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Names: Constine, Louis S., editor. | Tarbell, Nancy J., 1951- editor. |
Halperin, Edward C., editor.
Title: Pediatric radiation oncology / editors, Louis S. Constine, Nancy J.
Tarbell, Edward C. Halperin.
Description: Sixth edition. | Philadelphia, PA : Wolters Kluwer, [2016] |
Includes bibliographical references and index.
Identifiers: LCCN 2016020698 | ISBN 9781496342867
Subjects: | MESH: Neoplasms—radiotherapy | Child
Classification: LCC RC281.C4 | NLM QZ 275 | DDC 618.92/9920642—dc23 LC record a
https://lccn.loc.gov/2016020698
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Dedication
This book is dedicated both to our own children and to all those children diagnosed with
cancer. These children have taught us about life, bravery, pain, openness, innocence,
resilience, as well as clinical pediatric radiation oncology. To them we are forever grateful.
Through our patients we have learned to more profoundly appreciate our own families. We
pause to recognize those children who succumbed to cancer, and to feel gratitude for those
fortunate to have survived while retaining a childlike enthusiasm for living despite the burden
of malignancy. We hope that the sixth edition of Pediatric Radiation Oncology will serve as
some small reciprocation for what our patients have given to us.
Louis S. Constine
Nancy J. Tarbell
Edward C. Halperin
Contributors
James E. Bates, MD
Resident
Department of Radiation Oncology
University of Florida
Gainesville, Florida
Christian Carrie, MD
Chief
Department of Radiotherapy
Centre Léon Bérard
Ly on, France
Bow-Wen Chen, MD
Senior Pediatrician
Division of Pediatric Hematology and Oncology
Medical Director
Hematopoietic Stem Cell Research Laboratory
Koo Foundation Sun Ya-Sen Cancer Center
Taipei, Taiwan
Skye H. Cheng, MD
Chief
Department of Radiation Oncology
Director
Clinical Research Office
Deputy Chief
Department of Research
Koo Foundation Sun Yat-Sen Cancer Center
Taipei, Taiwan
Line Claude, MD
Assistant Head
Department of Radiation Oncology
Centre Léon Bérard
Ly on, France
Sughosh Dhakal, MD
Assistant Professor
Medical Director
Department of Radiation Oncology
James P. Wilmot Cancer Institute/Strong Memorial Hospital
University of Rochester Medical Center
Rochester, New York
Xavier Druet
Internship Department of Radiotherapy
Institut du cancer de Montpellier(ICM)
Montpellier, France
Ira J. Dunkel, MD
Associate Attending Phy sician
Department of Pediatrics
Memorial Sloan Kettering Cancer Center
New York, New York
Bree R. Eaton, MD
Assistant Professor
Department of Radiation Oncology
Winship Cancer Institute
Emory University
Atlanta, Georgia
Natia Esiashvili, MD
Associate Professor
Department of Radiation Oncology
Winship Cancer Institute
Woodruff Health Sciences Center
Emory University
Atlanta, Georgia
Marla B. Ferschl, MD
Associate Professor
Department of Anesthesia and Perioperative Care
Division of Pediatric Anesthesia
Program Director
Pediatric Anesthesia Fellowship Program
University of California
San Francisco, California
Debra L. Friedman, MD
Associate Professor of Pediatrics
E. Bronson Ingram Chair in Pediatric Oncology
Department of Pediatrics
Vanderbilt-Ingram Cancer Center
Cancer Control and Prevention Program
Director
Division of Hematology -Oncology
Vanderbilt University
Nashville, Tennessee
Hana Golan, MD
Department of Pediatric Hematology and Oncology
The Edmond and Lily Safra Children’s Hospital
Sheba Medical Center
Tel Hashomer, Israel
Daphne Haas-Kogan, MD
Professor and Chair
Department of Radiation Oncology
Brigham and Women’s Hospital
Dana-Farber Cancer Institute
Boston Children’s Hospital
Harvard Medical School
Boston, Massachusetts
Mary S. Huang, MD
Assistant Professor
Department of Pediatrics
Pediatric Hematology and Oncology Unit
Massachusetts General Hospital for Children
Boston, Massachusetts
Shannon M. MacDonald, MD
Associate Professor
Department of Radiation Oncology
Harvard Medical School
Radiation Oncologist
Department of Radiation Oncology
Massachusetts General Hospital
Boston, Massachusetts
Anita Mahajan, MD
Professor
Department of Radiation Oncology
Division of Radiation Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas
Brandon R. Mancini, MD
Chief Resident
Department of Therapeutic Radiology
Yale School of Medicine
Yale University
New Haven, Connecticut
Karen J. Marcus, MD
Associate Professor
Department of Radiation Oncology
Harvard Medical School
Division Chief
Division of Radiation Oncology
Boston Children’s Hospital
Boston, Massachusetts
Katherine K. Matthay, MD
Mildred V. Strouss Professor of Translational Research in Childhood Cancer
Chief
Pediatric Hematology and Oncology Unit
Department of Pediatrics
Leader
Pediatric Malignancies Program
University of California
School of Medicine
UCSF Benioff Children’s Hospital
San Francisco, California
Ronica H. Nanda, MD
Chief Resident
Department of Radiation Oncology
Winship Cancer Institute
Emory University
Atlanta, Georgia
Kenneth B. Roberts, MD
Professor
Department of Therapeutic Radiology
Yale School of Medicine
Yale University
Associate Chief
Department of Radiation Oncology
Yale-New Haven Hospital
New Haven, Connecticut
Stephanie A. Terezakis, MD
Associate Professor
Department of Radiation Oncology and Molecular Radiation Sciences
Johns Hopkins School of Medicine
Baltimore, Mary land
Howard J. Weinstein, MD
Chief
Pediatric Hematology and Oncology Unit
Massachusetts General Hospital for Children
Professor of Pediatrics
Harvard Medical School
Boston, Massachusetts
The preparation and collation of the sixth edition of this book is grounded in the multiple
previous editions that resulted from the dedication of the late Ruth Aultman in North Carolina
and Kentucky, Rebecca Bunker in Memphis, Laura Finger in Rochester, Erin Cromack and
Heidi Fliegauf in Boston, and Vera Rosario and Vilma Bordonaro in Valhalla. Emilie Moy er
and the staff of Lippincott Williams & Wilkins were, at all times, courteous and bey ond
helpful. The conscientiousness and skill of this staff has again given life to our book.
We are indebted to our mentors and teachers: J. Robert Cassady, Juan A. del Regato,
Sarah Donaldson, Samuel Hellman, Henry Kaplan, Rita M. Linggood, Jay Loeffler, Donald
Pinkel, Leon Rosenberg, Philip Rubin, Herman Suit, Samuel Thier, and John Truman.
The love of our families has been a source of constant strength to us.
CH A P TER 1
The Cancer Problem in Children
Edward C. Halperin
Page 1In 1900, cancer trailed ty phoid fever, malaria, smallpox, measles, scarlet fever,
whooping cough, diphtheria, croup, influenza, dy sentery, ery sipelas, tuberculosis, sexually
transmitted disease, meningitis, acute bronchitis, pneumonia, accidents, birth injuries, and
violence as a cause of death in children in the United States (1,2). Cancer mortality
constituted only 0.43% of mortality from all causes for children (1).
At the beginning of the 21st century, in
economically developed countries, many
children die every y ear from preventable
incidents such as traffic accidents, intentional
injuries, drowning, falls, fire, and poisoning. The
leading causes of death in infants are congenital
anomalies, disorders related to short gestation
and low birth weight, and sudden infant death
sy ndrome (3). The leading cause of death in
children older than 1 y ear is murder by a close Table 1.1 The Five Leading Causes of
relative. Cancer in children, however, has Death in the United States in 2011 for 1-
become a significant problem compared with to 19-Year-Olds
other causes of childhood mortality (4) (Table
1.1 ). In the United States, 1 in 285 children will be diagnosed with cancer before age 20
(5). In 2014, there were 10,450 new cases of cancer among children of age 0–14 y ears and
5330 new cases among children of age 15–19 y ears in the United States (5,6,7). Cancer is
now the leading natural cause of death among children between the ages of 1 and 14 y ears in
the United States (3). In late adolescence, homicide surpasses cancer as a cause of death.
Although cancer is a major cause of childhood death in developed countries, it continues
to trail infections as a cause of mortality in developing countries (6,8). In many parts of the
world, nutrition, housing, climate, and sanitation conditions create childhood mortality
statistics similar to those reported for industrialized countries in the early 20th century.
However, it is likely that future improvements in the standard of living, the success of
immunization programs, and dissemination of medical services will make inroads against
infectious disease, and thereby make childhood cancer a major cause of death in developing
nations.
Figure: The Five Leading Causes of Death in
the United States in 2011 for 1- to 19-Year-
Olds
RELATIVE FREQUENCY OF THE VARIOUS TYPES OF CHILDHOOD
CANCER
Page 3The mortality rate from childhood cancer has fallen dramatically in the United States.
Particularly impressive gains have been posted for acute ly mphocy tic leukemia (ALL), bone
tumors (predominantly osteosarcoma and Ewing sarcoma), Hodgkin disease, non-Hodgkin
ly mphoma, soft tissue sarcomas (including rhabdomy osarcoma and nonrhabdomy osarcoma
soft tissue sarcomas), and Wilms tumor. Although gains have also been achieved for acute
my elocy tic leukemia (AML), neuroblastoma, and brain tumors, the improvements have been
less dramatic or confined to certain subgroups or stages (Table 1.5 ). In general, however,
the diagnosis and treatment of childhood cancer has been one of the success stories of
modern medicine.
Table 1.5 Trends in 5-Year Relative Survival Rates for Children with Cancer (0–14 Years
of Age) in the United States at the Approximate Midpoint of the Last Four Decades
An estimated 1350 cancer deaths in children 0–14 y ears of age and 610 cancer deaths in
15-to-19-y ear-olds occurred in the United States in 2014. It is clear that when compared with
adult cancer, childhood cancer is a vanishingly rare event. For example, in 2015 there were
158,000 estimated deaths from lung cancer alone in the United States (6). The comparative
infrequency of childhood cancer is highlighted by the fact that more people in the United
States die of lung cancer in 1 week than children die of all forms of cancer in 1 y ear. Looking
at the impact of cancer solely in this manner is insufficient. If one looks at a death from
cancer in terms of potential y ears of life lost, then the death of an 8-y ear-old from ALL has a
greater statistical weight than the death of an 82-y ear-old from small cell carcinoma of the
lung. Therefore, the success of medical treatment of childhood cancer has a significant public
health impact when considered in terms of the person-y ears of potential life lost or lifetime
earnings saved. A lifetime is saved for every child cured of cancer.
Figure: Trends in 5-Year Relative Survival
Rates for Children with Cancer (0–14 Years
of Age) in the United States at the
Approximate Midpoint of the Last Four
Decades
FUNDING OF PEDIATRIC CANCER RESEARCH
In the United States, there is a significant federally funded pediatric cancer research
program. Research focuses on treatment in cancer biology and the management of long-
term cancer survivors (Table 1.6 ). We know very little about pediatric cancer prevention
in contrast to the extensive efforts in tobacco and alcohol consumption control, reduction in
sun exposure, and dietary interventions promoted to reduce adult cancer. Unfortunately, the
amount of U.S. federal inflation-adjusted dollars spent on pediatric cancer research has fallen
in recent y ears (Table 1.7 ).
Table 1.6 Percentage of Total Dollars Spent by Scientific Area in Pediatric Cancer
Research by the United States National Cancer Institute for Fiscal Year 2013
Table 1.7 The Yearly Investment of the United States National Cancer Institute in
Pediatric Cancer Research
Figure: Percentage of Total Dollars Spent by
Scientific Area in Pediatric Cancer Research
by the United States National Cancer
Institute for Fiscal Year 2013
Figure: The Yearly Investment of the United
States National Cancer Institute in Pediatric
Cancer Research
IS THE INCIDENCE OF CHILDHOOD CANCER INCREASING?
From 2007 to 2011, the overall incidence rate for childhood cancer has increased by 0.6%
per y ear for children <15 y ears of age and has remained stable for 15-to-19-y ear-olds. From
1970 to 2011, the death rate for childhood cancer decreased by 67% for children <15 y ears
of age and decreased by 58% for 15-to-19-y ear-olds (6). Incidence rates in the United States
and Europe have increased for ALL and AML, non-Hodgkin ly mphoma, and testicular germ
cell tumors and decreased for Hodgkin disease; they are stable for other tumors (5). Experts
disagree about what might account for these data. Some have asserted that new diagnostic
techniques such as computed tomography (CT), magnetic resonance imaging (MRI), needle
biopsy, and serum chemical markers are increasing the rate of diagnosis of childhood cancer.
This would render the increase in childhood cancer as merely an artifact of improved
diagnostic techniques. The counterargument is that the rise in the incidence of childhood
cancer continues unabated even when new techniques are not introduced, and the rise in
incidence may be linked to environmental toxins. So far, alleged links include pelvic
radiography of mothers during pregnancy, the use of radioactive nucleotides during
pregnancy, radon, solvents, parental occupational exposure, diet, environmental tobacco
smoke, alcohol, and infection. The alleged link to agricultural and home pesticide use is weak,
and many studies find no correlation (22,23). While it has been suggested that exposure to
magnetic fields emanating from electric transmission and distribution lines and certain
electrical household appliances may be associated with some childhood tumors, studies are
contradictory (24).
Page 4SEER, the Manchester Children’s Tumor Registry in northwestern England, a
registry for Queensland, Australia, the Greater Delaware Valley Pediatric Tumor Registry,
and a study from Canada indicate an increase in cancer incidence in children of
approximately 1% per y ear, although a study in Denmark did not find a rising incidence
(24,25,26,27,28).
If we accept the premise that the overall incidence of childhood cancer is rising, then we
must bear in mind two potential confounding factors. First, the frequency of childhood cancer
is so low that it takes only a few cases, in registries covering a small population base, to
suggest a change in incidence (28). Second, as previously suggested, with the improvement in
diagnostic tools in modern medicine, more children will be correctly diagnosed with cancer
as opposed to another diagnosis. This effect may be particularly important for brain tumors
(27).
WHAT DOES CURE MEAN IN PEDIATRIC ONCOLOGY?
The English word cure is derived from the Latin term cura and the Old French term cure,
both meaning “care.” The generally accepted definition in medicine for cure is “successful
medical treatment; the action or process of healing a wound, a disease, or a sick person;
restoration to health” (29). There are several mathematical and statistical definitions of cure.
In 1963, Easson and Russel (30) suggested a definition for cure that was a modification of an
earlier definition proposed in 1929 by Greenwood (31): “We can speak of cure when in time
—probably a decade or so after treatment—there remains a group of disease-free survivors
whose progressive death rates from all causes is similar to that of a normal population of the
same sex and age constitution.” Patients and clinicians, during the 1960s and 1970s, became
comfortable with transitioning from the concept of “indefinite remission” to “cure” (32).
Frei and Gehan (33) suggested that survival should also be associated with continuing
morbidity from the disease or its treatment. Cure is not achieved when treatment stops or
even after a 5-y ear disease-free period. For each child with cancer and his or her family, the
meaning of cure is different. For some patients, it is the knowledge that the disease is gone and
never coming back. To others, it is the statement that they are well today and want to be so
tomorrow. For all children with cancer, hope is the common denominator and getting on with
life is the goal (34).
One way of expressing the probability of survival is a relative survival rate. The relative
survival rate is the ratio of the observed percentage of survival to the percentage expected on
the basis of general population experience, adjusted for age, sex, race, and calendar y ear.
Using this definition, a population of patients would be cured when a graph plotting relative
survival rate showed a horizontal line (32).
Pinkel (35) summarizes the criteria of biologic cure as completion of all cancer
treatment, continuous freedom from cancer relapse, and minimal or no risk of subsequent
relapse. It is important to consider the continuous cancer-free survival (other commonly used
terms are relapse-free survival and event-free survival) and the overall survival in
constructing survival curves. Overall survival rates reflect factors other than biologic
curability, including death caused by complications of treatment and subjective factors such
as the patient’s will to continue living with cancer or its repeated relapses, the phy sician’s
determination to keep the patient alive, and the technical and financial resources available to
the phy sician and the patient.
Page 5The reported cure rates in pediatric cancer may be affected by artifacts of data
acquisition and analy sis. The zero-time shift or lead-time bias will extend the statistical length
of survival without prolonging life. This phenomenon occurs when a new screening test or
imaging study leads to the detection of a previously unknown tumor. Even if therapy is
ineffectual, survival is increased by the interval provided by the earlier detection of the
cancer. The Will Rogers effect occurs when there are improved techniques for detecting
cancer metastases. These new detection techniques allow patients to migrate from lower
stages of cancer to higher stages. Such migration improves survival in lower stages by
eliminating those with metastatic disease. Survival also improves in higher stages because of
the addition of people with minimal metastatic disease. Survival improves in each stage, but
overall survival for the cancer is unaffected. This phenomenon is named after the American
humorist Will Rogers (1879–1935) who is reputed to have remarked during the economic
depression of the 1930s that “when the Okies left Oklahoma and moved to California, they
raised the average intelligence in both states” (36) (see Sidebar).
THE GROWING POPULATION OF CHILDHOOD CANCER SURVIVORS
With improving cure rates in childhood cancer, it is apparent that we must move bey ond the
statistical definition of cure (14,37). Cure is more than the absence of disease. It is important
to provide the child with a functional cure, regaining or retaining the ability to make one’s way
in society without major handicaps and minimizing the need for a significant support. The
U.S. prevalence estimate for individuals diagnosed with cancer at <20 y ears of age who are
now living ≥15 y ears and <36 y ears after diagnosis is approximately 113,000 (7). About 1 in
530 y oung adults between the ages of 20 and 39 y ears of age is a childhood cancer survivor
(5). This means that the average adult primary care phy sician will have several long-term
survivors of childhood cancer in his or her practice.
The Childhood Cancer Survivor Study is a multicenter study funded by the NCI. This
study of more than 14,000 survivors of childhood cancer shows that survivors are at a higher
risk of impaired pulmonary function, growth abnormalities, endocrine dy sfunction, obesity,
phy sical limitations, infertility, cardiac problems, reduced quality of life, depression, special
educational needs, and second malignant neoplasms (38,39). Pulmonary complications may
develop y ears after treatment. Cancer survivors have higher rates of lung fibrosis,
emphy sema, pneumonia, pleurisy, and a need for oxy gen compared with sibling control
subjects. Survivors of childhood ALL treated with >20 Gy of cranial radiotherapy were
significantly more likely to be overweight or obese than sibling control subjects (39,40).
T H E WI L L ROG E RS E F F E CT
The Will Rogers effect occurs when a new staging test, such as diagnostic imaging, is
introduced into cancer management (44). Assume that you evaluate 100 children
with a specific histologic type of cancer. After they complete a staging workup, they
are assigned a stage. For example, Stage I—localized; Stage II— regional spread; Stage
III—metastatic. Let’s say the 100 patients are distributed as follows.
Now, we will enter the 5-year survival probabilities and determine the overall
survival, in this case 44 of the 100 patients.
Then a new staging test is discovered. By detecting small foci of tumor spread, some
patients are moved from Stage I to Stages II or III. By removing these bad prognosis
patients from Stage I, the survival for Stage I rises—even if therapy is not improving.
Some patients who were formerly Stage II are reassigned to Stage III because of the
detection of tumor spread. Similarly, the survival rate of Stage II rises by extracting
these “bad actors” from the pool of Stage II patients. The Stage III patient group
enlarges—having acquired patients with minimal-volume metastatic disease. These
patients with low-volume metastatic disease do better than the traditional patient
with metastatic disease. (Imagine the difference between lung metastases detected
by CT, for example, vs. conventional chest x-ray.)
The survival rates of Stages I–III have risen as a result of restaging with new
technology and stage redistribution, but not as a result of improved therapy.
Interestingly, although the survival probability for every stage of disease rose, the
overall survival is still 44 out of 100 patients. The introduction of a new test that more
precisely stages patients has deceived us into thinking that our therapy has improved
—but it has not. As described in the text, this is “The Will Rogers effect.”
Page 6Late mortality rates are declining among pediatric cancer survivors. Armstrong
et al. studied 34,033 patients who were y ounger than 21 y ears of age at the time of diagnosis
of cancer and were at least 5-y ear cancer survivors. Median follow-up was 21 y ears.
Overall, there were 3958 deaths in the population. The most common causes of death were
secondary cancers (46%), heart disease (15%), and lung disease (8%). When comparing the
all-cause mortality rates for patients treated for cancer from 1970 to 1974 to those treated
from 1990 to 1994, the rate fell substantially (12% vs. 6%, p < 0.001). A likely explanation for
this decline in late mortality is a combination of refinement in therapy to reduce treatment
intensity when it is not warranted and better supportive care when late ill effects of cancer
treatment occur. Of particular note is the decline in the use of cranial radiotherapy in the
treatment of ALL (86% in the 1970s to 54% in the 1980s to 22% in the 1980s), Wilms tumor
(77% vs. 54% vs. 49%), and Hodgkin ly mphoma (96% vs. 88% vs. 77%) (41,42).
Overtime there has also been a decrease in exposure of many patients to cardiotoxic
chemotherapy. Patients treated for Hodgkin disease in the 1970s had an average
anthracy cline exposure of 295 mg/m 2, which dropped to 193 mg/m 2 in the 1990s.
Planning for adequate limb function, ambulation, and activities of daily living is crucial
in planning a course of treatment. Rehabilitation, including phy sical, occupational, and
recreational therapy, play s an important part in follow-up care. A comprehensive pediatric
cancer rehabilitation program requires people with expertise in prosthetics, orthoses, ostomy
care, gait training, and pain management (43,44,45,46).
Attention to the child’s emotional status is also important. This includes preserving and
nurturing a sense of well-being on the part of the child and his or her family. Childhood
cancer survivors are more likely than their siblings to suffer sy mptoms of depression and
somatic distress (48). The family should be given every measure of support in dealing with
illness and restoring health. The diagnosis and treatment of cancer exert severe emotional and
financial strains on a family. The term psychological cure refers to the ability to put cancer
behind y ou and move on with life (30).
Parental separation and divorce, sibling behavior problems, and the weight of family
responsibilities during adversity complicate the treatment and rehabilitation of the child with
cancer (49,50). The pediatric radiation oncologist should ensure an ongoing relationship with
the child and family after treatment to contribute to rehabilitation. As the survival rates for
pediatric cancers improve, we will have an increasing population of y oung adults who are
cancer survivors. These people will pose new problems for medicine and society : What will
be appropriate medical surveillance for late effects of treatment, including secondary
malignancy ? How will these patients be counseled concerning reproduction? What special
needs will such people have concerning employ ment, disability and health insurance, and
psy chological support? (44). A survey of 1437 childhood cancer survivors, >18 y ears old and
>10 y ears postdiagnosis, showed decreased marriage rates in irradiated hematologic
malignancy survivors and generally lower rates of employ ment (Table 1.8 ) (51). The
pediatric radiation oncologist will play an important role in understanding these issues and
implementing solutions (52).
Table 1.8 Marriage, Employment, and Health Insurance in Adult Survivors of Childhood
Cancer: A Survey of 1437 Survivors >18 Years of Age and >10 Years Postdiagnosis Treated at
St. Jude Children’s Research Hospital
Figure:
Figure:
Figure:
Figure: Marriage, Employment, and Health
Insurance in Adult Survivors of Childhood
Cancer: A Survey of 1437 Survivors >18 Years
of Age and >10 Years Postdiagnosis Treated
at St. Jude Children’s Research Hospital
SITE OF CARE AND THE PEDIATRIC CANCER TEAM
The 1969 edition of Nelson Textbook of Pediatrics reported that childhood “leukemia is a
uniformly fatal malignant disease.” Advances in the treatment of pediatric malignancies in
the subsequent four decades have been remarkable. This success is the result of a complex,
multidisciplinary process administered by a team of professionals (53).
Combined-modality therapy has been a rewarding approach. In the United States, about
90% of children with cancer are cared for at a member institution of the Children’s Oncology
Group (COG), an NCI-supported clinical trials group with about 100 trials open at any time
(5). A coordinated group of medical and surgical specialists with expertise in the clinical care
of children with cancer and in basic and clinical research best direct the child’s care. The
complete pediatric cancer center participates in clinical trials and is staffed by a pediatric
medical oncologist, specially trained nurses, a pediatric diagnostic radiologist, surgeons with
expertise in pediatric oncology, anesthesiologists, psy chiatrists, phy siotherapists, phy sicians
assistants, and social workers. The group must also include a radiation oncologist committed to
pediatric care and with experience in radiotherapy for children (52,53) (Table 1.9 ).
Table 1.9 Requirements for a Pediatric Cancer Center
Participation of the patient’s parents and other significant family members is an integral
part of the team approach. Parents will soon become extremely knowledgeable about their
child’s illness, its treatment, and the associated complications. They will become careful
observers of phy sical signs and sy mptoms, and their report of changes in the child’s well-
being will be invaluable to caregivers. Parents often develop important skills such as the care
of indwelling venous access devices. Parents may be taught to administer medications, titrate
their dosages, and oversee sy mptom management.
Going to school is the normal day time activity for most children. The child with cancer
should be encouraged to live as normally as possible. Participation in school is encouraged to
whatever degree is reasonable. Many hospitals maintain a program for schooling children
during their cancer care. In some states, the hospital itself is accredited as a public school and
certified teachers are on staff. These teachers, working closely with the local school districts,
can help children keep up with their studies and be more readily integrated back into their
classrooms at home.
There is evidence that the diagnosis and treatment of some pediatric malignancies,
particularly those dependent on complex radiotherapy, are better conducted at university -
affiliated medical centers. The available data suggest that there is a benefit to treatment at a
university -based or regional cancer center when the treatment is rapidly evolving and when
complex treatment approaches with technically difficult surgery or radiotherapy are needed.
However, it appears that the site of treatment does not alter survival rates for patients in
whom a cure may be achieved with surgical intervention alone, for tumors for which there is
no significant curative treatment, and for tumors necessitating multimodality therapy when
the most up-to-date protocol information and the services of a consulting expert are available
in the community hospital (54,55,56,57,58,59,60).
Figure: Requirements for a Pediatric Cancer
Center
POSTGRADUATE TRAINING IN PEDIATRIC RADIATION ONCOLOGY
Page 8There are serious gaps in residency training in pediatric radiation oncology in the
United States. The incidence of childhood cancer is low. In addition, only a portion of
childhood cancer cases are appropriate for radiotherapy. When one also considers the fact
that pediatric cancer cases are not uniformly distributed among the radiation oncology
training programs in the United States, one can readily understand why many residency
programs see less than five pediatric cancer cases per y ear. In some residency programs, the
few pediatric radiation oncology cases that are seen are heavily weighted toward palliative
cases, total body irradiation for bone marrow transplantation, or late adolescents with Hodgkin
disease. Therefore, it is very likely that a person could go through 4 or 5 y ears of
postgraduate training in radiation oncology and never see a case of retinoblastoma,
neuroblastoma, Wilms tumor, or Langerhans cell histiocy tosis.
There is an intrinsic problem with the way academic medical centers count the number
of pediatric radiation oncology cases for U.S. residency training accreditation. In adult
radiation oncology, guidelines exist for the appropriate number of lung, colorectal, breast,
head and neck, and genitourinary malignancies necessary for training. In the case of
pediatric cancer, however, all forms of cancer are lumped together to reach an acceptable
number. Such a policy would never be acceptable in taking an inventory of the appropriate
number of adult cases for training.
Some residency programs try to solve the problem by sending residents for away
rotations. With a 1-month rotation at another center, residents are expected to acquire
sufficient pediatric training for the 4 or 5 y ears of the residency program. In 1 month, it is
entirely likely that a resident would never see a patient taken from consultation through
simulation and all the way through completion of a course of treatment. Long-term follow-up
is also impossible.
Some have proposed eliminating pediatric radiation oncology training from general
radiation oncology training. By this line of argument, pediatric radiation oncology would
become a subspecialty, which would entail a separate fellowship at the end of a residency.
Another proposed solution is to designate only certain residency programs as capable of
providing pediatric radiation oncology training by virtue of the adequate number of cases and
faculty with sufficient expertise. It is highly unlikely that there will be approved subspecialty
training in pediatric radiation oncology in the near future. The designated accrediting boards
in the United States have a series of requirements for subspecialty designation that are too
formidable to be met in the case of pediatric radiation oncology. Therefore, it remains likely
that for the foreseeable future, pediatric radiation oncology residency training will continue to
be inadequate (61,62). Insofar as the burden of childhood cancer is far higher in low- and
middle-income countries (LMIC) than it is in high-income countries, one might envision
residency education being benefited by trainees taking clinical rotations in these LMIC.
THE PROBLEM OF EVIL AND CHILDHOOD CANCER
The great biologist Charles Darwin (1809–1882) grappled with the concept that the
human mind could discern a rational explanation for evil in the world. In an 1860 letter to the
American botanist Asa Gray (1810–1888), Darwin wrote
…I cannot see as plainly as others do, and as I should wish to do, evidence of
design and beneficence on all sides of us. There seems to me too much misery
in the world. I cannot persuade myself that a beneficent and omnipotent G-d
would have designedly created the Ichneumonidae with the express intention
of their feeding within the living bodies of Caterpillars, or that a cat should
play with mice. Not believing this, I see no necessity in the belief that the eye
was expressly designed. On the other hand, I cannot anyhow be contented to
view this wonderful universe, and especially the nature of man, and to
conclude that everything is the result of brute force. I am inclined to look at
everything as resulting from designed laws, with the details, whether good or
bad, left to the working out of what we may call chance. Not that this notion
at all satisfies me. I feel most deeply that the whole subject is too profound for
the human intellect. A dog might as well speculate on the mind of Newton
(69).
The insolubility of the theological problem of evil, and the way in which it makes many
people turn away from a belief in a monotheistic God, was recognized by the great Jewish
phy sician-philosopher living and working in The Golden Age of Islamic Medicine,
Maimonides (1135–1204).
It is something which pains the heart and troubles the mind. From it alone
many throughout the generations have been drawn to completely reject belief.
It is the fact that we see in the world crooked judgment, the righteous
suffering while the wicked enjoy a good life. People say: “Why do these men
succeed in their ways, while that one and that one, who appear to be
righteous, are destroyed?” This is the root of rebellion within every nation and
tongue (70)
COMMON RESPONSES TO THE PROBLEM OF EVIL
Any practicing pediatric radiation oncologist will have heard and will accumulate, over their
career, an extensive collection of responses to the theological problem of evil. These
responses include:
There is no monotheistic God. Instead we live in a world of, at the least, Dualism. There
is a good god and a bad god—or there are multiple good gods and bad gods. They might
have names like God and Satan or may be we’ll call them something else but, whatever
we call them, sometimes one force is prevailing over the other and sometimes the
reverse. When there are floods, epidemics, and when innocent children die of cancer,
the evil force or evil god is in the driver’s seat. When people fall in love, when people
recover from illness, and when we financially prosper, we thank a good god for his/her
manifold blessings.
There is no monotheistic God. Instead, there is no God at all. Humans are on this earth
because of a collection of random events which, through the processes of evolution,
resulted in us being here. This same set of evolutionary processes made oncogenes and
tumor suppressor genes. Bad stuff happens. It just does and there is no point in asking the
“Why ?” question because there is no answer other than “Because it just does.” Bridges
collapse, a speeding car kills y our pet dog when he runs out into the street, and y our
patient dies of acute my elocy tic leukemia after a bone marrow transplant. Put on y our
big boy underwear and deal with it.
There is a God and He/She maintains a grand balance scale of justice. When y ou do
something wrong the Divine bean counter tallies it. Eventually y ou or y our descendants,
including y our children, are going to pay the piper for the misdeed—including y our
children or grandchildren getting cancer. Sometimes the misdeeds are not y ours as an
individual, but ours as a society or culture. If we act sufficiently badly as a city, then we
will be wiped out like Sodom and Gomorrah. If we act badly as a society, but not
sufficiently badly to be wiped out, then we’ll be punished by pestilence, including
childhood cancer.
Page 10There is a God and we achieve a greater knowledge of Him/Her and closeness
to the Divine via suffering. Suffering is redemptive because it educates and purifies. It is
a way to achieve true self-understanding and Divine Grace.
There is a God and He/She knows best. We don’t. Every thing happens for a reason. G-d
decided to have the sun come up this morning and go down tonight. God decided that y ou
would find y our life partner and marry him/her. God decided y ou would get into
medical school. God decided that a 9-y ear-old should get an aggressive pontine glioma.
There is a God, and He/She is doing the best He/She can under the circumstances.
He/She is unable to prevent the suffering of the innocent. Therefore, God joins with His
people in their suffering.
There is a God and He/She doesn’t get involved in the affairs of humankind. The good
and bad that happens to people is either of their doing or the result of evolution. You’re
free to pray if y ou want but y ou’re alway s going to get the Divine answering machine.
The pediatric radiation oncologist can be paraly zed into immobility by the question
“Why does this innocent child, who did nothing to deserve this, have cancer?” The child
with cancer, however, does not need a phy sician rendered numb by the cruelty of the
world, they need a phy sician prepared and capable of taking action. I have found that the
most satisfy ing response to the problem of evil is to be found in the writings of Joseph
Solovetchik. It is difficult to do justice to the breadth and depth of his extraordinary
exposition of the issue in a few sentences but, in essence, he say s the following: When
faced with evil in the world it is human nature to ask “Why ?” However, if one believes in
the existence of a God who exceeds all human comprehension, then there is no
imaginable language one can use to engage in a conversation with Him/Her about
“Why ?” Do not spend y our time and energy posing and seeking answers to an
unanswerable question. Rather, the only correct action for an ethical person is to expend
their time and energy to take action dealing with evil (71).
It is in taking action to diagnose, treat, and comfort his/her patients that the pediatric
radiation oncologist can best respond to the theological problem of evil.
REFERENCES
1. Dublin LI. Mortality Statistics of Insured Wage-Earners and Their Families. New York,
NY: Metropolitan Life Insurance Company ; 1919.
2. North SND. Special Reports: Mortality Statistics 1900–1904. Washington, DC: US
Government Printing Office; 1906:76–89.
3. Ventura SJ, Peters KD, Martin JA, et al. Births and deaths: United States, 1996. Mon Vital
Stat Rep. 1997;46:29–34.
4. American Academy of Pediatrics. Guidelines for the pediatric cancer center and role of
such centers in diagnosis and treatment. Pediatrics. 1986;77:916–917.
5. American Cancer Society. Special section: cancer in children and adolescents. In:
Cancer Facts and Figures 2014. Atlanta, GA: American Cancer Society ; 2014.
6. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
7. SEER Cancer Statistics. http://seer.cancer.gov ; http://seer.cancer.gov/iccol ;
http://seer.cancer.gov/publications/childhood .
8. Health Canada. Canadian Cancer Incidence Atlas, Vol. 1: Canadian Cancer Incidence.
Ottawa, ON: Minister of National Health and Welfare; 1995:138–139.
9. Anony mous. US incidence rates for selected childhood cancer. J Natl Cancer Inst.
2001;93:1201.
10. American Cancer Society. American Cancer Society Cancer Facts and Figures 2014.
Atlanta, GA: American Cancer Society ; 2014.
11. Plaschkes J. Epidemiology of neonatal tumours. In: Puri P, ed. Neonatal Tumours.
London, England: Springer-Verlag; 1996:1–10.
12. Halperin EC. Neonatal neoplasms. Int J Radiat Oncol Biol Phys. 2000;47:171–178.
13. Parkin DM, Stiller CA, Draper GJ, et al. eds. International Incidence of Childhood
Cancer. Ly on, France: World Health Organization, International Agency for Research on
Cancer; 1988;101–107.
14. Gurney JG, Davis S, Severson RK, et al. Trends in cancer incidence among children in
the US. Cancer. 1996;78:532–541.
15. Costillo L, Fluchel M, Dabezies A, et al. Childhood cancer in Uruguay 1992–1994.
Incidence and mortality. Med Pediatr Oncol. 2001;37:400–404.
16. Shah SH, Pervez S, Hassan SH. Frequency of malignant solid tumors in children. J
Pakistan Med Assoc. 2000;50:86–88.
17. Martin AA, Alpert JA, Reno JS, et al. Incidence of childhood cancer in Cuba (1986–
1990). Cancer. 1997;72:551–555.
18. Sriamporn S, Vatansapt V, Martin N, et al. Incidence of childhood cancer in Thailand
1988–1991. Paediatr Perinat Epidemiol. 1996;10:73–85.
19. Ocheni S, Bioha FI, Ibegbulam OG, et al. Changing patterns of childhood malignancies in
Eastern Nigeria. West African Med J. 2008;27:3–6.
20. McWhirter WR, Petroeschevsky AL. Childhood cancer incidence in Queensland, 1979–
1988. Int J Cancer. 1990;45:1002–1005.
21. Merrill RM, Feuer EJ. Risk-adjusted cancer incidence rates (United States). Cancer
Causes Control. 1996;7:544–552.
22. Massey -Stokes M, Lanning B. Childhood cancer and environmental toxins: the debate
continues. Fam Community Health. 2002;24:27–38.
23. Halperin EC, Miranda ML, Watson D, et al. Medulloblastoma and birth date: evaluating
three U.S. data sets. Arch Environ Health. 2004;59:26–30.
24. Kraut A, Tate R, Tran N. Residential electric consumption and childhood cancer in
Canada (1971–1986). Arch Environ Health. 1994;3(49):156–159.
25. Brown PD, Hertz H, Olsen JH, et al. Incidence of childhood cancer in Denmark 1943–
1984. Int J Epidemiol. 1989;18:546–555.
26. Rey nolds P, von Behren J, Gunier RB, et al. Childhood cancer and agricultural pesticide
use: an ecologic study in California. Environ Health Perspect. 2002;110:319–324.
27. Bunin GR, Feurer EJ, Witman PA, et al. Increasing incidence of childhood cancer: report
of 20 y ears experience from the Greater Delaware Valley Pediatric Tumor Registry.
Paediatr Perinat Epidemiol. 1996;10:319–338.
28. Cushman JH Jr. U.S. reshaping cancer strategy as incidence in children rises. New York
Times. September 29, 1997:1.
29. Compact Edition of the Oxford English Dictionary. Oxford, England: Oxford University
Press; 1985.
30. Easson EC, Russel MH. The cure of Hodgkin’s disease. BMJ. 1963;1:1704–1707.
31. Greenwood M. The Errors of Sampling of the Survivorship Table. London, England: His
Majesty ’s Stationery Office; 1929. Reports on Public Health and Medical Subjects, No.
33. Appendix I.
32. Barnes E. Between remission and cure: patients, practitioners and the transformation of
leukaemia in the late twentieth century. Chronic Iln. 2007;3:253–264.
33. Page 11 Frei E, Gehan EA. Definition of cure for Hodgkin’s disease. Cancer Res.
1971;31:1828–1833.
34. Podrasky PA. The family perspective of the cured patient. Cancer. 1986;58:522–523.
35. Pinkel D. Cure of the child with cancer: definition and perspective. In: Proceedings of the
National Conference on the Care of the Child with Cancer. New York, NY: American
Cancer Society ; 1979:191–200.
36. Feinstein AR, Sasin DM, Wells CK. The Will Rogers phenomenon: stage migration and
new diagnostic techniques as a source of misleading statistics for survival in cancer. N
Engl J Med. 1985;312:1604–1608.
37. Duenwald M, Grady M. Young survivors of cancer battle effects of treatment. New York
Times. January 8, 2002:1.
38. Mulrooney DA, Neglia JP, Hudson MM. Caring for adult survivors of childhood cancer.
Curr Treat Options Oncol. 2008;9:51–66.
39. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors
of childhood cancer. N Eng J Med. 2006;355:1572–1582.
40. Boughton B. Childhood cancer treatment causes complications later in life. Lancet Oncol.
2002;3:390.
41. Armstrong GT, Yasui Y, Chen Y, et al. Reduction in late mortality among 5-y ear
survivors of childhood cancer: a report from the Childhood Cancer Survivor Study
(CCSS). Abstract LMA2. Presented at: ASCO Annual Meeting; May 30–June 2, 2015;
Chicago, IL.
42. SanFilippo A. Late mortality rates have declined in pediatric cancer survivors. HemOnc
today. 2015;16:1, 10–11.
43. Gerber LH, Binder H. Rehabilitation of the child with cancer. In: Pizzo PA, Poplack DG,
eds. Principles and Practice of Pediatric Oncology. Philadelphia, PA: JB Lippincott;
1993:1079–1090.
44. Hammond D. Progress in the study, treatment and cure of the cancers of children. In:
Burchenal JH, Oehgen HF, eds. Cancer Achievement, Challenges, and Prospects for the
1980s. New York, NY: Grune & Stratton; 1981:171–190.
45. Hay s DM, Landsverk J, Ruccione K, et al. Employ ment problems and workplace
experience of childhood cancer survivors. In: Green DM, D’Angio GJ, eds. Late Effects
of Treatment for Childhood Cancer. New York, NY: Wiley -Liss; 1992:171–178.
46. Mey er WH. Principles of total care: rehabilitation. In: Fernbach DJ, Vietti TJ, eds.
Clinical Pediatric Oncology. St Louis, MO: Mosby ; 1991:285–294.
47. Changes in pediatric cancer treatments y ield reduced late mortality. ASCO Daily News.
Wrap up edition; 2015:2.
48. Zebrack BJ, Zeltzer LK, Whitten J, et al. Psy chological outcomes in long-term survivors
of childhood leukemia, Hodgkin’s disease, and non-Hodgkin’s ly mphoma: a report from
the childhood cancer survivor study. Pediatrics. 2002;110:42–52.
49. Craft AW, Pearson ADJ. Three decades of chemotherapy for childhood cancer: from
cure “at any cost” to “cure at least cost.” Cancer Surv. 1989;8:605–629.
50. Dickens M. Miracles of Courage: How Families Meet the Challenge of a Child’s Critical
Illness. New York, NY: Dodd, Mead; 1985.
51. Crom DB, Lensing SY, Rai SN, et al. Marriage, employ ment, and health insurance in
adult survivors of childhood cancer. J Cancer Surv. 2007;1:237–245.
52. Schwartz CL, Hobbie WL, Constine LS, et al. Survivors of Childhood Cancer: Assessment
and Management. St Louis, MO: Mosby ; 1994.
53. Labotka RJ. Book review of principles and practice of pediatric oncology. JAMA.
2002;288:894–895.
54. Meek RS. Pediatric oncology : the team approach of the medical center of Delaware.
Del Med J. 1988;60:169–172, 177–178.
55. Cohen ME, Duffner PK, Kun LE, et al. The argument for a combined cancer
consortium research data base. Cancer. 1985;56:1897–1901.
56. Duffner PK, Cohen ME, Flannery JT. Referral patterns of childhood brain tumors in the
state of Connecticut. Cancer. 1982;50:1636–1640.
57. Lennox EL, Stiller CA, Morris-Jones P, et al. Nephroblastoma: treatment during 1970–
1973 and the effect of inclusion in the first Medical Research Council trial. BMJ.
1979;2:567–569.
58. Kramer S, Meadows AT, Pastore G, et al. Influence of place of treatment on diagnosis,
treatment, and survival in 3 pediatric solid tumors. J Clin Oncol. 1984;2:917–923.
59. Stiller CA, Draper GJ. Treatment, centre size, trial entry and survival in acute
ly mphoblastic leukaemia. Arch Dis Child. 1989;64:798–807.
60. Griffel M. Wilms’ tumor in New York State: epidemiology and survivorship. Cancer.
1977;40:3140–3145.
61. Constine LS, Donaldson SS. Pediatric radiation oncology : subspecialty training? Int J
Radiat Oncol Biol Phys. 1992;24:881–884.
62. Halperin EC, Donaldson SS. Subspecialty training and certification in radiation oncology.
JACR. 2004;1:488–492.
63. Halperin EC, Travis J, Browning IR III, et al. Children are not supposed to die: combined
pediatric and radiation oncology grand rounds addresses severe illness and death. NC
Med J. 1997;58:445–448
64. Sacks J. Not in God’s Name: Confronting Religious Violence. NY: Schocken Books, 2015.
65. Camus A. The Plague. London, England: Penguin Books; 1960.
66. Epicuraenism. In: Encyclopaedia Britannica Micropaedia. Vol. 4. 15th ed. Chicago, IL:
Ency clopaedia Britannica; 1994:522.
67. Mark JL, ed. The Problem of Evil: A Reader. Malden, MA: Blackwell; 2001:xix–xxi.
68. Tooley M. The problem of evil. In: Borchert DM, ed. The Stanford Encyclopedia of
Philosophy. New York, NY: Macmillan Preference; 2005.
69. Darwin F, ed. The Life and Letters of Charles Darwin. Vol. 2. New York, NY: D. Appleton;
1919:105–106.
70. Schwartz Y, Goldstein Y. Shoah: a Jewish perspective on tragedy in the context of the
Holocaust. Brookly n, NY: Mesorah Publications; 1990.
71. Sokol M. Is there a “Halakhic” response to the problem of evil? Harvard Theol Rev.
1999;92:311–323.
CH A P TER 2
Leukemias in Children
Larry E. Kun
Page 12Leukemias are the most common cancer ty pes in children, representing nearly 30%
of all childhood cancers in North America. The most common leukemia is acute
ly mphoblastic leukemia (ALL), accounting for 80% of childhood leukemia and nearly 24%
of all cancers in children. Approximately 3000 children present with ALL annually in the
United States. ALL was the prototy pe childhood cancer documenting response and,
subsequently, cure with chemotherapy and the importance of combined modality therapy
that incorporated irradiation or site-specific chemotherapy for “sanctuary sites.” The
development of therapeutic approaches in ALL set another precedent in oncology,
demonstrating the value of serial, prospective clinical trials to introduce progressively more
successful treatment regimens. It is no exaggeration to attribute the early success in leukemia
control to the introduction of central nervous sy stem (CNS) irradiation, a fundamental
component of the earliest successful leukemia regimens developed in the 1960s that has been
extensively studied in serial intervals, identify ing subsets of ALL at higher risk for CNS
disease and weighing relative effectiveness and toxicities of CNS-directed chemotherapy or
irradiation (Fig. 2.1 ).
Approximately 20% of childhood leukemia presentations are acute my eloblastic
leukemia (AML), a disease that is more common in adults. Successful management of AML
has lagged behind that of ALL historically, and the role of radiation therapy remains poorly
identified. However, AML has been one of the more common indications for bone marrow
transplant (BMT) in children, and the use of total body irradiation (TBI) in this setting has
been rather common. Transplant regimens continue to evolve, with increasing indications for
radiation immunosuppression, as the host pool
for allogeneic transplants now commonly
includes matched unrelated and haploidentical
donors.
Reprinted from Pui CH, Evans WE. A 50-year journey to cure childhood acute lymphoblastic
leukemia. Semin Hematol. 2013;50(3):185–196. doi: 10.1053/j.seminhematol.2013.06.007.
ACUTE LYMPHOBLASTIC LEUKEMIA
Biology
ALL results from a clonal expansion of dy sregulated, immature ly mphoid cells. The linkage
of ALL subty pes to the major immunophenoty pic ly mphocy te lines provided the first
biologic understanding of the disease ty pes that correlate biologic characteristics with
common clinical features. B-precursor leukemias account for 85% of ALL cases in children.
Most cases of B-precursor ALL consist of leukemic clones from early pre–B-cell lines (55%;
cy toplasmic immunoglobulin [cIg] negative) or pre–B-cell lines (25%; cIg-positive). T-
precursor ALL accounts for 15% of cases of childhood ALL (1). B-cell-derived ALL
ty pically occurs in y oung children, associated with a wide range of clinical manifestations
and initial white blood cell (WBC) counts. Classically, T-cell ALL occurs in boy s over 10
y ears old and is more often associated with extramedullary involvement (mediastinal ly mph
nodes and the CNS) and high presenting WBC (2).
Page 13Enormous advances in the understanding of ALL have accompanied studies of
the cy togenetics and genome sequencing of this disease (3,4)(Fig. 2.2 ). Translocation
t(1;19) is ty pical of pre–B-cell immunophenoty pe, while translocation t(11;14) is often
present in T-cell immunophenoty pe. The earliest distinct molecular characteristic in
childhood leukemia was the demonstration of Philadelphia chromosome Ph+, associated with
chronic my elogenous leukemia in adults, in up to 5% of children with B-precursor ALL. Ph+
cases have translocation t(9;22) often in the presence of the BCR–ABL1 fusion gene; the
genoty pe has been associated with a relatively high risk of relapse, especially in adolescents
(3,5). Other genoty pes are also associated with relatively more aggressive disease requiring
intensive chemotherapy regimens to enjoy outcomes more comparable to the broad
category of B-cell leukemias. BCR–ABL1-like (Ph+ like) B-cell ALL accounts for 10% of B-
lineage leukemia, and those also showing IZKF1 have a less favorable prognosis. Between 5%
and 7% of B-lineage ALL express CRLFZ, including 50% of those with Down sy ndrome–
associated ALL; such presentations also require relatively intensive chemotherapy to
overcome a less favorable outcome (4). Pre–B-cell disease with t(1;19)(q23;p13) and
expression of TCF3–PBX1 fusion is associated with an increased risk of CNS relapse (6).
Infants less than 1 y ear old often show MLL rearrangement; high expression of FLT3 is
apparent in most infants not showing the MLL findings (4). Among the children and
adolescents presenting with T-cell ALL, the 15% with early T-cell precursor ALL have been
at relatively high risk and show immunologic, gene expression, and mutation findings all
suggestive of a my eloid leukemia, suggesting a stem cell leukemia (7).
Figure 2.2 Genotypes in childhood ALL, including genetic findings in B-cell lineage or all
ALL immunophenotypes; genetic findings unique to T-cell ALL are in purple shades. Reprinted
from Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med.
2004;350(15):1535–1548, with permission.
Clinical Presentation
The median age at presentation for ALL is 4 y ears, with a peak occurrence between 2 and 4
y ears. Boy s are more commonly affected than girls, particularly with T-cell ALL. ALL is
less common in African-American children. Earlier studies demonstrated unfavorable
outcome in adolescents and in African-American children; more recent results are similar
among children with standard-risk ALL (10). More aggressive disease has also been
associated with >10% Native American genetic ancestry (4).
Page 14The most common presenting sy mptoms include fever, bleeding, and bone pain.
Findings at diagnosis include ecchy moses or petechiae, signs of ly mph node enlargement,
and hepatosplenomegaly. The diagnosis is suspected with a complete blood count (CBC)
demonstrating the presence of immature ly mphoblasts in the peripheral blood or elevated
WBC (WBC is less than 10,000/mL in 50% of presentations, 10,000–50,000/mL in 30%, and
more than 50,000/mL in 15–20% at diagnosis). Less often, clinical sy mptoms or signs are
associated with extramedullary involvement of the CNS, testis, or kidney.
ALL is a sy stemic disease by definition, usually involving the bone marrow diffusely
and associated with ly mphoblastic infiltration, either microscopic or overt, in a number of
organ sy stems (e.g., ly mph nodes, liver, and spleen). CNS leukemia is usually asy mptomatic;
extensive leptomeningeal disease may be manifest clinically by irritability, headaches,
sometimes vomiting or unanticipated weight gain (the hy pothalamic sy ndrome), cranial
nerve palsies (especially VII; less often VI, III), or seizures. Advanced disease sometimes is
manifest by papilledema and diffuse retinal infiltration (Fig. 2.3 ). The pathophy siology
was demonstrated in Price and Johnson’s classic description of leukemic cells filling the
subarachnoid space well into Virchow–Robin spaces and throughout the basal cisterns (11).
Treatment: Chemotherapy
Therapy for ALL includes remission induction, CNS- directed therapy, intensification (or
consolidation), and continuation therapy. Ty pical remission induction combines corticosteroids
(prednisone), vincristine, and asparaginase. Dexamethasone is often substituted for
prednisone during CNS-directed therapy only (due to greater CNS penetration)(4,18).
Intensification (or consolidation) follows remission induction and incorporates aggressive
drugs and regimens to continue maximal early cy toreduction. The most commonly used
agents include methotrexate (MTX; at high dosages, ty pically 1–5 g/m 2 repeatedly during
this phase), 6-mercaptopurine (6-MP), and asparaginase. Reinduction is also a component of
consolidation, shown to improve disease control (25,26). Patients with BCR–ABL1 fusion gene
(Ph+) deficit and poor initial response (with positive MRD) appear to benefit from allogeneic
BMT in intensification (27). More recently, studies in the United Kingdom (UK) have shown
that augmented postremission chemotherapy can obviate the need for hematopoietic stem
cell transplant for clinical low- and standard-risk leukemia and positive MRD (28). In addition,
children with low-risk ALL and negative postinduction MRD can be successfully treated with
reduced therapy (29).
Page 15Continuation therapy is a routine part of therapy for ALL presentations
administered for ≥2 y ears (5,30). It is ty pically weekly low-dose MTX and 6-MP. The goal of
continuation therapy is to eliminate residual, slowly replicating leukemic blasts or to
sufficiently suppress leukemic cell division to allow programmed cell death to intervene.
Active CNS-directed therapy is given early during remission induction, consisting most
often today of intrathecal (IT) chemotherapy (methotrexate alone or as triple-IT therapy,
also including cy tarabine and hy drocortisone) along with intermediate-dose intravenous
methotrexate (and delay ed leucovorin rescue to diminish sy stemic toxicity of exposure to IT
methotrexate as it elutes into the sy stemic circulation). There is a balance of IT therapy, triple
agent versus methotrexate alone, and the use of higher dose intravenous methotrexate with
the latter to more directly address sy stemic disease. Studies have shown relatively more
effective CNS control with the TIT approach, but suggestions of better control of hematologic
and extramedullary (e.g., testicular) sites with the latter. (4,31) Selective use of preventive
CNS irradiation is addressed below.
Long-term leukemia-free survival is now achieved in over 85–90+% of children with
ALL (4,8,31,32,33,34). Low-risk ALL can be cured in 90–95% of cases, while standard-risk
patients can anticipate disease-free survival rates greater than 80%; children with high-risk
features are reported to show EFS of 50–70% depending on the threshold for defining high
risk (13,18,24,32,33).
Standard-risk ALL can be treated without CrI (14,42,43,45,47). The group for which CrI
may be beneficial is the cohort with T-cell ALL and presenting with WBC greater than
100,000/µL. Approximately 20% of children with T-cell ALL (or 2% of all children with
ALL) present with high WBC and seem to benefit from preventive CrI (14,54). Because HD-
MTX and IT-MTX have been associated with neurologic sequelae, there is also interest in
considering further CrI dosage reduction (12 Gy /8 fractions in the more recent BFM studies)
(43).
Dosage
Dosages for preventive CrI range from 12 to 18 Gy in current practice, with meta-analy ses
suggesting no difference between 18 and 24 Gy. Fractionation ty pically is at 150–180 cGy
once daily (2,23,25,59).
CNS Relapse
Despite CNS preventive therapy, 1–8% of children sustain an isolated CNS relapse (i.e., in the
presence of continuous, maintained hematologic remission) (23). CNS relapse is
asy mptomatic at diagnosis in 75% of cases (i.e., detected by routine surveillance lumbar
puncture). Sy mptoms and signs are apparent in 25% of children with CNS involvement and
include headaches with or without vomiting, papilledema, cranial nerve palsies (most often
VI and VII; also V), hy perphagia, and CNS hemorrhage (presenting with headaches,
seizures, change in mental status, and/or focal neurologic signs) (23,67,68).
Therapy for isolated CNS relapse includes sy stemic chemotherapy for reinduction, IT
chemotherapy (MTX alone or TIT) to clear the CSF, and irradiation. Clinical trials
documented CNS control following neuraxis irradiation, but overall disease control was
observed in only 50–70% of children after isolated CNS relapse following reinduction and
consolidation chemotherapy with CNS irradiation (67,69,70,71,72,73,74).
Page 18Serial trials in the Pediatric Oncology Group (POG) confirmed the benefit of
initial sy stemic and IT chemotherapy for isolated CNS relapse: POG 9061 interposed 6
months of chemotherapy prior to CSI (24 Gy /16 fx CrI, 15 Gy /10 fx SpI); secondary EFS
was 71% (67). The study also documented that early CNS relapse (<18 months postdiagnosis)
was much more aggressive, with secondary 4-y ear EFS 46% compared to 83% for those
who relapsed later than 18 months (67). As in most series after 1985, failures were
predominantly in the bone marrow, leading to POG 9412 that tested 1 y ear of sy stemic and
IT chemotherapy followed by delay ed “risk-adapted” CNS irradiation: CrI to 18 Gy for CNS
relapse >18 months after diagnosis, and CSI to 24 Gy CrI & 15 Gy SpI for earlier CNS
relapse (75). Results were similar to the earlier trial: 52% 4-y ear EFS with early CNS relapse
versus 78% with relapse ≥18 months postdiagnosis (75). The other significant factor related to
outcome was the NCI risk group (high risk: age <1 or >10 y ears; WBC >50,000 mL at
diagnosis); children in the high-risk group had a four-time greater likelihood of relapse
following isolated CNS relapse (75).
Radiotherapeutic Management
Treatment of testicular relapse involves sy stemic chemotherapy. Sy stematic testicular
irradiation has been eliminated from most current treatment regimens, reserving irradiation
for documented residual testicular infiltration following reinduction chemotherapy (73,78).
More recent national COG trials reserve irradiation for disease persistent after high-dose
MTX and induction chemotherapy (documented by biopsy of testes enlarged at completion
of induction). The Dutch Late Effects Study Group has reported successful management of
testicular relapse without local irradiation (78), and the approach in the more recent Total
ALL trials at St. Jude offer orchiectomy or testicular irradiation depending upon age and
testicular response to initial chemotherapy. Although late failure may be present with
unilateral disease, evidence of bilateral infiltration is usually apparent (76). When indicated,
irradiation is directed to both testes, usually by en face electron beam, calculating the energy
to deliver 90% of the dose to the posterior aspect of the testes based on measurements in the
treatment position. Attention to daily positioning is important, ensuring the descent of the testes
into the scrotum during therapy. The recommended dosage is 20–24 Gy, usually given at 200
cGy per fraction (76). The interest in limiting use of irradiation reflects sterility and Ley dig
cell hy pofunction following irradiation. There is y et preliminary data using chemotherapy
alone, reserving orchiectomy for local disease control in boy s who do not show prompt,
histologically verified disease control.
Reprinted from Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J
Med. 2004;350(15):1535–1548, with permission.
Figure:
The retinal photograph demonstrates advanced CNS leukemia with papilledema and retinal
infiltrate typical of ocular disease.
Figure:
Craniospinal irradiation for CNS leukemia. A: Sagittal CT simulation reconstruction showing
eye (yellow) and optic nerve (blue) at the midorbital level; cranial irradiation for CNS
leukemia includes the subarachnoid extension along the optic nerve sheath and the posterior
retina (see Fig. 2.6). B: Midline sagittal CT simulation reconstruction showing the cribriform
plate (red) volume providing margin at key anatomic regions (A and B) for craniospinal
therapy in ALL.
Figure:
Lateral field for cranial irradiation in ALL. Note margin below cribriform plate (pink) and
middle cranial fossa (blue). Targeted volume includes posterior eye (yellow) and orbit.
Figure: Indications for Preventive Cranial
Irradiation (pCrI)–Contemporary Studies
(2009)
ACUTE MYELOGENOUS LEUKEMIA
Approximately 20% of children with leukemia present with AML, representing nearly 500
children per y ear in the United States; nearly 40% of leukemic deaths in US children occur
with this form of leukemia (81). The disease occurs throughout the pediatric age range, with
greatest frequency in newborns and y oung children approximating 2 y ears old and a later
“peak” during adolescence. There is a high incidence of AML among y oung children with
Down sy ndrome (81). Presenting sy mptoms include sy mptoms and signs of pancy topenia
(pallor, fatigue, bleeding, infection, and fever) or leukostasis. Localized extramedullary tumor
deposits (chloromas or “granulocy tic sarcomas”) can present as sy mptomatic masses
involving the head and neck region, spinal cord, or brain. The initial WBC ty pically is below
50,000/mL; about 20% present with hy perleukocy tosis (WBC >100,000/mL). Clinical features
associated with outcome include ethnicity, age, and body weight: African Americans, older
age (>2 y ears and increasing age), and overweight habitus are associated with poorer
outcome (82,83,84,85). Unlike adults, it is rare for children to show initial my elody splasia
preceding actual AML. Secondary AML (ty pically due to alky lating agents or high doses of
topoisomerase II inhibitors (e.g., cy tarabine) also have poor prognosis (86).
Page 19CNS disease is documented at presentation in 10–15% of cases (23). CNS
disease at diagnosis is associated with high peripheral WBC, age <2 y ears, and ironically
favorable cy togenetic characteristics (t(l;11), t(8;21), inv(16)) (87).
AML has classically been categorized by cy tomorphology, based on the French-
American-British (FAB) classification and increasingly by molecular characteristics (82).
The common morphologic feature is the presence of Auer rods in cy toplasm of leukemic
blasts. Cell ty pes indicate primarily my eloblastic, monoblastic, or megakary ocy tic AML; the
megakary ocy tic form is common with Down sy ndrome and associated with favorable
response and prognosis, if traditional therapy resulted in acute toxicities and early toxic
deaths, recently ameliorated with dose reductions providing greater tolerance (81).
Cy togenetic abnormalities have been documented in a majority of children with AML. One
of the most common findings is translocation t(8;21), associated with AML1, a gene encoding
AML1CBF, a transcription factor essential for normal hematopoietic development (82,88).
The t(8;21) is often combined with inversion of chromosome 16(inv(16)) as “core binding
factor” AML, commonly present in AML M2; the t(8;21) translocation and inv(16) identify
favorable disease (82,88,89). The t(9;22) translocation is associated with a poor outcome.
Favorable AML (with t(8;21), inv(16), wild-ty pe FLT3, mutations of NPM1 or CEPBA; MRD
<0.1% after induction), high-risk disease (t(6;9), −7, −5, −5q; FAB M0 or M6, FAB M7; MRD
>5% after the first induction or >1% after the second induction), and intermediate-risk AML
(all others) are associated with 78%, 42%, and 55% 5-y ear survival, respectively
(10,11,81,82,90,91,92).
The mainstay of treatment for AML has been induction with daunorubicin (or idarubicin
or mitaxantrone) in conjunction with cy tarabine and etoposide; chlofarabine or gemtuzumab
may be included (82,86,93,94,95,96). Current regimens result in 80% remission but only 40–
50% event-free survival rates in children and 50–60% overall survival. Even more so than in
ALL, the finding of MRD upon completion of induction, by molecular or genetic analy sis, is
associated with a poor outcome (92). Postinduction therapy is somewhat controversial, data
suggesting the use of matched sibling or matched unrelated stem cell transplant (SCT) may
add to overall survival in high-risk and, potentially, standard risk AML (97). Although early
experience in pediatric AML had failed to prospectively identify a benefit with marrow
transplant, trials in POG and CCG demonstrated an apparent survival advantage for
allogeneic transplant (matched sibling SCT) when compared with chemotherapy alone or
autologous transplant (94,95,97). Conflicting data from the UK MRC studies show that even
matched sibling donor SCT reduced the frequency of relapse without improving survival (96).
In acute megakary ocy tic leukemias, the AML-BRM 04 study showed overall 5-y ear survival
of 70%, equivalent with or without SCT (98) Summary recommendations currently indicate
use of SCT (matched, related donor; increasingly, also matched unrelated/haploidentical
donor) with high-risk AML in first remission; indications in intermediate (or standard) risk
bey ond poor early responses are controversial (82,99).
Extramedullary Disease
Extramedullary disease is relatively common in AML at diagnosis. A Japanese cooperative
group series found signs of extramedullary leukemia in 23% of children. Disease was most
often epithelial (skin as nodules or infiltration in 26% or gingival, 14%; CNS, 14%; bone, 10%;
orbital, 8%). (100). The incidence of extramedullary disease in all sites in earlier BFM studies
was similar, while POG reported only 7–10% with extramedullary AML outside the CNS
(100,101,102). Extramedullary involvement is associated with high WBC and
my elomonoblastic or monoblastic subty pes (FAB M4, M5) (100,103). The incidence of CNS
involvement at diagnosis (10–15%) exceeds that seen with ALL (23,50,87,104). In serial St.
Jude trials, the incidence of CNS 2 disease (blasts present but WBC <5 mL in the CSF) was
12% (87). The combination of CNS disease at diagnosis with other extramedullary
involvement and WBC > 100,000 mL has been related to a high frequency of relapse (100).
The overall outcome in patients with CNS leukemia initially varies in the literature; the
outcome over four consecutive St. Jude trials suggests better survival for those with CNS 3 at
diagnosis, many of whom received CrI therapeutically as a part of primary therapy (87).
More recent experience, with limited numbers, suggests similarly favorable outcome may
relate more to associated favorable cy togenetics seen in the CNS cohort than an impact of
therapy (87,100). Overall survival in AML is now approaching the 70% level with wide
variations amongst demographic characteristics and genetic identifications.
Radiotherapeutic Management
Volume
TBI is a central component of HSCT in most malignant hematologic and many genetic
disease states. The target volume encompasses the entire body. Techniques include a variety
of phy sical configurations to achieve a field size adequate to subtend the entire body. For
infants and small children, an anterior–posterior (AP:PA) configuration on the floor often
allows sufficient field size and easy reproducibility. For larger children and adolescents, one
of the extended distance techniques uses opposed lateral fields, providing table positioning and
some degree of tissue compensation from the arms to reduce the excess lung dose secondary
to increased transmission through the lungs. AP:PA techniques (achieved with sitting or
standing positions or with the supine or prone body rotated to be roughly perpendicular to the
incident beam) offer the advantage of partial blocking for compensation or diminution of dose
to critical structures (most often lungs; in some instances, kidney s) (141,142) (Fig. 2.6 ).
The incidence of interstitial pneumonitis is one of the major dose-limiting, regimen-
related, often fatal acute toxicities; the cause is multifactorial including transplant mode
(sy ngeneic associated with the lowest incidence, allogeneic associated with an incidence that
parallels the severity of acute GVHD), the combined conditioning regimen, and the radiation
dose, dose rate, and fractionation (129,141,142,143,144,145,146,147,148). Most current
techniques compensate for added transmission through the measured lung volume and also
deliver a dosage to the midplane of the lungs 10–15% lower than the dose to the total body ;
heterogeneity corrected dose levels are suggested to reduce serious pulmonary complications
when planning approximately 12 Gy TBI (128,141,142,144,145,148,149). Lung blocks should
include the pulmonary volumes identified on
AP:PA radiographs, ty pically excluding the
upper mediastinum (i.e., thy mus) from the lung
shields. In lateral body techniques, the added
width of the thorax in most children and
adolescents compensates for the lung
transmission. Tomotherapy has been used to
deliver total marrow/total ly mphoid irradiation,
the helical techniques providing targeted
marrow/ly mphoid doses while delivering 50–
80% less dose to critical viscera (146,150,151).
Page 22Based on an initial testicular failure
rate in 4 of 28 boy s, Shank and colleagues at
Memorial/Sloan Kettering Cancer Center (152)
recommended the addition of a testicular boost
in TBI. The use of a 4-Gy testicular boost
essentially eliminated testicular relapse. A
subsequent French experience (with TBI and
high-dose cy tosine arabinoside and busulfan)
used 12 Gy TBI in six fractions or 9–10 Gy as a Figure 2.6 A: “AP:PA” technique using
single fraction with no testicular “boost” in two- supine/prone positioning, respectively, on
thirds of the boy s treated; no testicular failures rotating couch (St. Jude), patient secured
were recorded (128). with whole body Vac-Loc and rotated 90º
Children with isolated CNS relapse may to provide incident lateral beam. Shown,
benefit from CrI given immediately before the PA with lung compensators. B: Simple
start of the conditioning regimen; data is “AP:PA” on-the-floor technique for infants
controversial. CrI to 6–12 Gy in 4–8 fractions
timed to be in close temporal subtended by vertical beam. Shown, PA
proximity /continuity with TBI has resulted in with lung compensators.
essentially eliminating second relapse without
transplant-related mortality in series reporting HSCT for isolated CNS relapse
(119,124,125,133,134).
1. Pui CH, Behm FG, Crist WM. Clinical and biologic relevance of immunologic marker
studies in childhood acute ly mphoblastic leukemia. Blood. 1993;82(2):343–362.
2. Moghrabi A, Levy DE, Asselin B, et al. Results of the Dana-Farber cancer institute ALL
consortium protocol 95-01 for children with acute ly mphoblastic leukemia. Blood.
2007;109(3):896–904.
3. Carroll WL, Bhojwani D, Min DJ, et al. Childhood acute ly mphoblastic leukemia in the
age of genomics. Pediatr Blood Cancer. 2006;46(5):570–578.
4. Pui CH, Evans WE. A 50-y ear journey to cure childhood acute ly mphoblastic leukemia.
Semin Hematol. 2013;50:185–196.
5. Arico M, Baruchel A, Bertrand Y, et al. The seventh international childhood acute
ly mphoblastic leukemia workshop report: Palermo, Italy, January 29–30, 2005.
Leukemia. 2005;19(7):1145–1152.
6. Jeha S, Pei D, Raimondi SC, et al. Increased risk for CNS relapse in pre-B cell leukemia
with the t(1;19)/TCF3-PBX1. Leukemia. 2009;23:1406–1409.
7. Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell precursor leukaemia: a
subty pe of very high-risk acute ly mphoblastic leukaemia. Lancet Oncol. 2009;10:147–
156.
8. Pui CH, Mullighan CG, Evans WE, et al. Pediatric acute ly mphoblastic leukemia: where
are we going and how do we get there? Blood. 2012;120:1165–1174.
9. Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours
after radiotherapy and antimetabolites. Lancet. 1999;354(9172):34–39.
10. Page 23Pui CH, Boy ett JM, Hancock ML, et al. Outcome of treatment for childhood
cancer in black as compared with white children. The St Jude Children’s Research
Hospital experience, 1962 through 1992. JAMA. 1995;273(8):633–637.
11. Price RA, Johnson WW. The central nervous sy stem in childhood leukemia. I. The
arachnoid. Cancer. 1973;31(3):520–533.
12. Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and
treatment assignment for children with acute ly mphoblastic leukemia. J Clin Oncol.
1996;14(1):18–24.
13. Pui CH, Campana D, Pei D, et al. Treatment of childhood acute ly mphoblastic leukemia
without prophy lactic cranial irradiation. N Engl J Med. 2009;360(26):2730–2741.
14. Moricke A, Reiter A, Zimmermann M, et al. Risk-adjusted therapy of acute
ly mphoblastic leukemia can decrease treatment burden and improve survival: treatment
results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-
BFM 95. Blood. 2008;111(9):4477–4489.
15. Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual
disease measurements in the context of risk-based therapy in childhood acute
ly mphoblastic leukaemia: a prospective study. Lancet Oncol. 2015;16:465–474.
16. Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal
residual disease in children with acute ly mphoblastic leukaemia. Lancet.
1998;351(9102):550–554.
17. Pui CH, Relling MV, Downing JR. Acute ly mphoblastic leukemia. N Engl J Med.
2004;350(15):1535–1548.
18. Pui CH, Evans WE. Treatment of acute ly mphoblastic leukemia. N Engl J Med.
2006;354(2):166–178.
19. Pui CH, Sandlund JT, Pei D, et al. Results of therapy for acute ly mphoblastic leukemia in
black and white children. JAMA. 2003;290(15):2001–2007.
20. Mahmoud HH, Rivera GK, Hancock ML, et al. Low leukocy te counts with blast cells in
cerebrospinal fluid of children with newly diagnosed acute ly mphoblastic leukemia. N
Engl J Med. 1993;329(5):314–319.
21. Pui CH, Sallan S, Relling MV, et al. International Childhood Acute Ly mphoblastic
Leukemia Workshop: Sausalito, CA, 30 November-1 December 2000. Leukemia.
2001;15(5):707–715.
22. Gajjar A, Harrison PL, Sandlund JT, et al. Traumatic lumbar puncture at diagnosis
adversely affects outcome in childhood acute ly mphoblastic leukemia. Blood.
2000;96(10):3381–3384.
23. Pui CH, Howard SC. Current management and challenges of malignant disease in the
CNS in paediatric leukaemia. Lancet Oncol. 2008;9(3):257–268.
24. Trigg ME, Sather HN, Reaman GH, et al. Ten-y ear survival of children with acute
ly mphoblastic leukemia: a report from the Children’s Oncology Group. Leuk Lymphoma.
2008;49(6):1142–1154.
25. Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in childhood acute
ly mphoblastic leukemia despite reduced use of anthracy clines and cranial radiotherapy :
results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood.
2000;95(11):3310–3322.
26. Pui CH, Sandlund JT, Pei D, et al. Improved outcome for children with acute
ly mphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children’s
Research Hospital. Blood. 2004;104(9):2690–2696.
