high-grade large STS should include GTV
plus 3-cm margins longitudinally and be confined by the end of a compartment; and
radial margins would be 1.5 cm in areas not confined by intact fascial barrier, bone, or
skin surface (73). At the final report of the results of RTOG 0630, local control using
these margins and IGRT was high with 5 local failures out of 79 evaluable patients
(treated with IGRT without concurrent chemotherapy), all of which were in field, none
marginal. Grade ≥2 late toxicity at 2 years was 10.5%, which compared favorably with
those seen in the NCIC trial (62,76). A deformable RTOG Consensus Atlas of
Musculoskeletal Anatomy (CAMAS) of the compartments and structures of the lower
extremities was also developed as a part of this trial and may become a useful tool for
designing anatomically appropriate target volumes (77).
As noted before, certain tumor histologies such as acral myxoinflammatory

1069
fibrosarcoma or superficial myxofibrosarcoma, or in cases where fascial planes have
been violated, more generous margins may be necessary (23,78,79). Careful
consideration of the biopsy, prior surgical details (if any), and the histologic subtype
and compartment involved are necessary to adequately cover the target at risk.

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Figure 34.6 Postoperative boost with 16 Gy for calf sarcoma after resection with positive margins along the

1071
neurovascular bundle. A: Axial. B: Sagittal. C: Coronal. D: DVH showing attempt to conform the boost dose
while sparing a strip of medial soft tissue. E: Note the metal artifact from the plate, seen on the DRR AP film,
which was placed at the time of the resection for stabilization of the tibia to prevent fracture due to periosteal
stripping. F: Daily surface imaging combined with weekly CBCT allowed for use of 5 mm for PTV.

Figure 34.7 Grade 2 leiomyosarcoma involving the deltoid muscle. A: Note the extensive suspicious peritumoral
edema along the deltoid muscle from origin to insertion. B: Immobilization with custom immobilization to
reproducibly position the shoulder and the right arm.

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Figure 34.8 A: Preoperative IMRT plan for deltoid sarcoma using daily CBCT for IGRT to allow for a 5-mm
PTV (dark purple) around the CTV (red). The longitudinal margins of this target fan out around the insertion
points of deltoid and include suspicious peritumoral edema that extends around the humerus. B: Axial isodose
plan. C: Sagittal. D: Coronal. E: Dose–volume histogram shows that less than 50% of the humerus and right
shoulder joint receives full dose.

Dose and Fractionation

Preoperative RT
50 Gy in 2 Gy per fraction is a standard dose fractionation given preoperatively to the
volumes as detailed above followed by at least 3 weeks of recovery prior to resection. In
chemoradiation protocols used for high-grade sarcomas at some centers, a 10%
reduction in dose or a change from 2 Gy per fraction to 1.8 Gy per fraction (to 50.4 Gy)
is commonly done to reduce the potentially added impact of chemotherapy on already
high acute wound healing complication rates. Timing from completion of
chemoradiation to surgery is also adjusted to 5 weeks (80).

Boost for Positive Margin or Gross Disease

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(BRT boost in more detail below) can deliver 16 Gy as low-dose rate or a high-dose rate
(14 Gy twice daily × 4 days or 25 Gy for gross residual disease). Intraoperative
electron RT of 10 to 15 Gy given either after or preceding external beam radiation
therapy (EBRT) has also been used for boost with high local control rates without
increase in acute or late morbidity (81–85). It is unclear whether given the long interval
between preoperative RT and postoperative recovery whether EBRT is beneficial as a
modality for boosting a positive margin. Some studies found modest or no impact of
EBRT boost on local control but higher risk of fracture, fibrosis, edema, and joint
stiffness from the high cumulative dose (86,87).

Hypofractionation
There is limited experience using hypofractionation in sarcoma. A series on 60 patients
with median size 12-cm tumor treated with chemotherapy and either hypofractionated
3DRT with 35 Gy in 10 fractions or standard 46 to 50 Gy in 23 to 25 fractions found
that those treated with hypofractionation had significantly superior local control rate,
DFS, and cause-specific survival compared with conventional fractionation (88).
Another study reported the use of preoperative stereotactic body radiation therapy
(SBRT) for 13 patients with high-grade extremity sarcomas using expansion of 0.5 cm
radially and 3 cm longitudinally to a dose of 35 Gy in 5 fractions or 40 Gy in 5
fractions for deeper tumors. Maximum skin dose was constrained to 46 Gy. Surgery was
done at a median of 37 days after SBRT. All patients had negative margins and 4/13
required planned vacuum-assisted wound closure but no other wound complications.
This initial experience warrants further follow-up (89).

Treatment Set-up and Uncertainties


Proper positioning for extremity sarcomas can be challenging even with immobilization.
A study evaluated 236 treatments in 15 patients with extremity sarcoma to assess
whether surface imaging could improve patient positioning and reduce the necessary
CTV (67). Intrafraction motion is small (2.1-mm mean 3D vector shift 1.3-mm
systematic and random errors). However, the mean interfraction error was 7.6 mm and
systematic and random errors were 3 to 4 mm in each direction. The required PTV
margins were 1 cm, 1.2 cm, and 1.3 cm in the anterior–posterior, superior–inferior, and
lateral directions, respectively. With surface alignment the mean root mean square
(RMS) errors for uncorrected position were 4.7 mm and were reduced to 2.2 mm with 4
degrees of freedom surface alignment and down to 1.7 mm for 5 degrees of freedom
surface alignment. Based on this, the author’s institution uses daily surface imaging
with weekly cone beam CT (67). Another study registered planning CT with CBCT
acquired before delivery of image-guided IMRT and found that a uniform 5-mm PTV
margin was necessary to cover intrafractional and interfractional systematic error and
random error (90). RTOG 0630 required the use of either daily kV or MV orthogonal
imaging or CBCT pretreatment to allow for use of 5 mm as PTV (76). 5-mm PTV,
however, is not adequate if set-up is checked with only weekly KV or MV portal
imaging, particularly in the lower extremity. Figure 34.9 shows CBCT for daily
alignment for a sarcoma involving the shoulder joint to allow sparing of the joint.
Other uncertainties may come from changes in the sarcoma with preoperative
therapy. Adaptation of the plan may be necessary for sarcomas. Imaging of STS after
preoperative RT can show either enlargement or shrinkage. In one study 20% of cases
had an increase in tumor volume but all cases had clear surgical margins and no local
recurrence. In 80% of tumors, maximal diameter was reduced by 13.5% and median

1074
volume reduction was 33% (91). Another study quantified tumor volume on T1
gadolinium–enhanced sequences and correlated to pathologic response; median
decrease in tumor volume was 13.8% for nonmyxoid low-grade sarcomas, 82.1% for
myxoid liposarcomas, and <1% for high-grade sarcomas, despite a variety of
pathologic responses (92). Careful attention must be paid to potential changes in tumor
size, whether by clinical examination and measurement of the circumference of the limb
at the site of the tumor, evaluation of larger than expected changes in patient set-up, or
review of surface or CBCT used for image guidance for changes. Reevaluation of the
initial radiation treatment plan may be necessary if the plan no longer adequately
covers the target. Figure 34.10 shows an example where 3D plan for a tumor
anticipated to potentially swell (due to chemoradiation) was more robust than an IMRT
plan. Allowing flash for tumors anticipated to potentially swell from induction
chemotherapy may help reduce the need for replanning.

Other Radiation Modalities

Brachytherapy
BRT has particular appeal compared to EBRT, especially prior to the availability of 3D
and IMRT techniques: targeted dose distribution with the treatment field defined at the
time of resection with the surgeon, low integral dose and short treatment times. The
American Brachytherapy Society consensus statement for sarcoma brachytherapy
provides a comprehensive guide to the use of this technique in soft tissue sarcomas:

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Figure 34.9 CBCT used for daily treatment alignment. In this case the CBCT was superior to surface imaging
for ensuring dose conformality around the right shoulder joint. A: Coronal. B: Sagittal. C: Axial. D: Couch
correction based on CBCT alignment. E: Vision RT surface imaging.

BRT is most often accomplished as interstitial implants by passing hollow needles


through the skin and soft tissue at least 1 to 2 cm away from the wound incision. The
catheters are placed 1 to 1.5 cm apart in parallel or perpendicular to the incision
depending on the curvature of the extremity so as to avoid distortion of the catheters
postoperatively. The CTV should encompass the entire area at risk as either a single
plane or multiple planes. Surgeons usually can help place radio-opaque clips to allow
visualization for planning. Catheters are then sutured and anchored to the external skin

1076
with fixation buttons. Tissue expanders, gel foam, drains, or inflatable material may be
used to protect normal tissues. Once the wound is healed, catheters are numbered for
correct identification and the positions of the catheters at the skin are marked to ensure
consistent depth between fractions. Patients are planned postoperatively using CT
simulation with “dummy ribbons” which help identify potential source positions. The
quality of implant is measured as D90 (dose to 90% of the CTV), V100 (percent of CTV
receiving 100% isodose), and V150. Surgical incision is limited to <100% isodose and
source should not be closer than 0.5 cm from the skin surface.

Figure 34.10 Planning needs to take into consideration potential changes in tumor between simulation and start
of treatment or potentially during treatment. In the example, a 15-cm chest wall sarcoma was planned using
both IMRT and 3D. On CBCT and clinical assessment at the verification simulation, the tumor had increased
significantly in size after the first cycle of interdigitated MAID (mesna,adriamycin, ifosfamide, and
dacarbazine). A: IMRT plan showing before (top left) and after (bottom left) the tumor swelling and the
shortfall in blue (bottom right). B: DVH comparison of tumor coverage with IMRT on the initial and
replanning CT shows decreased PTV and CTV coverages using an IMRT plan. C: 3D CRT plan showing
before (top left) and after (bottom left) the tumor swelling. D: DVH comparison of tumor coverage with 3D
CRT with adequate flash had no PTV or CTV shortfall.

BRT treatments for extremity sarcomas are most commonly delivered using iridium-
192 seeds as low-dose rate or as high-dose rate; the latter avoids radiation exposure to
the personnel and can be given as an outpatient. For LDR, the prescription is delivered
to the lowest continuous isodose rate line covering CTV (usually 5 mm from the plane of
the implant) at a dose of 45 to 50 Gy over 4 to 6 days at 0.45 to 0.5 Gy/hr, or to 15 to
25 Gy over 2 to 3 days at 0.45 to 0.5 Gy/hr with 45 to 50 Gy of EBRT. For HDR, the
recommended prescription dose is 30 to 54 Gy over 4 to 7 days at 2 to 4 Gy BID, or 12
to 20 Gy over 2 to 3 days at 2 to 4 Gy BID, with 6-hour intervals. Pulse dose rate (PDR)
is a way to use remote after-loading delivering dose in short bursts at hourly doses that

1077
is radiobiologically comparable to LDR. To limit the impact of wound healing, time to
source loading more than 5 days and good implant geometry can help lower wound
healing complication (93).
There are no randomized comparisons between EBRT versus BRT as monotherapy, or
EBRT versus EBRT plus BRT as a boost. The American Brachytherapy Society (ABS)
guidelines on brachytherapy recommend BRT monotherapy be reserved for sarcomas
resected with negative margins or pediatrics or previously irradiated patients, but for
>5 cm, high grade, or incompletely resected or recurrent but not previously irradiated
sarcomas, EBRT to the larger volume at risk with BRT as a boost may provide better
coverage (94). The randomized phase III trial mentioned above showed that for high-
grade tumors local control was higher versus no surgery alone (89% vs. 66%), although
it is unclear why the same advantage was not seen in low-grade sarcomas (30).

Intensity-Modulated Radiation Therapy


Growing evidence suggests that IMRT can potentially provide better dosimetric normal
tissue sparing and tumor coverage than 3D RT for extremity soft tissue sarcomas. A
study found that using a tight margin at the soft tissue/bone interface in patients with
tumors approaching but not directly involving the femur, a 5-field coplanar IMRT plan
can result in better bone sparing than a 3D conformal plan with two to three beams
with wedges or partial transmission blocks as compensators (95). Compared to 3D CRT,
IMRT reduced the volume of surrounding soft tissues excluding the PTV receiving
prescription dose by 78%, the volume of femur receiving full prescription by 57%, D05
in femur by about 2.2 Gy, mean dose to femur by about 2.4 Gy, volume of surrounding
soft tissue by 13%, volume of skin by 45%, hot spots on the skin, and mean dose to the
skin by 14%, all statistically significant. In a follow-up study of 41 patients with
primary STS treated with limb-sparing surgery and adjuvant IMRT (7 preoperatively to
a median dose of 50 Gy and 34 postoperatively to a median dose of 63 Gy) acute and
late toxicities appeared to be acceptable and local control was high at 94% at 5 years
(96,97). Complication rates were acceptable: 9.8% noninfectious wound complications;
7.l3% grade 2 and 2.4% grade 3 infectious wound complications. Two patients had
bone fracture (4.8%) without periosteal stripping or bone resection. Grade 1 or 2 joint
stiffness occurred in 46.3%, grade 1 or 2 edema in 31.7%, and grade 1 or 2 nerve
damage in 26.7% (96).
A prospective phase II trial of image-guided IMRT (IG-IMRT) for extremity sarcoma to
conform dose and avoid normal tissues (skin flaps for wound closure, bone, or other
uninvolved tissue) in 70 patients (59 evaluable), found that wound complication rate
was 30.5% (comparable to the NCIC SR2 trial) but primary closure was more often with
IMRT than the NCIC SR2 trial (93.2% vs. 71.4%) and there were no fractures. Local
control rate was high with only 6.8% local recurrence at 49 months of follow-up (98).
A comparison of IMRT versus EBRT in 319 patients found higher local control rate at
5 years (92% vs. 85%) despite higher-grade lesions and more close/positive margins
with lower grade ≥2 radiation dermatitis (31% vs. 49%). However, 3.5% of patients
had grade ≥2 neuropathy compared to fractionation but overall risk was low (99). A
comparison of IMRT (10 with preoperative 50 Gy and 53 with postoperative RT 63 Gy)
versus adjuvant BRT with LDR to 45 Gy for high-grade extremity STS found local
control was better with IMRT (92% vs. 81%, P = 0.04) and that IMRT was the only
predictor of improved local control on multivariate analysis despite worse features
(positive/close margins <1 mm, large tumors >10 cm, and bone/nerve
stripping/resection) (100). The authors suggest that IMRT should be the treatment of

1078
choice for primary high-grade extremity sarcoma. Longer follow-up will be necessary to
see if indeed IMRT is superior to other techniques, though these initial studies are
promising.
Some aspects unique to IMRT that warrant attention include potentially greater dose
inhomogeneity and hot spots, which may cause unanticipated acute toxicity, for
example, in soft tissue, skin, or nerves. For sarcomas not involving skin yet close to the
skin, a 3- to 5-mm rind of skin may need to be contoured and used as a planning
objective to avoid hot spots in the soft tissue critical for wound healing. Another
concern is the use of multiple beams (often 5 or more) in IMRT, which bathes a larger
circumference of the extremity with low-dose radiation and whether that affects edema
and secondary malignancy rates. For large fields, it may be necessary to divide fields
into subfields (95).
Ultimately, the choice of modality should be individualized for each patient, the type
of CTV to be covered, the normal tissue to be avoided. Collaboration with the orthopedic
surgeon to define potential tissue, which will be critical to wound closure, may also be
helpful. In upper thigh/groin sarcomas closer to the pelvis, IMRT may significantly
reduce dose to vulva, perineum, anus, rectum, and femoral heads. Around the shoulder
complex, IMRT may help reduce dose to the brachial plexus. Around paraspinal
muscles, chest wall, or other truncal (nonvisceral) sarcomas, IMRT may be helpful for
reduction of dose to spinal cord, lung, and other internal organ dose while conforming
dose to potentially complex, irregular target volumes than the more convex targets in
distal extremities. In the distal parts of the extremities (including hands, feet, fingers,
toes), 3D conformal therapy may be quite adequate while IMRT may not be necessary.

Proton Radiotherapy
At this point, proton therapy’s role in extremity and truncal soft tissue sarcoma is not
established. Generally, because of the marked reduction in integral dose, protons can be
considered and are accepted on most protocols for children with soft tissue sarcomas.
Young adults with hip/truncal sarcoma may also benefit from proton beam therapy to
spare reproductive, pelvic, or other critical organs, but the long-term benefits remain to
be studied.

