Prostate Cancer: Science and Clinical Practice

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Prostate Cancer

Science and Clinical Practice

Second Edition

Edited by

Jack H. Mydlo

Department of Urology, Temple University Hospital, Philadelphia, PA, USA

Ciril J. Godec

Department of Urology, SUNY Downstate University School of Medicine, Brooklyn, NY

Long Island College Hospital, Long Island, NY, USA

Table of Contents

Cover

Title page

Copyright

List of Contributors

Preface

Part I: Etiology, Pathology, and Tumor Biology

Chapter 1: Population Screening for Prostate Cancer and Early Detection

Abstract

Introduction

Specific criticisms of the USPSTF report

Screening special at-risk populations

Impact of age on prostate screening decisions

Screening/risk assessment in young men

Screening PSA in older men

Conclusions

Chapter 2: Inflammation and Infection in the Etiology of Prostate Cancer

Abstract

Introduction

Histologic prostatic inflammation and prostate cancer

Proliferative inflammatory atrophy

Mechanisms of inflammatory carcinogenesis

Clinical prostatitis and prostate cancer

Infection

Prostatic calculi and other physical or chemical irritants

Changes in genes associated with infection/inflammation that increase the risk of PCA

Diet and prostate cancer risk

Biomarkers for inflammation and prostate cancer

Chemoprevention with ASA or NSAIDs

Conclusions

Chapter 3: Androgen Receptor

Abstract

Introduction

Androgen receptor structure and function

Androgen receptor and the prostate

Androgen receptor activity in castration-resistant prostate cancer

Conclusions

Chapter 4: Novel Research on Fusion Genes and Next-Generation Sequencing

Abstract

Recurrent translocations in prostate cancer

Spectrum of point mutation and copy number alterations in prostate cancer

Conclusions

Chapter 5: Should Gleason Score 6 Still Be Called Cancer?

Abstract

Introduction

Molecular characteristic of Gleason pattern 3 versus 4

Natural history of treated Gleason 6 cancer

Natural history of untreated Gleason 6 cancer

Undergrading

Nomenclature

Conclusions

Chapter 6: High Grade Prostatic Intraepithelial Neoplasia and Atypical Glands

Abstract

Introduction

High-grade prostatic intraepithelial neoplasia

Atypical small acinar proliferation

Conclusions

Chapter 7: Prostate Cancer in the Elderly

Abstract

Introduction

The magnitude of prostate cancer in elderly men

Pathologic characteristics

PSA screening and diagnosis with prostate biopsy

Treatment

Patient preferences and treatment practice patterns in the elderly with prostate cancer

Fitness for prostate cancer treatment in the elderly

Treatment of prostate cancer in elderly patients

Conclusions

Chapter 8: Prostate Cancer and Other Primary Malignancies

Abstract

Background

Prostate cancer and bladder cancer

Prostate cancer and kidney cancer

Prostate cancer and colorectal cancer

Treatment of multiple malignancies

Chapter 9: Biopsy Prophylaxis, Technique, Complications, and Repeat Biopsies

Abstract

Biopsy prophylaxis

Biopsy technique and specimen processing

Complications

Repeat biopsies

Conclusions

Chapter 10: Total and Free PSA, PCA3, PSA Density and Velocity

Abstract

Introduction

PSA

PSA Density

PSA Velocity

PCA3

Chapter 11: Imaging in Localized Prostate Cancer

Abstract

Introduction

Ultrasound

Magnetic resonance imaging

MR spectroscopic imaging

PET/CT

Conclusions

Part II: Genetic Susceptibility and Hereditary Predisposition, Screening, and Counseling

Chapter 12: Prostate Cancer Prevention: Strategies and Realities

Abstract

Introduction

Chemoprevention

Lifestyle factors in prostate cancer prevention

The future of prostate cancer prevention

Acknowledgment

Chapter 13: Prostate-Specific Antigen Screening Guidelines

Abstract

What is PSA?

What is the natural history of prostate cancer?

Are prostate cancer treatments effective?

Is prostate-specific antigen an effective screening test?

Are there risks associated with PSA screening?

What advice should physicians give their patients?

Future directions and research needs

Part III: Epidemiology

Chapter 14: Cancer of the Prostate: Incidence in the USA

Abstract

Introduction

Modern trends in prostate cancer diagnosis in the United States

Risk factors for the development of prostate cancer

Future of prostate cancer incidence in the United States

Chapter 15: International Trends in Prostate Cancer

Abstract

Incidence rates of prostate cancer

PSA screening

Genetic links

Mortality

Conclusions

Chapter 16: Race, Ethnicity, Marital Status, Literacy, and Prostate Cancer Outcomes in the United States

Abstract

Epidemiology

Prostate cancer disparity in African-American men

Marital status and prostate cancer outcomes

The impact of literacy and numeracy

Strategies to reduce disparity in high-risk populations

Chapter 17: Hereditary Prostate Cancer

Abstract

Introduction

Epidemiologic studies of family history and prostate cancer risk

Segregation and linkage studies

Genome-wide association studies in prostate cancer

Next-generation sequencing in prostate cancer

Direct to consumer genetic testing

Conclusions

Chapter 18: Neuroendocrine Prostate Cancer

Abstract

Introduction

Neuroendocrine cells in the healthy prostate

Neuroendocrine differentiation in prostate cancer

Clinical challenges and opportunities

Conclusions

Chapter 19: Breast and Prostate Cancers: A Comparison of Two Endocrinologic Malignancies

Abstract

Introduction

History

Epidemiology

Risk factors

Screening

Prevention

Endocrinology

Molecular cross talk

Management

Advanced disease

Dormancy

Discussion

Part IV: Prevention of Prostate Cancer

Chapter 20: Heart Healthy = Prostate Healthy and S.A.M. are the Ideal Natural Recommendations for Prostate Cancer

Abstract

Key points

Introduction

Primary prevention trials utilizing a pharmacologic agent – the untold story

Notable dietary supplement cancer prevention trials – the untold story

Multivitamins and other dietary supplements – less is more

Lifestyle matters (heart healthy = prostate healthy)

The importance of S.A.M. (statins, aspirin, and/or metformin) and prostate cancer

Conclusions – solving the diet and supplement debate

Chapter 21: Effects of Smoking, Alcohol, and Exercise on Prostate Cancer

Abstract

Introduction

Cigarette smoking

Alcohol

Physical activity

Conclusions

Chapter 22: Environmental and Occupational Exposures and Prostate Cancer

Abstract

Introduction

Agent Orange

Pesticides and farming

Endocrine disruptors

Vitamin D and sunlight

Metals

Rubber manufacturing

Whole body vibration

Other exposures

Conclusions

Chapter 23: Level-1 Data From the REDUCE Study and the PCPT Data

Abstract

Introduction

Incidence

Factors for increased risk of prostate cancer

5-alpha-reductase inhibitors

The Prostate Cancer Prevention Trial (PCPT)

Reduction by Dutasteride of Prostate Cancer Events (REDUCE)

The controversy

Conclusions

Part V: Conservative Management

Chapter 24: Decision Support for Low-Risk Prostate Cancer

Abstract

Introduction

Defining indolent prostate cancer

Individualized predictions

Which prediction model to use?