27. Patte C, Auperin A, Michon J, et al. The Societe Francaise d’Oncologie Pediatrique
LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden
and initial response in 561 unselected children with B-cell ly mphomas and L3 leukemia.
Blood. 2001;97(11):3370–3379.
28. Vora A, Goulden N, Mitchell C, et al. Augmented post-remission therapy for a minimal
residual disease-defined high-risk subgroup intermediate-risk acute ly mphoblastic
leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2014;15:809–
818.
29. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and y oung adults
with low-risk acute ly mphoblastic leukaemia defined by minimal residual disease
(UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14:199–209.
30. Childhood ALL Collaborative Group. Duration and intensity of maintenance
chemotherapy in acute ly mphoblastic leukaemia: overview of 42 trials involving 12,000
randomised children. Lancet. 1996;347(9018):1783–1788.
31. Pui CH, Pei D, Campana D, et al. A revised definition for cure of childhood acute
ly mphoblastic leukemia. Leukemia. 2014;28:2336–2343.
32. Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of
childhood acute ly mphoblastic leukemia. N Engl J Med. 2003;349(7):640–649.
33. Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive
trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995.
Berlin-Frankfurt-Munster. Leukemia. 2000;14(12):2205–2222.
34. Eden T. Translation of cure for acute ly mphoblastic leukaemia to all children. Br J
Haematol. 2002;118(4):945–951.
35. Johnson R. An experimental therapeutic approach to L1210 leukemia in mice: Combined
chemotherapy and central nervous sy stem irradiation. J Natl Cancer Inst. 1964;32:1333–
1341.
36. Hustu HO, Aur RJ. Extramedullary leukaemia. Clin Haematol. 1978;7(2):313–337.
37. Simone JV, Aur RJ, Hustu HO, et al. Three to ten y ears after cessation of therapy in
children with leukemia. Cancer. 1978;42 (2 suppl):839–844.
38. George P, Hernandez K, Hustu O, et al. A study of “total therapy ” of acute ly mphocy tic
leukemia in children. J Pediatr. 1968;72(3):399–408.
39. Aur RJ, Simone JV, Hustu HO, et al. A comparative study of central nervous sy stem
irradiation and intensive chemotherapy early in remission of childhood acute
ly mphocy tic leukemia. Cancer. 1972;29(2):381–391.
40. George SL, Aur RJ, Mauer AM, et al. A reappraisal of the results of stopping therapy in
childhood leukemia. N Engl J Med. 1979;300(6):269–273.
41. Pui CH. Toward optimal central nervous sy stem-directed treatment in childhood acute
ly mphoblastic leukemia. J Clin Oncol. 2003;21(2):179–181.
42. Schrappe M, Reiter A, Henze G, et al. Prevention of CNS recurrence in childhood ALL:
results with reduced radiotherapy combined with CNS-directed chemotherapy in four
consecutive ALL-BFM trials. Klin Padiatr. 1998;210(4):192–199.
43. Rivera GK, Raimondi SC, Hancock ML, et al. Improved outcome in childhood acute
ly mphoblastic leukaemia with reinforced early treatment and rotational combination
chemotherapy. Lancet. 1991;337(8733):61–66.
44. Abromowitch M, Ochs J, Pui CH, et al. Efficacy of high-dose methotrexate in childhood
acute ly mphocy tic leukemia: analy sis by contemporary risk classifications. Blood.
1988;71(4):866–869.
45. LeClerc JM, Billett AL, Gelber RD, et al. Treatment of childhood acute ly mphoblastic
leukemia: results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol.
2002;20(1):237–246.
46. Pullen J, Boy ett J, Shuster J, et al. Extended triple intrathecal chemotherapy trial for
prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute
ly mphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol.
1993;11(5):839–849.
47. Mahoney DH Jr, Shuster JJ, Nitschke R, et al. Intensification with intermediate-dose
intravenous methotrexate is effective therapy for children with lower-risk B-precursor
acute ly mphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol.
2000;18(6):1285–1294.
48. Waber DP, Turek J, Catania L, et al. Neuropsy chological outcomes from a randomized
trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS
treatment in acute ly mphoblastic leukemia: findings from Dana-Farber Cancer Institute
ALL Consortium Protocol 95-01. J Clin Oncol. 2007;25(31):4914–4921.
49. Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal fluid examination in
children with acute ly mphoblastic leukemia: significance of low leukocy te counts with
blasts or traumatic lumbar puncture. J Clin Oncol. 2003;21(2):184–188.
50. Loning L, Zimmermann M, Reiter A, et al. Secondary neoplasms subsequent to Berlin-
Frankfurt-Munster therapy of acute ly mphoblastic leukemia in childhood: significantly
lower risk without cranial radiotherapy. Blood. 2000;95(9):2770–2775.
51. Walter AW, Hancock ML, Pui CH, et al. Secondary brain tumors in children treated for
acute ly mphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol.
1998;16(12):3761–3767.
52. Conter V, Schrappe M, Arico M, et al. Role of cranial radiotherapy for childhood T-cell
acute ly mphoblastic leukemia with high WBC count and good response to prednisone.
Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster
groups. J Clin Oncol. 1997;15(8):2786–2791.
53. Page 24Mitchell CD, Richards SM, Kinsey SE, et al. Benefit of dexamethasone
compared with prednisolone for childhood acute ly mphoblastic leukaemia: results of the
UK Medical Research Council ALL97 randomized trial. Br J Haematol.
2005;129(6):734–745.
54. Clarke M, Gay non P, Hann I, et al. CNS-directed therapy for childhood acute
ly mphoblastic leukemia: Childhood ALL Collaborative Group Overview of 43
Randomized Trials. J Clin Oncol. 2003;21(9):1798–1809.
55. Edelmann MN, Ogg RJ, Scoggins MA, et al. Dexamethasone exposure and memory
function in adult survivors of childhood acute ly mphoblastic leukemia: a report from the
SJLIFE cohort. Pediatr Blood Cancer. 2013;60:1778–1784.
56. Edelmann MN, Krull KR, Liu W, et al. Diffusion tensor imaging and neurocognition in
survivors of childhood acute ly mphoblastic leukaemia. Brain. 2014;137:2973–2983.
57. Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced neurotoxicity and
leukoencephalopathy in childhood acute ly mphoblastic leukemia. J Clin Oncol.
2014;32:949–959.
58. Armstrong GT, Reddick WE, Petersen RC, et al. Evaluation of memory impairment in
aging adult survivors of childhood acute ly mphoblastic leukemia treated with cranial
radiotherapy. J Natl Cancer Inst. 2013;105:899–907.
59. Richards S, Pui CH, Gay on P; Childhood Acute Ly mphoblastic Leukemia Collaborative
Group (CALLCG). Sy stematic review and meta-analy sis of randomized trials of central
nervous sy stem directed therapy for childhood acute ly mphoblastic leukemia. Pediatr
Blood Cancer. 2013;60:185–195.
60. Kelly MJ, Trikalinos TA, Dahabreh IJ, et al. Cranial radiation for pediatric T-lineage
acute ly mphoblastic leukemia: a sy stematic review and meta-analy sis. Am J Hematol.
2014;89:992–997.
61. Vora A, Andreano A, Pui CH, et al. Influence of cranial radiotherapy on outcome in
children with acute ly mphoblastic leukemia treated with contemporary therapy. J Clin
Oncol. 2016;34:919–926.
62. Halperin EC, Laurie F, Fitzgerald TJ. An evaluation of the relationship between the
quality of prophy lactic cranial radiotherapy in childhood acute leukemia and institutional
experience: a Quality Assurance Review Center-Pediatric Oncology Group study. Int J
Radiat Oncol Biol Phys. 2002;53(4):1001–1004.
63. Weiss E, Krebeck M, Kohler B, et al. Does the standardized helmet technique lead to
adequate coverage of the cribriform plate? An analy sis of current practice with respect
to the ICRU 50 report. Int J Radiat Oncol Biol Phys. 2001;49(5):1475–1480.
64. Cherlow JM, Sather H, Steinherz P, et al. Craniospinal irradiation for acute ly mphoblastic
leukemia with central nervous sy stem disease at diagnosis: a report from the Children’s
Cancer Group. Int J Radiat Oncol Biol Phys. 1996;36(1):19–27.
65. Pui CH, Mahmoud HH, Rivera GK, et al. Early intensification of intrathecal
chemotherapy virtually eliminates central nervous sy stem relapse in children with acute
ly mphoblastic leukemia. Blood. 1998;92(2):411–415.
66. Kun LE. CNS disease at diagnosis: a continuing challenge in childhood ly mphoblastic
leukemia. Int J Radiat Oncol Biol Phys. 1996;36(1):257–259.
67. Ritchey AK, Pollock BH, Lauer SJ, et al. Improved survival of children with isolated
CNS relapse of acute ly mphoblastic leukemia: a pediatric oncology group study. J Clin
Oncol. 1999;17(12):3745–3752.
68. Ha CS, Chung WK, Koller CA, et al. Role of radiation therapy to the brain in leukemic
patients with cranial nerve palsies in the absence of radiological findings. Leuk
Lymphoma. 1999;32(5–6):497–503.
69. Ribeiro RC, Rivera GK, Hudson M, et al. An intensive re-treatment protocol for children
with an isolated CNS relapse of acute ly mphoblastic leukemia. J Clin Oncol.
1995;13(2):333–338.
70. Kun LE, Camitta BM, Mulhern RK, et al. Treatment of meningeal relapse in childhood
acute ly mphoblastic leukemia. I. Results of craniospinal irradiation. J Clin Oncol.
1984;2(5):359–364.
71. Winick NJ, Smith SD, Shuster J, et al. Treatment of CNS relapse in children with acute
ly mphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol.
1993;11(2):271–278.
72. Kumar P, Kun LE, Hustu HO, et al. Survival outcome following isolated central nervous
sy stem relapse treated with additional chemotherapy and craniospinal irradiation in
childhood acute ly mphoblastic leukemia. Int J Radiat Oncol Biol Phys. 1995;31(3):477–
483.
73. Gay non PS, Qu RP, Chappell RJ, et al. Survival after relapse in childhood acute
ly mphoblastic leukemia: impact of site and time to first relapse—the Children’s Cancer
Group Experience. Cancer. 1998;82(7):1387–1395.
74. Hagedorn N, Acquaviva C, Fronkova E, et al. Submicroscopic bone marrow involvement
in isolated extramedullary relapses in childhood acute ly mphoblastic leukemia: a more
precise definition of “isolated” and its possible clinical implications, a collaborative study
of the Resistant Disease Committee of the International BFM study group. Blood.
2007;110(12):4022–4029.
75. Barredo JC, Devidas M, Lauer SJ, et al. Isolated CNS relapse of acute ly mphoblastic
leukemia treated with intensive sy stemic chemotherapy and delay ed CNS radiation: a
pediatric oncology group study. J Clin Oncol. 2006;24(19):3142–3149.
76. Bowman WP, Aur RJ, Hustu HO, et al. Isolated testicular relapse in acute ly mphocy tic
leukemia of childhood: categories and influence on survival. J Clin Oncol.
1984;2(8):924–929.
77. Rivera GK, Pinkel D, Simone JV, et al. Treatment of acute ly mphoblastic leukemia. 30
y ears’ experience at St. Jude Children’s Research Hospital. N Engl J Med.
1993;329(18):1289–1295.
78. van den BH, Langeveld NE, Veenhof CH, et al. Treatment of isolated testicular
recurrence of acute ly mphoblastic leukemia without radiotherapy —report from the
Dutch Late Effects Study Group. Cancer. 1997;79(11):2257–2262.
79. Bunin N, Rivera G, Goode F, et al. Ocular relapse in the anterior chamber in childhood
acute ly mphoblastic leukemia. J Clin Oncol. 1987;5(2):299–303.
80. Patel SV, Herman DC, Anderson PM, et al. Iris and anterior chamber involvement in
acute ly mphoblastic leukemia. J Pediatr Hematol Oncol. 2003;25(8):653–656.
81. Meshinchi S, Arceci RJ. Prognostic factors and risk-based therapy in pediatric acute
my eloid leukemia. Oncologist. 2007;12(3):341–355.
82. Rubnitz JE. Childhood acute my eloid leukemia. Curr Treat Options Oncol. 2008;9(1):95–
105.
83. Razzouk BI, Estey E, Pounds S, et al. Impact of age on outcome of pediatric acute
my eloid leukemia: a report from 2 institutions. Cancer. 2006;106(11):2495–2502.
84. Aplenc R, Alonzo TA, Gerbing RB, et al. Ethnicity and survival in childhood acute
my eloid leukemia: a report from the Children’s Oncology Group. Blood. 2006;108(1):74–
80.
85. Lange BJ, Gerbing RB, Feusner J, et al. Mortality in overweight and underweight
children with acute my eloid leukemia. JAMA. 2005;293(2):203–211.
86. Rubnitz JE, Gibson B, Smith FO. Acute my eloid leukemia. Pediatr Clin N Am.
2008;55:21–51.
87. Abbott BL, Rubnitz JE, Tong X, et al. Clinical significance of central nervous sy stem
involvement at diagnosis of pediatric acute my eloid leukemia: a single institution’s
experience. Leukemia. 2003;17(11):2090–2096.
88. Lowenberg B, Downing JR, Burnett A. Acute my eloid leukemia. N Engl J Med.
1999;341(14):1051–1062.
89. Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cy togenetics on
outcome in AML: analy sis of 1,612 patients entered into the MRC AML 10 trial. The
Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood.
1998;92(7):2322–2333.
90. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in
pediatric AML. Blood. 2006;108(12):3654–3661.
91. Mrozek K, Marcucci G, Paschka P, et al. Clinical relevance of mutations and gene-
expression changes in adult acute my eloid leukemia with normal cy togenetics: are we
ready for a prognostically prioritized molecular classification? Blood. 2007;109(2):431–
448.
92. Campana D. Determination of minimal residual disease in leukaemia patients. Br J
Haematol. 2003;121(6):823–838.
93. Lange BJ, Smith FO, Feusner J, et al. Outcomes in CCG-2961, a children’s oncology
group phase 3 trial for untreated pediatric acute my eloid leukemia: a report from the
children’s oncology group. Blood. 2008;111(3):1044–1053.
94. Smith FO, Alonzo TA, Gerbing RB, et al. Long-term results of children with acute
my eloid leukemia: a report of three consecutive Phase III trials by the Children’s Cancer
Group: CCG 251, CCG 213 and CCG 2891. Leukemia. 2005;19(12):2054–2062.
95. Page 25Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow
transplantation versus intensive consolidation chemotherapy for acute my eloid leukemia
in childhood. Pediatric Oncology Group. N Engl J Med. 1996;334(22):1428–1434.
96. Gibson BE, Wheatley K, Hann IM, et al. Treatment strategy and long-term results in
paediatric patients treated in consecutive UK AML trials. Leukemia. 2005;19(12):2130–
2138.
97. Woods WG, Neudorf S, Gold S, et al. A comparison of allogeneic bone marrow
transplantation, autologous bone marrow transplantation, and aggressive chemotherapy
in children with acute my eloid leukemia in remission. Blood. 2001;97(1):56–62.
98. Schweitzer J, Zimmermann M, Rasche M, et al. Improved outcome of pediatric patients
with acute megakary oblastic leukemia in the AML-BFM 04 trial. Ann Hematol.
2015;94:1327–1336.
99. Ribera JM, Ortega JJ, Oriol A, et al. Comparison of intensive chemotherapy, allogeneic,
or autologous stem-cell transplantation as postremission treatment for children with very
high risk acute ly mphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol.
2007;25(1):16–24.
100. Kobay ashi R, Tawa A, Hanada R, et al. Extramedullary infiltration at diagnosis and
prognosis in children with acute my elogenous leukemia. Pediatr Blood Cancer.
2007;48(4):393–398.
101. Chang M, Raimondi SC, Ravindranath Y, et al. Prognostic factors in children and
adolescents with acute my eloid leukemia (excluding children with Down sy ndrome and
acute promy elocy tic leukemia): univariate and recursive partitioning analy sis of patients
treated on Pediatric Oncology Group (POG) Study 8821. Leukemia. 2000;14(7):1201–
1207.
102. Vormoor J, Ritter J, Creutzig U, et al. Acute my elogenous leukemia in children under 2
y ears—experiences of the West German AML studies BFM-78, -83, and -87, AML-BFM
Study Group. Br J Cancer. 1992;66:S63–S67.
103. Johnston DL, Alonzo TA, Gerbing RB, et al. Risk factors and therapy for isolated central
nervous sy stem relapse of pediatric acute my eloid leukemia. J Clin Oncol.
2005;23(36):9172–9178.
104. Creutzig U, Zimmermann M, Ritter J, et al. Treatment strategies and long-term results in
paediatric patients treated in four consecutive AML-BFM trials. Leukemia.
2005;19(12):2030–2042.
105. Pession A, Rondelli R, Basso G, et al. Treatment and long-term results in children with
acute my eloid leukaemia treated according to the AIEOP AML protocols. Leukemia.
2005;19(12):2043–2053.
106. Ribeiro RC, Razzouk BI, Pounds S, et al. Successive clinical trials for childhood acute
my eloid leukemia at St Jude Children’s Research Hospital, from 1980 to 2000. Leukemia.
2005;19(12):2125–2129.
107. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med.
2006;354(17):1813–1826.
108. Lake RA, Robinson BW. Immunotherapy and chemotherapy —a practical partnership.
Nat Rev Cancer. 2005;5(5):397–405.
109. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host
disease in human recipients of allogeneic-marrow grafts. N Engl J Med.
1979;300(19):1068–1073.
110. Thomas ED. ALL and bey ond: implications for other hematologic malignancies.
Leukemia. 1997;11(suppl 4):S43–S45.
111. Schrauder A, von SA, Schrappe M, et al. Allogeneic hematopoietic SCT in children with
ALL: current concepts of ongoing prospective SCT trials. Bone Marrow Transplant.
2008;41(suppl 2): S71–S74.
112. Shenoy S, Smith FO. Hematopoietic stem cell transplantation for childhood malignancies
of my eloid origin. Bone Marrow Transplant. 2008;41(2):141–148.
113. Davies SM, Ramsay NK, Klein JP, et al. Comparison of preparative regimens in
transplants for children with acute ly mphoblastic leukemia. J Clin Oncol.
2000;18(2):340–347.
114. Hongeng S, Krance RA, Bowman LC, et al. Outcomes of transplantation with matched-
sibling and unrelated-donor bone marrow in children with leukaemia. Lancet.
1997;350(9080):767–771.
115. Bunin N, Aplenc R, Kamani N, et al. Randomized trial of busulfan vs total body
irradiation containing conditioning regimens for children with acute ly mphoblastic
leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow
Transplant. 2003;32(6):543–548.
116. Vettenranta K. Current European practice in pediatric my eloablative conditioning. Bone
Marrow Transplant. 2008;41 (suppl 2):S14–S17.
117. Entz-Werle N, Suciu S, van der Werff ten Bosch, et al. Results of 58872 and 58921 trials
in acute my eloblastic leukemia and relative value of chemotherapy vs allogeneic bone
marrow transplantation in first complete remission: the EORTC Children Leukemia
Group report. Leukemia. 2005;19(12):2072–2081.
118. Oliansky DM, Camitta B, Gay non P, et al. Role of cy totoxic therapy with hematopoietic
stem cell transplantation in the treatment of pediatric acute ly mphoblastic leukemia:
update of the 2005 evidence-based review. Biol Blood Marrow Transplant. 2012;18:505–
522.
119. Eapen M, Zhang MJ, Devidas M, et al. Outcomes after HLA-matched sibling
transplantation or chemotherapy in children with acute ly mphoblastic leukemia in a
second remission after an isolated central nervous sy stem relapse: a collaborative study
of the Children’s Oncology Group and the Center for International Blood and Marrow
Transplant Research. Leukemia. 2008;22(2):281–286.
120. Thomas ED, Clift RA, Hersman J, et al. Marrow transplantation for acute
nonly mphoblastic leukemic in first remission using fractionated or single-dose
irradiation. Int J Radiat Oncol Biol Phys. 1982;8(5):817–821.
121. Ravindranath Y, Chang M, Steuber CP, et al. Pediatric Oncology Group (POG) studies of
acute my eloid leukemia (AML): a review of four consecutive childhood AML trials
conducted between 1981 and 2000. Leukemia. 2005;19(12):2101–2116.
122. Willemze AJ, Geskus RB, Noordijk EM, et al. HLA-identical haematopoietic stem cell
transplantation for acute leukaemia in children: less relapse with higher biologically
effective dose of TBI. Bone Marrow Transplant. 2007;40(4):319–327.
123. Abrahamsson J, Clausen N, Gustafsson G, et al. Improved outcome after relapse in
children with acute my eloid leukaemia. Br J Haematol. 2007;136(2):229–236.
124. Harker-Murray PD, Thomas AJ, Wagner JE, et al. Allogeneic hematopoietic cell
transplantation in children with relapsed acute ly mphoblastic leukemia isolated to the
central nervous sy stem. Biol Blood Marrow Transplant. 2008;14(6):685–692.
125. Eapen M, Zhang MJ, Devidas M, et al. Outcomes after HLA-matched sibling
transplantation or chemotherapy in children with acute ly mphoblastic leukemia in a
second remission after an isolated central nervous sy stem relapse: a collaborative study
of the Children’s Oncology Group and the Center for International Blood and Marrow
Transplant Research. Leukemia. 2008;22:281–286.
126. Schrauder A, Reiter A, Gadner H, et al. Superiority of allogeneic hematopoietic stem-
cell transplantation compared with chemotherapy alone in high-risk childhood T-cell
acute ly mphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol.
2006;24(36):5742–5749.
127. Woolfrey AE, Anasetti C, Storer B, et al. Factors associated with outcome after unrelated
marrow transplantation for treatment of acute ly mphoblastic leukemia in children.
Blood. 2002;99(6):2002–2008.
128. Bordigoni P, Esperou H, Souillet G, et al. Total body irradiation-high-dose cy tosine
arabinoside and melphalan followed by allogeneic bone marrow transplantation from
HLA-identical siblings in the treatment of children with acute ly mphoblastic leukaemia
after relapse while receiving chemotherapy : a Societe Francaise de Greffe de Moelle
study. Br J Haematol. 1998;102(3):656–665.
129. Corvo R, Paoli G, Barra S, et al. Total body irradiation correlates with chronic graft
versus host disease and affects prognosis of patients with acute ly mphoblastic leukemia
receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol
Phys. 1999;43(3):497–503.
130. Zecca M, Pession A, Messina C, et al. Total body irradiation, thiotepa, and
cy clophosphamide as a conditioning regimen for children with acute ly mphoblastic
leukemia in first or second remission undergoing bone marrow transplantation with
HLA-identical siblings. J Clin Oncol. 1999;17(6):1838–1846.
131. Biagi E, Rovelli A, Balduzzi A, et al. TBI, etoposide and cy clophosphamide as a
promising conditioning regimen for BMT in childhood ALL in second remission. Bone
Marrow Transplant. 2000;26(11):1260–1262.
132. Alexander BM, Wechsler D, Braun TM, et al. Utility of cranial boost in addition to total
body irradiation in the treatment of high risk acute ly mphoblastic leukemia. Int J Radiat
Oncol Biol Phys. 2005;63(4):1191–1196.
133. Alexander BM, Wechsler D, Braun TM, et al. Utility of cranial boost in addition to total
body irradiation in the treatment of high risk acute ly mphoblastic leukemia. Int J Radiat
Oncol Biol Phys. 2005;63:1191–1196.
134. Page 26Aldoss I, Al Malki MM, Stiller T, et al. Implications and management of central
nervous sy stem involvement before allogeneic hematopoietic cell transplantation in
acute ly mphoblastic leukemia. Biol Blood Marrow Transplant. 2015;22:571–588.
135. Flowers ME, Doney KC, Storb R, et al. Marrow transplantation for Fanconi anemia with
or without leukemic transformation: an update of the Seattle experience. Bone Marrow
Transplant. 1992;9(3):167–173.
136. MacMillan ML, Auerbach AD, Davies SM, et al. Haema-topoietic cell transplantation in
patients with Fanconi anaemia using alternate donors: results of a total body irradiation
dose escalation trial. Br J Haematol. 2000;109(1):121–129.
137. Socie G, Devergie A, Girinski T, et al. Transplantation for Fanconi’s anaemia: long-term
follow-up of fifty patients transplanted from a sibling donor after low-dose
cy clophosphamide and thoraco-abdominal irradiation for conditioning. Br J Haematol.
1998;103(1):249–255.
138. Castro-Malaspina H, Childs B, Laver J, et al. Hy perfractionated total ly mphoid
irradiation and cy clophosphamide for preparation of previously transfused patients
undergoing HLA-identical marrow transplantation for severe aplastic anemia. Int J
Radiat Oncol Biol Phys. 1994;29(4):847–854.
139. Kroger N, Zabelina T, Renges H, et al. Long-term follow-up of allogeneic stem cell
transplantation in patients with severe aplastic anemia after conditioning with
cy clophosphamide plus antithy mocy te globulin. Ann Hematol. 2002;81(11):627–631.
140. Bunin N, Aplenc R, Iannone R, et al. Unrelated donor bone marrow transplantation for
children with severe aplastic anemia: minimal GVHD and durable engraftment with
partial T cell depletion. Bone Marrow Transplant. 2005;35(4):369–373.
141. Broerse JJ, Dutreix A, Noordijk EM. Phy sical, biological and clinical aspects of total
body irradiation. Radiother Oncol. 1990;18(suppl 1):1–2.
142. Harden SV, Routsis DS, Geater AR, et al. Total body irradiation using a modified standing
technique: a single institution 7 y ear experience. Br J Radiol. 2001;74(887):1041–1047.
143. Cosset JM, Girinsky T, Malaise E, et al. Clinical basis for TBI fractionation. Radiother
Oncol. 1990;18(suppl 1):60–67.
144. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in
patients with acute my eloid leukemia in first remission: a randomized trial of two
irradiation regimens. Blood. 1990;76(9):1867–1871.
145. Gopal R, Ha CS, Tucker SL, et al. Comparison of two total body irradiation fractionation
regimens with respect to acute and late pulmonary toxicity. Cancer. 2001;92(7):1949–
1958.
146. Schultheiss TE, Wong J, Liu A, et al. Image-guided total marrow and total ly mphatic
irradiation using helical tomotherapy. Int J Radiat Oncol Biol Phys. 2007;67(4):1259–
1267.
147. Sampath S, Schultheiss TE, Wong J. Dose response and factors related to interstitial
pneumonitis after bone marrow transplant. Int J Radiat Oncol Biol Phys. 2005;63(3):876–
884.
148. Della VA, Ferreri AJ, Annaloro C, et al. Lethal pulmonary complications significantly
correlate with individually assessed mean lung dose in patients with hematologic
malignancies treated with total body irradiation. Int J Radiat Oncol Biol Phys.
2002;52(2):483–488.
149. Soule BP, Simone NL, Savani BN, et al. Pulmonary function following total body
irradiation (with or without lung shielding) and allogeneic peripheral blood stem cell
transplant. Bone Marrow Transplant. 2007;40(6):573–578.
150. Wong JY, Forman S, Somlo G, et al. Dose escalation of total marrow irradiation with
concurrent chemotherapy in patients with advanced acute leukemia undergoing
allogeneic hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2013;85:148–
156.
151. Kim JH, Stein A, Tsai N, et al. Extramedullary relapse following total marrow and
ly mphoid irradiation in patients undergoing allogeneic hematopoietic cell transplantation.
Int J Radiat Oncol Biol Phys. 2014;89:75–81.
152. Shank B, O’Reilly RJ, Cunningham I, et al. Total body irradiation for bone marrow
transplantation: the Memorial Sloan-Kettering Cancer Center experience. Radiother
Oncol. 1990;18(suppl 1):68–81.
153. Thomas E, Storb R, Clift RA, et al. Bone-marrow transplantation (first of two parts). N
Engl J Med. 1975;292(16):832–843.
154. Gale RP, Butturini A, Bortin MM. What does total body irradiation do in bone marrow
transplants for leukemia? Int J Radiat Oncol Biol Phys. 1991;20(3):631–634.
155. Soejima T, Hirota S, Tsujino K, et al. Total body irradiation followed by bone marrow
transplantation: comparison of once-daily and twice-daily fractionation regimens. Radiat
Med. 2007;25(8):402–406.
156. Kim TH, Ry bka WB, Lehnert S, et al. Interstitial pneumonitis following total body
irradiation for bone marrow transplantation using two different dose rates. Int J Radiat
Oncol Biol Phys. 1985;11(7):1285–1291.
157. Peters LJ, Withers HR, Cundiff JH, et al. Radiobiological considerations in the use of
total-body irradiation for bone-marrow transplantation. Radiology. 1979;131(1):243–247.
158. Clift RA, Buckner CD, Appelbaum FR, et al. Long-term follow-Up of a randomized trial
of two irradiation regimens for patients receiving allogeneic marrow transplants during
first remission of acute my eloid leukemia. Blood. 1998;92(4):1455–1456.
159. Cheng JC, Schultheiss TE, Wong JY. Impact of drug therapy, radiation dose, and dose
rate on renal toxicity following bone marrow transplantation. Int J Radiat Oncol Biol
Phys. 2008;71(5):1436–1443.
160. Corvo R, Lamparelli T, Bruno B, et al. Low-dose fractionated total body irradiation (TBI)
adversely affects prognosis of patients with leukemia receiving an HLA-matched
allogeneic bone marrow transplant from an unrelated donor (UD-BMT). Bone Marrow
Transplant. 2002;30(11):717–723.
161. Bieri S, Helg C, Chapuis B, et al. Total body irradiation before allogeneic bone marrow
transplantation: is more dose better? Int J Radiat Oncol Biol Phys. 2001;49(4):1071–1077.
CH A P TER 3
Supratentorial Brain Tumors
Bree R. Eaton, Shannon M. MacDonald, Larry E. Kun, and Nancy J. Tarbell
Page 27Twenty percent of all neoplasms in children arise in the central nervous sy stem
(CNS). The incidence of CNS tumors in children has increased over the past three decades
(1). The current World Health Organization (WHO) classification of CNS neoplasms is
summarized in Table 3.1 (2,3); a new WHO classification scheme, with major emphasis
on genomic diagnoses and classification, will be released in 2016.
Over half of pediatric CNS tumors arise in the supratentorial brain. Anatomically, the
supratentorial cranial compartment (Fig. 3.1 ) includes the cerebral hemispheres (frontal,
parietal, temporal, and occipital lobes), the diencephalon (hy pothalamus, the optic chiasm,
and the thalamic, caudate nucleus, putamen, and basal ganglion structures, the latter
generally considered together as the thalamic region), the pineal region (pineal gland and
posterior third ventricular region), and the sellar/suprasellar region. Tumors can be
categorized by anatomic region, correlating with clinical signs and specific histioty pes:
suprasellar lesions (including glial tumors of the optic chiasm and adjacent hy pothalamic
area, craniophary ngioma, and germ cell tumors [GCTs]), central deep-seated lesions
(gliomas of the thalamic region and tumors of the pineal region, including germ cell,
embry onal, and glial neoplasms), and peripheral lesions (gliomas, ependy momas, and
embry onal tumors of the cerebral hemispheres).
Table 3.1 Histopathologic
Classification of CNS Tumors—WHO
Classification 2007
Figure 3.1 A: Axial MRI demonstrating key anatomic sites from the interorbital frontal
lobes, through the superior suprasellar region (optic tracts, hypothalamus), midbrain, and
superior cerebellar vermis (posterior to midbrain). B: Coronal MRI through central
suprasellar location with posterior chiasm, hypothalamic nuclei, anterior aspect of third
ventricle (between R and L hypothalamic nuclei), lateral ventricles (above third), and mid-
temporal lobes. C: Sagittal MRI demonstrating supratentorial brain, tentorium and
underlying cerebellum (with central fourth ventricle), brainstem (pons with medulla below
and tegmentum of midbrain contiguously above), tectal plate (cerebral aqueduct delineates
this in midline from anteroinferior tegmentum), pineal gland, and suprasellar structures
(optic chiasm and infundibulum of pituitary–hypothalamic stalk).
Although most brain tumors are sporadic, a number of pediatric brain tumor presentations are
associated with recognized neurocutaneous or other genetic sy ndromes, as outlined in Table
3.2 (6).
Low-grade astrocy tomas are a diverse group of tumors that collectively represent the most
common category of pediatric brain tumors (1). Management is variable and dependent on
tumor location, patient age, presence of a genetic mutation, and, often, phy sician and parental
preference. Outcomes are generally favorable; the goal of treatment is durable disease
control or cure with preservation of function. The most frequent site of origin is in the
cerebellum (see Chapter 4 ) followed by the deep midline diencephalon (thalamus,
hy pothalamus, optic chiasm and nerves, basal ganglia, and related structures) and the
cerebral hemispheres. In contrast to adults who are most commonly diagnosed with high-
grade astrocy tomas, the majority of supratentorial tumors occurring in childhood are low-
grade astrocy tomas. Low-grade gliomas of the optic pathway and hy pothalamus have
distinct features and are discussed below as a separate group.
Page 30A subset of diffuse low-grade tumors extends across two or three lobes, often
with no obvious or dominant mass lesion; the diffuse pattern of involvement is classified as
gliomatosis cerebri (9). Ty pical unifocal low-grade gliomas occasionally present with
subarachnoid dissemination; the incidence is approximately 3%, most often seen in tumors
located in the diencephalon (9,10).
Diagnostic imaging generally reveals a lesion that is isointense on CT and T1 MRI
sequences and hy perintense on T2 sequence (5). Pilocy tic astrocy tomas (PAs) enhance
briskly and diffusely, but most other low-grade tumors show little or no enhancement with
gadolinium (5). Scattered calcifications may be present. Tumors may include small or
dominant cy sts; some degree of cy st formation is common in JPAs. MRI is the imaging
modality of choice. Due to the variability of enhancement, T1 sequences may not provide
the best demarcation of the tumor borders; post-gadolinium T2-FLAIR images are often
preferred (Fig. 3.2B ).
Histopathology of low-grade astrocy tomas is characterized by low cellularity, little
nuclear aty pia, and few, if any, mitotic figures. Although the term “low grade” applies to all
pediatric gliomas that are not anaplastic, the various histioty pes differ in the degree of
infiltration, relative aggressiveness, and prognosis. JPAs and diffuse fibrillary astrocy tomas
comprise the majority of pediatric low-grade gliomas. Figure 3.3 depicts histologic
features of these two most commonly encountered low-grade astrocy tomas. Less common
low-grade astrocy tomas include gemistocy tic astrocy tomas, pleomorphic
xanthoastrocy tomas, desmoplastic infantile astrocy tomas, protoplasmic astrocy tomas, and
subependy mal giant cell astrocy tomas. These tumors are generally classified by the WHO
histologic criteria (2). The WHO sy stem categorizes PA as grade I and other differentiated
astrocy tomas including all diffuse astrocy tomas, as grade II; anaplastic astrocy toma and
glioblastoma multiforme are coded as grade III and grade IV, respectively (2). Broniscer et
al. (11) reported a cumulative rate of malignant transformation amongst pediatric grade II
astrocy tomas of 7% at 15 y ears postdiagnosis, a
much lower frequency than has been reported in
adults. PAs almost uniformly retain low-grade
characteristics even when uncontrolled or
recurrent (11).
PAs are characterized by elongated bipolar astrocy tes organized in a parallel array of
glial fibers, giving a hairlike or piloid appearance. The sparsely cellular tumors are signified
by microcy sts and Rosenthal fibers (amorphous eosinophilic material formed by plump,
degenerating astrocy tes). Macroscopically, visible cy stic components often are present,
sometimes with less prominent solid tumor components. The tumors may be circumscribed
or may extend along white matter tracts, depending on the location (Fig. 3.4 ). PA is the
most common tumor in the diencephalic region and comprises 25% of hemispheric
astrocy tomas. The tumor ty pically is nonaggressive, although multifocal presentation, rapid
progression, and dissemination may occur (12).
Page 31
Figure 3.4 A: A 7-year-old boy with JPA of optic chiasm and optic tracts (without
neurofibromatosis), involving and distorting chiasm (A, top) with spread along optic tracts
(A, bottom). B: Increased tumor size, enhancement along optic tracts noted 7 months
postradiotherapy (post-RT), attributed to transient posttherapy effects (B, top and bottom).
C: Same levels with marked, spontaneous reduction in tumor volume compared to
preirradiation or MRI 7 months post-RT (Figures B); note normal chiasm (C, top). Patient
now 5.5 years post-RT, with intervening (R) middle cerebral infarct (C, bottom; same time
as C, top).
Pilomy xoid tumors have recently been defined as a subset of low-grade gliomas,
previously classified with pilocy tic astrocy tomas. Pilomy xoid tumors have a my xoid matrix
with highly monomorphic piloid cells; they may demonstrate an arrangement resembling
perivascular rosettes; they are usually solid with less prominent cy stic components and lack
Rosenthal fibers (13). These tumors are considered to be more aggressive than classical
pilocy tic astrocy tomas and are categorized by the WHO as grade II, although little data y et
confirm the clinical implications of this diagnosis (2).
Grade II astrocy tomas are characterized by a greater degree of infiltration; the
proliferation index may exceed that of the PA, and a greater number of molecular
aberrations are apparent. Diffuse fibrillary astrocy tomas consist of long, thin cells highlighted
by a crisscrossing background matrix of cy toplasmic glial filaments. Gemistocy tic
astrocy tomas are less common, presenting as benign-appearing, often circumscribed lesions
with a high rate of recurrence; these tumors often demonstrate malignant degeneration within
several y ears after initial presentation and are associated with worse survival than other grade
II astrocy tomas (14,15). Protoplasmic astrocy tomas are characterized by large, rounded
astrocy tes with abundant cy toplasm and a background largely devoid of fibrils. Grade II
astrocy tomas are more often associated with local recurrence and may present with
malignant progression (11).
Pleomorphic xanthoastrocy tomas present as superficial tumors in the cerebral
hemispheres. Despite an aggressive histologic appearance with cellular pleomorphism and
numerous mitoses, the behavior of pleomorphic xanthoastrocy tomas is quite benign; the
tumor is classified as grade II. Long-term disease control usually is obtained through surgery
alone; a proportion of cases does recur late and occasionally shows malignant degeneration
(16). A small percentage of these lesions show mitotic activity, areas of necrosis, and a high
proliferative index at initial diagnosis and are designated as anaplastic pleomorphic
xanthoastrocy toma. The latter may be somewhat more aggressive clinically (16).
Subependy mal giant cell astrocy tomas are a distinct subty pe of sharply marginated
tumors that occur along the linings of the lateral ventricles. The lesions occur in the setting of
tuberous sclerosis; children often have seizures and show significant developmental delay s
(17). Subependy mal giant cell tumors are almost alway s managed with surgical resection
alone.
Genomic alterations involving BRAF are common in low-grade astrocy tomas and
gangliogliomas, carry prognostic significance, and provide options for targeted therapy (18).
BRAF-activating mutations are common in sporadic PAs, most often in infratentorial or
midline-located tumors, and are associated with a more favorable prognosis and reduced risk
of progression to high-grade gliomas. Approximately two-thirds of pleomorphic cases and up
to 40% of gangliogliomas carry the BRAFV600E point mutation. This mutation has been
recognized as a poor prognostic factor and is found in tumors that progress to HGG (18).
Page 32Therapy
Surgery
For low-grade gliomas amenable to complete surgical resection, surgery is generally the first
and sole intervention providing excellent control of disease. Total resection is usually feasible
for tumors arising in the cerebral hemispheres with reports indicating gross total resection
(GTR) in 90% of cerebral hemispheric and cerebellar astrocy tomas (19). Low recurrence
rates are reported for both PA and other astrocy tomas after total resection. Data from the
Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) study of primary
surgery in low-grade gliomas reported a 5-y ear progression free survival of 92% after GTR,
ranging from 95-100% for PAs and gangliogiomas to 80% for diffuse astrocy tomas (20).
Resection of tumors involving the dominant medial temporal lobe, motor strip region, or the
Broca speech cortex may not be possible without inducing severe neurologic deficits. Partial
resection may provide initial intervention for decompression and histopathologic diagnosis.
Low-grade gliomas of the diencephalon and optic pathway are technically challenging
due to the deep location and eloquent area; however, contemporary series report successful
resection for selected tumors in this region (21,22). Long-term disease control is ty pically
achieved by total resection. The CCG–POG study notes a progression-free survival after
surgery alone of 50–60% for diencephalic tumors, much lower than for lesions originating in
the cerebellum or cerebral hemispheres where GTR is more common (20).
Radiation Therapy
Radiation therapy is an established, effective treatment for low-grade gliomas, achieving
tumor response and durable disease control in a significant proportion of pediatric cases
(19,23,24) (Fig. 3.2 ). An analy sis from Pollack et al. (19) showed improved disease
control at 10 y ears after irradiation following incomplete resection of cerebral hemispheric
astrocy tomas: 82% progression-free survival with irradiation versus 42% after surgery alone;
there was no significant benefit in overall survival. A phase II prospective study published by
Merchant et al. (24) demonstrated excellent event-free survival (87% and 74% at 5 and 10
y ears, respectively ) and overall survival (over 90% at 10 y ears) for children treated with
three-dimensional (3D) conformal irradiation to the MRI-defined tumor volume. These
outcomes compared favorably to the literature and have been associated with excellent
functional outcomes (25). Proton therapy also provides an opportunity to minimize radiation
associated sequelae by further reducing the dose delivered to the normal brain in these
patients (26). The decreased volume of normal brain exposed to moderate or high radiation
doses using conformal techniques with small margins may significantly decrease some of the
serious radiation-induced side effects (27). A study from Greenberger et al. (28)
demonstrated excellent results with the use of proton therapy for low-grade gliomas, with a 6-
y ear PFS rate of 89.7%. Treatment toxicity was minimal, with no significant declines in
neurocognitive functioning among patients age 7 y ears and older, and visual acuity stabilized
or improved in 83% of patients at risk for radiation-induced injury to the optic pathway s (28).
Care must be taken to accurately delineate tumor volumes, addressing white matter
tracts in defining the clinical tumor volume (CTV). Merchant et al. (24) suggest a minimal
margin (as small as 5 mm) may be adequate for well-demarcated tumors. The recently
completed Children’s Oncology Group (COG) study ACNS0221 utilized a 5-mm
anatomically limited CTV margin around the gross tumor volume (GTV) in a multi-
institutional trial; the trial has y et to be reported.
There are no contemporary data suggesting a benefit to postoperative irradiation for
completely resected low-grade astrocy tomas. Current indications for radiation therapy after
a near total resection (with imaging evidence of disease residual) include sy mptoms or signs
that might improve with irradiation or postsurgical progression in a location not amenable to
safe, definitive second resection. Other factors that are taken into consideration are histologic
subty pe and biology (29). Chemotherapy is ty pically considered prior to irradiation for
y oung children or for patients with neurofibromatosis (NF1) or cognitive delay.
For incompletely resected low-grade astrocy tomas, early administration of irradiation
may not benefit the patient (30). Reports from the large CCG–POG low-grade trial confirm
previous institutional data suggesting that a significant proportion of incompletely resected
astrocy tomas remain indolent over 3–5 y ears; progression-free survival rate at 5 y ears is
55% after near total or subtotal resection (20). A decision to observe children with residual
astrocy toma should involve all subspecialties (neurosurgery, radiation oncology, pediatric
neuro-oncology ) indicating the obligation for regular clinical follow-up and imaging that
allows one to comfortably observe a child with the anticipation that treatment can be initiated
upon documented tumor progression. Such an approach balances the recognized efficacy of
radiation therapy with potential toxicities related, in part, to the anatomic location and volume
of the tumor and the age of the patient. Inherent in such an approach is the commitment to
intervene appropriately with documented disease progression, including use of primary
radiation therapy, additional surgery, or chemotherapy as indicated.
PAs predominate in hy pothalamic and OPTs. Prolonged progression-free survival after
irradiation alone for these tumors reflects both the indolent nature of tumors in this site and the
efficacy of irradiation. Survival rates in excess of 80% at 10 y ears after irradiation are
common for these tumors (24,31). In thalamic astrocy tomas, pilocy tic histology is less
prevalent; 10-y ear survival results range from 33% to 60% after therapy (24,31,32).
Page 33Gliomatosis cerebri and bithalamic astrocy tomas represent supratentorial
counterparts of the more common, diffusely infiltrating pontine astrocy tomas. The infiltrating
supratentorial tumors respond to radiation therapy both sy mptomatically and by imaging, but
recurrence and progression are ty pically apparent within a y ear (9,32).
Chemotherapy
Chemotherapy has been used with increasing frequency for low-grade gliomas as a strategy
to delay or avoid radiation therapy ; with the availability of molecularly targeting agents (e.g.,
vemurafenib) for the low-grade gliomas that harbor the BRAFV600E mutation, there is more
interest in preirradiation pharmacologic approaches. Primary chemotherapy for low-grade
gliomas was studied initially in centrally located tumors that tend to occur in y ounger patients
and are not amenable to resection. Cy totoxic chemotherapy provides disease control for
months to y ears with stable disease or partial response; most tumors progress within 3–4
y ears, often requiring radiation therapy at that time. The age below which chemotherapy is
more appropriate is controversial and dependent on factors such as tumor size and location,
presence of NF mutation, or developmental or neurocognitive delay s. Packer et al. (33)
reported age to be the only significant prognostic factor, with 3-y ear progression-free
survival rate of 74% for children ≤5 y ears old versus 39% for older children. In COG, the age
of ≤10 y ears was chosen for trial eligibility in studies evaluating chemotherapy as initial
treatment.
Favorable control rates and relative absence of serious toxicity have established
carboplatin and vincristine as the “standard” first-line chemotherapy for low-grade gliomas
in y ounger children (33). Carboplatin hy persensitivity occurs over time, often limiting further
administration of this regimen (34). Temozolomide, an alky lating agent with modest
responsiveness in recurrent low-grade gliomas, has been used with carboplatin/vincristine to
prolong drug tolerance (35). The five-drug University of California at San Francisco (UCSF)
regimen (6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine, TPCV) is
similarly efficacious. A randomized trial comparing carboplatin/vincristine to this regimen
has been completed by COG, suggesting equal or greater efficacy with this five-drug
regimen: 5-y ear event-free survival was 39% with carboplatin and vincristine versus 52%
with TPCV, not a statistically significant difference, and toxicity was greater with TPCV (36).
The 5-y ear OS for the entire population was 86%, with y ounger age, larger tumor size, and
thalamus location predicted for worse outcomes (36). Bevacizumab in combination with
irinotecan has been investigated for recurrent low-grade glioma with promising response
rates in heavily pretreated patients (37). Other sy stemic therapies for recurrent or refractory
low-grade gliomas include vinblastine, temozolamide, and lenolidomide alone or in
combination with other chemotherapeutic agents. Novel targeted therapies are also under
investigation.
The decision to proceed with chemotherapy or irradiation relates to patient age and
clinical presentation; consideration should involve consultation with and discussion amongst a
multidisciplinary team reviewing relative risks and benefits with the patient’s family. Factors
bey ond age alone include sy mptoms and signs, potential for additional neurocognitive
deficits, the likelihood of durable benefit from respective chemotherapeutic regimens, and the
radiation volume and modality -specific dosimetry related to relative potential toxicities.
Although not proven to be problematic, there is no confirmation that the response rate and
durability of disease control following radiation therapy are independent of prior failure on
chemotherapy.
Radiotherapeutic Management
Volume
Fusion of MRI with CT imaging is critical to determine the extent of disease defining the GTV
for treatment planning. T1 gadolinium-enhanced imaging may be ideal for PA; for diffuse
astrocy toma (grade II) and the less common low-grade neoplasms, T2-FLAIR or T2
sequences are most useful as the tumor rarely shows contrast enhancement throughout,
though all MRI sequences should be reviewed. The CTV may be defined as a 5- to 10-mm
anatomic expansion; a prospective study at St. Jude indicated a dearth of marginal
recurrences with a 1-cm anatomic expansion of the GTV to define the CTV (24), and a
recent prospective COG study has been completed using a 5-mm anatomic expansion. An
additional 3–5 mm geometric expansion defines the planning target volume (PTV). The use
of small margins requires a careful review of all neuroimaging with great attention to detail
including all cy stic and solid components of the tumor in the GTV, as well as daily image
guidance to minimize setup uncertainty. Similar guidelines appear to be appropriate for grade
II (fibrillary ) astrocy tomas, recognizing that most such tumors in children have apparent
margins on imaging. Shrinking fields ty pically are not used in PAs; when target volumes for
infiltrating fibrillary astrocy tomas are used, fields may be reduced to more narrowly
encompass the obvious tumor after delivery of 50.4 Gy. For tumors with a cy stic component,
a CT or limited sequence MRI during radiation therapy may prove useful to evaluate changes
in the cy stic portion of the tumor during treatment. Diffuse low-grade gliomas can be
associated with gliomatosis cerebri or bithalamic astrocy tomas; both may be histologically
WHO grade II, but the pattern of growth indicates a degree of aggressiveness and infiltration
requiring large-volume irradiation based on guidelines for malignant gliomas (9,32). For
gliomatosis cerebri that is bilateral and involving much of the cerebral hemispheres, corpus
callosum, and, sometimes, thalamic nuclei, volumes defined by disease extent may approach
the whole brain; use of an imaging-defined “boost” or partial brain irradiation where possible
initially remain the accepted standards (9,38).
Astrocy tomas with multifocal presentations or subarachnoid seeding generally are
treated with craniospinal irradiation (CSI), although the need to cover the entire neuraxis is
controversial and unproven (10,39).
Dosage
There is little definitive dose–response data specific for pediatric astrocy tomas. The adult
low-grade glioma trials have established no clear benefit for dosage levels greater than 45 Gy
(40,41). Pediatric national trials employ doses approaching the established tolerance of
critical CNS structures (i.e., 50–54 Gy ). The primary justification is the long-term disease
control rates documented in studies of pediatric PA and other low-grade astrocy tomas. For
children y ounger than 5 y ears, a delay in irradiation is appropriate as clinical signs permit,
and when radiation therapy is needed, a dose of 50–54 Gy with optimal conformality is
standard.
Page 34Technique
Ideal techniques achieve close conformation of the high-dose region to a well-defined local
target volume. 3D conformal or intensity -modulated photon irradiation, or use of intensity -
modulated proton beam therapy is ideal to achieve conformality, with potential differences in
sparing adjacent dose-limiting structures (e.g., optic chiasm, ey e, and pituitary –hy pothalamic
region) and in intralesional homogeneity. Given the nature of low-grade gliomas and
recognized dose-related toxicities, attention to dose–volume histograms (DVH) and a 3D
image-based radiation plan is critical in designing treatment techniques. Multiple fields, based
on single-plane or noncoplanar techniques, may be used to achieve a dose distribution
maximally conformed to the target volume (Fig. 3.5 ). The impact of low-dose irradiation
on broader regions of the developing brain has not y et been fully explored; dose–volume
modeling suggests correlations between low-dose volumes and cognitive deficits (42). Early
results suggest that 3D conformal techniques achieve greater sparing of neuropsy chological
function, for example, than past experience has shown for conventional therapies (43). The
phy sical properties of protons allow for further reduction in the amount of brain exposed to
low-dose irradiation (26)(Fig. 3.6 ). The optimal conformality of intensity -modulated,
photon or proton therapy is likely to be associated with less pronounced late toxicities as a
result of diminished high- and low-dose exposure of normal tissue volumes (26,27,28).
Figure 3.5 Optic chiasm/hypothalamic glioma presenting for radiation therapy at 4 years
old following imaging evidence of progression after two chemotherapy regimens (A1–A3) B:
target volumes for this case depicted for axial (B1), sagittal (B2), and coronal (B3) planes.
Note CT dosimetry using IMRT 6 MeV photons with: GTV (green) with 5–10 mm anatomic
expansion for CTV (blue); geometric 3-mm expansion for PTV (red).
Figure 3.6 A: DVH derived as a composite plan from 10 cases of optic chiasm gliomas,
comparing 3D conformal RT (photon is red/dashed) and scanning proton beam (blue/solid). B:
Estimated IQ change based upon dose–volume effect models, depicting Wechslar Individual
Achievement Test (WIAT) spelling for 3D conformal RT (photon, red/dotted) and scanning
protons (blue/solid). (From Merchant TE, Hua CH, Shukla H, et al. Proton versus photon
radiotherapy for common pediatric brain tumors: comparison of models of dose
characteristics and their relationship to cognitive function. Pediatr Blood Cancer.
2008;51:110–117, with permission.)
Results
Overall, outcomes for low-grade gliomas are quite favorable. Prognosis is related to age at
diagnosis and degree of surgical resection; older children usually enjoy more favorable
outcome. GTR is consistently linked to improved progression-free survival (19,20). Although
low-grade gliomas are often considered one entity for the purposes of clinical trials and
management, they represent diverse histioty pes with variable prognoses as documented in
series reporting detailed histopathologic analy ses. Advances in pathology, particularly better
molecular and genetic classification, should further categorize tumors and lead to the
development of targeted agents and modifications in treatment.
Long-term disease-free survival has been reported in 90% of children after complete
resection of cerebral hemispheric tumors; for similarly managed thalamic tumors, smaller
series report 60–90% survival (19, 22,23,24,32). Incomplete resection alone results in
approximately 50% progression-free survival at 5 y ears (20). The addition of therapeutic
irradiation has been shown to achieve progression-free survival in hemispheric astrocy tomas
in approximately 80% of children measured at 10 y ears (19,24). For thalamic tumors treated
primarily with irradiation, 40–50% survive free of progression (31,32). Hy pothalamic tumors
have a favorable outcome after primary irradiation, with 10-y ear progression-free survival
rates of 70–85% (31,45,46). Particularly when one is treating central (diencephalic) PAs, it is
noteworthy that tumor size may appear to increase approximately 3–12 months after
irradiation, often by apparent intralesional necrosis or cy st formation; such changes ty pically
remit over several months. The majority of lesions respond by imaging criteria after
radiation therapy (both by size and gradual loss of enhancement), but the median time to
objective response is greater than 15 months (Fig. 3.4 ) (45). Low-grade gliomas involving
both right and left thalamic regions (i.e., bithalamic tumors) have an aggressive course
similar to that of the more diffuse gliomatosis cerebri or pontine gliomas (32).
Figure:
A: JPA of (L) thalamus, presenting in a 4-year-old boy—cystic and solid, largely enhancing
tumor on T1-gadolinium MRI. B: JPA visualized on T2-FLAIR sequence postcontrast. Note
even better tumor definition. C: Note leptomeningeal metastasis in
hypothalamus/chiasmatic JPA, a finding largely at diagnosis in <10% of cases.
Figure:
Histologic features of the most common pediatric low-grade gliomas: JPA (L) and diffuse
fibrillary astrocytoma (R). JPAs (WHO grade I) show biphasic architecture with more cellular
areas that tend to have the Rosenthal fibers and loose areas with microcysts. Cells are
elongated, bilpolar, and have thin “hair-like” processes. Diffuse fibrillary astrocytomas (WHO
grade II) consist of long, thin cells highlighted by a crisscrossing background of cytoplasmic
glial filaments; nuclear atypia often apparent.
Figure:
A: A 7-year-old boy with JPA of optic chiasm and optic tracts (without neurofibromatosis),
involving and distorting chiasm (A, top) with spread along optic tracts (A, bottom). B:
Increased tumor size, enhancement along optic tracts noted 7 months postradiotherapy
(post-RT), attributed to transient posttherapy effects (B, top and bottom). C: Same levels
with marked, spontaneous reduction in tumor volume compared to preirradiation or MRI 7
months post-RT (Figures B); note normal chiasm (C, top). Patient now 5.5 years post-RT,
with intervening (R) middle cerebral infarct (C, bottom; same time as C, top).
Figure:
Optic chiasm/hypothalamic glioma presenting for radiation therapy at 4 years old following
imaging evidence of progression after two chemotherapy regimens (A1–A3) B: target
volumes for this case depicted for axial (B1), sagittal (B2), and coronal (B3) planes. Note CT
dosimetry using IMRT 6 MeV photons with: GTV (green) with 5–10 mm anatomic expansion
for CTV (blue); geometric 3-mm expansion for PTV (red).
Figure:
A: DVH derived as a composite plan from 10 cases of optic chiasm gliomas, comparing 3D
conformal RT (photon is red/dashed) and scanning proton beam (blue/solid). B: Estimated IQ
change based upon dose–volume effect models, depicting Wechslar Individual Achievement
Test (WIAT) spelling for 3D conformal RT (photon, red/dotted) and scanning protons
(blue/solid).
(From Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common
pediatric brain tumors: comparison of models of dose characteristics and their relationship
to cognitive function. Pediatr Blood Cancer. 2008;51:110–117, with permission.)
OPTIC PATHWAY TUMORS
OPTs represent 5% of childhood brain tumors. OPTs may involve one or several anatomic
sections of the optic sy stem (optic nerves, optic chiasm, optic radiations) (Fig. 3.4 ). They
can be small and localized or extensive and infiltrative. Chiasmatic gliomas are commonly
grouped with hy pothalamic gliomas as a single entity. OPTs occur predominantly in y oung
children; 25% present before 18 months of age, and 50% present before 5 y ears (45,46). Up
to 25% of childhood OPTs occur in children with NF1 (47,48). Careful neuro-ophthalmologic
examination ± screening MRIs should be standard for patients with NF1 (47,49) where 20%
develop OPT’s (48,49).
Clinical presentation is most often with diminished vision. In y oung children, increased
intracranial pressure, endocrinopathies, and diencephalic sy ndrome may predominate.
Histologically, more than 90% of OPTs are low-grade astrocy tomas, most often PAs (more
than 65% of cases) and grade II astrocy tomas (25%), with infrequent gangliogliomas or
hamartomas; malignant gliomas are uncommon (45,46).
The nature of OPTs has been debated. While acknowledging the sometimes indolent
nature of OPTs, disease progression is documented in 75–85% of children, ty pically within 2
y ears of initial presentation (46,50,51). Tumors confined to the optic nerve(s) may behave in
a more hamartomatous fashion. Children with NF1 have a more indolent course with lower
rates of progression and longer latency intervals (51). Signs of a more malignant behavior of
OPTs include extension to or invasion of the adjacent hy pothalamus and posterior extension to
the optic tracts (up to and including the lateral geniculate bodies) and optic radiations.
Infrequently, optic chiasmatic and hy pothalamic tumors demonstrate diffuse leptomeningeal
disease (19,39). Mortality within 10 y ears of diagnosis is uncommon, although ultimate
disease-related mortality has been documented in 10% of cases (46,50). Also to be noted is
the rare but documented occurrence of spontaneous regression of OPTs (52).
Page 36Lesions extending to or originating in the hy pothalamus may be somewhat more
aggressive than lesions confined to the visual pathway s (46,53). Preliminary data suggest
adequate retrieval with secondary therapy at the time of progression during observation
(46,53).
Therapy
Surgery
Surgery has been the preferred treatment for unilateral tumors of the optic nerve amenable
to surgical resection with acceptable morbidity. In a series of 623 optic gliomas reported by
Alvord and Lofton (54), complete surgical excision was performed in 60% of the optic nerve
tumors; the failure rate was 15% among this population at 20 y ears. Progression occurred in
70% of children with untreated lesions within 6 y ears of diagnosis, although it was rarely
associated with tumor-related mortality (54). Observation may be selected, especially if
there is residual vision associated with a lesion confined to the intraorbital optic nerve. Most
series indicate more indolent, perhaps truly hamartomatous behavior in children with
neurofibromatosis (46,48).
Page 37For lesions involving the optic chiasm, there are limited data suggesting a role for
surgical resection, though decompression or limited resection may be successful in restoring
vision (55). Series from the Hospital for Sick Children, Toronto, and New York University
suggest a somewhat broader role for local excision in selected presentations. The latter
authors indicate removal of lesions of partially infiltrating low-grade optic pathway
astrocy tomas with surprisingly little added visual compromise; approximately 50% of such
cases have remained stable without further intervention for 3–5 y ears (21,22). Care should be
taken to avoid visual compromise or other surgical complications as alternative therapies are
quite successful.
Ty pical chiasmatic lesions that involve components of the visual pathway s bey ond the
optic chiasm and hy pothalamic region (i.e., with imaging extension to the optic nerves, optic
tracts, or optic radiation) may be managed without biopsy confirmation. Most of these tumors
are low-grade astrocy tomas and can be managed based on the clinical and imaging
diagnosis. Globular tumors that involve the chiasm and hy pothalamus are best biopsied if this
can be performed safely ; a small percentage of these lesions may be GCTs, unusual ty pes of
low-grade neoplasms, or more aggressive malignant gliomas.
Radiation Therapy
Irradiation is indicated for significant visual or neurologic deficits at presentation or
documented progression by clinical evaluation or neuroimaging after observation, surgery, or
chemotherapy. Radiation therapy is highly effective for OPTs: 10-y ear progression-free
survival rates exceed 80% (28,45,56,57). Although overall survival at 10 y ears is unaffected
by the initial therapeutic approach (i.e., observation, resection, chemotherapy, or irradiation),
progression-free survival rates at 5 and 10 y ears are higher after radiation therapy (31,46).
Serial imaging studies document significant tumor response in more than 50% of children
after irradiation (45). Transient postirradiation tumor enlargement, often in the setting of
central cy stic degeneration, has been well documented (45). Close observation and medical
management (i.e., steroids) rather than aggressive intervention for presumed tumor
progression is advised, particularly for lesions that may appear to progress within 3–12
months after radiation. Visual improvement has been reported in 25–35% of children after
irradiation (28,45). Visual deterioration is reported in 10–20% of children after irradiation,
largely related to cy stic degeneration (and consequent increased mass effect at the chiasm)
or unrecognized elevated intracranial pressure (45,46). Vision should be monitored closely
during the radiation course and in the months following completion.
Balancing the indications for radiation therapy and the timing requires judgment and,
often, serial evaluations to determine the nature of the disease process. OPTs are associated
with unique late radiation-related sequelae. The y oung age at diagnosis, central location, and
often extensive anatomic involvement challenge the ability to deliver adequate radiation
therapy while preserving neurocognitive function; the problem is further accentuated in
children with NF1, itself associated with cognitive delay s. There is also concern about late
vascular events: the incidence of occlusive vasculopathy at the circle of Willis in children
with brain tumors is highest among those with OPTs, especially in y ounger children (58).
Moy amoy a sy ndrome is characterized by obliteration of the major vessels at the circle of
Willis; incomplete brain perfusion is provided by collaterals and peripheral meningeal
vessels. The sy ndrome has been noted after irradiation, perhaps related to cicatricial
constriction of vessels tracking through chiasmal and hy pothalamic gliomas. An incidence of
at least 18% has been reported, especially noted among children less than 2–3 y ears and
those with NF1 (58). A baseline magnetic resonance angiography (MRA) prior to irradiation
to document vascular status is important, often revealing occult vascular compromise due to
the tumor itself; the baseline is important to more easily detect changes after treatment.
There is also a heightened concern regarding the risk of second malignancy in patients with
NF1 (59). Hormonal dy sfunction is also a long-term concern with the use of radiotherapy for
tumors in this location.
Chemotherapy
Because of the radiation-associated morbidities in y oung children with OPT, chemotherapy is
the accepted first line therapy used in effort to delay radiation therapy (46, 53,60). In a
French Society of Pediatric Oncology Study, patients >1 y ear old or with a CR/PR to
chemotherapy had a 3-y ear PFS of 66% (60). Lack of a response to chemotherapy and age
<1 y ear were factors that predicted for an inferior outcome with chemotherapy alone, with
3-y ear PFS ranging from 44–53%. Chemotherapy in this study consisted of alternating
carboplatin/procarbazine, etoposide/cisplatin, and vincristine/cy clophosphamide. Second-line
chemotherapy was offered at tumor progression, resulting in a radiotherapy -free survival of
61% at 5 y ears (60). An 18-month regimen of carboplatin and vincristine for low-grade
gliomas including those of the hy pothalamic region and OPTs reported significant objective
tumor response (greater than 50% tumor reduction in one-third of patients), early progression
in only 10%, and 3-y ear progression-free survival that ranged from 75% for children
y ounger than 5 y ears to 39% for those older than 5 y ears (33,61). Similar results have been
reported with the UCSF five-drug regimen (36).
Early experience suggests favorable outcome with secondary irradiation following post-
chemotherapy progression; recent observations suggest that long-term radiation disease
control and function are not diminished with prolonged preirradiation intervals (46, 53, 57,60).
Toxicity with carboplatin and vincristine has been limited, and early data suggest continued
intellectual development during chemotherapy (33). There is a balance between duration of
disease control (clearly superior with radiation therapy ) and less durable control with
chemotherapy, but apparently without the serious morbidities associated with irradiation in the
y ounger age group. Data from St. Jude has demonstrated that visual acuity in the worse ey e
is negatively impacted by the receipt of chemotherapy or tumor progression prior to the
delivery of radiation (62). In current practice, most children below 5–10 y ears receive
chemotherapy as the initial intervention, with some centers extending this to all prepubertal
children. It is important not to avoid irradiation, even in y ounger children, when progressive
visual loss is apparent despite chemotherapy.
Dosage
The extensive literature on radiation therapy for OPTs ty pically calls for dose levels of 50–54
Gy, most often at 180 cGy per fraction (24,28,45,57). Reduction to 50 Gy at 150 cGy daily
may be considered for children y ounger than 3 y ears (31).
OLIGODENDROGLIOMA
Oligodendrogliomas in children are rare, with only 6% of these tumors occurring in the
pediatric population (64). The generally circumscribed tumors occur most often in the
cerebral hemispheres. In adults, loss of chromosome 1p or 19q and isocitrate dehy drogenase
(IDH1) mutation are noted in 50–80% of cases, and each are both prognostic and predictive
of response to treatment (65,66,67). In pediatric oligodendrogliomas 1p19q codeletion was
noted in 25% of cases, primarily in adolescents (68,69,70). Treatment recommendations are
based largely on adult experience with surgery and irradiation. Adults show excellent
response to procarbazine, lomustine, and vincristine (PCV) or to temozolomide
chemotherapy, particularly in oligodendrogliomas with 1p19q codeletion, IDH1 mutations, or
p53 mutations (66,67,71). Given differences in biology, it is unclear whether chemosensitivity
can be extrapolated to children.
Total surgical resection is the treatment of choice for accessible lesions. GTR has been
documented in 25–56% of all cases, and has been associated with significantly improved PFS
and OS, apparently more so in children and adolescents (72,73). The 5-y ear progression-free
survival rate after total excision is reported at 100% in the Washington University School of
Medicine Series (72).
For incompletely resected oligodendrogliomas, a short-term benefit for radiation
therapy has been documented. In a randomized trial evaluating the use of early versus
delay ed irradiation, adjuvant therapy (54 Gy ) was shown to significantly improve PFS to 5.3
y ears versus 3.4 y ears, though there was no significant difference in OS (74). Adjuvant
irradiation ty pically is withheld for differentiated oligodendrogliomas in children, even with
incomplete resection. Anaplastic oligodendrogliomas are managed similarly to other
malignant supratentorial gliomas in children, although the outcome tends to be superior to
those with anaplastic astrocy toma and glioblastoma.
Combined radiation therapy and PCV has been associated with excellent disease control
in adults, resulting in improved overall survival compared with radiation therapy alone among
patients with 1p19q codeleted or IDH1 mutated anaplastic oligodendroglioma (66,67,71). The
addition of PCV has also been demonstrated to benefit grade II gliomas (75). Temozolomide
has demonstrated efficacy in both low- and high-grade oligodendrogliomas and is often used
in preference to PCV (76,77).
GANGLIOGLIOMA
Neurocy tomas are clinically indolent tumors that present as intraventricular lesions, usually
in the lateral ventricles with attachment to the midline septum pellucidum; most are diagnosed
in adolescents and y oung adults. Neurocy tomas are composed of small neuronal cells thought
to represent a benign neoplasm derived from cells midway in the maturation process of
neuronal differentiation (82). These tumors are genetically distinct from the
oligodendrogliomas and dy sembry oplastic neuroepithelial tumors (DNETs), with which they
can be confused both clinically and histologically (82). Neurocy tomas are generally
resectable. Prognosis has been related to the rate of proliferation (83). These tumors respond
to irradiation; small series have suggested improved outcome in cases with less than total
resection when followed by radiation therapy (local or anatomically defined target volume;
dose ≥54 Gy in 30 fractions reported to be superior to lower doses) (81,83).
Page 39DNETs are biologically indolent, often large cerebral cortical tumors ty pically
presenting with a long-standing seizure history (84). Sy mptoms ty pically arise in children
y ounger than 12 y ears; the mean age at diagnosis is 14 y ears (84). The tumors may be
considered quasi-hamartomatous, classically are well demarcated, and show no contrast on
MRI; uncommonly, DNETs present as complex solid and cy stic lesions with enhancement,
calcification, and intralesional hemorrhage (85). These tumors may be followed, but surgery
often is needed for seizure control; although they appear to be responsive to irradiation, there
is no documented role for postoperative therapy.
MALIGNANT GLIOMAS
Therapy
Surgery
Surgical resection often has been limited in extent by the poorly circumscribed nature of the
tumor and the attendant lack of aggressive neurosurgical intent. The large CCG series
indicated that more than 90% resection (gross total and near total, by definition) was achieved
in only 37% of cases: 49% of lesions arising in the superficial cerebral hemispheres, 45% of
lesions arising in the cerebellum, and 8% of those arising in the central structures
(diencephalons, midbrain) (94). There is a significant relationship between degree of
resection and outcome. Five-y ear progression-free survival in the initially reported CCG-945
experience was 44% and 26% for anaplastic astrocy tomas and glioblastoma, respectively,
after more than 90% removal, compared with 22% and 4%, respectively, after less
aggressive resection (94).
RADIATION THERAPY
Chemotherapy
The large EORTC–NCIC prospective adult trial has convincingly shown the advantage of
temozolomide in conjunction with surgery and irradiation in adult glioblastoma: 2-y ear
survival rate increased from 11% to 27%, and 5-y ear survival rate, from 2% to 10% (100).
The advantage of chemotherapy was apparent in all clinical settings (age, extent of resection,
performance status; the impact of chemotherapy correlated most closely with the presence
or absence of MGMT methy lation). Unfortunately, the pediatric experience has not been as
favorable with temozolomide: the rate of objective response in phase II trials with recurrent
malignant gliomas has been quite disappointing (12%), and prospective primary management
phase II trials of temozolomide following surgery and radiation have shown no benefit in
progression-free survival (PFS) or overall survival (OS) in comparison with historical controls
(2-y ear OS 21%) (101,102). An early pediatric trial of 58 patients, CCG 943, reported an
apparent benefit when pCV chemotherapy (vincristine, lomustine, and prednisone) was
added after radiation therapy, with 5-y ear event-free survival (EFS) approaching 45% with
chemotherapy compared with 17% for those who received irradiation alone (103). The
subsequent CCG-945 trial, compared pCV chemotherapy to eight drugs in 1 day (8-in-1) and
found no significant difference in outcome according to the two chemotherapy regimens with
5-y ear OS and PFS of 33% and 36%, respectively, and greater toxicity with the 8-in-1
regimen (104). Later follow-up of this study with central independent review by five
neuropathologists reclassified a significant number of the tumors as low-grade gliomas (86).
After central review, overall survival at 5 y ears was 79% among children with low-grade
gliomas and 22% among children with high-grade gliomas, a finding similar to the
radiotherapy only arm of previous studies (86). The COG study ACNS 0126 examined the
effect of temozolomide delivered concurrently and adjuvantly with radiation in comparison
with historical controls from the CCG-945 trial. The 3-y ear EFS rate for AA was 13% in
ACNS 0126 compared with 22% in CCG-945, and the 3-y ear EFS rate for GBM was 7% in
ACNS0126 compared with 15% in CCG-945 (105). The results of ACNS 0126 demonstrated
that temozolomide failed to improve outcomes for children with high-grade gliomas.
However, EFS was significantly greater among patients without overexpression of the O6-
methy ltransferase gene (MGMT) in both studies (105,106) and methy lation (silencing) of the
MGMT has been associated with improved response to temozolomide in pediatric GBM (107).
MGMT methy lation status may be a useful marker to select patients for temozolamide
treatment.
Page 40Interest in overcoming the theoretical blood–brain barrier and the potential
advantage of dosage intensification have stimulated investigation of high-dose chemotherapy
with autologous bone marrow rescue in childhood malignant gliomas (108,109). Attempts to
utilize relatively high-dose therapy with granulocy te-colony stimulating factor (GCSF)
support (short of doses requiring peripheral stem cell support) in CCG resulted in 42%
progression prior to irradiation and an additional 15% failing to complete 12 weeks of
chemotherapy due to toxicities; over 20% of cases were unable to proceed to scheduled
radiation therapy (109).