Dose Constraints and Complications


Consistently, limb-conserving therapy with adjuvant radiation has shown high local
control rates as discussed above. Patients overall enjoy good, long-term quality of life
with limb-conserving therapy, though across different anatomic sites, functional
outcomes can vary. A quality of life study evaluating 149 patients with deep soft tissue
sarcomas and 58 patients with superficial sarcomas found that treatment of superficial
sarcomas does not significantly affect function as assessed with the Musculoskeletal
Tumor Society (MSTS 1993) score or the Toronto Extremity Salvage Score (TESS);
however, treatment of deep soft tissue sarcomas leads to significant reduction of both
scores. Gait handicap, limping, dressing, sitting, bending, and bathing affect function
depending on the location of the tumor (101).
Acute complications during preoperative or postoperative treatment include skin
reactions that are generally self-limited. Aside from groin sites or superficial or
contaminated tumors requiring bolus, attention to the skin and subcutaneous dose for
deep tumors generally allows patients to complete treatment without severe
desquamation. The most common acute complication with preoperative RT is wound
healing delay. Lower extremity STS is associated with higher acute wound complication

1079
rates (32%) compared to upper extremity STS (17%) (102,103). Medial compartments
are associated with higher wound reoperation and edema and nerve damage more
frequently in the posterior compartment (104). Proximity of target volumes to the skin
surface of <3 mm is associated with preoperative RT, in addition to diabetes, tumor
>10 cm, and vascular zed flap/split-thickness skin graft closure (105). Tumors in the
adductor compartment, high grade, proximal lower extremity, smoking, and obesity are
other additional predictors for wound complication (106). A study showed a trend
toward higher wound healing complication rate for those who had surgery after 6
weeks versus <4 weeks (28% vs. 34%, P = 0.08) (107). General recommendations for
dose constraint in radiation treatment for STS include sparing a minimum of 3 cm strip
of uninvolved soft tissue (2D and 3D concept), avoiding entrance or exit through the
contralateral extremity, genital organs or perineum for tumors in the upper thigh and
pelvic region, avoidance of bolus unless necessary (though in some postoperative cases
adequate skin flash and build-up may be desirable to cover potential contamination),
and limiting hot spots. Skin care throughout and after radiation treatment, gentle
handling of tissue, planned reconstruction with vascularized flaps, meticulous
hemostasis, avoidance of wound closure under tension, minimizing dead space by using
rotational or free tissue transfers, wound drainage, compression dressings,
immobilization of the limb until adequate initial wound healing, and omitting
postoperative RT for a subgroup of patients without tumor cut-through or any residual
viable tumors are some of the ways that have been recommended to reduce wound
healing complication (108).
Late effects in soft tissue is related to both volume and dose of RT. RTOG 0630 is
encouraging that careful tailoring of preoperative RT target volume using MRI
sequences and standardizing target volumes for STS, combined with IGRT to allow
reduced PTV, can reduce late effects including fibrosis, edema, and joint stiffness
compared to larger volumes used in the past (76). As shown in the NCIC SR2 trial, late
effects are greater with postoperative RT versus preoperative RT (62,63). A recently
completed VORTEX study in the United Kingdom randomized postoperative sarcoma
patients to either a larger versus a smaller postoperative clinical target volume (109).
Whether postoperative target volume can be safely reduced awaits the results of this
study.
Bone fractures after adjuvant RT in limb salvage patients can be quite morbid and
tend to occur within long bones with an average time to fracture of 4 years, with the
majority within 5 years of treatment (39). These fractures have a high nonunion rate
and can be quite morbid. Overall fractures these are infrequent: 4.5% to 7.6% from
preop RT in the 2D to 3D era (38,58,104,110), 3.4% with BRT (93), 4% to 6.4% with
IMRT (97,103). One of the dose parameters found to correlate with fracture is V40. The
risk of RT-induced fracture appears to be reduced if V40 <64%. Mean dose to bone
<37 Gy or maximum dose anywhere along length of bone <59 Gy are also significantly
associated with lower risk of fracture (38). Mean dose to bone greater than 40 Gy and
femoral neck location has also been associated with higher risk of fracture (40). A
nomogram to predict radiation-associated fracture of the femur for STS using variables
including periosteal stripping <10 cm versus 10 to 20 or >20 cm, sex (female worse
than male), age at surgery, anterior compartment worse than adductor or posterior
compartment, tumor size, high radiation dose was found to have high sensitivity and
specificity in predicting pathologic fracture risk (39). Confining the CTV to bone when
there is no radiographic evidence of invasion and optimizing these dosimetric
parameters as well as prophylactic intramedullary fixation for high-risk patients may
help reduce this morbid effect.

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Reirradiation
In patients with recurrent tumor after prior RT, reirradiation if the recurrence is
amenable to conservative excision can be considered; however, high morbidity can be
seen with additional course of RT (111). In a study of 14 patients undergoing
reirradiation (13 with EBRT with or without BRT and one with BRT), for recurrent
extremity or trunk STS, 50% of patients had serious complications leading to
reoperation of permanent impairment of limb function and only 1 remained disease-free
without complications (111–114). Another series found that retreatment dose (median
49.5 Gy) and cumulative dose 100 Gy (93 to 120 Gy) salvaged 36% of patients but
60% had wound complication (113). A study of 26 patients using after loading BRT
(192IR) prescribed between 50 and 80 cGy an hour to 0.5 cm from the implant to a
mean dose of 47.2 Gy after mean prior EBRT of 55.6 Gy found 19% had complications
and found local control in 52% of patients. Reirradiation of patients with recurrent STS
therefore must carefully balance the higher risks of complications and the functional
outcomes of the salvaged limb versus amputation. The difficulty of salvaging recurrent
STS confirms the importance of optimizing upfront management of these patients.

RETROPERITONEAL SARCOMAS
Natural History and Treatment
Retroperitoneal sarcomas (RPS) comprise ∼15% of soft tissue (3). Their size, typically
>10 cm, and the complex retroperitoneal anatomy (see Fig. 34.1) make treatment
challenging (42). Wide surgical margins are not achievable; narrowly negative margins
are achieved in ∼60% to 70% of patients (115) although local recurrence (LR) is
frequent even with negative margins (116). Conventional EBRT is problematic because
the required target dose may exceed small bowel, kidney, and liver tolerance. Many RPS
deaths are from uncontrolled locoregional disease, although intermediate and high-
grade RPS have significant rates of distant metastases (117). Although patients with
high-grade RPS are at risk for distant recurrence, there is no level-one evidence that
adjuvant chemotherapy mitigates this risk (118). Given the uncertain benefit of
adjuvant chemotherapy for RPS, it remains investigational (118).
Because of many RPS deaths are related to locoregional disease, improvements in
local tumor control (LC) might improve overall survival, currently ∼50% at 5 years,
although RPS can recur even after 5 years (119,120), illustrated by the Toronto report
of 5- and 10-year survival rates of 36% and 14%, respectively and 5-year locoregional
relapse-free rate of 28% at 5 years dropping to only 9% at 10 years (119).
RPS poses significant surgical challenges. Incomplete (R2) resections are not curative.
There is clear benefit with macroscopically complete (R0 or R1) resection (120–122),
the standard for localized, operable RPS (123). Satisfactory margins may require en-bloc
removal of adjacent viscera (42). Approximately 30% to 40% of gross total RPS
resections have microscopically (+) margins, although their prognostic significance is
unclear, in part reflecting pathologic margin assessment limitations related to specimen
sampling and the complex and variable anatomy (116). Given these limitations, even
patients with (–) margins are at risk for relapse and prognostic factor studies do not
demonstrate a clear association between margin status and LR (116,120).
There is no level-one evidence that postoperative radiation improves LC after R0/R1
resections (124). Many groups do not administer postoperative EBRT after R1 resection,
concerned about potential toxicity to fixed bowel in the tumor bed (125,126). In a small
trial conducted at the U.S. NCI, 35 patients were randomized to receive (1)

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postoperative EBRT 50 to 55 Gy (35 to 40 Gy to an extended field +15 Gy to boost
field) or (2) misonidazole plus electron IORT and postoperative EBRT (35 to 40 Gy)
(127). LR rate was 6/15 (40%) with IORT plus EBRT versus 16/20 (80%) with EBRT
alone (P < 0.001). Significant radiation-related enteritis occurred in 10/20 patients
receiving only higher-dose EBRT compared to 2/15 with IORT and lower-dose EBRT (P
< 0.05), although peripheral neuropathy rates were higher in the IORT + EBRT group,
attributed to overlapping IORT fields and misonidazole. Given the small sample size,
toxicity, and relatively high-LR rates in both arms, the trial is not considered definitive
and has not changed the standard of care. Nevertheless, several other reports of IORT
+ EBRT suggest high rates of LC with higher radiation doses achievable with IORT
(128–130). IORT, generally one 10 to 15 Gy fraction, can, however, be associated with
neural injury or ureteral stricture (131).
Some retrospective reports suggest that EBRT improves LC (123) or delays LR (119),
while others report no value (120,132). In general, these reports, primarily of
postoperative EBRT, include small patient numbers and contain little information on the
treatment selection criteria.
Although both pre- and postoperative EBRT are options, a recent international expert
panel agreed (126) that preoperative RT is well-tolerated, has potential advantages
(133,134), and is preferable to postoperative RT. The advantages for preoperative
irradiation include displacement of much small bowel from the CTV (discussed below)
by the tumor itself, resulting in less toxicity, (2) better gross tumor delineation for
radiotherapy planning, (3) potential for higher-dose delivery to portions of tumor, (4)
potentially lower risk of intraperitoneal dissemination of otherwise viable tumor at
surgery, and (5) possibly higher biologic effectiveness of preoperative radiotherapy.
Disadvantages of postoperative irradiation include bowel frequently falling back into
the RT target area after tumor resection (Fig. 34.2); potentially lower bowel mobility
due to postoperative adhesion formation (resulting in greater dose to fixed loops of
bowel than they were mobile and moving in and out of the treatment field); and the
appropriate dose may be 60 to 66 Gy (i.e., the dose used for postoperative extremity
sarcoma radiation), which is often not tolerable to large abdominopelvic volumes; and
the target volume is more difficult to delineate. While preoperative irradiation also has
potential disadvantages including limited histologic sampling, delay of definitive
surgery, and the quandary posed by positive margins following preoperative RT (86),
the expert consensus panel endorsed preoperative radiation when RT was to be
employed.
In a series of preoperative radiation for RPS from Toronto (135), although the
radiation volume was large (median 7.3 L), preoperative EBRT (median dose, 45 Gy)
was associated with EORTC/RTOG acute toxicity scores <2. In a phase I trial from M.D.
Anderson, patients received preoperative EBRT in escalating doses combined with low-
dose infusional doxorubicin (136). At the maximum dose of 50.4 Gy, preoperative
chemoradiation was well tolerated, with only 18% of participants having grade 3 or 4
nausea. Similarly, a recent series of 31 patients treated with 50 Gy of preoperative RT
at Brigham and Women’s Hospital reported a >grade 3 acute GI toxicity rate of only
3% (137). The low toxicity of preoperative EBRT to these large volumes likely relates to
tumor displacement of much of the bowel from the CTV.
In reports on preoperative EBRT, outcomes appear improved compared to those
expected with surgery alone (138). However, absent level-one data, it is not possible to
determine whether this improvement is real or from selection or other confounding
factors. A randomized study of preoperative radiation versus surgery alone conducted
by the American College of Surgeons Oncology Group (ACOSOG) was terminated early

1082
because of poor accrual. A similar EORTC-led study is currently underway, accruing
well, and will hopefully define the role of preoperative EBRT
(https://clinicaltrials.gov/ct2/show/NCT01344018).

Figure 34.11 A: CT-guided biopsy of a high-grade fibrosarcoma of the second metacarpal. Custom
immobilization device is shown in B: lateral view C: AP view. D: Coronal isodose plan for 3D CRT. E: Axial
isodose plan.

In a dosimetric study, intensity-modulated photons (IMRT) were superior to 3D


conformal photons for RPS (139). Bossi et al. (140) delivered preoperative IMRT
(50 Gy) to a limited CTV encompassing the posterior abdominal wall region at higher
risk for relapse in patients with retroperitoneal liposarcomas; at 27-month median
follow-up, 2/18 patients so treated had an LR. Tzeng et al. (141) safely delivered dose-
painted, dose-escalated preoperative IMRT of 45 Gy to a standard risk volume and
57.5 Gy to the high-risk posterior RPS margin where surgical margins were predicted to
be positive; the actuarial risk of LR at 2 years was 20%. In an effort to further reduce
LR, DeLaney et al. are conducting a phase I/II study with IMRT and IMPT cohorts
testing the hypotheses that further dose escalation to this high-risk margin is possible
with advanced preoperative dose-painting radiation techniques; although protons have

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a lower integral dose (up to ∼60% lower (142)), conformal IMRT might also safely
allow permit dose escalation (https://clinicaltrials.gov/ct2/show/NCT01659203).

Management Guidelines
Given the rarity of RPS, most radiation, surgical, and medical oncologists do not have
extensive experience with treating it. Studies have shown better outcomes for patients
with sarcoma who are managed at centers with experience (143). For this reason,
multidisciplinary consultation at high-volume sarcoma centers is recommended for
patients with RPS. Furthermore, both a surgical oncologist and radiation oncologist
should assess the patient at the time of diagnosis and prior to definitive management.
Consultation with a medical oncologist may also be advisable, especially if the histology
is high grade. It is ideal for multimodality experts to assess the patient together, but
multimodality management conferences or tumor boards are another appropriate forum
in which to discuss management following individual consultations.

Figure 34.12 Treatment set-up and plans for foot sarcoma. A: MRI images showing axials on top and coronal
and sagittal on bottom. B and C: Immobilization using a supportive ankle mold. D: IMRT plan allowing for
maximal sparing of uninvolved bone from high dose both pre- and postoperatively.

1084
Because level-one evidence for the use of RT for retroperitoneal sarcoma is not
available, treatment recommendations may be guided by patient eligibility for ongoing
clinical trials, including those mentioned above, as well as practice guidelines such as
those published by the National Comprehensive Cancer Network. When preoperative
radiation is recommended, the patient must be deemed a surgical candidate, the tumor
must be resectable with intent for macroscopic complete resection, and there should be
no symptoms requiring urgent immediate resection, such as bowel obstruction. The
patient must have localized tumor and be judged a suitable candidate for RT to the
prescription dose of 50.4 Gy with acceptable toxicity (defined by the ability to meet
normal organ constraints).
For preoperative radiation planning/treatment, patients are immobilized with arms
elevated. 4D CT simulation is performed for lesions above the pelvic brim where tumor
motion may occur (144). For RT planning, gross tumor volume (GTV) is defined by CT
or MRI T1 plus contrast images (126). If 4D CT showed GTV motion, an iGTV is defined
capturing motion. The average risk CTV1 is anatomically constrained 1- to 1.5-cm
expansion on the GTV or iGTV with edited reduction at bone, renal, and hepatic
interfaces (0 mm), bowel and air cavity (5 mm), and skin (3 mm) (126). CTV1 is
expanded fully into retroperitoneal muscles but not beyond the peritoneal compartment
or intact fascia. For RPS extending into the thigh through inguinal canal, the inferior
margin would be 3 cm below the GTV and thigh radial margin would be 1.5 cm (i.e.,
similar to extremity sarcoma), but not beyond the compartment, intact fascia, or bone.
There have been studies looking at radiation exclusively to a high-risk posterior target
volume (140) or as a dose–escalated boost to that volume (140), to typically include
tumor margin along posterior retroperitoneal musculature, ipsilateral prevertebral
space, major vessels, or organs to be left in situ after surgery, including ∼1.5 cm of the
GTV abutting the anticipated positive margin and expanding 5 to 10 mm into the
tissues at risk (2). Weekly cone-beam CT scans demonstrated changes in tumor size and
position over the course of treatment and can be important for positional verification
and assessing the need for adaptive replanning (144).

Figure 34.13 Axial (A) and coronal CT (B) scans of a patient with a dedifferentiated liposarcoma.

1085
Figure 34.14 Axial (A) and coronal (B) images from postoperative CT scan on a patient with a dedifferentiated
liposarcoma, illustrating the problem of bowel falling into the anatomic region previously occupied by tumor,
and making postoperative radiation very difficult to deliver because of the large volume of bowel that would be in
the postoperative radiation fields.