Clinical applicability

Future perspectives

Conclusions

Chapter 25: Active Surveillance: Rationale, Patient Selection, Follow-up, and Outcomes

Abstract

Introduction

Background

The rationale for surveillance: the natural history and molecular biology of low-grade prostate cancer

Genetic features of low-grade prostate cancer

Metastatic potential

Who is a candidate?

Surveillance follow-up protocols

Conclusions

Part VI: Surgery

Chapter 26: Preoperative Risk Assessment

Abstract

Introduction

Life expectancy

Predictors of final pathology

Partin Tables

Preoperative predictors of biochemical recurrence

D’Amico criteria

CAPRA score

Stephenson nomogram

Preoperative predictors of mortality

The use of pretreatment imaging to predict outcomes

Conclusions

Chapter 27: Is Surgery Still Necessary for Prostate Cancer?

Abstract

Stage migration: increased incidence of localized prostate cancer

Comparative effectiveness research (CER) among different approaches

Challenges to CER among treatments for localized PCa

Risk stratification of localized PCa

Comparing oncological outcomes: RCTs and observational studies

Comparing HRQOL

Comparing costs: who pays?

High-risk disease and surgery as part of a multimodal approach

Salvage RP

Conclusions

Chapter 28: Indications for Pelvic Lymphadenectomy

Abstract

Introduction

Risk stratification for performing pelvic lymphadenectomy

Anatomic extent of pelvic lymphadenectomy

Does pelvic lymph node dissection confer a therapeutic benefit (i.e., a survival advantage)

Can preoperative imaging aid the decision process to perform LND?

Conclusions

Chapter 29: The Surgical Anatomy of the Prostate

Abstract

The prostate

Seminal vesicles

Fasciae

Pelvic musculature

Neuroanatomy

Vascular anatomy

Chapter 30: Radical Retropubic Prostatectomy

Abstract

Introduction

Indications and contraindications

Operative technique

Radical prostatectomy additional considerations

Postoperative complications

Outcomes

Conclusions

Chapter 31: Radiation-Resistant Prostate Cancer and Salvage Prostatectomy

Abstract

Radiotherapy for prostate cancer

Detection of a recurrence after radiotherapy

Postradiotherapy prostate biopsy when recurrence is strongly suspected

Imaging studies to detect a recurrence after radiotherapy

Salvage radical prostatectomy

Complications and quality of life

Conclusions

Chapter 32: Postradical Prostatectomy Incontinence

Abstract

Introduction

Epidemiology and pathophysiology of urinary incontinence after radical prostatectomy

Evaluation of men with postprostatectomy incontinence

Conservative therapy

Surgical planning

Urethral bulking agents

Periurethral constrictors

Continence balloon device

Perineal slings

Artificial urinary sphincter

Stem cell therapy

Conclusions

Chapter 33: Prognostic Significance of Positive Surgical Margins and Other Implications of Pathology Report

Abstract

Introduction

Positive surgical margins

Tertiary Gleason pattern

Lymphovascular invasion

Seminal vesicle invasion

Lymph node positive disease

Conclusions

Acknowledgment

Chapter 34: Open Versus Robotic Prostatectomy

Abstract

Introduction

Surgical technique

Factors influencing outcomes

Functional outcomes

Cost consideration

Conclusions

Chapter 35: The Technique of Robotic Nerve-Sparing Prostatectomy

Abstract

Introduction

Historical perspective

Evolution of nerve-sparing with robotic surgery

Vattikuti Institute prostatectomy

Conclusions

Chapter 36: Anterior Approach to Robotic Radical Prostatectomy

Abstract

Introduction

Patient selection

Patient setup

Access

Surgical steps

Postop

Conclusions

Chapter 37: Posterior Approach to Robotic-Assisted Laparoscopic Radical Prostatectomy

Abstract

Introduction

Relevant anatomy

Posterior approach procedure

Discussion

Conclusions

Chapter 38: The Technique of Robotic Nerve Sparing Prostatectomy: Extraperitoneal Approach

Abstract

Introduction

The technique

Special considerations

Chapter 39: Clinical and Pathologic Staging of Prostate Cancer

Abstract

Introduction

Clinical staging of prostate cancer

Pathologic staging of prostate cancer

Chapter 40: Management of Bladder Neck Contracture in the Prostate Cancer Survivor

Abstract

Introduction

Epidemiology and pathophysiology

Management of BNC

Stress urinary incontinence after BNC therapy

Conclusions

Chapter 41: Reimbursement for Prostate Cancer Treatment

Abstract

Introduction

Economics of open versus robotic radical prostatectomy

Economics of radiation therapy for prostate cancer

Conclusions

Part VII: Radiation Therapy

Chapter 42: Fundamentals of Radiation Treatment for Prostate Carcinoma – Techniques, Radiation Biology, and Evidence Base

Abstract

Introduction

Fundamentals of radiotherapy

Overview of radiation biology

Treatment options in radiotherapy

Acknowledgments

Chapter 43: Radiation with Hormonal Therapy

Abstract

Introduction

Types of androgen deprivation therapy used with radiation therapy

Treatment of high-risk prostate cancer with radiation therapy

The benefit of androgen deprivation therapy in combination with radiation therapy

Dose-escalated radiotherapy and androgen deprivation therapy

Androgen deprivation therapy and radiotherapy after prostatectomy

Side effects of androgen deprivation therapy

Conclusions

Chapter 44: Brachytherapy for Prostate Cancer: An Overview

Abstract

Introduction

Brief historical background of prostate brachytherapy

Technical aspects and sequencing of brachytherapy for prostate cancer

LDR-BT: clinical outcomes

HDR-BT: clinical outcomes

Follow-up after prostate brachytherapy

Conclusions

Chapter 45: Intensity Modulated Radiotherapy and Image Guidance

Abstract

Introduction

Conformal radiation therapy: from conventional 2D to 3D-CRT to IMRT

Dose escalation

Target delineation

Prostate motion

Image guidance

Conclusions

Chapter 46: Proton Beam Therapy

Abstract

Introduction

Historical perspective

Physics rationale

Clinical evidence

Evolving applications and considerations

Chapter 47: Radiotherapy After Radical Prostatectomy: Adjuvant Versus Salvage Approach

Abstract

Introduction

Adjuvant radiotherapy

Salvage radiotherapy

Future directions

Conclusions

Chapter 48: Emerging Modalities in Radiation Therapy for Prostate Cancer

Abstract

Introduction

Identification of patients for radiation therapy

Target identification

Hypofractionation

Future combined modality treatment

Adaptive radiation therapy

New treatment modalities

Part VIII: Clinical Dilemmas

Chapter 49: Management of PSA Recurrences After Radical Prostatectomy

Abstract

Introduction

Definition and natural history

Diagnostic work-up

Treatment options

Conclusions

Chapter 50: Salvage Therapy for Locally Recurrent Prostate Cancer After External Beam Radiation Therapy