Current trials in COG and the Pediatric Brain Tumor Consortium (PBTC) focus on the
addition of molecular targeting agents such as anti-angiogenic compounds targeting VEGF
and related angiogenesis pathway s, as well as EGFR, PDGF, and mTOR inhibitors
administered concurrently or sequentially with irradiation. Integrin inhibitors and dendritic
cell vaccines are also currently being investigated (110).
Radiotherapeutic Management
Volume and Technique
The target volume is best defined by the enhancing lesion and surrounding low-density
change using both pre- and postoperative MRI that includes gadolinium-enhanced T1
sequence and the larger region often identified only on T2 (or T2 FLAIR). Detailed reviews
of imaging and histologic extent in malignant gliomas and clinical patterns of failure have
suggested that a 1- to 2-cm margin bey ond the tumor/tumor bed and associated T2 (or
FLAIR) abnormality define the initial CTV, with
subsequent reduction to the residual enhancing
tumor and/or tumor bed (on postoperative MRI)
with 0.5–1 cm expansion define the “boost” CTV
(Fig. 3.7 ). Imaging guidelines reflect findings
of histologic infiltration in the “surrounding
edema” in most supratentorial malignant glioma
cases (92). Despite this, most studies indicate that
central failures (within the high-dose volume)
y et predominate in these cases (111). The use of
image-guided radiation planning in pediatric
malignant gliomas is important in sparing the
normal brain. IMRT is the current standard to
better spare critical normal structures (e.g., optic
chiasm and nerves, brainstem) (112).
Dosage
The conventional dose–volume relationships in
children have favored levels of approximately
45–54 Gy to the initial CTV, with a total of 60 Gy
to the “boost” volume as defined above based on
adult guidelines. Figure 3.7 Glioblastoma multiforme
presenting in an 8-year-old boy, involving
Page 41Results (L) thalamus in a “nodular” pattern, status
post minimal resection (A–C). D: MR
Median survival times for pediatric malignant
spectroscopy map demonstrates
gliomas are 18–24 months (86,104). Event-free
quantitative ratio of choline:NAA. E: 3D
survival rate at 3–5 y ears is as high as 45%
conformal plan with GTV (green), 2-cm 3D
among the minority of patients in whom GTR is
anatomic expansion to CTV (blue), and 3-
confirmed by postoperative neuroimaging and
mm geometric expansion to PTV (red).
treated subsequently with both irradiation and
chemotherapy (20, 94,104). For the 65–75% of
childhood malignant gliomas with residual disease identifiable after surgery, the progression-
free survival rate at 3–5 y ears is only 5–20%, slightly higher among the anaplastic
astrocy tomas than the glioblastomas (95). Infants with high-grade gliomas have considerably
better long-term survival than older patients, with 5-y ear OS reaching 66%, suggesting a
different tumor biology among this age group (113).
Figure:
Glioblastoma multiforme presenting in an 8-year-old boy, involving (L) thalamus in a
“nodular” pattern, status post minimal resection (A–C). D: MR spectroscopy map
demonstrates quantitative ratio of choline:NAA. E: 3D conformal plan with GTV (green), 2-cm
3D anatomic expansion to CTV (blue), and 3-mm geometric expansion to PTV (red).
EMBRYONAL CNS TUMORS (PRIMITIVE NEUROECTODERMAL
TUMORS OR SPNET AND PINEOBLASTOMA)
The WHO classification of embry onal CNS tumors clarifies earlier controversies regarding
PNETs (2). The tumor consists of undifferentiated neuroepithelial cells with areas of
divergent differentiation toward glial, neuronal, and mesenchy mal lines. In 1983, Rorke
introduced the PNET as a unify ing concept, grouping together the “small round blue cell”
CNS tumors, with or without specific differentiation but sharing common histologic and
clinical features (e.g., tendency to seed along the CSF pathway s and relative responsiveness
to irradiation and chemotherapy (114). Recent biologic studies and gene profiling have
demonstrated markers specific for medulloblastomas (e.g., isochromosome 17p), separating
the classical posterior fossa embry onal tumor from the several supratentorial PNET
“subty pes” (115).
The current WHO classification outlines specific embry onal histioty pes (Table 3.1 ).
Medulloepithelioma is the most primitive embry onal tumor, histologically showing features
of primitive medullary epithelium and primitive tubular structures; focal differentiation
toward glial, neuronal, or mesenchy mal lines is often present. Ependy moblastoma is a poorly
differentiated embry onal tumor with ependy mal differentiation marked by multilay ered
rosettes similar to those seen in retinoblastoma (Flexner–Wintersteiner rosettes) (2),
classically felt to be a specific embry onal neoplasm, different from the differentiated and
anaplastic ependy momas (discussed in Chapter 4 ). Cerebral neuroblastoma ranges
histologically from an undifferentiated tumor similar to the extra-CNS childhood
neuroblastoma, to lesions demonstrating ganglionic differentiation (115). The recent
molecular classification will likely redefine sPNET’s for the upcoming WHO modification to
include major subgroups: embry onal tumor with multi-lay ered rosettes (ETMR); MYCN-
amplified and IDH/H3F3A expressing, respectively, high-grade gliomas; ependy moblastoma,
and the aty pical teratoid/rhabdoid tumor (AT/RT). The new classification identifies 30% of
tumors expressing high-grade glioma features, 15% intra-CNS counterparts of
neuroblastoma, and 10% as ETMR characterized (4,117,118). AT/RT is a biologically and
clinically unique embry onal tumor that is discussed in Chapter 4 with infant neoplasms.
Pineoblastoma is categorized as a pineal parenchy mal tumor by the WHO, though
ty pically (as here) grouped with embry onal tumors and managed similarly to other sPNETs
(2). The tumor is believed to arise from pineal parenchy mal cells, histologically signified by
undifferentiated small round cells, usually including scattered Homer–Wright rosettes. The
tumor may mimic retinoblastoma, including fleurettes and Flexner–Wintersteiner rosettes
(116).
The clinical outcomes of the supratentorial embry onal tumors have been inferior to
those of medulloblastoma; the different supratentorial entities show vary ing survival rates
dependent on subty pe as well as age, disease extent, and therapy ; recent reports that
pineoblastoma enjoy s favorable outcome compared to other supratentorial PNETs require
further substantiation (119).
The supratentorial embry onal tumors occur
more commonly in y ounger children.
Embry onal tumors ty pically present as solid or
partially cy stic lesions (Fig. 3.8 ). Although
sPNET and cerebral neuroblastoma may
present as well-demarcated lesions, most
embry onal tumors are generally invasive.
Leptomeningeal dissemination is apparent at the
time of diagnosis or at the time of initial tumor Figure 3.8 Classical pineoblastoma
recurrence or progression in approximately one- presenting in a 3-year-old child with
third of children (119,120,121); there is some large, complex solid, and cystic pineal
controversy regarding the frequency of CSF tumor.
failure in initially localized cerebral
neuroblastoma, but most reports indicate CNS
dissemination at a rate similar to that of the other embry onal tumor ty pes (120,121).
Therapy
Surgical resection is the first step in the management of sPNET, which may be resectable in
up to 50–60% of cases (119,120). A report from the COG demonstrated the complete
resection is associated with improved survival among patients with sPNET receiving adjuvant
craniospinal irradiation and chemotherapy (122). Pineoblastomas are generally approached
for stereotactic biopsy or limited resection (123).
Postoperative irradiation is indicated for the embry onal CNS tumors. Classic studies
indicate disease control in less than 25% of cases with sPNET and pineoblastoma without
adjuvant treatment (124). A review of the SIOP/UKCCSG experience showed high rates of
disease control with CSI for pineoblastomas with or without chemotherapy (125). The use of
immediate postoperative irradiation and subsequent chemotherapy in CCG resulted in a 60%
survival rate in children over 1.5–3 y ears with pineoblastomas (123). For children age 3 y ears
and older, 5-y ear survival rates approach 80% for patients with pineoblastoma and 45% for
nonpineal sPNETs treated with craniospinal irradiation with concurrent carboplatin and
adjuvant cy clophosphamide-based chemotherapy (122). Results in other series highlight
interest in high-dose chemotherapy (e.g., high-dose methotrexate in the HIT regimens from
the German studies or high-dose therapy with peripheral stem cell rescue) following
irradiation (126,127).
Dosage
The dosage of CSI is comparable to that used in high-risk medulloblastoma, with full neuraxis
dosages of 35–36 Gy in children older than 3–5 y ears (122,129,130). The HIT 2000 trial
showed no advantage to hy perfractionated irradiation to higher numerical doses (131). Data
from St. Jude suggest that reduced neuraxis irradiation (23.4 Gy ) may be appropriate in
localized sPNET with limited or no postoperative residual when combined with dose-intensive
chemotherapy (126). The primary tumor volume is treated to a cumulative dose of 54 Gy
with volume reduction at 45–50.4 Gy if necessary, as above.
Figure:
Classical pineoblastoma presenting in a 3-year-old child with large, complex solid, and cystic
pineal tumor.
CRANIOPHARYNGIOMA
Craniophary ngiomas are benign tumors of epithelial origin believed to arise from remnants
of Rathke’s pouch in the suprasellar region. The ty pical adamantinomatous
craniophary ngioma is a calcified, cy stic tumor derived from embry onic cell rests of enamel
organs located adjacent to the tuber cinereum along the pituitary stalk. The
adamantinomatous craniophary ngioma seen in children and adolescents includes solid
components and often large, complex cy sts filled with fluid containing high lipid content and
cholesterol granules, described as “crankcase oil.” Up to 10% may present as purely cy stic
lesions (132). The less common papillary craniophary ngioma occurs almost exclusively in
adults, is rarely calcified, and often presents as a solid lesion without cy st formation.
Papillary craniophary ngiomas commonly carry a BRAF V600E mutation and may respond
well to targeted therapy (133).
Craniophary ngiomas are well-circumscribed, encapsulated extra-axial lesions. The
tumor has an interdigitating pattern of adhesion to adjacent neurologic structures, including
the optic chiasm, major vessels at the circle of Willis, the tuber cinereum (along the pituitary
stalk), and the hy pothalamus. Infiltration into the tuber cinereum and the presence of small
tumor islets in the adjacent hy pothalamus document the potential for local invasiveness.
Grading sy stems proposed for craniophary ngioma are based largely on the degree of
hy pothalamic involvement (e.g., none vs. abutting/displacing vs. involving/infiltrating, the
latter marked by absence of the hy pothalamus on imaging) (132).
Anatomically, 70–90% of childhood craniophary ngiomas involve the retrochiasmatic
region, usually extending superiorly into the third ventricle and along the hy pothalamus (Fig.
3.9 ) (132). The multicy stic lesion may include cy stic extension into the basal cisterns,
even into the posterior fossa. In 10–30% of cases, the tumor presents in a prechiasmatic
location between the optic nerves, pushing the chiasm posteriorly (132). Prechiasmatic
tumors are more surgically accessible and less adherent to vital suprasellar structures.
Figure 3.9 A (column on L): Craniopharyngioma in a 5-year-old boy showing typical solid
component in region of tuber cinereum (suprasellar cistern) and cystic components
extending into the third ventricle/interpeduncular region and upper sella; T1-gadolinium
imaging. B (column on R): 3.5 years following simple drainage of the superior cyst and 54
Gy per 30 fractions using 3D conformal RT. Small residual solid component off inferior tuber
cinereum just posterior to optic chiasm shown in sagittal (top) and axial MRI (middle),
largely calcified as noted in accompanying CT without contrast (bottom).
Children present with visual field deficits and/or impaired acuity and sy mptoms of
elevated intracranial pressure (headaches, nausea, vomiting). Endocrine deficits at diagnosis
are apparent in 50–90% of children studied, most often diminished growth hormone, but also
diabetes insipidus (10–20% of cases preoperatively ), and decreased gonadotropin, thy roid-
stimulating hormone, or adrenocorticotropic hormone (25% incidence) (134). Changes in
personality and altered cognitive function have been noted in up to 50% of children at
presentation (135).
Therapy
The treatment of craniophary ngiomas is one of the most controversial issues in pediatric
neuro-oncology. Total resection is often curative in this technically “benign” neoplasm.
Numerous contemporary series reporting primary surgical intent in children note attempted
total resection in 50–80% of cases (136,137,138). Postoperative imaging indicates residual
calcification or obvious tumor in 15–50% of “totally resected” cases (132,136,137,138). The
rate of clinical recurrence even after imaging confirmed total resection is 15–30%, linked to
tumor volume and location (136,137,138).
Balanced against the low failure rate after aggressive surgery are risks of perioperative
mortality (1–3%) and major postoperative morbidity (significant visual loss, vascular events,
or added neurologic deficits) in 10–20% of cases (135,136,137,138). The skill and experience
of the surgeon are important; tumor control and morbidity rates correlate with the number of
cases performed annually. Extensive resection is associated with a 90% incidence of diabetes
insipidus, a relatively difficult endocrine deficit to manage, and often marked hy pothalamic
obesity in ≥50% of cases (137,139). Hy pothalamic obesity is associated with uncontrollable
appetite and correlated with a 15–20% incidence of behavioral problems (e.g., anger or
aggressive behavior including rage or violence) related to hy pothalamic damage (135).
Transphenoidal resection may be favored over open resection as it has been associated with a
reduced risk of serious perioperative complications (136,138).
Page 43Given the morbidity associated with aggressive surgical resection, biopsy or
limited resection followed by adjuvant radiation therapy may be the preferred primary
approach. The literature confirms long-term disease control in 75–90% of children with
primary radiation therapy following limited surgery (137,140). In a sy stematic review of 109
studies of children with craniophary ngioma, there was no difference in disease control
among patients treated with GTR versus STR followed by radiotherapy ; 5-y ear PFS 77% for
GTR alone versus 73% for STR and radiotherapy (140). The use of adjuvant irradiation
following subtotal resection in contemporary, image-based radiation series results in PFS as
high as 98% at 5 y ears, outcomes that are markedly improved compared with STR alone (5-
y ear PFS of 43%, although longer term follow-up can show late recurrences between 5 and
10 y ears in a significant proportion of cases) (140,141). Limited resection followed by
adjuvant RT is associated with a reduced risk of diabetes insipidus and panhy popituitarism
compared with aggressive surgery ; obesity may be slower in onset and less dramatic, if still
problematic with the combined modality approach (137). Early reports of proton beam
therapy for craniophary ngioma demonstrate good clinical outcomes and favorable late
affects (142,143). Single-fraction radiosurgery has been used for postoperative residual when
limited in size and anatomically positioned to allow avoidance of the chiasm and
hy pothalamus (144).
Acute reactions are rare during or after limited volume brain irradiation, while
anticipated endocrine changes reflect initial tumor- or surgery -related damage to the
hy pothalamic region; later endocrinopathies include growth hormone deficiency and less
frequent accelerated or delay ed sexual development; diminished thy roid-stimulating
hormone or adrenocorticotropic hormone secretion. Radiation-related diabetes insipidus is
distinctly uncommon. Comparative reports of neurocognitive and overall functional levels
favor children treated by limited surgery and irradiation compared to those with aggressive
total resection (145). Late vascular events are well documented in more than 20% of
survivors, related to surgery and irradiation and ranging from localized vascular narrowing to
moy amoy a sy ndrome with occlusion of major vessels of the circle of Willis (146).
The option of incomplete resection and observation, delay ing irradiation until later
progression, is unattractive in most instances. Despite the low-grade histology of
craniophary ngiomas, clinically detectable progression is apparent in up to 70% of
incompletely removed tumors within 3 y ears (140,147). Second surgery is associated with
less likelihood of GTR and higher surgical morbidity (148). Results of delay ed irradiation at
the time of recurrent disease are reported to be inferior to those achieved with planned
postoperative irradiation (149).
Cy st enlargement within the first y ear or so of irradiation may not represent progressive
tumor. A majority of children with early cy stic enlargement ultimately have stabilization and
later regression of the cy st or need simple cy st aspiration for associated neurologic
sy mptoms. Progressive but isolated cy stic enlargement following surgery or more than 1–2
y ears following irradiation may require therapy for durable control. There have been
positive results with intracy stic bleomy cin (more as a caustic agent) or irradiation using 32P
or 186Re, pure beta emitters. Use of interferon-alpha has been reported of value in a small
series in y oung children with largely cy stic presentations (150,151,152).
The controversy regarding primary treatment includes the balance of high rates of
immediate postsurgical sequelae and recognized rates of late postirradiation sequelae. Long
debated among neurosurgeons and radiation oncologists, recent statements often converge on
a judgmental approach reserving “radical” resection for cases with prechiasmatic or limited
retrochiasmatic lesions (in particular, avoiding surgery likely to result in hy pothalamic
damage) while pursuing limited surgery and irradiation in the more common, sizable
posterior and superior lesions. Coordinated care is important, and there is increasing
recognition that the overall quality of life in children with craniophary ngioma is challenging
as these children face multiple limitations related to visual, neurovascular, intellectual,
behavioral, and endocrine deficits.
Dosage
A radiation dose response has been documented at 50–54 Gy using 180-cGy fractions daily,
noting apparent improvement with dose levels approximating 54 Gy compared to levels of
<50 Gy (31,155,156). Data supporting dose levels above 55 Gy is less convincing and late
complications, including chiasmal injury, are increased with dosages greater than 60 Gy
(157).
Results
Disease control rates for craniophary ngioma are reported at 80–90% 5 y ears after surgery
or limited surgery and irradiation, with a poorly quantified late decrement in disease-free
survival bey ond 5 y ears. Such results are achievable among those selected for surgery who
have successfully undergone GTR or who receive limited resection followed by irradiation
(Table 3.3 ). Late recurrences and rare treatment-related mortality (largely
neuroendocrine or vascular following surgery or irradiation, or postirradiation
carcinogenesis) are reported well bey ond 5–10 y ears (158). Most data suggest that
postoperative irradiation is indicated with imaging evidence of residual disease (136,138,140).
Control rates after limited surgery and irradiation are equivalent to those of radical resection
(137,140). Quality of life is particularly important in a tumor setting marked by significant
potential neurologic deficits (vision, integrity of major cerebral vasculature), hy pothalamic
dy sfunction, and neurocognitive compromise.
Intracranial GCTs are rare in North America and Europe, representing less than 2–4% of
pediatric CNS neoplasms; in Japan and Taiwan, they are reported to represent up to 11% of
childhood brain tumors (159). The full range of germ cell histioty pes presents as primary
CNS tumors: pure germinomas (60–70% of intracranial GCTs), “malignant” germ cell ty pes
(embry onal carcinomas, endodermal sinus tumors, and choriocarcinomas, collectively 15–
20% of CNS GCTs), and teratomas (benign, immature, and malignant ty pes, 15–20%) (159).
Malignant teratomas are admixtures of benign teratomatous lesions with one or more
malignant germ cell lines such as embry onal carcinoma, endodermal sinus tumor, or
choriocarcinoma or with malignant elements of rhabdomy osarcoma, neuroblastoma, or
epithelial carcinoma. GCTs are conventionally categorized into two highly prognostic
histologic subgroups: pure germinomas and nongerminomatous (or “malignant”) germ cell
tumors (NGGCTs). NGGCTs include GCTs with any malignant germ cell component and/or
any tumor that secretes AFP or high levels of beta-HCG (levels >100–200 IU considered
“high”). Some international trials have classified these tumors simply as “secreting” and
“nonsecreting” based on the high likelihood of secretion from malignant germ cell
components and lack thereof from pure germinomas. Pure germinomas carry a much more
favorable prognosis, and require less aggressive therapy than NGGCTs.
Page 45CNS GCTs usually occur as midline third ventricular lesions. These tumors most
often arise in the pineal region at the posterior third ventricle (50–60% of presentations) or
from the infundibulum/pituitary stalk in the suprasellar region at the anterior recess of the
third ventricle (30–35% of cases) (160). Less common locations for primary intracranial
GCTs include the basal ganglia or thalamic nuclei. Involvement of multiple tumor sites around
the third ventricle is common, most often the pineal and suprasellar regions concurrently ;
such tumors are referred to as “multiple midline germinomas” and appear to represent
multicentric tumor development or subependy mal infiltration around the ventricle rather than
subarachnoid or CSF pathway metastasis. Up to 20% of intracranial germinomas present as
multiple midline tumors, especially noted in adolescent males (Fig. 3.11 ). This
phenomenon is much more frequently encountered with pure germinomas, but has been
reported with NGGCTs. Leptomeningeal spread through the cerebrospinal axis may be seen,
but is much less common.
Pineal germinomas occur with a higher prevalence in adolescent males. Suprasellar
germinomas occur throughout the first two decades; there is no gender predilection for this
location. Teratomas tend to occur in y ounger children, and other malignant histioty pes (e.g.,
embry onal carcinoma, endodermal sinus tumor) generally present in older children,
adolescents, and y oung adults.
Page 46GCTs are the most common tumors arising in the pineal region. A unique
spectrum of neoplasms presents a broad
differential diagnosis for tumors arising in the
posterior third ventricular region (Table 3.4 ).
Approximately 80% of the pineal region tumors
in children and adolescents are GCTs (60–70%)
or pineal parenchy mal tumors (10–20%). In
very y oung children, the most common tumor
ty pe is the pineoblastoma. Less common
histioty pes include glial tumors (astrocy tomas,
ependy momas), arachnoid cy sts and the
embry onal pineoblastomas. Pineocy tomas are
“mature” parenchy mal cell neoplasms which
are rare in children, clinically benign in
adolescents but potentially malignant in y ounger Figure 3.11 Midline multifocal
children. The differential diagnosis for germinoma involving suprasellar
suprasellar tumors is rather broad, including (anterior arrow) and pineal gland
astrocy tomas and craniophary ngiomas (posterior arrow) regions. This
(together, more than 80% of lesions in this phenomenon is typically seen with pure
location) as well as GCTs. germinomas in adolescent males.
Table 3.4 Pineal Region Tumors—Relative Incidence
Pineal GCTs present most often with increased intracranial pressure caused by
compression of the adjacent Sy lvian aqueduct. Ocular signs are classically noted as the
Parinaud sy ndrome: a triad of decreased upward gaze, abnormal pupillary responses
described as near-light dissociation (limited constriction to light but retained pupillary
response to accommodation; otherwise known as the Argy ll–Robertson pupil), and
convergence ny stagmus. Findings occur as a result of pressure from the pineal tumor on the
superior colliculus of the tectum. In suprasellar GCTs, the classic triad of presenting
sy mptoms is diabetes insipidus, precocious or delay ed sexual development, and visual
deficits. Diabetes insipidus or other sy mptoms of suprasellar disease in conjunction with an
apparently isolated pineal tumor are virtually diagnostic of a multiple midline germinoma
and should be treated as such (161). Conversely, care should be taken in evaluating the pineal
region with suprasellar tumors (162).
Page 47Evaluation for GCT should include MRI of the brain with and without gadolinium
with thin cuts (≤2.5 mm thickness, no skip) through the suprasellar and pineal regions. A
screening MRI of the spine should be obtained with axial images through any regions
suspicious for disease. Lumbar puncture with CSF cy tology and CSF AFP and beta-HCG
should be obtained with caution, especially in children with large pineal tumors or potentially
persistent increased intracranial pressure. Serum AFP and beta-HCG should also be
measured. AFP is usually present in serum and CSF in embry onal carcinoma, endodermal
sinus tumor, or malignant teratoma. beta-HCG is elevated in a subset of germinomas: 10–
20% of pure germinomas show levels above 10 IU, up to 70–100 IU; levels above 100–200
IU are found in germinomas with sy ncy tiotrophoblastic giant cells); significant elevation
(ty pically more than 1000 IU) is diagnostic of choriocarcinoma (159,163). COG ultimately
recognized values > 100 IU/L as indicative of NGGCT; this may be a conservative number. If
there is any detectable elevation of AFP above institutional norm (generally, serum >5–10
ng/dL; CSF >2–5 ng/dL), this is diagnostic of malignant germ cell histioty pes; the tumor is
classified as an NGGCT. Additional baseline studies should include a full evaluation of
hy pothalamic and pituitary function, ophthalmologic examination, and baseline
neuropsy chological testing. Diagnostic studies, implications regarding disease ty pe and extent,
and therapeutic decisions are outlined in an “international consensus” statement,
unfortunately devoid of authorship from radiation oncologists (164).
Therapy
Treatment of CNS GCTs is controversial, from the decision to establish histology to the role of
surgery, radiation parameters, and the role of chemotherapy. Although excellent disease
control has been reported in series based on clinical and imaging diagnosis (i.e., without
histologic confirmation), specific radiation, chemotherapy, and surgical interventions are best
guided by a histologic diagnosis (Table 3.5 ). At present, clinicians routinely recommend
confirmation of pathology for all GCTs when attainable, and particularly for those with
negative markers in serum and CSF. When there is a significant elevation of tumor markers in
serum or CSF (any clear elevation of AFP or marked elevation of beta-HCG, ty pically more
than 100 IU), clinicians may consider the diagnosis of an NGGCT without a biopsy. Similarly,
a classical imaging presentation with beta-HCG above normal but <100 IU, or appearance of
multiple midline tumors without AFP elevation are considered pathognomonic of
germinomas by many clinical investigators. Others advocate for histologic verification in all
settings, as some studies indicate important prognostic implications based on histologic
subty pes (159,164). Recent COG studies allow enrollment onto germinoma treatment without
histologic confirmation if serum and/or CSF beta-HCG is ≤ 50 and AFP is ≤ 10 (or institutional
norm), or in the setting of bifocal involvement, normal AFP and beta-HCG is ≤ 100.
Table 3.5 Intracranial Germinoma—Outcome
Radiation therapy has for long been the standard sole treatment or an essential element
of treatment for pure germinomas; it is an important component of multimodality therapy for
NGGCTs (170,173,174) Intracranial pure germinomas are quite chemoresponsive; the use of
combined chemotherapy and whole-ventricle and reduced-dose irradiation is now the
standard approach in treating these tumors (171,174). The use of chemotherapy alone has
been associated with unacceptable recurrence and mortality rates for GCTs (175). For
NGGCTs, irradiation alone has achieved disease control in only 20–45% of tumors, and
combined-modality therapy, also including chemotherapy and potential surgical resection, is
standard (176,177).
Surgery
The goal of surgical resection or biopsy is to provide accurate diagnosis, and in some cases,
improve disease control. For patients with suspected GCT without elevation of tumor markers,
biopsy is mandatory to confirm diagnosis of germinoma and to attempt to rule out malignant
germ cell components. Contemporary surgical techniques permit stereotactic or open biopsy
for both suprasellar and pineal region tumors with low rates of morbidity and mortality (178).
Although it is clear that limited tissue sampling may lead to misdiagnosis for some patients,
particularly in the setting of a mixed histology tumor, aggressive upfront resection is not
advocated by the majority of institutions in Europe and North America as higher rates of
morbidity and mortality have been encountered; delay ed surgery for persistent disease after
chemotherapy is preferred (179). However, more aggressive resection is advocated by some
authors for therapeutic and prognostic implications and is routinely performed in Japan. In the
past, there was some suggestion that surgery or biopsy predisposed the patient to a higher risk
of subarachnoid dissemination; this has been refuted.
Page 48There is no known advantage to achieving a GTR for pure germinomas.
However, a benefit of surgical resection for NGGCT has been suggested if y et somewhat
controversial (176,177). Some series have shown a trend toward improved control with more
aggressive resection for malignant histioty pes. As stated above, others advocate initial
chemotherapy with consideration of second-look surgery for tumors or components of
tumors that do not respond. Often, teratoma components of these tumors do not respond to
chemotherapy and may even grow during chemotherapy. For these cases, surgical resection
is therapeutic and provides local control.
For patients with pineal region tumors that present with hy drocephalus, decompression of
the ventricles is required, often urgently. The placement of a ventriculoperitoneal shunt or
external ventricular drain can provide relief of hy drocephalus. Endoscopic third
ventriculostomy (ETV) is a particularly attractive, alternative method of treating
hy drocephalus by diverting CSF flow and obtaining a biopsy under direct visualization. This
procedure is performed by inserting and guiding a ventriculoscope through the lateral and
third ventricles and then carefully creating a hole in the thin membrane of the floor of the
third ventricle and establishing flow between the third ventricle and the prepontine cistern
(Fig. 3.12 ). ETV also allows for close inspection of the ventricular sy stem and may be
more sensitive than MRI for detection of metastatic deposits (180).
Page 49Radiation Therapy
For pure germinomas, radiation therapy has
been the major curative modality. Long-term
disease control rates range from 80% to more
than 90–95% with the use of irradiation alone
(165,166,167,168,169,170, 173, 176,181).
Analy ses of radiation therapy volume have
demonstrated excellent outcomes with whole
ventricular irradiation for patients with localized
disease, and suggest a limited role for
craniospinal irradiation, while the use of focal
tumor bed irradiation alone has resulted in an Figure 3.12 Sagittal T1-gadolinium
unacceptable rate of ventricular failures image showing third ventriculostomy
(181,182,183). The current standard is whole defect. Endoscopic third ventriculoscopy
ventricular irradiation to a reduced dose (ETV) alleviates hydrocephalus by
followed by primary tumor bed boost for creating flow from the ventricle to the
prepontine space.
patients with localized disease; CSI is reserved
for patients with CNS dissemination (164).
Whether primary radiation therapy or combined chemotherapy and radiation is the best
course of treatment is often a complex decision based on tumor site and extent, the child’s
age, and the child’s functional status at presentation, presenting a choice between irradiation
alone or a combination of chemotherapy and reduced-dose, limited-volume irradiation. The
COG trial, ACNS 0232, attempted to determine the better treatment; radiation alone or
chemotherapy and response-based reduced volume and dose irradiation. Unfortunately, this
trial closed due to poor accrual leaving this important question unanswered. However, most
pediatric oncologists favor chemotherapy followed by reduced-dose RT in an effort to
minimize radiation-associated sequelae.
For NGGCTs, combined chemotherapy and irradiation is the standard, again with some
uncertainty regarding the appropriate radiation volume (local is not often advocated, while
series report favorable outcomes following whole ventricle, whole brain, or craniospinal
volumes) (176). The use of stereotactic radiosurgery to boost local disease visible on imaging
and persistent after chemotherapy and fractionated radiation therapy is rational, but
investigational for children with persistent NGGCT that cannot be safely removed by surgery
(184).
Chemotherapy
Intracranial GCTs are chemosensitive, with excellent objective response rates documented
for cy clophosphamide; carboplatin; cisplatin and etoposide; ifosfamide, carboplatin, and
etoposide; and cisplatin, etoposide, and bleomy cin (175,185). Objective response rates
approach 100% for germinomas.
Several series using preirradiation chemotherapy and limited-volume, “response-
adjusted” attenuation of radiation doses have shown excellent disease control rates
(164,165,171,172). Initially explored in the United States by Allen with the use of
cy clophosphamide and, later, platinating agents, this treatment has resulted in a large
proportion of complete or substantial responses, with long-term disease control after local
irradiation to reduced dose levels of 24–36 Gy (186,187). Carboplatin, most often in
combination with etoposide, has replaced cisplatin for germinomas because the drug is
associated with fewer long-term sequelae (172). The major short-term morbidity has been
difficulties handling fluid and electroly te balance in children with suprasellar tumors, often
associated with diabetes insipidus and/or salt-wasting sy ndromes. This has been associated
with early mortality during chemotherapy (175). The aim of combined chemotherapy and
irradiation has not been to improve disease control, but to potentially improve long-term
functional outcomes by decreasing radiation doses and/or volumes (188).
The use of chemotherapy alone for intracranial germinomas has been tested in the
international protocols coordinated by Balmaceda et al. (175) This trial included pure
germinomas and NGGCTs. The first drug regimen tested (carboplatin, etoposide, bleomy cin,
± cy clophosphamide) achieved high initial response rates, but disease progression or
recurrence occurred in 50% of patients (both pure germinomas and NGGCTs); unacceptable
chemotherapy -related mortality approximated 10% (175). Failures occurred primarily in the
primary site at the ventricular sy stem, with <5% in the spine. Although Merchant et al. (189)
reported sy stematic salvage following chemotherapy -alone failure with high-dose
cy clophosphamide and CSI, the more aggressive combined therapy regimen is excessive in a
significant cohort of children who would enjoy favorable outcome with less intensive initial
radiation therapy.
For NGGCTs, prognosis with irradiation alone is inadequate; overall long-term survival
rates approximate 20–40%. The addition of platinum-based chemotherapy has markedly
improved outcome, with short-term survival rates in excess of 70%. Chemotherapy has
become a standard component of therapy for these tumors prior to irradiation (176,177).
Chemotherapy on both the French Society of Pediatric Oncology (SFOP) and recent COG
protocols used alternating cy cles of carboplatin/etoposide and ifosphamide/etoposide (190).
The recently published COG ACNS 0122 study included six preirradiation cy cles of this
chemotherapy followed by craniospinal and boost irradiation in patients with a complete or
partial response after induction chemotherapy, with or without second look surgery ;
chemotherapy was well tolerated and 5-y ear EFS and OS were 84% and 93%, respectively
(190). Among patients with a complete or partial response to chemotherapy, EFS was 92%
and OS 98% (190).Given the excellent outcomes on ACNS 0122, the currently ongoing COG
trial ACNS 1123 utilizes the same induction chemotherapy backbone of six cy cles of
alternating carboplatin/etoposide and ifosphamide/etoposide, and offers whole ventricular
radiation rather than CSI in patients with complete or partial response to chemotherapy.
Page 50High-dose chemotherapy with stem cell rescue has shown promise for relapsed
GCTs (191). This strategy was recommended for patient without a CR or PR to induction
therapy on ACNS 0122. Two patients with residual disease received consolidation thiotepa and
etoposide chemotherapy with peripheral blood stem cell rescue followed by CSI and both
patients were without evidence of disease at the time of study reporting, 39 and 52 months
after treatment (190).
Radiotherapy Management
Volume and Technique
There has been continuing debate regarding the need for large-volume irradiation (full
cranial or CSI or, alternatively, the entire ventricular sy stem) for localized GCTs, both pure
germinomas and NGGCTs. The concept originated in the pre-CT era when Sung et al. (192)
showed a more than 10% risk of subarachnoid dissemination in pineal region GCTs; among
biopsied suprasellar germinomas, neuraxis dissemination occurred in 43%. Several more
recent studies have proposed limiting the radiation volume to the primary tumor alone, the
third ventricle, the whole ventricular sy stem, or the whole brain. When volumes are larger
than the involved field (i.e., ventricles, whole brain), a higher dose is administered as a
“boost” to the primary tumor.
Evidence of disease bey ond the primary site is apparent in 10–20% of intracranial
germinomas at diagnosis. Third ventricular disease occurs as multiple midline presentations,
classically involving the pineal and suprasellar recesses but sometimes showing multiple
subependy mal nodules along the linings of the ventricle (third and, less often, lateral). Overt
spinal seeding is rarely demonstrable by imaging. CSF involvement has been documented in
fewer than 15% of cases (192).
A large proportion of clinical series reporting disease control rates higher than 90% in the
past y ears have been based on low-dose CSI as a component of therapy (165,173,176,181).
Other series report nearly similar results following more limited radiation volumes
(166,181,182,183).The incidence of spinal failure, specifically, has been reported to be 0–
10% after irradiation to cranial volumes only (166,181). In light of these data, there is
recognition that CSI has only a marginal benefit for pure germinomas treated solely by
radiation therapy (182). The potential gain is controversial and must be weighed against the
potential added toxicities of 24–25 Gy to the neuraxis. In considering the debate on
therapeutic volume, some studies reporting functional outcome or quality of life among long-
term survivors of CSI in childhood and adolescence have shown remarkably normal
achievement (188). Perhaps the most concerning morbidities associated with low-dose CSI in
this setting are secondary neoplasms and cardiac dy sfunction, the latter y et difficult to
quantify.
Though somewhat older series report high rates of disease-free survival with vary ing
volumes identified as “local” without further description, radiation volumes limited to the
local tumor bed only, without inclusion of the ventricles, have been associated with significant
rates of ventricular or periventricular relapses in recent series (165,193). The most common
approach for localized germinomas has now migrated toward treatment of the full ventricular
sy stem (the “large field” component) followed by a boost to the site(s) of initial disease
(194).
All patients with metastatic disease at diagnosis require CSI: 24–30 Gy with irradiation
alone or 21–24 Gy with combined chemotherapy and irradiation; local doses to the primary
and large metastatic foci remain 45 Gy or 30–36 Gy, cumulative, the former for radiation
alone and the latter, combined therapy.
Whole-ventricular radiation is a sizable volume; however, using modern techniques
(IMRT or proton radiation therapy ), one can spare a substantial amount of cortical tissue
when compared with full cranial irradiation (Fig. 3.13 ). This whole-ventricular volume
can be challenging to define and should be done carefully and often with the help of a
neuroradiologist. The whole-ventricular volume should include the lateral, third, and fourth
ventricles as well as the suprasellar and pineal cisterns. Inclusion of the prepontine cistern is
also recommended for patients who have undergone a third ventriculostomy. A contouring
guideline for the whole ventricular volume is available on the COG and QARC websites. An
additional 3–5mm PTV margin is then applied to create the whole ventricular PTV. Current
COG protocols define the local “boost” volume as the MRI-defined residual disease at the
time of treatment planning and all tissue initially involved or in contact with tumor at the time
of diagnosis with a 5-mm anatomically confined margin and an additional 3–5 mm PTV
margin. For tumors with multiple midline involvement, the initial radiation volume should
include the neuraxis or the entire ventricular sy stem at a minimum. Local radiation volumes
have included the primary tumor only, using a 1- to 2-cm anatomic expansion to define the
CTV, or broader fields encompassing at least the third ventricle. Care should be taken to
ensure that the local volume is encompassed by the larger initial ventricular target volume.
Image-guided therapies using multiple (often noncoplanar) fields, stereotactic radiotherapy,
or proton beam are dosimetrically superior in treating midline GCTs.
Figure 3.13 A: Axial and sagittal images of intensity-modulated photon radiation therapy
(L) and proton therapy (R) plans for whole ventricular irradiation. Both techniques are highly
conformal; care should be taken to accurately define the whole ventricular volume. B:
Proton “stereotactic boost” to residual disease following chemotherapy and standard
radiation therapy for NGGCT of the pineal gland.
For NGGCTs, there seems to be consensus that even in the setting of chemotherapy, high
radiation doses are required. However, the appropriate volume is controversial. Studies using
chemotherapy followed by CSI plus a boost to the primary site have y ielded long-term
survival rates of 67–74% (163, 164). The recently reported Phase II COG study for NGGCT,
ACNS 0122, delivered six cy cles of alternating carboplatin/etoposide and
ifosphamide/etoposide followed by CSI to a dose of 36 Gy and an involved field boost to
deliver a total dose of 54 Gy to the tumor bed; results were excellent, with a 5-y ear EFS and
OS being 84% and 93%, respectively (190). Limited trials from Europe and Japan have
documented excellent disease-free survival for chemotherapy followed by whole ventricular
or local field irradiation for patients with NGGCT (186,195). Response to chemotherapy has
been found to be a prognostic factor for NGGCTs (190). The COG trial ACNS 1123 is testing
the use of reduced volume radiation for patients with a complete or partial response to
induction chemotherapy. These patients will receive 30.6 Gy of whole ventricle radiation
therapy followed by a local boost of an additional 23.4 Gy. Second-look surgery is also
recommended for patients without a complete response to chemotherapy. Patients with only
mature teratoma or fibrosis found at the time of second-look surgery are considered to have
had a complete response. For those who cannot safely undergo a second surgical, prognosis is
poor. Incorporation of a final stereotactic radiosurgical “boost” to the local tumor site may be
appropriate for persistent, unresectable NGGCTs.
Page 51Dosage
A total dosage of 40–45 Gy is appropriate for pure germinomas when radiotherapy is used
alone. The elective dose to the neuraxis (i.e., for M0 disease) is 21–24 Gy ; in patients with
positive cy tology, neuraxis levels of 24–30 Gy have been used successfully. Similarly, in
patients receiving full ventricular volumes, the dose to the initial volume is 21–24 Gy, though
the COG study ACNS 1123 has tested the use of 18 Gy whole ventricle radiation in patients
with localized germinoma and a complete response to chemotherapy. The primary area(s) of
tumor involvement require a total dose of approximately 45 Gy in the absence of
chemotherapy. In conjunction with chemotherapy, patients with pure germinoma receive
radiation doses of approximately 30 Gy after complete or near CR, with doses in the range of
36 Gy for patients with partial or incomplete response. Patients with less than partial response
receive full-dose irradiation (45 Gy ). Successful salvage (for patients with progressive or
recurrent disease during or after primary chemotherapy ) has been reported with 30 Gy to
the neuraxis and 45–50 Gy to the local tumor region (189).
Patients with NGGCT receive chemotherapy first. Consolidative irradiation generally
has been delivered in doses in excess of 50 Gy to the primary site of disease. The use of CSI
is somewhat controversial, but is considered the standard treatment in North America. Local
field radiation to a dose of 54–59.4 Gy is the standard in many European countries; it was the
standard treatment on the recently presented SFOP and SIOP studies (186). The ongoing
COG study for NGGCT is exploring reduced volume irradiation (whole ventricle to 30.6 Gy
followed by boost of 23.4 Gy ) for patients with a complete or partial response to induction
chemotherapy (180).
Results
Five-y ear disease-free survival rates of 90–95% are documented in pure germinomas treated
with primary radiation therapy (165,166,167,168,173,176,181). Comparable results are
reported with induction chemotherapy and more limited irradiation (164,165,171,172,187). It
is important to recognize a 10% incidence of late failure (between 5 and 15 y ears) (196).
Disease control with primary chemotherapy has been only about 50% (175). Treatment
choice is often based on tumor and patient characteristics and phy sician and/or parental
biases, though chemotherapy followed by reduced-dose WVRT and involved field boost is
favored by most pediatric oncologists (194).
For NGGCTs, survival after radiation alone is inadequate, and platinum-based
chemotherapy is standard for all patients (190,194). Volume remains controversial, with the
most recent standard in the United States being CSI followed by boost, but the current COG
protocol is testing reduced volume irradiation (whole ventricle followed by boost) for selected
patients. Malignant germ cell ty pes that do not respond completely to chemotherapy carry a
worse prognosis, and continue to be a therapeutic challenge. The use of combined-modality
therapy has been associated with EFS rates approaching 85% (190). With further
understanding of this disease and improvements in therapy, one would hope to bring the
outcomes of malignant germ cell ty pes closer to that of pure germinomas.
Figure:
Midline multifocal germinoma involving suprasellar (anterior arrow) and pineal gland
(posterior arrow) regions. This phenomenon is typically seen with pure germinomas in
adolescent males.
Figure: Pineal Region Tumors—Relative
Incidence
Figure: Intracranial Germinoma—Outcome
Figure:
Sagittal T1-gadolinium image showing third ventriculostomy defect. Endoscopic third
ventriculoscopy (ETV) alleviates hydrocephalus by creating flow from the ventricle to the
prepontine space.
Figure:
A: Axial and sagittal images of intensity-modulated photon radiation therapy (L) and proton
therapy (R) plans for whole ventricular irradiation. Both techniques are highly conformal;
care should be taken to accurately define the whole ventricular volume. B: Proton
“stereotactic boost” to residual disease following chemotherapy and standard radiation
therapy for NGGCT of the pineal gland.
REFERENCES
1. Page 52 Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics,
2014. CA Cancer J Clin. 2014;64:83–103.
2. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the
central nervous sy stem. Acta Neuropathol. 2007;114:97–109.
3. Louis DN, Ohgaki H, Wiestler OD. WHO Classification of Tumors of the Central Nervous
System. 4th ed. Ly on, France: IARC Press; 2007.
4. Sturm D, Orr BA, Toprak UH, et al. New brain tumor entities emerge from molecular
classification of CNS-PNETs. Cell. 2016;164:1060–1072.
5. Mechtler L. Neuroimaging in neuro-oncology. Neurol Clin. 2009;27:171–201, ix.
6. Villani A, Malkin D, Tabori U. Sy ndromes predisposing to pediatric central nervous
sy stem tumors: lessons learned and new promises. Curr Neurol Neurosci Rep.
2012;12:153–164.
7. Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous
sy stem in survivors of childhood cancer: a report from the Childhood Cancer Survivor
Study. J Natl Cancer Inst. 2006;98:1528–1537.
8. Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes among adult survivors of
childhood central nervous sy stem malignancies in the Childhood Cancer Survivor Study.
J Natl Cancer Inst. 2009;101:946–958.
9. Perkins GH, Schomer DF, Fuller GN, et al. Gliomatosis cerebri: improved outcome with
radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56:1137–1146.
10. Bian SX, McAleer MF, Vats TS, et al. Pilocy tic astrocy toma with leptomeningeal
dissemination. Childs Nerv Syst. 2013;29:441–450.
11. Broniscer A, Baker SJ, West AN, et al. Clinical and molecular characteristics of
malignant transformation of low-grade glioma in children. J Clin Oncol. 2007;25:682–
689.
12. Hukin J, Siffert J, Cohen H, et al. Leptomeningeal dissemination at diagnosis of pediatric
low-grade neuroepithelial tumors. Neuro Oncol. 2003;5:188–196.
13. Burger PC, Cohen KJ, Rosenblum MK, et al. Pathology of diencephalic astrocy tomas.
Pediatr Neurosurg. 2000;32:214–219.
14. Krouwer HG, Davis RL, Silver P, et al. Gemistocy tic astrocy tomas: a reappraisal. J
Neurosurg. 1991;74:399–406.
15. Babu R, Bagley JH, Park JG, et al. Low-grade astrocy tomas: the prognostic value of
fibrillary, gemistocy tic, and protoplasmic tumor histology. J Neurosurg. 2013;119:434–
441.
16. Ida CM, Rodriguez FJ, Burger PC, et al. Pleomorphic xanthoastrocy toma: natural history
and long-term follow-up. Brain Pathol. 2015;25:575–586.
17. Shepherd CW, Scheithauer BW, Gomez MR, et al. Subependy mal giant cell astrocy toma:
a clinical, pathological, and flow cy tometric study. Neurosurgery. 1991;28:864–868.
18. Kieran MW. Targeting BRAF in pediatric brain tumors. Am Soc Clin Oncol Educ Book.
2014:e436–e440.
19. Pollack IF, Claassen D, al-Shboul Q, et al. Low-grade gliomas of the cerebral
hemispheres in children: an analy sis of 71 cases. J Neurosurg. 1995;82:536–547.
20. Wisoff JH, Sanford RA, Heier LA, et al. Primary neurosurgery for pediatric low-grade
gliomas: a prospective multi-institutional study from the Children’s Oncology Group.
Neurosurgery. 2011;68:1548–1554; discussion 54–55.
21. Wisoff JH, Abbott R, Epstein F. Surgical management of exophy tic chiasmatic-
hy pothalamic tumors of childhood. J Neurosurg. 1990;73:661–667.
22. Hoffman HJ, Soloniuk DS, Humphrey s RP, et al. Management and outcome of low-
grade astrocy tomas of the midline in children: a retrospective review. Neurosurgery.
1993;33:964–971.
23. Shaw EG, Wisoff JH. Prospective clinical trials of intracranial low-grade glioma in
adults and children. Neuro Oncol. 2003;5:153–160.
24. Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for
pediatric low-grade glioma. J Clin Oncol. 2009;27:3598–3604.
25. Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for
pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine,
and hearing deficits. J Clin Oncol. 2009;27:3691–3697.
26. Eaton BR, Yock T. The use of proton therapy in the treatment of benign or low-grade
pediatric brain tumors. Cancer J. 2014;20:403–408.
27. Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common
pediatric brain tumors: comparison of models of dose characteristics and their
relationship to cognitive function. Pediatr Blood Cancer. 2008;51:110–117.
28. Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine,
neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas.
Int J Radiat Oncol Biol Phys. 2014;89:1060–1068.
29. Bowers DC, Gargan L, Kapur P, et al. Study of the MIB-1 labeling index as a predictor
of tumor progression in pilocy tic astrocy tomas in children and adolescents. J Clin Oncol.
2003;21:2968–2973.
30. Mishra KK, Puri DR, Missett BT, et al. The role of up-front radiation therapy for
incompletely resected pediatric WHO grade II low-grade gliomas. Neuro Oncol.
2006;8:166–174.
31. Bloom HJ, Glees J, Bell J, et al. The treatment and long-term prognosis of children with
intracranial tumors: a study of 610 cases, 1950-1981. Int J Radiat Oncol Biol Phys.
1990;18:723–745.
32. Reardon DA, Gajjar A, Sanford RA, et al. Bithalamic involvement predicts poor
outcome among children with thalamic glial tumors. Pediatr Neurosurg. 1998;29:29–35.
33. Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children
with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86:747–754.
34. Lafay -Cousin L, Sung L, Carret AS, et al. Carboplatin hy persensitivity reaction in
pediatric patients with low-grade glioma: a Canadian Pediatric Brain Tumor Consortium
experience. Cancer. 2008;112:892–899.
35. Chintagumpala M, Eckel SP, Krailo M, et al. A pilot study using carboplatin, vincristine,
and temozolomide in children with progressive/sy mptomatic low-grade glioma: a
Children’s Oncology Group study dagger. Neuro Oncol. 2015;17:1132–1138.
36. Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for
treatment of low-grade glioma in y oung children: a report from the Children’s Oncology
Group. J Clin Oncol. 2012;30:2641–2647.
37. Packer RJ, Jakacki R, Horn M, et al. Objective response of multiply recurrent low-grade
gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer. 2009;52:791–795.
38. Kandula S, Saindane AM, Prabhu RS, et al. Patterns of presentation and failure in
patients with gliomatosis cerebri treated with partial-brain radiation therapy. Cancer.
2014;120:2713–2720.
39. Gajjar A, Bhargava R, Jenkins JJ, et al. Low-grade astrocy toma with neuraxis
dissemination at diagnosis. J Neurosurg. 1995;83:67–71.
40. Shaw E, Arusell R, Scheithauer B, et al. Prospective randomized trial of low-versus high-
dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a
North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern
Cooperative Oncology Group study. J Clin Oncol. 2002;20:2267–2276.
41. Karim AB, Maat B, Hatlevoll R, et al. A randomized trial on dose-response in radiation
therapy of low-grade cerebral glioma: European Organization for Research and
Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys. 1996;36:549–
556.
42. Merchant TE, Kiehna EN, Li C, et al. Modeling radiation dosimetry to predict cognitive
outcomes in pediatric patients with CNS embry onal tumors including medulloblastoma.
Int J Radiat Oncol Biol Phys. 2006;65:210–221.
43. Merchant TE, Kiehna EN, Miles MA, et al. Acute effects of irradiation on cognition:
changes in attention on a computerized continuous performance test during radiotherapy
in pediatric patients with localized primary brain tumors. Int J Radiat Oncol Biol Phys.
2002;53:1271–1278.
44. Kida Y, Kobay ashi T, Mori Y. Gamma knife radiosurgery for low-grade astrocy tomas:
results of long-term follow up. J Neurosurg. 2000;93(suppl 3):42–46.
45. Tao ML, Barnes PD, Billett AL, et al. Childhood optic chiasm gliomas: radiographic
response following radiotherapy and long-term clinical outcome. Int J Radiat Oncol Biol
Phys. 1997;39:579–587.
46. Janss AJ, Grundy R, Cnaan A, et al. Optic pathway and hy pothalamic/chiasmatic
gliomas in children y ounger than age 5 y ears with a 6-y ear follow-up. Cancer.
1995;75:1051–1059.
47. Page 53 Prada CE, Hufnagel RB, Hummel TR, et al. The use of magnetic resonance
imaging screening for optic pathway gliomas in children with neurofibromatosis ty pe 1.
J Pediatr. 2015;167:851–856 e1.
48. Sy lvester CL, Drohan LA, Sergott RC. Optic-nerve gliomas, chiasmal gliomas and
neurofibromatosis ty pe 1. Curr Opin Ophthalmol. 2006;17:7–11.
49. Listernick R, Louis DN, Packer RJ, et al. Optic pathway gliomas in children with
neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task
Force. Ann Neurol. 1997;41:143–149.
50. Nicolin G, Parkin P, Mabbott D, et al. Natural history and outcome of optic pathway
gliomas in children. Pediatr Blood Cancer. 2009;53:1231–1237.
51. Grill J, Laithier V, Rodriguez D, et al. When do children with optic pathway tumours
need treatment? An oncological perspective in 106 patients treated in a single centre. Eur
J Pediatr. 2000;159:692–696.
52. Piccirilli M, Lenzi J, Delfinis C, et al. Spontaneous regression of optic pathway s gliomas
in three patients with neurofibromatosis ty pe I and critical review of the literature. Childs
Nerv Syst. 2006;22:1332–1337.
53. Gnekow AK, Kortmann RD, Pietsch T, et al. Low grade chiasmatic-hy pothalamic
glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within
a comprehensive treatment strategy —report from the multicenter treatment study for
children and adolescents with a low grade glioma—HIT-LGG 1996—of the Society of
Pediatric Oncology and Hematology (GPOH). Klin Padiatr. 2004;216:331–342.
54. Alvord EC Jr, Lofton S. Gliomas of the optic nerve or chiasm—outcome by patients’ age,
tumor site, and treatment. J Neurosurg. 1988;68:85–98.
55. Sawamura Y, Kamada K, Kamoshima Y, et al. Role of surgery for optic
pathway /hy pothalamic astrocy tomas in children. Neuro Oncol. 2008;10:725–733.
56. Paulino AC, Mazloom A, Terashima K, et al. Intensity -modulated radiotherapy (IMRT)
in pediatric low-grade glioma. Cancer. 2013;119:2654–2659.
57. Oh KS, Hung J, Robertson PL, et al. Outcomes of multidisciplinary management in
pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2011;81:e481–e488.
58. Ullrich NJ, Robertson R, Kinnamon DD, et al. Moy amoy a following cranial irradiation
for primary brain tumors in children. Neurology. 2007;68:932–938.
59. Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis 1
patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol.
2006;24:2570–2575.
60. Laithier V, Grill J, Le Deley MC, et al. Progression-free survival in children with optic
pathway tumors: dependence on age and the quality of the response to chemotherapy —
results of the first French prospective study for the French Society of Pediatric
Oncology. J Clin Oncol. 2003;21:4572–4578.
61. Packer RJ. Chemotherapy : low-grade gliomas of the hy pothalamus and thalamus.
Pediatr Neurosurg. 2000;32:259–263.
62. Awdeh RM, Kiehna EN, Drewry RD, et al. Visual outcomes in pediatric optic pathway
glioma after conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2012;84:46–51.
63. Fuss M, Hug EB, Schaefer RA, et al. Proton radiation therapy (PRT) for pediatric optic
pathway gliomas: comparison with 3D planned conventional photons and a standard
photon technique. Int J Radiat Oncol Biol Phys. 1999;45:1117–1126.
64. Mork SJ, Lindegaard KF, Halvorsen TB, et al. Oligodendroglioma: incidence and
biological behavior in a defined population. J Neurosurg. 1985;63:881–889.
65. Levin N, Lavon I, Zelikovitsh B, et al. Progressive low-grade oligodendrogliomas:
response to temozolomide and correlation between genetic profile and O6-
methy lguanine DNA methy ltransferase protein expression. Cancer. 2006;106:1759–
1765.
66. Cairncross JG, Wang M, Jenkins RB, et al. Benefit from procarbazine, lomustine, and
vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol.
2014;32:783–790.
67. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine,
and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-
term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344–
350.
68. Kreiger PA, Okada Y, Simon S, et al. Losses of chromosomes 1p and 19q are rare in
pediatric oligodendrogliomas. Acta Neuropathol. 2005;109:387–392.
69. Buccoliero AM, Castiglione F, Degl’Innocenti DR, et al. IDH1 mutation in pediatric
gliomas: has it a diagnostic and prognostic value? Fetal Pediatr Pathol. 2012;31:278–282.
70. Raghavan R, Balani J, Perry A, et al. Pediatric oligodendrogliomas: a study of molecular
alterations on 1p and 19q using fluorescence in situ hy bridization. J Neuropathol Exp
Neurol. 2003;62:530–537.
71. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for
anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol.
2013;31:337–343.
72. Creach KM, Rubin JB, Leonard JR, et al. Oligodendrogliomas in children. J Neurooncol.
2012;106:377–382.
73. McGirt MJ, Chaichana KL, Attenello FJ, et al. Extent of surgical resection is
independently associated with survival in patients with hemispheric infiltrating low-grade
gliomas. Neurosurgery. 2008;63:700–707; author reply 7–8.
74. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delay ed
radiotherapy for low-grade astrocy toma and oligodendroglioma in adults: the EORTC
22845 randomised trial. Lancet. 2005;366:985–990.
75. Shaw EG, Wang M, Coons SW, et al. Randomized trial of radiation therapy plus
procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-
grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012;30:3065–3070.
76. Fisher BJ, Hu C, Macdonald DR, et al. Phase 2 study of temozolomide-based
chemoradiation therapy for high-risk low-grade gliomas: preliminary results of
Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys. 2015;91:497–
504.
77. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential
radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or
temozolomide. J Clin Oncol. 2009;27:5874–5880.
78. Dudley RW, Torok MR, Gallegos DR, et al. Pediatric low-grade ganglioglioma:
epidemiology, treatments, and outcome analy sis on 348 children from the surveillance,
epidemiology, and end results database. Neurosurgery. 2015;76:313–319; discussion 9;
quiz 9–20.
79. Johnson JH Jr, Hariharan S, Berman J, et al. Clinical outcome of pediatric
gangliogliomas: ninety -nine cases over 20 y ears. Pediatr Neurosurg. 1997;27:203–207.
80. Nishio S, Takeshita I, Fujii K, et al. Supratentorial astrocy tic tumours of childhood: a
clinicopathologic study of 41 cases. Acta Neurochir (Wien). 1989;101:3–8.
81. Rades D, Fehlauer F, Ikezaki K, et al. Dose-effect relationship for radiotherapy after
incomplete resection of aty pical neurocy tomas. Radiother Oncol. 2005;74:67–69.
82. Fujisawa H, Marukawa K, Hasegawa M, et al. Genetic differences between
neurocy toma and dy sembry oplastic neuroepithelial tumor and oligodendroglial tumors.
J Neurosurg. 2002;97:1350–1355.
83. Leenstra JL, Rodriguez FJ, Frechette CM, et al. Central neurocy toma: management
recommendations based on a 35-y ear experience. Int J Radiat Oncol Biol Phys.
2007;67:1145–1154.
84. Ranger A, Diosy D. Seizures in children with dy sembry oplastic neuroepithelial tumors
of the brain—a review of surgical outcomes across several studies. Childs Nerv Syst.
2015;31:847–855.
85. Campos AR, Clusmann H, von Lehe M, et al. Simple and complex dy sembry oplastic
neuroepithelial tumors (DNT) variants: clinical profile, MRI, and histopathology.
Neuroradiology. 2009;51:433–443.
86. Fouladi M, Hunt DL, Pollack IF, et al. Outcome of children with centrally reviewed low-
grade gliomas treated with chemotherapy with or without radiotherapy on Children’s
Cancer Group high-grade glioma study CCG-945. Cancer. 2003;98:1243–1252.
87. Pietsch T, Tay lor MD, Rutka JT. Molecular pathogenesis of childhood brain tumors. J
Neurooncol. 2004;70:203–215.
88. Louis DN, Holland EC, Cairncross JG. Glioma classification: a molecular reappraisal.
Am J Pathol. 2001;159:779–786.
89. Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-
grade gliomas reveals key differences with the adult disease. J Clin Oncol.
2010;28:3061–3068.
90. Pollack IF, Hamilton RL, James CD, et al. Rarity of PTEN deletions and EGFR
amplification in malignant gliomas of childhood: results from the Children’s Cancer
Group 945 cohort. J Neurosurg. 2006;105:418–424.
91. Page 54 Eisenstat DD, Pollack IF, Demers A, et al. Impact of tumor location and
pathological discordance on survival of children with midline high-grade gliomas treated
on Children’s Cancer Group high-grade glioma study CCG-945. J Neurooncol.
2015;121:573–581.
92. Halperin EC, Bentel G, Heinz ER, et al. Radiation therapy treatment planning in
supratentorial glioblastoma multiforme: an analy sis based on post mortem topographic
anatomy with CT correlations. Int J Radiat Oncol Biol Phys. 1989;17:1347–1350.
93. Chan JL, Lee SW, Fraass BA, et al. Survival and failure patterns of high-grade gliomas
after three-dimensional conformal radiotherapy. J Clin Oncol. 2002;20:1635–1642.
94. Wisoff JH, Boy ett JM, Berger MS, et al. Current neurosurgical management and the
impact of the extent of resection in the treatment of malignant gliomas of childhood: a
report of the Children’s Cancer Group trial no. CCG-945. J Neurosurg. 1998;89:52–59.
95. Pollack IF, Boy ett JM, Yates AJ, et al. The influence of central review on outcome
associations in childhood malignant gliomas: results from the CCG-945 experience.
Neuro Oncol. 2003;5:197–207.
96. Varlet P, Soni D, Miquel C, et al. New variants of malignant glioneuronal tumors: a
clinicopathological study of 40 cases. Neurosurgery. 2004;55:1377–1391; discussion 91–
92.
97. Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and
chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226–231.
98. Venneti S, Santi M, Felicella MM, et al. A sensitive and specific histopathologic prognostic
marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol.
2014;128:743–753.
99. Tsien C, Moughan J, Michalski JM, et al. Phase I three-dimensional conformal radiation
dose escalation study in newly diagnosed glioblastoma: Radiation Therapy Oncology
Group Trial 98-03. Int J Radiat Oncol Biol Phys. 2009;73:699–708.
100. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a
randomised phase III study : 5-y ear analy sis of the EORTC-NCIC trial. Lancet Oncol.
2009;10:459–466.
101. Broniscer A, Chintagumpala M, Fouladi M, et al. Temozolomide after radiotherapy for
newly diagnosed high-grade glioma and unfavorable low-grade glioma in children. J
Neurooncol. 2006;76:313–319.
102. Lashford LS, Thiesse P, Jouvet A, et al. Temozolomide in malignant gliomas of
childhood: a United Kingdom Children’s Cancer Study Group and French Society for
Pediatric Oncology Intergroup Study. J Clin Oncol. 2002;20:4684–4691.
103. Sposto R, Ertel IJ, Jenkin RD, et al. The effectiveness of chemotherapy for treatment of
high grade astrocy toma in children: results of a randomized trial—a report from the
Childrens Cancer Study Group. J Neurooncol. 1989;7:165–177.
104. Finlay JL, Boy ett JM, Yates AJ, et al. Randomized phase III trial in childhood high-grade
astrocy toma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-
day regimen—Childrens Cancer Group. J Clin Oncol. 1995;13: 112–123.
105. Cohen KJ, Pollack IF, Zhou T, et al. Temozolomide in the treatment of high-grade
gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol.
2011;13:317–323.
106. Pollack IF, Hamilton RL, Sobol RW, et al. O6-methy lguanine-DNA methy ltransferase
expression strongly correlates with outcome in childhood malignant gliomas: results
from the CCG-945 Cohort. J Clin Oncol. 2006;24:3431–3437.
107. Donson AM, Addo-Yobo SO, Handler MH, et al. MGMT promoter methy lation
correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma.
Pediatr Blood Cancer. 2007;48:403–407.
108. Finlay JL, Goldman S, Wong MC, et al. Pilot study of high-dose thiotepa and etoposide
with autologous bone marrow rescue in children and y oung adults with recurrent CNS
tumors—The Children’s Cancer Group. J Clin Oncol. 1996;14:2495–2503.
109. MacDonald TJ, Arenson EB, Ater J, et al. Phase II study of high-dose chemotherapy
before radiation in children with newly diagnosed high-grade astrocy toma: final analy sis
of Children’s Cancer Group Study 9933. Cancer. 2005;104:2862–2871.
110. MacDonald TJ, Aguilera D, Kramm CM. Treatment of high-grade glioma in children
and adolescents. Neuro Oncol. 2011;13:1049–1058.
111. McDonald MW, Shu HK, Curran WJ Jr, et al. Pattern of failure after limited margin
radiotherapy and temozolomide for glioblastoma. Int J Radiat Oncol Biol Phys.
2011;79:130–136.
112. Hermanto U, Frija EK, Lii MJ, et al. Intensity -modulated radiotherapy (IMRT) and
conventional three-dimensional conformal radiotherapy for high-grade gliomas: does
IMRT increase the integral dose to normal brain? Int J Radiat Oncol Biol Phys.
2007;67:1135–1144.
113. Sanders RP, Kocak M, Burger PC, et al. High-grade astrocy toma in very y oung children.
Pediatr Blood Cancer. 2007;49:888–893.
114. Rorke LB. The cerebellar medulloblastoma and its relationship to primitive
neuroectodermal tumors. J Neuropathol Exp Neurol. 1983;42:1–15.
115. Pfister S, Remke M, Toedt G, et al. Supratentorial primitive neuroectodermal tumors of
the central nervous sy stem frequently harbor deletions of the CDKN2A locus and other
genomic aberrations distinct from medulloblastomas. Genes Chromosomes Cancer.
2007;46:839–851.
116. Rubinstein LJ. Embry onal central neuroepithelial tumors and their differentiating
potential—a cy togenetic view of a complex neuro-oncological problem. J Neurosurg.
1985;62:795–805.
117. Zaky W. Revisiting management of pediatric brain tumors with new molecular insights.
Cell. 2016;164:844–846.
118. Gajjar A, Bowers DC, Karajannis MA, et al. Pediatric brain tumors: innovative genomic
information is transforming the diagnostic and clinical landscape. J Clin Oncol.
2015;33:2986–2998.
119. Reddy AT, Janss AJ, Phillips PC, et al. Outcome for children with supratentorial primitive
neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer.
2000;88:2189–2193.
120. Cohen BH, Zeltzer PM, Boy ett JM, et al. Prognostic factors and treatment results for
supratentorial primitive neuroectodermal tumors in children using radiation and
chemotherapy : a Childrens Cancer Group randomized trial. J Clin Oncol. 1995;13:1687–
1696.
121. Hong TS, Mehta MP, Boy ett JM, et al. Patterns of failure in supratentorial primitive
neuroectodermal tumors treated in Children’s Cancer Group Study 921, a phase III
combined modality study. Int J Radiat Oncol Biol Phys. 2004;60:204–213.
122. Jakacki RI, Burger PC, Kocak M, et al. Outcome and prognostic factors for children with
supratentorial primitive neuroectodermal tumors treated with carboplatin during
radiotherapy : a report from the Children’s Oncology Group. Pediatr Blood Cancer.
2015;62:776–783.
123. Jakacki RI, Zeltzer PM, Boy ett JM, et al. Survival and prognostic factors following
radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal
region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol.
1995;13:1377–1383.
124. Kosnik EJ, Boesel CP, Bay J, et al. Primitive neuroectodermal tumors of the central
nervous sy stem in children. J Neurosurg. 1978;48:741–746.
125. Pizer BL, Weston CL, Robinson KJ, et al. Analy sis of patients with supratentorial
primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study. Eur
J Cancer. 2006;42:1120–1128.
126. Chintagumpala M, Hassall T, Palmer S, et al. A pilot study of risk-adapted radiotherapy
and chemotherapy in patients with supratentorial PNET. Neuro Oncol. 2009;11:33–40.
127. Hinkes BG, von Hoff K, Deinlein F, et al. Childhood pineoblastoma: experiences from the
prospective multicenter trials HIT-SKK87, HIT-SKK92 and HIT91. J Neurooncol.
2007;81:217–223.
128. Jimenez RB, Sethi R, Depauw N, et al. Proton radiation therapy for pediatric
medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for
very y oung children treated with upfront chemotherapy. Int J Radiat Oncol Biol Phys.
2013;87:120–126.
129. Timmermann B, Kortmann RD, Kuhl J, et al. Role of radiotherapy in the treatment of
supratentorial primitive neuroectodermal tumors in childhood: results of the prospective
German brain tumor trials HIT 88/89 and 91. J Clin Oncol. 2002;20:842–849.
130. Page 55 McBride SM, Daganzo SM, Banerjee A, et al. Radiation is an important
component of multimodality therapy for pediatric non-pineal supratentorial primitive
neuroectodermal tumors. Int J Radiat Oncol Biol Phys. 2008;72:1319–1323.
131. Gerber NU, von Hoff K, Resch A, et al. Treatment of children with central nervous
sy stem primitive neuroectodermal tumors/pinealoblastomas in the prospective
multicentric trial HIT 2000 using hy perfractionated radiation therapy followed by
maintenance chemotherapy. Int J Radiat Oncol Biol Phys. 2014;89:863–871.
132. Puget S, Garnett M, Wray A, et al. Pediatric craniophary ngiomas: classification and
treatment according to the degree of hy pothalamic involvement. J Neurosurg.
2007;106:3–12.
133. Brastianos PK, Shankar GM, Gill CM, et al. Dramatic response of BRAF V600E mutant
papillary craniophary ngioma to targeted therapy. J Natl Cancer Inst. 2016;108.
134. Merchant TE, Williams T, Smith JM, et al. Preirradiation endocrinopathies in pediatric
brain tumor patients determined by dy namic tests of endocrine function. Int J Radiat
Oncol Biol Phys. 2002;54:45–50.
135. Dolson EP, Conklin HM, Li C, et al. Predicting behavioral problems in
craniophary ngioma survivors after conformal radiation therapy. Pediatr Blood Cancer.
2009;52:860–864.
136. Fahlbusch R, Honegger J, Paulus W, et al. Surgical treatment of craniophary ngiomas:
experience with 168 patients. J Neurosurg. 1999;90:237–250.
137. Schoenfeld A, Pekmezci M, Barnes MJ, et al. The superiority of conservative resection
and adjuvant radiation for craniophary ngiomas. J Neurooncol. 2012;108:133–139.
138. Mortini P, Losa M, Pozzobon G, et al. Neurosurgical treatment of craniophary ngioma in
adults and children: early and long-term results in a large case series. J Neurosurg.
2011;114:1350–1359.
139. Vinchon M, Weill J, Delestret I, et al. Craniophary ngioma and hy pothalamic obesity in
children. Childs Nerv Syst. 2009;25:347–352.
140. Clark AJ, Cage TA, Aranda D, et al. A sy stematic review of the results of surgery and
radiotherapy on tumor control for pediatric craniophary ngioma. Childs Nerv Syst.
2013;29:231–238.
141. Merchant TE, Kun LE, Hua CH, et al. Disease control after reduced volume conformal
and intensity modulated radiation therapy for childhood craniophary ngioma. Int J Radiat
Oncol Biol Phys. 2013;85:e187–e192.
142. Luu QT, Loredo LN, Archambeau JO, et al. Fractionated proton radiation treatment for
pediatric craniophary ngioma: preliminary report. Cancer J. 2006;12:155–159.
143. Pulsifer MB, Sethi RV, Kuhlthau KA, et al. Early cognitive outcomes following proton
radiation in pediatric patients with brain and central nervous sy stem tumors. Int J Radiat
Oncol Biol Phys. 2015;93:400–407.
144. Hasegawa T, Kobay ashi T, Kida Y. Tolerance of the optic apparatus in single-fraction
irradiation using stereotactic radiosurgery : evaluation in 100 patients with
craniophary ngioma. Neurosurgery. 2010;66:688–694; discussion 94–95.
145. Merchant TE, Kiehna EN, Kun LE, et al. Phase II trial of conformal radiation therapy
for pediatric patients with craniophary ngioma and correlation of surgical factors and
radiation dosimetry with change in cognitive function. J Neurosurg. 2006;104:94–102.
146. Desai SS, Paulino AC, Mai WY, et al. Radiation-induced moy amoy a sy ndrome. Int J
Radiat Oncol Biol Phys. 2006;65:1222–1227.
147. Hetelekidis S, Barnes PD, Tao ML, et al. 20-y ear experience in childhood
craniophary ngioma. Int J Radiat Oncol Biol Phys. 1993;27:189–195.
148. Kalapurakal JA, Goldman S, Hsieh YC, et al. Clinical outcome in children with recurrent
craniophary ngioma after primary surgery. Cancer J. 2000;6:388–393.
149. Kalapurakal JA, Goldman S, Hsieh YC, et al. Clinical outcome in children with
craniophary ngioma treated with primary surgery and radiotherapy deferred until
relapse. Med Pediatr Oncol. 2003;40:214–218.
150. Zheng J, Fang Y, Cai BW, et al. Intracy stic bleomy cin for cy stic craniophary ngiomas in
children. Cochrane Database Syst Rev. 2014;9:CD008890.
151. Hasegawa T, Kondziolka D, Hadjipanay is CG, et al. Management of cy stic
craniophary ngiomas with phosphorus-32 intracavitary irradiation. Neurosurgery.
2004;54:813–820; discussion 20–22.