Intraoperative radiation can be considered for a boost to the high-risk retroperitoneal


margin at the time of surgery (128–130). Postoperative radiation may be added after
intraoperative radiation has been given a patient who did not receive preoperative
radiation, but in patients who have not received intraoperative radiation, postoperative
radiation if often not feasible without exceeding bowel constraints and is not given in
many sarcoma centers. Figures 34.13 to 34.15 show images of a case of retroperitoneal
sarcoma and the use of preoperative radiation with differential dose painting of
standard clinical risk target volume and high-risk target volume using IMRT and
protons.

Figure 34.15 Standard clinical risk target volume (CTV1) and high-risk boost region (CTV2) in a patient with
undifferentiated pleomorphic sarcoma of the retroperitoneum receiving preoperative radiation to 50.4 GyRBE to
CTV1 and 57.4 GyRBE to CTV2 with scanned beam protons.

1086
BONE SARCOMAS
Primary bone sarcomas are uncommon, with an estimated 2,970 new cases in the
United States in 2016 (2). Because these tumors are relatively uncommon and present in
a variety of anatomic locations, most clinicians see these tumors infrequently. Because
successful treatment with good functional outcome may require specialized surgical
expertise including complex reconstructive techniques, aggressive chemotherapy, and
sophisticated radiation techniques, referral to centers with experienced
multidisciplinary sarcoma teams is the most appropriate management strategy.
The common histologic subtypes in order of frequency include osteosarcomas,
chondrosarcomas, Ewing sarcoma, and chordoma. Chemotherapy is a critical
component of all patients with Ewing sarcoma and most patients with intermediate and
high-grade osteosarcomas. In contrast, chondrosarcomas and chordomas respond poorly
to chemotherapy, which is not commonly used as a component of primary treatment.
Surgery is the preferred treatment for the primary site in the majority of patients and
results in very high rates of local control in patients with extremity tumors. In the case
of primary extremity osteosarcomas, for example, the rate of local control with
chemotherapy and surgical resection is over 90% (145). In contrast, osteosarcoma
lesions of the head and neck, spine, and pelvis, local control with surgery and
chemotherapy is less favorable. The local recurrence rate for lesions in the pelvis was
70% in 67 patients reported by the Cooperative Osteosarcoma Study Group, with
recurrence developing in 31 of 50 (62%) who underwent resection and 16 (94%) of 17
who did not (146). Of 22 patients with spinal osteosarcomas reported by Ozaki et al.
(147), 15 (68%) experienced local failure. For patients with head and neck
osteosarcoma, local control is achieved in approximately 50% of patients, with the
mandible the most favorable site, followed by the maxilla and then extragnathic sites
(zygoma, orbit, nasoethmoid, and cranial bones) (148,149).
Radiotherapy can be useful in helping to secure local control in these unfavorable
sites, which include pelvis, sacrum, spine, and craniofacial tumors (146,150). Radiation
can be employed as neoadjuvant (preoperative), adjuvant (postoperative or
intraoperative), or primary local therapy depending upon the site and type of tumor,
the availability and acceptability of the surgical option, and the efficacy of the
chemotherapy. Neoadjuvant (preoperative) radiotherapy can be delivered prior to
resection of spine (151) or pelvic sarcomas (152). Adjuvant radiation is employed for
patients with bone sarcomas with positive or inadequate margins and in selected other
situations that might include presentation with a pathologic fracture (153), poor
histologic response to chemotherapy (154), or intralesional excision of or
intramedullary rod placement through a radiographically or cytologically benign-
appearing lesion later found to be sarcoma on review of final pathologic material.
Radiotherapy as the primary local therapy without surgery is used for medically
inoperable patients, for patients with axial Ewing sarcomas or extremity Ewing
sarcomas where surgery would compromise function (155), and for patients with
primary bone tumors involving the upper sacrum (37,156), portions of the pelvis, the
base of skull, and the ethmoid/sphenoid sinus region where complete resection is either
not technically possible or acceptable to the patient (158,159).
Ewing sarcomas are quite radiation sensitive, and the original description of this
tumor by James Ewing made note of the fact that the radiation sensitivity of this tumor
was one of the features distinguishing it from other bone sarcomas (160). Unresected
tumors or gross residual disease is usually treated with 55.8 Gy in association with
chemotherapy (155). Consideration of higher doses for high-risk bulky axial tumors may

1087
be appropriate. Vertebral lesions, because of spinal cord constraints, have often been
treated to doses of 45 to 50 Gy. Microscopic residual disease is usually treated to 50.4
Gy.
Chondrosarcomas and osteogenic sarcomas require doses of approximately 66 Gy for
control of microscopic residual disease and doses of >70 Gy for control of gross
residual disease (151). Because most osteosarcomas are treated in conjunction with
chemotherapy, the MGH has managed patients (particularly younger patients) with
unresectable or gross residual osteosarcoma with induction chemotherapy with using
adriamycin, platinum, and methotrexate per established protocols and then, after ∼12
weeks of chemotherapy, deliver radiation of 72 Gy in 40 fractions of 1.8 Gy daily via
shrinking field technique concurrent with chemotherapy, generally ifosfamide/etoposide
(150). Chondrosarcomas in patients with gross disease have been generally managed
with 70 to 77.4 Gy at 1.8 to 2 Gy tissues (151). Chordomas require doses of ∼70 Gy for
microscopic residual disease and doses of >75 Gy for control of gross residual disease
(151).
Chapter 19 provides additional discussion of the use of protons for osteosarcomas,
chondrosarcomas, Ewing sarcoma, and chordoma, and the readers are referred to that
chapter for these clinical results. Some additional important experience with photons
includes that from The Princess Margaret Hospital and colleagues in Toronto who
reported on 60 patients who underwent surgery and photons for extracranial high-risk
CS (161). Preoperative RT (median dose 50 Gy) and postoperative RT (median dose 60
Gy) were used in 40% and 60% of the patients, respectively. Sites included pelvis/lower
extremity (48%), chest wall (22%), spine/paraspinal (17%), and head and neck (13%).
Median follow-up was 75 months. The crude local control rate was 90%. Patients with
R0, R1, and R2 resections had local control rates of 100%, 94%, and 42%, respectively.

SBRT FOR SARCOMAS


The most common sites of metastasis for most soft tissue and bone sarcomas are the
lungs, followed by bone and soft tissue. Although pulmonary metastatic disease is
generally incurable, lung metastasectomy in patients with lung metastases has shown a
not-insignificant percentage of patients surviving long-term (7% to 18%) and 3-year
oversurvival ranging from 23% to 71% (19,162–172). However, not all patients are
medically operable; reports of pulmonary metastasectomy found that up to 1/3 of
patients were not surgical candidates. Recently SBRT has been shown to be a feasible
and effective option for local control. This topic is addressed in more detail elsewhere in
the book but we will briefly describe the key studies related to sarcomas. A study of 50
patients with five or fewer lung metastases including sarcomas treated to 50 Gy in 5 Gy
per fraction found 83% local control of treated lesions with 2% grade 3 toxicity (173).
The first study of SBRT for PM from STS primary reported high local lesion control of
97% at 3 years for 67/69 patients who received 50 Gy in 10 fractions (BED 2 Gy =
62.5). None had grade ≥3 toxicity with median survival of 2.1 years (0.8 to 11.5 years)
with SBRT versus 0.6 years without SBRT (P = 0.002) (174). Another study using SBRT
of 54 Gy in 3 to 4 fractions in 16 high-grade sarcoma patients found 94% local control
at 43 months without any radiation pneumonitis or esophagitis to be safe and effective
in pulmonary metastases in soft tissue sarcoma (175). Other studies since have found
SBRT to be safe and effective for pulmonary metastases from both bone and soft tissue
sarcomas (176–178). SBRT therefore should be considered among the options available
for sarcoma patients with pulmonary lung metastases (Fig. 34.17).

1088
Figure 34.17 SBRT plan 50 Gy in 10 Gy per fraction × 5 fractions for a patient with a solitary lung metastasis
who had recurred after bilateral pulmonary metastasectomy and deemed not to be a candidate for reoperation.

KEY POINTS
• Soft tissue and bone sarcomas are rare malignancies that can arise from connective tissue
throughout the body. Proper assessment and management by experienced centers are
associated with optimal outcomes.
• Adjuvant radiotherapy either as preoperative RT or postoperative RT combined with wide
surgical excision leads to high local control rate with good functional outcomes in truncal and
extremity soft tissue sarcoma.
• Optimal treatment of truncal and extremity soft tissue sarcoma require careful assessment of
the feasibility of limb salvage, the planned surgical approach, the role and sequencing of
adjuvant RT, and potential acute and late effects.
• The use of customized immobilization, advanced imaging and consensus atlas for target
volume definition, and image guidance in RT delivery can reduce the RT field. A recent trial
showed that these modern techniques of preoperative RT is associated with decreased late
effects.
• For retroperitoneal sarcoma, preoperative RT is the preferred approach in combination with
resection because of high recurrence rate with surgery alone. Simultaneous integrated boost is
a strategy to escalate the dose to the high-risk retroperitoneal margin.
• For bone sarcomas, advanced techniques such as protons allow adequate dose to be achieved
for high local control.
• Stereotactic radiotherapy can offer an ablative, nonsurgical option for the management of
oligometastases from bone and soft tissue sarcoma.

QUESTIONS
1. What bone constraints have been found to be significantly associated with
reduced risk of fractures after adjuvant RT for extremity soft tissue sarcomas
near or abutting long bones?

1089
A. Mean bone dose <45 Gy
B. V40 <64%
C. Max dose <70
D. V50 <30%
2. What PTV is recommended when IGRT is not used?
A. 3 mm
B. 5 mm
C. 10 mm or more
D. 0 mm
3. Preoperative RT compared to postoperative RT for extremity sarcoma is
associated with:
A. Higher rate of fibrosis, joint stiffness, and edema
B. Higher rate of acute wound complications
C. Lower rate of fibrosis, joint stiffness and edema
D. Both B and C
4. For interstitial brachytherapy in soft tissue sarcoma, implant loading is most
optimal for reducing wound necrosis:
A. >5 days after catheter placement
B. Intraoperatively
C. One day postoperatively
D. There is no limitation
5. When radiation therapy is employed for retroperitoneal sarcoma, the preferred
approach is:
A. Brachytherapy
B. SBRT
C. Preoperative radiation
D. Postoperative radiation

ANSWERS
1. B
2. C
3. D
4. A
5. C

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1100
Index

Note: Page numbers followed by f indicate figures; those followed by t indicate


tables.
A
AAPM. See American Association of Physicists in Medicine (AAPM)
AAPM Report 23, 309
AAPM Report 39, 41
AAPM Task Group 25, 291, 294
AAPM Task Group 70, 309
AAPM Task Group 100, 113
AAPM Task Group 101, 233
AAPM Task Group 166, 377
AAPM TG-43 formalism, 247–248, 248f, 471
Abdomen, 500f, 501
radiation-induced toxicity of, 371
ABS. See American Brachytherapy Society (ABS)
ABS Guidelines Definitive Radiation Therapy
for cervical cancer HDR intracavitary brachytherapy, 441t
for cervical cancer LDR intracavitary brachytherapy, 440t
Abscopal effect, 358
Absolute dosimetry
in scanned proton fields, 321
in scattered proton fields, 319–320
Accelerated fractionation, 346–347
Accelerated hyperfractionation, 347
Accelerated partial breast irradiation (APBI)
patient selection for, 562
treatment planning for, 562–563
Accelerator-mounted imaging systems, 7–8
Acceptance testing
for IMRT, 105
process proposed IAEA, 105–106
in quality assurance, 41, 103, 105–106
ACOSOG Z0011 study, 556–557
Active breathing control (ABC) system, 173
components of, 173f
Acuros XB implementation of BTE, 55–56, 56f, 57f
Acute esophagitis, 370
Acute leukemia, 576–577
Acute lymphocytic leukemia (ALL), 593
ADEPT, 517
ADEPT trial, 517
Adjuvant radiation therapy (ART), for prostate cancer, 467–468
ADT. See Androgen deprivation therapy (ADT)

1101
Adult medulloblastoma craniospinal irradiation, 333
Air gap factor method, 296
AJCC TNM staging system
for bladder cancer, 480t
for testicular cancer, 487t
Algorithms, for treatment planning, 100–101
brachytherapy, 61–74
calculation, 101
clinical application of, 102–103
computer programs for, 101, 102t
development and implementation, 101–103
IAEA TRS-430 questionnaire, 102t
photon dose calculations, 46–57
conditions of charged particle equilibrium, 49
discrete ordinates method, 54–57
electron contamination, 52
kernel spatial variance, 52, 52f
modeling primary photons incident on phantom, 50–51, 51f
Monte Carlo (MC) technique, 53–54
patient representation in, 46–47
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
superposition/convolution, 49–52
radiation database for, 101–102
radiation therapy process and, 99f
ALL. See Acute lymphocytic leukemia (ALL)
American Association of Physicists in Medicine (AAPM), 9, 66, 98, 247, 249
American Brachytherapy Society (ABS), 251, 439
guidelines interstitial HDR brachytherapy for gynecologic cancer, 445t
American College of Surgeons Oncology Group (ACOSOG), 638
American Society for Radiation Oncology (ASTRO), 9
recommendations regarding proton beam therapy, 332
Anal cancer, 413–418
chemotherapy for, 418
diagnostic evaluation of, 413
treatment options for, 413
treatment planning for, 413–418
normal tissue tolerances in, 415–416
radiotherapy dose, 416
radiotherapy fields and techniques, 416, 418
radiotherapy target in, 414–415
simulation, 413–414
Analog simulations, 53
Anaplastic thyroid cancer (ATC), 518, 518f
Androgen deprivation therapy (ADT)
for prostate cancer, 457–458
Angular density of electrons, 54
APBI. See Accelerated partial breast irradiation (APBI)
Aperture generation methods, 139
Applicators

1102
for cervical cancer intracavitary insertions, 281f
electron, 291, 291f
in HDR brachytherapy, 260
for orthovoltage unit, 529, 529f
Arc therapy for IMRT, 141–143
VMAT plan optimization, approaches to, 143
VMAT treatment planning problem, 141–143
Artifacts
of CT, 14
light breathing, 15f
temporal aliasing, 14, 15f
MRI, 17
ASTRO. See American Society for Radiation Oncology (ASTRO)
Astrocytoma
high-grade, 590
low-grade, 589–590
ATC. See Anaplastic thyroid cancer (ATC)
ATRT. See Atypical teratoid rhabdoid tumors (ATRT)
Attenuator (compensator), cross-sectional schematic of, 530f
Attila, 55
Atypical teratoid rhabdoid tumors (ATRT), 587
Automated image registration, 22–23, 23f
Automated image segmentation, of multiple repeat CT data set, 189f
Axial computed tomography image
from IMRT plan, 465f
of seminal vesicles, 462f
Axillary region, 498f
B
BAO. See Beam angle optimization (BAO)
Basal cell carcinomas, 534–536, 545f
Beam angle optimization (BAO), 145–146
Beam modeling, 152–153
Beam shaping, 134–135
Beamlets, 124
Beam’s eye views (BEV), 21–22
image of thoracic tumor, 22f
BED. See Biological equivalent dose (BED)
Benign, 333
Bethe–Bloch equation, 150
BEV. See Beam’s eye views (BEV)
Biochemical failure, 381
Biochemical relapse-free survival (bRFS), 468
Biological equivalent dose (BED), 380
basic fallacies of, 368
caution of, 368
dose/fractionation, 368
in high dose-rate brachytherapy, 263–264
prostate, 468–469
dose fractionation, 468–469

1103
target volume definition, 468
treatment technique, 469
Biologically effective dose (BED) model, 347–349
Bixels, 124
Bladder, radiation-induced toxicity of, 371–372
Bladder cancer
bladder-sparing approaches, 481–482. See also Prostate cancer
diagnosis of, 479–480
nonbladder sparing treatment approaches for, 481
overview, 479
postoperative radiotherapy for, 483
prognosis of, 483–484
risk stratification in, 479
RTOG protocols for invasive, 482t
staging in, 479–480, 480t
Bladder cancer (continued)
survival rate after radical cystectomy for, 482t
treatment options for, 480–482
treatment planning for, 482–483
bladder field, 482–483
simulation, 482–483
tumor boost, 483
whole bladder field in, 482–483, 483f
Blood-oxygen-level dependent (BOLD) effect, 573
Boltzmann transport equations (BTEs), 54–55
Acuros XB implementation of, 55–56
Boltzmann–Fokker–Planck transport equation, 56
Bolus, 300–301
Bone Sarcomas, 640
BP. See Bragg peak (BP)
Brachial plexopathy, 370
Brachial plexus, radiation-induced toxicity of, 370
Brachytherapy, 632–633
Boltzmann transport technique in, 71–73, 73f
defined, 244
dose distributions
asymmetric, 68–69, 69f
three-dimensional, 69–71, 70f, 71f
dose rate calculation
around encapsulated cylindrical source, 65–66, 65f
around line source, 64–65, 65f
around point source, 62–64, 62f, 63f
Boltzmann transport technique, 71–73, 73f
future directions in, 73–74
Monte Carlo transport technique, 71–73, 73f
three-dimensional, 68–69, 69–71, 69f, 70f, 71f
two-dimensional formalism, 66–68
electronic, 533, 534f
encapsulation in low energy problem and, 66
endobronchial, 608