Abstract

Introduction

Evaluation

Local salvage treatment options

Investigational modalities

Systemic therapy

Conclusions

Chapter 51: Management of Locally Advanced (Nonmetastatic) Prostate Cancer

Abstract

Introduction

Treatment options

Conclusions

Acknowledgments

Part IX: Advanced Prostate Cancer

Chapter 52: Androgen Deprivation Therapy: Appropriate Patients, Timing to Initiate ADT, and Complications

Abstract

Introduction

Androgen deprivation therapy

Combination therapy

Timing

General complications of ADT

Conclusions

Chapter 53: Bone Health in Prostate Cancer

Abstract

Introduction

Bone physiology and metabolism

ADT-associated osteoporosis and fractures

Detection and prevention of ADT-associated osteoporosis and fractures

Biology of bone metastasis in prostate cancer

Development of bone metastasis

Imaging for bone metastasis

Novel biomarkers for bone metastasis

Prevention of bony metastasis

Localized therapy with EBRT

Management of bone pain

Treatment and management of acute spinal cord compression and pathologic fractures

Prevention of skeletal-related events in prostate cancer

Bone-targeted agents

Receptor activator of nuclear factor-kappa B (RANK) signaling pathway inhibitors

Radiopharmaceuticals (systemic bone-seeking agents)

Disease modifying agents

Novel and emerging therapies

American Urologic Association guideline recommendations for optimal bone health in prostate cancer

Practical management for optimal bone health

Chapter 54: Castration Resistant Prostate Cancer: Role of Chemotherapy

Abstract

Introduction

FDA-approved chemotherapy regimens for mCRPC

Other chemotherapy regimens for mCRPC

When to start chemotherapy?

Duration of chemotherapy

The future of chemotherapy in mCRPC

Conclusions

Chapter 55: Antiandrogen Monotherapy in the Treatment of Prostate Cancer

Abstract

Introduction

The androgen receptor

Androgen-dependent and androgen-independent prostate growth

Steroidal antiandrogens

Nonsteroidal antiandrogens

Antiandrogen monotherapy

Commentary

Conclusions

Chapter 56: Sipuleucel-T – A Model for Immunotherapy Trial Development

Abstract

Introduction

Elucidating the mechanism of action of sipuleucel-T

Enhancing immunogenicity

Interrogation of the neoadjuvant milieu

Using the sipuleucel-T experience as a paradigm for immunotherapy development

Incorporating sipuleucel-T in the clinical states paradigm

Biomarkers of immune response

Conclusions

Chapter 57: Second-Line Hormonal for Castrate-Resistant Prostate Cancer

Abstract

Introduction

First-generation antiandrogens

Estrogens

Cyproterone

Megestrol acetate

Ketoconazole

Aminoglutethimide

Corticosteroids

Second-generation antiandrogens

Abiraterone

Conclusions

Part X: Cryoablation, HIFU and Focal Therapy

Chapter 58: Salvage Cryoablation of the Prostate

Abstract

Introduction

Detection of radiorecurrent prostate cancer

History of cryosurgery

Patient selection for salvage cryoablation

Oncological efficacy of salvage cryoablation

Focal cryotherapy

Complications

Conclusions

Chapter 59: High-Intensity Focused Ultrasound

Abstract

Introduction

How HIFU works

Histopathologic changes associated with HIFU

Guidelines for the use of HIFU

Oncological outcomes

Complications of HIFU and quality of life considerations

Focal HIFU

HIFU in specific settings

Management of HIFU failures

HIFU: future research

Conclusions

Chapter 60: Focal Therapy for Prostate Cancer

Abstract

Introduction

Goals of focal therapy

Candidate selection

Methods for disease mapping

Modalities for focal treatment

Follow-up

Limitations of therapy

Conclusions

Chapter 61: Quality of Life: Impact of Prostate Cancer and its Treatment

Abstract

Introduction

The trifecta, the pentafecta

Instruments for QOL research

Prostate cancer HRQOL studies

HRQOL outcomes of prostate cancer treatment

Spousal/partner assessment of quality of life (QOL)

Impact of quality of life (QOL) changes on overall outcome of treatment

Conclusions

Chapter 62: Impact of Prostate Cancer Treatments on Sexual Health

Abstract

Erectile dysfunction

Anejaculation

Orgasm Changes

Sexual incontinence

Changes in sexual desire

Penile length loss

Part XI: Govermental Policies

Chapter 63: Coding and Billing for Diagnosis and Treatment of Prostate Cancer

Abstract

Introduction

Diagnoses

Prostate cancer screening

Office consultative services (urological consultations)

Diagnostic procedure coding for carcinoma of the prostate

Coding for surgical procedures for carcinoma of the prostate

Coding for drug management of prostatic carcinoma

Other drugs used in the treatment of prostatic carcinoma

Coding for pathological services

MRI-assisted transrectal ultrasound (for fusion-guided biopsy of the prostate gland)

Chapter 64: Health Policy for Prostate Cancer: PSA Screening as Case Study

Abstract

PSA testing: an ongoing dialogue

The statistics

Policy concerns around PSA screening

What considerations should drive prostate cancer policy?

Variations in guidelines and recommendations

The role of shared decision making (SDM)

The way forward

Chapter 65: Legal Implications of Prostate Cancer Screening

Abstract

Introduction

Prostate cancer screening recommendations: a brief review

Clinical practice guidelines: an introduction

The legal implications of prostate cancer screening: clinical practice guidelines and medical malpractice law

Conclusions

Part XII: New Horizons for Prostate Cancer

Chapter 66: New Markers for Prostate Cancer Detection and Prognosis

Abstract

Introduction

Who should be biopsied?

Who should be rebiopsied?

Who should be treated vs monitored?

Therapeutic response assessment

Conclusions

Chapter 67: Testosterone Therapy in Hypogonadal Men with Prostate Cancer

Abstract

Background

Testosterone supplementation following definitive therapy for localized prostate cancer

Can patients on active surveillance with symptomatic hypogonadism receive testosterone therapy?

How is the new thinking being employed in practice?

Subject Index

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List of Contributors

Philip H. Abbosh MD, PhD,     Department of Surgical Oncology, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA

Firas Abdollah MD,     Vattikuti Urology Institute & VUI Center for Outcomes Research Analytics and Evaluation, Henry Ford Hospital, Detroit, MI, USA

Mohan P. Achary PhD,     Department of Radiation Oncology and Radiology, Temple University School of Medicine, Philadelphia, PA, USA

Shaheen Alanee MD, MPH,     Division of Urology, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA

Peter C. Albertsen MD, MS,     Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA

Yousef Al-Shraideh MD,     Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

Gerald Andriole MD,     Division of Urological Surgery, Washington University in St. Louis, St. Louis, MO, USA

Janet E. Baack Kukreja MD,     Department of Urology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

Richard K. Babayan MD,     Boston University School of Medicine, Boston, MA, USA

Brock R. Baker BS,     Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA

Christopher E. Bayne MD,     Department of Urology, The George Washington University, Washington, DC, USA

Marijo Bilusic MD, PhD,     Department of Medical Oncology, Fox Chase Cancer Center/Temple University, Philadelphia, PA, USA

Leonard P. Bokhorst MD,     Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands

David B. Cahn DO, MBS,     Department of Urology, Einstein Healthcare Network, Philadelphia, PA, USA