152. Cavalheiro S, Di Rocco C, Valenzuela S, et al. Craniophary ngiomas: intratumoral
chemotherapy with interferon-alpha: a multicenter preliminary study with 60 cases.
Neurosurg Focus. 2010;28:E12.
153. Combs SE, Thilmann C, Huber PE, et al. Achievement of long-term local control in
patients with craniophary ngiomas using high precision stereotactic radiotherapy. Cancer.
2007;109:2308–2314.
154. Boehling NS, Grosshans DR, Bluett JB, et al. Dosimetric comparison of three-
dimensional conformal proton radiotherapy, intensity -modulated proton therapy, and
intensity -modulated radiotherapy for treatment of pediatric craniophary ngiomas. Int J
Radiat Oncol Biol Phys. 2012;82:643–652.
155. Regine WF, Kramer S. Pediatric craniophary ngiomas: long term results of combined
treatment with surgery and radiation. Int J Radiat Oncol Biol Phys. 1992;24:611–617.
156. Minniti G, Saran F, Traish D, et al. Fractionated stereotactic conformal radiotherapy
following conservative surgery in the control of craniophary ngiomas. Radiother Oncol.
2007;82:90–95.
157. Varlotto JM, Flickinger JC, Kondziolka D, et al. External beam irradiation of
craniophary ngiomas: long-term analy sis of tumor control and morbidity. Int J Radiat
Oncol Biol Phys. 2002;54:492–499.
158. Rajan B, Ashley S, Gorman C, et al. Craniophary ngioma—a long-term results following
limited surgery and radiotherapy. Radiother Oncol. 1993;26:1–10.
159. Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: a clinical
analy sis of 153 histologically verified cases. J Neurosurg. 1997;86:446–455.
160. Villano JL, Propp JM, Porter KR, et al. Malignant pineal germ-cell tumors: an analy sis of
cases from three tumor registries. Neuro Oncol. 2008;10:121–130.
161. Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and y oung
adults. N Engl J Med. 2000;343:998–1007.
162. MacDonald SM, Desai N, Heller G, et al. MRI changes in the “normal” pineal gland
following chemotherapy for suprasellar germ cell tumors. Pediatr Hematol Oncol.
2008;25:5–15.
163. Allen J, Chacko J, Donahue B, et al. Diagnostic sensitivity of serum and lumbar CSF
bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer. 2012;59:1180–1182.
164. Baranzelli MC, Patte C, Bouffet E, et al. Nonmetastatic intracranial germinoma: the
experience of the French Society of Pediatric Oncology. Cancer. 1997;80:1792–1797.
165. Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT 96: final report of outcome of
a prospective, multinational nonrandomized trial for children and adults with intracranial
germinoma, comparing craniospinal irradiation alone with chemotherapy followed by
focal primary site irradiation for patients with localized disease. Neuro Oncol.
2013;15:788–796.
166. Bamberg M, Kortmann RD, Calaminus G, et al. Radiation therapy for intracranial
germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J
Clin Oncol. 1999;17:2585–2592.
167. Cho J, Choi JU, Kim DS, et al. Low-dose craniospinal irradiation as a definitive treatment
for intracranial germinoma. Radiother Oncol. 2009;91:75–79.
168. Eom KY, Kim IH, Park CI, et al. Upfront chemotherapy and involved-field radiotherapy
results in more relapses than extended radiotherapy for intracranial germinomas:
modification in radiotherapy volume might be needed. Int J Radiat Oncol Biol Phys.
2008;71:667–671.
169. Haddock MG, Schild SE, Scheithauer BW, et al. Radiation therapy for histologically
confirmed primary central nervous sy stem germinoma. Int J Radiat Oncol Biol Phys.
1997;38:915–923.
170. Hardenbergh PH, Golden J, Billet A, et al. Intracranial germinoma: the case for lower
dose radiation therapy. Int J Radiat Oncol Biol Phys. 1997;39:419–426.
171. Kretschmar C, Kleinberg L, Greenberg M, et al. Pre-radiation chemotherapy with
response-based radiation therapy in children with central nervous sy stem germ cell
tumors: a report from the Children’s Oncology Group. Pediatr Blood Cancer.
2007;48:285–291.
172. Allen JC, DaRosso RC, Donahue B, et al. A phase II trial of preirradiation carboplatin in
newly diagnosed germinoma of the central nervous sy stem. Cancer. 1994;74:940–944.
173. Page 56 Wolden SL, Wara WM, Larson DA, et al. Radiation therapy for primary
intracranial germ-cell tumors. Int J Radiat Oncol Biol Phys. 1995;32:943–949.
174. Matsutani M; Japanese Pediatric Brain Tumor Study G. Combined chemotherapy and
radiation therapy for CNS germ cell tumors—the Japanese experience. J Neurooncol.
2001;54:311–316.
175. Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation—a novel
approach for newly diagnosed CNS germ cell tumors: results of an international
cooperative trial—The First International Central Nervous Sy stem Germ Cell Tumor
Study. J Clin Oncol. 1996;14:2908–2915.
176. Calaminus G, Bamberg M, Baranzelli MC, et al. Intracranial germ cell tumors: a
comprehensive update of the European data. Neuropediatrics. 1994;25:26–32.
177. Robertson PL, DaRosso RC, Allen JC. Improved prognosis of intracranial non-
germinoma germ cell tumors with multimodality therapy. J Neurooncol. 1997;32:71–80.
178. Regis J, Bouillot P, Rouby -Volot F, et al. Pineal region tumors and the role of stereotactic
biopsy : review of the mortality, morbidity, and diagnostic rates in 370 cases.
Neurosurgery. 1996;39:907–912; discussion 12–14.
179. Calaminus G, Bamberg M, Harms D, et al. AFP/beta-HCG secreting CNS germ cell
tumors: long-term outcome with respect to initial sy mptoms and primary tumor
resection—results of the cooperative trial MAKEI 89. Neuropediatrics. 2005;36:71–77.
180. Reddy AT, Wellons JC III, Allen JC, et al. Refining the staging evaluation of pineal region
germinoma using neuroendoscopy and the presence of preoperative diabetes insipidus.
Neuro Oncol. 2004;6:127–133.
181. Haas-Kogan DA, Missett BT, Wara WM, et al. Radiation therapy for intracranial germ
cell tumors. Int J Radiat Oncol Biol Phys. 2003;56:511–618.
182. Rogers SJ, Mosleh-Shirazi MA, Saran FH. Radiotherapy of localised intracranial
germinoma: time to sever historical ties? Lancet Oncol. 2005;6:509–519.
183. Shikama N, Ogawa K, Tanaka S, et al. Lack of benefit of spinal irradiation in the primary
treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180
patients. Cancer. 2005;104:126–134.
184. Hasegawa T, Kondziolka D, Hadjipanay is CG, et al. The role of radiosurgery for the
treatment of pineal parenchy mal tumors. Neurosurgery. 2002;51:880–889.
185. Kellie SJ, Boy ce H, Dunkel IJ, et al. Primary chemotherapy for intracranial
nongerminomatous germ cell tumors: results of the second international CNS germ cell
study group protocol. J Clin Oncol. 2004;22:846–853.
186. Buckner JC, Peethambaram PP, Smithson WA, et al. Phase II trial of primary
chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin
Oncol. 1999;17:933–940.
187. Allen JC, Kim JH, Packer RJ. Neoadjuvant chemotherapy for newly diagnosed germ-
cell tumors of the central nervous sy stem. J Neurosurg. 1987;67:65–70.
188. Sutton LN, Radcliffe J, Goldwein JW, et al. Quality of life of adult survivors of
germinomas treated with craniospinal irradiation. Neurosurgery. 1999;45:1292–1297;
discussion 7–8.
189. Merchant TE, Davis BJ, Sheldon JM, et al. Radiation therapy for relapsed CNS
germinoma after primary chemotherapy. J Clin Oncol. 1998;16:204–209.
190. Goldman S, Bouffet E, Fisher PG, et al. Phase II trial assessing the ability of neoadjuvant
chemotherapy with or without second-look surgery to eliminate measurable disease for
nongerminomatous germ cell tumors: a Children’s Oncology Group Study. J Clin Oncol.
2015;33:2464–2471.
191. Modak S, Gardner S, Dunkel IJ, et al. Thiotepa-based high-dose chemotherapy with
autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell
tumors. J Clin Oncol. 2004;22:1934–1943.
192. Sung DI, Harisiadis L, Chang CH. Midline pineal tumors and suprasellar germinomas:
highly curable by irradiation. Radiology. 1978;128:745–751.
193. Alapetite C, Brisse H, Patte C, et al. Pattern of relapse and outcome of non-metastatic
germinoma patients treated with chemotherapy and limited field radiation: the SFOP
experience. Neuro Oncol. 2010;12:1318–1325.
194. Murray MJ, Bartels U, Nishikawa R, et al. Consensus on the management of intracranial
germ-cell tumours. Lancet Oncol. 2015;16:e470–e477.
195. Matsutani M, Ushio Y, Abe H, et al. Combined chemotherapy and radiation therapy for
central nervous sy stem germ cell tumors: preliminary results of a Phase II study of the
Japanese Pediatric Brain Tumor Study Group. Neurosurg Focus. 1998;5:e7.
196. Rich TA, Cassady JR, Strand RD, et al. Radiation therapy for pineal and suprasellar germ
cell tumors. Cancer. 1985;55:932–940.
CH A P TER 4
Tumors of the Posterior Fossa and the
Spinal Canal
Torunn I. Yock, Larry E. Kun, Shannon M. MacDonald, and Nancy J. Tarbell
Page 57The posterior fossa occupies the lower half of the posterior cranial vault, bounded
anteriorly by the clivus and posterior clinoid and inferiorly by the occipital bone and foramen
magnum. Superiorly, the margin is defined by the tentorium cerebellae, that portion of the
dura mater extending from the basisphenoid adjacent to the posterior clinoid, rising to cover
the cerebellum, and extending posteriorly and inferiorly to insert at the level of the inion (the
prominent midline outpouching of the occipital bone). The cerebellum and brainstem are
located within the posterior fossa.
Nearly one-half of all childhood brain tumors arise in the posterior fossa. The most
common ty pes are medulloblastoma, low-grade astrocy tomas, and ependy momas (see
Table 3.1 ) (1,2,3).
MEDULLOBLASTOMA
Figure 4.1 Medulloblastoma, originating classically in the cerebellar vermis (A, B), with
signs of subarachnoid spread in the hypothalamic region (B) and along the spine (C).
The Chang (35) staging sy stem for medulloblastoma was developed in the pre-CT era
and includes both T stage, which is based on the size and invasiveness of the primary tumor at
surgery (“T stage”), and evidence of spread outside the posterior fossa (“M stage”) (Table
4.1 ). However, in the modern MRI and surgical era, T stage is no longer of prognostic
value and only the M staging is still used to stage medulloblastoma patients (36,37). M stage is
based on subarachnoid metastasis, progressively coding abnormal CSF cy tology (M1) or
imaging evidence of noncontiguous tumor in the cranium (M2) or spine (M3). Extraneural
disease (most often confined to the bone marrow or bone) is present in fewer than 2% of
cases at presentation, coded as M4. M stage remains a significant prognostic factor and is
incorporated into our risk stratification of patients, which affects intensity of therapy
(37,38,39,40).
Table 4.1 Chang Staging for Medulloblastomaa a A pre-CT era system described by
Chang (35), modified by J. Langston (personal communication, 1988).
Page 59Current clinical trials and standard management in North America define
clinical risk categories for medulloblastoma as average risk (children older than 3 y ears with
no metastatic disease after near total or total resection, with less than 1.5 cm 2 residual on
early postoperative imaging) or high risk (overt metastatic disease based on CSF cy tology or
neuroimaging, or the presence of more than 1.5 cm 2 residual on early postoperative
imaging). In 2008, recognition of the prognostic importance of histologic subty pe resulted in
the COG exclusion of children with diffuse anaplastic or large cell variant tumors (but
otherwise standard risk) from the national standard risk protocol, which randomized y oung
children to 23.4 Gy or 18 Gy CSI. Given the “intermediate risk,” the consensus was that such
patients should be eligible for the COG high-risk study. Thus, the high-risk study was renamed
“other than average risk.” There has been controversy on how best to treat these children
given the substantial late effects caused by full 36 Gy CSI dose in the y ounger children. A
current multicenter protocol led by St. Jude investigators includes “intermediate risk”
category that reflects this ty pe of patient (clinicaltrials.gov number NCT01878617). Children
y ounger than 3 y ears of age are classified as having infant medulloblastoma (41). With
appropriately aggressive surgical intent in most centers in the United States and Europe, more
than 65–75% of children above 3 y ears of age are staged as average risk. Of the 25–35%
staged as high risk, more than 85% present with metastatic disease at diagnosis: primarily M3
(60%), but also M1 (30%), and M2 (10%); significant residual tumor at the primary site is
present in >15% of cases (19,41,42).
Page 60Therapy
Surgery
Harvey Cushing’s (5) classic 1930 report of his experience with medulloblastoma
demonstrated the inability of surgery alone to cure this tumor; only 1 of 61 patients survived 3
y ears after surgery with or without limited irradiation.
Maximal judicious surgical resection underlies most contemporary series (37,38). Gross
total resection (GTR) is defined as no evidence of residual tumor seen at surgery and
negative postoperative imaging, and near-total resection (NTR) is defined as minimal residual
with more than 90% resection estimated by the surgeon and less than 1.5 cm 2 residual on
postoperative imaging. Combined results with GTR and NTR reveal superior outcome in
comparison to subtotal (51–90% resection) or partial (11–50% removal) resection and biopsy
only (less than 10% removal) (38). Data from the Children’s Cancer Group (CCG) indicate
gross total or near total resection in approximately 90% of children (37,38). Survival appears
to correlate significantly with amount of tumor residual as documented on immediate
postoperative imaging; data confirming the value of minimal residual disease are most
apparent among children with M0 disease (38,43). In an earlier CCG trial, 5-y ear event-free
survival (EFS) was 78% for children with M0 disease and less than 1.5 cm 2 residual,
compared with 54% for those with larger residual volumes (37). For tumors adherent to or
invading the brainstem, a report from St. Jude Children’s Research Hospital showed no
advantage to pursuing GTR compared with NTR, with none of the cases exhibiting more than
1.5 cm 2 residual; morbidity appeared to be greater with the more aggressive surgical
approach (44). With maximal safe resection a principle of therapy, the impact of minimal
residual tumor (<1.5 cm 2) is difficult to discern; key is the distinct advantage of treatment on
an average-risk regimen whenever possible, assuming such is a “given” for M0 disease
(19,38,45,46,47).
Operative mortality has been reduced to 2% or less in pediatric neurosurgical centers.
However, aggressive surgery may be associated with significant morbidity (38,48,49). The
posterior fossa sy ndrome has been described in 15–40% of children after posterior fossa
craniotomy (50,51,52). The sy ndrome is signified by difficulty swallowing, emotional
lability, truncal ataxia, mutism, and, less often, respiratory failure; recent imaging data
suggest that the etiology may be a cerebellocerebral diaschisis (51). Sy mptoms and signs
ty pically are noted after a 12- to 24-hour period of initially uneventful postoperative
recovery. Disabling neurologic signs can improve dramatically, but can take many months
after surgery. Those children with severe posterior fossa sy ndrome are less likely to make a
full recovery and may have late neurologic and neurocognitive consequences (52,53,54).
Significant neurologic recovery does not appear impaired by the use of radiotherapy despite
a lack of major improvement early in the course of irradiation (52,53,54).
The routine use of ventriculoperitoneal (VP) shunts to reduce intracranial pressure
before posterior fossa craniotomy resulted in significant improvement in operative morbidity
and mortality, when introduced 50 y ears ago. Children with VP shunts ty pically become
shunt dependent. Shunt failure or infection may complicate long-term survival, necessitating
revision or replacement in nearly 25% of children measured 5 y ears after insertion. In many
centers, it is standard to place a ventricular drain (ventriculostomy ), as needed, at the time of
surgery. The surgeon often can document reestablishment of CSF flow after fourth
ventricular tumor resection. Later, shunt insertion may be needed in 20–25% of children
(38,55,56). A delay ed shunt insertion approach provides phy siologic CSF dy namics for the
majority of children, avoiding potential late events related to an indwelling VP shunt.
Radiation Therapy
The efficacy of radiation therapy in medulloblastoma was reported within a decade of
Cushing’s initial description of the tumor. Cutler et al. (57) reported the radiation
responsiveness of medulloblastoma and the value of preventive irradiation of the entire
neuraxis based on Cushing’s clinical series. The seminal report documenting cure of
medulloblastoma with craniospinal irradiation (CSI) was published by Bloom et al. in 1969
(58), documenting 32% survival at 5 y ears and 25% disease-free survival at 10 y ears.
Numerous reports have subsequently confirmed increasing rates of disease control with
modern radiation techniques; at standard CSI dose levels, radiation therapy alone achieves
durable disease control in 65–75% of patients with average-risk disease (Table 4.2 )
(36,59). Modifications of radiation volume, dosage, and fractionation have been explored.
The outcome following postoperative irradiation alone in average-risk medulloblastoma using
conventional radiation parameters (Pediatric Oncology Group [POG]–CCG trial, one arm of
which used CSI to 36 Gy, posterior fossa boost to 54 Gy resulting in 65% 7-y ear EFS in a
large cohort evaluated largely by CT my elography rather than spinal MRI scans) has been
used as a basis for nonrandomized comparisons in establishing current standards for
combined modality therapy in North America. The result is sy stematic reduction in CSI
dosage (to 23.4 Gy ) with well-documented efficacy now in average-risk disease when
combined with contemporary cis-platinum–based chemotherapy (19,60,61,62). Agreement
on combined chemoradiation is based on disease control rates that appear to be superior to
those achieved with irradiation alone for both average-risk and high-risk presentations, a
randomized European trial demonstrating improved outcome with chemoradiation compared
to contemporary radiation therapy alone, and several studies suggesting improvement in the
risk:benefit ratio based on dose–volume modeling and evolving clinical data (61,
63,64,65,66,67).
Page 61
Chemotherapy
Phase II trials have documented the chemoresponsiveness of medulloblastoma to alky lating
agents (cy clophosphamide, CCNU [lomustine]), platinum compounds (cisplatin, carboplatin),
etoposide (administered orally or intravenously ), antimetabolites (methotrexate), and
camptothecins (topotecan) (68,69,70,71).
The sentinel trial documenting the efficacy of adjuvant chemotherapy was reported by
CCG, combining the attenuated CSI dose in average-risk patients that had just shown only
55% EFS at 5 y ears in the POG–CCG with concurrent vincristine and postirradiation cis-
platinum, vincristine, and CCNU; the 79% progression-free survival (PFS) at 5 y ears
confirmed earlier institutional experience to show among the best disease control rates in this
disease (36,39,60). The International Society for Pediatric Oncology (SIOP)/United Kingdom
Children’s Cancer Study Group (UKCCSG) PNET-3 trial showed improved EFS with limited
preirradiation chemotherapy and full-dose irradiation versus equivalent irradiation alone:
78% EFS at 5 y ears with preirradiation vincristine, etoposide, carboplatin, and
cy clophosphamide compared to 65% with irradiation alone (63). A large randomized trial
assessing reduced-dose CSI followed by cisplatin and vincristine with “standard” CCNU
versus cy clophosphamide confirmed overall EFS of more than 80% with no difference in
disease control on either chemotherapy arm; early analy sis suggests a larger number of
secondary neoplasms may be apparent in the cy clophosphamide arm (62). St. Jude reported
a sizable prospective trial using postirradiation “compressed” cy clophosphamide, vincristine,
and cisplatin; 83% EFS was obtained without vincristine during irradiation and with a reduction
in ototoxicity attending postirradiation cisplatin when the latter was given with amifostine
(19,72). The standard of care for children with average-risk medulloblastoma throughout
North America has been accepted as reduced-dose CSI (23.4 Gy ) followed by
chemotherapy including an alky lating agent, vincristine, and cisplatin (Table 4.3 ).
For patients with high-risk disease, studies through the 1990s ty pically showed 5-y ear
EFS at the 40–50% level following full-dose irradiation and chemotherapy (46,47). St. Jude’s
SJMB96 study has shown 70% 5-y ear EFS following the same compressed chemotherapy
noted above, preceded by full-dose CSI (19). Randomized trials have shown somewhat
conflicting results regarding the sequence of postoperative therapy : POG showed >60% 5-
y ear EFS in high-risk medulloblastoma regardless of postoperative/preirradiation
chemotherapy (cy clophosphamide, vincristine, cisplatin) or the opposite sequence, both using
full-dose CSI (75). The German HIT’91 trial showed superior results with postoperative
irradiation followed by CCNU/vincristine/cisplatin compared to postoperative
ifosfamide/etoposide/high-dose methotrexate/cisplatin cy tosine arabinoside followed by
irradiation: 83% 5-y ear EFS compared to 53%, respectively, for M0 patients; no difference
was noted in the M2–3 cohort, both at <40% EFS (47). CCG 9931 documented a 17% PD rate
during a prolonged, 5-month preirradiation regimen, again showing only 43% EFS in high-risk
disease (67). Similar trials have noted that outcome in average-risk patients receiving
preirradiation chemotherapy correlates with response to chemotherapy ; in the Milan trial,
those with CR/PR to preirradiation chemotherapy enjoy ed 94% PFS compared to 61% if only
SD or PD attended chemotherapy (74). Several studies note the time to initiating irradiation is
conversely related to disease control (46,56).
For disease recurrent after radiation therapy (with or without chemotherapy ), numerous
studies demonstrate chemotherapy responsiveness to single agents, multiagent combinations,
and high-dose therapy with hematologic stem cell rescue. Except in the infant setting, best
defined as “radiation therapy naïve,” durable secondary disease control following initial CSI
has only rarely been achieved despite aggressive, high-dose chemotherapy and further
irradiation (76,77,78,79,80). Local irradiation can provide further control at the primary site
(81). Trials of intrathecal chemotherapy in this setting are of interest, but to date with only
limited phases I and II data (82).
Radiotherapeutic Management
Volume
Medulloblastoma is the seminal tumor identified with subarachnoid dissemination. The need
for full CSI has been recognized for more than five decades. In reviewing serial treatment
regimens in Sweden, Landberg et al. (83) noted serial improvements in survival rates with
increasing radiation volume: 5% 10-y ear survival after limited posterior fossa irradiation,
15% after irradiation to the posterior fossa and spinal canal, and 53% after CSI. Reported
failures in the subfrontal region additionally indicate the need to completely encompass the
cranial and spinal subarachnoid spaces; such failures clearly represent inadequate dosage to
the subfrontal area, a potential site of geographic miss even in the era of 3D, imaging-based
treatment planning (84,85,86,87). Other parameters key to appropriate CSI encompassing the
entire subarachnoid volume are discussed below (see Techniques, p. 61 –64 ).
Page 63Historically, the standard boost field included the whole posterior fossa. Use of
3D conformal radiation therapy (3D CRT) to the entire posterior fossa provided some
reduction in cochlear dose, important in children receiving cisplatin and at risk for both
chemotherapy - and radiation-related ototoxicity (Table 4.4 ) (66,72,91,92,93,94). The use
of conformal radiotherapy techniques such as IMRT, 3D conformal RT or proton therapy
targeting only the tumor bed has been shown to be equivalent to treatment encompassing the
entire posterior fossa, with in-field or posterior fossa recurrences at or below the 5% level
even with more limited boost volumes (45,61,66,90). Initial experience with a 2-cm
anatomically defined clinical target volume (CTV) expansion of the gross tumor volume
(GTV) (postoperative tumor bed) showed few if any posterior fossa failures outside the
targeted volume (91,95,88). The St. Jude SJMB96 trial confirmed local disease control in 95%
of cases with the 2-cm CTV; the recent MSFOP 98 and current COG trials are testing a 1.5-
cm CTV expansion, while a previous study from the University of Washington and the
current SJMB03 study have studied a 1-cm anatomically defined expansion to identify the
CTV (45,61,90). The recently closed COG trial (ACNS 0331) (ClinicalTrials.gov
Identifier:NCT00085735) randomized patients to either tumor bed boost or whole posterior
fossa boost, but the results of the trial have not y et been published as of the submission of this
book. However, preliminary results were reported at the spring COG meeting in 2016
indicated that the 18 Gy CSI arm met inferiority requirements but that there was no
difference between the boost arms.
Dosage
Medulloblastoma is a radiosensitive tumor. In vitro studies by Fertil and Malaise (98)
demonstrated a favorable surviving fraction in vitro at 2 Gy (28%), comparable to most other
embry onal pediatric tumors and notably different from the clinically less responsive
malignant gliomas. Earlier data indicated a correlation between dosage to the primary tumor
site and the outcome; local disease control and survival were consistently related to posterior
fossa dosages of ≥50–55 Gy using conventional fractionation at 160–180 cGy per fraction
(55,96,99). The use of limited volume boost to 59.4 Gy for patients with imaging evidence of
residual disease at the primary site has been reported, with no clear evidence that escalation
bey ond 55 Gy is fruitful (91,88).
Page 64Recent trials support the use of 23.4 Gy (at 180 cGy /fraction) to the neuraxis for
average-risk presentations when combined with effective chemotherapy as discussed above
(62). Largely in response to age-related concerns regarding neurocognitive changes, a small
pilot study of 18-Gy CSI for 10 children y ounger than 10 y ears was undertaken at the
Children’s Hospital of Philadelphia and at the University of Pennsy lvania. Disease control in
seven of ten children was initially reported with apparently only minor neuropsy chologic
deficits (100). Subsequent reports suggest failures following the 18-Gy level may be more
apparent with time (73). The current COG average-risk medulloblastoma protocol
randomizes children with average-risk disease between 3- and 8-y ears-old to 23.4-Gy CSI or
18-Gy CSI, prospectively addressing the potential efficacy and relative toxicities of further
reduction in CSI dosage.
For patients with high-risk disease, particularly those with overt metastasis (including M1
in most studies in addition to M2–3), 36 Gy to the neuraxis remains the standard. Several
studies have used 39.6–40 Gy for cases with significant bulk disease through the intracranial
and spinal meninges (19).
Trials of hy perfractionated CSI include neuraxis dosages of 30–48.4 Gy at 100–110 cGy
per fraction twice daily, with an interfraction interval greater than 6 hours; cumulative
dosages for the posterior fossa have been 66–72 Gy with similar fractionation
(67,90,101,102). Long-term results of the French M-SFOP 98 trial showed 75% 6-y ear PFS in
average-risk medulloblastoma after hy perfractionated CSI (36 Gy in 36 fractions) with tumor
bed boost (cumulative dosage, 68 Gy in 68 fractions); the goal with equivalent total CSI dose
for average-risk disease treated with irradiation alone was to reduce toxicity while preserving
equivalent disease control (59,90). A concurrent Milan study used preirradiation
chemotherapy and hy perfractionated accelerated radiation therapy for M+ disease, with
1.36 Gy b.i.d. to 31.2–39 Gy (depending on age and response to chemotherapy ), with 1.5 Gy
b.i.d. to the posterior fossa to cumulative levels of 59–60 Gy ; at investigator’s option, cases
with overt primary residual or progressive tumor received additional treatment to a reduced
target volume to 9 Gy ; preliminary reports seem favorable albeit without details regarding
long-term toxicities to date (74). The potential value of altered fractionation has y et to be
demonstrated.
Technique
The goal of achieving uniform dosage throughout the subarachnoid space, encompassing the
entire intracranial vault and spinal canal, is one of the more technically demanding aspects of
radiation oncology. Several techniques are appropriate for CSI administration (103). The
fundamental is the use of opposed lateral fields including the cranium and upper cervical
spinal canal, matching a posterior spinal field including the full spinal subarachnoid space or,
in larger children, the upper one half of the spinal canal (with a separate, matched lower
posterior spinal field) (Figs. 4.2 and 4.3 ).
Figure 4.2 Consideration of spinal volume for craniospinal irradiation. A: Nerve root
seeding in medulloblastoma; this figure first appeared in the Bulletin of the Los Angeles
Neurological Society (8:1–10, 1943), representing advanced, diffuse leptomeningeal seeding.
B: Typical anatomy of the nerve roots demonstrating the extension of the subarachnoid
space laterally along the nerve root to a location in the neural foramen.
Figure 4.3 Craniospinal irradiation (CSI). Basic technique for CSI including lateral cranial
volume (A) and appropriately matched posterior spinal field(s) (B). C: Prone positioning with
aquaplast mask.
Defining the lower border of the spinal field should alway s be based on the lowest level
of the thecal sac as determined by MRI, ty pically at or below S2 (Fig. 4.4E and 4.5 )
(108,109). The width of the spinal field should be sufficient to dosimetrically encompass the
full width of the spinal canal to the dorsal nerve roots laterally. Adequate lateral coverage at
the lower sacral margin is appropriate to cover the sacral foramina (Fig. 4.2 ) (109).
Several institutions have reported the relative advantage in using intensity -modulated photon
irradiation or, more recently, proton beam approaches (Fig. 4.5 ) (110,111). Proton spinal
irradiation significantly spares the underly ing heart, breasts, and soft tissues; long-term
follow-up is not available as y et documenting late effects (110,112,113,114). Homogeneity in
planning and delivering CSI with protons is
challenging; introduction of scanning beam
technology seems to provide more optimal
dosimetry (Fig. 4.6 ) (115).
Page 66The brain and upper cervical spine
are treated with lateral fields. The collimators
for the lateral fields are angled to match the
divergence of the posterior spinal field
(Fig.4.3 ). The cranial fields must Figure 4.5 Craniospinal irradiation.
accommodate serial decreases in length to Use of multiple “IMRT minibeam”
feather the junction zone; discrete readjustments compensates for diameters in lateral
of the junction by 5–10 mm/week are ty pical, if cranial volumes and depths in posterior
there is some literature regarding daily spinal volumes to provide relatively
modulation of the junction (116). A table angle homogeneous dose distribution for photon
generally is used to correct for caudal CSI. Note lateral dosimetric projection
divergence of the craniocervical fields confirms adequacy of lower thecal sac
(Fig.4.3 ). Although detailed analy sis shows coverage (see Fig. 4.4A ).
only minimal inhomogeneity if a correcting
table angle is not used (103), full 3D attention at the junction zone permits more confident
abutting of the lateral craniocervical and posterior spinal fields. Even with the ideal
craniocervical match using asy mmetric jaws, it is important to feather all junctional zones,
shifting the anatomic junction site by at least 5 mm every 8–9 Gy, effectively once a week
(117). Helical tomotherapy has been used, with excellent handling of the complex, full
neuraxis (118).
The cranial fields include the entire intracranial subarachnoid space. The most difficult
area is at the level of the cribriform plate, where there is often little margin to allow one to
block the ey es and dosimetrically encompass the critical subfrontal cribriform site (86). With
passively scattered proton therapy, oblique beam configurations are required to reduce
incidental lens dose (120) which can also be used for pencil beam techniques. Although a
single PA cranial field is another viable alternative for pencil beam proton therapy as well.
Boost techniques ty pically include either (1) 3D CRT or IMRT to encompass the posterior
fossa, or (2) using similar techniques to encompass the tumor bed alone, using anatomically
corrected 3D expansion by 1–2 cm to define the CTV (45,61,66,90,88,120). With photon
irradiation, the differences between IMRT or 3D CRT and conventionally planned 2D therapy
are impressive in relatively sparing the cochlea, temporal lobes, and brainstem (12,45,61,66).
The recently closed COG trial in average-risk medulloblastoma randomized all cohorts
between 3D based therapy to the posterior fossa or to the tumor bed (using a 1.5-cm
anatomic expansion → CTV and a 3- to 5-mm
geometric expansion → PTV (COG:
ACNS0331). In nonprotocol settings, there is now
sufficient information to suggest the adequacy of
boost volumes confined to the tumor bed
(61,66,90,88). This sophisticated approach entails
analy zing the initial tumor extent based upon
preoperative MRI and identify ing margins of the
posterior fossa tumor bed using CT and, ideally,
fused preoperative MR imaging. Figure 4.7
demonstrates boost confined to the tumor bed).
The goal of image-guided irradiation and narrow
margins in targeting the tumor bed is to diminish
the dosage to the cochlea which remains
especially important with combined irradiation
and cisplatin, as well as the temporal lobes, and
the hy pothalamic–pituitary region (Fig. 4.7 ).
Several reports document the theoretical
Figure 4.6 Spinal irradiation (CSI). A:
advantage of proton beam therapy for the
Comparison of dosimetry with single PA
“boost” volume, based on significant further
field, PBRT versus photon. B: PBRT
reduction in normal tissue doses to the key
dosimetry closely conforming to spinal
anatomic regions noted: cochlea, temporal lobes,
canal and vertebral body (to ensure
and pituitary –hy pothalamic region (12,112,121).
relatively “normal” growth).
Page 67
Figure 4.7 Tumor bed boost for resected medulloblastoma. GTV = tumor bed (green) with
1-cm anatomic 3D expansion to provide protocol-specified (SJMB03) CTV (blue) and further 3-
mm geometric expansion to establish PTV (red). Shown are transverse planes (A = MRI, B =
CT at level of cochlea, shown in blue) and sagittal plane (C = MRI in midline showing spinal
cord, brainstem, chiasm in yellow, and pituitary in green).
The quality of radiation therapy has been correlated with improved outcome, based on
both volume adequacy (in several but not all prospective cooperative group reviews) and
duration of therapy (with several reports indicating inferior disease control when the interval
to complete irradiation exceeds 45 day s) (55,63,96,122,123,124).
Delivery
CSI results in acute changes in the peripheral blood counts. Monitoring for neutropenia or
thrombocy topenia, most often noted during or after the third week of CSI without preceding
chemotherapy, is critically important. CSI is currently interrupted if absolute neutrophil count
falls below 1000 cells per milliliter, and the child is also febrile. Overall radiation treatment
time must be kept short (<45–50 day s) or there will be a decrement in disease control
(122,123). When necessary to permit completion of neuraxis irradiation, granulocy te colony -
stimulating factor may be used to correct neutropenia; thrombocy topenia may necessitate
platelet transfusion (125). Irradiation is ty pically initiated with CSI. Nausea and vomiting are
generally more pronounced in older children and in those with significant postoperative
emesis. Use of antiemetics is important in preventing and treating nausea and vomiting, which
may be more difficult to control. Ondansetron usually is successful. Rarely, corticosteroids
may be necessary at low dosage levels, particularly early in the postoperative period.
Nutritional support during CSI is mandatory as children often go from completion of
irradiation to adjuvant chemotherapy.
Page 68Results
Long-term disease-free survival after surgery and irradiation should approach the 70% level
overall (Tables 4.2 and 4.3 ). Factors associated with more favorable outcome include
age greater than 3 y ears, localized presentations (i.e., M0), and tumors amenable to near total
or total resection. The more effective combinations of radiation therapy and chemotherapy
for children older than 3 y ears show long-term disease control in 80% of those with average-
risk disease, and 60–70% of those with high-risk medulloblastoma (Table 4.3 )
(19,59,62,74). The impact of histology, biologic findings, and genetic analy ses is increasingly
important, as summarized above. Future studies seek improvement in disease control and
reduction in functional limitations attendant to therapy.
Figure:
Medulloblastoma, originating classically in the cerebellar vermis (A, B), with signs of
subarachnoid spread in the hypothalamic region (B) and along the spine (C).
Figure: Chang Staging for
Medulloblastomaa
a A pre-CT era system described by Chang (35), modified by J. Langston (personal
communication, 1988).
Figure: Medulloblastoma—Results of
Postoperative Radiation Therapy (No
Chemotherapy)
Figure: Selected Major Medulloblastomas
Studies Reporting Outcome with
Postoperative Irradiation Combined with
Chemotherapy
Figure: Medulloblastoma—Radiation
Therapy (Data Reporting Reduced
Tumor/Target Volume Techniques)
Figure:
Consideration of spinal volume for craniospinal irradiation. A: Nerve root seeding in
medulloblastoma; this figure first appeared in the Bulletin of the Los Angeles Neurological
Society (8:1–10, 1943), representing advanced, diffuse leptomeningeal seeding. B: Typical
anatomy of the nerve roots demonstrating the extension of the subarachnoid space laterally
along the nerve root to a location in the neural foramen.
Figure:
Craniospinal irradiation (CSI). Basic technique for CSI including lateral cranial volume (A)
and appropriately matched posterior spinal field(s) (B). C: Prone positioning with aquaplast
mask.
Figure:
Craniospinal irradiation (CSI). A: Lateral cranial volume defined to encompass the
subarachnoid space, with attention to the cribriform plate (blue), shown in (B). C: Posterior
spinal volume, here divided for upper (thoracic) spine with lateral margins to dosimetrically
include the neural foramina. D: Posterior spinal volume for lower (lumbosacral) spine,
including “flair” to encompass sacral neural foramina (see Fig. 4.2). E: MRI depicting lower
thecal sac.
Figure:
Craniospinal irradiation. Use of multiple “IMRT minibeam” compensates for diameters in
lateral cranial volumes and depths in posterior spinal volumes to provide relatively
homogeneous dose distribution for photon CSI. Note lateral dosimetric projection confirms
adequacy of lower thecal sac coverage (see Fig. 4.4A).
Figure:
Spinal irradiation (CSI). A: Comparison of dosimetry with single PA field, PBRT versus photon.
B: PBRT dosimetry closely conforming to spinal canal and vertebral body (to ensure
relatively “normal” growth).
Figure:
Tumor bed boost for resected medulloblastoma. GTV = tumor bed (green) with 1-cm
anatomic 3D expansion to provide protocol-specified (SJMB03) CTV (blue) and further 3-mm
geometric expansion to establish PTV (red). Shown are transverse planes (A = MRI, B = CT at
level of cochlea, shown in blue) and sagittal plane (C = MRI in midline showing spinal cord,
brainstem, chiasm in yellow, and pituitary in green).
EMBRYONAL AND MALIGNANT GLIAL TUMORS IN INFANTS AND
YOUNG CHILDREN
Children y ounger than 3 y ears account for 15–25% of pediatric CNS neoplasms (1,126,127).
Sy mptoms in this age group usually include enlarged head, lethargy, and vomiting. Tumors
are predominantly supratentorial; in comparison to older children, infant tumors are more
often malignant and may be more frequently metastatic at diagnosis (129). The most
common tumor ty pes include astroglial tumors (primarily low grade; among infants <1 y ear
old, up to 25% are high-grade malignant gliomas), the embry onal neoplasms
(medulloblastoma and the supratentorial embry onal tumors, including PNETs and
pineoblastomas), and ependy momas (129,130,131). Aty pical teratoid/rhabdoid tumors
(AT/RTs) occur predominantly in this age group (7,132,133). A significant proportion of
intracranial teratomas and choroid plexus tumors present in y oung children below 12–18
months of age (127,130). Infantile desmoplastic neuroepithelial tumors (desmoplastic
infantile gangliogliomas and astrocy tomas) also arise predominantly in the very y oung.
These lesions often are quite large, are peripherally located, and appear aggressive
histologically, but ty pically display rather “benign,” low-grade behavior, rarely recurring
after primary resection (7,134,135).
Survival rates for the embry onal brain tumors presenting in children y ounger than 3–4
y ears are lower than for older children (130,131,136,137). Tumor ty pe, pattern of growth,
and the therapeutic ratio for both surgery and radiation therapy are unfavorable when
compared to older children (38,138,139). Operative morbidity and mortality rates are higher
in infants than in older children; after radiation therapy, cognitive dy sfunction, somatic
alterations, endocrine deficits, and neurotoxicity are more pronounced than in older children
(64,65,130,140).
For malignant gliomas, however, y oung age portents a better prognosis than that of older
children and adults, based on apparent differences in biology and disease response to
chemotherapy (141,142,143,144).
Therapy
For embry onal tumors with long-established chemosensitivity, a number of trials between
1985 and 2000 explored the use of prolonged primary postoperative chemotherapy using
delay ed, diminished, or no irradiation (depending on the goals and philosophy of the group or
institution) (Table 4.5 ). Several large series documented a high rate of
chemoresponsiveness to a “standard” four-drug regimen (including cy clophosphamide,
cisplatin, vincristine, etoposide) or to sy stemic methotrexate; durable disease control without
irradiation was limited to 25–35% of cases in most trials, ty pically in those with localized
disease amenable to complete resection at diagnosis
(128,130,131,140,146,147,149,150,155,156,157).
Surgery
As in older children, complete resection is often the primary predictor of disease control; for
infant medulloblastoma, the differences in outcome strongly favor attempted GTR in every
major series regardless of the ty pe and intensity of postoperative management
(128,130,131,146,147,148,149). In the initial Baby POG study, OS for medulloblastoma was
40%, compared with 60% for the one third of children who had undergone GTR and 69% for
those with GTR and localized disease (128). In the latest published GHOP trial, PFS among all
M0 cases falls from 82% to 50% based on the absence or presence of residual tumor
postsurgery, respectively (148).
Delay ed definitive surgery has been utilized for sizable medulloblastomas or
supratentorial PNETs in this age group. After initial chemotherapy, tumors may be reduced in
size and vascularity, resulting in more successful tumor resection (131,150).
Choroid plexus tumors are often malignant carcinomas in this age group. The tumors
ty pically arise in the lateral ventricles; histology can be uncertain in predicting benign or
malignant behavior, with carcinomas marked largely by brain invasiveness and aty pia.
Complete resection alone appears to be adequate therapy, with few recurrent tumors
following imaging-confirmed removal even without added chemotherapy or irradiation
(168,169,170). Young children with choroid plexus carcinoma (CPC) may have a p53
germline mutation and a recent analy sis shows those patients with a germline mutation who
received radiotherapy faire worse than those whose regimens omit radiotherapy (171).
Radiation Therapy
Evolving combinations of sy stematic or selected consolidative irradiation, “standard”
irradiation for disease progression, or multimodality salvage regimens incorporating low or
high-dose radiation therapy have resulted in radiation therapy as a component of therapy for
nearly half of all surviving children in this admittedly “vulnerable” age group
(128,140,147,149,150,158). Important in the context of current strategies is identification of
those cases most likely to benefit from local irradiation, with consensus developing toward
noting those with classic (nondesmoplastic) histology and localized medulloblastoma or those
with incompletely resected M0 desmoplastic medulloblastoma. Using “early ” planned
irradiation, ty pically within the first 4 months of postoperative chemotherapy, is key to
avoiding the scenario of requiring more aggressive irradiation (volume and dose) and
chemotherapy (dose) for those who progress during or after more prolonged chemotherapy.
In AT/RT, even earlier initiation of radiation therapy (4–8 weeks) may be key to improving
outcome depending on the chemotherapy, as noted above.
Although salvage CSI (at therapeutic dosage levels of 30–36 Gy using 180-cGy daily
fractions) has been successful in controlling more than 40% of recurrent medulloblastomas,
the ultimate 40–60% disease control was balanced by a median IQ of only 62 at 7 y ears
(140). The latter finding has dampened enthusiasm for salvage CSI, at least at dosage levels
greater than 24 Gy, in this age group.
Chemotherapy
The initial van Ey s study of primary mechlorethamine (nitrogen mustard), vincristine,
procarbazine, and prednisone (MOPP) chemotherapy at M.D. Anderson Cancer Center
showed long-term survival in 8 of 11 infants with medulloblastoma; 6 had not received
radiation therapy (172).
The first POG trial with initial postoperative chemotherapy was reported in 1993 (131).
The regimen included cy cles of cy clophosphamide with vincristine and cisplatin with
etoposide; response rates varied between medulloblastoma (48% partial and complete
response rate among those with imaging residual) and malignant gliomas (60%) (131). PFS
and OS rates, respectively, at 5 y ears were 32% and 40% for medulloblastoma, 43% and
50% for malignant gliomas, and 0% and 0% for pineoblastomas; overall 5-y ear survival was
27% for supratentorial PNETs (128). As in subsequent infant trials, failures bey ond 2 y ears
have been uncommon except with ependy momas (130,140,149,150,155).
Page 71Most of the subsequent infant studies have used variations of the four-drug
regimens noted in the first POG trial; more intensive regimens have shown benefit in specific
subsets of infant malignant tumors (146,173). The Head Start series of dose-intensive
chemotherapy have evolved to similar four-drug induction with second surgery for residual
local tumor, followed by my eloablative doses of thiotepa, etoposide, and carboplatin. In the
selected M0 resected medulloblastoma cohort, EFS at 5 y ears was 52%; OS of 70% those
requiring irradiation for disease progression; toxicity has remained a problem with this
approach (149). The French experience with high-dose chemotherapy, reported excellent
disease control with busulfan–thiotepa and local irradiation for children with progressive
disease following conventional chemotherapy alone (157). Results from CCG-99703 phase
I/II dose escalation study of thiotepa for infants with malignant tumors revealed that
medulloblastoma patients with M0 disease had 5-y ear EFS and OS of 72% and 76%, whereas
M+ patients had rates of 30% and 51%, respectively. Five-y ear EFS for AT/RT was 37.5%
and for pineal and nonpineal supratentorial PNET, it was 35% and 29%, respectively (174).
Radiotherapeutic Management
Volume and Technique
Recently completed studies in COG and PBTC have sought to confirm the role for local
irradiation in “high-risk” infant medulloblastoma, a group defined as those with localized
disease (M0) following incomplete resection (“R1” in the developing terminology for this
setting) or with classical histology M0 disease following complete resection (“R0”: imaging-
confirmed GTR) or R1 (175). Data from these trials, suggest excellent overall disease control
with the addition of posterior fossa irradiation for the M0 medulloblastoma cohort (176).
Given data in older children restricting “boost” volumes to the tumor bed, tumor bed
irradiation in the infant or y oung children trials is now currently used. Recent and current
infant studies in COG incorporate local tumor bed volume for AT/RT and allow elective local
tumor bed irradiation in high-risk medulloblastoma (ACNS0333, ACNS0334); a similar trial in
PBTC requires local irradiation as well in the M0 setting (PBTC 026). Guidelines for radiation
volume in the ongoing clinical trials parallel to those noted above for medulloblastoma and in
Chapter 3 for supratentorial PNETs. The GTV is defined as the tumor bed and residual
tumor following initial resection, ideally requiring fusion of preoperative MRI and the
planning set of CT and MRI imaging (Fig. 4.7 ). Changes in tumor residual may be
apparent after induction chemotherapy or, selectively, where second surgery has preceded
irradiation; in such instances, changes in areas of the normal brain that were contiguous with
the primary tumor need to be traced through sequential preoperative and intervening image
sets to the time of simulation. In the infant population, the current trials define the CTV as a 1-
cm anatomic expansion of the GTV and require an additional 3–5 mm or greater geometric
expansion to identify the PTV, depending on immobilization and repositioning in a cohort
requiring daily sedation/anesthesia for proper radiation therapy.
3D, IMRT, and now proton therapy are commonly used to diminish dose to the critical
medial temporal lobe–hippocampus region (important with regard to intellectual
development), the cochlea, and the pituitary –hy pothalamic regions. With any technique, it is
important to account for inhomogeneity and avoid overdosage or hot spots to the upper
cervical spine or brainstem especially with primary posterior fossa tumors. It is clear that
potent adjuvant and neoadjuvant chemotherapy affects tolerance to the neural structures and
some injury has been reported (177,178,179,180,181). The potential advantage for proton
beam irradiation may be best realized in the setting of infant tumors, reflecting both
intralesional homogeneity and further sparing of critical normal structures
(111,112,113,114,182).
The use of CSI in this age group has been discouraged since conventional dosages to the
neuraxis (30–36 Gy ) result in unacceptable functional consequences in children y ounger than
3 y ears of age (130,140). Efficacy is not y et demonstrated for this intervention,
recommended in AT/RTs, for example, for children older than 12–18 months of age
(108,146,150,183).
Dosage
For infant embry onal CNS tumors, response-adjusted irradiation is a component of most open
trials in North America. Most regimens use 45–50 Gy to the planning target volume (PTV)
for children up to 18–24 months of age and 54 Gy for those bey ond 18–24 months old. Note
that the French series that combined high-dose chemotherapy and local posterior fossa
consolidation for progressive medulloblastoma used only 36-Gy total dosage to the posterior
fossa (158,183). Although dose:response data are unavailable, AT/RTs are treated with similar
dose regimens, the ongoing COG trial calling for a reduced CTV at 45–50 Gy with an
additional 5.4 Gy to a reduced CTV2 derived from a 5-mm anatomic expansion of the GTV.
The indications for CSI in this age group are discussed above. When used for consolidation in
a protocol setting following complete response to chemotherapy, an age-adjusted regimen of
18- to 23.4-Gy CSI has been recommended.
Results
The most positive results in more recent infant medulloblastoma studies show OS rates
approaching 45–76%, notably more positive for those with M0 presentations, desmoplastic
histology, and initial complete resection (Table 4.5 ) (146,147,148,150). Supratentorial
PNET and AT/RTs in this age group have done less well, with few survivors in the older studies
(128,131,145,155,184). However, recent results from CCG-99703 demonstrate 5-y ear OS
rates of 41% and 63%, respectively (174).
Figure: Malignant Infant Brain Tumors—
Outcome in Selected Prospective Primary
Management Trials
EPENDYMOMAS (INFANTS, CHILDREN, AND ADOLESCENTS)
Intracranial ependy momas represent 5–8% of intracranial neoplasms in children. More than
90% of pediatric ependy momas occur as intracranial tumors; primary spinal cord tumors are
relatively uncommon in children, where ependy momas represent 25% of primary spinal
tumors. Two-thirds of ependy momas in children present as posterior fossa lesions, arising
along the linings of the fourth ventricle or at the cerebellopontine angle (CPA). Tumors
originate from the ventricular floor as midline neoplasms, where attachment is commonly
noted at the level of the obex (the caudal most aspect of the fourth ventricle along the
posterior surface of the medulla, where the fourth ventricle ends and the central spinal canal
begins). It is quite common for such tumors to grow into the foramina of Luschka (on either
side of the brainstem) toward and to the CPA (185,186,187,188). Presentation in the CPA is
noted less commonly, occurring particularly in very y oung children (189). Fourth ventricular
tumors also extend caudally bey ond foramen magnum and into the upper cervical spine;
extension is either from caudal growth from foramen of Luschka or, more commonly,
through the foramen of Magendie and then posteriorly from the cervicomedullary junction
caudally (190). Growth below the foramen magnum marks nearly 50% of fourth ventricular
lesions (Fig. 4.8 ) (185,186,188). Supratentorial ependy momas account for one-third of
childhood presentations, occurring predominantly as extraventricular cerebral hemispheric
tumors; growth is commonly adjacent to the third or lateral ventricular regions (190,191).
Page 72
Figure 4.8 Posterior fossa ependymoma, typically extending from the region of the fourth
ventricle, through the right foramen of Luschka (A) and caudally beyond the
cerebellopontine angle along the cervicomedullary junction to a level below the foramen
magnum (B).
Ependy momas consist histologically of poly gonal cells with large vesicular nuclei and
cy toplasmic granules. Characteristic are ependy mal rosettes, formed by tumor cells oriented
radially around a central lumen; cells also have a tendency to orient themselves around blood
vessels, forming perivascular pseudorosettes (7,192). Molecular genetic analy ses highlight the
origin of ependy momas from populations of neural progenitor cells that are genetically
distinct in the supratentorial, posterior fossa, and spinal regions—anatomically related patterns
of gene expression and regions of chromosomal loss or gain mark the three sites
independently (193).
There has been much debate over the clinical significance of the histologic classification
or grading of ependy momas in the past (7,192). The WHO classification now defines
ependy momas as grade 1 (subependy momas or my xopapillary spinal ependy momas),
grade 2 (“classical ependy momas,” including cellular, papillary, clear cell, and tancy tic
ty pes), and grade 3 (anaplastic) (7,192). Subependy momas are benign neoplasms most often
arising beneath the fourth ventricular wall, but also similarly adjacent to the lateral ventricles.
My xopapillary tumors are “often indolent” lesions occurring primarily in y oung adults,
specifically in the region of the cauda equina. Cellular tumors occur in extraventricular
regions with a relatively low mitotic rate. Papillary ependy momas present along the
ventricular surfaces. Clear cell tumors mimic oligodendrogliomas histologically, occurring
primarily as supratentorial lesions; there is a suggestion that this variant is somewhat
aggressive. Tancy tic tumors grow as fascicles, usually within the spinal cord. Anaplastic
ependy momas are marked by high mitotic rate, microvascular proliferation, and
pseudopalisading necrosis (7,192). Ependy moblastoma are extremely rare, highly malignant
primitive embry onal tumors occurring in infants as supratentorial lesions with features of an
ependy mal neoplasm; they are not considered in the classification of ependy momas, but
rather as embry onal tumors and have been renamed as embry onal tumor with abundant
neuropil and true rosettes (ETANTR) (194).
There have been conflicting reports regarding the correlation between tumor grade
(ependy moma vs. anaplastic ependy moma) and survival. Three of the most prominent
neuropathologists in the 1980s reported no correlation between anaplasia or grade and clinical
behavior (195,196,197). More recent series identify histology as one of the dominant features
related to disease control after aggressive surgery and irradiation (192,198,199). Merchant et
al. (199) report the St. Jude historical experience, noting 5-y ear EFS of 86% among the
children with grade II ependy momas and 61% in patients with anaplastic tumors (p = 0.005).
Extent of surgical resection was the primary driver of prognosis, however, with 5-y ear EFS
of 82% in those with a gross total resection and 41% in those with a subtotal resection. A large
proton series also found that the predominant driver of disease control was surgical resection.
Merchant’s report similarly documents a significant correlation between anaplastic histology
and a higher rate of distant failure (199).
Page 73The biology of ependy momas has been of considerable interest and much work
has been done in this arena. However, again, this is an evolving story and the number of
subgroups of ependy moma appears less well defined than in medulloblastoma. See the table
below for molecular and clinical features of subgroups that are starting to take shape (Table
4.6 ).
Table 4.6 Molecular Subgroups of Ependymoma
Ependy momas are somewhat more common in boy s, although y oung children show
equal sex distribution or even a slight female predominance. The median age at diagnosis is
4–5 y ears; one-third occur in children y ounger than 3 y ears, with ty pically inferior likelihood
of disease control (185,186,200,201). Ependy momas represent a somewhat higher proportion
of CNS tumors in infants and y oung children (127).
Sy mptoms usually are nonspecific and related to fourth ventricular obstruction with
headaches, vomiting, and ataxia. Children with disease involving the CPA often show torticollis
or cranial nerve signs (including unilateral hearing loss and facial weakness) (189). MRI often
shows a nonhomogeneously enhancing lesion, diagnostic when there is characteristic
involvement through the foramen of Luschka EP.4. The patterns of extension in and around
the cervicomedullary region are noted above (190,202). CT often shows stippled
calcification.
Therapy
Surgery
Extent of resection is the dominant factor influencing outcome
(152,185,186,189,200,201,203,204). Fourth ventricular lesions usually are adherent along the
brainstem, especially at the level of the obex, where surgical damage can result in significant
cardiorespiratory compromise. Total or near total resection is achievable in approximately
two-thirds or more in the more recent series (199,205) realized in the majority of cases
(152,185,186,201,202,203,204). Current image-guided neurosurgical techniques and
recognition of the importance of gross total resection have allowed some major referral
centers to achieve gross total resection in 80% or more of instances, sometimes requiring a
second procedure to complete surgery before adjuvant irradiation (188,189,191,199). Even in
very y oung children, complete or near complete resection is often feasible prior to initiating
further therapy. The relationship between extent of resection (or degree of residual on
postoperative MRI) and disease control has been apparent for several decades, with EFS
averaging 50–75% after gross total resection compared with 30–45% with incomplete
removal (Table 4.7 ) (186,189,191,200,201,202,203). Even in cases with metastatic disease
at diagnosis, the impact of GTR on both 5-y ear EFS and OS is impressive, with 35% and 59%
reported in a retrospective multi-institutional review (207).
Total resection is associated with a low but acknowledged rate of operative mortality
(2.5% or less) and morbidity (10–25% incidence of new neurologic deficits postoperatively )
(152). Postoperative cranial nerve deficits are common, including components of the
posterior fossa sy ndrome (e.g., significant difficulties with speech, swallowing, and balance)
(49,152,185,186,189). The proximity of vital centers makes gross total resection in the fourth
ventricle rather challenging, particularly for those arising in or extending to the CPA
(153,190,208). Total resection of supratentorial ependy momas is more readily achieved
(191,208). The St. Jude experience with gross total resection in 96% of tumors originating in
the CPA is marked by a 30% major complication rate, including need for tracheostomy
(almost alway s transient, with removal between 3 and 12 months postsurgery ), gastrostomy
feeding tube (similarly ), or major cranial nerve palsies (189). The rationale, continued
improvement in neurologic function over time, and overall functional status of often y oung
children has encouraged the neurosurgical team to continue aggressive resection for primary
presentations, second surgery before irradiation, or for local recurrence (188,199). In y oung
children with moderate disease residual, the option of initial chemotherapy with delay ed
surgery prior to irradiation has been noted for some time and is still under exploration
(151,209).
Page 75Chemotherapy
Ependy momas are only modestly chemosensitive tumors, with objective responses most
apparent after exposure to cisplatin and oral etoposide (186,188,209,221,222). The only
prospective, randomized trial that tested adjuvant chemotherapy (CCNU, vincristine,
prednisone) after surgery and irradiation was completed by CCG in the early 1980s and
tested adjuvant (223). The trial was small, but there was no suggestion of improved disease
control with chemotherapy ; a subsequent randomized trial of adjuvant
CCNU/vincristine/prednisone versus the “8-in-1” regimen showed no improvement in either
arm of the trial; the group concluded that local tumor control was the dominant issue,
inadequately addressed sy stemically (221). Needle reported a limited-institution pilot study in
children 3 to 14 y ears old, where moderately aggressive carboplatin/vincristine alternating
with ifosfamide/etoposide resulted in a 74% 5-y ear PFS rate, noting half the cohort had
incomplete resection; the data reflect a combination intentionally derived from infant
protocols, and it is in the latter setting that further assessment of dose-intensive chemotherapy
is ongoing (224).
Gilbertson’s documentation of ERBB2 and ERBB4 coexpression in >75% of
ependy momas specimens has prompted studies in the PBTC testing lapatinib, a molecular
targeting agent active in preclinical models against ERBB expressing xenografts (225).
Preliminary reports have not been encouraging with this approach, but trials of molecular
agents are ongoing.
Infant studies may be interpreted positively in documenting that approximately 20–25%
of children with ependy momas can be controlled with surgery and chemotherapy, absent
radiation therapy ; the more recent UKCCSG/SIOP study alone shows radiation-free EFS at 5
y ears of 42% (151,204,209,217). The CCG 9921 experience resulted in postoperative,
postchemotherapy 5-y ear EFS of 32% with OS of 59% (146). The multidrug regimens have
included the traditional four-drug combination (cisplatin, etoposide, vincristine, and
cy clophosphamide) or, more recently, the UKCCSG/SIOP dose-intensive regime including
sequential carboplatin and vincristine, high-dose methotrexate and vincristine,
cy clophosphamide, and cisplatin (151,209). The St. Jude experience with a carboplatin-based
regimen showed 33% 5-y ear PFS and 62% OS in a series utilizing postchemotherapy
irradiation with any imaging evidence of residual (150). The impact of irradiation on disease
control in y oung children had early been suggested in the first POG infant brain tumor study :
children 2 to 3 y ears old received irradiation after 1 y ear of chemotherapy, and those
y ounger than 2 y ears old were scheduled to receive irradiation after 2 y ears of
chemotherapy. Long-term disease control was significantly higher in the older cohort,
interpreted as likely to be related to earlier irradiation (209). Part of the rationale for
continuing primary chemotherapy in this age group is the potential ability for
postchemotherapy (including postprogression) surgery and irradiation to achieve ultimate
disease control: the overall 5-y ear survival in the SFOP series was 59% despite the 22% rate
of PFS (204). Timmermann et al. (226) concluded that the 27% EFS at 3 y ears following HIT
SKK 87 and 92 chemotherapy (highly high-dose methotrexate based, both sy stemic and
intrathecal) is inadequate, resulting in local failures in 75% of cases prior to irradiation and an
early OS rate (at 3 y ears) of 56%.
Radiotherapeutic Management
Volume
Target volumes for postoperative irradiation have evolved from whole brain to posterior fossa
to outlining the local tumor bed only over the past two decades, from full posterior fossa
therapy to local tumor bed volumes and consideration of high-dose volumes restricted to
residual tumor sites (129,185,186,202,203,227,228). Posterior fossa ependy momas tend to
adhere to the floor of the fourth ventricle and to cranial nerves and vessels rather than
invading the brainstem or adjacent normal brain, suggesting that limited margins may be
appropriate for this tumor. Recurrence patterns are predominantly local, within the high-dose
volume; detailed patterns of failure analy ses show 50–70% of failures confined to the
primary site, an additional 10–20% involving the primary site and the neuraxis, and 10–40%
involving the neuraxis alone (185,201,202,210,211,227,228,229,230). As local control rates
improve, recently noted at more than 85% at 5–7 y ears with aggressive surgery and optimal
radiation therapy, the percentage of failures involving the neuraxis or limited to the neuraxis
has increased (152,199). For the 85–90% of children presenting with localized ependy momas,
current recommendations for the GTV include the tumor bed and residual tumor based on
both pre- and postoperative imaging. Optimal planning requires fusion of MRI studies to the
planning CT, carefully assessing common patterns of disease extension (foramina of Luschka,
circumferentially around the brainstem to encase the basilar artery, into foramen of
Magendie and bey ond foramen magnum to the upper spinal canal (189,190,199). The GTV is
expanded anatomically by 1 cm to form the CTV, curtailed at fixed anatomic borders; a final
3D geometric expansion of 3–10 mm provides the PTV (203,231) (Fig. 4.9 ).
Page 76
Figure 4.9 Ependymoma, fourth ventricle, following near total resection: (A, B) RT
planning for 6-MeV photons using IMRT (L) compared to scatter-beam protons (center) and
intensity-modulated proton beam therapy (IMPT, R). Axial imaging through level of cochlea
(A) and pituitary (B). GTV (red) and 1-cm anatomic expansion to CTV (yellow); brainstem
(green), cochlea (red), and pituitary (red) shown. C: Comparative DVH for three modalities
showing coverage of GTV, cochlea (RC, LC), brainstem (BS), whole brain (WB). D: DVH showing
coverage of GTV, pituitary (PT) and hypothalamus (HT) and temporal lobes (TL).
The incidence of neuraxis dissemination at diagnosis varies between 7% and 15% in the
recent literature (154,186,210,232). Bloom et al. initially reported a high frequency of
seeding among high-grade posterior fossa ependy momas, recommending CSI for such
presentations (233,234). Late follow-up of Bloom’s Roy al Marsden experience reported
neuraxis dissemination in only 2 of 33 children with local posterior fossa tumor control, also
noting no difference between children who had received CSI and those treated with only local
volumes (234). Although vary ing significantly among recent reports, the prospective St. Jude
series noted a 12% rate of failure limited to the neuraxis (i.e., with primary tumor control),
notably related to histology : 5% for differentiated ependy momas versus 17% for anaplastic
tumors, data that remarkably reproduced Bloom’s earlier experience (129,199,228,232,234).
Except for patients with neuraxis dissemination at diagnosis, no ongoing trial incorporates CSI
as primary management.
Page 77Dosage
It has been difficult to define a dose–response relationship in ependy momas, largely
reflecting differences in the proportion of completely resected cases and other factors (age,
histology ) that impact local tumor control. Data from CHOP suggest improved disease
control with doses of >54 Gy (210). The excellent local control noted in Merchant’s series was
based largely on 59.4 Gy, although the infant cohort y ounger than 18 months in that series
received only 54 Gy ; no statistical difference was noted in tumor control related to dose.
Awaiting the larger, multi-institutional COG trial, one is tempted to recommend 59/4 Gy,
noting that the technique should spare the chiasm and upper spinal cord dose bey ond the 54-
Gy level (152,188,199,). There have been trials of hy perfractionated delivery, with doses of
60–66 Gy delivered as 100 cGy twice daily through the SFOP; although readily tolerated, no
advantage in outcome measures was apparent (235).
Technique
The standard of practice now entails use of 3D CRT or IMRT or proton therapy to target the
tumor bed with a CTV expansion of 1–1.5 cm and a PTV expanded by an additional 5–7 mm,
depending on the immobilization techniques and experience of the treating institution (Fig.
4.9 ). Comparative dosimetry reveals advantages in normal tissue sparing at the cochlea
and in the nearby optic chiasm and upper spinal cord with IMRT or proton therapy
(188,236,230). The potential advantage of PBRT is apparent in considerable dose sparing;
prospective clinical data are anticipated as the experience matures at MGH and begins at
other PBRT facilities in the United States and abroad. Important in the very y oung population
is dose to critical structures such as the brainstem. Excellent work by Indelicato et al. (178) at
the University of Florida has helped delineate dose constraints to the brainstem with proton
radiotherapy which is especially relevant in the very y oung population who suffer a
disproportionate burden of the treatment related radiation injury. They recommend that when
possible to try to keep the mean dose to the brainstem below 52.4 Gy and that the maximum
dose to the brain stem should not exceed 56.6 Gy. A commentary that accompanies this
article nicely reviews the literature in this area and is a helpful adjunct to this study as well
(180).
Figure:
Posterior fossa ependymoma, typically extending from the region of the fourth ventricle,
through the right foramen of Luschka (A) and caudally beyond the cerebellopontine angle
along the cervicomedullary junction to a level below the foramen magnum (B).
Figure: Molecular Subgroups of
Ependymoma
Figure: Ependymoma—Outcome Following
Surgery and Irradiation
Figure:
Ependymoma, fourth ventricle, following near total resection: (A, B) RT planning for 6-MeV
photons using IMRT (L) compared to scatter-beam protons (center) and intensity-modulated
proton beam therapy (IMPT, R). Axial imaging through level of cochlea (A) and pituitary (B).
GTV (red) and 1-cm anatomic expansion to CTV (yellow); brainstem (green), cochlea (red), and
pituitary (red) shown. C: Comparative DVH for three modalities showing coverage of GTV,
cochlea (RC, LC), brainstem (BS), whole brain (WB). D: DVH showing coverage of GTV, pituitary
(PT) and hypothalamus (HT) and temporal lobes (TL).
BRAINSTEM GLIOMA
The duration of sy mptoms correlates with the ty pe of brainstem glioma. Children with
DIBSG report a consistently brief history of neurologic sy mptoms, ty pically measured in
weeks and certainly less than 6 months. Neurologic signs associated with the pontine DIBSGs
include cranial nerve deficits, long tract signs, and ataxia; dy spraxia and dy sphagia are also
rather common (241,242). Elevated intracranial pressure secondary to obstructive
hy drocephalus is often present in midbrain tumors or the expansile dorsally exophy tic tumors
that fill the fourth ventricle, but noted in fewer than 15% of children with pontine DIBSGs
(Fig. 4.13 ). The focal brainstem tumors are often associated with prolonged, more limited
sy mptoms, findings confined to deficits in one or two cranial nerves alone, ataxia, or
dy spraxia, ty pically with minor long tract signs and a history measured in months or y ears
(233,237,238,240,242,243,244,245).
Figure 4.13 Brainstem astrocytomas. A: Dorsally exophytic brainstem juvenile pilocytic
astrocytoma presents as a sizable lesion filling the fourth ventricle but is attached only along
the floor at the level of the pontomedullary junction (B, postoperative); appearance 4 years
after irradiation for documented postsurgical progression shows decreased mass effect and
lack of enhancement.
Page 78MRI is the definitive test for diagnosis and delineation of tumor extent and ty pe
(Figs. 4.11 –4.13 ). The ty pical diffusely infiltrating pontine glioma is homogeneous and
hy pointense on T1 imaging but readily appreciated on T2 sequence. DIBSGs expand the
pons, often showing exophy tic growth in the ventral, dorsal, and/or lateral directions as
infiltrating lesions with indistinct margins; gadolinium enhancement is usually absent or
minimal, occasionally noted in a ring-enhancing manner. Diffusion tensor imaging (DTI) and
tractography often show sparing of the dorsal columns of the pons with infiltration splay ing
the longitudinal tracts. Focal brainstem tumors by definition show distinct margins, ty pically
enhancing briskly. 18FDG PET is hy permetabolic in DIBSG; imaging–histologic correlations
show hy peractivity only among grade 4 or glioblastoma cases; anaplastic astrocy tomas were
isometabolic with normal brain or hy pometabolic, while low-grade fibrillary gliomas (grade
2) were isometabolic (246,247,248).
As a group, brainstem tumors constitute approximately 10% of intracranial tumors in
children. The peak incidence occurs between the ages of 5 and 9 y ears; boy s are affected
more commonly than girls. The most common presenting sy mptoms for DIBSGs include
diplopia, lateralizing motor weakness, and difficulty with speech, swallowing, and walking.
Neurologic signs include ataxia, cranial nerve palsies (most common are the pontine nerves,
VI and VII, followed by the medullary nerves, IX, X, XI, and XII, and, less often, the
midbrain nerves, III, IV, and V), and long tract signs (motor weakness, most often
hemiparesis) (238,241). A review of the anatomy of the brainstem readily demonstrates why
this constellation of signs occurs (Fig. 4.10 ).
Page 79Tumors of the midbrain and medulla may be diffuse or focal; even diffuse
tumors ty pically show much less infiltration and expansion of the brainstem than seen with
the pontine gliomas. Focal intrinsic tumors do occur in the pons, often as localized tumors of a
cranial nerve nucleus or along the cerebellopontine peduncle.
Biopsy of the classic, diffusely infiltrating pontine glioma is generally unnecessary
(238,241,242,244,245,246,247,248,249). Following trials in the 1980s of sy stematic open
biopsy that y ielded some of the basic knowledge correlating imaging and histopathology,
biopsy -related neurologic compromise has led most US and European centers to biopsy only
the 15–20% of “aty pical” brainstem tumors, often demonstrating JPA or fibrillary grade 2
astrocy toma (246). Stereotactic guidance has resulted in a rather safe approach to the
brainstem tumors, with series from Paris, Germany, and Brussels showing current
histopathology and clinic-imaging correlations while reporting only minor, ty pically transient
new neurologic deficits in approximately 10% of instances (246,250,251). The more recent
biopsy series shows rather divergent histopathology, clearly dependent on selection criteria
for biopsy : 22 of 24 children showed anaplastic astrocy toma or glioblastoma, with 1 PNET
and 1 JPA reported from Hospital Necker-Enfants, compared to 10 of 20 in a more selected
series from Brussels, the remainder showing grade 2 low-grade fibrillary astrocy toma, JPA,
PNET, or germ cell tumor (250,251). There is no consistent correlation between histology and
outcome; all diffusely infiltrating pontine tumors show extremely poor duration of response to
irradiation and median survival of less than 1 y ear (241,245,252,253). Brainstem tumors have
been shown to express ERBB1, with the degree of overexpression or less common
amplification proportional to increasing histologic grade (254). The finding suggests that ErbB
or EGFR inhibitors may be worth study ing in these tumors, allowing “selected” therapeutic
interventions. A trial of an EGFR inhibitor showed a little efficacy with 1-y ear PFS of 21%
and 1-y ear overall survival of 56%, but in most studies median OS is less than 1 y ear (255). A
small subset of DIBSG may show CNS dissemination. Gururangan et al. (256) described
neuraxis metastasis in 17% of 96 patients at a median of 15 months after diagnosis, presenting
as parenchy mal dissemination (e.g., apparently noncontiguous disease extending from the
pontine primary site to the internal capsule), leptomeningeal metastasis, or subependy mal
spread.
Hoffman et al. (243) identified a highly specific brainstem tumor: the dorsally exophy tic
“benign” brainstem tumor. The lesion characteristically fills the fourth ventricle, presenting
with sy mptoms and signs of elevated intracranial pressure. In most cases, the tumor enhances
briskly with gadolinium (Fig. 4.13 ). The origin from the floor of the fourth ventricle (the
dorsal surface of the pons or medulla, with the tumor often arising at the pontomedullary
junction) may be suggested by MRI but is usually apparent only at the time of surgery. These
tumors are almost alway s JPA histologically ; the prognosis has been quite favorable
(249,257,258).
Focal tumors of the pons are uncommon. One specific presentation includes isolated
facial nerve palsy or similar, limited neurologic dy sfunction associated with a small,
enhancing intrapontine lesion (233). Such tumors are JPAs and enjoy a favorable prognosis
(Fig. 4.11 ) (241,259).
Page 80Tumors of the midbrain may involve the tegmentum or the tectal plate.
Tegmental tumors usually are fibrillary astrocy tomas (WHO, grade 2). The tumors may
involve the tegmentum focally or may infiltrate through much of the midbrain. Lesions may
show uniform enhancement or little contrast enhancement. Presenting signs include
extraocular muscle palsy or long track involvement. Biopsy is preferred, especially for
lesions contiguous with the pineal region.