1104
equipment, 6
in gynecologic cancers, 438–445
interstitial, 443–445
intracavitary, 438–443
low-dose rate. See Low-dose rate (LDR) brachytherapy
Monte Carlo transport technique in, 71–73
for prostate cancer, 458
quality assurance of, 111–112
radial dose function, 67
radioisotope, 533
for skin cancer, 533
sources, 245
three-dimensional treatment planning, 69–71
treatment planning algorithms in, 61–74
Bragg peak (BP), 88, 150, 151, 152, 207, 326, 608
protons, 327f
Brain
anatomy of, 569
radiation necrosis of, 368
Brain metastases, 577
Brainstem
dose-volume histograms of, 324f
radiation-induced toxicity of, 368
Breast
anatomy of, 550–553, 551f
blood supply in, 552f
conservation, 554
Breast cancer, 335
breast anatomy, 550–553, 551f
blood vessels, 550, 552f
lymphatic drainage, 550–553, 552f
clinical presentation of, 553–554
dose and fractionation
breast conservation, 561–562
mastectomy scar boost, 562
postmastectomy, 562
tumor bed boost, 562
epidemiology of, 553
helical tomotherapy for, 561
histologic subtypes of, 553–554
IBC, 554
IMRT for, 561
noninvasive, 553
overview, 550
partial breast irradiation
patient selection for, 562
treatment planning for, 562–563
patient selection
for breast conservation, 554
for omission of radiotherapy, 554

1105
for postmastectomy, 554
simulation for, 554–556
breathhold, 555–556, 556f
postmastectomy, 555
prone, 555
supine intact breast, 555
treatment planning for
breast conservation, 556–557
chest wall, tangent fields for, 557, 558f
dose modulation, 559, 561
intact breast, tangent fields for, 557, 558f
internal mammary nodal coverage, 558f, 559
nodal targets, inclusion of, 557, 558f
normal tissue dose constraints, 561
posterior axillary field, 559
postmastectomy, 557
supraclavicular/axillary field, 559, 560f
three-field dual isocenter, 558f, 559
three-field single isocenter, 557, 558f, 559
treatment imaging, 561
volume modulated arc therapy (VMAT) for, 561
Breast conservation
dose and fractionation, 561–562
patient selection for, 554
treatment planning for, 556–557
Breast implant, differential dose-volume histogram for, 276f
Breast setup, in-house simulation, 33f
Breathing movement, 172–173
Bremsstrahlung, 47
production, 289
splitting, 53
bRFS. See Biochemical relapse-free survival (bRFS)
BTEs. See Boltzmann transport equations (BTEs)
C
California Endocurietherapy Center (CEC), 445
Cancers
anal, 413–418
bladder, 479–484
cervical, 426–427
colorectal, 408–413
esophageal, 397–401
gastric, 401–404
head and neck, 509–525
ovarian, 428–429
pancreatic, 404–408
prostate, 123f, 453–473
skin, 527–546
survival curves for, 341f, 344f
testicular, 486–491

1106
thyroid, 518
uterine, 427–428
vaginal, 429–430
vulvar, 429
Carbon ions therapy, 6, 327–328
CBCT. See Cone-beam computed tomography (CBCT)
CBCT image quality, limitations of, 180
CEC. See California Endocurietherapy Center (CEC)
Cell survival models, 379–382, 380f
Central nervous system, radiation-induced toxicity of, 368–369
brain, 368
brainstem, 368
chiasm and optic nerves, 369
spinal cord, 368–369
Central nervous system tumors
adult medulloblastoma craniospinal irradiation, 333
craniospinal irradiation, 577–580
diffusion tensor imaging, 573
dosimetric margins in, 573
embryonal tumors, 586–587, 588f
ependymomas, 581–582
general management of, 571–572
high-grade gliomas in, 581
high-resolution CT scan for, 572
immobilization in, 576
IMRT for, 575
intracranial meningioma, 333
low-grade gliomas in, 580–581
magnetic resonance spectroscopy for, 573
medical therapy for, 571–572
meningiomas, 581
metastatic, epidemiology of, 569, 571
MRI for, 572–573
multimodality imaging in, 572–575
partial brain radiation in, 580
PBT for, 333
benign, 333
pituitary tumors, 581
positioning in, 575–576
primary, epidemiology of, 569
proton therapy for, 575
simulation, 576, 580
spinal tumors, 582
staging of, 571
surgical therapy for, 572
treatment planning for, 580
volume definition, 573
WHO grades of, 569, 570t
whole brain radiation therapy in, 576–580
workup for, 571

1107
Central ray
difference profiles, 108f–109f
doses along, 109f
percentage depth doses, 107f
Cervical cancer. See also Breast cancer
ABS guidelines interstitial HDR brachytherapy for, 445t
interstitial HDR brachytherapy guidelines for, 445t
midline blocks used in patients with, 432f
PET-guided brachytherapy planning for, 443, 443f
radiotherapeutic management of, 426–427
tandem and ovoid applicator used for, 438, 438f
Charged particle equilibrium (CPE), 49
Charged-particle beams, 5–6
carbon ion, 6
electrons beams, 5–6
proton beam, 6
CHART. See Continuous hyperfractionated accelerated radiotherapy (CHART)
CHARTWEL, 347
Chemotherapy
for anal cancer, 418
for colorectal cancer, 412
for gastric cancer, 404
for testicular cancer, 488
Chiasm and optic nerves, radiation-induced toxicity of, 369
Children’s Oncology Group (COG), 585
Child–Turcotte–Pugh (CTP) Class, 237
Chondrosarcoma, 333–334, 642
Chordomas, 334
CI. See Coverage index (CI)
Cisplatin-based chemotherapy, for cochlea, 369
Clinical proton field, 96
Clinical target volume (CTV)
in central nervous system tumors, 573
defined, 3
dumbbell-shaped, 461f
example of double-scattered field delivery, 323f
in HDR, 264
problem of geometric variation and, 168
in prostate, 458–460, 461f
in seminal vesicles, 460
in thorax cancers, 601
uncertainty of, 3–4
CN. See Conformation number (CN)
Cochlea, radiation damage to, 369
COG. See Children’s Oncology Group (COG)
Collimator scatter, 48
Collimators
circular, 529f
multi-leaf, 134–135, 135f
Colorectal cancer, 408–413

1108
chemotherapy for, 412
diagnostic evaluation, 408–409
prognosis of, 413
radiotherapy fields and techniques for, 411–412
treatment options for, 409
treatment planning for, 409–413
normal tissue tolerances in, 411
radiotherapy dose, 411
radiotherapy target in, 410
simulation, 409–410
Commissioning, 103. See also Quality assurance (QA)
defined, 98
in IGRT, 187–188
in QA, 103, 106–111
automated and knowledge-based planning, 110
autosegmentation, 111
image registration, 110–111
IMRT, 109–110
of other components, 107t
photon beams, 106–109, 107f, 107t, 108f, 109f
for SBRT, 233–234
for skin cancer, 528
Compton scatter, 47–48
Computed tomography angiography (CTA), 208–209
Computed tomography (CT), 12–16, 209–213
acquisition for treatment planning, 13–14
acquisition modes, 14
artifacts of, 14
light breathing, 15f
temporal aliasing, 14, 15f
for brain patient, 37f
cone-beam, 16
fiducial rod system, 209–210, 209f
four-dimensional (4D) CT scanning, 15–16
gantry tilt, 210f
of human abdomen, 14f
image, breast patient, 32f
imaging moving anatomy, 14–15
linear attenuation coefficient, 12
phantoms, 210–211, 212f, 213
scan for masked-based system, 210, 211f
tables, 210
volumetric imaging in treatment room, 16
Winston–Lutz phantom and, 212f
Computed tomography simulator
defined, 7
for treatment planning, 7
virtual simulation and, 7
Condensed history electron transport technique, 53
Cone beam CT, 573

1109
Cone-beam computed tomography (CBCT), 16
Conformation number (CN), 278
Contamination electrons, 49
Continuous hyperfractionated accelerated radiotherapy (CHART), 347
Contour irregularity, in pencil beam models, 81
Conventional fractionation, 346
Convolution/superposition method, 49–50, 50f
Cooper ligaments, 550
Cord/brainstem buffer, 523f
Coulomb scattering, 288–289
Coverage index (CI), 277
CPE. See Charged particle equilibrium (CPE)
Craniopharyngioma, 591–595
Craniospinal irradiation, 577–580
CT. See Computed tomography (CT)
CT scanners, for treatment planning, 7
CT simulation
defined, 29
immobilization devices and, 32, 35f
process, 32–34
CTA. See Computed tomography angiography (CTA)
CT-compatible testicular shield, 500f
CTLA-4. See Cytotoxic T-lymphocyte-associated antigen (CTLA-4)
CT-simulator, 7, 41
wide bore, 34f
CTV. See Clinical target volume (CTV)
Cu-ATSM, 19
Cutaneous melanoma, skin cancer, 536
CyberKnife™ system, 183–184, 184f
Cytotoxic T-lymphocyte-associated antigen (CTLA-4), 358
D
4D computed tomography imaging, 32, 181–182
respiration-correlated 4D CBCT, 182
respiration-correlated 4DCT, 181–182
3D conformal radiation therapy (CRT), 8
2D photons, 329
3D photons, 329
2D radiographic imaging, 178–179
3D tomographic imaging, 179–181
digital tomosynthesis, 181
hybrid cone-beam CT, 181
kV cone-beam CT, 179–180
kV helical CT, 179–180
MV cone-beam CT, 180–181
MV helical CT, 180–181
DAO. See Direct aperture optimization (DAO)
DCIS. See Ductal in situ carcinoma (DCIS)
Dedifferentiated liposarcoma, 640f
Deformable image registration (DIR), 23–24

1110
in IGRT, 188
Delta rays, 48
Depth-dose distribution
central axis, 80
Depth-dose electron beams, 6
DET. See Distal edge tracking (DET)
Deterministic approaches, to optimization, 265–268
convergent searches, 266
heuristic approaches, 265–266
point-dose optimization, 266–267
polynomial optimization, 267–268
DICOM. See Digital Imaging and Communications in Medicine (DICOM)
Diffuse infiltrating pontine gliomas (DIPG), 590
Diffuse large B-cell lymphoma (DLBCL), 494–495, 496
Diffusion tensor imaging (DTI), 17
Digital Imaging and Communications in Medicine (DICOM)
in IGRT, 189
Digital tomosynthesis (DTS), 181
Digitally reconstructed radiographs (DRRs), 21–22
beam’s eye views and, 21–22
images, 463f
DIPG. See Diffuse infiltrating pontine gliomas (DIPG)
DIR. See Deformable image registration (DIR)
Direct aperture optimization (DAO) methods, 124, 137–141
aperture generation methods, 139
approximate dose calculation, 140
FMO + sequencing approach, limitations of, 137–138
gradient-based leaf position optimization, 139–140
local leaf position optimization, 139–141
optimize leaf positions, 140–141, 140f
for step-and-shoot IMRT, 138–139
stochastic search methods, 139
Discrete ordinates method, 54–57
Acuros XB implementation of BTE, 55–56
photon beam calculations, transport equations for, 55
transport equations, derivation of, 54–55
Distal edge tracking (DET), 162
Distance optimization, in HDR brachytherapy, 266
DLA. See Dose limiting annulus (DLA)
DLBCL. See Diffuse large B-cell lymphoma (DLBCL)
DMLC. See Dynamic multileaf collimator (DMLC)
DNR. See Dose nonuniformity ratio (DNR)
Dose calculations, 153–155
engine, 152
Monte Carlo method, 154–155
primary dose, 152, 155f
quality assurance in, 101
secondary dose, 152–153, 155f
Dose distributions
asymmetric, 68–69, 69f

1111
in high dose-rate brachytherapy, 273–274
three-dimensional, 69–71, 70f, 71f
Dose index, 279
Dose limiting annulus (DLA), 522f
Dose nonuniformity ratio (DNR), 277
Dose planning, radiosurgery, 214–216, 215f, 216f
Dose rate calculation, in brachytherapy
around encapsulated cylindrical source, 65–66, 65f
around line source, 64–65, 65f
around point source, 62–64, 62f, 63f
Boltzmann transport technique, 71–73, 73f
future directions in, 73–74
Monte Carlo transport technique, 71–73, 73f
three-dimensional, 68–69, 69–71, 69f, 70f, 71f
two-dimensional formalism, 66–68
Dose-deposition matrix, 125
Dose–volume effects, 129–130
dose–volume histogram, 130
equivalent uniform dose (EUD), 129–130
Dose–volume histograms (DVH), 130, 377, 378–382
and cell survival models, 380–382, 380f
constraints for OAR, 462t
for HDR brachytherapy, 275–276, 275f, 276f
for HDR prostate implant, 275f
for head and neck (H&N) cancers, 520t, 521t
ideal target, 378–379, 379f
for mandible, 380f
for normal organ (parotid), 379f
for parotid glands and brainstem, 324f
for PTV, 381–382, 382f
Dosimetrists, 10
Dosimetry checks, 114–115
Double scattering, in scattered proton fields, 317–319
DRRs. See Digitally reconstructed radiographs (DRRs)
DTI. See Diffusion tensor imaging (DTI)
DTS. See Digital tomosynthesis (DTS)
Ductal in situ carcinoma (DCIS), 553
DVH. See Dose–volume histograms (DVH)
Dwell positions
around point, 266f
in HDR brachytherapy, 283–284
simulate line source, 284f
Dwell times, 259
Dwell weights, 259
Dynamic delivery, IMRT, 137, 137f
Dynamic multileaf collimator (DMLC), 186–187
E
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 554
Eastern Cooperative Oncology Group (ECOG), 517

1112
EBCTCG. See Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
EBRT. See External-beam radiation therapy (EBRT)
Eclipse Electron Monte Carlo, 292
ECOG. See Eastern Cooperative Oncology Group (ECOG)
ECOMP. See Electronic tissue compensation (ECOMP)
Effective point source, 295
vs. virtual point source, 295–296
EFRT. See Extended field radiotherapy (EFRT)
EI. See External volume index (EI)
Elective nodal irradiation (ENI), 603
Electromagnetic field tracking system, 185f
Electron arc therapy, for skin cancer, 532–533
dwell factor for, 533
electron beam geometry and setup, 532
monitor unit for, 532–533
Electron beam radiotherapy
basic physics and properties of, 288–296
air gap factor, 296
effective point source, 295, 296
field shaping, 290–295, 291f
isodose distributions, 290, 290f, 291f, 292f
percent depth dose, 289–290, 289f, 293f
shielding, 290–295
virtual point source, 295, 296
bolus in, 300–301
calibration and monitor units in, 301–302
central axis percentage depth-dose, change in, 290–295
with change in beam energy, 296–298, 297f, 298f
with change in field size, 292–294, 293f, 294f
with change in SSD, 294–295, 295f
electron arc therapy, 309
electron dose prescription in, 302
electron–electron field junctions for, 304–306, 305f, 306f, 307f
energy mixing in, 309
en-face beams, 302–303
future, 310
heterogeneities and, 299–300, 299f
in irregular fields, 296
mixing with photon beams
monitor unit verification, 309
total skin electron irradiation, 309
overview, 288
photon–electron field junctions for, 306–308, 308f
skin collimation in, 303–304, 304f
on sloping surface, 296–298, 297f, 298f
surface irregularities and, 298–299, 298f
total limb irradiation in, 309
Electron beams, 5–6
basic physics and properties of, 288–296
block, 532t