Daniel J. Canter MD,     Department of Urology, Fox Chase Cancer Center and Einstein Healthcare Network, Philadelphia, PA, USA

David Y.T. Chen MD, FACS,     Department of Surgical Oncology, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA

Ronald C. Chen MD, MPH,     Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA

Juan Chipollini MD,     Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA

Peter L. Choyke MD,     Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Matthew R. Cooperberg MD, MPH,     Department of Urology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

Anthony Costello MD, FRACS, FRCSI,     Departments of Urology and Surgery, Royal Melbourne Hospital and University of Melbourne, Melbourne; Epworth Prostate Centre, Epworth Healthcare, Melbourne, Australia

E. David Crawford MD,     University of Colorado Health Science Center, Aurora, CO, USA

Curtiland Deville MD,     Johns Hopkins University, The Sidney Kimmel Comprehensive Cancer Center, Sibley Memorial Hospital, Washington, DC, USA

Essel Dulaimi MD,     Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA

Danuta Dynda MD,     Division of Urology, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA

John B. Eifler MD,     Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Cesar E. Ercole MD,     Center for Urologic Oncology, Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH, USA

Daniel D. Eun MD,     Department of Urology, Temple University Hospital, Philadelphia, PA, USA

Wouter Everaerts MD, PhD,     Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne; Department of Urology, Royal Melbourne Hospital, Parkville; and Epworth Prostate Centre, Epworth Healthcare, Richmond, Victoria, Australia

Izak Faiena MD,     Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Michael A. Ferragamo MD, FACS,     Department of Urology, State University of New York, University Hospital, Stony Brook, NY, USA

Chandra K. Flack MD,     Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

Tullika Garg MD, MPH,     Urology Department, Geisinger Health System, Danville, PA, USA

Awet Gherezghihir MD,     Department of Surgery (Urology), The Penn State Milton S. Hershey Medical Center, Hershey, PA, USA

Ciril J. Godec MD, PhD,     Department of Urology, SUNY Downstate University School of Medicine, Brooklyn, NY; Long Island College Hospital, Long Island, NY, USA

Leonard G. Gomella MD,     Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Richard E. Greenberg MD, FACS,     Division of Urologic Oncology, Fox Chase Cancer Center, and Temple University School of Medicine, Philadelphia, PA, USA

Baruch Mayer Grob MD,     Urology Section, Hunter Holmes McGuire VA Medical Center, and Division of Urology, Virginia Commonwealth University Health System, Richmond, VA, USA

Giorgio Guazzoni MD,     Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy

Thomas J. Guzzo MD, MPH,     Division of Urology, The Hospital of the University of Pennsylvania, Philadelphia, PA, USA

Ahmed Haddad MBChB, PhD,     Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Maahum Haider MD,     Department of Urology, University of Washington School of Medicine, Seattle, WA, USA

Andrew C. Harbin MD,     Department of Urology, Temple University Hospital, Philadelphia, PA, USA

Eric M. Horwitz MD,     Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

Ahmed A. Hussein MD,     Department of Urology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA; Department of Urology, Cairo University, Oula, Giza, Egypt

Timothy Ito MD,     Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

Thomas W. Jarrett MD,     Department of Urology, The George Washington University, Washington, DC, USA

Lawrence C. Jenkins MD, MBA,     Sexual and Reproductive Medicine Program, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, USA

Joshua R. Kaplan MD,     Department of Urology, Temple University School of Medicine, Philadelphia, PA, USA

Mark H. Katz MD,     Boston University School of Medicine, Boston, MA, USA

Louis R. Kavoussi MD, MBA,     The Arthur Smith Institute for Urology, Hofstra North Shore LIJ School of Medicine, New Hyde Park, NY, USA

Jonathan Kiechle MD,     Department of Urology, University Hospital Case Medical Center, Case Western Reserve University, Cleveland, OH, USA

Simon P. Kim MD, MPH,     Department of Urology, University Hospital Case Medical Center, Case Western Reserve University, Cleveland, OH; Cancer Outcomes and Public Policy Effectiveness Research, COPPER Center, Yale University, New Haven, CT, USA

Laurence Klotz MD,     Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

Michael O. Koch MD,     Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

Chandan Kundavaram MD,     Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Alexander Kutikov MD, FACS,     Department of Urology, Fox Chase Cancer Center, Einstein Urologic Institute, Philadelphia, PA, USA

Costas D. Lallas MD, FACS,     Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Paul H. Lange MD, FACS,     Department of Urology, University of Washington School of Medicine; Institute of Prostate Cancer Research, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Massimo Lazzeri MD, PhD,     Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy

Daniel W. Lin MD,     Department of Urology, University of Washington School of Medicine, Seattle; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Yair Lotan MD,     Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Casey Lythgoe MD,     Division of Urology, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA

Danil V. Makarov MD, MHS,     Department of Urology, Population Health, and Health Policy, NYU School of Medicine, New York, NY, USA

Mark Mann MD,     Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

David M. Marcus MD,     Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

Viraj A. Master MD, PhD, FACS,     Department of Urology, Emory University, Atlanta, GA, USA

Joshua J. Meeks MD, PhD,     Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

Neil Mendhiratta BA,     School of Medicine, New York University Langone Medical Center, New York, NY, USA

Mani Menon MD,     Vattikuti Urology Institute & VUI Center for Outcomes Research Analytics and Evaluation, Henry Ford Hospital, Detroit, MI, USA

Edward M. Messing MD, FACS,     Department of Urology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

Curtis T. Miyamoto MD,     Department of Radiation Oncology and Radiology, Temple University School of Medicine, Philadelphia, PA, USA

Parth K. Modi MD,     Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Jahan J. Mohiuddin BS,     Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA

M. Francesca Monn MD, MPH,     Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

Francesco Montorsi MD,     Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy

Daniel Moon MBBS(Hon), FRACS,     Division of Cancer Surgery, University of Melbourne, Peter MacCallum Cancer Centre, Melbourne; Robotic Surgery, Epworth Healthcare, Melbourne, Australia

Kelvin A. Moses MD, PhD,     Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Judd W. Moul MD, FACS,     Department of Surgery and the Duke Cancer Institute, Division of Urology, Duke University School of Medicine, Durham, NC, USA

Mark A. Moyad MD, MPH,     Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA

Phillip Mucksavage MD,     Perelman School of Medicine, University of Pennsylvania, Pennsylvania, USA

John P. Mulhall MD, MSc, FECSM, FACS,     Sexual and Reproductive Medicine Program, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, USA

Declan G. Murphy MB, FRCS Urol,     Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne; Department of Urology, Royal Melbourne Hospital, Parkville; and Epworth Prostate Centre, Epworth Healthcare, Richmond, Victoria, Australia

Jack H. Mydlo MD, FACS,     Department of Urology, Temple University Hospital, Philadelphia, PA, USA

Joel B. Nelson MD,     Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Jaspreet Singh Parihar MD,     Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Daniel C. Parker MD,     Department of Urology, Temple University Hospital; Department of Urology, Fox Chase Cancer Center, Einstein Urologic Institute, Philadelphia, PA, USA

Lisa Parrillo MD,     Department of Urology, Perelman Center for Advanced Medicine, Philadelphia, PA, USA