Tectal plate tumors usually are quite small and well demarcated, confined to the tectal
plate (Fig. 4.14 ). MRI shows the focal nature of tectal lesions, most often signified by brisk
enhancement; biopsy generally confirms juvenile pilocy tic histology (WHO, grade 1). These
tumors ty pically are indolent; observation alone usually is the treatment of choice
(240,241,248,260). If the tumor is anatomically confined to the tectum and stable over an
initial 3- to 6-month period of observation, biopsy may be deferred unless there is evidence
of tumor progression necessitating therapy (241,259). When lesions are aty pical (e.g.,
cy stic), larger than 10 cc in volume, or when there is some question whether the lesion
originated in the adjacent pineal region, biopsy may be needed at diagnosis. If it is confirmed
as a low-grade astrocy toma, observation is appropriate.
Figure 4.14 Tectal plate glioma. A: A sagittal postcontrast MRI image of a child with a
juvenile pilocytic astrocytoma of the tectum. The tumor (T) is nonenhancing. A third
ventriculostomy defect is seen (arrow). B: Typical signal characteristics and enhancement
pattern of low-grade gliomas, here in tectal plate. Low-grade gliomas are hypointense on T1
MRI sequences and may not enhance with gadolinium (a and b, left). They are hyperintense
on T2 sequences (b, center). These tumors remain hyperintense on T2 FLAIR images (c, right),
but CSF hyperintensity is suppressed. C: Proton plan for JPA of the tectum. Axial and sagittal
images demonstrate the high conformality of proton radiation. DVH (D) and images
demonstrate the minimal dose delivered to surrounding critical structures including the
hypothalamus, pituitary gland, optic chiasm, and temporal lobes.
Therapy
Surgery
The role of surgery in classic pontine gliomas is limited. Interest in biopsy in the current era is
largely to define the biology of the more common DIBSG and to document diagnosis for the
aty pical brainstem tumors, both intrinsic and exophy tic (249,261,262).
For dorsally exophy tic tumors, judicious incomplete resection will establish the diagnosis
(by surgical observation of the origin from the brainstem and histology ) and reduce the
obstructing mass in the fourth ventricular region. Although there is no documented advantage
to aggressive surgery, it may be advantageous to remove the bulk of the lesion posteriorly,
establishing CSF flow and reducing the bulk of tumor when it can be reasonably separated
from the underly ing margin of normal, functioning brainstem. Aggressive resection as a
primary intervention is often associated with unnecessary morbidity (257,258). Partial
resection alone is associated with 50–70% freedom from progression at 5–10 y ears
(243,244,257,258).
Page 81Small focal lesions intrinsic to the pons may be biopsied if safely approachable;
one cannot insist on biopsy if the differential diagnosis is limited and the biopsy -associated
morbidity is high (233,241).
Lesions in the tegmentum should be biopsied, although the potential morbidity of
stereotactic biopsy is recognized because of the proximity of the central veins. Occasional
resection has been reported for midbrain tumors (239,262). Tumors of the lower medulla or
cervicomedullary region are similar to low-grade astrocy tomas of the spinal cord. Biopsy
and attempted gross total resection have been reported; results after surgery alone have been
impressive but limited to a small number of neurosurgical centers (239,261,263). Histology
usually is low-grade astrocy toma (WHO, grade 2). Malignant gliomas have been reported
(261).
Radiation Therapy
Children with diffusely infiltrating pontine gliomas often respond impressively to irradiation.
Up to 70% show improvement in neurologic sy mptoms and signs over the course of
irradiation; objective reduction in tumor on MRI is apparent within 8–12 weeks of initiating
irradiation. Unfortunately, signs of progressive disease are apparent sy stematically within 6–
12 months (241,264).
Clinical response has also been noted in tegmental midbrain lesions and tumors of the
medulla, where radiation therapy is more likely to achieve long-term disease control
(241,265). For tectal plate or dorsally exophy tic pontomedullary astrocy tomas, irradiation is
ty pically deferred until signs of disease progression are apparent on imaging
(240,244,248,257,258). Once progression has been documented on serial imaging (noted in
25–40% of dorsally exophy tic tumors), there has been almost uniform disease control
measured out to more than 5 y ears after local irradiation (244,257,258). Intrinsic focal
pontine lesions often require irradiation at diagnosis to control attendant neurologic signs
(233). With the availability of precision volume techniques (i.e., 3D CRT or fractionated
radiosurgery ), the risk:benefit ratio may favor earlier radiation intervention in localized, low-
grade brainstem lesions (266,267).
Chemotherapy
Despite documented transient response, there is little evidence of efficacy for chemotherapy
in brainstem tumors. An earlier prospective, randomized trial of CCNU, vincristine, and
prednisone showed no benefit in these tumors despite purported efficacy in supratentorial
high-grade gliomas (268). Adjuvant studies with concurrent or sequential chemotherapy or,
more recently, trials incorporating molecular targeting agents (inhibitors of EGFR, PDGFR;
HDAC (histone deacety lase inhibitors) and VEGF inhibitors) have failed to alter the PFS or
OS data in this disease (269,270,271,272,273). Despite efficacy in adults with hemispheric
malignant gliomas, temozolomide has shown no advantage in DIBSG in children (274).
Preirradiation chemotherapy regimens have shown some responsiveness, but early disease
progression during chemotherapy and a lack of objective benefit in postirradiation intervals to
progression have largely dampened enthusiasm for this approach, if a limited recent French
trial testing preirradiation BCNU, cisplatin, and high-dose methotrexate continues to generate
interest (275,276,277,278).
Recently, there has been better biologic and molecular understanding of diffuse intrinsic
pontine gliomas that may provide targets for drug therapy. Genomic interrogation of DIPG
tumors from biopsies and autopsies, have revealed histone mutations specifically K27M
H3.3/H3.1 mutations in 80% and activin A receptor, ty pe 1 (ACVR1) mutations in 25% of
diffuse intrinsic pontine gliomas, providing renewed hope for future success in identify ing
effective therapies as both appear to be driver mutations (279,280).
For focal, low-grade gliomas, the use of chemotherapy before irradiation is an
extrapolation from diencephalic low-grade tumors, which may be rational in selected settings
(281). For the majority of children, even those y ounger than 4 y ears old, sy mptomatic or
progressive dorsally exophy tic or focal pontine lesions can be treated effectively with focal
radiation techniques. It is difficult to anticipate any significant advantage in delay ing
definitive therapy with intervening chemotherapy.
Radiotherapeutic Management
Volume
MRI and autopsy studies document contiguous extension of pontine gliomas linearly through
the adjacent medulla or midbrain and axially into the brachium pontis, the CPA, and adjacent
portions of the cerebellar hemispheres (237,242,282). Neuraxis metastasis has been noted in
up to 15% of children with DIBSG, involving the subarachnoid space (primarily about the
brainstem, the basal cistern, or the upper cervical cord, but also into the spinal canal), direct
or noncontiguous appearance cephalad into thalamic white matter, or subependy mally within
the ventricular sy stem (241,256,283,284). A small proportion of focal, low-grade brainstem
lesions (often JPAs) are associated with neuraxis dissemination, most often noted at diagnosis
(233,285). In almost all instances, the pattern of failure for DIBSG includes the primary
pontine tumor alone or in conjunction with other sites as above (282,286). Local irradiation is
indicated, with target volumes subtending both the pons and the contiguous regions both
linearly (adjacent midbrain and medulla) and axially (adjacent peduncles and, where
indicated, contiguous anterior cerebellum). The best estimate of tumor extent is ty pically on
T2 or T2 flair sequences to define the GTV (242,266). Microscopic margins along the white
matter tracts provide a 1- to 2-cm anatomic expansion to identify the CTV. It is important to
note that tumors extending rostrally into the midbrain or higher will show larger axial CTVs at
the upper midbrain and contiguous internal capsules than at the primary pontine level, simply
a matter of anatomically covering sites of direct extension. For infiltrating tumors of the
midbrain and medulla, margins of 1–1.5 cm along white matter tracts bey ond the T2 or flair
extent are appropriate.
Focal lesions of the tectum can be treated with limited target volumes; treatment of
discrete lesions generally entails treating only the identifiable tumor with a 1 cm or less CTV
for 3D conformal or IMRT (241,266). Fractionated stereotactic radiosurgery (also called
stereotactic radiotherapy ) and radiosurgery have been used for the latter tumor ty pes
(197,266,267).
Page 82For dorsally exophy tic tumors, the volume can conform to the disease process
based on MRI; the anterior margin at the brainstem should encompass at least 5 mm of
apparently normal brainstem ventral to the tumor as documented on MRI. A 3D CRT or IMRT
approach can spare radiation dosage to the temporal lobes, especially important in this y oung
age group.
Dosage
A decade-long series of trials in the 1980s and 1990s explored the impact of high-dose,
hy perfractionated irradiation for brainstem gliomas. Despite dosage escalations from 66 Gy
to 70 to 72 Gy and ultimately to 75.6–78 Gy (with twice-daily fractions of 100–126 cGy ), no
durable improvement was documented in disease control or survival. The outcome after
conventionally fractionated irradiation to 54–55.8 Gy (180 cGy once daily ) or
hy perfractionated irradiation to between 70 and 78 Gy has been consistently documented at
median times to progression of only 6–8 months, median survival approaching 1-y ear, and 2-
y ear survival rates of only 10% (241,245,264,265,287). A randomized trial ultimately
documented the equivalence of conventional and hy perfractionated schedules (288). A trial
of accelerated fractionation in Europe, using 180 cGy twice daily with interfraction intervals
of 8 hours to 48.6 and 50.4 Gy, showed similar results, with 32% survival at 1 y ear and 11% at
2 y ears (289). It is unclear whether paucifractionated approaches with fraction sizes of 3 Gy
(to 39 Gy /13 fractions) or 5.5 Gy (to 33 Gy /6 fractions) achieve equivalent or inferior results
compared to conventionally fractionated regimens (290).
Technique
Radiotherapy for these tumors employ s a CT scan for planning and a fusion MRI and the use
of either 3D conformal RT or IMRT that enable one to spare the temporal lobes and aspects of
the cochlea. GTV encompasses all of the enhancing and T2 or Flair signal abnormality. The
CTV is a 1- to 2-cm expansion superiorly and inferiorly with a 1-cm anatomically confined
expansion axially, which means likely the CTV will be trimmed to stay within the boney
confines of the posterior fossa anteriorly but extend posteriorly to tracks of the cerebellar
peduncles to cover microscopic spread. With usual immobilization and repositioning, one
ty pically identifies an additional 3 to 5 mm geometric expansion to define the PTV.
For focal brainstem gliomas (including tectal plate lesions, dorsally exophy tic
pontomedullary tumors, and focal intrinsic lesions of the midbrain, pons, or medulla), tumor
size, margination, and location demand highly conformal 3D CRT, IMRT, or proton
radiotherapy approaches to minimize dosage bey ond the primary target volume while
maintaining intralesional homogeneity in the CTV within 5% (246) (Fig. 4.14 ).
Radiosurgery for focal brainstem gliomas is not recommended. CT-based planning with a
fusion MRI should encompass all gross residual disease based on T2, Flair and T1 post
gadolinium sequences and coverage of the tumor bed as well if resection was employ ed.
CTV margins should be 5 to 10 mm and anatomically confined.
Children with DIBSGs usually need corticosteroids at diagnosis to control neurologic
sy mptoms. For those not receiving corticosteroids at the initiation of radiation therapy, one
should consider initiating a low-dose regimen (e.g., dexamethasone at 2–4 mg twice daily )
only for children with large intrinsic tumors or early development of additional or progressive
neurologic signs. Irradiation generally is well tolerated, and one can commonly taper
dexamethasone during the course of irradiation, often discontinuing steroid support by the
fifth or sixth week of therapy. Reducing the dexamethasone dose is important both for
secondary drug effects and to control cushingoid features that can make repositioning in
immobilizing masks problematic as the face expands secondary to steroids. The newer
biologic agents often show cutaneous reactions that require management within and well
bey ond the radiation volumes (291,292).
A significant proportion of patients with brainstem tumors demonstrate clinical and
imaging evidence of apparent progressive tumor within 1–4 months of completing radiation
therapy (263,293). MR spectroscopy and PET studies may be of help in differentiating early
tumor progression from the “pseudoprogression” often comparable to that seen in adults with
hemispheric glioblastoma (242,294). Imaging changes during this interval include focal
enhancement (often in a previously nonenhancing lesion), cy st formation (or cy stic
degeneration), or intralesional hemorrhage and necrosis (242,289,293). The problem is
recognized in cooperative group trials, where patients may be coded formally as “disease
progression,” but maintained on study without interruption of postirradiation therapy until
resolution or progression is ultimately clear. Similar changes, with apparent tumor progression
and worsening of neurologic signs, can occur 1–4 months after irradiation for focal intrinsic
JPAs (Fig. 4.11 ). Medical support, including corticosteroids, may be necessary until the
lesion regresses over several months.
Results
Approximately 60–70% of patients with classic pontine gliomas show improvement in
functional status after irradiation. Time to progression may be difficult to document in this
tumor sy stem; cooperative group studies report median time to progression of 6–8 months.
Overall survival is the primary endpoint for comparing therapies, providing an objective
parameter reflecting primary management and recognizing that little prolonged secondary
benefit has been documented from secondary therapies. Median survival is 8–12 months in
patients selected for high-risk DIBSG studies, and the proportion surviving at 2 y ears is less
than 10–20% (241,242,245,264,265,273,286,287). There is some suggestion that y ounger
children (<3 y ears old) may show superior outcome, perhaps related to the biology of such
uncommon presentations (295).
Children with focal, intrinsic tumors of the midbrain or medulla show long-term survival
after irradiation of 50–70% (237,240,241,265). Survival at 10 y ears after surgery with or
without necessary irradiation for dorsally exophy tic brainstem gliomas approaches 75%
(241,243,257,258). Similar rates are quoted for the focal pontine lesions of limited size after
localized irradiation (235).
Figure:
A lower pontine glioma interferes with motor function on one side of the body and with
contralateral function of the sixth and seventh cranial nerves. These two cranial nerves are
most commonly affected by brainstem tumors. Ataxia can result from involvement of the
fibers of the middle cerebellar peduncle.
Figure:
Focal, intrinsic pontomedullary juvenile pilocytic astrocytoma, after biopsy (3/12/99).
Appearance 6 weeks after radiation therapy (54 Gy in 30 fractions): symptoms progressed
from isolated right sixth nerve palsy with subtle left hyperreflexia to complete right seventh
nerve palsy and dense left hemiparesis, associated with intralesional necrosis and expansion
of the lesion (6/24/99). Patient treated supportively, with gradual improvement of left
hemiparesis but persistent right seventh and sixth nerve palsies, associated with virtual
resolution of lesion showing residual area of focal encephalomalacia on late imaging follow-
up (3/12/03).
Figure:
Brainstem gliomas: classic and most common diffusely infiltrating pontine glioma.
Figure:
Brainstem astrocytomas. A: Dorsally exophytic brainstem juvenile pilocytic astrocytoma
presents as a sizable lesion filling the fourth ventricle but is attached only along the floor at
the level of the pontomedullary junction (B, postoperative); appearance 4 years after
irradiation for documented postsurgical progression shows decreased mass effect and lack of
enhancement.
Figure:
Tectal plate glioma. A: A sagittal postcontrast MRI image of a child with a juvenile pilocytic
astrocytoma of the tectum. The tumor (T) is nonenhancing. A third ventriculostomy defect is
seen (arrow). B: Typical signal characteristics and enhancement pattern of low-grade
gliomas, here in tectal plate. Low-grade gliomas are hypointense on T1 MRI sequences and
may not enhance with gadolinium (a and b, left). They are hyperintense on T2 sequences (b,
center). These tumors remain hyperintense on T2 FLAIR images (c, right), but CSF
hyperintensity is suppressed. C: Proton plan for JPA of the tectum. Axial and sagittal images
demonstrate the high conformality of proton radiation. DVH (D) and images demonstrate the
minimal dose delivered to surrounding critical structures including the hypothalamus,
pituitary gland, optic chiasm, and temporal lobes.
CEREBELLAR ASTROCYTOMAS
Page 83Cerebellar astrocy tomas make up 10–15% of childhood brain tumors and 25% of
posterior fossa neoplasms. These tumors are ty pically low grade, well circumscribed, and
slowly growing with prominent cy st formation (296,297). Cushing (191) was the first to
describe the entity in 1931, commenting on the “benign” nature of cerebellar astrocy tomas,
associated with low morbidity and mortality.
The cerebellum is one of the most common sites of origin for low-grade gliomas in
children. The vast majority of cerebellar astrocy tomas are low grade: JPAs (WHO, grade 1)
comprise 80–95% of cases, and diffuse fibrillary astrocy tomas (WHO, grade 2) account for
5–15% (298,299,300,301). Biphasic architecture is characteristic of JPAs, with more cellular
areas that tend to have Rosenthal fibers (degenerating astrocy tic processes and loose areas
with microcy sts). Cells are elongated, bilpolar, and have thin “hair-like” processes (hence,
piloid) (298). Diffuse fibrillary astrocy tomas tend to be less circumscribed, more infiltrative
and expansile, with a less favorable prognosis relative to JPA; the diffuse tumors arise
specified, or as oligoastrocy tomas (298,299,302,303). Malignant gliomas are quite
uncommon in the childhood cerebellum.
The median age at diagnosis is 5–6 y ears, with 20% of cases y ounger than 3 y ears old;
astrocy tomas of this location are rarely found in infants (296,300,304). Presenting sy mptoms
often are confined to those associated with elevated intracranial pressure (headaches,
vomiting, etc.), with less frequent altered cerebellar function (primarily ataxia, poor
coordination, or dy spraxic speech); cranial nerve deficits are uncommon.
The majority of tumors arise in the cerebellar hemispheres; approximately one-third
are primary vermis lesions. Most tumors are confined to the cerebellum; a minority extends
to the cerebellopontine peduncle or the posterior aspect of the brainstem
(296,297,300,304,305). The most characteristic appearance on CT or MRI is a large, well-
circumscribed tumor with prominent cy sts (unilocular or multilocular). The nodular or solid
portion of the tumor characteristically enhances briskly. The cy st wall may or may not
demonstrate contrast enhancement. The nodular and cy stic components are considered part
of the tumor; both components should be addressed at the time of surgery (300,304,306).
Cerebellar JPAs have uncommonly been associated with multifocal CNS involvement,
representing either neuraxis dissemination or concurrent multifocal presentation (307,308).
Therapy
Surgery
Surgical resection is the treatment of choice for cerebellar astrocy tomas. The amount or
degree of resection has been found to be the most important prognostic factor for outcome in
patients with low-grade gliomas (137). For classic cy stic cerebellar astrocy tomas, gross total
resection has been reported in 70–90% of cases (299,300,302,309). PFS for these children is
in excess of 90%. Even in the setting of documented residual, many tumors remain indolent.
After surgery - and imaging-confirmed gross total resection, recurrence is uncommon, noted
at 5–10% in major series (300,302,303,304,305,309,310). After incomplete resection, disease
progression has been reported in 30–60% of cases at 5 y ears or more. Importantly, long-term
survival remains above 65% (297,300,302,309). Infiltrative tumors and diffuse fibrillary
astrocy tomas are less likely to be amenable to gross total resection and are associated with a
higher rate of disease progression or recurrence (300,311). Despite the indolent nature of
these tumors, the median time to recurrence is about 2 y ears (297,300,302,305). Children
who experience tumor recurrence amenable to surgery may benefit from a second surgery.
This is generally recommended if the tumor can be totally resected or substantially debulked
without great risk of neurologic compromise.
Radiation Therapy
There is no established role for radiation therapy in the primary management of cerebellar
astrocy tomas that are amenable to gross total resection. Prognostic factors that may predict
relapse after initial surgery alone should be considered. Most series indicate greater risk of
later disease progression in recurrent tumors, infiltrative tumors, astrocy tomas that cannot be
completely resected, and tumors with diffuse fibrillary histology or more aggressive
histologic subty pes (296,297,299,300,304,309).
Indications for radiation therapy include progression of incompletely resected tumors
that are not amenable to second surgery and incomplete surgical resection following
recurrence. This is an uncommon situation for JPA, but is seen more frequently in tumors
with diffuse fibrillary histology (300,303). Chemotherapy is the preferred initial adjuvant
treatment for these more aggressive presentations in very y oung children (312). There are no
data substantiating improvement in disease control with postoperative irradiation following a
complete resection (304,309,313). Infrequent malignant gliomas seem to benefit from
immediate postoperative irradiation, but overall prognosis in these cases is poor (311).
Chemotherapy
Because most low-grade gliomas located in the cerebellum are amenable to surgical
resection and do not require adjuvant therapy, it is relatively rare to use chemotherapy for
this specific tumor site. Multiple chemotherapeutic agents have been shown to delay
progression (312,314,315,316). The most commonly administered regimen is the
combination of carboplatin and vincristine. A more extensive review of the use of
chemotherapy for low-grade gliomas is included in the “Low-Grade Supratentorial
Astrocy tomas” section in Chapter 3 .
Radiotherapeutic Management
Indications for radiation therapy are generally limited to documented progressive or
recurrent disease after or on chemotherapy in the y ounger patients or progressive or
recurrent disease in the older children (300,313). Lesions with an infiltrative pattern involving
the peduncle or brainstem may require early radiation therapy when sy mptomatic or
progressive. Such lesions are targeted with limited anatomic expansion of 0.5–1 cm around
the GTV as defined on MRI with image registration to include immediate preoperative
disease and residual at the tumor bed (317). The prescription dose is generally 50–54 Gy
(318).
Page 84The treatment of high-grade cerebellar astrocy tomas generally includes
multiple modalities. Postoperative irradiation to the local tumor is recognized as the standard
of care (300,313). CSF dissemination is a recognized pattern of failure; neuraxis irradiation is
ty pically considered only when overt CNS metastasis is documented (300,307,308,313).
Results
OS rates in childhood cerebellar astrocy tomas are more than 80% at 10–20 y ears
(296,297,300,304). Survival rates are highest among those with tumors confined to the
cerebellar hemispheres or vermis, JPA histology, and those amenable to gross total resection.
For incompletely resected diffuse astrocy tomas, long-term survival rates of 50–80% have
been reported (296,299,300,302,305). It is interesting that children with cerebellar
astrocy tomas demonstrate cognitive and adaptive deficits despite posterior fossa location and
therapy limited to surgery alone (319). This risk does not seem to be associated with surgical
or medical complications.
SPINAL CORD NEOPLASMS
Spinal cord neoplasms are uncommon in children. These tumors are divided into two main
groups: intradural and extradural. Intradural lesions are further classified into those involving
the spinal cord itself (intramedullary ) or arising outside of the spinal cord parenchy ma from
the cauda equina or intradural components of the nerve roots (extramedullary ). Extradural
tumors are by definition neoplasms that arise outside the nervous sy stem with extension into
the spinal canal through the neural foramina. Extradural tumors that gain access to the spinal
canal can then extend linearly bey ond the cord segment of entry, accounting for the
“dumbbell” description; such presentations are most common in neuroblastomas,
paravertebral soft tissue tumors of the Ewing ty pe (i.e., peripheral PNET), or neurofibromas
(320). Management of extradural presentations is discussed in Chapters 9 , 11 and
12 .
Primary (intramedullary ) spinal cord neoplasms account for approximately 5% of CNS
neoplasms in children (321). The median age is between 8 and 9 y ears with a slight male
predominance (322,323). The relative histologic and anatomic frequencies of spinal cord
tumors in children are almost mirror image proportions of those in adults: astrocy tomas
account for approximately 60% of primary spinal cord tumors in children, while
ependy momas account for 30% (321,324,325,326). Other gliomas (gangliogliomas,
oligodendrogliomas) and neurilemomas (neurofibromas usually associated with
neurofibromatosis ty pe I) comprise the remaining 10% (321,324,327,328,329).
More than 80% of pediatric spinal cord astrocy tomas are low-grade neoplasms, most
often fibrillary and less commonly juvenile pilocy tic in ty pe. Astrocy tomas occur primarily
in the cervical and thoracic regions of the cord, presenting as circumscribed or more
infiltrating lesions (Fig. 4.15 ). The tumors diffusely widen the involved cord; tumor length
averages six spinal cord segments (321). More than 30% are associated with sizable
intraspinal cy sts (324,327,329). The cy sts ty pically extend in cephalad and caudal directions
from the solid tumor, representing fluid-filled components that may be more than double the
overall length of the lesion. Differentiating true tumor-derived cy sts from common sy rinx
formation related to obstruction of the central canal is often difficult. Malignant gliomas
(high-grade astrocy tomas: anaplastic astrocy toma and glioblastoma multiforme) account for
fewer than 20% of astrocy tic lesions. Spinal malignant gliomas are clinically aggressive
lesions and carry a poor prognosis. The literature suggests that such tumors may be more
common in infants (324,326,327,329). Holocord astrocy tomas extend over much of the
length of the cervicothoracic cord. The majority of these tumors are infiltrating (fibrillary )
astrocy tomas and often represent lengthy cy stic extensions of relatively more localized
neoplasms, recognizing the solid tumor components may y et involve a significant length of
the spinal cord (325,330,331). Less common glial tumors include oligodendrogliomas and
gangliogliomas. These tumors usually are discrete and well-circumscribed intraspinal lesions
that occur in the cervical, thoracic, or cervicomedullary junction regions. Presenting
characteristics are similar to those of the astrocy tomas (325,332,333).
Page 85Spinal cord tumors represent 5% or less of all ependy momas in children
(324,334). The majority arise in the low thoraco-lumbar region, involving the conus
medullaris or the cauda equina. Most such ependy mal lesions are histologically differentiated
ependy momas, most often grade 1 my xopapillary ependy moma (334). These tumors are
low-grade, indolent lesions signified histologically by papillary growth and mucin formation
(335). Two thirds occur in the cauda equina, presumably arising from the filum; 30% present
as tumors of the conus medullaris and 5% as aty pical my xopapillary tumors of the cervical
or thoracic cord (335) (Fig. 4.16 ). Despite their benign histology and tendency for slow
growth, local recurrence and dissemination superiorly in the spine and sometime brain is not
uncommon, particularly after incomplete resection. As compared to adults, children have
been shown to have a more aggressive disease course with a greater risk of recurrence and
dissemination to other regions of the spine (336). In contrast, ependy momas of the cervical or
thoracic cord tend to be discrete, focal intramedullary lesions (328,337).
Figure 4.16 Myxopa-pillary ependymoma of the cauda equina, documenting extensive
disease that involves the cauda and nerve roots (A); postoperative imaging shows residual
and subarachnoid deposits (B) and (C). Disease controlled at 5 years following surgery and
CSI.
Spinal cord tumors usually present with slowly progressive sy mptoms. The average
duration of sy mptoms in most studies is 2–9 months, but some children report sy mptoms for
y ears prior to diagnosis (320,338,339). The most common sy mptoms include pain and
weakness corresponding to the level of the lesion. Pain is classically greater at night, when the
child is recumbent (331,332). Younger children may present with torticollis or hy potonia
and/or variability of reflexes on examination (339). It is not rare to see lower thoracic cord
pain evaluated as an intra-abdominal process, including by laparotomy for suspected
appendicitis. Numbness or sphincter dy sfunction occurs in 10% of cases (324,325,330).
Sy mptoms and signs of elevated intracranial pressure may be noted at diagnosis of a
primary, localized spinal cord tumor (340).
MRI is the standard imaging mode for assessment of spinal cord neoplasms. One can
usually distinguish intramedullary from extramedullary lesions; tumor extent is generally
well appreciated. It is sometimes difficult to discern subtle cy stic changes from solid tumor
extension; intraoperative ultrasound can be a more sensitive tool in this regard. Fibrillary
astrocy tomas and gangliogliomas usually are nonenhancing tumors, best delineated on T2
sequences. JPAs enhance uniformly. Ependy momas ty pically are enhancing lesions. In
evaluating spinal cord tumors, it is important to image the entire length of the spinal canal; one
can see “skip” intramedullary involvement uncommonly in astrocy tomas. In ependy momas,
it is standard to image the entire neuraxis; rarely, intracranial ependy momas can present
sy mptomatically as a “primary ” intraspinal or cauda equina tumor with an occult
intracranial primary. Subarachnoid dissemination can occur in malignant gliomas and
ependy momas (327,337).
Page 86Therapy
Surgery
The primary management for most intradural spinal tumors is surgery. Current technology
and experience with intramedullary lesions have greatly facilitated gross total resection for a
large percentage of pediatric intraspinal neoplasms. The use of midline my elotomy and
ultrasonic dissection has allowed discrete dissection of intraspinal gliomas. Pediatric
neurosurgeons report low rates of long-term morbidity after judicious complete resection,
often technically approached from just outside the tumor margin, rather than after biopsy
with attendant intralesional swelling or potential hemorrhage (325,326,328,330,333,334,341).
Spinal evoked potentials guide the surgical procedure, allowing intraoperative monitoring to
confirm preservation of long tract function (330,333). Postoperative increased neurologic
deficit is reported to be limited and often transient for tumors above the T9 level; intraspinal
astrocy tomas at the T9–T12 level may be associated with greater postoperative morbidity, in
part due to complexities of the vascular supply in this region (325,326,328,330).
The goal of surgery for spinal cord tumors is to establish a pathologic diagnosis and
perform a complete excision without major compromise of neurologic function; when
complete excision is not possible, maximal safe removal will often relieve sy mptoms with
less compromise postoperatively than biopsy alone. Summary data from 10 earlier studies
combining pediatric and adult experience indicated total excision in 16% of low-grade spinal
gliomas (primarily astrocy toma) (327,330,331,341). For low-grade histologies, Epstein’s New
York experience indicates PFS after surgery alone exceeding 90% at more than 5 y ears in
spinal cord and cervicomedullary junction tumors, data that have been confirmed in smaller
studies (241,324,329,330,334). The high rates of disease control after surgery, with acceptable
morbidity, confirm the role for primary surgical management for low-grade astrocytomas in
experienced neurosurgical centers, most data suggesting a correlation between degree of
resection and outcome (338,342). For incompletely resected tumors, second surgery may be
considered immediately (when anatomically approachable, before postoperative gliosis sets
in) or at relapse when added risks may seem more justified. For high-grade gliomas outcome
is poor regardless of degree of resection, with only anecdotal survival bey ond 3 y ears for
anaplastic astrocy tomas or glioblastomas (324,327,328,329).
For spinal ependy momas, gross total resection has been documented in 25–100% of
cases in series often combining pediatric and adult experience (325,328,335,336,337,343).
My xopapillary ependy momas in children are often amenable to gross total resection.
Although detailed dissection often is necessary for lesions that adhere to numerous nerve
roots comprising the cauda, earlier data from the Roy al Marsden Hospital indicate total
resection in 42% of 24 cases of cauda equina tumors, with 92% PFS at 5 y ears (337). For
lesions of the conus medullaris, the earlier studies indicated resection in only 2 of 14 cases
(337). By contrast, McCormick et al. (343) indicated resection in all 23 children and adults
with intramedullary tumors, only 1 of whom experienced recurrence. A recent study
indicates a higher rate of recurrence in children (64% vs. 32% in adults at a median follow-up
of 6.1 y ears) (336). Surgery alone has been associated with survival rates at 5 y ears of 86–
100% (263,325,333,334,337).
Chemotherapy
Experience using chemotherapy is limited, but small series do report apparent efficacy for
carboplatin and vincristine in low-grade spinal astrocy tomas (344). The combination of
irinotecan and cisplatin was also found to be safe and effective in a small cohort of children
under the age of 3 y ears with progressive disease after administration of carboplatin and
vincristine (345). Currently, there is no clear role for chemotherapy for the treatment of
spinal cord ependy momas. For high-grade tumors of the spinal cord multimodality therapy
including chemotherapy is generally used, but despite aggressive treatment, prognosis is poor
(346).
Radiation Therapy
The use of postoperative irradiation for spinal cord tumors has been controversial and largely
inconsistent. With improved neurosurgical methods, there appears to be no clear benefit from
sy stematic postoperative radiation therapy for low-grade spinal gliomas or ependy momas in
children (325,326,327,334).
The literature documents 50–60% survival rates at 5 y ears after surgery and irradiation
for largely incompletely resected spinal astrocy tomas (324,327,334,347,348). Lacking
comparative data, a rational approach includes maximal surgical resection. For incompletely
resected tumors, one can support observation for low-grade gliomas (especially pilocy tic
histologies, but also other low-grade gliomas in prepubertal children where the risk:benefit
ratio may favor delay ing radiation intervention). Although long-term freedom from
progression has been documented after incomplete surgery alone, postoperative radiation
therapy is generally indicated for sizable residual tumors that are unlikely to be amenable to
later, more complete resection (324,326,334,347,349). If one elects to follow a child with
suspected or definite residual disease, it is important to commit to later second surgery (when
feasible) and irradiation (unless the second surgery results in imaging-confirmed total
resection) with evidence of progressive disease (based on imaging or on changes in
sy mptoms or neurologic signs).
Page 87For spinal cord ependy momas, there is evidence supporting surgery alone for
intramedullary tumors and for initial management of cauda equina tumors
(325,328,333,343,348). The indolent nature of my xopapillary tumors favors observation in
the setting of total resection or minimal residual disease (327,334,337,349). Recurrence rates
after complete resection are relatively low, but disease progression after incomplete resection
for children may be high (327,328,337). In the setting of recurrence or tumor progression,
treatment generally consists of second surgery followed by irradiation. Although the impact
of histologic grade in ependy momas is apparent in adult studies, anaplastic ependy momas of
the spine are uncommon in children; extrapolation from the adult data suggests a role for
postoperative irradiation for such lesions (328,337,347).
Radiotherapeutic Management
Volume
Neuraxis staging is an important component of preirradiation assessment for intramedullary
tumors of all ty pes. When radiation is indicated, local irradiation is used for most spinal cord
tumors. Localized intramedullary astrocy tomas and ependy momas are generally treated to
the tumor bed, based on preoperative and postoperative MRI; a margin of 1–2 cm
longitudinally is indicated for low-grade, focal lesions. For astrocy tomas, one ty pically sees
decompression or obliteration of the rostral and caudal cy stic components after resection of
the solid tumor. In such instances, it appears that radiation therapy can be limited to the solid
tumor bed (327,329,330,334,337,341). For spinal ependy momas, local volumes are also
indicated (327,334,337). For cauda equina tumors, there is some debate regarding the use of
local or craniospinal volumes. Recent studies suggest regional irradiation that includes a 2- to
3-cm margin above the initial tumor volume (ty pically into the conus), and caudal coverage
to include the proximal sacral nerve roots axially and the bottom of the thecal sac
longitudinally (334,335,337). For patients with disseminated low-grade astrocy tomas, the
radiation volume is controversial with some advocating the use of local irradiation and others
recommending inclusion of the entire craniospinal axis (350,351). Age-dependent
consideration of full neuraxis irradiation is indicated when the pattern of involvement is truly
leptomeningeal. Careful consideration of tumor and patient characteristics in these cases is
paramount.
Dosage
The local radiation dose for spinal cord astrocy tomas and other glial histioty pes has ty pically
been reported as 50.4 Gy using daily fractions of 180 cGy. This is based at least as much on
estimated cord tolerance as it is on documentation of dose to achieve local control. Single-
institution and collected studies indicate no apparent dose–response relationship bey ond 50
Gy ; it is difficult to find data differentiating outcome at 50 versus 54 Gy for astrocy tomas
(327,348). For ependy momas, similar analy ses indicate a response at the 45- to 50.4-Gy
level, although recent studies have favored a dose of 50.4 Gy (327,348,349). With current
localization techniques, the use of 50.4–54 Gy at 180 cGy per fraction is considered
acceptable to target volumes discussed above (334). In cases of disseminated disease, 36–
39.6 Gy is common for areas that are not involved with imaging evident disease.
Technique
Current techniques for spinal cord tumors use image-guided definition of the target volume,
with 3D CRT or IMRT or proton radiotherapy approaches to avoid excessive irradiation of the
underly ing viscera, especially the kidney s, lung, or heart. Electrons have also been used.
Protons provide excellent sparing of tissues anterior to the spinal canal or vertebral body and
should decrease rates of acute and long-term toxicities to these anterior organs (Figure
4.6B ). Among the planning parameters should be reasonably homogeneous irradiation of
the vertebral bodies for children who have not reached full height.
Results
OS in spinal cord astrocy tomas is estimated as 80% at 5 y ears and 55% at 10 y ears
(324,329,333). Prognosis is affected by histologic grade and the extent of surgical resection.
For ependy momas, OS is comparable, with recent figures indicating 90% 5-y ear survival.
Outcome depends on the site of origin (with long-term survival rates greater than 90% for
cauda equina tumors and 60% for intramedullary tumors or those arising in the conus
medullaris) (325,326,328,337,349). Patients with complete resection appear to enjoy a
favorable outcome in some studies (326,327,328,337).
Figure:
Intramedullary spinal cord astrocytoma. A: Lesion involving the cervicothoracic cord. B: The
child is free of disease after subtotal resection and irradiation.
Figure:
Myxopa-pillary ependymoma of the cauda equina, documenting extensive disease that
involves the cauda and nerve roots (A); postoperative imaging shows residual and
subarachnoid deposits (B) and (C). Disease controlled at 5 years following surgery and CSI.
REFERENCES
1. Gurney JG, Davis S, Severson RK, et al. Trends in cancer incidence among children in
the U.S. Cancer. 1996;78:532–541.
2. Barnholtz-Sloan JS, Sloan AE, Schwartz AG. Relative survival rates and patterns of
diagnosis analy zed by time period for individuals with primary malignant brain tumor,
1973–1997. J Neurosurg. 2003;99:458–466.
3. McNeil DE, Cote TR, Clegg L, et al. Incidence and trends in pediatric malignancies
medulloblastoma/primitive neuroectodermal tumor: a SEER update—Surveillance
Epidemiology and End Results. Med Pediatr Oncol. 2002;39:190–194.
4. McKean-Cowdin R, Razavi P, et al. Trends in childhood brain tumor incidence, 1973–
2009. J Neurooncol. 2013;115(2):153–160.
5. Cushing H. Experiences with the cerebellar medulloblastomas: a critical review. Acta
Pathol Microbiol Scand. 1930;1:1–86.
6. Bailey J, Cushing H. Medulloblastoma cerebelli, common ty pe of mid-cerebellar glioma
of childhood. Arch Neurol Psy chiatry. 1925;14:192–224.
7. Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours of the Central
Nervous System. 4th ed. Geneva, Switzerland: World Health Organization; 2007.
8. Fan X, Eberhart CG. Medulloblastoma stem cells. J Clin Oncol. 2008;26:2821–2827.
9. Wechsler-Rey a R, Scott MP. The developmental biology of brain tumors. Annu Rev
Neurosci. 2001;24:385–428.
10. Pomeroy SL, Tamay o P, Gaasenbeek M, et al. Prediction of central nervous sy stem
embry onal tumour outcome based on gene expression. Nature. 2002;415:436–442.
11. Burger PC, Grahmann FC, Bliestle A, et al. Differentiation in the medulloblastoma—a
histological and immunohistochemical study. Acta Neuropathol. 1987;73:115–123.
12. Rubin JB, Rowitch DH. Medulloblastoma: a problem of developmental biology. Cancer
Cell. 2002;2:7–8.
13. Gilbertson RJ. Medulloblastoma: signalling a change in treatment. Lancet Oncol.
2004;5:209–218.
14. Page 88 de Bont JM, Packer RJ, Michiels EM, et al. Biological background of pediatric
medulloblastoma and ependy moma: a review from a translational research perspective.
Neuro Oncol. 2008;10:1040–1060.
15. Lamont JM, McManamy CS, Pearson AD, et al. Combined histopathological and
molecular cy togenetic stratification of medulloblastoma patients. Clin Cancer Res.
2004;10:5482–5493.
16. Brown HG, Kepner JL, Perlman EJ, et al. “Large cell/anaplastic” medulloblastomas: a
Pediatric Oncology Group study. J Neuropathol Exp Neurol. 2000;59:857–865.
17. Eberhart CG, Kepner JL, Goldthwaite PT, et al. Histopathologic grading of
medulloblastomas: a Pediatric Oncology Group study. Cancer. 2002;94:552–560.
18. Garre ML, Cama A, Bagnasco F, et al. Medulloblastoma variants: age-dependent
occurrence and relation to Gorlin sy ndrome—a new clinical perspective. Clin Cancer
Res. 2009;15:2463–2471.
19. Gajjar A, Bowers DC, Karajannis MA, et al. Pediatric brain tumors: innovative genomic
information is transforming the diagnostic and clinical landscape. J Clin Oncol.
2015;33(27):2986–2998.
20. Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy
followed by high-dose chemotherapy and stem-cell rescue in children with newly
diagnosed medulloblastoma (St. Jude Medulloblastoma-96): long-term results from a
prospective, multicentre trial. Lancet Oncol. 2006;7:813–820.
21. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: an
international meta-analy sis of transcriptome, genetic aberrations, and clinical data of
WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol.
2012;123(4):473–484.
22. Northcott PA, Korshunov A, Pfister SM, et al. The clinical implications of
medulloblastoma subgroups. Nat Rev Neurol. 2012;8(6):340–351.
23. Northcott PA, Shih DJ, Peacock J, et al. Subgroup-specific structural variation across
1,000 medulloblastoma genomes. Nature. 2012;488(7409):49–56.
24. Northcott PA, Shih DJ, Remke M, et al. Rapid, reliable, and reproducible molecular sub-
grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123(4):615–626.
25. Tay lor MD, Northcott PA, et al. Molecular subgroups of medulloblastoma: the current
consensus. Acta Neuropathol. 2012;123(4):465–472.
26. Shih DJ, Northcott PA, Remke M, et al. Cy togenetic prognostication within
medulloblastoma subgroups. J Clin Oncol. 2014;32(9):886–896.
27. Amlashi SF, Riffaud L, Brassier G, et al. Nevoid basal cell carcinoma sy ndrome: relation
with desmoplastic medulloblastoma in infancy —a population-based study and review of
the literature. Cancer. 2003;98:618–624.
28. Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by
hedgehog pathway blockade. Science. 2002;297:1559–1561.
29. Ellison DW, Onilude OE, Lindsey JC, et al. Beta-catenin status predicts a favorable
outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study
Group Brain Tumour Committee. J Clin Oncol. 2005;23:7951–7957.
30. Clifford SC, Lusher ME, Lindsey JC, et al. Wnt/Wingless pathway activation and
chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas
associated with a favorable prognosis. Cell Cycle. 2006;5:2666–2670.
31. Gilbertson R. Paediatric embry onic brain tumours: biological and clinical relevance of
molecular genetic abnormalities. Eur J Cancer. 2002;38:675–685.
32. Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy
before radiotherapy as compared to immediate radiotherapy followed by maintenance
chemotherapy in the treatment of medulloblastoma in childhood: results of the German
prospective randomized trial HIT’91. Int J Radiat Oncol Biol Phys. 2000;46:269–279.
33. Fouladi M, Gajjar A, Boy ett JM, et al. Comparison of CSF cy tology and spinal magnetic
resonance imaging in the detection of leptomeningeal disease in pediatric
medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol. 1999;17:3234–3237.
34. Helton KJ, Gajjar A, Hill DA, et al. Medulloblastoma metastatic to the suprasellar region
at diagnosis: a report of six cases with clinicopathologic correlation. Pediatr Neurosurg.
2002;37:111–117.
35. Chang CH, Housepian EM, Herbert C Jr. An operative staging sy stem and a megavoltage
radiotherapeutic technic for cerebellar medulloblastomas. Radiology. 1969;93:1351–
1359.
36. Thomas PR, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: final analy sis of
trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol.
2000;18:3004–3011.
37. Zeltzer PM, Boy ett JM, Finlay JL, et al. Metastasis stage, adjuvant treatment, and
residual tumor are prognostic factors for medulloblastoma in children: conclusions from
the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol. 1999;17:832–
845.
38. Albright AL, Wisoff JH, Zeltzer PM, et al. Effects of medulloblastoma resections on
outcome in children: a report from the Children’s Cancer Group. Neurosurgery.
1996;38:265–271.
39. Packer RJ, Sutton LN, Elterman R, et al. Outcome for children with medulloblastoma
treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg.
1994;81:690–698.
40. Bailey CC, Gnekow A, Wellek S, et al. Prospective randomised trial of chemotherapy
given before radiotherapy in childhood medulloblastoma—International Society of
Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO):
SIOP II. Med Pediatr Oncol. 1995;25:166–178.
41. Packer RJ, Rood BR, MacDonald TJ. Medulloblastoma: present concepts of stratification
into risk groups. Pediatr Neurosurg. 2003;39:60–67.
42. Sanders RP, Onar A, Boy ett JM, et al. M1 Medulloblastoma: high risk at any age. J
Neurooncol. 2008;90:351–355.
43. Bourne JP, Gey er R, Berger M, et al. The prognostic significance of postoperative
residual contrast enhancement on CT scan in pediatric patients with medulloblastoma. J
Neurooncol. 1992;14:263–270.
44. Gajjar A, Sanford RA, Bhargava R, et al. Medulloblastoma with brain stem involvement:
the impact of gross total resection on outcome. Pediatr Neurosurg. 1996;25:182–187.
45. Douglas JG, Barker JL, Ellenbogen RG, et al. Concurrent chemotherapy and reduced-
dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for
average-risk medulloblastoma: efficacy and patterns of failure. Int J Radiat Oncol Biol
Phys. 2004;58:1161–1164.
46. Tay lor RE, Bailey CC, Robinson KJ, et al. Outcome for patients with metastatic (M2-3)
medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer.
2005;41:727–734.
47. von HK, Hinkes B, Gerber NU, et al. Long-term outcome and clinical prognostic factors
in children with medulloblastoma treated in the prospective randomised multicentre trial
HIT’91. Eur J Cancer. 2009;45:1209–1217.
48. Aguiar PH, Plese JP, Ciquini O, et al. Transient mutism following a posterior fossa
approach to cerebellar tumors in children: a critical review of the literature. Childs Nerv
Syst. 1995;11:306–310.
49. Cochrane DD, Gustavsson B, Poskitt KP, et al. The surgical and natural morbidity of
aggressive resection for posterior fossa tumors in childhood. Pediatr Neurosurg.
1994;20:19–29.
50. Eberhart CG, Cohen KJ, Tihan T, et al. Medulloblastomas with sy stemic metastases:
evaluation of tumor histopathology and clinical behavior in 23 patients. J Pediatr
Hematol Oncol. 2003;25:198–203.
51. Miller NG, Reddick WE, Kocak M, et al. Cerebellocerebral diaschisis is the likely
mechanism of postsurgical posterior fossa sy ndrome in pediatric patients with midline
cerebellar tumors. Am J Neuroradiol. 2010;31;288–294.
52. Korah MP, Esiashvili N, Mazewski CM, et al. Incidence, risks, and sequelae of posterior
fossa sy ndrome in pediatric medulloblastoma. Int J Radiat Oncol Biol Phys.
2010;77(1):106–112.
53. Souweidane MM. Posterior fossa sy ndrome. J Neurosurg Pediatr. 2010;5(4):325–326;
discussion 326–328.
54. Avula S, Mallucci C, Kumar R, et al. Posterior fossa sy ndrome following brain tumour
resection: review of pathophy siology and a new hy pothesis on its pathogenesis. Childs
Nerv Syst. 2015;31(10):1859–1867.
55. Oy harcabal-Bourden V, Kalifa C, Gentet JC, et al. Standard-risk medulloblastoma
treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation
therapy : a French Society of Pediatric Oncology Study. J Clin Oncol. 2005;23:4726–
4734.
56. Page 89 Grill J, Lellouch-Tubiana A, Elouahdani S, et al. Preoperative chemotherapy in
children with high-risk medulloblastomas: a feasibility study. J Neurosurg. 2005;103:312–
318.
57. Cutler EC, Sosman MC, Vaughan WW. Place of radiation in treatment of cerebellar
medulloblastoma: report of 20 cases. Am J Roentgenol Radium Ther Nucl Med.
1936;35:429–453.
58. Bloom HJG, Glees J, Bell J. The treatment and prognosis of medulloblastoma in children.
AJR Am J Roentgenol. 1969;105:43–62.
59. Carrie C, Grill J, Figarella-Branger D, et al. Online quality control, hy perfractionated
radiotherapy alone and reduced boost volume for standard risk medulloblastoma: long-
term results of MSFOP 98. J Clin Oncol. 2009;27:1879–1883.
60. Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with
medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant
chemotherapy : a Children’s Cancer Group Study. J Clin Oncol. 1999;17:2127–2136.
61. Merchant TE, Kun LE, Krasin MJ, et al. Multi-institution prospective trial of reduced-
dose craniospinal irradiation (23.4 Gy ) followed by conformal posterior fossa (36 Gy )
and primary site irradiation (55.8 Gy ) and dose-intensive chemotherapy for average-
risk medulloblastoma. Int J Radiat Oncol Biol Phys. 2008;70:782–787.
62. Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy
followed by adjuvant chemotherapy for newly diagnosed average-risk
medulloblastoma. J Clin Oncol. 2006;24:4202–4208.
63. Tay lor RE, Bailey CC, Robinson KJ, et al. Impact of radiotherapy parameters on
outcome in the International Society of Paediatric Oncology /United Kingdom Children’s
Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0–M1
medulloblastoma. Int J Radiat Oncol Biol Phys. 2004;58:1184–1193.
64. Mulhern RK, Merchant TE, Gajjar A, et al. Late neurocognitive sequelae in survivors of
brain tumours in childhood. Lancet Oncol. 2004;5:399–408.
65. Merchant TE, Kiehna EN, Li C, et al. Modeling radiation dosimetry to predict cognitive
outcomes in pediatric patients with CNS embry onal tumors including medulloblastoma.
Int J Radiat Oncol Biol Phys. 2006;65:210–221.
66. Breen SL, Kehagioglou P, Usher C, et al. A comparison of conventional, conformal and
intensity -modulated coplanar radiotherapy plans for posterior fossa treatment. Br J
Radiol. 2004;77:768–774.
67. Allen J, Donahue B, Mehta M, et al. A phase II study of preradiotherapy chemotherapy
followed by hy perfractionated radiotherapy for newly diagnosed high-risk
medulloblastoma/primitive neuroectodermal tumor: a report from the Children’s
Oncology Group (CCG 9931). Int J Radiat Oncol Biol Phys. 2009;74:1006–1011.
68. Heideman RL, Kovnar EH, Kellie SJ, et al. Preirradiation chemotherapy with
carboplatin and etoposide in newly diagnosed embry onal pediatric CNS tumors. J Clin
Oncol. 1995;13:2247–2254.
69. Kovnar EH, Kellie SJ, Horowitz ME, et al. Preirradiation cisplatin and etoposide in the
treatment of high-risk medulloblastoma and other malignant embry onal tumors of the
central nervous sy stem: a phase II study. J Clin Oncol. 1990;8:330–336.
70. Mastrangelo R, Lasorella A, Riccardi R, et al. Carboplatin in childhood
medulloblastoma/PNET: feasibility of an in vivo sensitivity test in an “up-front” study.
Med Pediatr Oncol. 1995;24:188–196.
71. Stewart CF, Iacono LC, Chintagumpala M, et al. Results of a phase II upfront window of
pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial
primitive neuroectodermal tumor. J Clin Oncol. 2004;22:3357–3365.
72. Fouladi M, Chintagumpala M, Ashley D, et al. Amifostine protects against cisplatin-
induced ototoxicity in children with average-risk medulloblastoma. J Clin Oncol.
2008;26:3749–3755.
73. Jakacki RI, Feldman H, Jamison C, et al. A pilot study of preirradiation chemotherapy
and 1800 cGy craniospinal irradiation in y oung children with medulloblastoma. Int J
Radiat Oncol Biol Phys. 2004;60:531–536.
74. Gandola L, Massimino M, Cefalo G, et al. Hy perfractionated accelerated radiotherapy
in the Milan strategy for metastatic medulloblastoma. J Clin Oncol. 2009;27:566–571.
75. Tarbell NJ, Friedman HS, Yock TI, et al. High-Risk Medulloblastoma: A Pediatric
Oncology Group (POG 9031) Randomized Trial of Chemotherapy before or after
Radiation Therapy, J Clin Oncol. 2013;31(23):2936–41.
76. Shih CS, Hale GA, Gronewold L, et al. High-dose chemotherapy with autologous stem
cell rescue for children with recurrent malignant brain tumors. Cancer. 2008;112:1345–
1353.
77. Butturini AM, Jacob M, Aguajo J, et al. High-dose chemotherapy and autologous
hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and
supratentorial primitive neuroectodermal tumors: the impact of prior radiotherapy on
outcome. Cancer. 2009;115:2956–2963.
78. Massimino M, Gandola L, Spreafico F, et al. No salvage using high-dose chemotherapy
plus/minus reirradiation for relapsing previously irradiated medulloblastoma. Int J Radiat
Oncol Biol Phys. 2009;73:1358–1363.
79. Gururangan S, Krauser J, Watral MA, et al. Efficacy of high-dose chemotherapy or
standard salvage therapy in patients with recurrent medulloblastoma. Neuro Oncol.
2008;10:745–751.
80. Gajjar A. High-dose chemotherapy for recurrent medulloblastoma: time for a
reappraisal. Cancer. 2008;112:1643–1645.
81. Saran F, Baumert BG, Creak AL, et al. Hy pofractionated stereotactic radiotherapy in the
management of recurrent or residual medulloblastoma/PNET. Pediatr Blood Cancer.
2008;50:554–560.
82. Kramer K, Humm JL, Souweidane MM, et al. Phase I study of targeted
radioimmunotherapy for leptomeningeal cancers using intra-Ommay a 131-I-3F8. J Clin
Oncol. 2007;25:5465–5470.
83. Landberg TG, Lindgren ML, Cavallin-Stahl EK, et al. Improvements in the radiotherapy
of medulloblastoma, 1946–1975. Cancer. 1980;45:670–678.
84. Wara WM, Le QT, Sneed PK, et al. Pattern of recurrence of medulloblastoma after low-
dose craniospinal radiotherapy. Int J Radiat Oncol Biol Phys. 1994;30:551–556.
85. Sun LM, Yeh SA, Wang CJ, et al. Postoperative radiation therapy for medulloblastoma—
high recurrence rate in the subfrontal region. J Neurooncol. 2002;58:77–85.
86. Gripp S, Kambergs J, Wittkamp M, et al. Coverage of anterior fossa in whole-brain
irradiation. Int J Radiat Oncol Biol Phys. 2004;59:515–520.
87. Donnal J, Halperin EC, Friedman HS, et al. Subfrontal recurrence of medulloblastoma.
Am J Neuroradiol. 1992;13:1617–1618.
88. Wolden SL, Dunkel IJ, Souweidane MM, et al. Patterns of failure using a conformal
radiation therapy tumor bed boost for medulloblastoma. J Clin Oncol. 2003;21:3079–
3083.
89. Kimura H, Ng JM, Curran T. Transient inhibition of the Hedgehog pathway in y oung
mice causes permanent defects in bone structure. Cancer Cell. 2008;13:249–260.
90. Carrie C, Muracciole X, Gomez F, et al. Conformal radiotherapy, reduced boost volume,
hy perfractionated radiotherapy, and online quality control in standard-risk
medulloblastoma without chemotherapy : results of the French M-SFOP 98 protocol. Int J
Radiat Oncol Biol Phys. 2005;63:711–716.
91. Merchant TE, Happersett L, Finlay JL, et al. Preliminary results of conformal radiation
therapy for medulloblastoma. Neurooncol. 1999;1:177–187.
92. Williams GB, Kun LE, Thompson JW, et al. Hearing loss as a late complication of
radiotherapy in children with brain tumors. Ann Otol Rhinol Laryngol. 2005;114:328–331.
93. Hua C, Bass JK, Khan R, et al. Hearing loss after radiotherapy for pediatric brain
tumors: effect of cochlear dose. Int J Radiat Oncol Biol Phys. 2008;72:892–899.
94. Merchant TE, Gould CJ, Xiong X, et al. Early neuro-otologic effects of three-
dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol Biol
Phys. 2004;58:1194–1207.
95. Fukunaga-Johnson N, Lee JH, Sandler HM, et al. Patterns of failure following treatment
for medulloblastoma: is it necessary to treat the entire posterior fossa? Int J Radiat Oncol
Biol Phys. 1998;42:143–146.
96. Miralbell R, Bleher A, Huguenin P, et al. Pediatric medulloblastoma: radiation treatment
technique and patterns of failure. Int J Radiat Oncol Biol Phys. 1997;37:523–529.
97. Merchant TE, Wang MH, Haida T, et al. Medulloblastoma: long-term results for patients
treated with definitive radiation therapy during the computed tomography era. Int J
Radiat Oncol Biol Phys. 1996;36:29–35.
98. Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines is correlated with
radioresponsiveness of human tumors: analy sis of 101 published survival curves. Int J
Radiat Oncol Biol Phys. 1985;11:1699–1707.
99. Page 90 Jenkin D, Goddard K, Armstrong D, et al. Posterior fossa medulloblastoma in
childhood: treatment results and a proposal for a new staging sy stem. Int J Radiat Oncol
Biol Phys. 1990;19:265–274.
100. Goldwein JW, Radcliffe J, Johnson J, et al. Updated results of a pilot study of low dose
craniospinal irradiation plus chemotherapy for children under five with cerebellar
primitive neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol Biol Phys.
1996;34:899–904.
101. Hudes RS, Gajjar A, Heideman RL, et al. High dose hy perfractionated craniospinal
irradiation (HF-CSI): feasibility, acute toxicity, outcome and late sequelae. Proceedings
of the 40th Annual ASTRO Meeting, 1999;185.
102. Prados MD, Wara WM, Edwards MS, et al. Hy per-fractionated craniospinal radiation
therapy for primitive neuroectodermal tumors: early results of a pilot study. Int J Radiat
Oncol Biol Phys. 1994;28:431–438.
103. Tatcher M, Glicksman AS. Field matching considerations in craniospinal irradiation. Int J
Radiat Oncol Biol Phys. 1989;17:865–869.
104. Mah K, Danjoux CE, Manship S, et al. Computed tomographic simulation of craniospinal
fields in pediatric patients: improved treatment accuracy and patient comfort. Int J
Radiat Oncol Biol Phys. 1998;41:997–1003.
105. Parker WA, Freeman CR. A simple technique for craniospinal radiotherapy in the supine
position. Radiother Oncol. 2006;78:217–222.
106. South M, Chiu JK, Teh BS, et al. Supine craniospinal irradiation using intrafractional
junction shifts and field-in-field dose shaping: early experience at Methodist Hospital. Int
J Radiat Oncol Biol Phys. 2008;71:477–483.
107. Christ G, Denninger D, Dohm OS, et al. Craniospinal radiotherapy in an advanced
technique. Strahlenther Onkol. 2008;184:530–535.
108. Dunbar SF, Barnes PD, Tarbell NJ. Radiologic determination of the caudal border of the
spinal field in cranial spinal irradiation. Int J Radiat Oncol Biol Phys. 1993;26:669–673.
109. Halperin EC. Concerning the inferior portion of the spinal radiotherapy field for
malignancies that disseminate via the cerebrospinal fluid. Int J Radiat Oncol Biol Phys.
1993;26:357–362.
110. Parker W, Filion E, Roberge D, et al. Intensity -modulated radiotherapy for craniospinal
irradiation: target volume considerations, dose constraints, and competing risks. Int J
Radiat Oncol Biol Phys. 2007;69:251–257.
111. Wilson VC, McDonough J, Tochner Z. Proton beam irradiation in pediatric oncology : an
overview. J Pediatr Hematol Oncol. 2005;27:444–448.
112. Yock TI, Tarbell NJ. Technology insight: proton beam radiotherapy for treatment in
pediatric brain tumors. Nat Clin Pract Oncol. 2004;1:97–103.
113. Mu X, Bjork-Eriksson T, Nill S, et al. Does electron and proton therapy reduce the risk of
radiation induced cancer after spinal irradiation for childhood medulloblastoma?—a
comparative treatment planning study. Acta Oncol. 2005;44:554–562.
114. St Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional
X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat
Oncol Biol Phys. 2004;58:727–734.
115. Timmermann B, Lomax AJ, Nobile L, et al. Novel technique of craniospinal axis proton
therapy with the spot-scanning sy stem: avoidance of patching multiple fields and
optimized ventral dose distribution. Strahlenther Onkol. 2007;183:685–688.
116. Yom SS, Frija EK, Mahajan A, et al. Field-in-field technique with intrafractionally
modulated junction shifts for craniospinal irradiation. Int J Radiat Oncol Biol Phys.
2007;69:1193–1198.
117. Kiltie AE, Povall JM, Tay lor RE. The need for the moving junction in craniospinal
irradiation. Br J Radiol. 2000;73:650–654.
118. Sterzing F, Schubert K, Sroka-Perez G, et al. Helical tomotherapy —experiences of the
first 150 patients in Heidelberg. Strahlenther Onkol. 2008;184:8–14.
119. Cochran DM, Yock TI, Adams JA, et al. Radiation dose to the lens during craniospinal
irradiation—an improvement in proton radiotherapy technique. Int J Radiat Oncol Biol
Phys. 2008;70:1336–1342.
120. Huang E, Teh BS, Strother DR, et al. Intensity -modulated radiation therapy for pediatric
medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol
Phys. 2002;52:599–605.
121. Lee CT, Bilton SD, Famiglietti RM, et al. Treatment planning with protons for pediatric
retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with
other conformal techniques? Int J Radiat Oncol Biol Phys. 2005;63:362–372.
122. Paulino AC, Wen BC, May r NA, et al. Protracted radiotherapy treatment duration in
medulloblastoma. Am J Clin Oncol. 2003;26:55–59.
123. del Charco JO, Bolek TW, McCollough WM, et al. Medul-loblastoma: time-dose
relationship based on a 30-y ear review. Int J Radiat Oncol Biol Phys. 1998;42:147–154.
124. Carrie C, Alapetite C, Mere P, et al. Quality control of radiotherapeutic treatment of
medulloblastoma in a multicentric study : the contribution of radiotherapy technique to
tumour relapse. The French Medulloblastoma Group. Radiother Oncol. 1992;24:77–81.
125. Marks LB, Halperin EC. The use of G-CSF during craniospinal irradiation. Int J Radiat
Oncol Biol Phys. 1993;26:905–906.
126. Childhood Brain Tumor Consortium. Supplement Report: Primary Brain Tumors in the
United States, 2004. Hinsdale, IL: Central Brain Tumor Registry of the United States,
2008.
127. Larouche V, Huang A, Bartels U, et al. Tumors of the central nervous sy stem in the first
y ear of life. Pediatr Blood Cancer. 2007;49:1074–1082.
128. Duffner PK, Horowitz ME, Krischer JP, et al. The treatment of malignant brain tumors
in infants and very y oung children: an update of the Pediatric Oncology Group
experience. Neuro Oncol. 1999;1:152–161.
129. Bloom HJ, Glees J, Bell J, et al. The treatment and long-term prognosis of children with
intracranial tumors: a study of 610 cases, 1950–1981. Int J Radiat Oncol Biol Phys.
1990;18:723–745.
130. Cohen BH, Packer RJ, Siegel KR, et al. Brain tumors in children under 2 y ears:
treatment, survival and long-term prognosis. Pediatr Neurosurg. 1993;19:171–179.
131. Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delay ed
radiation in children less than three y ears of age with malignant brain tumors. N Engl J
Med. 1993;328:1725–1731.
132. Mey ers SP, Khademian ZP, Biegel JA, et al. Primary intracranial aty pical
teratoid/rhabdoid tumors of infancy and childhood: MRI features and patient outcomes.
AJNR Am J Neuroradiol. 2006;27:962–971.
133. Packer RJ, Biegel JA, Blaney S, et al. Aty pical teratoid/rhabdoid tumor of the central
nervous sy stem: report on workshop. J Pediatr Hematol Oncol. 2002;24:337–342.
134. Taratuto AL, Monges J, Ly ly k P, et al. Superficial cerebral astrocy toma attached to dura
—report of six cases in infants. Cancer. 1984;54:2505–2512.
135. Lonnrot K, Terho M, Kahara V, et al. Desmoplastic infantile ganglioglioma: novel
aspects in clinical presentation and genetics. Surg Neurol. 2007;68:304–308.
136. Jenkin D, Greenberg M, Hoffman H, et al. Brain tumors in children: long-term survival
after radiation treatment. Int J Radiat Oncol Biol Phys. 1995;31:445–451.
137. Tekautz TM, Fuller CE, Blaney S, et al. Aty pical teratoid/ rhabdoid tumors (AT/RT):
improved survival in children 3 y ears of age and older with radiation therapy and high-
dose alky lator-based chemotherapy. J Clin Oncol. 2005;23:1491–1499.
138. Wisoff JH, Boy ett JM, Berger MS, et al. Current neurosurgical management and the
impact of the extent of resection in the treatment of malignant gliomas of childhood: a
report of the Children’s Cancer Group trial no. CCG-945. J Neurosurg. 1998;89:52–59.
139. Albright AL, Wisoff JH, Zeltzer PM, et al. Current neurosurgical treatment of
medulloblastoma in children. Pediatr Neurosurg. 1989;177:633–641.
140. Walter AW, Mulhern RK, Gajjar A, et al. Survival and neurodevelopmental outcome of
y oung children with medulloblastoma at St. Jude Children’s Research Hospital. J Clin
Oncol. 1999;17:3720–3728.
141. Duffner PK, Krischer JP, Burger PC, et al. Treatment of infants with malignant gliomas:
the Pediatric Oncology Group experience. J Neuro Oncol. 1996;28:245–256.
142. Dufour C, Grill J, Lellouch-Tubiana A, et al. High-grade glioma in children under 5
y ears of age: a chemotherapy only approach with the BBSFOP protocol. Eur J Cancer.
2006;42:2939–2945.
143. Page 91 Frappaz D. High-grade gliomas: babies are not small adults! Pediatr Blood
Cancer. 2007;49:879–880.
144. Sanders RP, Kocak M, Burger PC, et al. High-grade astrocy toma in very y oung children.
Pediatr Blood Cancer. 2007;49:888–893.
145. Jakacki RI, Zeltzer PM, Boy ett JM, et al. Survival and prognostic factors following
radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal
region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol.
1995;13:1377–1383.
146. Gey er JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred
radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer
Group. J Clin Oncol. 2005;23:7621–7231.
147. Grill J, Sainte-Rose C, Jouvet A, et al. Treatment of medulloblastoma with postoperative
chemotherapy alone: an SFOP prospective trial in y oung children. Lancet Oncol.
2005;6:573–580.
148. Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood medulloblastoma by
postoperative chemotherapy alone. N Engl J Med. 2005;352:978–986.
149. Dhall G, Grodman H, Ji L, et al. Outcome of children less than three y ears old at
diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head
Start” I and II protocols. Pediatr Blood Cancer. 2008;50:1169–1175.
150. Fouladi M, Gururangan S, Moghrabi A, et al. Carboplatin-based primary chemotherapy
for infants and y oung children with CNS tumors. Cancer. 2009;115:3243–3253.
151. Grundy RG, Wilne SA, Weston CL, et al. Primary postoperative chemotherapy without
radiotherapy for intracranial ependy moma in children: the UKCCSG/SIOP prospective
study. Lancet Oncol. 2007;8:696–705.
152. Shim KW, Kim DS, Choi JU. The history of ependy moma management. Childs Nerv
Syst. 2009;25:1167–1183.
153. Massimino M, Giangaspero F, Garre ML, et al. Salvage treatment for childhood
ependy moma after surgery only : pitfalls of omitting “at once” adjuvant treatment. Int J
Radiat Oncol Biol Phys. 2006;65:1440–1445.
154. Qian X, Goumnerova LC, De GU, et al. Cerebrospinal fluid cy tology in patients with
ependy moma: a bi-institutional retrospective study. Cancer. 2008;114:307–314.
155. Gey er J, Zelter P, Boy ett J, et al. Survival of infants with primitive neuroectodermal
tumors or malignant ependy momas of the CNS treated with eight drugs in 1 day : a
report from the Children’s Cancer Group. J Clin Oncol. 1994;12:1607–1615.
156. Rutkowski S, Gerber NU, von HK, et al. Treatment of early childhood medulloblastoma
by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol. 2009;11:201–
210.
157. Hong TS, Mehta MP, Boy ett JM, et al. Patterns of treatment failure in infants with
primitive neuroectodermal tumors who were treated on CCG-921: a phase III combined
modality study. Pediatr Blood Cancer. 2005;45:676–682.
158. Ridola V, Grill J, Doz F, et al. High-dose chemotherapy with autologous stem cell rescue
followed by posterior fossa irradiation for local medulloblastoma recurrence or
progression after conventional chemotherapy. Cancer. 2007;110:156–163.
159. Blaney SM, Kocak M, Gajjar A, et al. Pilot study of sy stemic and intrathecal
mafosfamide followed by conformal radiation for infants with intracranial central
nervous sy stem tumors: a pediatric brain tumor consortium study (PBTC-001). J
Neurooncol. 2012;109(3):565–571.
160. Rorke LB, Packer RJ, Biegel JA. Central nervous sy stem aty pical teratoid/rhabdoid
tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996;85:56–65.
161. Squire SE, Chan MD, Marcus KJ. Aty pical teratoid/rhabdoid tumor: the controversy
behind radiation therapy. J Neurooncol. 2007;81:97–111.
162. Biegel JA, Fogelgren B, Zhou JY, et al. Mutations of the INI1 rhabdoid tumor suppressor
gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous
sy stem. Clin Cancer Res. 2000;6:2759–2763.
163. Biegel JA, Kalpana G, Knudsen ES, et al. The role of INI1 and the SWI/SNF complex in
the development of rhabdoid tumors: meeting summary from the workshop on childhood
aty pical teratoid/rhabdoid tumors. Cancer Res. 2002;62:323–328.
164. Burger PC, Yu IT, Tihan T, et al. Aty pical teratoid/rhabdoid tumor of the central nervous
sy stem: a highly malignant tumor of infancy and childhood frequently mistaken for
medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol. 1998;22:1083–
1092.
165. Buscariollo DL, Park HS, Roberts KB, et al. Survival outcomes in aty pical teratoid
rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology,
and End Results analy sis. Cancer. 2012;118(17):4212–4219.
166. Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children
with newly diagnosed CNS aty pical teratoid rhabdoid tumor. J Clin Oncol. 2009;27:385–
389.
167. Slavc I, Chocholous M, Leiss U, et al. Aty pical teratoid rhabdoid tumor: improved long-
term survival with an intensive multimodal therapy and delay ed radiotherapy —The
Medical University of Vienna Experience 1992–2012. Cancer Med. 2014;3(1):91–100.
168. Duffner PK, Kun LE, Burger PC, et al. Postoperative chemotherapy and delay ed
radiation in infants and very y oung children with choroid plexus carcinomas—the
Pediatric Oncology Group. Pediatr Neurosurg. 1995;22:189–196.
169. Krishnan S, Brown PD, Scheithauer BW, et al. Choroid plexus papillomas: a single
institutional experience. J Neurooncol. 2004;68:49–55.
170. Jeibmann A, Wrede B, Peters O, et al. Malignant progression in choroid plexus
papillomas. J Neurosurg. 2007;107:199–202.
171. Bahar M, Kordes U, Tekautz T, et al. Radiation therapy for choroid plexus carcinoma
patients with Li–Fraumeni sy ndrome: advantageous or detrimental? Anticancer Res.
2015;35(5):3013–3017.
172. Ater JL, van Ey s J, Woo SY, et al. MOPP chemotherapy without irradiation as primary
postsurgical therapy for brain tumors in infants and y oung children. J Neurooncol.
1997;32:243–252.
173. Strother D, Kepner J, Aronin P, et al. Dose-intensive (DI) chemotherapy (CT) prolongs
event-free survival (EFS) for very y oung children with ependy moma (EP)—results of
Pediatric Oncology Group (POG) study 9233. Proc Am Soc Clin Oncol. 2000;19:585a
(abstract 2302).
174. Cohen BH, Gey er JR, Miller DC, et al.. Pilot study of intensive chemotherapy with
peripheral hematopoietic cell support for children less than 3 y ears of age with
malignant brain tumors, the CCG-99703 Phase I/II Study —a report from the Children’s
Oncology Group. Pediatr Neurol. 2015;53(1):31–46.
175. Blaney SM, Boy ett J, Friedman H, et al. Phase I clinical trial of mafosfamide in infants
and children aged 3 y ears or y ounger with newly diagnosed embry onal tumors: a
pediatric brain tumor consortium study (PBTC-001). J Clin Oncol. 2005;23:525–531.
176. Blaney SM, Tagen M, Onar-Thomas A, et al. A phase-1 pharmacokinetic optimal dosing
study of intraventricular topotecan for children with neoplastic meningitis: a Pediatric
Brain Tumor Consortium study. Pediatr Blood Cancer. 2013;60(4):627–632.