1113
commissioning of, 111
range of depth of 90% isodose lines of, 513t
for skin cancer, 530–531, 530f, 531t
Electron contamination, 52
Electron dose calculations, sample criteria of acceptability for, 104t
Electron Gamma Shower (EGS4) code, 53
Electron transport, 48–49
Electron Transport (ETRAN) code, 53
Electronic brachytherapy, 533, 534f
Electronic portal imaging devices (EPIDs), 8, 169, 178
in CNS tumor, 573
in MV CBCT, 180–181
Electronic tissue compensation (ECOMP), 561
Elekta Synergy™ unit, 180f
Embryonal tumors of CNS, 586–587, 588f
Emission tomography, 18–19
PET in radiation planning, 18–19
PET/CT scanners, 19
Endobronchial brachytherapy, 608
Energy layer, 152
Energy loss, in IMPT, 150–151
En-face beams, 302–303
ENI. See Elective nodal irradiation (ENI)
EORTC 10981-22023 AMAROS trial, 557
EORTC-GELA group, 498
Ependymomas, 333, 581–582, 587–589
EPIDs. See Electronic portal imaging devices (EPIDs)
EQD2. See Equivalent dose in 2-Gy fractions (EQD2)
Equieffective dose, 381
Equipments, for treatment planning, 5–10
accelerator-mounted imaging systems, 7–8
computers, 8
external beam units, 5–6
charged-particle beams, 5–6
x-ray beams, 5
patient load vs. treatment units, 6–7
brachytherapy equipment, 6
imaging equipment, 6
PET/CT, 7
simulator, 7
Equivalent dose in 2-Gy fractions (EQD2), 381–382, 382f
Equivalent uniform dose (EUD), 129–130, 385–386
ERD. See Extrapolated response dose (ERD)
Erectile dysfunction, 372
Esophageal cancer, 335, 397–401
chemotherapy for, 401
diagnostic evaluation, 397–398
prognosis of, 401
radiotherapy fields and techniques for, 401
treatment options for, 398

1114
treatment planning of, 398–400
CT-based, 399
normal tissue tolerances in, 399
PET imaging, 399–400
radiotherapy dose in, 400
radiotherapy target, 398–399
simulation, 398
Esophageal tumors, 399
Esophagus, radiation-induced toxicity of, 370
ESTRO. See European Society for Therapeutic Radiology and Oncology (ESTRO)
EUD. See Equivalent uniform dose (EUD)
Euler angles, 70
European Society for Therapeutic Radiology and Oncology (ESTRO), 249
Ewing’s sarcoma, 333, 594, 641
Exit beam, 531–532
Extended field radiotherapy (EFRT), 434–436
External beam dose calculation algorithm, 102t
External beam units, 5–6
charged-particle beams, 5–6
x-ray beams, 5
low-energy megavoltage, 5
medium- or high-energy megavoltage, 5
External volume index (EI), 278
External-beam radiation therapy (EBRT)
for gynecologic cancers, 430–438
for prostate cancer, 457
Extrafocal radiation, 48
Extranodal lymphomas, 498–499
Extranodal marginal zone lymphoma, 497
Extrapolated response dose (ERD), 348
Eye shields, 291
F
Failure mode and effects analysis (FMEA), 113
Fault tree analysis (FTA), 113
FDG. See Fluorodeoxyglucose (FDG)
Femoral head, radiation-induced toxicity of, 372
Fermi–Eyges multiple scattering theory, in pencil beam models, 78–80
Fiducial rod system, 209–210, 209f
Field of view (FOV), 14
Field-shaping devices, 319
Figures of merit, HDR treatment planning, 276–278
conformity number, 278
dose outside target, 278
dose uniformity, 277
target coverage, 276–277
Five-fraction thoracic stereotactic body irradiation, guidelines in, 372t
FLAIR, 573
Fletcher–Suit–Delclos device, 438
Fluence map, for IMRT, 124–125, 125f

1115
aperture decomposition of, 135–136, 135f
Fluorodeoxyglucose (FDG), 7
Fluoroscopic imaging, with implant fiducials, 183–184
FMEA. See Failure mode and effects analysis (FMEA)
fMRI. See Functional MRI (fMRI)
Follicular lymphoma, 497
Four-dimensional (4D) CT scanning, 15–16
FOV. See Field of view (FOV)
Fractionation, 227, 340–352
accelerated, 346–347
accelerated hyperfractionation, 347
BED model for, 347–349
cell survival curves, 340–341
conventional, 346
with dose per fraction, 342f
in high dose-rate brachytherapy, 262–263
hyperfractionation, 346
hypofractionation, 347
linear quadratic theory, 340–341, 341f
LQ model in clinical practice, 349–352
overview, 340
rationale for, 341–346
redistribution, 345–346
reoxygenation and oxygen effect, 343–344
repair, 342–343
repopulation, 344–345, 344f, 345f
schemes with typical parameters, 346t
strategies, 346–347
in testicular cancer, 490
FSaII fibrosarcoma tumor, radiation survival curves of, 357f
FTA. See Fault tree analysis (FTA)
Functional MRI (fMRI), 17, 18f
G
Gamma rays, PET and, 18
GammaKnife, 205, 205f, 206, 221, 222
Gantry angles, in SBRT, 230t
Gastric cancer, 401–404
chemotherapy for, 404
diagnostic evaluation, 402
prognosis in, 404
radiotherapy fields and techniques in, 403–404
treatment options for, 402
treatment planning of, 402–403
CT-based, 402
normal tissue tolerances in, 403
PET imaging, 402
radiotherapy dose in, 403–404
radiotherapy target, 403
simulation, 402–403

1116
Gastrointestinal tract cancer
anal cancer, 413–418
chemotherapy for, 418
diagnostic evaluation of, 413
treatment options for, 413
treatment planning for, 413–418
normal tissue tolerances in, 415–416
colorectal cancer, 408–413
chemotherapy for, 412
diagnostic evaluation, 408–409
prognosis of, 413
radiotherapy fields and techniques for, 411–412
treatment options for, 409
treatment planning for, 409–412
esophageal cancer, 397–401
chemotherapy for, 401
diagnostic evaluation, 397–398
prognosis of, 401
radiotherapy fields and techniques for, 401
treatment options for, 398
treatment planning of, 398–400
gastric cancer, 401–404
chemotherapy for, 404
diagnostic evaluation, 402
prognosis in, 404
radiotherapy fields and techniques in, 403–404
treatment options for, 402
treatment planning of, 402–403
overview, 397
pancreatic cancer, 404–408
chemotherapy for, 408
diagnostic evaluation of, 404–405
prognosis of, 408
treatment options for, 405
treatment planning for, 405–408
Gating, 32
Gaussian pencil-beam model, 92, 94–95
Gaussian proton pencil-beam model, 91–96
Gaussian spread, 90–91, 91f
GBBS. See Grid-based Boltzmann solvers (GBBS)
GBD. See Golden beam data (GBD)
GCIG. See Gynecologic Cancer Intergroup (GCIG)
GEC-ESTRO. See Group Européen de Curiethérapie-European Society for Therapeutic
Radiology and Oncology (GEC-ESTRO)
Genitourinary tract cancer
bladder cancer, 479–484
prostate cancer, 453–473
testicular cancer, 486–491
Geometric optimization, in HDR brachytherapy, 265–266
Germ cell tumors, pediatric intracranial, 590–591

1117
Germinomas, 590–591, 591f
Gleason grade, in prostate cancer, 455
Glioblastoma, 335
GOG. See Gynecologic Oncology Group (GOG)
GOG 122 trial, 428
GOG 150 trial, 428
Gold eye shields, 546f
Gold fiducial marker seeds, 460f
Golden beam data (GBD), 98
Gradient calculation, in IMRT, 132–134
gradient descent, improvements to, 133–134
convexity, 134
including second derivatives, 133–134
nonnegativity constraint, handling of, 133
Gradient descent method, 132
Gradient-based leaf position optimization, 139–140
Gradients, radiosurgery, 206–207, 207f
Grid-based Boltzmann solvers (GBBS), 73
Gross disease, 632
Gross tumor volume (GTV), 168
in central nervous system tumors, 573
defined, 3, 168
in prostate, 458–460
PTV vs., 219
in thorax cancers, 600–601
Group Européen de Curiethérapie-European Society for Therapeutic Radiology and
Oncology (GEC-ESTRO), 441, 442f
GTV. See Gross tumor volume (GTV)
Gynecologic Cancer Intergroup (GCIG), 436
Gynecologic cancers
brachytherapy in, 438–445
interstitial, 443–445
intracavitary, 438–443
cervical cancer, 426–427
clinical outcome studies in, 434
computerized dosimetry in, 445
extended field radiotherapy for, 434–436
external-beam therapy for, 430–438
ovarian cancer, 428–429
overview, 426
pelvic-inguinal radiotherapy, 436–437
radiotherapeutic management of, 426–430
radiotherapy techniques for, 430–445
stereotactic body radiotherapy for, 437–438
uterine cancer, 427–428
vaginal cancer, 429–430
vulvar cancer, 429
whole abdominal radiotherapy for, 437
whole pelvic radiotherapy, 430–434, 434f
Gynecologic Oncology Group (GOG), 426

1118
H
Harmonic peripheral dose (HPD), 277
Harmonic treatment dose (HTD), 277
HCC. See Hepatocellular carcinoma (HCC)
HDR iridium-192 (Ir-192) brachytherapy, 471–472
Head and neck
radiation-induced toxicity of, 369–370
skin cancer with perineural invasion, 536
Head and neck (H&N) cancers, 123f
ART and, 523–524
defining dose volume histogram for, 520t, 521t
dose distribution for, 523f
dose limiting annulus (DLA), 522f
epidemiology of, 509
IGRT and, 523–524
IMRT for, 509–510
incidence of, 509
larynx (cT1N0) for, 510f
normal tissue dose constraints for standard fractionation adjuvant/definitive
radiation therapy, 519t–520t
novel radiation therapy and, 524–525
overview, 509
radiation-induced toxicity of, 369–370
target volumes by dose and disease site for, 512t–517t
treatment of, 509–524
dose constraints for, 518–519
dosimetric considerations for, 519t–520t, 519–521, 521t
future, 524–525
general principles for, 509–510
organs at risk for, 518–519
physics challenges, 521–523
recommendations for, 510, 517–518
tumor site and gross tumor volume (GTVp) delineations of, 511t–512t
Heart, radiation-induced toxicity of, 370–371
Hepatocellular carcinoma (HCC), for SBRT, 237–240, 335
metastases, 240
pancreas, 239–240
prostate, 238–239, 239f
spine, 237–238, 238f
Heuristic approaches, to optimization, 265–266
HIF-1α. See Hypoxia-inducible factor 1-alpha (HIF-1α)
High dose rate (HDR) brachytherapy. See also Low-dose rate (LDR) brachytherapy
absolute dose to reference location in, 270, 273
advantages, 259–260
biological equivalent dose in, 263–264
conformity number, 278
disadvantages, 260
dose limitations, 273
dose outside target, 278
dose prescription, 270, 273

1119
dose uniformity, 277
dose–volume histograms (DVH), 275–276, 275f, 276f
equivalent treatments for, 264t
general considerations of, 259–260
inhomogeneity correction using discrete-ordinates algorithm, 272f
maximum contiguous dose in, 274
maximum significant dose in, 273–274
optimization in, 264–270
for cervical cancer intracavitary applications, 268, 270, 271f
convergent searches for, 266
deterministic approaches to, 265–268
distance, 266
geometric, 265–266
inhomogeneity correction, 270, 272f
manual, 268, 269f
point-dose, 266–267
polynomial, 267–268
stochastic approaches to, 268
volume, 266
planning for implantation, 280–284
appliance selection and placement, 281–283
breast implant, 283f
dwell positions, 283–284, 284f
interstitial implants, 282–283, 283f
intracavitary insertions, 281–282, 281f
planar implant, 283f
quality assurance for, 278–280
indicators of reasonableness, 278–280
interstitial implants, 279–280
intraluminal tests for, 278–279
pretreatment checks in, 280
tandem and ovoids in, 279
treatment unit programming in, 280
unified index in, 280
radiobiological considerations of, 260–264
fractionation, 262–263
prescription doses, 262–264
therapeutic ratio, 260–262
relative doses to specified volumes in, 273
tandem and ovoid applicator used for, 438f
treatment plan evaluation, 270–278
dose prescription, 270, 273
figures of merit, 276–278
quantitative assessment of implants, 274–276
target coverage, 276–277
visual evaluation, 273–274
vs. LDR brachytherapy, 259–260
High dose rate techniques, in gynecologic cancer, 439–442
High-dose region, 275
High-energy electron beams, 288. See also Electron beam radiotherapy

1120
High-grade astrocytoma, 590
High-grade gliomas, 581
Hilus, 598
Histogram reduction, 385–386
HL. See Hodgkin’s lymphomas (HL)
Hodgkin’s disease, 593
Hodgkin’s lymphomas (HL), 494
combined modality for, 496
indications for radiotherapy in, 496
prognostic factors for early stage, 495t
Hogstrom algorithm, for calculation of dose distribution, 82f
HPD. See Harmonic peripheral dose (HPD)
HTD. See Harmonic treatment dose (HTD)
Hybrid cone-beam CT, 181
Hyperfractionation, 346, 604
accelerated, 347
Hypofractionation, 347, 604, 632
Hypoxia-inducible factor 1-alpha (HIF-1α), 356–357, 358f, 358f
I
IAEA. See International Atomic Energy Agency (IAEA)
IBC. See Inflammatory breast cancer (IBC)
ICI. See Immune checkpoint inhibitor (ICI)
ICRU. See International Commission on Radiation Units and Measurements (ICRU)
ICRU Report 50, 302
ICRU Report 62, 302
ICRU Report 71, 302
ICRU Report 83, 109
IDC. See Invasive ductal carcinoma (IDC)
IEC. See International Electrotechnical Commission (IEC)
IFRT. See Involved field radiotherapy (IFRT)
IGCCG. See International Germ Cell Cancer Collaborative Group (IGCCG)
IGRT. See Image-guided radiation therapy (IGRT)
ILC. See Invasive lobular carcinoma (ILC)
Image fusion techniques, 110, 214
Image registration, 22–24, 110–111
automated, 22–23, 23f
deformable image registration, 23–24, 24f
in IGRT, 188
Image-guided radiation therapy (IGRT), 5, 377
anatomic variations in, 191–195, 193f
commissioning in, 187–188
correcting dosimetric deviations in, 193–195
correction strategies in, 190–195
3D conformal radiotherapy, 177
data management, 189
DMLC in, 186–187
dosimetric consequences in, 191–195
facilitating tools, 189
future prospective, 195

1121
image guidance, 178f
image registration, 188
information technology infrastructure for, 189
inter-fractional imaging modalities, 178–183
2D radiographic imaging, 178–179
magnetic resonance imaging, 182
optical surface imaging, 183
patient position correction, 183
positron emission tomography, 182–183
respiration-correlated (4D) computed tomography imaging, 181–182
tomographic imaging, 179–181
ultrasound, 183
interfractional setup error correction, 190
management of intrafractional tumor motion, 190
mobile treatment couch approach in, 187
and motion compensation, 183–187
movable gantry approach in, 187
online vs. offline corrections, 190
overview, 177–178
population-based and individualized margins, 190–191
prototype MRI-guided real-time volumetric tracking system for, 186f
quality assurance for, 187–188
real-time electromagnetic localization and tracking in, 185
requirements and considerations of, 187–189
selection of technology in, 189
setup error in, 192f
Imaging, 12–25. See also specific class of imaging techniques
bi-planar image-based target definition, 207–209
computed tomography, 12–16
CT, 209–213
data sets used in treatment, 12–25, 13f
acquired images, 12–20
processed images, 21–25
emission tomography, 18–19
equipment for, 6
magnetic resonance imaging, 16–18
modalities in radiation therapy, 13f
MRI, 213–215
overview of, 12
process, 21–25
automated image registration, 22–23, 23f
beam’s eye views of, 21–22, 22f
deformable image registration (DIR), 23–24, 24f
digitally reconstructed radiographs (DRRs), 21–22
image registration, 22
scientific visualization challenges, 25
segmentation, 21
segmentation nomenclature, 21, 21t
volume visualization, 24–25, 24f
projection, 19