Neal Patel MD,     Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Christian P. Pavlovich MD,     James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, MD, USA

Albert Petrossian MD,     Division of Urology, Virginia Commonwealth University Health System, Richmond, VA, USA

Eugene Pietzak MD,     University of Pennsylvania Health Care System, Pennsylvania, USA

Peter Pinto MD,     Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Zachary Piotrowski MD,     Department of Urology, Fox Chase Cancer Center, and Temple University School of Medicine, Philadelphia, PA, USA

Michel A. Pontari MD,     Department of Urology, Temple University School of Medicine, Philadelphia, PA, USA

Sanoj Punnen MD,     Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA

Jay D. Raman MD,     Department of Surgery (Urology), The Penn State Milton S. Hershey Medical Center, Hershey, PA, USA

Adam C. Reese MD,     Department of Urology, Temple University School of Medicine, Philadelphia, PA, USA

Fairleigh Reeves MB, BS,     Departments of Urology and Surgery, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia

Simon Van Rij MD, PhD,     Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne; Department of Urology, Royal Melbourne Hospital, Parkville; and Epworth Prostate Centre, Epworth Healthcare, Richmond, Victoria, Australia

Benjamin T. Ristau MD,     Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Monique J. Roobol PhD,     Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands

Simpa S. Salami MD, MPH,     The Arthur Smith Institute for Urology, Hofstra North Shore LIJ School of Medicine, New Hyde Park, NY, USA

Amirali H. Salmasi MD,     Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Sandeep Sankineni MD,     Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Kristen R. Scarpato MD, MPH,     Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

George R. Schade MD,     Department of Urology, University of Washington School of Medicine, Seattle, WA, USA

Matthew S. Schaff MD,     Department of Urology, Temple University Hospital, Philadelphia, PA, USA

Samir V. Sejpal MD, MPH,     Department of Radiation Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

Neal D. Shore MD, FACS,     Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC, USA

Jay Simhan MD,     Department of Urology, Fox Chase Cancer Center, Einstein Urologic Institute, Philadelphia, PA, USA

Susan F. Slovin MD, PhD,     Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medicine, Weill-Cornell Medical College, USA

Marc C. Smaldone MD,     Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

Joseph A. Smith, Jr. MD,     William L. Bray Professor of Urologic Surgery, Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Andrew J. Stephenson MD, FACS, FRCS(C),     Center for Urologic Oncology, Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA

Ewout W. Steyerberg PhD,     Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands

C.J. Stimson MD, JD,     Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Siobhan Sutcliffe PhD,     Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO, USA

Samir S. Taneja MD,     Department of Urology and Radiology, New York University Langone Medical Center, New York, NY, USA

Vincent Tang MBBS, MSc, DIC, FRCS Urol,     Department of Urology, Royal Melbourne Hospital, Melbourne, Australia; Division of Cancer Surgery, University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Australia

Timothy J. Tausch MD,     Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA

James Brantley Thrasher MD,     Department of Urology, University of Kansas Medical School, Kansas City, KS, USA

Taryn G. Torre MD,     Division of Urology, Radiation Oncology Associates, a Division of Virginia Urology, Richmond, VA, USA

Edouard J. Trabulsi MD, FACS,     Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Baris Turkbey MD,     Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Robert M. Turner, II MD,     Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Willie Underwood, III MD, MPH, MSci,     Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA

Goutham Vemana MD,     Division of Urological Surgery, Washington University in St. Louis, St. Louis, MO, USA

Shilpa Venkatachalam PhD, MA,     NYU Langone Medical Center, NYU School of Medicine, New York, NY, USA

Karen H. Ventii PhD,     School of Medicine, Emory University, Atlanta, GA, USA

Alan Wein MD, PhD(Hon),     Department of Urology, Perelman Center for Advanced Medicine, Philadelphia, PA, USA

Jonathan L. Wright MD, MS,     Department of Urology, University of Washington School of Medicine, Seattle; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Hadley Wyre MD,     Department of Urology, University of Kansas Medical School, Kansas City, KS, USA

Isaac Yi Kim MD, PhD,     Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Melissa R. Young MD, PhD,     Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA

James B. Yu MD,     Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA

Nicholas G. Zaorsky MD,     Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

Sync Reading Stream

What's this?

Preface

The field of urology has changed so much since the first edition of this book came out in 2003. Robotic surgery was still in its infancy, PSA screening was very active, and the economics of health care were different than they are today.

Many of the previous contributors of the first edition of this book have retired or passed, and therefore we have a new generation of innovative, talented, dedicated urologists who have made up the majority of this second edition. New chapters concerning testosterone replacement, legal ramifications of PSA screening, and billing codes have also been included.

The aim of the editors has been to get the latest, most comprehensive topics together in one book that would be of great value to the student, resident, researcher, scientist, and practicing urologist. The next decade will see another generation of new urologists and new therapies for urologic diseases. For now, we hope that this book covers everything you need to know about prostate cancer and its treatment.

Jack H. Mydlo

Ciril J. Godec

Part I

Etiology, Pathology, and Tumor Biology

Chapter 1: Population Screening for Prostate Cancer and Early Detection

Chapter 2: Inflammation and Infection in the Etiology of Prostate Cancer

Chapter 3: Androgen Receptor

Chapter 4: Novel Research on Fusion Genes and Next-Generation Sequencing

Chapter 5: Should Gleason Score 6 Still Be Called Cancer?

Chapter 6: High Grade Prostatic Intraepithelial Neoplasia and Atypical Glands

Chapter 7: Prostate Cancer in the Elderly

Chapter 8: Prostate Cancer and Other Primary Malignancies

Chapter 9: Biopsy Prophylaxis, Technique, Complications, and Repeat Biopsies

Chapter 10: Total and Free PSA, PCA3, PSA Density and Velocity

Chapter 11: Imaging in Localized Prostate Cancer

Chapter 1

Population Screening for Prostate Cancer and Early Detection

Judd W. Moul MD, FACS    Department of Surgery and the Duke Cancer Institute, Division of Urology, Duke University School of Medicine, Durham, NC, USA

Abstract

Population screening for prostate cancer (PCa) is a very controversial and hot topic! In the first 20 years from adoption of the prostate-specific antigen (PSA) test, some organizations supported population-based screening as PSA testing came into widespread use. However, in May 2012, the US Preventive Services Task Force (USPSTF), a government-supported organization, issued a recommendation that PSA testing no longer be performed. In fact, this was not just a guideline against population-based screening but in using PSA in any early detection program. Updated results from the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial show that PSA-screened patients have a lower PCa-specific mortality that has further improved with longer follow up. The USPSTF and other organization committees do not separate the distinction between risks of PSA screening and treatment of diagnosed PCa and this muddies the water with regard to shared decision discussions. The USPSTF only considered mortality in their analyses, ignoring the burden of suffering from advanced cancer. Recent analyses of the ERSPC trial data show a lower rate of progression to metastatic disease and improved quality of life scores for the screened patient population. Furthermore, the USPSTF did not acknowledge that active surveillance is also a standard-of-care treatment approach. They did not make any exception to their recommendation to discourage PSA testing even for those with a familial history of PCa, nor for individuals of African ancestry and other ethnic groups with known higher PCa incidence and mortality rates. In 2013, the American Urological Association (AUA) revised their guidelines also recommending against population-based screening, but advocating for informed decision and generally recommending PSA testing every-other-year for healthy men between the ages of 55 and 69. The AUA, however, abandoned its support for a baseline risk-stratification PSA test for young men in the 40s age group. The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology advocate for a shared decision between patients and their caregivers and do not favor blanket population-based screening. I favor joint decision making based on a patient and physician dialogue concerning the need for PSA screening. I also support the use of a baseline PSA test as a risk stratification tool. This chapter will review the PSA controversy and provide data to support rational early detection methods for PCa.