177. Murphy ES, Merchant TE, Wu S, et al. Necrosis after craniospinal irradiation: results
from a prospective series of children with central nervous sy stem embry onal tumors. Int
J Radiat Oncol Biol Phys. 2012;83(5):e655–e660.
178. Indelicato DJ, Flampouri S, Rotondo RL, et al. Incidence and dosimetric parameters of
pediatric brainstem toxicity following proton therapy. Acta Oncol. 2014;53(10):1298–
1304.
179. McGovern SL, Okcu MF, Munsell MF, et al. Outcomes and acute toxicities of proton
therapy for pediatric aty pical teratoid/rhabdoid tumor of the central nervous sy stem. Int
J Radiat Oncol Biol Phys. 2014;90(5):1143–1152.
180. Yock TI, Constine LS, Mahajan A. Protons, the brainstem, and toxicity : ingredients for an
emerging dialectic. Acta Oncol. 2014;53(1z0):1279–1282.
181. Gunther JR, Sato M, Chintagumpala M, et al. Imaging changes in pediatric intracranial
ependy moma patients treated with proton beam radiation therapy compared to intensity
modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(1):54–63.
182. Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common
pediatric brain tumors: comparison of models of dose characteristics and their
relationship to cognitive function. Pediatr Blood Cancer. 2008;51:110–117.
183. Dupuis-Girod S, Hartmann O, Benhamou E, et al. Will high dose chemotherapy
followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in
y oung children treated for medulloblastoma? J Neurooncol. 1996;27:87–98.
184. Duffner PK, Cohen ME, Sanford RA, et al. Lack of efficacy of postoperative
chemotherapy and delay ed radiation in very y oung children with pineoblastoma—
Pediatric Oncology Group. Med Pediatr Oncol. 1995;25:38–44
185. Page 92 Nazar GB, Hoffman HJ, Becker LE, et al. Infratentorial ependy momas in
childhood: prognostic factors and treatment. J Neurosurg. 1990;72:408–417.
186. Veelen-Vincent ML, Pierre-Kahn A, Kalifa C, et al. Ependy moma in childhood:
prognostic factors, extent of surgery, and adjuvant therapy. J Neurosurg. 2002;97:827–
835.
187. Mack SC, Tay lor MD. The genetic and epigenetic basis of ependy moma. Childs Nerv
Syst. 2009;25:1195–1201.
188. Merchant TE, Fouladi M. Ependy moma: new therapeutic approaches including radiation
and chemotherapy. J Neurooncol. 2005;75:287–299.
189. Sanford RA, Merchant TE, Zwienenberg-Lee M, et al. Advances in surgical techniques
for resection of childhood cerebellopontine angle ependy momas are key to survival.
Childs Nerv Syst. 2009;25:1229–1240.
190. Yuh EL, Barkovich AJ, Gupta N. Imaging of ependy momas: MRI and CT. Childs Nerv
Syst. 2009;25:1203–1213.
191. Chakraborty A, Harkness W, Phipps K. Surgical management of supratentorial
ependy momas. Childs Nerv Syst. 2009;25:1215–1220.
192. Godfraind C. Classification and controversies in pathology of ependy momas. Childs
Nerv Syst. 2009;25:1185–1193.
193. Tay lor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of
ependy moma. Cancer Cell. 2005;8:323–335.
194. Ferri Niguez B, Martinez-Lage JF, Almagro MJ, et al. Embry onal tumor with abundant
neuropil and true rosettes (ETANTR): a new distinctive variety of pediatric PNET: a
case-based update. Childs Nerv Syst. 2010;26(8):1003–1008.
195. Rawlings CE III, Giangaspero F, Burger PC, et al. Ependy momas: a clinicopathologic
study. Surg Neurol. 1988;29:271–281.
196. Rorke LB. Relationship of morphology of ependy moma in children to prognosis. Prog
Exp Tumor Res. 1987;30:170–174.
197. Ross GW, Rubinstein LJ. Lack of histopathological correlation of malignant
ependy momas with postoperative survival. J Neurosurg. 1989;70:31–36.
198. Pollock BE. Gamma Knife surgery for focal brainstem gliomas. J Neurosurg.
2007;106:6–7.
199. Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric
ependy moma: a prospective study. Lancet Oncol. 2009;10:258–266.
200. Horn B, Heideman R, Gey er R, et al. A multi-institutional retrospective study of
intracranial ependy moma in children: identification of risk factors. J Pediatr Hematol
Oncol. 1999;21:203–211.
201. Pollack IF, Gerszten PC, Martinez AJ, et al. Intracranial ependy momas of childhood:
long-term outcome and prognostic factors. Neurosurgery. 1995;37:655–666.
202. Rousseau P, Habrand JL, Sarrazin D, et al. Treatment of intracranial ependy momas of
children: review of a 15-y ear experience. Int J Radiat Oncol Biol Phys. 1994;28:381–
386.
203. Merchant TE, Jenkins JJ, Burger PC, et al. Influence of tumor grade on time to
progression after irradiation for localized ependy moma in children. Int J Radiat Oncol
Biol Phys. 2002;53:52–57.
204. Grill J, Le Deley MC, Gambarelli D, et al. Postoperative chemotherapy without
irradiation for ependy moma in children under 5 y ears of age: a multicenter trial of the
French Society of Pediatric Oncology. J Clin Oncol. 2001;19:1288–1296.
205. Macdonald SM, Sethi R, Lavally B, et al. Proton radiotherapy for pediatric central
nervous sy stem ependy moma: clinical outcomes for 70 patients. Neuro Oncol.
2013;15(11):1552–1559.
206. Palm T, Figarella-Branger D, Chapon F, et al. Expression profiling of ependy momas
unravels localization and tumor grade-specific tumorigenesis. Cancer. 2009;115:3955–
3968.
207. Zacharoulis S, Ji L, Pollack IF, et al. Metastatic ependy moma: a multi-institutional
retrospective analy sis of prognostic factors. Pediatr Blood Cancer. 2008;50:231–235.
208. Hukin J, Epstein F, Lefton D, et al. Treatment of intracranial ependy moma by surgery
alone. Pediatr Neurosurg. 1998;29:40–45.
209. Duffner PK, Krischer JP, Sanford RA, et al. Prognostic factors in infants and very y oung
children with intracranial ependy momas. Pediatr Neurosurg. 1998;28:215–222.
210. Shu HK, Sall WF, Maity A, et al. Childhood intracranial ependy moma: twenty -y ear
experience from a single institution. Cancer. 2007;110:432–441.
211. Mansur DB, Perry A, Rajaram V, et al. Postoperative radiation therapy for grade II and
III intracranial ependy moma. Int J Radiat Oncol Biol Phys. 2005;61:387–391.
212. Conklin HM, Li C, Xiong X, et al. Predicting change in academic abilities after
conformal radiation therapy for localized ependy moma. J Clin Oncol. 2008;26:3965–
3970.
213. Merchant TE, Kiehna EN, Li C, et al. Radiation dosimetry predicts IQ after conformal
radiation therapy in pediatric patients with localized ependy moma. Int J Radiat Oncol
Biol Phys. 2005;63:1546–1554.
214. Di Pinto M, Conklin HM, Li C, et al. Investigating verbal and visual auditory learning
after conformal radiation therapy for childhood ependy moma. Int J Radiat Oncol Biol
Phys. 2010;77(4):1002–1008.
215. Merchant, TE, Bendel AE, Sabin N, et al. A Phase II trial of conformal radiation therapy
for pediatric patients with localized ependy moma, chemotherapy prior to second
surgery for incompletely resected ependy moma and observation for completely
resected, differentiated, supratentorial ependy moma. Int J Radiat Oncol Biol Phys.
2015;93(3S):S1.
216. Merchant TE, Boop FA, Kun LE, et al. A retrospective study of surgery and reirradiation
for recurrent ependy moma. Int J Radiat Oncol Biol Phys. 2008;71:87–97.
217. Bouffet E, Tabori U, Bartels U. Paediatric ependy momas: should we avoid
radiotherapy ? Lancet Oncol. 2007;8:665–666.
218. Eaton BR, Chowdhry V, Weaver K, et al. Use of proton therapy for re-irradiation in
pediatric intracranial ependy moma.” Radiother Oncol. 2015;116(2):301–308.
219. Stafford SL, Pollock BE, Foote RL, et al. Stereotactic radiosurgery for recurrent
ependy moma. Cancer. 2000;88:870–875.
220. Messahel B, Ashley S, Saran F, et al. Relapsed intracranial ependy moma in children in
the UK: patterns of relapse, survival and therapeutic outcome. Eur J Cancer.
2009;45(10):1815–1823.
221. Robertson PL, Zeltzer PM, Boy ett JM, et al. Survival and prognostic factors following
radiation therapy and chemo-therapy for ependy momas in children: a report of the
Children’s Cancer Group. J Neurosurg. 1998;88:695–703.
222. Needle MN, Molloy PT, Gey er JR, et al. Phase II study of daily oral etoposide in
children with recurrent brain tumors and other solid tumors. Med Pediatr Oncol.
1997;29:28–32.
223. Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, et al. Adjuvant chemotherapy of
childhood posterior fossa ependy moma: cranio-spinal irradiation with or without
adjuvant CCNU, vincristine, and prednisone: a Children’s Cancer Group study. Med
Pediatr Oncol. 1996;27:8–14.
224. Needle MN, Goldwein JW, Grass J, et al. Adjuvant chemotherapy for the treatment of
intracranial ependy moma of childhood. Cancer. 1997;80:341–347.
225. Gilbertson RJ, Bentley L, Hernan R, et al. ERBB receptor signaling promotes
ependy moma cell proliferation and represents a potential novel therapeutic target for
this disease. Clin Cancer Res. 2002;8:3054–3064.
226. Timmermann B, Kortmann RD, Kuhl J, et al. Role of radiotherapy in anaplastic
ependy moma in children under age of 3 y ears: results of the prospective German brain
tumor trials HIT-SKK 87 and 92. Radiother Oncol. 2005;77:278–285.
227. Paulino AC. The local field in infratentorial ependy moma: does the entire posterior fossa
need to be treated? Int J Radiat Oncol Biol Phys. 2001;49:757–761.
228. Goldwein JW, Corn BW, Finlay JL, et al. Is craniospinal irradiation required to cure
children with malignant (anaplastic) intracranial ependy momas? Cancer. 1991;67:2766–
2771.
229. Oy a N, Shibamoto Y, Nagata Y, et al. Postoperative radiotherapy for intracranial
ependy moma: analy sis of prognostic factors and patterns of failure. J Neurooncol.
2002;56:87–94.
230. Schroeder TM, Chintagumpala M, Okcu MF, et al. Intensity -modulated radiation therapy
in childhood ependy moma. Int J Radiat Oncol Biol Phys. 2008;71:987–993.
231. Merchant TE, Mulhern RK, Krasin MJ, et al. Preliminary results from a phase II trial of
conformal radiation therapy and evaluation of radiation-related CNS effects for
pediatric patients with localized ependy moma. J Clin Oncol. 2004;22:3156–3162.
232. Merchant TE, Haida T, Wang MH, et al. Anaplastic ependy moma: treatment of pediatric
patients with or without craniospinal radiation therapy. J Neurosurg. 1997;86:943–949.
233. Page 93 Edwards MS, Wara WM, Ciricillo SF, et al. Focal brain-stem astrocy tomas
causing sy mptoms of involvement of the facial nerve nucleus: long-term survival in six
pediatric cases. J Neurosurg. 1994;80:20–25.
234. Vanuy tsel LJ, Bessell EM, Ashley SE, et al. Intracranial ependy moma: long-term results
of a policy of surgery and radiotherapy. Int J Radiat Oncol Biol Phys. 1992;23:313–319.
235. Conter C, Carrie C, Bernier V, et al. Intracranial ependy momas in children: society of
pediatric oncology experience with postoperative hy perfractionated local radiotherapy.
Int J Radiat Oncol Biol Phys. 2009;74:1536–1542.
236. MacDonald SM, Safai S, Trofimov A, et al. Proton radiotherapy for childhood
ependy moma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol
Phys. 2008;71:979–986.
237. Barkovich AJ, Krischer J, Kun LE, et al. Brain stem gliomas: a classification sy stem
based on magnetic resonance imaging. Pediatr Neurosurg. 1990;16:73–83.
238. Albright AL, Price RA, Guthkelch AN. Brain stem gliomas of children. A
clinicopathological study. Cancer. 1983;52:2313–2319.
239. Vandertop WP, Hoffman HJ, Drake JM, et al. Focal midbrain tumors in children.
Neurosurgery. 1992;31:186–194.
240. Ternier J, Wray A, Puget S, et al. Tectal plate lesions in children. J Neurosurg.
2006;104:369–376.
241. Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol
Phys. 1998;40:265–271.
242. Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brainstem
gliomas. J Clin Oncol. 2006;24:1266–1272.
243. Hoffman HJ, Becker L, Craven MA. A clinically and pathologically distinct group of
benign brain stem gliomas. Neurosurgery. 1980;7:243–248.
244. Stroink AR, Hoffman HJ, Hendrick EB, et al. Diagnosis and management of pediatric
brain-stem gliomas. J Neurosurg. 1986;65:745–750.
245. Freeman CR, Bourgouin PM, Sanford RA, et al. Long term survivors of childhood brain
stem gliomas treated with hy perfractionated radiotherapy —clinical characteristics and
treatment related toxicities—the Pediatric Oncology Group. Cancer. 1996;77:555–562.
246. Schumacher M, Schulte-Monting J, Stoeter P, et al. Magnetic resonance imaging
compared with biopsy in the diagnosis of brainstem diseases of childhood: a multicenter
review. J Neurosurg. 2007;106:111–119.
247. Kwon JW, Kim IO, Cheon JE, et al. Paediatric brain-stem gliomas: MRI, FDG-PET and
histological grading correlation. Pediatr Radiol. 2006;36:959–964.
248. Yamaguchi S, Terasaka S, Kobay ashi H, et al. Indolent dorsal midbrain tumor: new
findings based on positron emission tomography. J Neurosurg Pediatr. 2009;3:270–275.
249. Pierre-Kahn A, Hirsch JF, Vinchon M, et al. Surgical management of brain-stem tumors
in children: results and statistical analy sis of 75 cases. J Neurosurg. 1993;79:845–852.
250. Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions
in children. J Neurosurg. 2007;107:1–4.
251. Pirotte BJ, Lubansu A, Massager N, et al. Results of positron emission tomography
guidance and reassessment of the utility of and indications for stereotactic biopsy in
children with infiltrative brainstem tumors. J Neurosurg. 2007;107:392–399.
252. Shrieve DC, Wara WM, Edwards MS, et al. Hy perfractionated radiation therapy for
gliomas of the brainstem in children and in adults. Int J Radiat Oncol Biol Phys.
1992;24:599–610.
253. Mantravadi RV, Phatak R, Bellur S, et al. Brain stem gliomas: an autopsy study of 25
cases. Cancer. 1982;49:1294–1296.
254. Gilbertson RJ, Hill DA, Hernan R, et al. ERBB1 is amplified and overexpressed in high-
grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res. 2003;9:3620–
3624.
255. Pollack IF, Stewart CF, Kocak M, et al. A phase II study of gefitinib and irradiation in
children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain
Tumor Consortium. Neuro Oncol. 2011;13(3):290–297.
256. Gururangan S, McLaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis
metastases in children with diffuse pontine glioma. J Neurooncol. 2006;77:207–212.
257. Pollack IF, Hoffman HJ, Humphrey s RP, et al. The long-term outcome after surgical
treatment of dorsally exophy tic brain-stem gliomas. J Neurosurg. 1993;78:859–863.
258. Khatib ZA, Heideman RL, Kovnar EH, et al. Predominance of pilocy tic histology in
dorsally exophy tic brain stem tumors. Pediatr Neurosurg. 1994;20:2–10.
259. Farmer JP, Montes JL, Freeman CR, et al. Brainstem gliomas—a 10-y ear institutional
review. Pediatr Neurosurg. 2001;34:206–214.
260. Boy dston WR, Sanford RA, Muhlbauer MS, et al. Gliomas of the tectum and
periaqueductal region of the mesencephalon. Pediatr Neurosurg. 1991;17:234–238.
261. Epstein F, McCleary EL. Intrinsic brain-stem tumors of childhood: surgical indications. J
Neurosurg. 1986;64:11–15.
262. Lesniak MS, Klem JM, Weingart J, et al. Surgical outcome following resection of
contrast-enhanced pediatric brainstem gliomas. Pediatr Neurosurg. 2003;39:314–322.
263. Epstein F, Wisoff J. Intra-axial tumors of the cervicomedullary junction. J Neurosurg.
1987;67:483–487.
264. Freeman CR, Krischer JP, Sanford RA, et al. Final results of a study of escalating doses
of hy perfractionated radiotherapy in brain stem tumors in children: a Pediatric
Oncology Group study. Int J Radiat Oncol Biol Phys. 1993;27:197–206.
265. Prados MD, Wara WM, Edwards MS, et al. The treatment of brain stem and thalamic
gliomas with 78 Gy of hy perfractionated radiation therapy. Int J Radiat Oncol Biol Phys.
1995;32:85–91.
266. Combs SE, Steck I, Schulz-Ertner D, et al. Long-term outcome of high-precision
radiotherapy in patients with brain stem gliomas: results from a difficult-to-treat patient
population using fractionated stereotactic radiotherapy. Radiother Oncol. 2009;91:60–66.
267. Yen CP, Sheehan J, Steiner M, et al. Gamma knife surgery for focal brainstem gliomas.
J Neurosurg. 2007;106:8–17.
268. Jenkin RD, Boesel C, Ertel I, et al. Brain-stem tumors in childhood: a prospective
randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A
report of the Children’s Cancer Study Group. J Neurosurg. 1987;66:227–233.
269. Allen J, Siffert J, Donahue B, et al. A phase I/II study of carboplatin combined with
hy perfractionated radiotherapy for brainstem gliomas. Cancer. 1999;86:1064–1069.
270. Walter AW, Gajjar A, Ochs JS, et al. Carboplatin and etoposide with hy perfractionated
radiotherapy in children with newly diagnosed diffuse pontine gliomas: a phase I/II
study. Med Pediatr Oncol. 1998;30:28–33.
271. Turner CD, Chi S, Marcus KJ, et al. Phase II study of thalidomide and radiation in
children with newly diagnosed brain stem gliomas and glioblastoma multiforme. J
Neurooncol. 2007;82:95–101.
272. Pollack IF, Jakacki RI, Blaney SM, et al. Phase I trial of imatinib in children with newly
diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor
Consortium report. Neuro Oncol. 2007;9:145–160.
273. Korones DN, Fisher PG, Kretschmar C, et al. Treatment of children with diffuse intrinsic
brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children’s Oncology
Group phase II study. Pediatr Blood Cancer. 2008;50:227–230.
274. Broniscer A, Iacono L, Chintagumpala M, et al. Role of temozolomide after
radiotherapy for newly diagnosed diffuse brainstem glioma in children: results of a
multi-institutional study (SJHG-98). Cancer. 2005;103:133–139.
275. Dunkel IJ, Garvin JH Jr, Goldman S, et al. High dose chemotherapy with autologous
bone marrow rescue for children with diffuse pontine brain stem tumors—Children’s
Cancer Group. J Neurooncol. 1998;37:67–73.
276. Jennings MT, Sposto R, Boy ett JM, et al. Preradiation chemotherapy in primary high-risk
brainstem tumors: phase II study CCG-9941 of the Children’s Cancer Group. J Clin
Oncol. 2002;20:3431–3437.
277. Frappaz D, Schell M, Thiesse P, et al. Preradiation chemotherapy may improve survival
in pediatric diffuse intrinsic brainstem gliomas: final results of BSG 98 prospective trial.
Neuro Oncol. 2008;10:599–607.
278. Kretschmar CS, Tarbell NJ, Barnes PD, et al. Pre-irradiation chemotherapy and
hy perfractionated radiation therapy 66 Gy for children with brain stem tumors—a phase
II study of the Pediatric Oncology Group, Protocol 8833. Cancer. 1993;72:1404–1413.
279. Castel D, Philippe C, Calmon R, et al. . Histone H3F3A and HIST1H3B K27M mutations
define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and
phenoty pes. Acta Neuropathol. 2015;130(6):815–827.
280. Page 94 Hennika T, Becher OJ. Diffuse intrinsic pontine glioma: time for cautious
optimism. J Child Neurol. 2015; Epub ahead of print.
281. Allen JC, Siffert J. Contemporary chemotherapy issues for children with brainstem
gliomas. Pediatr Neurosurg. 1996;24:98–102.
282. Halperin EC. Pediatric brain stem tumors: patterns of treatment failure and their
implications for radiotherapy. Int J Radiat Oncol Biol Phys. 1985;11:1293–1298.
283. Yoshimura J, Onda K, Tanaka R, et al. Clinicopathological study of diffuse ty pe
brainstem gliomas: analy sis of 40 autopsy cases. Neurol Med Chir (Tokyo). 2003;43:375–
382.
284. Donahue B, Allen J, Siffert J, et al. Patterns of recurrence in brain stem gliomas:
evidence for craniospinal dissemination. Int J Radiat Oncol Biol Phys. 1998;40:677–680.
285. Gajjar A, Bhargava R, Jenkins JJ, et al. Low-grade astrocy toma with neuraxis
dissemination at diagnosis. J Neurosurg. 1995;83:67–71.
286. Frazier JL, Lee J, Thomale UW, et al. Treatment of diffuse intrinsic brainstem gliomas:
failed approaches and future strategies. J Neurosurg Pediatr. 2009;3:259–269.
287. Freeman CR, Kepner J, Kun LE, et al. A detrimental effect of a combined
chemotherapy –radiotherapy approach in children with diffuse intrinsic brain stem
gliomas? Int J Radiat Oncol Biol Phys. 2000;47:561–564.
288. Mandell L, Kadota R, Douglass EC, et al. It is time to rethink the role of
hy perfractionated radiotherapy in the management of children with newly diagnosed
brainstem? Results of a Pediatric Oncology Group Phase III trial comparing
conventional versus hy perfractionated radiotherapy. Int J Radiat Oncol Biol Phys.
1997;39:143.
289. Lewis J, Lucraft H, Gholkar A. UKCCSG study of accelerated radiotherapy for pediatric
brain stem gliomas—United Kingdom Childhood Cancer Study Group. Int J Radiat
Oncol Biol Phys. 1997;38:925–929.
290. Janssens GO, Gidding CE, Van Lindert EJ, et al. The role of hy pofractionation
radiotherapy for diffuse intrinsic brainstem glioma in children: a pilot study. Int J Radiat
Oncol Biol Phys. 2009;73:722–726.
291. Haas-Kogan DA, Banerjee A, Kocak M, et al. Phase I trial of tipifarnib in children with
newly diagnosed intrinsic diffuse brainstem glioma. Neuro Oncol. 2008;10:341–347.
292. Fouladi M, Nicholson HS, Zhou T, et al. A phase II study of the farnesy l transferase
inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma,
medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children’s
Oncology Group study. Cancer. 2007;110:2535–2541.
293. Packer RJ, Zimmerman RA, Kaplan A, et al. Early cy stic/ necrotic changes after
hy perfractionated radiation therapy in children with brain stem gliomas—data from the
Children’s Cancer Group. Cancer. 1993;71:2666–2674.
294. Panigrahy A, Nelson MD Jr, Finlay JL, et al. Metabolism of diffuse intrinsic brainstem
gliomas in children. Neuro Oncol. 2008;10:32–44.
295. Broniscer A, Laningham FH, Sanders RP, et al. Young age may predict a better outcome
for children with diffuse pontine glioma. Cancer. 2008;113:566–572.
296. Ilgren EB, Stiller CA. Cerebellar astrocy tomas—clinical characteristics and prognostic
indices. J Neurooncol. 1987;4:293–308.
297. Schneider JH Jr, Raffel C, McComb JG. Benign cerebellar astrocy tomas of childhood.
Neurosurgery. 1992;30:58–62.
298. Bigner DD, McLendon RE, Bruner JM. Russell & Rubinstein’s Pathology of Tumors of the
Nervous System. Vol. 1, 6th ed. London, England: Arnold; 1998.
299. Hay ostek CJ, Shaw EG, Scheithauer B, et al. Astrocy tomas of the cerebellum—a
comparative clinicopathologic study of pilocy tic and diffuse astrocy tomas. Cancer.
1993;72:856–869.
300. Pencalet P, Maixner W, Sainte-Rose C, et al. Benign cerebellar astrocy tomas in children.
J Neurosurg. 1999;90:265–273.
301. Desai KI, Nadkarni TD, Muzumdar DP, et al. Prognostic factors for cerebellar
astrocy tomas in children: a study of 102 cases. Pediatr Neurosurg. 2001;35:311–317.
302. Ilgren EB, Stiller CA. Cerebellar astrocy tomas: therapeutic management. Acta
Neurochir (Wien). 1986;81:11–26.
303. Gjerris F, Klinken L. Long-term prognosis in children with benign cerebellar
astrocy toma. J Neurosurg. 1978;49:179–184.
304. Sgouros S, Fineron PW, Hockley AD. Cerebellar astrocy toma of childhood: long-term
follow-up. Childs Nerv Syst. 1995;11:89–96.
305. Tomita T, McLone DG. Medulloblastoma in childhood: results of radical resection and
low-dose neuraxis radiation therapy. J Neurosurg. 1986;64:238–242.
306. Campbell JW, Pollack IF. Cerebellar astrocy tomas in children. J Neurooncol.
1996;28:223–231.
307. Pollack IF, Hurtt M, Pang D, et al. Dissemination of low grade intracranial astrocy tomas
in children. Cancer. 1994;73:2869–2878.
308. Prados M, Mamelak AN. Metastasizing low grade gliomas in children—redefining an old
disease. Cancer. 1994;73:2671–2673.
309. Garcia DM, Marks JE, Latifi HR, et al. Childhood cerebellar astrocy tomas: is there a role
for postoperative irradiation? Int J Radiat Oncol Biol Phys. 1990;18:815–818.
310. Sutton LN, Cnaan A, Klatt L, et al. Postoperative surveillance imaging in children with
cerebellar astrocy tomas. J Neurosurg. 1996;84:721–725.
311. Kulkarni AV, Becker LE, Jay V, et al. Primary cerebellar glioblastomas multiforme in
children. Report of four cases. J Neurosurg. 1999;90:546–550.
312. Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children
with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86:747–754.
313. Larson DA, Wara WM, Edwards MS. Management of childhood cerebellar
astrocy toma. Int J Radiat Oncol Biol Phys. 1990;18:971–973.
314. Lee MJ, Ra YS, Park JB, et al. Effectiveness of novel combination chemotherapy,
consisting of 5-fluorouracil, vincristine, cy clophosphamide and etoposide, in the
treatment of low-grade gliomas in children. J Neurooncol. 2006;80:277–284.
315. Packer RJ, Jakacki R, Horn M, et al. Objective response of multiply recurrent low-grade
gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer. 2009;52:791–795.
316. Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for
treatment of low-grade glioma in y oung children: a report from the Children’s Oncology
Group. J Clin Oncol. 2012;30(21):2641–2647.
317. Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for
pediatric low-grade glioma. J Clin Oncol. 2009;27:3598–3604.
318. Merchant TE, Zhu Y, Thompson SJ, et al. Preliminary results from a Phase II trail of
conformal radiation therapy for pediatric patients with localised low-grade astrocy toma
and ependy moma. Int J Radiat Oncol Biol Phys. 2002;52:325–332.
319. Beebe DW, Ris MD, Armstrong FD, et al. Cognitive and adaptive outcome in low-grade
pediatric cerebellar astrocy tomas: evidence of diminished cognitive and adaptive
functioning in National Collaborative Research Studies (CCG 9891/POG 9130). J Clin
Oncol. 2005;23:5198–5204.
320. Schick U, Marquardt G. Pediatric spinal tumors. Pediatr Neurosurg. 2001;35:120–127.
321. DeSousa AL, Kalsbeck JE, Mealey J Jr, et al. Intraspinal tumors in children—a review of
81 cases. J Neurosurg. 1979;51:437–445.
322. Zileli M, Coskun E, Ozdamar N, et al. Surgery of intrame-dullary spinal cord tumors.
Eur Spine J. 1996;5:243–250.
323. Goh KY, Velasquez L, Epstein FJ. Pediatric intramedullary spinal cord tumors: is surgery
alone enough? Pediatr Neurosurg. 1997;27:34–39.
324. Reimer R, Onofrio BM. Astrocy tomas of the spinal cord in children and adolescents. J
Neurosurg. 1985;63:669–675.
325. Nadkarni TD, Rekate HL. Pediatric intramedullary spinal cord tumors—critical review
of the literature. Childs Nerv Syst. 1999;15:17–28.
326. Albright AL. Pediatric intramedullary spinal cord tumors. Childs Nerv Syst. 1999;15:436–
438.
327. Curran WJ Jr, D’Angio GJ. Nonsurgical management of spinal tumors. In: Ashley DG,
Curran WJ Jr, D’Angio GJ, et al. Spinal Tumors in Children and Adolescents, the
International Review of Child Neurology. New York, NY: Raven Press; 1990:71–84.
328. Innocenzi G, Raco A, Cantore G, et al. Intramedullary astrocy tomas and ependy momas
in the pediatric age group: a retrospective study. Childs Nerv Syst. 1996;12:776–780.
329. Rossitch E Jr, Zeidman SM, Burger PC, et al. Clinical and pathological analy sis of spinal
cord astrocy tomas in children. Neurosurgery. 1990;27:193–196.
330. Page 95 Epstein F. Spinal cord astrocy tomas of childhood. Prog Exp Tumor Res.
1987;30:135–153.
331. Epstein F, Epstein N. Surgical management of holocord intramedullary spinal cord
astrocy tomas in children. J Neurosurg. 1981;54:829–832.
332. Pascual-Castroviejo I. Spinal Cord Tumors in Children and Adolescents. New York, NY:
Raven Press; 1990.
333. Houten JK, Weiner HL. Pediatric intramedullary spinal cord tumors: special
considerations. J Neurooncol. 2000;47:225–230.
334. Merchant TE, Kiehna EN, Thompson SJ, et al. Pediatric low-grade and ependy mal
spinal cord tumors. Pediatr Neurosurg. 2000;32:30–36.
335. Sonneland PR, Scheithauer BW, Onofrio BM. My xopapillary ependy moma—a
clinicopathologic and immunocy tochemical study of 77 cases. Cancer. 1985;56:883–
893.
336. Bagley CA, Wilson S, Kothbauer KF, et al. Long term outcomes following surgical
resection of my xopapillary ependy momas. Neurosurg Rev. 2009;32:321–334.
337. Whitaker SJ, Bessell EM, Ashley SE, et al. Postoperative radiotherapy in the
management of spinal cord ependy moma. J Neurosurg. 1991;74:720–728.
338. Crawford JR, Zaninovic A, Santi M, et al. Primary spinal cord tumors of childhood:
effects of clinical presentation, radiographic features, and pathology on survival. J
Neurooncol. 2009;95:259–269.
339. Bouffet E, Pierre-Kahn A, Marchal JC, et al. Prognostic factors in pediatric spinal cord
astrocy toma. Cancer. 1998;83:2391–2399.
340. Rifkinson-Mann S, Wisoff JH, Epstein F. The association of hy drocephalus with
intramedullary spinal cord tumors: a series of 25 patients. Neurosurgery. 1990;27:749–
754.
341. Epstein F, Epstein N. Surgical treatment of spinal cord astrocy tomas of childhood—a
series of 19 patients. J Neurosurg. 1982;57:685–689.
342. Minehan KJ, Brown PD, Scheithauer BW, et al. Prognosis and treatment of spinal cord
astrocy toma. Int J Radiat Oncol Biol Phys. 2009;73:727–733.
343. McCormick PC, Torres R, Post KD, et al. Intramedullary ependy moma of the spinal
cord. J Neurosurg. 1990;72:523–532.
344. Townsend N, Handler M, Fleitz J, et al. Intramedullary spinal cord astrocy tomas in
children. Pediatr Blood Cancer. 2004;43:629–632.
345. Mora J, Cruz O, Gala S, et al. Successful treatment of childhood intramedullary spinal
cord astrocy tomas with irinotecan and cisplatin. Neuro Oncol. 2007;9:39–46.
346. Allen JC, Aviner S, Yates AJ, et al. Treatment of high-grade spinal cord astrocy toma of
childhood with “8-in-1” chemotherapy and radiotherapy : a pilot study of CCG-945.
Children’s Cancer Group. J Neurosurg. 1998;88:215–220.
347. Linstadt DE, Wara WM, Leibel SA, et al. Postoperative radiotherapy of primary spinal
cord tumors. Int J Radiat Oncol Biol Phys. 1989;16:1397–1403.
348. O’Sullivan C, Jenkin RD, Doherty MA, et al. Spinal cord tumors in children: long-term
results of combined surgical and radiation treatment. J Neurosurg. 1994;81:507–512.
349. Chun HC, Schmidt-Ullrich RK, Wolfson A, et al. External beam radiotherapy for
primary spinal cord tumors. J Neurooncol. 1990;9:211–217.
350. Chan HS, Becker LE, Hoffman HJ, et al. My xopapillary ependy moma of the filum
terminale and cauda equina in childhood: report of seven cases and review of the
literature. Neurosurgery. 1984;14:204–210.
351. Chinn DM, Donaldson SS, Dahl GV, et al. Management of children with metastatic spinal
my xopapillary ependy moma using craniospinal irradiation. Med Pediatr Oncol.
2000;35:443–445.
CH A P TER 5
Retinoblastoma
Jasmine H. Francis, Suzanne L. Wolden, David H. Abramson, and Ira J.
Dunkel
PAGE 96INCIDENCE
Retinoblastoma (RB) is the most common primary ey e tumor in children and usually afflicts
children less than 5 y ears of age. It occurs in about 1/20,000 live births, resulting in about 250–
350 new cases per y ear in the United States. In the higher-income nations, retinoblastoma
almost alway s presents with intraocular disease that may threaten the ey e and vision, but
extraocular disease is uncommon, occurring in less than 5% of cases. In contrast, extraocular
retinoblastoma remains a common problem in lower-income countries and is usually fatal.
Many phy sicians believe that retinoblastoma is more common in lower- or middle-
income countries, but a population-based study in Argentina determined that the incidence
there is comparable to that of higher-income countries (1).
GENETICS
Retinoblastoma was one of the first examples demonstrating the potential genetic etiology of
cancer. Hereditary retinoblastoma presents in a Mendelian autosomal dominant pattern with
90% penetrance, but only 10% of patients have a family history of the disease.
Retinoblastoma occurs in two forms: Patients with unilateral disease present with a single
focus of tumor at a median age of about 24 months, while patients with bilateral disease
present with multifocal tumors at a median age of about 12 months. Knudson proposed his
classical two-hit model in 1971 after noting that the timing of tumor development (earlier
diagnosis of bilateral tumors than of unilateral tumors) suggested that at least two events
would be responsible for the development of the tumor. Patients with multifocal bilateral
disease are germline carriers for the first hit, with only one second hit necessary to develop
retinoblastoma in a susceptible cell. Unilateral unifocal patients usually have a normal
germline genome, but develop both hits in the progenitor tumor cell (2).
The nature of these hits was suggested by kary oty pic abnormalities on the long arm of
chromosome 13 in tumors. In 1986, the “hit” was discovered to be a mutation in the RB1 gene
on chromosome 13q14 (3). It is likely that most patients with bilateral or multifocal disease
have a germline RB1 mutation (as mosaicism may be as common as 15% of patients), while
most (85%) patients with unilateral disease have a sporadic RB1 mutation only in the
retinoblastoma tumor cells. The first hits are usually point mutations or small deletions, while
the second hit is usually loss of the normal allele (loss of heterozy gosity ) (4).
DNA-based mutation identification can be performed at specialized laboratories, and
genetic counseling regarding RB1 genetic testing is part of the standard care of retinoblastoma
patients. Testing is clinically useful to identify the approximately 15% of unilateral survivors
at risk for secondary malignancy and/or transmission of the disease to their offspring, to
determine which relatives or offspring of survivors inherited the mutation and need to be
carefully clinically screened, and to allow bilateral survivors the option of considering
preimplantation genetic diagnosis and in vitro fertilization to avoid the risk of their child
inheriting their mutated RB1 gene (5).
An important recent discovery was that N-my c amplification appears to be an
alternative mechanism to retinoblastoma development that is responsible for about 1% of
unilateral cases (6). The current understanding regarding the molecular genetics of
retinoblastoma is impressive, but we still are not able to answer the question frequently posed
by parents of a child newly diagnosed with retinoblastoma in the absence of a family history :
Why did this happen to my child? It remains unclear whether this is an uncommon random
event or whether environmental exposures may be contributory (7).
CLINICAL ASSESSMENT
Page 98The three goals of treatment for retinoblastoma include preservation of life, ey e, and
vision. In the majority of the world, the priorities follow in this order. However, in some
countries, the cultural beliefs may necessitate the need to preserve the ey e at the expense of
risking life. Worldwide, half of the children diagnosed with retinoblastoma in 2015 will die of
disease that has metastasized. However, in North America, Europe, Japan, and other higher-
income parts of the world, the survival rate of retinoblastoma is greater than 95%. Treatment
modalities have changed with time and continue to evolve. We will outline below the current
treatment approaches.
Enucleation
An enucleation involves removing the ey e and retaining the orbital contents. It is a reasonable
and commonly used treatment for retinoblastoma, particularly in advanced cases and when
the intraocular pressure is elevated. In an enucleation, the six extraocular muscles are
detached from the globe and the optic nerve is severed near its exit at the optic foramen.
Obtaining a long segment of nerve is important, particularly if the tumor is within the nerve
since tumor at the cut section is associated with central nervous sy stem (CNS) metastasis and
a poor prognosis.
Once the ey e is removed, it is replaced with a spherical orbital implant and the
conjunctiva and Tenons are closed over this. Approximately 4 weeks after the surgery, the
socket is measured for a prosthesis which fits like a contact lens between the lids. It is
cosmetically similar to the fellow ey e, but may not move to the same degree. In y oung
children, orbital growth slows after enucleation and as the rest of the child grows, the orbit
may appear small (this is more common when the ey e is removed at a very y oung age)
(Fig. 5.4 ).
Laser
Laser can be applied as photocoagulation or as hy perthermia. Laser hy perthermia is
generated by a diode laser (810 nm) on continuous mode. A single spot, 0.8–2.0 mm in
diameter, is aimed at the tumor, ty pically with
an indirect ophthalmoscope and 20 diopter lens.
A power setting range between 100 and 2000
mW is selected based on the tumor response.
Intravenous indocy anine green may be used to
enhance the laser response (15). Tumors are
treated for a variable amount of time depending
on response: ty pically fundi or tumors with more
pigment will respond more rapidly and at lower
power settings. Tumors in the posterior pole or
posterior part of the ey e are more easily
accessible to laser compared to anteriorly Figure 5.4 Bilateral retinoblastoma
located tumors, which may require scleral treated with enucleation on one side with
indentation for adequate visualization. Laser is a prosthesis in place. A calcified fundus
particularly effective as a primary treatment for lesion is seen in the remaining eye.
tumors less than 3 mm in size, and requires an
average of 1.8 laser applications to cure a tumor.
Cryotherapy
Cry otherapy is the focal use of freezing temperatures to create intracellular ice formation to
treat retinoblastoma tumors. A tumor is localized and indented through the wall of the ey e
with a nitrous oxide cry oprobe (Fig. 5.5 ). The freeze (–90°C) is then applied until the
tumor is completely covered. The freeze–thaw cy cle is repeated at least three times (16).
Cry otherapy is most accessible to small tumors anterior to the equator, which can be reached
with the cry oprobe (posterior tumors are difficult to reach, and the risks of freezing the
macula or nerve increase posteriorly ).
Cry otherapy can induce acute retinal edema and accumulation of subretinal fluid. To
avoid retinal detachment, some ophthalmologists use laser to create a retinal barrier to fluid
leakage. Disruption of the retina by cry otherapy has the advantage of increasing the
intravitreal permeation of chemotherapy. Cry otherapy can cause a local inflammatory
reaction and pain, which may be mitigated with local anesthetics or topical steroids.
Advantages of 125I and 106Ru plaques include the ability to easily shield the patient as well
as staff from radioactivity. Because of the relatively short half-life of approximately 2
months, 125I plaques are assembled with a customized assortment of seeds for each case.
They also require shielding around the periphery of the plaque which necessitates very
precise placement. 106Ru plaques are preloaded in standard sizes and may be used
repeatedly owing to a half-life of just over 1 y ear. However, there is less control over
treatment time since the plaques are not custom loaded. They are thinner than other plaques
which can be an advantage for placement in y oung children. In experienced hands, all ty pes
of plaques have an excellent record of efficacy for retinoblastoma.
One of the most significant experiences with plaque brachy therapy for retinoblastoma is
from the Wills Ey e Hospital (21). They reported long-term outcomes for 208 tumors with an
overall 5-y ear control rate of 79%. The majority of patients (71%) had received previous
therapy and 35% had relapsed prior to brachy therapy. The vast majority of plaques were
125I and the median prescribed dose was 40 Gy. Risk factors for plaque failure included
vitreous and subretinal seeding as well as increased patient age. Complications at 5 y ears
included cataract in 31%, retinopathy in 27%, papillopathy in 26%, maculopathy in 25%, and
glaucoma in 11%. There were no cases of scleral necrosis and only one case of second
cancer in the field of plaque irradiation.
A team from Toky o reported a series of 101 retinoblastoma tumors in 85 patients treated
with 106Ru plaques as first- and second-line treatment (22). The median prescribed dose at
the apex was 47 Gy with a corresponding dose to the outer sclera of 162 Gy. Many patients
had advanced disease with vitreous (42%) and subretinal (36%) seeding. Local control and
ocular retention were 34% and 59%, respectively, at 2 y ears. Larger tumor size, tumor
seeding, and lower radiation doses were associated with local failure. The rate of
complications was low and included retinal detachment (13%), retinopathy (7%), rubeosis iris
(2%), and cataract (26%). There were no cases of secondary cancer attributable to
brachy therapy.
Plaque brachy therapy is increasingly used as an adjuvant or focal salvage after
sy stemic and/or intra-arterial chemotherapy. A recent report from Memorial Sloan Kettering
detailed the successful use of plaque therapy in 15 patients following ophthalmic artery
chemosurgery (23). Brachy therapy was an adjuvant in 2 patients and as salvage therapy in
13 patients. Twelve cases had localized vitreous seeding. Ocular retention was 79% with six
patients requiring enucleation and six ey es required additional treatment for relapse outside of
the target volume. Electroretinogram demonstrated stable or improved retinal function in the
majority of ey es following plaque therapy.
Plaque brachy therapy remains a useful tool in the treatment of focal retinoblastoma.
With proper patient selection and an experienced team, high rates of control are achieved in
the up-front and salvage setting. The major advantage over external beam therapy is that
plaques are not associated with bone hy poplasia or a significant risk of secondary cancers.
Apex doses of 40–45 Gy have been used traditionally, but most now advocate for lower doses
of 30–40 Gy, especially in patients who have received prior chemotherapy. A current
Children’s Oncology Group (COG) protocol, ARET12P1, calls for an apical dose of 36 Gy
when plaque brachy therapy is used following intra-arterial chemotherapy (24).
As radiation technique has been debated and evolved over decades, so has radiation
dose. Retinoblastoma is clearly a very radiosensitive tumor as it can be cured with modest
doses of radiotherapy alone. A large number of dosage and fractionation schedules have been
proposed for external beam treatment, ranging from 1.2 to 3.8 Gy per fraction with total
doses of 30–60 Gy. Many retrospective clinical series have been published, showing
conflicting data regarding dose–response relationship and the impact of tumor size and dose
on local control. The most traditional approach to EBRT dose has been 40–45 Gy in once
daily fractions of 1.8–2 Gy. This dose range has reliably produced excellent tumor control
with acceptable complication rates in the definitive treatment of retinoblastoma.
Page 103Now that radiotherapy is most often used after cy toreduction with sy stemic
chemotherapy, modification of EBRT dose should be considered. There is concern that the
complication rate, especially retinopathy, may be greater with the combination of
chemotherapy and radiation. In the CHLA series, 24–36 Gy was successfully used as salvage
after failure of chemotherapy (41). Additional study is needed to determine the optimal dose
of radiotherapy following chemotherapy but in the absence of a clinical trial, 36 Gy seems
appropriate based on currently available data.
Figure:
Bilateral retinoblastoma treated with enucleation on one side with a prosthesis in place. A
calcified fundus lesion is seen in the remaining eye.
Figure:
Cryotherapy for retinoblastoma.
Figure:
Placement of 125I radioactive plaque.
Figure: Eye Preservation Following External
Beam Irradiation: Selected Series Reese–
Ellsworth Group
Figure:
Radiation dosimetry comparison for a retinoblastoma treated with protons versus intensity-
modulated (IMRT) photons.
CHEMOTHERAPY FOR INTRAOCULAR DISEASE
In the mid-1990s, it became clear that chemotherapy was effective against retinoblastoma
and it provided an alternative to enucleation and external beam radiation. As the treatment of
retinoblastoma has evolved over the y ears, so too has the delivery method of chemotherapy :
becoming increasing more localized, and some would argue, more invasive. The following
section will describe the delivery of intravenous, periocular, intra-arterial, and intravitreal
chemotherapy for the treatment of retinoblastoma.
Intravenous Chemotherapy
Sy stemic chemotherapy was first reported to be effective against retinoblastoma in 1953. It
was intermittently used at first, but finally adopted by many centers in the 1990s as an
alternative to enucleation and external beam radiation (46). The most commonly used
regimen consists of vincristine, carboplatin, and etoposide, and in conjunction with focal
therapy (laser, cry otherapy, and/or plaque brachy therapy ) has been associated with about a
90% chance of radiation and enucleation-free survival for ey es with less advanced disease
(RE group I–III) versus about a 30% chance for ey e with more advanced disease (RE group
IV–V) (47).
Investigators from Philadelphia described their experience in several papers. Seventy -
five ey es in 47 patients were treated with six cy cles of vincristine, carboplatin and etoposide
with local therapies and all 39 RE group I to III ey es were cured without EBRT (48). Thirty
Reese–Ellsworth group V ey es were treated and 53% required EBRT and/or enucleation.
Subsequently they reported that this strategy produced inferior results in 30 patients with
unilateral retinoblastoma (49). For RE group I to IV ey es, 38% required EBRT and/or
enucleation by 5 y ears, while 100% of group V ey es required one or both. Finally, this group
also reported the outcome of 158 retinoblastoma-containing ey es in 103 patients treated with
six cy cles of vincristine, carboplatin, and etoposide (39). EBRT was used in 10% of RE group
I–IV ey es and 47% of RE group V ey es. Ey e survival was 85% for RE group I–IV ey es and
47% for RE group V ey es.
Some centers will use single-agent carboplatin, particularly in y oung children less than 3
months of age, in order to bridge them until they are of an optimal age and size for other
delivery methods (such as ophthalmic artery chemosurgery ) (50).
The most important potential acute side effect of intravenous chemotherapy is
my elosuppression, which may be associated with need for admission for fever and
neutropenia and/or and blood product transfusions. Ototoxicity is uncommon, but may be
more frequent in y oung infants (51,52). A rare, but potentially very serious side effect is
secondary acute my eloid leukemia (AML), and the risk of secondary malignancy in patients
with a germline RB1 mutation receiving this treatment is not y et completely elucidated.
Periocular Chemotherapy
Periocular chemotherapy is a method of injecting chemotherapy (1-2 mL) under one of the
lay ers of tissue (Tenon’s) that surrounds the ey e. The needle does not enter into the ey e.
Instead, the chemotherapy bathes the outside of the ey e, transitions through the wall, and into
the vitreous. This treatment may be given in conjunction with other therapies (intra-arterial
chemotherapy or intravitreal chemotherapy ). Ty pically, treatments are given weekly, one to
eight times. Occasionally, patients may experience swelling and redness of their ey e and
ey elids, which resolves with time.
Carboplatin is the mostly widely used drug for periocular injection (59). In a nonhuman
primate model, it was demonstrated that in comparison with intravenous administration, the
drug levels after periocular injection were seven to nine times higher in the ey e and 90% less
in the blood (60). Though there were fewer effects on bone marrow, periocular injections of
carboplatin cause (in 50% of cases) severe local reactions including scarring and, rarely, loss
of vision (61,62). Recently, topotecan has been administered as a periocular injection: while
its local toxicity profile is more favorable to carboplatin (63), its efficacy is questionable.
Intravitreal Chemotherapy
Intravitreal chemotherapy involves injecting a small amount (approximately 0.05–0.1 mL)
of chemotherapy through the wall of the ey e and into the vitreous (64). The procedure is
done on an outpatient basis while the child is under anesthesia. Injections are ty pically given
weekly to monthly for one to approximately eight times. There is no pain associated with this
treatment, although the sclera and conjunctiva may appear red for a couple of day s to weeks.
This method is particularly useful at treating vitreous seeds, which are little fragments of
tumor that break off and float in the jelly (vitreous) of the ey e. Melphalan is the most
frequently injected medication, although other drugs have been used. Recent published
evidence demonstrates that 25–30 mcg of intravitreous melphalan can result in ocular
survival rates of 83–100% (64,65). While intravitreal melphalan can cause toxic effects to the
retina and even the anterior segment of the ey e (66), it saves ey es with vitreous seeding that
once would have been enucleated.
Figure:
Angiogram during intra-arterial chemotherapy procedure.
EXTRAOCULAR RETINOBLASTOMA
Retinoblastoma may potentially spread outside the ey e via different routes. It may grow
contiguously through the choroid and sclera into the orbit, hematogenously metastasize to the
bone, bone marrow, and/or liver, extend directly through the optic nerve to the brain, and/or
invade the subarachnoid space surrounding the optic nerve and disseminate to the
leptomeninges via the cerebrospinal fluid (CSF). The ey e has limited ly mphatic drainage
(through the conjunctiva), so ly mphatic spread is rare, but regional nodal metastasis may
rarely occur.
Extraocular retinoblastoma may be present at initial diagnosis in lower-income
countries, but in higher-income countries it is almost alway s a later event, occurring several
months postenucleation. The presenting signs and sy mptoms can vary, depending on the
affected sites. Orbital recurrences are often diagnosed following a parent’s observation that
the child’s ocular prosthesis is no longer fitting well or may present as a visible mass. Bone
disease may present with pain or a mass. Bone marrow disease is often asy mptomatic, but
may be suspected if the patient has abnormal low blood counts. Liver metastases are usually
asy mptomatic and discovered only upon evaluation of extent of the disease. CNS disease,
either directly due to the metastases or indirectly via hy drocephalus, may cause headache,
irritability, emesis, and/or focal neurologic signs.
When a child is suspected or known to have extraocular retinoblastoma, a thorough
evaluation to determine the extent of disease should be expeditiously performed. It should
include brain and orbit MRI with and without contrast, spine MRI with and without contrast (if
the brain MRI or CSF cy tology are positive or CNS disease is otherwise suspected), lumbar
puncture for CSF cy tology, bone marrow aspirate and biopsy, bone scan and abdominal
computed tomography (CT) with IV contrast. The results allow assignment of a stage via
International Retinoblastoma Staging Sy stem (67) (Table 5.4 ).
Table 5.4 International
Retinoblastoma Staging System
Figure: International Retinoblastoma
Staging System
TREATMENT DUE TO HIGH-RISK ENUCLEATION PATHOLOGY
Page 105In higher-income countries, enucleation is usually curative for patients with
intraocular retinoblastoma, but a small proportion will suffer an extraocular recurrence.
Many investigators have attempted to correlate the histopathologic features of the enucleation
specimen with risk of extraocular recurrence, usually focusing on invasion of the postlaminar
optic nerve, choroid, and sclera. Which findings warrant prescription of postenucleation
adjuvant chemotherapy in an attempt to decrease the risk of later development of overt
metastatic disease remains controversial.
The Children’s Oncology Group completed a study (COG ARET0332) that attempted to
prospectively determine the prevalence of high-risk histopathologic features such as choroidal
involvement, optic nerve invasion, scleral and anterior segment involvement in patients with
unilateral retinoblastoma treated with enucleation. They also aimed to estimate the event-free
survival (extraocular or metastatic disease) and survival of patients with unilateral
retinoblastoma with and without high-risk features. Patients with (1) massive choroid
replacement, (2) any posterior uveal involvement with any optic nerve involvement or (3)
optic nerve involvement posterior to the lamina cribrosa were treated with six cy cles of
intravenous carboplatin, vincristine, and etoposide given once every 4 weeks, while the other
patients were followed without postenucleation therapy. Preliminary results (published in
abstract form) indicate that 2 of 93 (2.2%) patients treated with chemotherapy suffered
extraocular recurrences (68).
While the COG ARET0332 results are very impressive, it was a nonrandomized trial and
the risk to similar patients observed without chemotherapy might be comparable. For
example, Argentine investigators reported 167 patients with isolated choroidal invasion (35
with massive invasion) encountered from 1989 to 2010. Most (n = 136) did not receive
adjuvant therapy and the probabilities of 5-y ear event-free and overall survival were 98.1%
and 98.7%, respectively. Children with massive invasion had statistically significantly lower
event-free survival than those with lesser invasion (94.2% vs. 99.2%), but that did not impact
overall survival (98.7% vs. 99.2%) (69).
Similarly, patients with isolated postlaminar optic nerve invasion may fare well without
adjuvant therapy. We and the Buenos Aires group reviewed our experiences regarding 224
patients with unilateral retinoblastoma whose ey e had been enucleated as the primary
therapy from 1980 to 2001. Twenty -five patients had isolated postlaminar optic nerve
invasion, without major choroidal and/or sclera invasion. Four received chemotherapy and 21
were observed and no patient suffered a recurrence (70).
We believe that it remains unclear whether patients with isolated choroidal or
postlaminar optic nerve invasion should receive adjuvant chemotherapy. While it is possible
that adjuvant therapy may reduce the risk of development of overt extraocular disease, at
best it is likely to be a small reduction and whether or not that outweighs the risks and
inconvenience of unnecessary treatment for the others remains controversial.
TREATMENT OF OVERT EXTRAOCULAR DISEASE
Stage 4a Disease
In contrast to patients with stage 2 or 3 disease, patients with stage 4a or 4b metastatic
retinoblastoma fare poorly when treated with conventional chemotherapy and EBRT. Two
reports from Argentina and Brazil noted that only 1 of 40 patients survived following
treatment with conventional dose chemotherapy and radiation therapy (74,76).
However, patients with stage 4a retinoblastoma are potentially curable when their
treatment is intensified to include high-dose chemotherapy with autologous stem cell rescue
(ASCR). A number of groups from around the world have demonstrated in small series that
various high-dose chemotherapy regimens with ASCR appeared promising with
approximately two-thirds of patients achieving event-free survival (77,78,79,80,81,82).
Page 106Our group has reported the largest experience that we are aware of regarding
the use of intensive multimodality therapy for patients with stage 4a retinoblastoma (83). We
treated 15 patients with bone marrow (n = 14), bone (n = 10), orbit (n = 9), and/or liver (n =
4) disease. Induction chemotherapy usually consisted of vincristine, cy clophosphamide,
cisplatin, and etoposide. The high-dose chemotherapy regimen included carboplatin and
thiotepa alone (n = 1) or with etoposide (n = 5) or topotecan (n = 7). Bone marrow cleared at
first postinitiation of chemotherapy examination in all patients and stem cells were harvested
after a median of 3.5 cy cles of chemotherapy (range 3–6 cy cles). Two patients progressed
prior to high-dose chemotherapy and died. Thirteen received high-dose chemotherapy at a
median of 6 months postdiagnosis of metastases (range 4–8 months). Ten were
retinoblastoma-free in first remission at a median follow-up of 103 months (range 34–202
months) while three recurred (two in the CNS, one in the mandible) 14–20 months
postdiagnosis of metastases. Retinoblastoma-free and event-free survival at 5 y ears were
67% (95% confidence interval 38–85%) and 59% (95% confidence interval 31–79%). Six of
the 10 survivors received radiation therapy, and three developed secondary osteosarcoma 14,
4, and 9 y ears after diagnosis of metastatic disease. We concluded that intensive
multimodality therapy including high-dose chemotherapy with autologous hematopoietic
stem cell rescue was curative for the majority of patients with stage 4a metastatic
retinoblastoma treated and that the contribution of EBRT is unclear.
For painful bone metastases, palliative radiotherapy is appropriate and highly effective.
Depending upon field size, location, and life expectancy, ty pical palliative regimens of 3 Gy
× 10 fractions, 4 Gy × 5 fractions, or 8 Gy × 1 fraction may be used. Because retinoblastoma
is a highly radiosensitive tumor, high-dose stereotactic body radiotherapy (SBRT) is not
necessary. In the palliative setting, radiotherapy may be used liberally to relieve sy mptoms
since secondary cancers are no longer a concern.
LATE EFFECTS
Cataracts
The natural lens of the ey e is particularly sensitive to radiation and cataracts (mainly
subcapsular) are a well-known consequence of treatment. The link between exposure to
ionizing radiation and cataract formation was first recognized in survivors of the atomic
bomb, nuclear plant workers, and later in patients treated with radiation for head and neck
cancers. The mechanism of damage is unclear but is speculated to involve free-radical
formation and inefficient dissipation of heat. Studies suggest that a minimum of a single 2 Gy
dose or a cumulative dose of 5.5 Gy over 3 months is sufficient to cause a cataract. Delivery
method, energy of the source, dose per fraction, location and size of tumor, and age of patient
heavily influence development of a lenticular opacity. The latency of cataract formation
ranges from 6 months to 30 y ears, and an average of 2–3 y ears.
Radiation-induced cataracts after EBRT for retinoblastoma can be removed successfully
and vision can be corrected. Brooks et al. (106) removed cataracts in 38 patients with
retinoblastoma (42 ey es) from 1973 to 1989. Nineteen ey es (45%) had final visual acuities of
20/20 to 20/50, while the 12 ey es (29%) with macular tumors had postoperative visual acuities
of 20/80 to counting fingers. The risks of cataract removal after retinoblastoma treatment
include ambly opia, retinal detachment, and the risk of tumor dissemination if retinoblastoma
was not controlled.
Orbital Development
Children treated with EBRT or enucleation are at significant risk for orbital and midfacial
growth retardation. Radiation to the ossification centers may cause bone growth arrest,
necrosis of cartilaginous structures, and bony deformities. In long-term survivors of
retinoblastoma, these orbital growth abnormalities may be apparent. Over the y ears,
investigators have sought to quantify the changes in orbital development. Imhof et al. (107)
examined children treated at Utrecht University Hospital in the Netherlands and followed for
a mean of approximately 8 y ears. Direct measurements were made of the orbital width and
height and the orbital–tragus distance. In general, high-dose-per-fraction EBRT had been used
(3 Gy per fraction × 15 = 45 Gy, 8-MV photons). The mean orbital width, height, and
distance between the tragus and the outer orbital edge were significantly shorter in irradiated
orbits compared with nonirradiated orbits in patients with unilateral retinoblastoma and
compared with control ey es. Enucleation with EBRT was not worse than EBRT alone. Other
groups have reported similar findings.
Page 108Hy potelorism, enophthalmos, depressed temporal bones, atrophy of the
temporalis muscle, anophthalmic socket sy ndrome, and narrow and deep orbits have been
reported (108). These effects are accentuated if EBRT is used in the very y oung (less than 6
months of age) and at dosages greater than 35 Gy (109).
PAGE 111NEUROBLASTOMA
Neuroblastoma (NB) is a malignancy derived from embry onic neural crest cells of the
peripheral sy mpathetic nervous sy stem. It is the most common extracranial solid tumor of
childhood, accounting for 15% of cancer-related deaths. The behavior of NB is marked by
clinical heterogeneity that leads to differences in behavior ranging from spontaneous
maturation in some patients to inexorable rapid metastatic progression in others. It was noted
as early as 1927 to be a tumor in which spontaneous maturation could occur, when Cushing
and Wolbach (1) reported the case of a 2-y ear-old boy whose thoracic paravertebral
sy mpathetic NB, over the course of 10 y ears, transformed into a completely differentiated
ganglioneuroma. However, advanced NB is the most lethal of childhood solid tumors, often
resistant to all attempts at disease eradication. The enigmatic behavior of this tumor is
beginning to be elucidated by new research into the genetic and biologic diversity, but the
treatment of advanced disease is a continuing challenge. This chapter discusses the biologic
features of NB associated with differing behavior, the evaluation and staging, and a risk-based
approach to therapy, with an emphasis on local control issues.
EPIDEMIOLOGY AND SCREENING
There are approximately 710 cases of NB annually in the United States, with an overall
incidence of 10.3 per million per y ear from birth to the age of 15 y ears. NB accounts for
nearly 10% of pediatric cancer in children y ounger than 15 y ears, making it the fourth most
common malignancy in children after leukemias, brain tumors, and ly mphomas. However, it
is the most common malignancy of children y ounger than 1 y ear, with an incidence of
nearly 60 per million, and about 20 per million in those aged 1–5 y ears (2). Ninety percent of
patients with NB are diagnosed by 10 y ears, 79% before 4 y ears, and 36% are infants
y ounger than 1 y ear. The incidence is slightly higher in boy s than in girls and is more
common in whites than in other race or ethnicities. The median age at diagnosis is 22 months.
NB is responsible for 15% of childhood cancer mortality, with an annual mortality rate of 5
per million for all children and 9 per million for the 0- to 4-y ear-old subgroup, although the
survival has increased over the past two decades (2).
NB arises from primitive (fetal) adrenergic neuroblasts of neural crest tissue, which
may explain its high incidence in infancy. In the embry o, continuous columns of neural crest
tissue form dorsolateral to the developing neural tissue. These columns are the precursors of
the spinal ganglia, the dorsal spinal nerve roots, and the chromaffin cells, which flank the
abdominal aorta. The largest of these masses is the adrenal medulla (Fig. 6.1 ). Most cases
of NB occur in an anatomic distribution consistent with the location of neural crest tissue (Fig.
6.2 ).
Page 112Several studies using sy stematic screening of neonates for NB have confirmed
the results of earlier autopsy studies by suggesting a much higher incidence of NB than is
clinically evident. More than 90% of NBs secrete vanilly lmandelic acid (VMA) or
homovanillic acid (HVA) in the urine, for which rapid quantitative screening methods have
been developed that have a high degree of sensitivity and specificity. Urinary catecholamine
screening for NB was initially proposed because the incidence of 8.7 per 1 million children
per y ear is comparable to or higher than that of other congenital diseases for which screening
is already in place, such as hy pothy roidism, galactosemia, and pheny lketonuria. The poor
prognosis for advanced NB in children older than
12 months at diagnosis compared with the
favorable outcome for those diagnosed in
infancy raised the expectation that diagnosis at
an earlier age might improve overall outcome.
However, the cumulative data from 30 y ears of
screening in Japan, the Quebec Neuroblastoma
Screening Project, and screening projects in
Europe have shown that screening infants by 6
months of age results in a significant increase in
the overall incidence of NB but fails to reduce
the incidence of advanced-stage disease with
poor prognosis. A publication from the Quebec
project conclusively showed that screening at 3 Figure 6.1 Migration of the neural
weeks and 6 months in a cohort of 476,654 crest in the human embryo.
infants born over a 5-y ear period had no impact
on overall mortality for the screened cohort compared with multiple control populations from
Minnesota, the Delaware Valley, Florida, and the rest of Canada, verify ing the results of the
earlier studies (3). A second study screened 1,475,773 children at 1 y ear of age in German
states and similarly revealed no impact on outcome (4). The screened group and children in
the control area had a similar incidence of stage 4 NB (3.7 cases per 100,000 screened
children and 3.8 per 100,000 controls) and a similar rate of death among children with NB
(1.3 deaths per 100,000 screened children and 1.2 per 100,000 control subjects). There was a
substantial rate of overdiagnosis in the screened group of children without benefit from the
screening.
The environmental and inherited factors involved in the pathogenesis of NB are largely
unknown, despite extensive epidemiologic and genetic studies. Given the y oung age at which
most NBs present, it has been suggested that environmental exposures before conception or
during pregnancy increase the risk of NB. Epidemiologic investigations have implicated fetal
exposure to diuretics, tranquilizers, hormones, pheny toin, alcohol, and tobacco as increasing
the risk of NB. However, these studies have lacked the statistical power to convincingly
demonstrate that these drugs are etiologic risk factors or have not been confirmed by
subsequent studies.
Although NB usually occurs sporadically, 1–2% of patients have a family history of the
disease. Familial NB is inherited in an autosomal dominant Mendelian fashion with
incomplete penetrance. Affected children from these families differ from those with
sporadic disease in that they are often diagnosed at an earlier age (usually infancy ) or they
have multiple primary tumors. Both germline
mutation and different hereditary -predisposition
loci may predispose to neuroblastoma. Multiple
groups have recently identified the anaplastic
ly mphocy te kinase (ALK) gene as a
predisposition gene in familial NB, responsible
for 80% of the familial cases, which is also
mutated in 10 to 15% of tumors from sporadic
NB (5). Other possible predisposition genes
include germline p53 mutations, as well as SNPs
identified in GWAS studies, including CASC15,
FLJ44180, BARD1, LMO1, HSD17B12,
DDX4/IL31RA, DUSP12, HACE1, LIN28B, and Figure 6.2 Common locations of
NBPF23. NB cases are also detected in other primary tumors in neuroblastoma. The
familial cancer congenital sy ndromes, including percentage is derived from data on 8369
Beckwith–Wiedemann sy ndrome, Li–Fraumeni tumors from the International
sy ndrome, Noonan sy ndrome (PTPN11), some Neuroblastoma Risk Group project.
subty pes of Fanconi anemia, and some Tumors arising in the neck and thorax
chromosomal breakage sy ndromes (6). NB has were significantly more common in
also been seen in several patients with children <18 months of age. (Data are
constitutional chromosomal rearrangements, from Vo KT, Matthay KK, Neuhaus J, et
including deletions overlapping putative tumor al. Clinical, biologic, and prognostic
suppressor loci at chromosome bands 1p36 and differences on the basis of primary tumor
11q14–23 (7). NB has been reported in patients site in neuroblastoma: a report from the
with other neural crest disorders such as the international neuroblastoma risk group
Hirschsprung disease and central hy poventilation project. J Clin Oncol. 2014;32:3169–76.)
sy ndrome; these cases are associated with a
germline mutation at chromosome 4p12 (PHOX2B gene) (6).
Figure:
Migration of the neural crest in the human embryo.
Figure:
Common locations of primary tumors in neuroblastoma. The percentage is derived from
data on 8369 tumors from the International Neuroblastoma Risk Group project. Tumors
arising in the neck and thorax were significantly more common in children <18 months of
age.
(Data are from Vo KT, Matthay KK, Neuhaus J, et al. Clinical, biologic, and prognostic
differences on the basis of primary tumor site in neuroblastoma: a report from the
international neuroblastoma risk group project. J Clin Oncol. 2014;32:3169–76.)
BIOLOGY
Page 113Cy togenetic and molecular studies in NB are providing new insights into its biology
and prognosis. Unfavorable biologic features include amplification of MYCN, deletion or loss
of heterozy gosity of chromosome 1p or 11q, and gains at 17q. In addition, any segmental
losses have been shown to be unfavorable in MYCN-nonamplified tumors (8). Favorable
biologic features include hy perdiploidy and overexpression of Trk A (9). Recognizing these
biologic pathway s in NB has improved the ability to treat children with risk-based therapy and
may lead to novel therapeutic approaches in the near future (Table 6.1 ).
Table 6.1 Genetic Aberrations in Neuroblastoma That Are Found at Diagnosis
MYCN amplification was the first, and is now the most widely accepted, biologic marker
of prognosis for NB (10). MYCN is in the family of MYC oncogenes that encode
transcriptional regulatory factors involved in the control of other genes. The amplification is
generally a consequence of an aberrant gain of multiple copies of the MYCN gene.
Homogeneously staining regions (HSRs, nonbanding regions of metaphase chromosomes that
stain homogeneously ) and double-minute chromatin bodies (fragments of HSRs) are a
manifestation of gene amplification. They are derived from the distal short arms of
chromosome 2, which contains the proto-oncogene MYCN. The excess number of MYCN
genes leads to overexpression of the n-my c protein and subsequent overproduction of growth-
promoting signals and stimulation of proliferation and tumorigenesis. Mice with aberrant
overexpression of MYCN develop NB, providing evidence that MYCN play s a prominent role
in NB development (11). MYCN amplification is most easily detected on fluorescent in situ
hy bridization of fresh tumor imprints, although it may also be tested by
immunohistochemistry, Southern blot, or poly merase chain reaction. Recent studies also show
that circulating MYCN DNA can be detected in advanced-stage NB with MYCN amplification
with a sensitivity of 75–85% (12).
Amplification of MYCN in primary NB has been shown to correlate with advanced stage
and a poor prognosis. Such amplification occurs in 30–40% of advanced-stage NB but in only
5–10% of low-stage or 4S disease and not at all in benign ganglioneuromas (13). Children who
have MYCN amplification in their tumor need more intensive or novel therapy to control the
disease. MYCN usually is an independent prognostic factor such that amplification portends an
unfavorable outcome, even in disease settings that would otherwise be favorable. MYCN
amplification is seldom identified in localized-stage disease (stage 1 and 2) or in stage 4S, but
may predict a poor outcome in these patients when present (14). Amplified MYCN is more
common in tumors from children older than 1 y ear with advanced stage and elevated ferritin,
neuron-specific enolase, lactate dehy drogenase, and chromosome 1p deletion (13).
Page 114DNA ploidy is also an important discriminator of response to chemotherapy for
NB. In infants with metastatic disease, the progression-free survival (PFS) was more than
90% for those with hy perdiploid tumors and 0% in diploid cases. Hy perdiploid tumors also
appear to counteract the unfavorable impact of MYCN amplification in low-stage tumors (14).
Ploidy is probably less useful as a prognostic marker in children older than 24 months, in
whom most tumors are diploid.
Specific chromosomal deletions often are present in NB. Deletion of the short arm of
chromosome 1 occurs in 30–50% of primary tumors and usually occurs at the distal end of
chromosome 1 in the area of 1p36. Loss of chromosome 1p strongly correlates with MYCN
amplification and is also associated with a poor prognosis. Loss of heterozy gosity of 1p in
tumors without MYCN amplification is an independent prognostic marker of outcome,
although this prognostic value is lost in MYCN-amplified tumors (15).
Partial gains at chromosome 17q are another common genetic alteration and are
associated with an adverse outcome. Gains on chromosome 17q have been linked to several
prognostic factors: age greater than 1 y ear, advanced-stage disease, deletion of chromosome
1p, and amplification of MYCN. It is the most common genetic alteration found in NB,
occurring in 50% of cases. However, whether 17q gain is an important independent marker of
prognosis has not y et been verified in a larger prospective multivariate analy sis.
In addition to gains and losses of genetic material, other genes that have been identified
as prognostically important include nerve growth factor receptor expression, telomerase
activity, and genes involved in invasion and metastasis, though currently these are not used in
clinical risk stratification. High levels of telomerase activity or rearrangements in the TERT
gene may also predict an aggressive tumor phenoty pe (16). Specific mutations are rare in
neuroblastoma, present in only about 10% of 240 tumors at diagnosis studied with next-
generation sequencing. The most commonly affected gene was ALK, mutated in nearly 10%
of cases. Other mutations found in 7 and 6 tumors, respectively, were PTPN11 and ATRX (17).
Figure: Genetic Aberrations in
Neuroblastoma That Are Found at Diagnosis
PATHOLOGY
NB is one of the small blue round cell tumors, along with the non-Hodgkin ly mphoma, Ewing
sarcoma, rhabdomy osarcoma, undifferentiated soft tissue sarcomas, and primitive
neuroectodermal tumors. The classic histologic subty pes of neuroblastic tumors include NB,
ganglioneuroblastoma, and ganglioneuroma, reflecting a pattern of increasing maturation and
differentiation (18). The cells of NB are small and uniformly sized, with dense
hy perchromatic nuclei and scant cy toplasm (Fig. 6.3 ). The cells may be densely packed,
separated by thin fibrils or bundles, and necrosis and calcification can occur. Neuritic
processes can be demonstrated in most cases, and pseudorosettes can be seen in 15–50% of
cases. The other end of the spectrum, ganglioneuroma, has mature ganglion cells, neuritic
processes, and Schwann cells and has more fibrillary material. Patients with ganglioneuroma
or ganglioneuroblastoma generally have localized tumors with favorable biologic
characteristics, explaining the excellent associated prognosis.