1122
quality assurance images, 20
response, 19
simulation images in, 19–20
surface, 20, 20f
ultrasound, 20, 183
video, 20
volumetric, 12
Imaging and Radiation Oncology Core (IROC), 233
Immobilization, 169
in central nervous system tumors, 576
for children, 585–586
Immune checkpoint inhibitor (ICI), 358
Immunotherapy, 357–358
IMPT. See Intensity-modulated proton therapy (IMPT)
IMRT. See Intensity-modulated radiation therapy (IMRT)
Inflammatory breast cancer (IBC), 554
Inhomogeneity correction, in HDR brachytherapy, 270, 272f
INRT. See Involved node radiotherapy (INRT)
Integral depth dose curves, 15
Intensity modulation
for IGRT, 5
for IMRT, 5
Intensity-modulated fields
delivery of, 127, 129f
illustration of, 127f
Intensity-modulated proton therapy (IMPT), 147, 150–164
individual fields and, 161f
nuclear interactions, 151
LET, 151
RBE, 151
pencil beam scanning, 151–152, 152f
proton interactions, basic physics of, 150–151
energy loss, 150–151
scattering, 150–151
treatment planning process, 152–163
beam modeling, 152–153
beam selection, 157–158
dose calculations, 153–155
evaluation of, 162–163
field shaping, 158–162
imaging for, 155–156
optimization, 158–162
plan design, 157–158
structure definition, 156–157
treatment to sacral chordoma, 163f
Intensity-modulated radiation therapy (IMRT, 634–635
acceptance testing for, 109–110
applications of, 122, 124
arc therapy for, 141–143
VMAT plan optimization, approaches to, 143

1123
VMAT treatment planning problem, 141–143
axial computed tomography image, 465f
beam angle optimization, 145–146
central nervous system tumors, 575
clinical outcome models in, 130, 143–145
concave target volumes, 122, 123f
controlling tradeoffs, 127–128
direct aperture optimization methods, 137–141
FMO + sequencing approach, limitations of, 137–138
local leaf position optimization, 139–141
for step-and-shoot IMRT, 138–139
dose distribution, 128f
dose-deposition matrix, 125
dose-volume effects, 129–130
dose-volume histogram (DVH), 130
equivalent uniform dose (EUD), 129–130
for endometrial nodal disease, 315f
fluence map for, 124–125, 125f
optimization, 127–132
gradient calculation in, 132–134
gradient descent, improvements to, 133–134
nonnegativity constraint, handling of, 133
for head and neck cancers, 509–510
head-and-neck cancer, 123f
integrating uncertainty in, 146–147
intensity-modulated fields, delivery of, 127, 129f
leaf sequencing for, 134–137
aperture decomposition of fluence maps, 135–136, 135f
beam shaping, 134–135
multi-leaf collimators, 134–135, 135f
as optimization problem, 136
sliding window sequencing, 135–136, 136f
step-and-shoot delivery vs. dynamic delivery, 136–137, 137f
optimization algorithms for, 130–132
basic gradient descent method, 132
handling of constraints via penalty functions, 132, 132f
visualization of fluence map, 131, 131f, 132f
organ motion in, 146–147
for pediatric malignancies, 586, 589f
plan for head-and-neck cancer, 127f
planning as optimization problem, formulation of, 125–126
prostate cancer, 123f
proton therapy in age of, 329–334
acute toxicity, 330, 330f
ASTRO recommendations, 332
clinical results with, 333–334
cost-effectiveness, 331–332
potential late toxicity, 330
radiation oncologist, requirements for, 332
secondary malignancy, 330–331

1124
spinal metastasis with, 123f
for thorax cancers, 604, 606
treatment plan, 126, 127f
Interfractional IGRT imaging modalities, 178–183
2D radiographic imaging, 178–179
magnetic resonance imaging, 182
optical surface imaging, 183
patient position correction, 183
positron emission tomography, 182–183
respiration-correlated (4D) computed tomography imaging, 181–182
respiration-correlated 4D CBCT, 182
respiration-correlated 4DCT, 181–182
tomographic imaging, 179–181
digital tomosynthesis, 181
hybrid cone-beam CT, 181
kV cone-beam CT, 179–180
kV helical CT, 179–180
MV cone-beam CT, 180–181
MV helical CT, 180–181
ultrasound, 183
Interfractional setup error correction, IGRT, 190
Interfractional tumor motion, dosimetric effects, 192–193
Internal mammary chain (IMC) electron field, 306–307
Internal target volume (ITV), 146
in thorax cancers, 601
International Atomic Energy Agency (IAEA), 98
International Commission on Radiation Units and Measurements (ICRU), 4
equieffective dose, 381
margins, 4f
recommendations for interstitial implant, 274, 277
tumor volumes and definitions, 459t
volumes, 4f
International cooperative group trial (INTERTECC), 434
International Electrotechnical Commission (IEC), 105
International Germ Cell Cancer Collaborative Group (IGCCG), 488
International Lymphoma Radiation Oncology Group (ILROG), 498, 499
Interstitial brachytherapy
in gynecologic cancers, 443–445
Interstitial implants
figures of merit, 276–278
conformity number, 278
dose outside target, 278
dose uniformity, 277
target coverage, 276–277
in high dose-rate brachytherapy, 282–283, 283f
ICRU recommendations for, 277
quantitative assessment of implants, 274–276
Interstitial prostate implant, isotopes used for, 471t
INTERTECC. See International cooperative group trial (INTERTECC)
Intracavitary brachytherapy

1125
dosimetry for tandem and ovoid insertion, 439f
in gynecologic cancers, 438–443
Intracavitary insertions, in high dose-rate brachytherapy, 281–282
Intracranial meningioma, 333
Intra-fractional real-time imaging and motion compensation, 183–187
electromagnetic localization and tracking, real-time, 185
fluoroscopic imaging with implant fiducials in, 183–184
MRI real-time cine imaging, 186
MRI real-time volumetric imaging, 186
optical fiducial motion surrogates, 184
PET real-time imaging, 186
tumor motion compensation, real-time, 186–187
video-based optical surface imaging, 185
Intrafractional tumor motion, in IGRT
dosimetric effects due, 193
management of, 190
Intraperitoneal 32P, 428–429
Intrarectal balloon device, for stablize prostate position, 459f
Intratreatment prostate movement, 171f
Invasive ductal carcinoma (IDC), 553
Invasive lobular carcinoma (ILC), 553
Inverse planning, 8
Involved field radiotherapy (IFRT), 497, 498f
Involved node radiotherapy (INRT), 497–498
Involved site radiotherapy (ISRT), 498
Ipilimumab, 358
IROC. See Imaging and Radiation Oncology Core (IROC)
Isodose distributions, 290, 290f, 291f
ISRT. See Involved site radiotherapy (ISRT)
ITV. See Internal target volume (ITV)
K
Kerma, in low-dose-rate brachytherapy, 247, 248, 250
Kernel spatial variance, 52, 52f
Kidney, 371
L
Lacrimal gland, 369
Larynx, radiation-induced toxicity of, 370
Larynx (cT1N0) cancer treatment field, 510f
Late salivary dysfunction, 369
Lateral spread parameter (σ) in pencil beam models, 79–80, 79f, 80f
Late-responding normal tissues, 342, 342f, 344
LCIS. See Lobular carcinoma in situ (LCIS)
Leaf sequencing, for IMRT, 134–137
aperture decomposition of fluence maps, 135–136, 135f
beam shaping, 134–135
defined, 135
multi-leaf collimators, 134–135, 135f
as optimization problem, 136

1126
sliding window sequencing, 135–136, 136f
step-and-shoot delivery vs. dynamic delivery, 136–137, 137f
Lentigo maligna, 536
LET. See Linear energy transfer (LET)
Leukemia, 593
acute, 576–577
Linac radiosurgery. See also Radiosurgery
bi-planar image-based target definition, 207–209
dose planning in, 215–216
historic development of, 203–205
imaging
CT, 209–213
MRI, 213–215
localization of, 206–207
overview, 203
planning of, 206–207
prescription isodose, 216–219
PTV vs. GTV, 219
system criteria for, 221–223
treatment, 206–207
delivery, 219–221
margin, 219
procedure, 223–224
Linear energy transfer (LET), 151
Linear quadratic (LQ) model, 349–352, 380
to SRS/SAbR, 358–359
Linear-quadratic cell-survival curve, 341f
Liver, radiation-induced toxicity of, 371
Liver metastases, SBRT for, 236–237
LKB model, 384, 385
Lobular carcinoma in situ (LCIS), 553
Localization technology, 169
Low dose rate techniques, in gynecologic cancer, 439–442
Low dose-rate permanent implants, of prostate, 71
Low-dose rate (LDR) brachytherapy. See also High dose rate (HDR) brachytherapy
basic physics concepts in, 245–250
penetrability of radionuclides, 245
developments in, 244
dosimetry, 247–249
equivalent treatments for, 264t
future developments, 252–253
overview, 244
radionuclides in, 245
physical properties of, 245t
sources, 245, 245t, 246f
calibrations, 249–250
TG-43 formalism, 247–248, 248f
treatment planning for, 250–252, 252t
vs. high dose-rate brachytherapy, 259–260
Low-dose region, 274

1127
Low-energy megavoltage x-ray beams, 5
Low-grade astrocytoma, 589–590
Low-grade gliomas, 580–581
Lugano classification, staging system for primary nodal lymphomas from, 495t
Lung cancer, 234–236, 335, 609–611. See also Thorax/lung cancers
diagnosis and staging for, 598–599
early stage, 234–235
NSCLC, 609–610
PBT for, 335
RTOG trials in, 234–235
SCLC, 610–611
tissue heterogeneity correction in, 605f
Lung lesions, SBRT couch and gantry angles for, 230t
Lungs
QUANTEC recommendations for, 387
radiation-induced toxicity of, 370
SBRT for
normal tissue dose constraints for, 608t
prospective trials in, 234–235
tumor
PBT for, 335
SBRT of central, 235f
Lymph node
target volume in, 460–461
visualization, 18
Lymphatic drainage of breast, 552f
Lymphomas
indications for treatment, 495–497
combined modality therapy, 496
radiation alone, 496–497
relapsed/refractory setting, 497
Lugano classification, staging system, 495t
overview, 494
prognosis of, 494–495
radiation therapy techniques
extranodal lymphomas, 498–499
field design, history of, 497–498
individualized patient care, 504
involved site radiotherapy, 498
motion management, 500–501
on-board imaging, 501–502
planning, 502–504
simulation, 499–500
staging in, 494–495, 495t
Lymphotropic nanoparticle-enhanced magnetic resonance imaging, 18
M
MA20 and EORTC 22922 trials, 556
Magnetic resonance angiography (MRA), 208
Magnetic resonance imaging (MRI), 16–18, 182, 213–215

1128
artifacts, 17
basics of, 16–18
for brain patient, 37f
functional, 17, 18f
lymph node visualization, 18
magnetic resonance spectroscopic imaging, 17–18
in radiation therapy, 18
scan of patient with liver tumor, 17f
target delineation with, 17
in treatment room, 18
Magnetic resonance spectroscopic imaging, 17–18
Malignant pleural mesothelioma (MPM), 613
Malignant spinal cord compression (MSCC), 569, 571
Mandible, osteoradionecrosis risk in, 369–370
Mantle cell lymphoma, 495
Manual reoptimization, in HDR brachytherapy, 268
Martinez Universal Perineal Interstitial Template (MUPIT), 439
Mask function, in dose computation models, 51
Mass stopping power, 88–89
Mastectomy scar boost, 562
Matched peripheral dose, 275
Mathematical pencil beams (MPB), 94
Maximum contiguous dose (MCD), 274
Maximum significant dose (MSD), 273–274
MCD. See Maximum contiguous dose (MCD)
MCNP. See Monte Carlo N-Particle Transport code (MCNP)
MCO. See Multicriteria optimization (MCO)
MCS. See Multiple Coulomb scattering (MCS)
MD Anderson Dose Escalation trial, 466t
Mean central dose, 274
Mean peripheral dose (MPD), 275
Mean proton range, 89
Mediastinal lymphoma, limited radiation fields for, 498f
Mediastinum, 500
Medical physicist, 9–10
roles and responsibilities of, 10t
Medium- or high-energy megavoltage x-ray beams, 5
Medulloblastoma, 333, 586–587
Megavoltage cone-beam CT (MV CBCT), 180–181
Megavoltage helical CT, 180–181
Megavoltage photon production, 47, 48f
Melanoma in situ. See Lentigo maligna
Memorial Sloan Kettering Cancer Center, 402, 437, 469, 471, 489
Meningiomas, 581
Merkel cell carcinoma, 536–537
Metal-oxide semiconductor field-effect transistor (MOSFET), 115
MF. See Mycosis fungoides (MF)
Mid-pelvic computed tomography (CT) image, 432f
MLC. See Multi-leaf collimators (MLC)
Mobile treatment couch approach, in IGRT, 187

1129
Model-based photon dose calculations
algorithms for, 46–57
conditions of charged particle equilibrium, 49
discrete ordinates method, 54–57
electron contamination, 52
kernel spatial variance, 52, 52f
modeling primary photons incident on phantom, 50–51, 51f
Monte Carlo method in, 53–54
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
superposition/convolution, 49–52
basic radiation physics for, 47–49
Compton scatter, 47–48
electron transport, 48–49
megavoltage photon production, 47, 48f
history of, 46
patient representation in, 46–47
Monte Carlo dose calculations, 154–155
Monte Carlo (MC) method
analog simulations, 53
in brachytherapy, 71–73
condensed histories, 53
for proton transport in patient, 94–96
of radiation transport, 53–54
radiotherapy dose calculations, 53–54
for treatment planning of photon and electron beams, 83
variance reduction techniques, 53
Monte Carlo N-Particle Transport code (MCNP), 53, 72
MOSFET. See Metal-oxide semiconductor field-effect transistor (MOSFET)
Motorized wedge, dose profiles, 108f
Movable gantry approach, in IGRT, 187
MPB. See Mathematical pencil beams (MPB)
MPD. See Mean peripheral dose (MPD)
MPM. See Malignant pleural mesothelioma (MPM)
MRA. See Magnetic resonance angiography (MRA)
MRI. See Magnetic resonance imaging (MRI)
MSCC. See Malignant spinal cord compression (MSCC)
MSD. See Maximum significant dose (MSD)
Multicriteria optimization (MCO), 321
Multi-leaf collimators (MLC), 108, 134–135, 134f, 135f
cross-beam profiles under, 109f
Multiple Coulomb scattering (MCS), 150–151, 289
MUPIT. See Martinez Universal Perineal Interstitial Template (MUPIT)
Muscle invasive disease, 481–482
MV CBCT. See Megavoltage cone-beam CT (MV CBCT)
Mycosis fungoides (MF), 537–541
radiation therapy indications, 537
radiation treatment techniques, 537–541
local radiation therapy, 537–538
total-skin electron therapy (TSET), 538, 538f–539f, 540–541

1130
Myxoid liposarcoma, 623
N
National Comprehensive Cancer Network (NCCN), 534, 639
National Institute of Standards and Technology (NIST), 249
Guidelines (NISTG-99), 471
NCCN. See National Comprehensive Cancer Network (NCCN)
Neuroblastoma, 592–593, 592f, 593f
NHLs. See Non-Hodgkin lymphomas (NHLs)
NIST. See National Institute of Standards and Technology (NIST)
Nongerminomatous germ cell tumors, 590–591
Non-Hodgkin lymphomas (NHLs), 494
combined modality for, 496
Noninvasive breast cancer, 553
Non-radiographic imaging
magnetic resonance imaging, 182
optical surface imaging, 183
ultrasound imaging, 183
Nonseminomatous germ cell tumors (NSGCT), 486
Nonsmall cell lung cancer (NSCLC), 327, 601, 604, 606, 609–610
Normal organ volume, 21t
Normal tissue complication probability (NTCP), 130, 378–380
nonuniform irradiation, 385–386
parallel organs in, 385, 388
serial organs in, 385
statistical models, 388
supporting data for, 386–390
uniform irradiation, 385–386
Normal tissue dose constraints
for conventionally fractionated external-beam radiotherapy, 602t
for lung SBRT, 608t
Normal tissue tolerances
in anal cancer, 415–416
basic facts about, 367–368
in colorectal cancer, 411
in esophageal cancer, 399
in gastric cancer, 403
for hypofractionated regimens, 365t–367t
of intracranial OAR, 574t
in pancreatic cancer, 406
for standard fractionation, 364t
variable impacts, 363t
NSCLC. See Nonsmall cell lung cancer (NSCLC)
NSGCT. See Nonseminomatous germ cell tumors (NSGCT)
NTCP. See Normal tissue complication probability (NTCP)
O
OAR. See Organs at risk (OAR)
OER. See Oxygen enhancement ratio (OER)
Optic structures