Keywords

prostate

cancer

screening

PSA

population-based screening

USPSTF

ERSPC

PLCO

Introduction

Prostate cancer (PCa) is the most commonly diagnosed new solid cancer and the second most common cause of cancer-related deaths in men in the United States. The American Cancer Society (ACS) estimated that approximately 241,740 new cases and 28,170 PCa-related deaths would occur in the United States in 2014.¹ PCa is now the second-leading cause of cancer death in men, exceeded only by lung cancer. It accounts for 29% of all male cancers and 9% of male cancer-related deaths.

The prostate-specific antigen (PSA) concentration in the blood is a test approved by the US Food and Drug Administration as an aid to the early detection of PCa. Screening with PSA has been widely used to detect PCa for decades in the United States and many industrialized nations but it continues to be controversial.²–⁵ Until a few years ago, the ACS and the American Urological Association (AUA) recommended PCa screening for men at average risk who are 50 years or older and have a life expectancy of at least 10 years, after the patient and physician discuss the risks and benefits of screening and intervention.⁶–⁷ Screening was recommended for higher-risk groups, such as African-American (AA) men, beginning at age 40 years. There is much debate over the sensitivity of PSA tests and the ultimate effect on morbidity and mortality of detecting PCa at early, potentially clinically insignificant stages, so called overdetection.⁸–⁹

In May 2012, the US Preventive Services Task Force (USPSTF) issued a new guideline against PSA testing and gave the test a D-rating indicating that it resulted in more harm than good.¹⁰ Since this time, the debate has been heated and the AUA and other organizations have now come together to oppose population-based screening.²–⁹ In this chapter, I will further explore this controversy and discuss the rationale and basis for using PSA in the early detection of PCa.

The USPSTF Firestorm

In May 2012, the USPSTF issued an opinion opposing PCa screening using the PSA test.¹⁰ The Task Force is an independent government-appointed panel of experts in prevention and evidence-based medicine composed of primary care providers (internists, pediatricians, family physicians, nurses, gynecologists/obstetricians, and health behavior specialists) who do not typically treat PCa patients. They receive funding from the US Government through the Department of Health and Human Services Agency for Health Care Research and Quality with the charge to conduct scientific evidence reviews of clinical preventive health care services and to develop recommendations for primary care clinicians and health systems.

The recommendations of the USPSTF ignited a firestorm of controversy. I was part of a group, composed of a number of recognized experts in the diagnosis and treatment of PCa, along with specialists in preventive medicine, oncology, and primary care, issued a brief commentary opposing their recommendations when they were initially published.¹¹ We also have articulated a critical analysis of the USPSTF and AUA recommendations.¹²

Specific criticisms of the USPSTF report

In the initial presentation of their review and analysis, the USPSTF proposed to answer four main questions.¹³ The first question asked if PSA-based screening decreases PCa-specific or all-cause mortality.

The Task Force based their recommendations on a review of five studies of the potential benefits of PSA testing but gave significant weight to only two of these studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was conducted in the United States from 1993 to 2001, randomly assigning 76,693 men aged 55–74 years at 10 US study centers to receive either screening, defined as annual PSA testing for 6 years and digital rectal examinations for 4 years or usual care as the control group.¹⁴ After 7 years of follow-up, there were 2820 PCas diagnosed in the screened group and 2322 in the control group (RR, 1.22; 95% CI, 1.16–1.29). The incidence of death per 10,000 person-years was 2.0 in the screened group and 1.7 in the control group (rate ratio, 1.13; 95% CI, 0.75–1.70).

The European Randomized Study of Screening for Prostate Cancer (ERSPC), with screening in all centers between 1994 and 2006, and ongoing continued follow-up and screening in several of the major centers, involved 162,000 men, aged 55–69 years, randomly assigned either to a group offered PSA screening once every 4 years or to a control group that did not receive screening.¹⁵ The cumulative incidence of PCa was 8.2% in the screened group and 4.8% in the control group, but the rate ratio for death from PCa in the screened group as compared with the control group was 0.80 (95% CI, 0.65–0.98; adjusted p = 0.04), resulting in decreased PCa-specific mortality. In the additional follow-up years 10 and 11, the rate ratio for death from PCa dropped to 0.62 (95% CI, 0.45–0.85; adjusted p = 0.003) for screened patients.¹⁶ The USPSTF maintained that the cancer-specific mortality advantages in the two studies did not justify the harms of screening. Since 2012, the ERSPC has updated results with 13 years of follow-up as well as additional analysis that further support a beneficial impact on mortality.¹⁷–²²

The critique is that the USPSTF did not acknowledge known methodological flaws in these two major studies. The best documented objection being contamination of the control populations by PSA screening performed outside the study protocols by subject choice. In the PLCO study, fully 44% of the control subjects had PSA tests performed prior to randomization, and 83% had at least one PSA test outside the study protocol at some point during the 6-year screening period of the trial. Out of these, the 17% had 1–2 tests, 42% had 3–4, and 24% had 5–6 PSA tests during the 6-year study period.²³–²⁵ This contamination of the control group invalidated the original comparison hypotheses of the study. There was also a significant protocol violation as 60–70% of the men with an abnormal PSA screening test failed to get a timely prostate biopsy, although 64% did eventually undergo a biopsy within 3 years.²⁵,²⁶ In the ERSPC trial, there was also nonprotocol screening, but far less than in the PLCO study. A reanalysis of the Rotterdam data set from the ERSPC trial, corrected for nonattendance and contamination, showed that PSA screening reduced the risk of dying of PCa by up to 31% as compared to the prior estimate of 20%.²⁷,²⁸

A further and perhaps even more serious problem with the USPSTF analysis of mortality was the inadequate follow-up time, median of about 6 years in the PLCO trial and 9 years in the ERSPC study. The time for the clinical evolution of PCa is much longer; in a Swedish study of an unscreened population, the lead time from onset of elevated PSA level to PCa diagnosis reached 10.7 years.²⁹ In a different Swedish study, a small cohort of 223 men with untreated localized PCa was followed for 32 years.³⁰ There were 90 (41.4%) local progression events and 41 (18.4%) cases of progression to distant metastasis. In total, 38 (17%) men died of PCa, but the relative rate of PCa-specific death increased from 4.9 at 5–9 years to 23.5 at 15–20 years, suggesting that cancer death accounts for a greater proportional mortality with advancing duration of the disease.