The most widely accepted sy stem of histologic classification is now the International
Neuroblastoma Pathology Committee Classification (INPC) (18), summarized in Table
6.2 . It is based on the highly prognostic sy stem developed by Shimada et al. (18) using
patient age, the presence of stroma (“rich” or “poor”) and nodularity, the degree of
differentiation, and the mitosis–kary orrhexis index (MKI). Differences between the original
Shimada classification and the INPC are (1) to subdivide the “undifferentiated” subty pe in the
former classification into two subty pes of undifferentiated and poorly differentiated in the
latter classification, based on the degree of cellular density and the number of tumor cells and
MKI (Fig. 6.4 ); and (2) to change the name of “stroma-rich, well differentiated” in the
former classification to “ganglioneuroma, maturing.” The INPC, based largely on the
Shimada sy stem, is now being used in protocols worldwide to facilitate comparisons of patient
groups. A retrospective analy sis of the Children’s Cancer Group (CCG) validated the
prognostic value of this sy stem combined with age (19). An additional modification in 2003
clarified the favorable and unfavorable subsets of ganglioneuroblastoma, nodular (20).
Finally, by international consensus, it was shown
that even if age were taken out of the INPC,
diagnostic category, MKI, and grade of
differentiation each had independent prognostic
significance (9).
(From Shimada H, Ambros IM, Dehner LP, et al. Terminology and morphologic criteria of
neuroblastic tumors: recommendations by the International Neuroblastoma Pathology
Committee. Cancer. 1999;86(2):349–363, with permission.) (See color plate.)
Figure:
The computed tomography scan shows a large retroperitoneal neuroblastoma that encases
the abdominal aorta and displaces the inferior vena cava. The left kidney is pushed laterally,
and calcifications are evident.
Figure: International Neuroblastoma
Pathology Committee System
CLINICAL PRESENTATION AND EVALUATION
The clinical presentation of NB depends on the site along the sy mpathetic nervous sy stem
chain from which the primary tumor develops (Fig. 6.2 ) and on the manifestations of
metastatic disease. This varies according to patient age. The abdomen is the most common
primary tumor location (50–80% of cases), and is most likely to have a less favorable
prognosis (21). Intra-abdominal primary tumors arise in the adrenals or in a paraspinal
location. The paraspinal tumors may have a dumbbell configuration wherein tumor extends
through the neural foramina and presents with a mass lesion in the spinal canal; extradural
spinal cord compression may occur. Extra-abdominal locations of the primary tumor, which
rarely exhibit MYCN amplification and have a more favorable prognosis, include sy mpathetic
ganglia in the neck (often initially thought to be ly mphadenitis), posterior mediastinum, and
pelvis (21).
Page 116The earliest sy mptoms or signs of NB may be a palpable abdominal mass
(often large, firm, irregular, and crossing the midline), a unilateral neck mass often causing
the Horner sy ndrome, spinal cord compression, respiratory compromise caused by thoracic
disease or hepatic metastases placing upward pressure on the diaphragm, or bowel and
bladder disturbances caused by compression from a pelvic mass. About 60% of children with
NB have metastatic disease (either ly mphatic or hematogenous) at the time of clinical
presentation. The sy mptoms in this setting are those of sy stemic illness: fever, weight loss,
weakness, or a general failure to thrive. In a few patients, the presenting sy mptoms are
related to secretory products of the tumor. For example, intractable diarrhea (from
vasoactive intestinal poly peptide) may rarely occur, usually in children with
ganglioneuroblastoma or ganglioneuroma. In another rare paraneoplastic sy ndrome, seen in
about 3% of patients, a child with NB presents with the opsoclonus (rapid multidirectional ey e
movements)–my oclonus–truncal ataxia sy ndrome. This paraneoplastic sy ndrome is
associated with early -stage NB; it is probably caused by development of antineuronal
antibodies, and neurologic deficits usually persist despite cure of the tumor (22). Bone
metastases present as pain, refusal to walk, skull masses, or proptosis with orbital ecchy mosis.
Skin metastases are common in neonates and generally have a blue tinge (the “blueberry
muffin” sign). NB may infiltrate the marrow and cause pancy topenia with resulting
complications (infection, pallor, lethargy, bleeding). Intracranial metastatic disease is rare,
seen in less than 2% of patients at diagnosis, and may be parenchy mal or meningeal, and in
infants it may cause cranial suture separation (23).
The standard diagnostic evaluation of NB
(Table 6.3 ) includes imaging and laboratory
testing with the goals of determining disease
extent and prognosis and identify ing markers of
disease activity. The primary tumor ty pically is
imaged radiographically and with computed
tomography (CT) scan or magnetic resonance
imaging (MRI). The classical radiographic sign
of adrenal NB is calcification in a suprarenal soft
tissue mass (Fig. 6.4 ). In the thorax, a plain
radiograph demonstrates a posterior mediastinal
mass. In both abdomen and chest, CT scan and
MRI are helpful in assessing possible ly mph
node metastases and intraspinal extension (24).
The search for distant, usually bony
metastasis must include scanning with 123I-
metaiodobenzy lguanidine (MIBG) or 18F-
fluorodeoxy glucose scan (for patients whose
tumor does not take up MIBG), with conventional Table 6.3 Clinical Evaluation of
radiographs as indicated. Bone metastases are Neuroblastoma (Minimum
most often periorbital, metaphy seal, and axial in Recommended Studies to Determine
location (Fig. 6.5 ). Bone scintigraphy is more the Extent of Disease)
sensitive than conventional radiographs but is
sometimes difficult to interpret in infants y ounger than 1 y ear. MIBG is a guanethidine
derivative that is similar in structure to norepinephrine and epinephrine. The compound is
taken up via the norepinephrine transporter into catecholaminergic cells and stored in the
chromaffin granules. It is highly sensitive and specific for skeletal and soft tissue metastases
of NB, taken up in more than 90% of primary and metastatic tumors (25). The MIBG is
labeled with 123I and scintigraphy is performed for imaging. Because MIBG depends on
functional uptake by tumor cells, it is also useful in distinguishing residual active tumor after
treatment from masses composed of scar tissue and may complement CT scans (Fig.
6.5 ). More recently, response by MIBG scan has been shown to be a useful prognostic
marker of response and survival (26). 99m Tc-diphosphonate bone scans continue to be used to
detect metastatic foci in the skeleton, in patients who are negative by MIBG, though positron
emission tomography scans with 18F-fluorodeoxy glucose are a newer modality that
complement MIBG for determination of tumor viability. Several studies have demonstrated
that positron emission tomography scanning can visualize NB, even in some cases where
MIBG is negative, although in other cases the converse is true (27).
Liver involvement may be evaluated by CT, ultrasound, or MIBG or PET scan in older
children because it is usually focal or nodular. In
infants it may be diffuse and not apparent by
imaging. For this reason, some authorities
recommend liver biopsies for diagnostic workup
of infants. Pulmonary parenchy mal metastases
rarely occur at diagnosis in NB, although at
relapse they may be seen in 7% of cases and
should be sought with CT scan. At diagnosis, lung
metastases are associated with MYCN
amplification and high lactic dehy drogenase
(LDH), and predict a worse outcome (23). In
contrast, metastases limited only to distant
ly mph nodes denote a favorable prognosis (28).
Page 117There may be extensive
involvement of the bone marrow by tumor
without a change in the peripheral blood counts,
with some bone marrow tumor present at
diagnosis in 80% of children with metastatic
disease (23). Therefore, bilateral bone marrow
aspiration and biopsy are performed routinely,
with some centers using 4–10 core biopsies to Figure 6.5 This 123I-
minimize sampling error. Small amounts of NB metaiodobenzylguanidine scan shows
cells may be difficult to distinguish from intense localization in the primary
hematopoietic elements. The diagnosis of NB in retroperitoneal mass. Widespread bone
the bone marrow can be confirmed when only metastases are evident, with large
small amounts of tumor are present with lesions in the distal right femur and
immunohistochemical stains on the core biopsy, proximal left humerus, but multiple other
often using neuron-specific enolase (NSE) as a lesions are seen on the dome of the skull,
marker, or with immunostaining on a right humerus, right rib, pelvis, and both
concentrated cy tology specimen from the femurs and tibias, and in a few
aspirate. This technology clearly is more retroperitoneal areas, probably
sensitive than conventional analy ses, detecting representing nodal spread. Physiologic
one tumor cell per 105–106 normal uptake is seen in the salivary glands,
mononuclear marrow cells. At present, tumor liver, and thyroid gland, which was
detected by immunocy tology that is not insufficiently blocked with potassium
extensive enough to be diagnosed by iodide drops.
conventional bone marrow microscopy does not
affect staging or risk group at diagnosis. Reverse transcriptase poly merase chain reaction (RT-
PCR) is being used in a number of prospective studies to further quantify the prognostic
impact of minimal residual disease (MRD) detected in blood or bone marrow after therapy.
Standardized methods for both immunocy tology and RT-PCR have been agreed upon by
international consensus (29).
NB is associated with elevated or abnormal production, secretion, and catabolism of
catecholamines (or metabolites) in 90% of cases. Catecholamines and metabolites may be
measured in the urine: norepinephrine, VMA, 3-methoxy -4-hy droxy pheny lgly col, or HVA.
Dopamine may be measured in urine or serum. Urinary catecholamines ty pically are
presented as ratios to urinary creatinine. The sy mptoms associated with excess
catecholamine production include flushing and sweating, pallor, headache, and hy pertension.
Figure: Clinical Evaluation of
Neuroblastoma (Minimum Recommended
Studies to Determine the Extent of Disease)
Figure:
This 123I-metaiodobenzylguanidine scan shows intense localization in the primary
retroperitoneal mass. Widespread bone metastases are evident, with large lesions in the
distal right femur and proximal left humerus, but multiple other lesions are seen on the
dome of the skull, right humerus, right rib, pelvis, and both femurs and tibias, and in a few
retroperitoneal areas, probably representing nodal spread. Physiologic uptake is seen in the
salivary glands, liver, and thyroid gland, which was insufficiently blocked with potassium
iodide drops.
STAGING AND PROGNOSTIC FACTORS
Staging
Subsequent to 1993, most investigators have used the staging sy stem internationally developed
in 1989 and modified in 1993, the INSS (Table 6.4 ), in an attempt to improve and unify the
previous definitions (30). Most recently, a further modification was introduced by consensus
of the International Neuroblastoma Risk Group (INRG) Task Force (Table 6.5 ) (20).
Understanding the nuances of these sy stems is important for interpreting and accurately
comparing data from various reports and determining therapy.
The INSS was developed in order to have a uniform staging so that studies could be
compared. In classify ing tumors that cross the midline, infiltration (extending by contiguous
invasion to or bey ond the opposite side of the vertebral bodies) was chosen to identify tumors
presumably less favorable than those that are pedunculated and simply drape over the
midline. The INSS used Arabic numbers to distinguish it from the letters and Roman numerals
of the prior sy stems. However, some inconsistencies were noted due to the fact that it was a
postsurgical staging sy stem with substantial reliance on the assessment of tumor resectability
and surgical examination of ly mph node involvement. In fact, many patients with stage 3
disease do not actually undergo surgical resection at diagnosis, and many stage 2 patients do
not have extensive ly mph node sampling, resulting in possibly inaccurate staging.
Furthermore, the separation of stage 2A and 2B depending on ly mph node involvement is of
questionable prognostic value for OS, unless the tumor has unfavorable biology (31).
Therefore, four further international conferences were held from 2004 to 2006, and a new
international staging sy stem was proposed by the INRG task force in which anatomic staging
was performed by radiologic imaging, rather than surgery. In the INRGSS (International
Neuroblastoma Staging Sy stem), locoregional tumors are staged L1 or L2 based on the
absence or presence of 1 or more of 20 image-defined risk factors (IDRFs) (32),
respectively. Metastatic tumors are defined as stage M, except for stage MS, in which
metastases are confined to the skin, liver, and/or bone marrow in children y ounger than 18
months of age. Within a 661-patient European clinical trial cohort, IDRFs were present (i.e.,
stage L2) in 21% of patients with INSS 1, 45% of
patients with INSS 2, and 94% of patients with
INSS 3 disease. Patients with INRGSS stage L2
disease had significantly lower 5-y ear event-
free survival than those with INRGSS stage L1
disease (78% ± 4% vs. 90% ± 3%; p = 0.0010)
(33).
Clinical
Stage and age continue to be critical determinants of outcome. The disease stage strongly
influences prognosis (Fig. 6.6 ). With surgery as primary therapy, more than 90% of
children with stage 1 and 2 disease survive and 85% of children with stage 4S survive,
whereas with multimodality therapy, the survival is 60–90% for INSS stage 3 disease but only
40% for stage 4 disease (34). However, age at diagnosis is another strong determinant of
outcome, which must be factored in with stage. Originally 12 months was recognized as the
cut-off for a favorable outcome, even in advanced disease, but more recently it has been
shown that this can be extended to 18 months as long as the biology of the tumor is favorable.
Infants y ounger than 18 months of age do better than older children with the same disease
stage, an effect that is dramatic for patients with advanced stage 3 and 4 disease (35). Infants
and toddlers without MYCN gene amplification and with stage 4 disease have more than 80%
long-term survival with modest chemotherapy, whereas children older than 18 months at
diagnosis with stage 4 have less than 40% survival with very intensive therapy. This may be
related to a higher rate of spontaneous tumor regression or tumor maturation in infants (35).
On the other hand, adults and adolescents with NB have a particularly poor long-term
survival, even with disease presenting without metastases, although their course may be
prolonged (36). Response to therapy is another important clinical prognostic factor for
patients with advanced disease (26).
Page 119
Figure 6.6 Overall survival according to International NB Staging System (INSS) stage of
1034 children with neuroblastoma treated on Children’s Cancer Group protocols from 1991
to 1995. INSS stage 1, n = 195; INSS stage 2, n = 117; INSS stage 3, n = 184; INSS stage 4S, n =
64; INSS stage 4, n = 474. (Courtesy of the Children’s Cancer Group Statistical Office.)
Page 120Biologic
Several nonspecific inflammatory serum markers have prognostic value in NB, including
ferritin, LDH, and NSE. All the three are more likely to be elevated in advanced disease and
are predictive of a worse outcome in univariate analy sis. Ferritin may be produced by NB
cells and thus reflects tumor burden or growth, or it may be necessary for NB cell growth.
An elevated serum ferritin level (more than 92 ng/mL) is found in up to half of patients with
advanced-stage disease but rarely in children with localized disease. PFS is lower for children
with elevated levels (9). NSE may be useful as a marker for following the response to
treatment. LDH may reflect tumor cell burden or turnover, and serum elevations (750–1500
IU/mL) have been found in some studies to be independently associated with a worse
prognosis (9).Two neural markers found in the serum of NB patients may also be markers of
disease activity and prognosis, including GD2 and chromogranin A, though these are not part
of the standard risk stratification criteria. In summary, numerous clinical, biochemical, and
genetic risk factors have been shown to have prognostic value in various studies, but the recent
multivariate analy sis by the INRG has shown
that for practical purposes patients can be
effectively placed into risk groups for
therapeutic assignment using the readily
available clinical and genetic factors. Those that
have appeared to be consistent over many y ears
and readily available to the clinician have been
combined to form a framework for risk
stratification in current therapeutic studies. Age,
INSS stage, histopathology, tumor cell ploidy,
MYCN gene copy number, LOH 1p and 11q are Figure 6.7 Event-free survival based
the factors used in risk stratification and therapy on COG risk stratification. The event-free
assignment for the current COG clinical trials in Kaplan–Meier survival curves calculated
North America, with very similar guidelines from the time of diagnosis for 5,829
used internationally (Tables 6.8 and 6.9 ). children enrolled onto ANBL00B1 (>2001)
The survival for low and intermediate risk or onto Children’s Cancer Group,
patients by this classification is more than 90% Pediatric Oncology Group studies (<2001)
(31,35,37), and that of the high-risk group between 1990 and 2010 were classified as
remains at about 40% (Fig. 6.7 ) (34,38) low-, intermediate-, and high-risk NBL at
(Tables 6.8 and 6.9 ). diagnosis based upon clinical and biologic
factors (age, International Neuroblastoma
Staging System stage, MYCN status, DNA
copy number and histologic grading).
(Reproduced from Park JR, Bagatell R,
London WB, et al. Children’s Oncology
Group’s 2013 blueprint for research:
neuroblastoma. Pediatr Blood Cancer.
2013;60:985–993, with permission.)
Table 6.7 International Neuroblastoma Risk Group Working Committee Modified
Response Criteria
Table 6.8 Children’s Oncology Group Neuroblastoma Risk Groups for Treatment
Table 6.9 INRG Risk Classification
Figure: International Neuroblastoma
Staging System
Figure: International Neuroblastoma Risk
Group (INRG) Staging System
Figure: International Neuroblastoma
Response Criteria
Figure:
Overall survival according to International NB Staging System (INSS) stage of 1034 children
with neuroblastoma treated on Children’s Cancer Group protocols from 1991 to 1995. INSS
stage 1, n = 195; INSS stage 2, n = 117; INSS stage 3, n = 184; INSS stage 4S, n = 64; INSS stage
4, n = 474.
(Reproduced from Park JR, Bagatell R, London WB, et al. Children’s Oncology Group’s 2013
blueprint for research: neuroblastoma. Pediatr Blood Cancer. 2013;60:985–993, with
permission.)
Figure: Children’s Oncology Group
Neuroblastoma Risk Groups for Treatment
Figure: INRG Risk Classification
SELECTION OF THERAPY
Low-risk tumors are managed with surgery alone unless sy mptomatic cord compression or
respiratory compromise necessitates a short course of chemotherapy. Patients in the low-risk
group with stage 1 or 2 disease have an expected 4-y ear survival of more than 95% with
surgery only, whereas infants with INSS 4S have more than 90% survival with supportive
care or a short course of chemotherapy (31,39). The smaller intermediate-risk group consists
of infants and toddlers with stage 4 disease (but no tumor MYCN amplification), favorable
biology stage 3, or INSS 4S with unfavorable histology or DNA index. Patients in this group
have been shown to have an estimated survival of more than 90% with moderate dosages of
chemotherapy for 4–8 months and primary tumor resection (35,37). Radiotherapy (RT) is
rarely used in the low- or intermediate-risk groups because of their favorable prognosis and
the fact that many of these patients are y ounger than 1 y ear. It is reserved for use in life- or
function-threatening situations. It is occasionally needed for cases of unresectable primary
disease remaining after chemotherapy or regional recurrences not controlled with
chemotherapy.
Page 121The high-risk group in NB consists primarily of patients with stage 4 disease of
any age who have MYCN amplified tumors, or children age 12–18 months (365–547 day s)
with any of the following three unfavorable biologic features (MYCN amplification,
unfavorable pathology and/or DNA index = 1), and all those with stage 4 disease who are
greater than 18 months of age at diagnosis. Also included are stage 3 with either tumor MYCN
amplification or those older than 18 months with unfavorable histopathology, stage 2 above 1
y ear of age with MYCN amplification, and stage 4S infants with MYCN gene amplification.
Despite the use of increasingly aggressive combined-modality treatments, which have higher
remission rates and durations, the long-term survival for INSS stage 4 disease in children who
are older than 18 months at diagnosis has remained less than 15% until the early 1990s. The
most recent phase III studies indicate that the 3-y ear EFS of this group has steadily increased
in the past decade to up to 50% with the use of my eloablative therapy and treatment for MRD
but is still far below the desired outcome (34).
Page 122Therapy for high-risk NB is divided into three phases: intensive induction
treatment, marrow ablative therapy, and management of MRD. The goal of induction
therapy is to achieve maximum reduction of tumor burden, including reduction of bone
marrow tumor (in vivo purging), within a timeframe that will minimize the risk of resistant
tumor clones and clinical progression. During or at the end of this phase, local control of bulky
disease is accomplished with delay ed surgery and local RT, which is usually given after
my eloablative therapy. Subsequently, very high dose marrow ablative therapy may be used
to try to overcome residual and potentially resistant tumor, followed by hematopoietic cell
transplant (HCT). The relapse rate of more than 40% even after such treatment has led to the
approach of using tumor-targeted therapies after my eloablative treatment to try to eliminate
microscopic resistant clones (minimal residual disease) (34).
Chemotherapy
As indicated earlier, chemotherapy is used in low-risk disease only for recurrence or for
sy mptomatic patients with compromised organ function. Intermediate-risk patients can
achieve long-term survival with moderate combination chemotherapy for 4–8 months (35).
The most effective induction regimens for obtaining complete or partial response are
combination of platinum-based regimens including other active drugs such as
cy clophosphamide, doxorubicin, etoposide, vincristine, and ifosfamide. Induction regimens
used in recent large cooperative studies are shown in Table 6.10 , with overall response
rates generally ranging from about 60% to 80% at the end of 5–6 months of treatment
(38,40,41). Most recently, the COG has incorporated two cy cles of topotecan with
cy clophosphamide into the N7 ty pe induction, with similar response rates and successful
peripheral blood stem cell harvests (42). The European group has tested a dose-intensive
schedule in a randomized trial of 262 patients that randomly assigned 132 patients to standard
and 130 patients to rapid treatment. The relative dose intensity of the rapid regimen was 1.94
compared with the standard regimen. My eloablation was given a median of 55 day s earlier
in patients assigned to the rapid regimen. Although OS did not differ, the 5-y ear EFS was
18.2% in the standard group and 30.2% in the rapid group, representing a difference of 12.0%
(1.8–22.3), p = 0.022 (43). However, the EFS in this study was apparently not different from
other recent protocols using less dose intensive regimens. Most of these regimens also include
surgery for residual disease, although the overall impact of complete resection on survival in
stage 4 disease is still contradictory.
Table 6.10 Induction Regimens for High-Risk Neuroblastoma Since 1985 (More Than 50
Patients)
Table 6.11 EFS for High-Risk Neuroblastoma in First Remission Using Myeloablative
Therapy and Hematopoietic Cell Transplant for Studies of More than 20 Patients
(From Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-
risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-
cis-retinoic acid: a Children’s Oncology Group study. J Clin Oncol. 2009;27(7):1007–1013, with
permission.)
THERAPY FOR MINIMAL RESIDUAL DISEASE
Despite improvements in EFS using my eloablative therapy, the relapse rate, even for patients
transplanted in complete response, remains high (34). For this reason, it has become
increasingly important to find new approaches to eliminate MRD with agents that will be
tolerable after my eloablative therapy. Immediately after HCT, when disease is likely to be
minimal, is the ideal window of time to eradicate resistant clones that are still present using
novel therapies not dependent on standard cy totoxic mechanisms.
In vitro, both all-trans-retinoic acid and 13-cis-retinoic acid cause decreased
proliferation and differentiation in NB cell lines, including some established from refractory
tumors. A phase II trial in children with relapsed NB using 13-cis-retinoic acid on a single
daily administration schedule of 100 mg/m 2 showed only 2 of 22 responses (63). However,
based on in vitro experiments with higher intermittent dosing, a phase I trial in children with
high-risk NB after HCT determined that a high-dose intermittent schedule of 13-cis-retinoic
acid after BMT had minimal toxicity, achieved levels that were effective against NB cell lines
in vitro, and resulted in complete bone marrow responses in 3 of 10 patients. A subsequent
phase III randomized trial by the CCG of children with high-risk NB completing consolidation
chemotherapy or ABMT showed that the 3-y ear EFS from the time of randomization was
significantly better for the patients randomized to receive 13-cis-retinoic acid (46% ± 6%)
than for those randomized to receive no further therapy (29% ± 5%; p < 0.03) (Fig. 6.9 )
(40). A European randomized trial of very low-dose continuous 13-cis-retinoic acid given
after transplant did not show any benefit (64). Other investigational retinoids, such as
fenretinide, are under investigation for use in MRD (65).
Figure 6.9 Event-free survival from posttransplant randomization for high-risk
neuroblastoma treated with chimeric anti-GD2 monoclonal antibody (ch14.18) with IL-2, GM-
CSF and isotretinoin (RA) versus isotretinoin alone for treatment of minimal residual disease.
The difference in 2-year EFS was 66.5% for the randomized immunotherapy arm, compared
to 46.5% for isotretinoin alone (p = 0.01). (Reproduced from Yu AL, Gilman AL, Ozkaynak MF,
et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N
Engl J Med. 2010;363:1324–1334, with permission.)
(Reproduced from Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF,
interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–1334, with
permission.)
SURGERY
Surgery has both a diagnostic and a therapeutic role. If the diagnosis has not been established
by bone marrow aspirate, biochemical testing, or skin biopsy, surgery provides histologic
confirmation of malignancy. Even in the presence of a clear, nonsurgically determined
diagnosis of NB, a tissue sample is important for biologic analy sis.
As previously stated, 20–40% of children present with localized disease. In children
without evidence of metastatic disease, an attempt at resection is warranted if substantial
morbidity (sacrifice of vital structures) can be avoided. Complete gross excision of the
primary tumor in localized disease is associated with a very high likelihood of cure
irrespective of the patient’s age. For patients with stage 1 or 2 disease, the cure rate exceeds
90% as stated above (31). The LNESG1 study in localized neuroblastoma (72) demonstrated
significantly worse overall survival (89% vs. 98%) and event-free survival (79% vs. 92%) for
patients with IDRF (L2 vs. L1). Moreover, L2 patients had higher surgical complication rates
versus L1 (17% vs. 5%). If the tumor is localized but unresectable because of its intimate
relationship with major blood vessels or other characteristics, the proper extent of surgery
may depend on tumor biology. In a study of 228 patients with INSS stage 3 NB, for children
who had elevated serum ferritin or tumors with unfavorable histopathology or MYCN
amplification, the EFS was improved by complete gross resection, whereas the extent of
resection did not appear to affect the children with biologically favorable tumors treated with
standard dose chemotherapy (73). Similar results were observed in the 427 patients on the
LNESG1 study (74), where MYCN amplification led to poor outcomes with surgery alone.
The optimal timing of the surgery is still under debate; it is possible that the advantages of
early resection are outweighed by a higher complication rate before chemotherapy
reduction followed by delay ed surgery. However, even when the primary tumor is
unresectable, defining its extent remains important for staging and determining optimal
additional local therapy with radiation. Employ ment of preoperative IDRFs as part of the
newer INRG staging sy stem has been shown predictive of completeness of resection (75).
Page 128Recurrence in the local or regional area of primary disease is a component of
relapse in a large proportion of children with high-risk NB, at rates ranging from 20% to 80%
in reports that often include local RT and my eloablative therapy. Both single-arm studies and
one randomized study demonstrate the benefit of local control measures for children with
advanced but nonmetastatic NB (73,76), but the impact of resection in stage 4 disease in the
past were mixed. However, as therapy intensity has improved control of metastatic disease
and survival, the importance of local control of the primary disease via gross total resection
and radiation therapy seems to have increased (77). A recent meta-analy sis shows for stage 3
NB GTR versus STR 5-y ear OS odds-ratio of 2.4 (95% CI 1.19–4.85) and 1.65 (95% CI 0.96–
1.91) for stage 4 disease (78). A series of 104 high-risk NB patients treated with resection prior
to HSCT at Duke university demonstrated no significant OS benefit to GTR, but there was
improved OS with >90% resection versus <90% (p < 0.008) (79). Current consensus still
supports that more extensive resection is associated with better survival outcomes, which may
be of greatest importance in the presence of high-risk disease features such as MYCN
amplification. As with early stage disease, data from NB97 for stage 4 patients demonstrate
IDRFs are predictive of extent of resection (80).
Second-look surgical procedures are commonly used in NB. Chemotherapy and
irradiation may produce significant interval regression of a bulky primary tumor. For patients
with residual tumor, surgery may then be performed to achieve a complete response.
Children who have localized NB converted to a resectable status by interval therapy and who
undergo complete excision have a better prognosis (76). Completely resecting the primary
tumor also appears feasible for patients with advanced disease; eventual complete excision
can be accomplished in up to 65% of patients (81). Resection after chemotherapy appears to
be associated with fewer complications than resection before chemotherapy. The Italian
Cooperative Group for Neuroblastoma has reported 145 patients with localized inoperable NB
or primary tumor excised with a tumor residue more than 2 mL. Ninety -four of the 145
(65%) achieved a complete or partial response with chemotherapy, and 75 (52%)
subsequently underwent complete resection (82).
Although the prognostic value of ly mph nodes has been controversial, and nodes
adherent to or removed with the primary tumor do not appear to predict prognosis, ly mph
nodes that are distinct (usually superior or inferior, but especially if bilateral or contralateral)
from the tumor are ideally sampled for complete staging and later considerations for RT
(28,32). However, this may be difficult for some patients with cervical or thoracic tumors or
infiltrative unresectable abdominal primaries. The utility of other prognostic factors suggests
that aggressive attempts to acquire this information are unwarranted. If RT is contemplated,
clips should be used to mark the tumor.
If treated surgically, dumbbell tumors are dealt with by a two-stage procedure. The
extraspinal component of the tumor is removed at a first operation. The extradural, intraspinal
portion of the tumor is removed later. However, if there is evidence of spinal cord
compression and if surgery is used, the laminectomy is performed first. Osteoplastic
laminotomy is preferable to minimize later deformity (83). Many institutions prefer to treat
spinal cord compression with chemotherapy to try to minimize late deformities. A study of
576 NB patients treated at Children’s Cancer Hospital of Egy pt reported 51 patients (9%) with
spinal cord compression at presentation, the majority of whom were treated nonsurgically,
with chemotherapy ± steroids with improved neurologic outcomes in the subset who were
sy mptomatic, driven only by the initial duration of sy mptoms (93% vs. 70%, ≤4 weeks vs. >4
weeks, p = 0.008) (84).
On occasion, infants with a small primary tumor and extensive liver metastases (stage
4S) warrant special surgical considerations. The enlarging liver may compromise respiratory
function from upward pressure on the diaphragm or compress the inferior vena cava or renal
vein. If chemotherapy or local irradiation does not adequately reduce hepatic size, a silastic
sheet may be inserted in the abdominal wall to allow room for liver expansion and reduce
compression of vital structures. Resection of the primary tumor does not influence survival in
stage 4S (39,85).
RADIATION THERAPY
Intermediate-Risk Disease
For children with regional NB on the less favorable end of the spectrum (i.e., INSS stage 3),
several reports support a survival advantage from the use of RT (Table 6.11 ).
Unfortunately, because of the previous multiple staging sy stems, many reports have
combined INSS stage 2B and INSS stage 3, making it difficult to discern whether radiation is
beneficial in both of these groups. As noted above, recent studies suggest that INSS stage 2B
disease does not necessitate RT, despite older reports showing improved survival with RT.
Patients with stage 3 disease who are more than 1 y ear old with MYCN amplification or
unfavorable pathology need additional treatment. For these children EFS is only 50–60%,
even with aggressive multimodality therapy (73). Only one randomized study of RT has
clearly delineated results for unresectable nonmetastatic disease. This POG study
randomized patients more than 1 y ear old with stage C NB to receive postoperative
chemotherapy or chemotherapy with regional RT (24–30 Gy, 16–20 fractions). Of 62 eligible
patients, in the chemotherapy arm 45% and 31% achieved complete remission and remained
disease-free, respectively, at a median of 35 months, and in the chemotherapy and RT arm
67% and 58% achieved complete remission and remain disease-free, respectively, at a
median of 23 months. Unfortunately, the chemotherapy used in this 10-y ear study was much
less dose intensive than current protocols, and there were no biologic risk factors reported,
rendering these results nearly impossible to interpret in the context of current therapy (93).
However, current reports seem to support the importance of local control in biologically
unfavorable high-risk stage 3 disease, although no further randomized trials have been
performed (76). All current protocols prescribe RT for residual disease after chemotherapy,
with the exception of infants and children with favorable biology (nonamplified MYCN,
favorable histology, hy perdiploid) (Table 6.12 ).
The completed COG study for intermediate risk disease (A3961), including stage 3 with
favorable biology and infant stage 4, used surgery to provide diagnostic material at
presentation and to attempt safe maximal resection of the primary tumor after
chemotherapy. Chemotherapy included cy clophosphamide, doxorubicin, carboplatin, and
etoposide. The duration of chemotherapy was based on the biologic risk factors. RT was
limited to situations in which there was clinical deterioration despite chemotherapy and
surgery or persistent tumor after chemotherapy and second-look surgery. This treatment
resulted in >90% survival for this group (35).
High-Risk Disease
Nearly half of all patients diagnosed with NB present with high-risk disease. Despite
concerted clinical and scientific efforts, the prognosis of children with high-risk NB remains
poor. Less than 30% of patients with high-risk disease who are more than 1 y ear old survive
more than 5 y ears. Historically, early attempts to use radiation to cure children with
advanced NB focused on large-volume RT, “segmental” or “sequential” fields administered
as fractionated or single doses. Mixed results in the face of significant toxicities diminished
enthusiasm for such radiation approaches, and they ultimately fell out of favor.
Page 130Although large-field RT has not proven efficacious, the concept of aggressive
sy stemic therapy has prevailed and has proven successful at improving outcomes for high-
risk patients. The randomized CCG 3891 trial showed superior clinical outcomes for patients
with high-risk NB who were treated with my eloablative chemotherapy and TBI with
transplantation of purged autologous bone marrow (40). Indeed, TBI has play ed a prominent
role in many my eloablative regimens. Table 6.10 summarizes studies that use autologous
or allogeneic BMT either with or without TBI as a component of their preparatory regimens.
For most reports EFS rates are on the order of 20–40%, although mortality continues to
increase as follow-up lengthens. As with older TBI protocols, trends in conditioning regimens
for stem cell transplantation have favored omitting TBI because it limits dosages of
my eloablative chemotherapy that can be administered and because of the increase in late
effects in y oung children.
Although the use of TBI for NB is nearly obsolete, an enlarging body of evidence
supports the use of local RT to the primary site and bulky metastatic sites. Disease recurrence
after BMT for NB is most common at previous sites of disease. Local radiation delivered
either in preparation for transplant or afterwards appears to reduce the risk of relapse at these
sites (81,94). Indeed, the current standard of care dictates that patients with high-risk disease
receive radiation to the primary disease site regardless of the extent of surgical resection and
to sites of metastatic disease that display persistent 131I-MIBG avidity on the pre–stem cell
transplant scans.
Several reports have specifically tackled the role of radiation to the primary tumor site in
uniform cohorts of patients with advanced NB. Such results strongly support the
administration of radiation to the primary site in high risk disease. These single-institution and
small consortium studies have reported excellent local control rates after treatment regimens
that consist of induction chemotherapy, delay ed primary surgery with attempted resection of
primary and bulky metastatic lesions, external beam radiation to the primary tumor site and
persistent metastatic areas, my eloablative chemotherapy, and infusion of stem cells. A report
from Japan describes a program of intensive chemotherapy and treatment of primary
disease with surgery and radiation for a group of children more than 1 y ear old with stage 4
disease, although a few patients with stage 3 disease and children y ounger than 1 y ear were
included. The 5-y ear EFS was 39% (50). CCG protocol 321P3 used a dose-intensive
combination of four chemotherapeutic agents followed by autologous purged BMT and
enrolled 99 children more than 1 y ear old with stage 4 and high-risk stage 3 disease. The 4-
y ear PFS was 40% (51). Despite TBI and local RT to residual disease, the primary site was
involved in more than 50% of the relapses (45). Better primary control was seen at Memorial
Sloan–Kettering Cancer Center in patients with stage 4 NB, who received higher dose local
radiation to primary tumor sites regardless of resection and had an actuarial locoregional
control rate of 84% at 5 y ears (94). An update of this single-institution experience reported a
10.1% probability of primary site failure among 99 patients, 92 of whom had no evidence of
disease in the primary site at the time of irradiation (95). Children received 1.5 Gy twice a
day to 21 Gy to the prechemotherapy, presurgery primary tumor volume and regional
ly mph nodes. Among seven patients with disease at the primary site at the time of irradiation,
three had disease that recurred locally. A similar treatment regimen was used by the German
multicenter NB trial in which 14 of 26 patients with advanced disease had disease that
relapsed, with 4 (29%) including the primary sites (96). Comparable regimens have resulted
in decreased local relapse rates, ranging from 0% to 17%. A report from St. Jude Children’s
Research Hospital on 63 patients with metastatic neuroblastoma demonstrated comparable 5-
y ear rates of local failure (35%) among patients receiving radiotherapy for local control
versus those who did not, despite higher rates of residual disease prior to consolidation therapy
(88% vs. 70%, p = 0.008) (97).
Page 131Although favorable local control rates have been reported in single-institution
and small consortium studies, large multi-institutional studies have lower rates of complete
total resections and differing chemotherapy regimens that limit direct comparisons of clinical
results. Therefore, it is not surprising that large, modern multi-institutional trials report higher
rates of local relapse. The CCG trial (CCG 3891) showed superior EFS for patients with high-
risk NB who were treated with my eloablative chemotherapy and TBI with transplantation of
purged autologous bone marrow, followed by treatment with 13-cis-retinoic acid. External
beam RT (EBRT) was prescribed for all patients with gross residual disease after induction
chemotherapy and surgery. Patients randomly assigned to the transplantation arm received
additional TBI as a component of the ablative regimen (40).
In CCG 3891, recurrence at the primary disease site was a major component of relapse.
Among 539 patients, 349 had recurrences, including 31 with isolated locoregional relapses,
148 with simultaneous local and distant recurrences, and 150 with distant relapses. At 5 y ears,
the estimated regional recurrence rate was 51% ± 5% among patients who received
continuation chemotherapy and 33% ± 7% among patients who received transplantation. The
difference in local relapse rates between the continuation chemotherapy and ABMT groups
was most pronounced in patients with MYCN-amplified tumors. Among patients with MYCN
amplification, the estimated 5-y ear local recurrence rate was 70% ± 10% for those who
received continuation chemotherapy and 25% ± 15% for patients who received ABMT (81).
Although CCG 3891 did not examine the benefit of local EBRT in a randomized fashion,
some conclusions were evident from an analy sis of RT administered in this trial. For patients
who received 10 Gy of EBRT to the primary site, the addition of 10 Gy of TBI and ABMT
resulted in lower local recurrence rates than continuation chemotherapy. The benefit of RT
was particularly evident when sy stemic treatment was optimized with my eloablative therapy
and 13-cis-retinoic acid (81). For patients with high-risk NB, we recommend EBRT to the
primary tumor site in the context of a my eloablative regimen that does not include TBI but
incorporates posttransplant therapy for MRD.
For patients with metastatic sites that do not warrant early sy mptomatic palliative
radiotherapy, current consensus on North American protocols specifies radiation of up to five
metastatic sites with persistent active disease demonstrated at the time of evaluation prior to
high-dose consolidative chemotherapy, as demonstrated on 131I-MIBG scan. A multi-
institutional analy sis of 43 patients with metastatic NB, including bone and soft-tissue sites of
metastasis, reported a reduced risk of relapse at bony sites with irradiation (25% vs. 17%, p =
ns) (98). A study from Bay lor examining EBRT to the primary tumor bed and metastatic sites
that remained MIBG-avid after induction chemotherapy included 21 sites of metastatic
disease that received 24 Gy and demonstrated local control of 74% (99).
CNS Metastases
Some controversy exists regarding whether increasingly aggressive multimodality therapy
for stage 4 disease has altered patterns of metastases. Some metastatic sites, although perhaps
rare in NB patients, pose unique therapeutic challenges, exemplified by CNS metastases. The
incidence of CNS metastases in children with high-risk stage 4 NB varies depending on
whether reporting at diagnosis (2%) or relapse (8–12%) (23,100).
In a COG study, all 648 patients with stage 4 NB in CCG 3881 and 3891 were analy zed
for sites of metastases. At diagnosis, the most common sites of metastases were bone
marrow, bone, ly mph nodes, and liver. The distribution of metastatic sites differed between
patients at diagnosis and those at first progression. Whereas the frequencies of bone, bone
marrow, liver, ly mph nodes, and skin metastases were lower at first progression than at
diagnosis, frequencies of adrenal, lung, and CNS metastases exhibited the opposite propensity.
Whereas CNS involvement was almost never seen at diagnosis, at first progression, CNS
metastases were more common in all age groups. Of all patients with stage 4 disease and
relapse, 11% of children y ounger than 1 y ear and 3% of children 1 y ear or older had CNS
metastases at relapse. Although the number of patients with CNS metastases was small, a few
trends were evident. All patients with CNS metastases were more than 1 y ear old, died within
1 y ear of diagnosis, and had both MYCN amplification (among those tested) and unfavorable
Shimada histopathology. Among patients with CNS metastases at diagnosis and those y ounger
than 1 y ear who progressed with CNS metastases, hematogenous spread to parenchy mal sites
was nearly absent. In contrast, for patients older than 1 y ear, CNS metastases at progression
appeared to result from hematogenous routes of spread (23).
A similar analy sis at the Institute Curie and Institute Gustave-Roussy confirmed that CNS
metastases at diagnosis are extremely rare but revealed an estimated 3-y ear risk of CNS
recurrence of 8% among patients with stage 4 disease, a rate that was stable over 15 y ears
(100). Patients with CNS recurrences were equally distributed among those with
parenchy mal lesions, those with only meningeal involvement, and those with a combination
thereof. Of note, 131I-MIBG scans did not reliably identify CNS recurrences, detecting
lesions in only 43% of those with known CNS metastases (100).
In contrast to the aforementioned studies, investigators at Memorial Sloan–Kettering
Cancer Center found more CNS metastases associated with increased intensity of curative
protocols for patients with stage 4 disease (101). In patients treated with earlier N4–5
protocols, 2% recurred in the CNS, whereas in those treated with more intensive N6–7
protocols, 12% experienced CNS metastases, perhaps reflecting the longer median survival
times in patients treated on N6–7. As patients live longer, metastases to sanctuary sites such as
the CNS may become more evident.
Although prospective head CT or MRI scans may better quantify the true incidence of
CNS metastases, the infrequent occurrence of such metastases does not justify routine CNS
imaging. Furthermore, although most studies do not support an increase in frequency of CNS
metastases in the past two decades, it is unclear whether the movement away from TBI for
stage 4 NB will result in increased metastases to sanctuary sites such as the CNS. The rarity
of CNS metastases does not justify prophy lactic CNS radiation; however, for a patient with
CNS recurrence the appropriate field of radiation remains unclear. In some instances, highly
localized stereotactic radiotherapy may provide durable control of intracranial metastases
(102).
Page 132CNS parenchy mal or meningeal metastatic relapse has portended a very short
survival in prior studies, with median survival of 3–6 months. However, with aggressive
surgery and local radiation, survival may be extended in some instances. Memorial Sloan
Kettering Cancer Center reported on a series of 29 children with NB and CNS relapse who
received either focal RT (13 patients) or low-dose craniospinal RT (CSI) ± intra-Ommay a
radioimmunotherapy (16 patients). Intrathecal radioimmunotherapy consisted of 131I-
monoclonal antibodies targeting GD2 or B7H3. At a median follow up of 28 months, 75% had
no evidence of CNS disease whereas all the patients in the focal radiotherapy group had died
(101).
NB occurs only rarely in adolescents and adults. More than one-third of patients are
diagnosed before the age of 1 y ear, whereas less than 5% of patients present after the age of
10 y ears (19). NB in adolescents and adults presents unique challenges that necessitate distinct
analy ses and therapeutic approaches.
NB in adolescents and adults is characterized by an indolent course, persistent disease,
multiple recurrences, and poor outcome (36). In studies examining patients who were
diagnosed with NB between the ages of 15 and 75 y ears, less than 5% of patients are long-
term survivors, without evidence of disease (106). Most aspects of clinical presentation are
similar to those of y ounger patients. For example, sites of metastatic disease are similar in
adolescents and y ounger children, most commonly found in bone marrow, ly mph nodes,
bone, and liver. However, distinct differences occur between y ounger patients and
adolescents with NB. Such differences in tumor histology and secretion of catecholamine
metabolites may reflect the unique entity of NB in adolescents and adults. The lower
frequency of MYCN amplification and secretion of catecholamine metabolites probably go
hand in hand with the more chronic nature of the disease in this age group (106).
Franks et al. (106) reported the experience of the CCG with NB in adults and adolescents.
This study examined 16 patients from the University of California, San Francisco (UCSF),
and 38 patients registered in the CCG, all 13 y ears or older. They found that older patients
experienced multiple recurrences; chronic, prolonged courses; and poor outcome regardless
of stage or site of disease. For example, although 25% of patients in the UCSF series had
pelvic primaries, a site that in y ounger patients is associated with more favorable outcome,
pelvic primaries were associated with outcomes as poor as those for adults and adolescents
with other primary sites (106). The indolent, chronic nature of NB in adults and adolescents
was reflected with a long median time to progression of 32 months. Although stage IV disease
recurred within a y ear from diagnosis in most patients, late recurrences were observed, as
long as 83 months after diagnosis. Furthermore, although y ounger patients with stage IV NB
have only a 3- to 4-month median survival after their first recurrence, similarly staged
adolescents experienced multiple recurrences and persistent disease after their first
recurrence. After their first recurrence, adolescents and adults had a median survival of 17
months, with a significant proportion surviving more than 4 y ears after recurrence (106).
Whereas the CCG and UCSF experiences demonstrate poor outcome for all adolescents,
regardless of stage, the French Society of Pediatric Oncology found that patients with stage I–
II disease fared well and had survival rates comparable to those of y ounger patients with
early stage disease (107). None of six patients with stage I–II disease experienced
recurrence. In contrast, adolescents with stage III disease experienced multiple recurrences,
with prolonged and chronic clinical courses. This is reflected in discordant PFS and OS rates
at 5 y ears, which were 28% and 86%, respectively. Adolescents with metastatic NB had low
PFS and OS rates of 18% and 27%, respectively, and exhibited poor responses to intensive
chemotherapy (107).
The poor outcome for adults and adolescents, even with localized disease, calls into
question the usual risk-based treatment in this age group. Aggressive multimodality therapy
may be appropriate even for patients with low-stage disease but certainly for patients with
INSS stage 3 and 4 disease. In the analy sis of the INRG database, the older patients who
received my eloablative therapy had a significantly better outcome than those treated with
nonmy eloablative therapy (36). In addition, higher radiation doses are appropriate. Doses to
the primary tumor site should be maximized, tailored to the individual disease sites, and
constrained by tolerance of adjacent normal tissues. For example, abdominal primary
tumors should be treated with 45 Gy, which constitutes small bowel tolerance, as long as the
dosage to the kidney s and liver can be kept within tolerance. Given the poor clinical outcome
for adults and adolescents with NB, creative approaches are warranted in the treatment of
such patients, including immunotherapy, differentiating agents, targeted RT using 131I-MIBG,
and biologic agents.
RADIOTHERAPEUTIC MANAGEMENT
Page 133Volume
The volume for radiation of regional NB is determined by imaging studies and by the
operating surgeon’s description. If ly mph node involvement is suspected or proven, a wide
field that covers the primary tumor site and involved ly mph nodes is appropriate. If the field
must cover a portion of the vertebral body, the full width of the bone should be encompassed
in preadolescent children. This will y ield uniform vertebral growth impairment and reduce
the severity of subsequent scoliosis as well as ensure coverage of the regional ly mph nodes.
Controversy surrounds the issue of whether next-echelon ly mph nodes (i.e., mediastinal
ly mph nodes with an upper abdominal primary tumor) need be radiated. Relapse in
nonradiated next echelon nodes can occur, albeit usually in conjunction with local or distant
failure. In the Duke experience of 33 patients with stage A to C, 12 relapsed. Only 1 of the 21
irradiated patients (5%) experienced an in-field failure, whereas 7 of the 12 not receiving RT
(58%) experienced local failures at the time of recurrence (p = 0.001). Routine next-echelon
nodal irradiation was not given. Five of the 12 patients who suffered a relapse had next-
echelon nodal failure as a component of relapse; only one case was an isolated next-echelon
nodal failure (103). Current analy sis of LN irradiation from A3973 did not show
improvement in local control or survival with extensive nodal irradiation (manuscript in
progress). Extensive nodal fields may contribute to late morbidity and limit the ability to give
chemotherapy, so most treatment approaches cover only the primary tumor volume and
involved nodal groups. With a dumbbell-shaped tumor, careful attention must be paid to the
intraspinal and extravertebral components of the tumor to ensure full coverage.
As previously discussed, RT may be used for INSS stage 4S–associated sy mptomatic
hepatomegaly. The entire liver need not be irradiated to induce tumor regression. The
therapist may use portals designed to avoid the kidney s and, in girls, the ovaries. One may use
a simple conventional setup with two lateral fields, parallel opposed or slightly angled
anteriorly, to treat the majority of the liver but spare the kidney s. Placing the posterior border
of the lateral field at the anterior aspect of the vertebral body accomplishes this objective.
The ovaries are generally avoided by keeping the inferior border of the field at or above the
superior iliac crest. Radiation doses for stage 4S hepatomegaly are low, usually 2–6 Gy in two
to four fractions, so it could be argued that the kidney s are in little danger of chronic injury
and that the liver could be treated with parallel, opposed anterior and posterior fields or a
single anterior field. Although these are acceptable field arrangement options, the infant
kidney is more sensitive to radiation than kidney s in older children. Children with stage 4S
disease have high likelihood of survival and, if possible, should not be subjected to risks of
lifetime reductions of glomerular filtration rates. Stage 4 NB with hepatomegaly may also be
treated for palliation with ports designed to cover the entire liver, using the opposed lateral
beams. NB metastases occur in a wide variety of locations. Bone and soft tissue sites are
irradiated with moderate margins using a variety of beam arrangements to minimize dose to
uninvolved regional tissues.
Dose
Classic radiobiologic analy ses reflect the relative radiosensitivity of NB cell lines in vitro but
produce conflicting results regarding the most appropriate fractionation schedules. The D0 for
most mammalian tumor cell lines is between 1.3 and 1.5 Gy. The n is usually between 1.5
and 10. The n is the extrapolation number and measures the width of the survival curve
shoulder. The D0 describes the final slope of the cell survival curve and is the dose required to
reduce survival from 0.1 to 0.037. Collated data on 11 NB cell lines derived from 7 patients
indicate moderate cellular radiosensitivity bey ond that seen for many other mammalian
tumors. The median n for NB is 1.36, and the D0 is 1.04 Gy (108). This low repair capacity
for radiation damage implies that little sparing would result from dose fractionation. Wheldon
et al. (109) used human NB grown as multicellular tumor spheroids (MTS) to confirm this
hy pothesis. There was no significant difference in the killing ability of single-dose and split-
dose irradiation. The absence of substantial interfraction repair capacity of MTS may provide
a radiobiologic rationale for treating NB with multiple fractions per day. Some NB cell lines
have a rapid doubling time. This would also suggest that the overall treatment time of a
fractionated course of radiation should be kept short to prevent tumor repopulation between
fractions. However, Deacon et al. (110) performed in vitro split-dose radiation of an NB cell
line and found a small but finite capacity for sublethal damage repair. There may be intrinsic
variability in repair capabilities between NB cell lines.
Although NB is radiosensitive in the laboratory, its clinical response to radiation is
variable, and in-field recurrences, although rare, do occur. Possible reasons for this
discrepancy include the following. First, the in vitro data may not reflect clinical NB because
cell culture techniques may select more radiosensitive cell lines. Second, NB, characterized
by certain microscopic and biochemical characteristics, may actually be a spectrum of
diseases. Genomic amplification of MYCN has been correlated with the stage and prognosis of
NB, suggesting that MYCN may have a role in determining the aggressiveness of human NB.
Clinical variability in radiosensitivity may reflect the variation in oncogene amplification in
NB. In defining the role of radiation for high-risk NB, adequate doses have been defined
empirically. Studies on patients now known not to have the needed radiation shaped standard
radiation dosages that were then translated into doses adequate for high-risk disease.
Historically, RT was administered to most patients with NB, with the exception of those with
stage I tumors. Radiation doses ranged from 10 to 45 Gy and were dictated by patient age
rather than stage of disease. In this era, in which patients with early -stage disease received
radiation, two studies examined the radiation dose of NB (111). Doses below 20 Gy were
deemed sufficient to achieve local control. However, the majority of patients included in both
studies probably would not receive RT in the current era. Nonetheless, the adequacy of doses
of less than 20 Gy was adopted for all stages of disease.
Page 134Emerging data suggest that although 20 Gy may be adequate for controlling
completely resected tumors, gross residual disease may necessitate higher dosages. The Joint
Center for Radiation Therapy analy zed radiation dosage and local control and concluded that
higher doses are necessary for local control of NB in older patients (111). The protocol design
of CCG 3891 also allowed a limited dose–response analy sis, suggesting that the combined
effect of external beam radiation and TBI improved local control (81).
Whereas the majority of patients on CCG 3891 had mediastinal and intra-abdominal
tumors and therefore received 10 Gy to the primary site, a subgroup of patients received 20
Gy delivered to extra-abdominal primary tumors. Of 36 patients with extra-abdominal
primaries, 6 patients received 20 Gy EBRT (2 also received TBI) and 30 patients received no
EBRT (10 of these received TBI). Local relapse rates at 5 y ears were 0% ± 0% and 44% ±
15% for patients with and without EBRT, respectively (p = 0.09). Thus, the data suggest a
dose–response relationship for local EBRT, although the optimal dosage to primary tumor sites
has not been established (81). In a series of 34 high-risk NB patients from Emory, 3-y ear
local control was 94%, suggesting EBRT doses in the range of 21 to 24 Gy as sufficient for
adequate local control (112).
As a basic guide for patients with high-risk NB, a minimum dose of 21 Gy, in either 1.8
Gy daily fractions or 1.5 Gy twice-daily fractions, should be delivered to the tumor volume
present before surgical resection. This dosage should be adequate for patients with a complete
surgical resection, but patients with incomplete surgical resections may benefit from higher
radiation dosages directed at gross residual disease in an attempt to improve upon poor local
control rates reported in the literature.
Several publications suggest that current local therapy for incompletely resected patients
is inadequate. Wolden et al. (94) reported on a series of patients with stage 4 NB receiving 1.5
Gy twice a day to 21 Gy to prechemotherapy, presurgery primary tumor volume and
regional ly mph nodes. The actuarial locoregional control rate at 5 y ears was 84%. An update
of this experience reported a 10.1% probability of primary site failure among 99 patients,
most of whom (92 patients) had no evidence of disease in the primary site at the time of
irradiation (95). Among seven patients with disease at the primary site at the time of
irradiation, three had disease that recurred locally. EBRT did not increase acute toxicity,
except for increased total parenteral nutrition administration.
An analy sis from the University Children’s Hospital in Cologne, Germany, reported that
36 Gy of EBRT administered to patients with incompletely resected primary tumors could
compensate for “the disadvantage of incomplete response to induction chemotherapy.” In this
report of the NB97 trial for patients 1 y ear of age or older with stage 4 NB, patients with
isolated localized residual disease had improved outcome following EBRT (3-y ear-EFS 100%,
3-y ear-OS 100%) compared to those not receiving EBRT despite residual tumor tissue (3-
y ear-EFS 20 ± 18%, p < 0.001; 3-y ear-OS 20 ± 18%, p < 0.001) (113).
Given high rates of local recurrence, particularly following an incomplete surgical
resection, and tolerable side effects of EBRT evident in multi-institutional trials, the current
COG high-risk study is assessing whether a boost to residual primary tumor in patients with
less than gross total resection will improve the 3-y ear local control rate compared to historical
controls. Thus, patients enrolled on ANBL0532 who have an incomplete surgical resection of
the primary tumor receive 21.6 Gy EBRT to the postinduction chemotherapy, preoperative
primary tumor volume and an additional boost of 14.4 Gy EBRT to the gross residual volume
(total dose of 36 Gy to gross residual tumor volume). A dose of 36 Gy is well within normal
tissue tolerance for most organs within the field of radiation, and kidney s and liver will likely
prove to be the dose-limiting structures. It should be noted that the volume that receives 36 Gy
is generally substantially smaller than the original preoperative tumor volume that receives
21.6 Gy. An example of a patient treated with such a radiation regimen is shown in Figure
6.10 .
Figure 6.10 A and B: Two axial sections demonstrating dose distributions to the primary
tumor volume (shown in red). CTV shown in red represents the postinduction chemotherapy,
preoperative tumor volume that received 21.6 Gy; CTV shown in light blue is the
postoperative residual disease that, per the COG ANBL0532 protocol, received a boost of 14.4
Gy for a total dose of 36 Gy. An IMRT plan was used and the isodose lines shown are 21.6 Gy
(dark blue) and 18.0 Gy (yellow) highlighting the relative sparing of the bony pelvis as well as
liver and kidneys. A and B: Two axial sections demonstrating isodose lines encompassing the
gross residual postoperative tumor volume that received an additional boost of 14.4 Gy to a
total dose of 36.0 Gy, as per the COG ANBL0532 protocol. The isodose line shown is 14.4 Gy
(green) and shows the volume that received a total dose of 36.0 Gy. This child is without
evidence of disease 2 years after radiation therapy. (With gratitude to Tarek Halabi, PhD,
Hospital Physicist.)
Several investigators have published recommendations for time and dose fractionation
schedules for the radiation of metastatic NB in bone or soft tissues with a wide range of daily
fractions of 2–8.5 Gy and total doses of 4–32 Gy. In a retrospective evaluation of palliative RT
for NB at Duke, there was no evidence of a dose–response relationship (114). However, all
total doses used in this study were low. The clinician must avoid selecting too low a dose for
palliation of painful bony or soft tissue lesions. Although most children with stage 4 NB die
from the malignancy, some live for 1 y ear or more after palliative local treatment. The dose
should be adequate to control the sy mptom for the remainder of the patient’s lifetime y et not
be so high as to have a significant likelihood of complications. Fractionation depends on
volume. Small fields may be treated with 16–20 Gy in four or five fractions, whereas large
volumes are better treated with 2–3 Gy per fraction to 20–30 Gy so as to allow for regional
normal tissue repair and recovery. In the preterminal case, where timely pain control is
desired with minimal trips to the RT department, one may administer 6–8 Gy once or twice
with moderate success. Palliation of hepatomegaly in stage 4S disease usually can be
accomplished by 2–6 Gy in two to four fractions. However, regression of the liver may be
slow. It is occasionally necessary to repeat the dose. If possible, one should allow a 2- to 3-
week interval to gauge response. If the dose is repeated such that the cumulative dosage
reaches 12 Gy, the infant’s kidney should be out of the field of irradiation.
Figure:
A and B: Two axial sections demonstrating dose distributions to the primary tumor volume
(shown in red). CTV shown in red represents the postinduction chemotherapy, preoperative
tumor volume that received 21.6 Gy; CTV shown in light blue is the postoperative residual
disease that, per the COG ANBL0532 protocol, received a boost of 14.4 Gy for a total dose of
36 Gy. An IMRT plan was used and the isodose lines shown are 21.6 Gy (dark blue) and 18.0 Gy
(yellow) highlighting the relative sparing of the bony pelvis as well as liver and kidneys. A and
B: Two axial sections demonstrating isodose lines encompassing the gross residual
postoperative tumor volume that received an additional boost of 14.4 Gy to a total dose of
36.0 Gy, as per the COG ANBL0532 protocol. The isodose line shown is 14.4 Gy (green) and
shows the volume that received a total dose of 36.0 Gy. This child is without evidence of
disease 2 years after radiation therapy. (With gratitude to Tarek Halabi, PhD, Hospital
Physicist.)
TECHNIQUES OF RADIATION
Some abdominal and pelvic sites are best treated with parallel, opposed anterior and posterior
portals. When possible, multiple fields should be used to spare normal tissues. We have often
found three-dimensional (3D) reconstruction of bulky localized disease useful. After
reconstruction of the tumor volume, conformal fields or intensity -modulated RT may be
used. A key benefit of computer planning in the treatment of abdominal NB is related to the
ability to localize the kidney s and liver in addition to the precise delineation of the areas at risk
for recurrent disease. Field position and blocking are used to minimize the dosage to normal
tissue. However, often anteroposterior/posteroanterior or minimally obliqued fields prove to
be best.
Page 135Improved imaging technology, specifically MRI and CT, and biologic,
metabolic imaging such as radiolabeled MIBG have improved delineation of tumor and
surrounding critical structures. Novel techniques capitalize on an improved definition of tumor
volumes, allowing clinicians to decrease the dosages delivered to critical structures while
maintaining or increasing the dose to tumor. The advent of other technical advances such as
multileaf collimation (MLC), digitally reconstructed radiographs (DRRs), and electronic
portal imaging have contributed to the integration of conformal radiation delivery. Intensity -
modulated radiotherapy (IMRT) has the potential to reduce morbidity (e.g., spare liver,
kidney s).
CT images are analy zed jointly by radiation oncologists, diagnostic radiologists, pediatric
oncologists, and pediatric surgeons. Once target volumes and critical structures are defined,
beam geometry and weighting are defined and dose distribution is calculated. Selection of
beam angles can be done by referencing axial images or by using beam’s ey e view (BEV).
BEV allows visualization of the relationship of tumor volumes to the volumes of critical
normal tissues as if looking from the origin of the beam. This allows beam angles and beam
shaping to be selected more intelligently. Once an initial plan has been developed, the
resulting dose distributions are calculated and evaluated by the clinician. The plan can then be
altered to improve on initial results, if necessary. The beam directions as well as their relative
weights and shapes are modified finally to optimize the 3D plan.
The last decade has seen rapid development of novel technical approaches to RT and its
application to pediatric malignancies in general and NB in particular. These include 3D
conformal RT (3D-CRT), IMRT, proton beam RT, intraoperative RT, and radiosurgery. In
particular circumstances, such cutting-edge technical innovations can be of great help, as
exemplified in Figure 6.11 . Shown is a paravertebral mass with extension into the spinal
canal that recurred locally after prior radiation therapy. Radiosurgery using the Cy berKnife
allowed sparing of the previously irradiated spinal cord.
Page 136
Figure 6.11 CyberKnife isodose lines and plan for the treatment of a paravertebral mass
with extension into the spinal canal. Red line denotes the tumor volume shown on sagittal
(A), and axial (B). This locally recurrent mass after prior radiation therapy required sparing
of the spinal cord that was achievable by CyberKnife treatment planning, as shown in the
figure. A total dose of 30 Gy in five 6 Gy fractions was prescribed to the dark blue isodose line.
The light blue and green lines denote the 20 and 35 Gy isodose lines, respectively.
Paulino et al. (115) compared the use of conventional techniques to IMRT specifically
for treatment of primary abdominal NBs. They found that although IMRT was superior to
parallel, opposed anteroposterior/posteroanterior fields prescribed to midplane with respect to
kidney doses, this advantage was at cost of higher mean doses to the liver, stomach, and
spleen. Furthermore, IMRT was not found to be superior to conventional
anteroposterior/posteroanterior field arrangements for lateralized tumors (115). However,
another report from St. Jude’s using IMRT for abdominal tumors, employ ed 4DCT to account
for phy siologic organ motion during the breathing cy cle and demonstrated 100% local control
while maintaining normal tissue constraints with minimal significant acute toxicity (116).
Thus, although IMRT has advantages of dose conformity that are particularly appealing in the
treatment of children, each case must be individualized and the best plan be utilized for each
individual patient. Excellent conformity is shown in Figure 6.12 in which IMRT allowed
sparing of ears and contralateral ey e while treating a maxillary sinus metastasis.
Figure 6.12 Axial (A), coronal (B), and sagittal (C) sections showing the dose distribution
for a right maxillary sinus metastasis that showed persistent 131I-MIBG uptake on the
pretransplant MIBG scan and therefore received 21.6 Gy. Radiation was administered using
an IMRT plan. Isodose lines, 21.6 Gy in blue and 18.0 Gy in yellow, demonstrate excellent
conformity with the tumor volume (shown in red) while sparing of the ears and contralateral
eye. (With gratitude to Tarek Halabi, PhD, Hospital Physicist.)
Proton beam therapy has been increasingly employ ed in the management of a variety
of pediatric cancers due to its characteristic Bragg peak, y ielding very steep dose gradients,
with the ability to decrease exit dose and thus advantageous in application of CSI, for
example, where organs anterior to the vertebral column can receive minimal dose. However,
practical benefits of application of proton beam radiation to other anatomic sites remain
controversial and are dependent upon the technique of proton beam generation, geometry of
beam angles, and volume of target (117). A Japanese series employ ed proton beam
radiotherapy for 14 patients with high-risk NB with the goal of regional organ sparing. Three-
y ear locoregional control was 82% with no severe acute toxicity reported (118). A dosimetric
study of five patients who underwent proton beam radiotherapy for retroperitoneal
neuroblastoma compared the proton plans with generated 3D conformal and IMRT plans and
concluded significant dose reduction to regional organs with the proton plan as compared to
IMRT or 3D. Moreover, upon modeling secondary cancer risks, the authors concluded risk
reduction of 24–83% with proton radiotherapy over 3D or IMRT (119).
Page 137Proton beam therapy is permitted on most current NB protocols, with the dose
reported as Gy Radiobiologic Equivalent (Gy E) where 1 Gy E equals the proton dose in Gy ×
1.1. The potential benefits of proton beam radiation must be weighed against recent
publications that highlight potentially higher toxicities observed after treatment of CNS tumors
with protons than with photons. In this context, one must acknowledge persistent uncertainties
related to proton dose deposition and biologic effects. A study examining imaging changes
following proton- or photon-based (IMRT) radiotherapy demonstrated more imaging changes
following proton-based radiation compared to photons-based IMRT. Furthermore, only proton
treated patients experienced grade 3 or 4 changes and had persistent sy mptoms, including one
grade 5 toxicity related to radiation necrosis documented at autopsy (120). A similar study
assessing brainstem toxicity following proton radiotherapy for pediatric brain or skull-base
tumors reported a 2-y ear cumulative incidence of grade 3 or higher brainstem toxicity of
2.1% ± 0.9%, with one grade 5 toxicity (121).
Figure:
CyberKnife isodose lines and plan for the treatment of a paravertebral mass with extension
into the spinal canal. Red line denotes the tumor volume shown on sagittal (A), and axial
(B). This locally recurrent mass after prior radiation therapy required sparing of the spinal
cord that was achievable by CyberKnife treatment planning, as shown in the figure. A total
dose of 30 Gy in five 6 Gy fractions was prescribed to the dark blue isodose line. The light blue
and green lines denote the 20 and 35 Gy isodose lines, respectively.
Figure:
Axial (A), coronal (B), and sagittal (C) sections showing the dose distribution for a right
maxillary sinus metastasis that showed persistent 131I-MIBG uptake on the pretransplant
MIBG scan and therefore received 21.6 Gy. Radiation was administered using an IMRT plan.
Isodose lines, 21.6 Gy in blue and 18.0 Gy in yellow, demonstrate excellent conformity with
the tumor volume (shown in red) while sparing of the ears and contralateral eye. (With
gratitude to Tarek Halabi, PhD, Hospital Physicist.)
INTRAOPERATIVE RADIATION THERAPY
Patients with high-risk disease often present with large abdominal primary tumors, abutting or
invading many dose-limiting normal tissues. External beam radiation to these tumors often
entails treatment of a large volume of normal tissue, including bowel, liver, kidney, bony
structures, and spinal cord. RT to NB occurring at other primary sites, including the thorax and
pelvis, similarly exposes normal tissues to the risk of long-term side effects. Long-term
toxicities associated with EBRT may be particularly severe in children (91,114,122,123,124).
Furthermore, EBRT may decrease renal function, resulting in diminished tolerance to high-
dose chemotherapy with stem cell transplant, as well as adjuvant immunotherapies.
Although EBRT play s a key role in NB treatment, several institutions have explored
intraoperative RT (IORT) (Table 6.13 ) as an effective radiation modality that may
minimize acute and long-term side effects. In contrast to conventional EBRT, IORT allows
treatment of high-risk areas at the time of primary resection. Critical structures can be
directly visualized and manipulated at the time of surgery, allowing their exclusion from the
radiation field if they are at low risk for microscopic disease. A high radiation dosage can be
delivered to residual tumor and areas at high risk for microscopic disease with minimal
radiation dosage to nearby normal tissues. A small number of studies have established the
potential for IORT as a treatment modality in infants and children, including patients with NB
(125,126,127,128). IORT in these studies is extremely well tolerated and may improve local
disease control.
Table 6.13 Intraoperative Radiotherapy for Neuroblastoma
UCSF reported on a cohort of 31 consecutive patients treated with IORT for newly
diagnosed high-risk NB. With follow-up ranging from 1.5 to 16.7 y ears (median 44 months), 1
of the 22 patients who had gross total resections experienced local recurrence. In contrast,
three of nine patients who had subtotal resections experienced local recurrence, despite
additional EBRT to the primary site postoperatively in two of these patients (129). The 3-y ear
estimate of local control, PFS, and OS rates were 85%, 47%, and 60%, respectively. Side
effects attributable to either the disease process or multimodality treatment were observed in
seven patients who developed either hy pertension or vascular stenosis. These late
complications resulted in the death of two patients; however, additional analy sis is needed to
determine the relative contributions of the disease process and specific components of the
multimodality treatment to these adverse events. Similarly, a series of 27 advanced-stage NB
patients treated with IORT in Japan, demonstrated excellent rates of local control with three
“in-field” recurrences in the absence of further EBRT, attributed to deep location,
displacement or shielding of tissues which ultimately evidenced disease involvement (130). In
another Japanese series, examination of long-term toxicity in neuroblastoma patients living
>4 y ears following IORT demonstrated spinal column deformity in 5 of 9 patients, though
only one patient was sy mptomatic (131).
Page 138IORT at the time of primary resection achieves excellent local control in
patients with high-risk NB and is well tolerated. IORT achieves control and survival rates
comparable to those of historical controls while avoiding the use of sy stematic EBRT.
Additional therapy with EBRT may not be warranted in high-risk patients with gross total
resection treated with IORT who have only microscopic residual disease, although more
conclusive evidence requires larger patient numbers and longer follow-up. Higher local
failure rates in patients with high-risk NB after incomplete resections or multiple positive
ly mph nodes warrant additional therapy with EBRT.
Figure: Intraoperative Radiotherapy for
Neuroblastoma
COMPLICATIONS
Patients with high-risk NB often present with large abdominal primaries, abutting or invading
many dose-limiting normal tissues. EBRT to these tumors often entails treating a large volume
of normal tissue, including bowel, liver, kidney, bony structures, and spinal cord. RT to NB
occurring at other primary sites, including the thorax and pelvis, similarly exposes normal
tissues to the risk of long-term side effects. Long-term toxicities associated with radiation are
particularly severe in children (129,132,133). EBRT may also decrease renal function,
resulting in diminished tolerance to high-dose chemotherapy with stem cell transplant.
Acute side effects during RT depend on the precise normal tissues included in the
radiation field. In the treatment of most primary tumors, whether thoracic or abdominal,
radiation to the gastrointestinal tract, particularly the small bowel, may cause nausea and
vomiting. Antiemetic medications are very effective in ameliorating such sy mptoms.
Diarrhea and abdominal pain occur less often, and dietary counseling is generally sufficient
to control such side effects. Some primary tumors and metastatic sites necessitate the
inclusion of significant regions of bone marrow, resulting in a fall in blood counts that
necessitates regular monitoring.
Long-term sequelae of radiation are of particular concern because most patients with
NB are very y oung and prone to such toxicities (123,132,133). Doses of approximately 20
Gy to bones produce only minimal deficits, although specific effects depend on the ty pe of
bone growth: radiation to epiphy ses of tubular bones leads to bone shortening, whereas
radiation to diaphy ses impairs bone modeling and thickness. Effects on bone are highly
dependent on patient age and radiation dose (91). Substantial impairment in bone growth has
been reported for doses greater than 30 Gy, and although doses of 10–20 Gy probably affect
all cell ty pes in maturing bones, such lower doses probably will produce more subtle clinical
sequelae. A report of the long-term side effects from localized NB studies NB90 and NB94
noted 73% late effects in patients receiving multimodal therapy with 50% within the RT field,
most commonly musculoskeletal abnormalities with doses greater than 31 Gy (134). For all
patients, regardless of delivered dose, shielding of bone growth plates will minimize potential
growth arrest and skeletal abnormalities. When one is treating regions close to vertebrae,
radiation of the entire vertebral bodies reduces the risk of scoliosis and other musculoskeletal
abnormalities.
A high incidence of spinal deformity has been seen in long-term survivors of NB.
Among the most common abnormalities are postsurgery or postradiation ky phosis or scoliosis
(103). The incidence of these abnormalities in 5-y ear survivors of NB with paraspinal tumors
ranges from 25% to 50%. Factors associated with development of spinal deformity include
irradiation at a very y oung age, orthovoltage irradiation, asy mmetric irradiation of the spine,
epidural spread of tumor, and laminectomy. In y oung children, a laminectomy may result in
growth abnormality, gibbus formation, and instability of the spine. Therefore, the y oung child
with a dumbbell-shaped tumor is at risk for spinal deformity, and every effort should be made
to minimize this and other late sequelae with the use of chemotherapy when possible as first-
line treatment for cord compression or surgical decompression using osteoplastic laminotomy
rather than traditional laminectomy (83).
In addition to musculoskeletal toxicities, local radiation may cause organ dy sfunction if
tolerance dosages are exceeded. Whole organ tolerance levels generally are presented as
dosages that cause a severe complication rate of 5% within 5 y ears of radiation completion.