1131
QUANTEC recommendations for, 388
Optical fiducial motion, 184
Optical surface imaging (OSI), 183
Optically stimulated luminescence (OSL), 115
Optimization, in HDR brachytherapy, 264–270
for cervical cancer intracavitary applications, 268, 270, 271f
convergent searches for, 266
deterministic approaches to, 265–268
distance, 266
geometric, 265–266
inhomogeneity correction, 270, 272f
manual, 268, 269f
point-dose, 266–267
polynomial, 267–268
stochastic approaches to, 268
volume, 266
Organs at risk (OAR), 168
in central nervous system tumors, 574–575
delineation, 443f
DVH constraints for, 462t
in head and neck cancers, 518–519
normal tissue tolerance of intracranial, 574t
in thorax cancers, 601–602
ORN. See Osteoradionecrosis (ORN)
orthovoltage x-ray unit, 529f
OSI. See Optical surface imaging (OSI)
OSL. See Optically stimulated luminescence (OSL)
Osteogenic sarcomas, 642
Osteoradionecrosis (ORN), 369–370
Outpatient treatment, in HDR brachytherapy, 260
Ovarian cancer, radiotherapeutic management of, 428–429
Oxygen enhancement ratio (OER), 343–344, 344f
P
Palliation, 604
Pancreas, SBRT for, 239–240
Pancreatic cancer, 404–408
chemotherapy for, 407f, 408
diagnostic evaluation of, 404–405
prognosis of, 408
treatment options for, 405
treatment planning for, 405–408
normal tissue tolerances, 406
radiotherapy dose, 406
radiotherapy fields and techniques in, 406–408
radiotherapy target, 405–406
simulation, 405
Parallel organs, in NTCP models, 388
Pareto-optimal treatment plans, 144
Pareto-surface navigation methods, 144–145

1132
Parietal pleura, 598
Parotid glands
dose-volume histograms of, 324f
radiation-induced toxicity of, 369
Partial brain radiation, 580
Passive scattering (PS), 150
Patient and organ movement, 168–174
geometric variation problem, 168
position correction, 169–170
adaptive, 170–174
off-line, 170
online, 169–170
positioning systems and, 169
setup variations and, 169
CTV and GTV, 169
minimizing impact of, 169
Patient load vs. treatment units, 6–7
Patient position
immobilization, 169
localization technology, 169
PBS. See Pencil-beam scanning (PBS)
PBT. See Proton beam therapy (PBT)
PCA3. See Prostate cancer antigen 3 (PCA3)
PDD. See Percentage depth dose (PDD); Percentage depth doses (PDD)
Pediatric malignancies
anesthesia in, 585
craniopharyngioma, 591–595
ependymoma, 333
Ewing’s sarcoma, 333, 594
Hodgkin’s disease, 593
immobilization, 585–586
IMRT for, 586, 589f
leukemia, 593
medulloblastoma, 333
neuroblastoma, 592–593, 592f, 593f
overview, 585–586
PBT for, 333
pediatric disease sites/treatment planning for
diffuse infiltrating pontine gliomas (DIPG), 590
embryonal tumors of CNS, 586–587, 588f
ependymomas, 587–589
germinoma/nongerminomatous germ cell tumors, 590–591
high-grade astrocytoma, 590
low-grade astrocytoma, 589–590
proton radiation for, 586, 588f
radiation delivery for children, 585
retinoblastoma, 333, 594–595, 594f, 595f
rhabdomyosarcoma, 333, 594
supratentorial primitive neuroectodermal tumors, 333
three-dimensional treatment planning for, 586

1133
Wilms’ tumor, 592
Pediatric Radiation Oncology Society (PROS), 585
Pelvic fields, 482–483
Pelvic-inguinal radiotherapy, gynecologic cancers, 436–437
Pelvis, radiation-induced toxicity of, 371–372
Pencil beam models
based on multiple scattering theory, 78–80
beam characterization in, 79–80
central axis distribution calculation, 80, 81
computer algorithm in, 82–83
in contour irregularity, 81
coordinate systems for, 79f
Gaussian function and, 79
Gaussian proton, 91–96
isodose distribution, 81, 81f
calculated vs. measured, 81f
lateral spread parameter (σ) in, 79–80, 79f, 80f
limitations of, 80–82
Monte Carlo (MC) methods and, 83
success of, 80–82
in tissue heterogeneities, 81–82, 82f
Pencil-beam scanning (PBS), 150, 151–152, 152f, 157f
field shaping for, 158–162
advanced optimization, 162
Bragg peak placement, 158
field-modifying devices, 161
fluence optimization, 158–161, 159f
irradiation of chest wall, 322f
optimization for, 158f
Pencil-beam scattered field implementation, 93–94
Penile bulb, 372
Percentage depth dose (PDD), 530
Percentage depth doses (PDD), 289–290, 289f
absolute difference, 107f
central ray, 107f
Perineural invasion, head and neck skin cancer with, 536
Peripheral dose, 274
Peripheral uniformity number (PUN), 278
Peripheral-mean ratio (PMR), 275
PET. See Positron emission tomography (PET)
PET/CT. See Positron emission tomography/computed tomography (PET/CT)
Phantom
heterogeneities, 52
modeling primary photons incident on, 50–51, 51f
ray-tracing, incident energy fluence through, 51–52, 51f
Pharyngeal constrictors, 370
Phase-space file, 53
Photon beam calculations, transport equations for, 55
Photon dose calculations
algorithms for, 46–57

1134
conditions of charged particle equilibrium, 49
discrete ordinates method, 54–57
electron contamination, 52
kernel spatial variance, 52, 52f
modeling primary photons incident on phantom, 50–51, 51f
Monte Carlo (MC) technique, 53–54
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
superposition/convolution, 49–52
basic radiation physics for, 47–49
Compton scatter, 47–48
electron transport, 48–49
megavoltage photon production, 47, 48f
history of, 46
patient representation in, 46–47
Photon dose calculations, sample criteria of acceptability for, 104t
Physical pencil beam (PPB), 94
Physicist, medical, 9–10
roles and responsibilities of, 10t
Physicist assistant, 10
Pituitary tumors, 581
PIVOT. See Prostate Cancer Intervention Versus Observation Trial (PIVOT)
Plane films, stereotactic system for, 208f
Planning target volume (PTV), 4
in central nervous system tumors, 573
in prostate, 458–460
in SBRT, 230
in thorax cancers, 601
PMR. See Peripheral-mean ratio (PMR)
Point-dose optimization, in HDR brachytherapy, 266–267
Polynomial optimization, in HDR brachytherapy, 267–268
Position correction, 169–170
adaptive, 170–174
adjustment, 169–170, 170f
decision, 169
measurement systems, 169
off-line, 170
online, 169–170
strategies for, 169–170, 170–172
Positioning
in central nervous system tumors, 575–576
in HDR brachytherapy, 259
systems, 169
Positron emission tomography (PET)
PET/CT scanners, 19
in radiation planning, 18–19
Positron emission tomography/computed tomography (PET/CT), 7, 42, 43, 43f
Postoperative Radiotherapy for Endometrial Carcinoma (PORTEC)-3 trial, 427
Postorchiectomy radiotherapy, in testicular cancer, 488
PPB. See Physical pencil beam (PPB)

1135
Prescription isodose, radiosurgery, 216–219, 217f, 218f, 220f, 220f
Primary dose calculation, 152, 155f
Prioritized optimization, IMRT, 143–144
Probabilistic approach, for IMRT planning, 146–147
Projection imaging, 19
PROS. See Pediatric Radiation Oncology Society (PROS)
Prospective gated image acquisition, 40
Prostate cancer, 123f, 453–473
BED, 468–469
dose fractionation, 468–469
target volume definition, 468
treatment technique, 469
clinical anatomy
anatomy, 453
local growth patterns, 453
regional and distant metastasis, 453
clinical assessment
bone scan for, 455
CT, 454–455
diagnosis, 454
Gleason grade for, 455
MRI for, 455
PET for, 455
PSA screening, 456
risk stratification, 454, 455t, 456t
for staging, 454–455, 454t
ultrasound, 454
dose fractionation for, 466–467
epidemiology of, 453
field setup for
immobilization, 461
localization, 461
simulation, 461
interstitial prostate implant isotopes used for, 471t
PBT for, 335–336
prognosis of, 472–473
radiation therapy in, 453–454
radioisotope implant for, 469–472
indications, 469
isotopes and dose, 471–472, 471t
target volume definition, 469–471
recurrence risk group by NCCN criteria, 455t
RT dose for, 468
SBRT for, 238–239, 239f
target volume in, 458–461
lymph node, 460–461
prostate, 458–460
seminal vesicles, 460
transperineal prostate brachytherapy, 470f
treatment options for

1136
active surveillance, 456–457
androgen deprivation therapy, 457–458
brachytherapy, 458
cryotherapy, 458
external beam radiation therapy, 457
other local therapies, 458
radical prostatectomy, 457
treatment algorithms, 456
watchful waiting, 456
treatment planning for
adjuvant/salvage EBRT, 467–468
EBRT in, 458–467
prostate bed, 468–469
radioisotope implant, 469–472
treatment technique for, 461–466
Prostate cancer antigen 3 (PCA3), 456
Prostate Cancer Intervention Versus Observation Trial (PIVOT), 456
Prostate movement
dominant modes of, 171f
intratreatment, 171f
Prostate-specific antigen (PSA), 381
Proton beam penumbra, 314–315, 315f
Proton beam radiotherapy, 635
absolute dosimetry, 321
clinical case analysis, 321–324
clinical properties of proton beam, 313–316
field-shaping devices in, 319
multi-criteria optimization in, 321
overview, 313
proton beam penumbra, 314–315, 315f
proton fields generation, 316–321
accelerators for, 316–317
scanned proton fields, 320–321
scattered proton fields, 317–320
range-compensators in, 314f
SOBP field in, 317–318, 319
Proton beam therapy (PBT), 6
and advanced technology photon therapy, 329–334
in age of IMRT, 329–334
acute toxicity, 330
ASTRO recommendations, 332
in bone and soft tissue sarcomas, 333–334
in central nervous system tumors, 333
clinical results with, 333–334
cost-effectiveness, 331–332
in ocular tumors, 333
in pediatric tumors, 333
potential late toxicity, 330
radiation oncologist, requirements for, 332
secondary malignancy, 330–331

1137
development of, 328–329
for head and neck tumors, 334–336
breast cancer, 335
esophageal cancer, 335
glioblastoma, 335
hepatocellular carcinoma, 335
lung cancer, 335
prostate, 335–336
history of, 328
for nasopharyngeal carcinoma, 334
for parotid gland carcinoma, 334
Proton fields generation, 316–321
accelerators for, 316–317
scanned proton fields, 320–321
absolute dosimetry, 321
multicriteria optimization in, 321
scattered proton fields, 317–320
absolute dosimetry in, 319–320
double scattering, 317–319
field-shaping devices and, 319
single scattering, 317
Proton lateral spread, dose computation, 90–91, 90f, 91f
Proton therapy, dose computation algorithm
dose distribution models, 91
dose to medium, 89–90, 90f
Gaussian proton pencil-beam model, 91–96
mass stopping power in, 88–89
physics of proton transport in medium and, 86–91
proton interaction in, 86–87
energy lose in, 87
inelastic, 87
proton lateral spread and, 90–91, 90f, 91f
relative biological effectiveness in, 87–88, 88f
scattered field implementation in, 92–93, 93f
pencil-beam, 94
scattered proton field composition, 93–94
water-equivalent depth and proton range, 89, 89f
Proton transport, Monte Carlo method for, 94–96
Protons, 326–327
Bragg peaks, 327f
for thorax/lung cancer, 608–609
vs. 2D photons, 329
PS. See Passive scattering (PS)
PSA. See Prostate-specific antigen (PSA)
PTV. See Planning target volume (PTV)
PUN. See Peripheral uniformity number (PUN)
Q
QA. See Quality assurance (QA)
QC. See Quality control (QC)

1138
Quality assurance (QA)
acceptance testing, 103, 105–106
administration, 116
beam-related information, display, 101
of brachytherapy, 111–112
commissioning of other components, 112, 112t
proton therapy, 111–112
special techniques, 112
commissioning in, 103, 106–111
automated and knowledge-based planning, 110
autosegmentation, 111
image registration, 110–111
IMRT, 109–110
of other components, 107t
photon beams, 106–109, 107f, 107t, 108f, 109f
conventional simulator, 41
current status, 98, 100
defined, 98
dose calculation, 101
dosimetry checks in, 114–115
errors in, 112–113
future possibilities, 100
for high dose rate brachytherapy, 278–280
indicators of reasonableness, 278–280
interstitial implants, 279–280
intraluminal tests for, 278–279
pretreatment checks in, 280
tandem and ovoids in, 279
treatment unit programming in, 280
unified index in, 280
historical perspective, 98, 100
for IGRT, 187–188
imaging and treatment isocenters, 187
imaging quality, 187
motion detection, 187–188
images, 19f, 20
initial dose calculation tests, 107t
methods for patient-specific, 114
patient data, 100–101
patient-specific tests in, 114
program and system documentation in, 113
and quality control, 112–116
reproducibility tests in, 114
risk management, 112
for SBRT, 233–234
system specifications, 103–105, 104t
sources of uncertainties, 103–104
suggested tolerances, 104–105
terminology associated with, 103
of total radiation therapy planning process, 115

1139
treatment planning process, 100–101
user training in, 113–114
Quality assurance team in radiation oncology (QUATRO), 115
Quality audits, 115
Quality control (QC), 103
defined, 98
and quality assurance, 112–116
QUANTEC. See Quantitative analysis of normal tissue effects in the clinic (QUANTEC)
Quantitative analysis of normal tissue effects in the clinic (QUANTEC), 362, 363
Quasi-Newton methods, 134
QUATRO. See Quality assurance team in radiation oncology (QUATRO)
R
Radial dose function, 67
Radiation oncologist, 9
Radiation retinopathy, in retina, 369
Radiation Therapy Oncology Group (RTOG), 115, 427
protocols for invasive bladder cancer, 482t
Radiation therapy planning process, QA of, 115
Radiation-induced liver disease (RILD), 236, 371
Radiation-induced optic neuropathy (RION), 369
Radiation-induced renal dysfunction, 371
Radiation modalities, 632–633
Radioisotope brachytherapy, 533
Radiosurgery
of arterial venous malformations, 206
bi-planar image-based target definition, 207–209
checklist for time-out prior to, 223f
defined, 203
dose planning in, 214–216
gradients, 206–207, 207f
historic development of, 203–205
imaging in
CT, 209–213
MRI, 213–215
localization of, 206–207
overview, 203
particle-beam treatments and, 207
planning of, 206–207
prescription isodose, 216–219
PTV vs. GTV, 219
single dose therapy vs. fractionated therapy, 204f
system criteria for, 221–223
treatment, 206–207
delivery, 219–221
errors, 222f
margin, 219
procedure, 223–224, 223f
ring-based SRS procedure, checklist for, 223, 224f
Radiosurgery beamline, single-scattered proton beam, 316f

1140
Radiotherapy. See also Radiosurgery
overview, 326–338, 327f
proton beam therapy
development of, 328–329
history of, 328
proton therapy in age of IMRT, 329–334
acute toxicity, 330
ASTRO recommendations, 332
in bone and soft tissue sarcomas, 333–334
in central nervous system tumors, 333
clinical results with, 333–334
cost-effectiveness, 331–332
in ocular tumors, 333
in pediatric tumors, 333
potential late toxicity, 330
radiation oncologist, requirements for, 332
secondary malignancy, 330–331
protons vs. photons role in, 326–336
Radiotherapy dose
for anal cancer, 416
for colorectal cancer, 411
in esophageal cancer, 400
in gastric cancer, 403–404
in pancreatic cancer, 406
Radiotherapy target
in anal cancer, 414–415
in colorectal cancer, 410
in esophageal cancer, 398–399
of gastric cancer, 403
of pancreatic cancer, 405–406
Range straggling, 150
Ray line geometries, in dose computation, 78
Ray-tracing, 91
incident energy fluence through phantom, 51–52, 51f
RBE. See Relative biologic effect (RBE)
RC-CBCT. See Respiration-correlated CBCT (RC-CBCT)
RCCT. See Respiration-correlated CT (RCCT)
Real-time electromagnetic localization and tracking, 185
Real-time tumor motion compensation
dynamic multileaf collimator approach, 186–187
in IGRT, 186–187
mobile treatment couch approach, 187
movable gantry approach, 187
RECIST. See Response Evaluation Criteria in Solid Tumors (RECIST)
Rectum, 387–388
radiation-induced toxicity of, 371
Relative biologic effect (RBE), 151, 327
in proton dose, 87–88
Relative dose homogeneity index, 277
Reproducibility tests, in QA, 114