Interim follow-up results from the Göteborg randomized population-based Prostate-Cancer Screening Trial with a median follow up of 14 years, heighten the concern that the Task Force recommendation was based on inadequate duration of follow-up.³¹ In this currently ongoing long-term study, 20,000 men aged 50–64 years were randomized either to a screening group to receive PSA testing every 2 years or to a nontested control group. There was a cumulative incidence of PCa of 12.7% in the screened group and 8.2% in the control group (hazard ratio, 1.64; 95% CI, 1.50–1.80; p < 0.0001). Yet despite a significantly higher incidence of PCa, the rate ratio for death from PCa for the screened group was lower at 0.56 (95% CI, 0.39–0.82; p = 0.002), a reduction of 44%.³¹

The second question that the USPSTF addressed was regarding the harms of PSA-based screening for PCa. The USPSTF considered false positive results (an elevated PSA level not leading to cancer diagnosis) as harmful. In the PLCO trial, the cumulative risk for at least one false-positive result was 13%, with a 5.5% risk for undergoing at least one unnecessary biopsy.³² In the ERSPC trial, 76% of the prostate biopsies did not show PCa.³³ In a prior review in 2008, the USPSTF noted that false-positive PSA test results can cause adverse psychological effects.³⁴ In addition, there were biopsy complications such as infection, bleeding, and urinary difficulties in both trials: 68 events per 10,000 evaluations in the PLCO study; while the Rotterdam center of the ERSPC trial reported that among 5,802 prostate biopsies, 200 men (3.5%) developed a fever, 20 (0.4%) experienced urinary retention, and 27 (0.5%) required hospitalization due to prostatitis or urosepsis.³³

The error in the Task Force argument is one of incomplete comparison, assuming that the absence of PSA screening completely avoids all diagnostic procedures. In fact, diagnostic procedures for PCa were frequently performed in the control groups of both studies. In the PLCO trial, the rate of diagnosis of PCa was only 20% less than in the screened group, possibly as a result of the very high level of nonprotocol screening that occurred. In the ERSPC trial, the PCa incidence rate was 8.2% in the screened group and 4.8% in the control group, but higher-grade cancer (Gleason score of 7 or more) was far more common in the control group than in the screened group (45.2% vs. 27.8%). The presence of metastatic disease was evaluated in a study conducted in four of the ERSPC centers where the necessary data were available. Metastatic disease was identified by imaging or by PSA values >100 ng/mL at diagnosis or during follow-up. After a median follow-up of 12 years, 666 men with metastatic PCa were detected; 256 in the screening arm and 410 in the control arm, resulting in a 42% (p = 0.0001) reduction in metastatic PCa for men who were actually screened.³⁵

In a separate analysis of the Rotterdam ERSPC cohort, the investigators determined that, of 42,376 men randomized during the period of the first round of the trial (1993–1999), 1151 and 210 in the screening and control arms, respectively, were diagnosed with PCa.³⁶ Of these men, 420 (36.5%) screen-detected and 54 (25.7%) controls underwent radical prostatectomy with long-term follow-up data (median follow-up 9.9 years). Men from the screening arm had a significantly higher progression-free survival (p = 0.003), metastasis-free survival (p < 0.001), and cancer-specific survival (p = 0.048).³⁶ Yet, after adjusting for tumor volume in the surgical specimen, there was no longer a significant difference in biochemical recurrence rate between the screening and control arms. Thus, the key advantage of the PSA screened group appeared to be surgical intervention at an earlier stage of tumor growth. If one considers diagnostic procedures harmful, then it is undeniable that patients with high-grade or advanced PCa will eventually endure more invasive and harmful diagnostic or therapeutic procedures with correspondingly greater anxiety than those with localized cancer.

The third question that the USPSTF addressed was related to the benefits of treatment of early-stage or screening-detected PCa. The USPSTF acknowledged strong evidence that treatment of localized PCa reduced mortality as compared to observation alone, the so-called watchful waiting. They endorsed a randomized controlled Scandinavian trial with 15 years of follow-up showing that radical prostatectomy resulted in a sustained decrease in PCa-specific mortality (15% vs. 21%; RR, 0.62; CI, 0.44–0.87) and all-cause mortality (RR, 0.75; CI, 0.61–0.92) while several additional studies of radical prostatectomy with durations of follow-up ranging from 4 years to 13 years, all showed a similar benefit.³⁷–⁴² The USPSTF also acknowledged an approximate 35% decrease in PCa-specific mortality with the alternative treatment of radiation therapy compared to observation alone.⁴³–⁴⁵ However, they also argued against the apparent benefit of definitive treatment primarily on the basis of the results of the Prostate Intervention Versus Observation Trial (PIVOT) study, which followed a cohort of 731 men with initially localized PCa for 12 years in the Veterans Administration Hospital system assigned randomly either to radical prostatectomy or observation alone.⁴⁶ During the median follow-up of 10 years, 171 of 364 men (47%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% CI, 0.71–1.08; p = 0.22).

Most studies support the USPSTF analysis showing that both surgery and radiotherapy for early stage PCa are superior to watchful waiting in terms of eventual mortality. The PIVOT Trial results were marred by the failure to recruit the 2000 patients required in the original study design, leaving it severely underpowered statistically. Furthermore, the average age of their patients at baseline was 67 years, old enough to subject the cohort to significant mortality from causes other than cancer. Although a life expectancy of at least 10 years was an entry criterion, by 10 years almost half of the participants had died, leaving only 176 men in the surgery group and 187 observation men, and by 15 years only 30% were alive. According to the Social Security Administration Actuarial Office, median life expectancy in the United States for men aged 67 would be an additional 17.2 years. Thus, it appears that they recruited men with a limited life expectancy. There was also significant crossover and control group contamination even in the limited numbers of men recruited, with 23% of men assigned to the surgical arm not receiving radical prostatectomies while another 20% of the control group were treated with either surgery or radiation therapy.

The PIVOT Trial analysis also clearly illustrates the problem of relying on overall mortality to assess the benefit of screening. Disease-specific mortality is a more accurate measure, but can be confounded by reporting discrepancies and the difficulty in obtaining reliable cause of death statistics. The argument has been made that excess mortality of a cohort is a better measure of the effect of screening, but the emphasis on mortality as the ultimate comparison variable ignores the additional reality of the burden of advanced cancer in the living.⁴⁷ The USPSTF provided no assessment of comparative benefit in terms of potential avoidance of local and distant spread of not yet fatal PCa.

Finally, the USPSTF addressed the harms of treatment of early-stage or screening-detected PCa. The USPSTF cited a 30-day perioperative mortality rate postprostatectomy of about 0.5% with rates of serious cardiac events about 3% and vascular events (including pulmonary embolism and deep venous thrombosis) about 2%.⁴⁸–⁵³ Due to the close proximity of the urinary tract and the penile nerves, radical prostatectomy carries a significant incidence of erectile dysfunction and other surgical complications. Surgical injuries to the rectum or the ureter range from 0.3% to 0.6%.⁴⁹,⁵³ The rate of urinary incontinence in comparison to watchful waiting is from two- to fourfold higher.⁵³–⁵⁷ Prostatectomy carries a 50–80% increased risk for erectile dysfunction as compared to watchful waiting.⁵³–⁵⁹ Radiotherapy does not interrupt the normal anatomy and therefore does not damage urinary continence and erectile function as much as prostatectomy.⁵⁹–⁶¹ Due to the proximity of the rectum to the radiation fields, this form of therapy is sometimes associated with bowel complaints, primarily bowel urgency.⁵⁹–⁶¹

It is undeniable that complications of surgery and radiotherapy are far lower at centers with specialization and experience in the treatment of PCa. For example, in the nationwide Scandinavian series, the 30-day mortality was only 0.11%.⁶² Surprisingly, despite the many problems associated with surgery or radiotherapy, in multiple quality of life comparison studies, patients who undergo active treatment reported similar or better physical and/or emotional subscale forms on the SF-36 test as compared to watchful waiting patients.⁵⁴–⁶⁰,⁶² The paradox of equivalent quality of life findings despite the sexual, urinary, and bowel issues may reflect a higher percentage of advanced cancer patients in the watchful waiting groups. Patients with advanced PCa report much lower quality of life scores than those with localized disease (48–51) and are susceptible to significant depression.⁶³–⁶⁶ In a Swedish database of PCa patients, the standardized mortality (SMR) risk of suicide was increased for 22,929 men with locally advanced nonmetastatic tumors (SMR, 2.2; 95% CI, 1.6–2.9) and for 8,350 men with distant metastases (SMR, 2.1; 95% CI, 1.2–3.6).⁶⁷

The USPSTF concluded that the complications of surgery and radiotherapy negatively impact the benefits of reduced mortality resulting from definitive treatment of PCa. The concern in their reasoning is failure to compare these complications with the harmful events associated with advanced PCa that occurs more frequently in unscreened and untreated populations. Manifestations of metastatic and advanced disease may include weight loss, pathologic fractures, spinal cord compression, hematuria, intractable pain, ureteral and/or bladder outlet obstruction, hydronephrosis, urinary retention, renal failure, and urinary incontinence.⁶⁸–⁷⁰ Disseminated PCa is frequently characterized by painful bone metastases.⁷¹–⁷⁴ Furthermore, hormonal therapy used to suppress the growth of advanced PCa has many undesirable side effects including vasomotor flushing, loss of libido, erectile dysfunction, gynecomastia, cognitive decline, anemia, osteoporosis, and dyslipidemia resulting in reduced quality of life.⁷⁵–⁷⁷

In limiting their analysis to mortality alone, the USPSTF ignored the burden of suffering of individuals surviving with advanced cancer. In order to perform a valid comparison of the screened and control populations, it is not enough to assess mortality; one must systematically analyze the complications of treatment of local cancer as well as the adverse effects of preventable advanced cancer, more common in unscreened groups.⁷⁸ The ERSPC investigators have approached this issue quantitatively to determine the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalanced the lower mortality in their screened population.⁷⁹ They found that annual screening of 1000 men between the ages of 55 and 69 years would result in 9 fewer deaths from PCa (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per PCa death avoided). Factoring in harm due to complications of diagnostic and treatment procedures, their analysis still showed 56 quality-of-life adjusted years gained by PSA screening.⁷⁹

Screening special at-risk populations

In the pure sense, population screening does not take into account patient history or special risk factors. Taking into account individual patient characteristics, risk factors, signs, and symptoms is case finding and not true screening. Nevertheless, the D-rating of the USPSTF implies that PSA and PCa early detection efforts should be discouraged whether it is true population screening, case finding or even in the setting of shared decision. The USPSTF blanket recommendation against PSA screening does not allow for special populations.

Hereditary PCa typically affects men at a younger age.⁸⁰–⁸³ In a Scandinavian study of 44,788 twins, hereditary factors were found to account for 42% of the overall risk of development of PCa.⁸⁴ It is certainly reasonable to screen individuals with a strong family history of PCa earlier and more frequently than the general population.

Men of African ancestry and ethnicity are at 1.4 times higher risk of being diagnosed and 2–3 times higher risk of dying from PCa compared to European-American men.⁸⁵ Advanced PCa occurred at a 4:1 ratio of black to white men in the Detroit Surveillance, Epidemiology and End Results registry database.⁸⁶ Similar imbalances are observed in the United Kingdom where health care is free and does not depend on socioeconomic status; in the PROCESS study in the London–Bristol area, black men had a threefold higher risk of PCa compared to white men.⁸⁷–⁸⁸

In addition to the USPSTF, the current AUA Best Practice Policy on PSA screening released in May 2013 was weak on making special recommendations for high-risk groups.⁸⁹ These guidelines do endorse PSA testing every other year between the ages of 55 and 69 and are patterned after the Göteborg arm of the ERSPC. However, this is to be considered only after shared decision/informed consent. Critics have contended that the new guidelines are soft on high-risk groups, particularly AA men.¹²

Impact of age on prostate screening decisions

The 2012 USPSTF guidelines was opposed to PSA testing irrespective of age.¹⁰ The expected lifespan in the United States for a male aged 75 is about 10 years.⁹⁰ In 2008, the USPSTF recommended against PSA screening of men over the age of 75.³⁴ It is plausible that the aging process in most 75-year-old men will progress to mortality prior to the advent of advanced PCa, but the current expected life span for men aged 45–50 years in the United States is about 30 years for whites and 27 years for blacks.⁹⁰ The recent blanket USPSTF recommendation may result in delayed diagnosis of potentially curable PCas in young men who will otherwise suffer advanced disease and death, and some otherwise healthy older men with high-grade PCa will also unnecessarily suffer advanced disease and cancer death.

Screening/risk assessment in young men

Whether PCa screening should include average-risk younger men is a subject of debate in the medical literature. The incidence of PCa in this age group is low, and the clinical significance of detected PCa in these men is unclear.⁹¹ Recent data suggest that a PSA value above 0.7 ng/mL in young men is associated with greater risk for development of PCa.⁹²

In 2006, the National Comprehensive Cancer Network (NCCN) adopted by nonuniform consensus a risk-stratification strategy for young men that includes a baseline PSA measurement at age 40 years and subsequent risk stratification based on the result of this initial test.⁹³ The NCCN early-detection protocol is supported by evidence that young men with PSA levels above the age-specific median are at greater risk for future PCa. In the Baltimore Longitudinal Study of Aging, the relative risk of PCa was 3.75 for men aged 40–49 years with a PSA level above the age-specific median of 0.6 ng/mL, whereas the risk was similar among men in their 50s with PSA levels above and below the age-specific median.⁹⁴ Similarly, among men aged 40–49 years who were at greater risk (either because of positive family history or AA race), a PSA level between the age-specific median (0.7 ng/mL) and 2.5 ng/mL was associated with a higher risk of PCa, with screening of 36 higher-risk men required to detect one additional case of cancer. The external validity of this finding is unclear; it is not known how many young men at average risk would need a PSA test to detect one additional case of cancer.⁹²

Overdiagnosis of PCa using current detection strategies is not insignificant and leads to potentially avoidable harms in the course of treatment.⁹⁵–⁹⁹ Etzioni et al. estimated an overdiagnosis rate of 29% among white patients aged <60 years, based on model comparisons to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database.⁹⁶ Similarly, using data from the ERSPC, Draisma et al. found an overdiagnosis rate of 27% for men aged 55 years.⁹⁵ High