1141
Respiration-correlated CBCT (RC-CBCT), 182
Respiration-correlated CT (RCCT), 181–182
Response Evaluation Criteria in Solid Tumors (RECIST), 19
Retina, radiation retinopathy in, 369
Retinoblastoma, 333, 594–595, 594f, 595f
Retroperitoneal sarcomas
history and treatment, 636–638
management guidelines, 638–640
Retrospective image reconstruction, 40
Rhabdomyosarcoma, 333, 594
Rigid image registration, in IGRT, 188
RILD. See Radiation-induced liver disease (RILD)
RION. See Radiation-induced optic neuropathy (RION)
Risk management, 112
Risk probability number (RPN), 113
RPN. See Risk probability number (RPN)
RTOG. See Radiation Therapy Oncology Group (RTOG)
RTOG 0236 study, 231, 234
S
SBRT. See Stereotactic body radiation therapy (SBRT)
Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), 456
Scanned proton fields, 320–321
absolute dosimetry, 321
multicriteria optimization in, 321
Scattered proton fields, 317–320
absolute dosimetry in, 319–320
composition, 93–94
double scattering, 317–319
field-shaping devices and, 319
single scattering, 317
Scatter/scattering
from beam modifiers, 48
Compton, 47–48
wedges, 51
SCLC. See Small cell lung cancer (SCLC)
Secondary dose calculation, 152–153, 155f
Sensorineural hearing loss (SNHL), 369
Serial organs, in NTCP models, 385
SFUD. See Single field, uniform dose (SFUD)
Shaped field, 158
SIB. See Simultaneous integrated boost (SIB)
Sievert integral, 65–66
Simulation
of anal cancer, 413–414
analog, 53
in bladder cancer, 482–483
for breast cancer, 554–556
in central nervous system tumors, 576, 580
of colorectal cancer, 409–410

1142
of esophageal cancer, 398
of gastric cancer, 402–403
images, 19–20, 19f
in lymphomas, 499–500
of pancreatic cancer, 405
of prostate cancer, 461
in thorax cancers, 600
Simulator, 7
acceptance testing for conventional, 41
computed tomography, 7
specifications of conventional, 7
Simultaneous integrated boost (SIB), 378
Single field, uniform dose (SFUD), 160, 160f
Single intensity-modulated field, 127f
Single scattering, in scattered proton fields, 317
Skin cancer
clinical considerations for, 541–544, 542f–546f
electron beam therapy for, 530–531, 532
extent and size of, 527
overview, 527
photon beam therapy for, 532
radiation delivery modalities for, 528–541
basal and squamous cell carcinomas, 534–536
calibration, 528
commissioning, 528
cutaneous melanoma, 536
electron arc therapy, 532–533
electron beam therapy, 530–531
electronic and radioisotope brachytherapy, 533
exit beam, (field defining devices, field shaping, and protection) from, 531–532
fractionation schedules, 534, 535t
Merkel cell carcinoma, 536–537
mycosis fungoides, 537–541
orthovoltage dose, 535t
superficial and orthovoltage therapy, 528–530
treatment setup, aspects of, 533–534
staging, 527–528
steps in planning irradiation for, 527
target volume determination in, 527–528
Skin collimation, 303–304, 304f
Skull base chordoma, 333–334
Sliding window decomposition, 135, 135f
Sliding window sequencing, 135–136, 136f
Small cell lung cancer (SCLC), 610–611
Small-bowel toxicity, 371
SNHL. See Sensorineural hearing loss (SNHL)
SOBP. See Spread-out Bragg peak (SOBP)
Soft-tissue and bone sarcomas
diagnosis of, 623–624
dose and fractionation, 632

1143
dose constraints and complications, 635–636
grade 2 leiomyosarcoma, 631f
history and treatment, 636–638
history, 622–623
intensity-modulated radiation therapy, 634–635
management guidelines, 638–640
orthogonal daily imaging, 629f
SBRT for, 642
staging for, 623–624, 624t
standard clinical risk target volume (CTV1), 641f
target volume definition, 628–629
treatment planning, 626–628
treatment set-up and plans for foot sarcoma, 639f
treatment set-up for T2bN0M0, 627f
treatment set-up and uncertainties, 632
SPCG-4. See Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4)
SPG. See Sum of positive gradients (SPG)
Sphere packing, 206
Spinal cord
injury, irradiation cause, 368–369
QUANTEC recommendations for, 386–387
radiation-induced toxicity of, 368–369
Spinal tumors, 582
Spine, SBRT for, 237–238, 238f
SPNETs. See Supratentorial primitive neuroectodermal tumors (SPNETs)
Spread-out Bragg peak (SOBP), 151f, 152
absolute dose calculations for, 88f, 94
in proton beam radiotherapy, 317–318, 319
scattered proton field composition and, 93–94
Squamous cell carcinomas, 534–536, 541–546, 542f–546f
SRS/SAbR, radiobiology of
cell survival curves, 357f
HIF-1α, role of, 356–357, 358f, 358f
indirect cell death from vascular damage by, 355–357, 357f
linear quadratic model applicability to, 358–359
mechanism of action for, 357f
overview, 355
radiation-induced immune enhancement with, 357–358
VEGF, role of, 356–357, 358f, 358f
Staffing, 8–10
ACR standards for, 9t
dosimetrists, 10
medical physicist, 9–10
roles and responsibilities of, 10t
radiation oncologist, 9
requirements for clinical radiation therapy, 9t
Standard clinical risk target volume (CTV1), 641f
Standard fractionation
abdomen, 371
central nervous system, 368–369

1144
head and neck, 369–370
hypofractionation and, 372
normal tissue tolerance for, 365t–367t
pelvis, 371–372
thorax, 370–371, 603–604
Step-and-shoot IMRT, 136–137
Stepping source device, 259
Stereoscopic optical surface imaging, 183
Stereotactic body radiation therapy (SBRT)
beams eye view (BEV) for lung, 231f
body frame for, 229f
of central lung tumor, 235f
commissioning for, 233–234
couch and gantry angles, for lung lesions, 230t
dosimetry, 230–233
in early stage lung cancer, 234–235
fusion of planning CT scan to cone beam CT scan, 228f
growth in number of radiation oncology articles dealing with, 378f
for gynecologic cancers, 437–438
for HCC, 237–240
metastases, 240
pancreas, 239–240
prostate, 238–239
spine, 237–238
for liver, 236–237
axial, coronal, and sagittal isodoses, 237f
of liver metastases, 236–237
of lungs
prospective trials in, 234–235
normal tissue dose constraints for, 232t
overview, 227
PTV in, 230
quality assurance for, 233–234
rationale and goals of, 227–228
simulations, 228–230
for thorax/lung cancers, 606
use of, 372
vacuum cushion for, 229f
Stochastic search methods, 139
Stomach, late radiation-induced toxicity, 371
Stopping power, dose computation, 88–89
Streaming term, 55
Subtotal nodal lymph node irradiation (STLNI), 497f
Sum of positive gradients (SPG), 136
Superficial and orthovoltage therapy, for skin cancer, 528–530
backscatter factors, 529
monitor unit calculation, 530
relative exposure factor, 529
stand-In/Off and attenuator correction, 529
treatment units, 528–529, 529f

1145
Superposition/convolution algorithm, for photon dose calculation, 49–52
under conditions of charged particle equilibrium, 49
convolution/superposition method, 49–50, 50f
electron contamination, 52
kernel spatial variance, 52, 52f
modeling primary photons incident on phantom, 50–51, 51f
phantom heterogeneities, 52
ray-tracing, incident energy fluence through phantom, 51–52, 51f
Supraclavicular and axillary nodal fields, 559, 560f
Supratentorial primitive neuroectodermal tumors (SPNETs), 333, 587
Surface imaging, 20, 20f
Symmetric chordoma wrapping, 323f
Symptomatic radiation pneumonitis, 370
T
Tangent fields for intact breast, 557, 558f
Target organ volume, 21t
Target volume
assessment of, 3–4
defined, 3
localization of, 3–4
Task Group 43 (TG43), 66–67
TCP. See Tumor control probability (TCP)
TDLU. See Terminal ductal lobular units (TDLU)
Tele-radium device, 204, 204f
Terma, 50, 51–52
Terminal ductal lobular units (TDLU), 550
Testicular cancer
AJCC TNM staging system for, 487t
diagnosis of, 486
dosage in, 490
fractionation in, 490
overview, 486
para-aortic fields for stage I, 489–490, 490f
postorchiectomy radiotherapy, 488
prognosis of, 490–491
radiation treatment fields for, 489–490
treatment options for, 486–489
chemotherapy, 488, 491t
observation/active surveillance, 488
radiotherapy, 488
stage I seminoma, 488, 491t
stage II seminoma, 488–489, 491t
treatment planning for, 489
Therapeutic ratio, 260–262
Thermoluminescent dosimeters (TLDs), 67, 114–115
Thermoplastic immobilization mask, 499f
Thorax
anatomy of, 598
cancer. See Thorax/lung cancers

1146
radiation-induced toxicity of, 370–371
Thorax/lung cancers
in CTV, 601
diagnostic workup for, 598–599
GTV in, 600–601
in ITV, 601
lung cancer, 609–611
NSCLC, 609–610
SCLC, 610–611
malignant pleural mesothelioma, 613
overview, 598
protons for, 608–609
in PTV, 601
RT delivery for
dose, 606–607
indications, 606
outcomes, 607–609
SBRT, 606, 607f
treatment delivery, 607
treatment planning, 606, 610f
RT principles for, 599–606
beam energy, 604
constraints for conventionally fractionated RT treatments, 602t
dose/fractionation, 603–604
elective nodal irradiation, 603
FDG-PET in, 602–603, 603f
heterogeneity, 604
immobilization, 600
IMRT, 604, 606
localization, 600
motion management, 600
organs at risk, 601–602
simulation, 600
target volumes, 600–601
staging, 598–599
thymomas, 613–614
tissue heterogeneity correction in, 605f
Thymomas, 613–614
indications, 613–614
postoperative RT, 614
preoperative RT, 614
treatment planning, 614
Thyroid, radiation-induced toxicity of, 370
Thyroid cancer, 518
Tissue heterogeneities
correction in lung cancer, 605f
in pencil beam models, 81–82, 82f
TLDs. See Thermoluminescent dosimeters (TLDs)
Tomotherapy, 141, 181f
Total nodal irradiation (TNI), 497f

1147
Total skin electron irradiation (TSEI), 309
Total-skin electron therapy (TSET), 538, 538f–539f, 540–541, 540f, 540t
Transperineal prostate brachytherapy, 470f
Transurethral resection of bladder tumor (TURBT), 479, 480
Treatment plan evaluation
biologic indices in, 382–386
NTCP models, 384–386
TCP models, 382–384
dose escalation protocols, design of, 386–390
dose-volume histograms in, 378–382
in HDR brachytherapy, 270–278
dose prescription, 270, 273
quantitative assessment of implants, 274–276
target coverage, 276–277
visual evaluation, 273–274
overview, 377–378
parallel model to clinical complication data, 389–390
Treatment planning, 3–10. See also Algorithms, for treatment planning
for adjuvant/salvage EBRT, 467–468
radical prostatectomy, 467–468
target volume definition, 468
algorithms in brachytherapy, 61–74
for anal cancer, 413–418
for bladder cancer, 482–483
for brachytherapy, 6
for central nervous system tumors, 580
for colorectal cancer, 409–413
CT scanners for, 7
3D systems for, 8
for EBRT, 458–467
dose fractionation, 466–467
field setup, 461
target volume definition, 458–461
treatment technique, 461–466
electron beams, 288–310
basic physics and properties of, 288–296
bolus in, 300–301
calibration, 301–302
electron–electron field junctions, 304–306
energy mixing, 309
en-face beams, 302–303
heterogeneities, 299–300
in irregular fields, 296
mixing with, 309–310
monitor units of, 301–302
photon–electron field junctions, 306–308
skin collimation, 303–304
on sloping surface, 296–298
surface irregularities and, 298–299
equipments to optimize, 5–10

1148
accelerator-mounted imaging systems, 7–8
brachytherapy equipment, 6
computers, 8
external beam units, 5–6
imaging equipment, 6
patient load vs. treatment units, 6–7
PET/CT, 7
simulator, 6–7
of esophageal cancer, 398–400
field shaping in, 7
of gastric cancer, 402–403
high dose-rate brachytherapy, 259–284
IMPT for, 150–164
intensity modulation in, 5
inverse planning, 8
isodose planning, 9
for pancreatic cancer, 405–408
for prostate bed, 468–469
for radioisotope implant, 469–472
indications, 469
isotopes and dose, 471–472, 471t
target volume definition, 469–471
for rectal cancers, 409–412
staffing and, 8–10
ACR standards for, 9t
dosimetrists, 10
medical physicist, 9–10
roles and responsibilities of, 10t
radiation oncologist, 9
requirements for clinical radiation therapy, 9t
target volume assessment and, 3–4
for testicular cancer, 489
treatment planning algorithms in, 61–74
treatment volume in, 4–5
Treatment planning algorithms
calculation, 101
clinical application of, 102–103
computer programs for, 101, 102t
development and implementation, 101–103
IAEA TRS-430 questionnaire, 102t
radiation database for, 101–102
radiation therapy process and, 99f
Treatment simulation, 29
anatomical and traditional approach in, 29–31
CT-simulation process, 32–34
4D CT-simulation process, 39–41, 40f
defined, 29
overview, 29
typical radiotherapy simulator and, 30f
typical simulation portal and, 31f

1149
verification simulation, 31
virtual simulation, 29
CT-simulator and, 31–32
process, 35–39
Treatment units vs. patient load, 6–7
TSEI. See Total skin electron irradiation (TSEI)
TSET. See Total-skin electron therapy (TSET)
Tumor bed boost, 562
Tumor boost, 483
Tumor cells, FDG and, 7
Tumor control probability (TCP), 130, 382–384
Tumor node metastasis (TNM) system, 599
Tumor volumes and definitions, by ICRU, 459t
U
Ultrasound imaging, 20, 20f, 183
Ultrasound transducer, 183
UN. See Uniformity number (UN)
Uniformity number (UN), 277
User training, in QA, 113–114
Uterine cancer
customized implant plans for, 444f
radiotherapeutic management of, 427–428
V
Vaginal cancer, radiotherapeutic management of, 429–430
Varian linear accelerator, 54f
Varian TrueBeam™ unit, 180f
Variance reduction techniques, 53
Vascular endothelial growth factor (VEGF), 356–357, 358f, 358f
VEGF. See Vascular endothelial growth factor (VEGF)
Verification simulation, 31, 34f
process, 34f, 35–39
VERO™ system, 184f, 187
Vesicourethral anastomosis (VUA), 468
Video imaging, 20
Video-based 3d optical surface imaging, 185
Vienna ring applicator, 444f
Virtual point source, 295
vs. effective point source, 295–296
Virtual simulation, 7, 29
based on three-dimensional reconstruction, 32f, 36f
CT-simulator and, 31–32, 34f
isocenter placement during, 36f
precaution in, 39–40
process, 35–39
spatial resolution and, 39
Visceral pleura, 598
VMAT. See Volumetric modulated arc therapy (VMAT)
Volume effect, 129–130

1150
Volume optimization, in HDR brachytherapy, 266
Volume visualization, 24–25, 24f
Volumetric arc therapy plan, during whole brain radiation therapy, 578f
Volumetric imaging, 12
MRI real-time, 186
in treatment room, 16
Volumetric modulated arc therapy (VMAT), 124, 177
DICOM specification of, 142
illustration of, 142–143, 143f
for IMRT, 141–143
plan optimization, 143
treatment planning problem, 141–143
Voxels, 125
VUA. See Vesicourethral anastomosis (VUA)
Vulvar cancer, radiotherapeutic management of, 429
W
WAFAC. See Wide-angle free-air chamber (WAFAC)
WART. See Whole abdominal radiotherapy (WART)
Whole abdominal radiotherapy (WART)
for gynecologic cancers, 437
isodose distributions from intensity-modulated, 437f
Whole brain radiation therapy, 576–580, 5779f
blocking for C2-whole brain fields, 577f
volumetric arc therapy plan, 578f
Whole pelvic field, 482–483
Whole pelvic radiotherapy, for gynecologic cancers, 430–434, 434f
Wide-angle free-air chamber (WAFAC), 250, 250f
Wilms’ tumor, 592
Worst-case approach, for IMRT planning, 146–147
X
X-ray beams
low-energy megavoltage, 5
medium- or high-energy megavoltage, 5

1151

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