These include the lungs (17.5 Gy ), kidney s (20 Gy ), liver (30 Gy ), small bowel (40 Gy ),
ovaries (10 Gy ), and testes (2 Gy ). These tolerance dosages are general guidelines and may
be lower in children and in patients who are also receiving chemotherapy. Skull and orbital
metastases are common in NB, often necessitating irradiation of normal brain tissue. The risks
of neurocognitive dy sfunction and endocrine abnormalities increase with higher dosages of
radiation, larger volumes of irradiated normal brain, and y ounger age at time of radiation.
Lens tolerance is as low as 10 Gy, and dosages to the lens should be minimized to prevent
cataract formation. Permanent alopecia is extremely rare after dosages of 21 Gy or less, but
permanent hair thinning may occur in a small proportion of children.
Investigators at Memorial Sloan–Kettering Cancer Center have described the spectrum
of long-term complications in a population of survivors of advanced-stage NB (133). The
study included 63 survivors with a median age at diagnosis of 3.0 y ears and a median follow-
up from diagnosis of 7.06 y ears. All patients had surgery and received chemotherapy, 89%
received RT, 62% immunotherapy, and 56% autologous stem cell transplant. The vast
majority of survivors (95%) experienced late complications that included hearing loss (62%),
primary hy pothy roidism (24%), ovarian failure (41% of females), musculoskeletal (19%),
and pulmonary (19%) abnormalities. As would be expected based on known toxicities of
specific drugs, survivors who received cisplatin were at greater risk for developing hearing
loss, and greater total doses of cy clophosphamide were associated with ovarian failure.
Although the majority of complications were moderate, 4% were deemed life-threatening.
Page 139Another report investigates potential post treatment complications of aortic
growth inhibition and Middle Aortic Sy ndrome in patients with NB. These investigators used
CT to analy ze effects of RT on the growth of the aorta in NB patients. Abdominal CT scans of
31 patients with intra-abdominal NB (stages II–IV), treated with RT (n = 20 IORT/EBRT, n =
11 EBRT alone), were analy zed retrospectively. The diameter of the abdominal aorta was
measured before and after RT in 31 patients with intra-abdominal NB (stages II–IV) (n = 20
IORT/EBRT, n = 11 EBRT alone). These data were compared to normal, predicted aortic
diameters of children and to a control group of children who did not undergo irradiation. They
found that mean aortic diameters pre-RT and post-RT and the growth of the aorta were
significantly lower than expected for patients with NB and when compared to the growth in a
control group with normal and nonradiated aorta. However, among the radiated patients,
there was no difference due to the ty pe of RT—IORT/EBRT versus EBRT alone. Seven
patients from the IORT ± EBRT group developed vascular complications that included
hy pertension, middle aortic sy ndrome, or death due to mesenteric ischemia, and critical
aortic stenosis that required aortic by pass surgery. These finds led the authors to recommend
that CT evaluations of RT-treated NB patients should include not only reports of changes in
tumor extension, but also documentation of perfusion, size, and growth of the aorta and its
branches over time (135).
Whereas side effects of local radiation depend on the exposed normal structures, TBI
carries inherent toxicities that, like local radiation, worsen with increasing radiation dosage
and decreasing patient age. Long-term side effects of TBI include risks of impaired growth,
chronic interstitial lung disease, cataracts, neurocognitive deficits, chronic renal insufficiency,
dental disturbances, and endocrinopathies (123,133,136,137). After fractionated TBI, a
majority of patients experience diminished height and endocrine deficits, most commonly
manifest by delay ed puberty, but only a minority of patients experience other major organ
toxicities.
Both local RT and TBI carry the risk of second malignancies. Intensive my eloablative
chemotherapy regimens may further potentiate risk of secondary cancers (138). In the
treatment of a malignancy with guarded prognosis such as high-risk NB, the risk of death
from recurrent disease clearly outweighs the risk of death from a second malignancy. One
may extrapolate from a large body of literature in pediatric Hodgkin disease survivors and
assume that children who are cured after receiving radiation for NB will develop additional
cancers 10–20 y ears later (139). Recent data from a SEER database analy sis from 1973 to
2006 of 2801 patients with neuroblastoma demonstrated an overall incidence of 1.2% (34
patients) secondary cancers, 47% of whom had radiation. However, for high-risk patients, the
cumulative incidence of secondary cancers was 10.4% at 30 y ears, as compared to 3.6% for
non–high-risk patients, p < 0.001 (140). Common radiation-related malignancies may include
breast cancer, sarcomas, ly mphomas, and other solid tumors. Long-term survivors of NB
need lifelong screening for late sequelae of RT.
TARGETED RADIONUCLIDES
Targeted radioisotope therapy using anti-GD2 antibody or MIBG for delivery of radiation in
the form of 131I has also been tested in clinical trials in relapsed and newly diagnosed NB
(105). Although responses were reported, 131I-MIBG has only recently advanced into
cooperative or phase III trials, possibly due to the my elosuppression and the lack of an
available commercialized form. MIBG is a guanethidine derivative that is structurally similar
to norepinephrine and therefore concentrates in the neurosecretory granules of
catecholamine secreting cells. Radiolabeled MIBG provides very sensitive and specific
visualization of primary and metastatic NB in 90% of tumors by scintigraphy (25). In an
attempt to deliver higher doses of tumor-specific RT and avoid normal organ toxicity, 131I-
MIBG therapy has been used in pilot trials since the mid-1980s, with more than 500 children
reported in the literature. Initially, it was shown to induce a 30–40% response rate in highly
refractory relapsed patients, without significant nonhematologic toxicity. At low and
moderate doses, up to 12 mCi/kg of 131I-MIBG, the main toxicity has been
thrombocy topenia, usually self-limited. Phase I dosage escalation studies showed that higher
doses, up to 18 mCi/kg, could be administered with bone marrow or peripheral blood stem cell
support to mitigate the neutropenia and thrombocy topenia, but still without other organ
toxicity, excepting a 10–15% incidence of hy pothy roidism caused by an uptake of some free
iodide by the thy roid gland (105). There are a few reports of patients with secondary
leukemia developing after MIBG therapy, but the estimated risk of this problem at 5 y ears
after therapy is only 4%, lower than with some chemotherapy regimens (105). Recent
studies are investigating the use of low-dose 131I-MIBG at diagnosis combined with
chemotherapy before surgical resection (141) or high-dose my eloablative chemotherapy
(61). The response rate in 22 patients treated in the phase I dose escalation of 131I-MIBG
with CEM my eloablative chemotherapy was 27%, and there were 5 patients surviving more
than 3 y ears. A phase II study confirmed the tolerability at 12 mCi/kg, the maximum
tolerable dose combined with CEM. A pilot COG study (ANBL09P1) is currently open testing
the use of 131I-MIBG after five cy cles of induction chemotherapy in newly diagnosed
patients, and preceding my eloablative therapy with BuMel. Additional investigations are
needed to determine the optimal timing and use of this targeted approach.
MOLECULARLY TARGETED AGENTS AND RADIOSENSITIZERS
Initially, irinotecan was tested with MIBG as a radiosensitizer, due to its known activity in
neuroblastoma and radiosensitizing properties in other solid tumors (142). Two studies
combining vincristine and irinotecan in two different schedules with MIBG showed efficacy
and tolerability up to the MTD of 18 mCi/kg, with a response rate of 25% (143). Another
recent example of a radiosensitizer with MIBG therapy is combining with histone deacety lase
inhibitors (HDACIs) that have emerged as a new concept in cancer therapy. Among
HDACIs, vorinostat is furthest along in clinical development and is the first agent in its class to
be approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T-
cell ly mphoma. Several studies have shown that HDACIs, including vorinostat, have
radiosensitizing functions in a variety of cancer models. The underly ing mechanism for
radiosensitization is not fully understood but studies show that vorinostat inhibits expression of
double-strand break repair enzy mes like Rad51 and Ku87.
Page 140Consortium studies, including those within COG, have examined vorinostat as a
single agent and in combination with additional agents (e.g., combined with isotretinoin in the
COG study ). These trials have demonstrated favorable safety profiles in adults and children.
Recent research lends considerable enthusiasm to combining vorinostat and 131I-MIBG
therapy for the treatment of NB. This study finds that not only does vorinostat sensitize NB
cells to radiation in vitro and in vivo, but also it increases expression of the norepinephrine
transporter (NET), which in turn enhances MIBG uptake by NB cells in a dose-dependent
fashion and increased efficacy of radiation in an NB xenograft model (144). Based on these
promising results, NANT conducted a phase I clinical trial (NANT 2007–03) in which
vorinostat was combined with 131I-MIBG therapy for resistant/relapsed NB. The overall
response rate was 17%, and the maximum tolerated dose was 18 mCi/kg of 131I-MIBG and
180 mg/m 2 of vorinostat for 14 day s (145).
Other targeted agents under investigation include inhibitors of specific activated genetic
pathway s, including ALK, Trk B, PI3 kinase, IGF1R, Aurora A kinase, and mTor (6,71).
FUTURE INVESTIGATIONS
Current treatment regimens for NB are risk-based; that is, the biologic characteristics of the
tumor are considered together with traditional clinical prognostic factors in determining the
optimal therapy. As data are accumulated, the most powerful independent prognostic
determinants will be clarified. Areas of active investigation include the following:
Page 145The clinical challenge in pediatric Hodgkin ly mphoma (HL) is to continue the
progress of achieving curability while diminishing the risk for the morbidities that
compromise quality of life and survival. The history of pediatric HL is, of course, the history
of Hodgkin ly mphoma. In 1832, Thomas Hodgkin (1) described seven patients with enlarged
absorbent (ly mphatic) glands not thought to result from inflammation. At the turn of the
century, Sternberg and Reed each described the multinucleated giant cell characteristic of HL
(2). Shortly after the discovery of X-ray s in 1902, Pusey (3) demonstrated the
radioresponsiveness of HL. In the 1930s, Gilbert (4) laid the foundation for definitive
treatment of HL with radiotherapy (RT), and Peters (5) provided additional definition of
important principles. During World Wars I and II, the ly mpholy tic effects of nitrogen mustard
were recognized (6), and over the next two decades, progress in safely combining multiple
chemotherapeutic agents to treat HL led to DeVita’s (7) report on the use of nitrogen mustard,
vincristine (Oncovin), procarbazine, and prednisone (MOPP) chemotherapy. Kaplan (2)
sy stematically studied the role of RT for HL during these decades. Concurrently, advances
were made in identify ing different pathologic subty pes, determining staging criteria,
improving diagnostic imaging capabilities, and developing effective chemotherapeutic
regimens. When the clonality of the Hodgkin–Reed–Sternberg (HRS) cell was finally
established in the 1960s, controversy over the malignant or inflammatory nature of HL
abated (8).
Although the biology and natural history of HL in children are similar to that in adults,
when irradiation techniques and dosages suitable for controlling disease in adults were
translated to the pediatric setting, substantial morbidities (primarily musculoskeletal growth
inhibition) were the result (9,10). It is in this context, new strategies for the treatment of
pediatric HL were developed by Donaldson and others (11,12,13,14,15,16,17,18,19).
Historically, children were thought to have a worse prognosis than adults (2). It is now
apparent that the reverse is true (20,21,22).
BIOLOGY
For many y ears, the rarity and distribution of malignant cells in pathologic material
precluded elucidation of the origin and evolution of the HRS cell. Advances in
immunohistology and molecular biology subsequently revealed that the HRS cell and its
variants most commonly derive from a neoplastic clone that originates from B ly mphocy tes
in ly mphoid germinal centers. Clonality can be demonstrated at diagnosis and relapse through
detection of unique nucleotide sequences, which molecularly fingerprint the HRS cell clone;
these sequences represent rearrangements of immunoglobulin variable-region (V) genes,
which are B-cell derived (23,24). Complicating this scenario is the finding by Kanzler et al.
(24) that flawed V genes, which would be lethal for normal B cells, are present in HRS cells
and prevent them from expressing immunoglobulin. Such cells would be expected to die of
apoptosis. Therefore, the genesis of classic HL (CHL) probably involves evasion by the HRS
cell of the apoptotic pathway. Deregulation of the nuclear transcription factor (NF-κB) in the
HRS cells has been hy pothesized as a mechanism that prevents apoptosis (25). Epstein–Barr
virus (EBV) and genes that monitor cell damage, such as p53, may play a role in the rescue
and repair of the HRS cells (24,26). EBV genome fragments can be found in HRS cells in 30–
50% of HL specimens, most commonly in the mixed-cellularity HL (MCHL) subty pe and
rarely in the nodular ly mphocy te-predominant HL (NLPHL) subty pe (27,28). The EBV
genome is temporally stable because it can be found at diagnosis and relapse. Finally, the
HRS cell can also have characteristics of T ly mphocy tes and the interdigitating reticulum
cell. Such evidence of a multilineage origin of the HRS cell may be explained by postulating
that the HRS cell is a hy bridoma resulting from fusion of different cell lines, provoked by a
virus or other agent. Cy togenetic data also show an unexpected frequency of B-cell
translocation (14:18) and bcl-2 gene involvement in HL, but these may derive from
by stander normal ly mphocy tes rather than the HRS cell (29). The complexity of elucidating
the etiology of HL continues to unfold and is illustrated by data that not only support the
association of infectious mononucleosis with EBV-positive HL, but also suggest that EBV-
negative HL has a different etiology (30). A pathogenetic model for HL is depicted in (Fig.
7.1 ), which suggests that the HRS cells arise in a germinal ly mphoid center from a clone
of antigen-stimulated B cells and through genetic changes achieve immortality and malignant
properties (31).
Figure 7.1 The derivation of Hodgkin and Reed–Sternberg cells in classic Hodgkin
lymphoma and lymphocytic and histiocytic cells in nodular lymphocyte-predominant
Hodgkin lymphoma. (From Thomas RK, Re D, Wolf J, et al. Part 1: Hodgkin’s lymphoma–
molecular biology of Hodgkin and Reed–Sternberg cells. Lancet Oncol. 2004;5:11–18.)
Page 146A curious characteristic of HL is the rarity (about 1%) of the malignant HRS
cell in specimens and the abundant reactive cellular infiltrate of ly mphocy tes, macrophages,
granulocy tes, and eosinophils. The histologic features and clinical sy mptoms of HL have
been attributed to the numerous cy tokines secreted by the HRS cells, which include interleukin
(IL)-1 and IL-6, and tumor necrosis factor (TNF) (32,33). IL-5 could be responsible for the
eosinophilia in MCHL, and transforming growth factor beta could be responsible for the
fibrosis in the nodular sclerosis subty pe. These cy tokines also enable the cells to evade
immunologic surveillance and promote their own replication (32).
Evidence that HL comprises a family of diseases includes the observation that HRS cells
can rarely be derivatives of cy totoxic T cells and that NLPHL is a distinctive and uncommon
ly mphoproliferative disorder. The ly mphocy tic and histiocy tic (L&H) cells characteristic of
NLPHL have folded and lobate nuclei among small ly mphocy tes and histiocy tes. The L&H
cells are also B-cell–derived but harbor V gene alterations, which differ from those in HRS
cells; whether the L&H cells are monoclonal is unclear (34,35). The clinical characteristics
of NLPHL differ from those of the subty pes of CHL by virtue of its indolence, excellent
prognosis, epidemiology, and response to chemotherapy. In the 2008 World Health
Organization (WHO)/Revised European–American Classification of Ly mphoid Neoplasia
(REAL) there is a clear distinction of NLPHL from CHL (36).
Several aspects of the biology of HL continue to unfold, and many have prognostic
applicability. For example, loss of CD15 expression may be a prognostic factor for PHL
clinical outcomes, although CD15 expression has been inconsistent possibly due to biologic or
technical variability (37,38). A high proliferative index (PI) may suggest
chemoresponsiveness and, as a result, a low pretreatment PI may be associated with poor
outcomes (37,38). Increased CD68 and CD163 expression in the microenvironment have also
been reported as predictors of inferior outcome in classicl HL (39,40). However, this finding
has not y et been confirmed in a pediatric cohort (41).
Figure:
The derivation of Hodgkin and Reed–Sternberg cells in classic Hodgkin lymphoma and
lymphocytic and histiocytic cells in nodular lymphocyte-predominant Hodgkin lymphoma.
HL appears to be unifocal in origin, with 90% of patients presenting in a pattern that suggests
contiguous ly mphatic spread (2,60). Most children are diagnosed on the basis of
supradiaphragmatic ly mph nodes, with mostly painless cervical adenopathy in 80%. The
nodes are generally firm and may be occasionally be tender. Mediastinal involvement occurs
in 76% of adolescents but in only 33% of 1- to 10-y ear-olds. Mediastinal disease may
produce sy mptoms such as dy spnea, cough, and superior vena cava sy ndrome. Axillary
adenopathy is less common (2). Associations exist between the mediastinum and the neck, the
neck and the ipsilateral axilla, the mediastinum and the hilum, and the spleen and abdominal
ly mph nodes (60). Isolated mediastinal or infradiaphragmatic HL is rare, occurring in fewer
than 5% of patients. About one-third of the patients have sy stemic “B” sy mptoms, as defined
in Table 7.1 (2,61).
Table 7.1 Ann Arbor Staging System with Cotswold Modifications for Hodgkin
Lymphoma
Figure: Ann Arbor Staging System with
Cotswold Modifications for Hodgkin
Lymphoma
PATHOLOGIC CLASSIFICATION
Page 148NLPHL (63): The distinctive cell is the L&H “popcorn” cell, which is CD20
(B-ly mphocy te marker) positive and CD15 negative. Classic HRS cells (which are
usually CD15 and CD30) are rare, as is the detection of EBV. Progressive transformation
of the germinal centers of ly mph nodes is often seen, and, in fact, can occur in the
absence of NLPHL. Therefore, it is important to distinguish these entities. NLPHL has a
long natural history, in its time to diagnosis and to relapse, reminiscent of that of indolent
non-Hodgkin ly mphomas (NHL). It is more common in y oung children (33% of all
patients are y ounger than 15 y ears), has a high male:female ratio (4:1), and commonly
involves a single ly mph node region with sparing of the mediastinum (64).
Ly mphocy te-rich (classic) HL: HRS cells (CD15) are identifiable against a background
predominantly of ly mphocy tes. Clinical behavior is similar to that of MCHL.
Mixed-cellularity (classic) HL: HRS cells (CD15) are common against a background of
abundant normal reactive cells (ly mphocy tes, plasma cells, eosinophils, histiocy tes).
This subty pe can be confused with peripheral T-cell NHL.
Nodular sclerosis (classic) HL: This subty pe is distinctive because of the presence of
collagenous bands that divide the ly mph node into nodules, which often contain an HRS
cell variant called the lacunar cell. NSHL often occurs in children, involves
supradiaphragmatic nodes, and spreads in an orderly manner along contiguous nodal
chains.
Ly mphocy te-depleted (classic) HL: This subty pe is rare and commonly confused with
NHL, particularly of the anaplastic large cell ty pe. HRS and pleomorphic variants are
common relative to the number of background ly mphocy tes. LDHL often is advanced at
diagnosis and has a poor prognosis.
Reed–Sternberg cell.
Figure: WHO Classification of Hodgkin
Lymphoma
STAGING
Using anatomic groups of regional ly mph nodes, the staging sy stem was designed for all age
groups, according to a modification of the sy stem devised at the 1970 Ann Arbor
Sy mposium. This was subsequently revised at the Cotswold’s Meeting, although not all
suggestions from those recommendations are consistently used (61).
A weakness of the Ann Arbor sy stem is its failure to consider disease bulk (either
dimension or number of involved sites) or specific patterns of involvement. For this reason,
subclassifications of the Ann Arbor staging sy stem have been proposed, particularly for
patients with large mediastinal adenopathy (LMA). LMA, most commonly defined as a mass
exceeding one-third the transverse diameter of the chest (intrathoracic width measured at the
dome of the diaphragm) on a standard upright posteroanterior (PA) chest radiograph, places a
patient at a greater risk for disease recurrence after radiation alone. Despite the requirement
to obtain chest CT scan for staging, bulk is still determined on current COG protocols by PA
upright chest radiograph. In the European Pediatric Hodgkin ly mphoma consortium
(EuroNet-PHL), bulk is defined by volumetric assessment of the mass and any mass >200
mL is considered bulky whether in the mediastinum or a peripheral nodal group.
The distribution of stages observed in children is somewhat different from that observed
in adults. Table 7.3 summarizes the demographic and clinical features of children,
adolescents, and y oung adults presenting with HL (65). Among 3571 consecutive patients with
HL treated at three pediatric centers, 18.1% were y ounger than 10 y ears and 81.4% were
11–16 y ears old. Stage I or II disease was present in 65.8% of children.
Table 7.3 Demographic and Clinical Characteristics at Presentation of Pediatric
Hodgkin Lymphoma
Figure: Demographic and Clinical
Characteristics at Presentation of Pediatric
Hodgkin Lymphoma
DIAGNOSTIC EVALUATION
Page 150After pathologic confirmation, the patient undergoes an extensive clinical staging.
This begins with a detailed history of sy stemic sy mptoms and evidence of cardiorespiratory
compromise or organ dy sfunction. The phy sical examination carefully records the location
and size of all palpable ly mph nodes. An evaluation of Waldey er ring, cardiorespiratory
status, and organomegaly is vital. Laboratory studies include complete blood count with
platelets and biochemical evaluation of renal and liver function. Acute phase reactants,
including ery throcy te sedimentation rate, C-reactive protein serum copper, and ferritin, may
be elevated at diagnosis and can be used as nonspecific marker of disease activity. Elevated
serum CD30 and CD25 have been correlated with advanced stage, the presence of
constitutional sy mptoms, and poor prognosis; however, these studies have not been widely
used to risk stratify and monitor patients during therapy (66,67,68). Patients with “B”
sy mptoms (fevers of unexplained origin, >10% unintended weight loss within the last 6
months and drenching night sweats) or stage III–IV disease historically underwent bone
marrow biopsy for routine staging (69). HL may present focally in the bone marrow and
bone marrow biopsy may miss the site of involvement. Thus, FDG-PET may evaluate all the
bone marrow at once and has been shown to have increased sensitivity and specificity
relative to bone marrow biopsy (70). The low y ield of a bone marrow evaluation in
asy mptomatic patients with localized disease (stage I and II) does not support routine use of
the procedure.
Imaging studies of the thorax should include a chest radiograph with a PA and lateral
view. It should be noted that the LMA ratio, if based on computed tomography (CT) scan
measurements, would increase the frequency of patient’s LMA since a mediastinal mass will
splay bilaterally in a reclined child. CT scans with contrast are essential for delineation of the
status of intrathoracic ly mph node groups (including the hila and cardiophrenic angle), lung
parenchy ma, pericardium, pleura, and the chest wall, demonstrating abnormalities in about
one half of patients with unremarkable chest radiographs (22,71). Distinguishing normal (or
hy perplastic) thy mus from nodes in children can be difficult.
Imaging of the abdomen and pelvis may involve an abdominal and pelvic CT scan or
magnetic resonance imaging (MRI). If CT is used, oral and intravenous contrast
administration is needed to accurately distinguish retroperitoneal and pelvic ly mph nodes
from other infradiaphragmatic structures. In cases with suboptimal contrast resolution of the
bowel, MRI may provide a better evaluation of the fat-encased retroperitoneal nodes (72). In
previous German and Pediatric Oncology Group (POG) trials using CT or MRI for staging,
the size of abdominal and pelvic ly mph nodes was used to define the extent of disease
involvement. Abdominal nodes less than 1.5 cm in diameter and pelvic nodes less than 2 cm
were considered negative, whereas abdominal nodes more than 2 cm in diameter and pelvic
nodes more than 3 cm were considered positive. This is no longer used in the positron
emission tomography (PET) era but an understanding is needed to interpret results of older
trials and ultimately, indeterminate nodes may require biopsy.
HL involving the liver and spleen is suggested by CT or MRI findings of organomegaly
with areas of abnormal density representing ly mphomatous deposits. Organ size alone does
not predict ly mphomatous involvement. PET scans are very sensitive at identify ing
involvement of liver and spleen.
Nuclear imaging with gallium-67 was historically used to stage and monitor treatment
response in children with HL. However, gallium had limitations because of its low resolution
and phy siologic bio-distribution, causing difficulties in evaluating abdominal and pelvic ly mph
nodes and necessitates delay ed imaging. PET is now recognized as an integral staging
modality for ly mphoma (73,74,75). Uptake of the radioactive glucose analog
fluorodeoxy glucose (FDG) correlates with proliferative activity in tumors undergoing
anaerobic gly coly sis. FDG-PET provides full-body imaging in which areas of abnormal
avidity have been correlated with treatment outcomes. PET does have limitations in the
pediatric setting (e.g., tracer avidity in nonmalignant thy mic rebound commonly observed
after completion of therapy for HL and uptake in the case of benign brown fat) (76). The
Deauville criteria is a scoring sy stem now used to assess the level of FDG uptake relative to
uptake in the liver and mediastinum. These criteria are used to give patients a “score” both
upfront in staging and to classify response, either interim or at completion of therapy (Fig.
7.3 ). Current clinical trials are intensify ing or de-escalating therapy based on
chemotherapy response scored by the Deauville criteria.
Figure 7.3 A: Deauville Criteria (images below courtesy of Steve Cho MD, University of
Wisconsin). B: Baseline FDG PET/CT—Coronal. Deauville 5, Lymphoma Multiple mediastinal
and abdominal retroperitoneal disease [Markedly increased uptake]. C: Postcycle-2 FDG
PET/CT—Coronal, Deauville 5, Residual Lymphoma.
Figure:
A: Deauville Criteria (images below courtesy of Steve Cho MD, University of Wisconsin). B:
Baseline FDG PET/CT—Coronal. Deauville 5, Lymphoma Multiple mediastinal and abdominal
retroperitoneal disease [Markedly increased uptake]. C: Postcycle-2 FDG PET/CT—Coronal,
Deauville 5, Residual Lymphoma.
PROGNOSTIC FACTORS
As the treatment of HL has improved, characteristics that influence outcome have diminished
in importance. However, several factors continue to influence the success and certainly the
choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and
biologic aggressiveness often are codependent. Also complicating the determination of
prognostic factors is that relevant variables often depend on staging evaluation and treatment.
Most data are based on reports that include primarily adults.
The disease stage persists as the most important prognostic variable. Patients with
advanced-stage disease, especially stage IV, have a worse outlook than those with early -stage
disease (77).
The bulk of disease is reflected by the disease stage and is determined more specifically
by the volume of distinct areas of involvement and the number of disease sites. LMA places a
patient at a greater risk for disease recurrence. While OS remains high due to the
effectiveness of salvage chemotherapy (2,22,78), patients with LMA have a somewhat lower
survival rate in most, but not all series (2,22,79). Patients with several sites of involvement,
generally defined as more than three sites, fare less well (22). Patients with stage IV disease
who have multiple organs involved fare especially poorly.
Page 152Nonwhite pediatric patients presented more frequently with advanced-stage
disease based on a study population derived from two South African hospitals although white
children had a lower OS (80). In this report, nonwhite pediatric patients had better survival
when compared to white pediatric patients of the same stage. However, in a study from St.
Jude Children’s Research Hospital, black pediatric patients had lower event-free survival
(EFS), but equivalent 5-y ear OS to white pediatric patients (81). The impact of race on
prognosis remains unclear particularly given the potential impact of socioeconomic, cultural,
and environmental differences between white and nonwhite populations that may play a role
in clinical outcomes.
Systemic (“B”) symptoms, which result from cy tokine secretion, reflect biologic
aggressiveness and confer a worse prognosis.
Laboratory studies/biologic markers, including the ery throcy te sedimentation rate, serum
ferritin, hemoglobin level, serum albumin, and serum CD8 antigen levels, have been reported
to predict a worse outcome (66,67,82,83). This could reflect disease biology or bulk. Other
investigational serum markers associated with an adverse outcome include soluble vascular
cell adhesion molecule-1 (84), TNF (85), soluble CD30 (28,86), beta-2-microglobulin (87),
transferrin, and serum IL-10 (88). Beta-2-microglobulin is the most commonly altered gene
in Reed–Sternberg cells with the majority of cases having inactivating mutations that lead to
the loss of major histocompatibility complex class I (MHC-1) expression. The absence of the
beta-2-microglobulin protein was associated with lower-stage disease, y ounger age at
diagnosis, and better clinical outcomes, including better survival and progression-free survival
(89). High levels of caspase 3 in HRS cells have been correlated with a favorable outcome
(90). Serum vascular endothelial growth factor (VEGF) levels may also have prognostic
implications. VEGF is a proangiogenic molecule involved in neovascularization of tumors.
Increased microvessel density associated with increased VEGF level expression has been
demonstrated in HL progression (91) and VEGF expression has been identified in HRS cells
(92). Pretreatment levels of angiogenic factors have been found to be significantly elevated
in HL patients compared to controls and high levels of VEGF have been associated with poor
survival (93). Serum VEGF levels have also been associated with treatment response in
children with HL (94). In a study by Ben Arush et al. (94), serum VEGF levels correlated
with treatment response in seven of nine children with HL. A significant reduction in serum
VEGF level was identified in patients with a partial or complete response based on an
assessment using PET-CT. The identification of angiogenic factors that play a role in the
clinical course of HL may have therapeutic implications for the use of anti-angiogenic agents
in the future. Other biologic factors that may enable prognostic modeling continue to be
discerned (95,96). A study from the Groupe d’Etude des Ly mphomes de l’Adulte (GELA)
prospectively analy zed the prognostic value of TNF, soluble receptors TNF-R1 and TNF-R2,
IL-10, IL1-RA, IL-6, and sCD30 in patients with an initial diagnosis of CHL. Five-y ear EFS
probability was predicted by segregating combinations of serum marker levels into four
prognostic classes, suggesting that a plasma cy tokine signature may predict clinical outcomes
in CHL (96).
Histologic subtype is relevant but may differ in children versus adults. For example,
adults with clinical stage I or II MCHL have a higher frequency of subdiaphragmatic relapse
which may indirectly influence survival (22). NSHL histology has conferred poor outcome in
some but not all studies (97). Patients with LDHL fare poorly. A report from the United
Kingdom Children’s Cancer Study Group assessing the relevance of histology in 331 children
is revealing. Fewer than 1% had LDHL, obviating any meaningful assessment of its
prognostic significance. For patients with other histologies treated with combined therapy, no
difference in outcome was observed (98). As previously discussed, patients with NLPHL
have distinctive differences in disease-free survival and OS.
Age is a significant prognostic factor in some studies. Survival rates for children with HL
approach 95%. In a report from Stanford, the 5- and 10-y ear survival rates for children
y ounger than 10 y ears with HL are 94% and 92%, respectively, compared with 93% and
86% for adolescents (11–16 y ears old) and 84% and 73% for adults (20). Although children
y ounger than 4 y ears with HL are uncommon, even these children appear to have an
excellent prognosis (21).
Imaging The rapidity of response to initial therapy is an important prognostic variable in
many forms of cancer, including HL. In some trials, the rapidity of response to
chemotherapy is used to determine subsequent therapy (99). There have been a number of
recent investigations evaluating early response to therapy, as measured by FDG-PET
imaging, as a possible marker of prognosis. The NPV of PET was evaluated in the GHSG
HD15 trial. After patients received BEACOPP-based chemotherapy, PET was used to assess
residual disease measuring greater than or equal to 2.5 cm in diameter. Progression-free
survival was significantly improved in PET negative patients (96%) as compared to PET
positive patients (86%) (p = 0.011) (100). PET done at the completion of chemotherapy
successfully guided the need for additional radiotherapy in this combined modality setting
(101). The relapse patterns suggested that local RT to PET-positive residual disease was
sufficient for patients with advanced stage HL with only 16% of patients who received
adequate RT relapsing compared to 24% with inadequate RT (102). In the setting of stem cell
transplant for refractory /recurrent HL, pretransplant functional imaging response has been
found to predict outcome. Patients with positive PET or gallium scans prior to undergoing
high-dose chemotherapy with autologous stem cell transplant had a significantly lower 3-
y ear PFS and OS rates than patients with negative functional imaging (103).
Most recently, attention has been paid to developing an International Prognostic Score
(IPS) for children (e.g., CHIPS). About 1721 patients with intermediate risk HL were treated
on Children’s Oncology Group protocol, AHOD0031 and 770 patients were randomized or
assigned to receive treatment with four cy cles of ABVE-PC and IFRT. Of the variables
examined, four were found to be predictive of adverse event-free survival (EFS) including
stage IV disease, large mediastinal adenopathy, albumin <3.5 and fever. Patients with CHIPS
0 or 1 (N = 589) had an EFS of nearly 90% compared to 78% with CHIPS 2 (N = 141) and
62% with CHIPS 3 (N = 32) (104).
Page 153Prognostic factors will continue to be influenced by choice of therapy ;
parameters such as disease, bulk, number of involved sites, and sy stemic sy mptoms are likely
to remain relevant to outcome. Nonetheless, as therapy becomes increasingly tailored to
prognostic factors and therapeutic response, overall outcome should become less affected by
those parameters.
SELECTION OF THERAPY
HL is one of the pediatric malignancies that has an adult counterpart with a similar natural
history and biology. The overall 5-y ear relative survival from the SEER database for 2002–
2008 was reported to be 84.7% with children and adolescents having a significantly better
HL-specific 5-y ear survival (96%) than adults (88%) (p < 0.001) (105). However, devising
the optimal therapeutic approach for children with this disease is complicated by their greater
risk for adverse effects. In particular, RT dosages and fields used in adults can cause profound
musculoskeletal retardation, including intraclavicular narrowing, shortened sitting height,
decreased mandibular growth, and decreased muscle development in the treated volume (see
Chapter 19 ) (9,10). Adults with early -stage HL were historically treated with full-dose
radiation as a single modality (22). However, in prepubertal children, despite a similar
success rate, this approach produced unacceptable sequelae (10,19,74,106). Additionally
complicating the treatment of children are sex-specific differences in chemotherapy -induced
gonadal injury. The desire to cure y oung children with minimal side effects has stimulated
attempts to reduce staging procedures, the intensity and ty pes of chemotherapy, and the
radiation dosage and volume. Because of the differences in the age-related developmental
status of children and the sex-related sensitivity to chemotherapy, no single treatment method
is ideal for all children.
Important studies using chemotherapy and low-dose radiation in children to effect cure
with tolerable sequelae were first undertaken at Stanford University. These trials used
chemotherapy in combination with lower dosages of RT for y oung children with early -stage
disease (2,11,12). An important sequence of studies performed by the German-Austrian
Pediatric Hodgkin’s Disease Study Group progressively refined the extent of staging and the
intensity of chemotherapy and radiation (14,16,107). Stage dependent chemotherapy and
radiation dosage and volume were used and these studies served as the paradigm for
refinement of the risk-adapted treatment approach that is currently used at most pediatric
treatment centers.
In general, the use of radiation and chemotherapy broadens the spectrum of potential
toxicities while reducing the severity of individual (drug- or radiation-related) toxicities. The
volume of radiation and the intensity and duration of chemotherapy are risk adapted, or
determined by prognostic factors at presentation, including presence of constitutional
sy mptoms, disease stage, and bulk.
EVOLUTION OF COMBINATION CHEMOTHERAPY
MOPP was the standard chemotherapy regimen used in the United States for many y ears
after DeVita et al.’s 1972 report (108). The major toxicities include an associated risk of acute
my eloid leukemia, azoospermia in more than 90% of boy s treated at any age, and a risk of
sterility in girls, which increases with age (109,110). Subsequently, the effectiveness of
Adriamy cin, bleomy cin, vinblastine, and dacarbazine (ABVD) as front-line chemotherapy
was established (111,112,113). Second malignancies and sterility were less common with
ABVD than with MOPP (114). The predominant adverse effects of ABVD are pulmonary
toxicity related to bleomy cin and cardiovascular toxicity secondary to Adriamy cin. These
side effects may be exacerbated by the addition of irradiation (115). Over the y ears, the
MOPP and ABVD regimens have undergone a variety of modifications, but the majority of
the chemotherapeutic regimens used today are derived from these two combinations.
The current era of risk-adapted response-based therapy for PHL presents several critical
issues regarding the role of RT.
For patients with PHL, is chemotherapy alone adequate without administering excessive
amounts or using overly aggressive combinations in terms of potential morbidities?
Embedded in this question are the relative toxicities of curative chemotherapy versus
less chemotherapy plus RT.
Can the rapidity and the completeness of the response to chemotherapy define the use of
RT, and how will functional imaging enhance the precision of this approach?
When RT is administered, then what is the appropriate target volume? Can RT be
restricted to initially involved ly mph nodes rather than chains (or regions) of nodes? In
what settings should RT be directed to areas of initial bulk disease or residual
postchemotherapy disease? Should involved organs, such as the liver, lung, and heart,
ever be irradiated?
If we use RT, what is the appropriate dose? Should this be dependent on the initial or
postchemotherapy extent of disease, bulk of disease, organ at risk, and age of the patient?
Inherent in these questions is the recognition that RT is effective in locally controlling PHL but
provokes a dose-dependent spectrum of toxicities. Most profound are musculoskeletal growth
inhibition, coronary artery disease and cardiomy opathy, pulmonary fibrosis, infertility, and
subsequent malignancies. However, eliminating RT necessitates more toxic chemotherapy
(either agents or amounts). Discerning the ideal balance will maximize cure while minimizing
toxicity. We address these questions in upcoming sections.
Few randomized controlled trials have prospectively compared chemotherapy alone
with combined-modality therapy in children and adolescents with HL (112,113,116,117,118).
In an important CCG trial reported by Nachman et al. (116), chemotherapy alone using the
COPP and ABV hy brid regimen was compared with combined-modality therapy including
low-dose involved-field radiation treatment (IFRT). Treatment assignment was risk-adapted
based on the presence of clinical features including the presence of “B” sy mptoms, hilar
adenopathy, mediastinal and peripheral ly mph node bulk, and the number of involved nodal
regions. Patients with favorable disease presentations received four cy cles of COPP and
ABV; those with unfavorable risk features received six cy cles of COPP and ABV. Patients
with stage IV HL received sequential cy cles of high-dose cy tarabine and etoposide, COPP
and ABV, and cy clophosphamide, vincristine, doxorubicin, and methy lprednisolone. Patients
achieving a complete response to chemotherapy were eligible for randomization to receive
low-dose IFRT or no further therapy. The trial was terminated prematurely because results
indicated a significantly higher number of relapses among patients treated with
chemotherapy alone. The 3-y ear EFS estimates according to patient randomization were
92% for patients treated with combined-modality therapy and 87% for those treated with
chemotherapy alone; the benefit of IFRT remained significant in the as-treated analy sis. The
difference was most marked in patients with stage IV disease, who had 90% EFS if
randomized to receive IFRT and 81% if randomized to receive chemotherapy alone. In a
recent update, Wolden et al. (119) reported 10-y ear clinical outcomes of the study after a
median follow-up of 7.7 y ears. Ten-y ear EFS and OS rates for the entire patient population
were 83.5% and 92.5%. In the as-treated analy sis for randomly assigned patients, the 10-
y ear EFS was 91.2% for patients who received IFRT and 82.9% for those that received no
further therapy (p = 0.004). There was no difference in OS for the two groups (97.1% for
those who received RT vs. 95.9% for no further therapy, p = 0.50). Inferior EFS was
associated with bulk disease, B sy mptoms, and nodular sclerosing histology.
Page 154Because of successful salvage therapy after relapse, estimates of OS do not
differ between the randomized groups in early follow-up. However, other investigations of
long-term outcomes after treatment for PHL implicate retrieval therapy after relapse as a
significant risk factor for neoplastic complications and early mortality (120,121). In the
German-Austrian Pediatric Hodgkin’s Disease Study Group (GPOH) HD-95 trial, relapse-
free survival rates were higher for patients treated with RT after partial response (93%) than
for those without RT after complete response (89%) (122). The difference was significant for
patients treated for advanced-stage but not early -stage disease. Kaplan–Meier analy sis after
5 y ears demonstrated that the DFS was lower in nonirradiated patients than in irradiated
patients (p = 0.049). Again, there was no difference in DFS with or without RT in favorable
patients. In the TG2 group (intermediate risk), DFS was 92% in patients who received RT
versus 78% in patients who did not. In the combined TG2+ TG3 (intermediate + high risk),
there was also a significant improvement in DFS for patients who received RT (91% vs. 79%).
Therefore, the omission of RT was only possible for early stage patients without sacrificing
DFS. OS rates remained stable as compared to prior studies suggesting that therapy reduction
was feasible (123).
These results were confirmed in the GPOH-HD 2002 study. In this study, all patients
received IFRT to 19.8 Gy except those in the early -stage (IA/B and IIA without extranodal
involvement) disease category who achieved an anatomic CR after induction therapy as
defined in GPOH-HD 95. In regions with <75% volume reduction, patients received a boost
to approximately 30 Gy, and residual masses >100 mL were boosted to approximately 35 Gy
(124). In this study, two to six cy cles of OEPA/ COPDAC in combination with IFRT produced
excellent results, with a 5-y ear EFS rate of approximately 89%.
Patients with stage I, IIA, or IIIA HL were randomized in a study conducted by the POG
to six courses of alternating MOPP/ABVD or four courses of MOPP/ABVD and IFRT to 25.5
Gy. At a median follow-up of 8.25 y ears, there were no significant differences in EFS or OS
rates between either arm. Eight-y ear EFS rates were 83% for chemotherapy alone and 91%
for combined-modality therapy (p = 0.151) while 8-y ear OS rates were 93.6% for
chemotherapy alone and 96.8% for chemotherapy and radiation (p = 0.785) (125).
Retrospective analy sis of the data showed that patients with early response to therapy had a
significantly better outcome, which supports the paradigm of response-based treatment.
In summary, numerous investigations have confirmed that chemotherapy alone is an
effective treatment approach for PHL. However, the higher cumulative dosages used in these
protocols predispose survivors to greater risks of acute and late toxicity associated with
alky lating agents, anthracy clines, and bleomy cin. Conversely, these protocols decrease the
potential for radiation-associated treatment complications including musculoskeletal growth
impairment, cardiopulmonary dy sfunction, and solid tumor carcinogenesis. Current
information suggests that children with advanced and unfavorable sy mptomatic or bulky
disease at presentation have better outcomes using a combined-modality approach.
Identify ing the prognostic features of patients who need radiation to optimize disease control
is a focus of many ongoing pediatric trials.
RISK AND RESPONSE-ADAPTED THERAPY
Numerous investigations published in the 1990s supported the use of a risk-adapted treatment
assignment based on clinical features at disease presentation
(14,16,64,107,116,117,122,123,124,125,126,127,128,129,130). Parameters have varied
according to individual studies, but those used most often in risk assessments include the
presence of “B” sy mptoms, mediastinal and peripheral ly mph node bulk, number of involved
nodal regions, and Ann Arbor stage. These studies uniformly evaluated treatment outcomes
using a lower number of multiagent chemotherapy cy cles in clinically staged patients with
favorable clinical presentations.
Revised International Workshop Criteria have also recently been proposed for response
assessment to incorporate imaging with PET in addition to CT given the increased specificity
and sensitivity of PET compared to CT (131,132). A recent study conducted by Brepoels et
al. (133) compared these revised criteria incorporating PET versus the criteria using CT alone
to predict clinical outcome and found that the revised criteria predicted response more
accurately.
HL may still be cured even after initial treatment programs fail. Relapse usually occurs
within 4 y ears, and usually in 1–2 y ears but late relapse is not rare. The choice of therapy for
such patients depends on the initial treatment and the disease characteristics at the time of
relapse. A spectrum of treatment options exist (144). This section focuses on the role of
radiation in the setting of refractory or relapsed therapy.
Page 158For children who relapse after treatment that includes chemotherapy,
conventional (standard-dose) salvage chemotherapy regimens are of limited success,
increasing disease-free survival and OS in only 10–50% (144). Fortunately, other strategies
can be effective. The selection of the most appropriate salvage regimen is based on several
considerations, including the following:
Did the patient achieve a complete remission, or was the disease refractory ?
If a complete response was achieved, was it durable (longer than 1 y ear)?
Did the relapse occur in nodal or extranodal sites, and, as a corollary, was the stage at
relapse early or advanced?
The patients with the most favorable prognosis are those who have disease recurrence only at
a prolonged interval after an initial complete response and in a limited nodal pattern. In fact,
these patients may have a superior outcome (EFS as high as 80%) if treated with high-dose
chemotherapy and autologous stem cell rescue (145,146). In addition, a recent review by
Harker–Murray et al. (147) suggests that a non–stem cell transplant approach for patients with
late relapse >12 months, absent extranodal disease, no B sy mptoms, and CR to reinduction
chemotherapy could be efficacious. On the opposite end of the spectrum are patients who
have chemotherapy -refractory disease and are never cured by conventional salvage
chemotherapy.
Patients who relapse after regimens that include chemotherapy have been treated with
high-dose chemotherapy and hematopoietic stem cell rescue (144,145,148). Three- to 5-y ear
survival probabilities of 25–80%, depending on characteristics at relapse, have been reported
(primarily in adults) after such treatment (146,149,150). Only one prospective study
randomizing refractory or relapsed patients with HL to high-dose chemotherapy and stem
cell rescue or conventional-dose chemotherapy has been performed. Data specific to
children with recurrent HL are limited. However, an analy sis of 81 pediatric patients with HL
who underwent ABMT and were reported to the European Bone Marrow Transplant Group
demonstrated a similar outcome to a case matched group of adults similarly treated (151).
Claviez et al. (152) found an increased risk of relapse and lower progression-free survival
bey ond 9 months when pediatric patients received reduced intensity compared to a
my eloablative conditioning regimen prior to undergoing allogeneic stem cell transplant,
although OS was not different between the two groups. The United Kingdom Children’s
Cancer Study Group performed a review of 51 pediatric patients with relapsed or refractory
HL who underwent autologous stem cell transplant and 78 patients who underwent
conventional salvage treatment without stem cell transplant. There were no statistically
significant differences in OS between the two cohorts including those patients who had a short
initial remission after primary therapy (153). Prognostic factors for unfavorable outcome
include the duration of initial response to chemotherapy, “B” sy mptoms at relapse,
disseminated pulmonary or bone marrow disease at relapse, and more than minimal disease
at the time of transplantation (146,150). Patients with poor prognostic factors have a reported
5- to 10-y ear OS of 20–25% (154). Female sex, lactate dehy drogenase level ratio (the
absolute LDH level divided by the upper limit of the laboratory normal value) of greater than
one and short interval from diagnosis to autologous stem cell transplant (≤15 months) have
also been reported as negative predictive factors in pediatric patients (155). A variety of
preparative regimens provide similar outcome (148,156).
Page 159The basis for including RT in the setting of high-dose chemotherapy and stem
cell rescue for HL is twofold: These aggressive salvage programs still fail to cure a large
proportion of patients, and ample data show that many patients with progressive, recurrent
HL after chemotherapy do not exhibit a cross-resistance to radiation (144,157,158).
Moreover, most patients relapse in sites of previous involvement, mostly nodal (146,159,160).
The majority of patients undergoing auto stem cell transplant are conditioned with
carmustine, etoposide, cy tarabine (Ara-C), and melphalan (BEAM). ISRT may be given
after recovery for localized relapse particularly in patients who have not y et received
radiation as part of their primary therapy.
In considering the role of ISRT in the setting of high-dose chemotherapy and stem cell
rescue, three essential questions must be answered: Does RT to sites of recurrent or
refractory HL diminish relapse at these sites? If so, then what is the impact on freedom from
relapse, EFS, and OS? Is the associated morbidity of ISRT acceptable? Data from several
series support an affirmative answer to these questions (145,148,161,162).
In a Stanford report, patients with stage I–III disease at relapse who received ABMT and
IFRT had a 3-y ear freedom from relapse of 100% and OS of 85%, compared with 67% and
60%, respectively, for patients not receiving IFRT (162). For patients not previously irradiated,
IFRT was associated with an improved freedom from relapse of 85% and OS of 93%, in
contrast to 57% and 55%, respectively, for those previously irradiated. Morbidity was similar
to that of those not irradiated, although RT may have contributed to the peri-transplant death
of two patients.
Central issues relating to the use of RT are the dosage, target volume, and timing with
respect to transplantation. RT dosages generally are 20–36 Gy, in 1.5- to 2.0-Gy fractions.
This variation relates to potential normal tissue toxicity and the value of higher radiation
dosages in patients with identifiable tumor that demonstrates radiation responsiveness (148).
Radiation volume can vary and include treatment to all sites of initial disease, recurrent
disease, persistent disease after salvage chemotherapy, persistent disease after the
preparative regimen for transplantation, or all nodal sites (145,146,148). RT can be
administered before high-dose chemotherapy to place patients in a minimal disease state. RT
can also be administered after high-dose chemotherapy in patients that are high risk for
sy stemic relapse if BMT is delay ed in any way and to reduce RT-related peri-transplant
morbidity such as esophagitis, pneumonitis, cardiomy opathy, and veno-occlusive disease.
Possible disadvantages of this approach include the loss of the pretransplant cy toreductive
effect and the theoretical carcinogenic effect of RT on the newly proliferating hematopoietic
sy stem (145,146,148).
Retrieval therapies for higher risk relapse have been evaluated in combination with stem
cell transplant, primarily autologous stem cell transplant. COG study AHOD00P1 evaluated a
combination of ifosfamide and vinorelbine for pediatric patients in first relapse showing a
good overall response rate of 72% and the majority of patients were able to undergo stem
cell transplant (163). For patients who relapsed after transplant or are refractory in the
upfront setting, a combination of gemcitabine and vinorelbine has been studied and was found
to have an overall response rate of 76% (164).
Because of the historically high transplant-related mortality associated with allogeneic
transplantation, autologous hematopoietic stem cell transplantation has been preferred for
patients with relapsed HL. However, reduced-intensity allogeneic transplantation has
demonstrated acceptable rates of transplant-related mortality (165). Nonmy eloablative
conditioning regimens have varied, but most often they use fludarabine or low-dose TBI to
provide a nontoxic immunosuppression. If successful, the procedure establishes a graft-
versus-ly mphoma effect and provides a platform for adoptive cellular immunotherapy.
Evaluation of the effectiveness of this approach has been limited by reports describing
treatment outcomes in small heterogeneous patient cohorts assigned to a variety of
conditioning regimens in a nonrandom fashion. A longer follow-up period is needed to
determine the efficacy of this approach.
Future study for relapsed/refractory disease will focus on risk-stratify ing patients in the
relapsed setting. In the COG, patients will be grouped into low, intermediate, and high risk
groups based on CHIPs score at initial diagnosis, duration of initial CR, and initial response to
prior therapy. Long-term OS is markedly different for patients with relapsed disease
depending on these factors and ranges from <30% for the highest risk to >95% for the lowest
risk patients (166) and therefore, retrieval therapies will be de-escalated or intensified
according to patient group.
TARGETED THERAPIES
Novel sy stemic therapy combinations with the use of monoclonal antibody immunotherapy
targeting cell surface antigens has found its way into the primary and relapsed setting. CD30
is a transmembrane gly coprotein that is present on Reed–Sternberg cells. Brentuximab
vedotin is an antibody drug conjugate that links an anti-mitotic agent (MMAE) and an anti-
CD30 antibody. The release of MMAE intracellularly results in the disruption of the
microtubule network and results in G2/M cell cy cle arrest and apoptosis. An initial study by
Younes et al. (167) demonstrated evidence of regression in relapsed CD30+ malignancies in
85% of patients (167). A phase II study evaluating brentuximab in the relapsed HL setting
demonstrated 75% response rate of which 34% had a CR (168). However, the combination of
brentuximab and ABVD resulted in increased pulmonary toxicity due to the inclusion of
bleomy cin. Thus, in the pediatric setting, brentuximab is currently being combined with AVE-
PC regimen in high-risk disease in combination with radiation for LMA and slow responding
disease. Brentuximab is also being used in high-risk patients in the St Jude–Stanford–Dana–
Farber consortium substituting vincristine in the OEPA/COPDac combination.
RADIOTHERAPEUTIC MANAGEMENT
Page 160The curability of PHL, the complexity of current treatment approaches, and the
vulnerability of the developing child to radiation and chemotherapy require the involved
radiation oncologist to thoroughly understand the role of radiation and to deliver it with skill.
As discussed earlier, most newly diagnosed children are treated with risk-adapted
chemotherapy alone or combined modality therapy including low-dose radiation. Because
most children are treated in institutional (or multi-institutional) studies, the radiation oncologist
should confirm all aspects of the diagnostic workup and staging and must also understand
study requirements in order to deliver appropriate radiation. In a review of the DAL-HD-90
trial (German–Austrian pediatric multicenter trial), up-front centralized review of patients in
the study altered the treatment approach in a large number of children (169). Central review
can identify deviations quickly and institutions that modify their treatment fields based upon
such review can almost entirely eliminate deviations (170). Unpublished data from the POG
also support the superior outcome of children treated with appropriate radiation fields and
dosages, in contrast to cases in which protocol violations occurred.
VOLUME CONSIDERATIONS
Most children with HL are treated with combined chemotherapy and low-dose radiation.
Meticulous and judiciously designed fields are necessary for optimizing disease control and
tissue damage. The definitions of such fields depend on the anatomy of the region in terms of
ly mph node distribution, patterns of disease extension into regional areas, and consideration
for match line problems should disease recur. Historically, involved fields ty pically included
not just the identifiably abnormal ly mph nodes but the entire ly mph node region containing
the involved nodes. The traditional definitions of ly mph node regions can be helpful but are
not necessarily sufficient. For example, the cervical and supraclavicular ly mph nodes were
historically treated when abnormal nodes were located any where in this area; this is
consistent with the anatomic definition of ly mph node regions used for staging purposes (171).
Care must be taken to shield relevant normal tissues such as the breast and ovaries. Radiation
field definition is evolving. For example, it is appropriate to treat the axilla or mediastinum
without the supraclavicular volume and the inguinal nodes without the iliacs depending on the
size and distribution of involved nodes at presentation. Field definitions often are protocol-
specific, but excessively small fields usually are inappropriate. Every effort should be made
to exclude unnecessary normal tissues (e.g., breast tissue in a child with isolated mediastinal
disease and no axillary involvement). Treatment of involved supradiaphragmatic fields
requires precision because of the distribution of ly mph nodes and the critical adjacent normal
tissues. These fields can be simulated with the arms up over the head or down with hands on
the hips. The former pulls the axillary ly mph nodes away from the lungs, allowing greater
lung shielding. However, the axillary ly mph nodes then move into the vicinity of the humeral
heads, which should be blocked in growing children. Therefore, the position chosen involves
weighing concerns regarding ly mph nodes, lung, and humeral heads. Attempts should be
made to exclude or position breast tissue. When the decision is made to include some or all of
a critical organ in the radiation field, such as liver, kidney, or heart, then normal tissue
constraints, depending on the chemotherapy used and patient age, are critical.
Three-dimensional conformal therapy is now utilized routinely. Equally weighted
anterior and posterior fields are still used appropriately for daily treatment depending on the
clinical scenario. Anteriorly weighted fields
excessively irradiate the anterior heart, with
associated cardiac morbidity (172). Dosage
calculations should be based on the patient
separation at the central axis. A full mantle field
is rarely required but when treated, nodes in the
neck and axilla receive a higher dosage because
the patient’s body is thinner than at the mid-
thorax. Therefore, separate axillary, neck, and
low mediastinal dosimetry should be performed,
and compensating filters or other modifications
should be used to minimize inhomogeneity with
3D conformal approaches. Extended source-to- Figure 7.6 Coronal view on CT
skin distances decrease dosage inhomogeneity in simulation scan of ISRT field in the
these different areas. With 3D-based planning, mediastinum including contours
appropriate target coverage can be assessed depicting the postchemotherapy GTV
while minimizing doses to normal structures. If (green); CTV (pink); PTV (blue).
chemotherapy has been given, then the width of
the field generally is based on the postchemotherapy residual disease, whereas the cephalad–
caudad dimension respects the original disease extent (Fig. 7.6 ). As previously stated,
humeral head blocks are appropriate unless bulky axillary adenopathy would thereby be
shielded.
The entire heart and lungs are rarely treated and when treated, dosages tend not to
exceed 10–16 Gy, depending on the distribution of disease and chemotherapy used. More
specifically, whole heart and whole lung irradiation is generally no longer recommended.
Current protocols omit whole lung in the setting of complete response to chemotherapy
(171). The approaches to radiotherapy in pediatric HL are highly protocol dependent because
some children treated for advanced-stage HL receive RT only to areas of initial bulk disease
or post chemotherapy residual disease. When the subdiaphragmatic region is being treated,
the radiation dosage to the kidney s must be minimized. Usually the upper pole of the left
kidney is within the irradiated volume when treating the spleen. A treatment planning CT with
IV contrast, and diagnostic information obtained from the CT or MRI (coronal slices from a
thoracic MRI will reveal the relationship of the spleen to the kidney ) are helpful in drawing
the blocks. Four-dimensional CT scan should be obtained to assess spleen organ motion with
respiration to allow for a margin. When the pelvis is being treated, special attention must be
given to the ovaries and testes. The ovaries should be relocated, marked with surgical clips,
laterally along the iliac wings or centrally behind the uterus if there is concern for their
location within the field. In this manner, appropriate shielding may be used. The testes
receive 5–10% of the administered pelvic dosage, which is sufficient to cause transient or
permanent azoospermia, depending on the total pelvic dosage. The greatest shielding can be
afforded to the testes if the patient is placed in a frog-legged position with an individually
fitted testes shield. If multileaf collimation is available, the multileaf can be placed over the
testes, additionally decreasing the transmitted dosage. Clearly, careful planning and judgment
are necessary. As previously stated, RT for unfavorable and advanced HL is variable and
protocol dependent. Although RT remains the standard when patients are treated with
combined-modality therapy, restricting RT to areas of initial bulky disease (generally defined
as larger than 5 cm at the time of disease presentation) or postchemotherapy residual disease
(generally defined as larger than 2 cm or residual PET avidity ) is under investigation.
Involved-Node Radiotherapy
The EORTC-GELA introduced the concept of involved-node radiotherapy (INRT) (174). This
uses all available clinical information including pre- and postchemotherapy imaging with CT
and FDG-PET scan to define the treatment field according to the prechemotherapy extent of
disease. Based on the EORTC-GELA guidelines, any visualized ly mph node after CRu should
be included in the clinical target volume (CTV) and normal structures displaced by enlarged
ly mph nodes should not be included in the CTV. The GHSG defines the margin of the
planning target volume (PTV) as 2 cm in the axial direction and 3 cm in the craniocaudal
direction although the EORTC-GELA group reduces this margin to 1–1.5 cm (175).
Controversy still exists regarding the optimum margins for the application of INRT
(174,175,176,177).
To apply the INRT concept and the high precision required to cover the full extent of
disease using INRT, both pre- and postchemotherapy CT and FDG-PET scans should be
performed in the treatment position (177). In a study of early -stage HL patients by Girinsky
et al. (178), PET identified 36% of involved ly mph nodes that were radiographically occult
on CT scan. Therefore, evaluation with FDG-PET scan prior to chemotherapy may help to
delineate the complete extent of clinical disease. Initial clinical data with the use of INRT is
emerging. Campbell et al. (179) reviewed clinical outcomes of patients with limited stage HL
treated with EFRT, IFRT, and INRT ≤5cm, similar to ISRT. No marginal recurrences or
locoregional failures occurred with INRT.
The application of INRT requires that all available clinical information is utilized to
appropriately reduce treatment field size without sacrificing the excellent clinical outcomes
that are attainable with standard therapy (Fig. 7.6 ).
CT scan imaging enables 3D planning and enhanced anatomic localization for treatment field
design and dose calculations. Three-dimensional conformal radiation (3D-CRT) and intensity -
modulated radiotherapy (IMRT) are methods used to deliver tightly conformal doses to the
tumor volume. Steep dose gradients are achieved to spare normal structures, particularly for
patients who are at risk for treatment complications. It is important to note that the use of
conformal approaches is based on delineation of the appropriate volume to be irradiated, and
not on anatomic definitions and structures as is true for traditional anterior/posterior (two-
field) approaches.
“Forward planning” is used to create 3D-CRT plans whereby the phy sician, phy sicist, or
dosimetrist determines the nature of the radiation beams that will accomplish a desirable
radiation dose distribution. Using IMRT, the delivery of a tightly conformal radiation dose with
a steep dose gradient to spare normal structures can be achieved. It is particularly
advantageous in its ability to create concavities to avoid treatment of surrounding tissues and
utilizes multiple treatment fields to accomplish this goal. Although an increased number of
treatment fields improve conformality, the radiation dose is spread over a larger volume of
tissue as a result. IMRT also requires additional monitor units to deliver treatment compared to
conventional methods. Therefore, total body dose is increased due to increased leakage
radiation. The impact of IMRT in children is a special consideration. Children are known to be
at higher risk for the development of secondary malignancies after radiation (ICRU 60). The
use of multiple beams with IMRT results in a larger area of the body receiving a low dose
compared to conventional techniques (“low-dose” bath effect). IMRT for the pediatric
population remains controversial given the concerns for long-term toxicities including late
growth disorders and the development of second malignancies. Increased radiation scatter
may have a greater impact on oncogenic risk given the smaller body habitus of children as a
result of the closer proximity of organs at risk and PTV compared to adults (184,185).
Page 164IMRT has been adopted as a standard treatment for various malignancies
including prostate and head and neck cancer. However, the role of IMRT has been limited in
the treatment of PHL due to the low doses required for treatment, the need to identify with
certainty the target ly mph nodes, as well as the limitations in the dosimetric advantage of
IMRT when treating a large field. However, it should alway s be a primary therapeutic goal to
minimize exposure to critical normal tissues even when the doses are already low enough to
be considered “safe.” The use of IMRT may result in a dosimetric advantage in select cases
particularly when apply ing the involved-site or involved-node approach. For example,
patients who are referred for RT before or after stem cell transplant may have received prior
radiation or have higher risk for radiation pneumonitis. In a patient who has received prior
radiation, IMRT may allow reirradiation of relapsed or refractory disease given the
proximity of previously irradiated normal structures. IMRT may also have a potential benefit
in highly select patients with bulky mediastinal disease or after bleomy cin administration for
the sparing of lung and heart (Fig. 7.9 ) Dose–volume histograms of conventional and
IMRT plans, respectively, in a patient with bulky mediastinal disease.
Figure 7.9 CT-based planning images depicting a historic mantle RT (A), compared to
standard involved-field radiation treatment (IFRT) (B), and involved-node RT (INRT) (C) for a
patient with stage I disease involving the mediastinum. The postchemotherapy volume of
initially involved paratracheal nodes is depicted in dark red and the cardiac silhouette is also
evident. Demonstration of the reduction in dose to breast, lung, heart, and thyroid for the
female patient shown in. (From Hodgson DC, Hudson MM, Constine LS. Pediatric Hodgkin
lymphoma: maximizing efficacy and minimizing toxicity. Semin Radiat Oncol.
2007;17(3):230–242, with permission.)
(From Hodgson DC, Hudson MM, Constine LS. Pediatric Hodgkin lymphoma: maximizing
efficacy and minimizing toxicity. Semin Radiat Oncol. 2007;17(3):230–242, with permission.)
Figure:
Radiation treatment plans (A) using 3DCRT (left), protons (middle), and IMRT (right). The
initial staging PET scan demonstrating extent of disease is depicted in (B) along with the
field borders in (C).
(From Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node proton therapy in combined
modality therapy for Hodgkin lymphoma: results of a phase 2 study. Int J Radiat Oncol Biol
Phys. 2014;89(5):1053–1059, with permission.)
DOSAGE CONSIDERATIONS
Kaplan (2) constructed a radiation dose–response curve for HL, but limitations of its current
applicability include its use of kilovoltage data. Reports demonstrate that lower radiation
dosages provide excellent local control, with variables including tumor size and fractionation
schedule (192,193). In the absence of chemotherapy, subclinical disease is reliably (95%)
controlled with 25–30 Gy, small bulk disease (variously defined but less than 5 cm in most
reports) necessitates 30–35 Gy, and large bulk disease an additional 5–10 Gy. The dosages per
fraction should be 1.5–1.8 Gy daily, five times a week. Patients treated with large volumes
may tolerate only 1.5-Gy fractions. In the setting of combined therapy, certainly the intensity
of the chemotherapy is important to consider in the choice of the radiation dosage and
volume. However, dosages of 15–25 Gy are ty pical, with shrinking fields and boosts
individualized. In general, dosages of more than 25 Gy are uncommon in pediatrics. Of
interest in this regard is the DAL-HD-90 trial, in which dosages of 20–25 Gy were
administered in combination with OEPA or OPPA, with or without COPP. The radiation
dosages administered were 20–25 Gy, with a local boost of 5–10 Gy for insufficient remission
after chemotherapy. Tumor burden, indicated by bulky disease or number of involved nodes,
proved not to be prognostically significant (134).
SEQUENCE OF THERAPY
The most effective sequence of therapy in the setting of combined chemotherapy and
irradiation has not been established. However, chemotherapy usually is the first modality.
This allows assessment of drug response, maximization of the amount of drug treatment, and
shrinkage of disease and more limited fields of irradiation. Occasionally, focal irradiation
before chemotherapy is necessary because of airway obstruction.
RESULTS
In assessing the results of therapy for HL, specific reports must be evaluated for the
following:
The actuarial 10-y ear survival for children with early -stage disease is 85–95%, and for
children with advanced-stage disease it is 70–90% (106). However, the toxicities vary greatly
between the treatment strategies. In fact, in the current era, essentially all patients will be
treated with combined chemotherapy and radiation, or chemotherapy alone, with the rare
exception of fully mature adolescents with very limited NLPHD who may be candidates for
radiation alone.
Page 166Although relapse-free survival and OS are excellent for patients with favorable,
early -stage disease, patients with unfavorable disease continue to fare less well. It is critical to
appreciate the extent to which death from causes other than recurrence of HL compromises
OS. Several investigators have observed a greater risk of mortality in long term survivors of
PHL than in the general population (120,121,192). In the first 10 y ears after diagnosis, deaths
were most commonly attributable to HL; with subsequent follow-up, subsequent cancers and
cardiovascular disease contributed to higher mortality rates than in age- and sex-matched
population control subjects. This is illustrated in (Fig. 7.11 ), which demonstrates the
cumulative incidence functions for cause-specific deaths among survivors of PHL treated at
St. Jude Children’s Research Hospital (120). Standardized incidence ratios in this cohort
showed a 12-fold elevated risk for all second malignancies, 11-fold elevated risk for a second
solid tumor, and 33-fold elevated risk of breast cancer in female patients. Standardized
mortality ratios also indicated greater mortality from cardiovascular disease (22; 95% CI, 8–
48) and infection (18; 95% CI, 7–38). Importantly, HL consistently accounts for the majority
of events in studies of long-term survivors; furthermore, relapse of HL is associated with a
higher risk of subsequent events, including second cancers and cardiovascular disease. These
findings underscore the need to proceed cautiously with therapeutic modifications because a
reduced treatment intensity or duration may compromise disease control and promote late
treatment complications.
Figure 7.11 Cumulative incidence functions for cause-specific deaths among St. Jude
children’s research hospital cohort with Hodgkin disease from second malignancy, Hodgkin
disease, cardiac disease, infection, and accident or suicide. Ten- and 20-year estimates are
shown, with 95% confidence intervals in parentheses. (From Hudson MM, Poquette CA, Lee J,
et al. Increased mortality after successful treatment for Hodgkin’s disease. J Clin Oncol.
1998;16(11):3592–3600, with permission.)
(From Hudson MM, Poquette CA, Lee J, et al. Increased mortality after successful treatment
for Hodgkin’s disease. J Clin Oncol. 1998;16(11):3592–3600, with permission.)
COMPLICATIONS
Page 169Devising new strategies to treat children with HL is problematic because of the
overall success of current treatment regimens. However, grouping patients into different risk
categories allows investigators to construct protocols intended to diminish therapy -induced
toxicity for patients with favorable prognoses, improve treatment effectiveness for patients
with unfavorable prognoses, and aim for both goals in patients who are intermediate in their
prognosis. Unfortunately, the ability to conduct clinical trials in which the differences in
survival between treatment arms are likely to be small is compromised by the large patient
numbers necessary to detect such differences. If a reduction in treatment toxicity is the
intended goal of a new regimen, then many y ears of follow-up are necessary to prove
effectiveness. Some generalizations regarding ongoing efforts in clinical trials for PHL are as
follows:
Patients with early -stage disease (I, IIA without bulk disease) have an excellent
prognosis. Therefore, the intensity and duration of chemotherapy can be decreased
along with the use of RT. Evaluation of response-based paradigms can help tailor therapy
to de-escalate appropriately.
Patients with disease of an intermediate stage or with characteristics indicating that their
prognosis is intermediate (II with bulky disease, IIB, IIIA) are appropriate for studies
that intend to increase efficacy without increasing toxicity. By using response-based
paradigms, treatment can be tailored to optimize the chemoradiotherapeutic approach.
Patients with advanced-stage disease (IIIB, IV) need more effective treatment
regimens. These might include increasing dosage intensity or the rate of drug delivery
and combining agents into new regimens and incorporating targeted agents. The use of
hematopoietic growth factors may assist in drug delivery. Defining the role of RT in such
trials will continue to be an important objective and potential dose escalation for slow
responding or incompletely responding patients may be necessary.
Of interest, ongoing trials are continuing to evaluate the paradigm of early response using
functional imaging as a prognostic factor for therapy reduction or intensification.
Finally, immunotherapeutic approaches are under development and investigation, such
as the use of antiferritin antibody joined with y ttrium-90 (240), EBV-specific cy totoxic T
ly mphocy tes (241), and anti-PD1 monoclonal antibodies blocking ligand activation of the
PD1 receptor on activated T cells. If effective, these novel approaches will provide an
alternative to cy totoxic treatment approaches with potentially fewer adverse long-term
treatment effects.
REFERENCES
1. Hodgkin T. On some morbid appearances of the absorbent gland and spleen. Med Chir
Trans. 1832;17:68–114.
2. Kaplan H. Hodgkin’s Disease. Cambridge, MA: Harvard University Press; 1980.
3. Pusey W. Cases of sarcomas and of Hodgkin’s disease treated by exposures to X ray s: a
preliminary report. JAMA. 1902;38:166–170.
4. Gilbert R. Radiotherapy in Hodgkin’s disease (malignant granulomatosis): anatomic and
clinical foundations, governing principles, results. Am J Roentgenol. 1939;41:198–241.
5. Peters M. A study of survival in Hodgkin’s disease treated radiologically. Am J
Roentgenol. 1950;63:299–311.
6. Goodman L, Wintrobe M, Dameshe W, et al. Nitrogen mustard therapy : use of methy l-
bis-(chloroethy l)amine hy drochloride for Hodgkin’s disease, ly mphosarcoma, leukemia
and certain allied and miscellaneous disorders. JAMA. 1946;132:126–131.
7. DeVita VTJ, Canellos G, Moxley J. A decade of combination chemotherapy of
advanced Hodgkin’s disease. Cancer. 1972;30:1495–1504.
8. Seif G, Spriggs A. Chromosome changes in Hodgkin’s disease. J Natl Cancer Inst.
1967;39:557–570.
9. Donaldson SS, Kaplan HS. Complications of treatment of Hodgkin’s disease in children.
Cancer Treat Rep. 1982;66(4):977–989.
10. Mauch PM, Weinstein H, Botnick L, et al. An evaluation of long-term survival and
treatment complications in children with Hodgkin’s disease. Cancer. 1983;51(5):925–932.
11. Donaldson SS, Glatstein E, Rosenberg SA, et al. Pediatric Hodgkin’s disease. II. Results of
therapy. Cancer. 1976;37(5):2436–2447.
12. Donaldson SS, Link MP. Combined modality treatment with low-dose radiation and
MOPP chemotherapy for children with Hodgkin’s disease. J Clin Oncol. 1987;5(5):742–
749.
13. Donaldson SS, Link MP. Hodgkin’s disease. Treatment of the y oung child. Pediatr Clin
North Am. 1991;38(2):457–473.
14. Schellong G, Bramswig JH, Hornig-Franz I, et al. Hodgkin’s disease in children:
combined modality treatment for stages IA, IB, and IIA. Results in 356 patients of the
German/Austrian Pediatric Study Group. Ann Oncol. 1994;5(suppl 2):113–115.
15. Schellong G. The balance between cure and late effects in childhood Hodgkin’s
ly mphoma: the experience of the German–Austrian Study Group since 1978. Ann
Oncol. 1996;7(suppl 4):67–72.
16. Schellong G. Treatment of children and adolescents with Hodgkin’s disease: the
experience of the German–Austrian Paediatric Study Group. Baillieres Clin Haematol.
1996;9(3):619–634.
17. Oberlin O, Boilletot A, Leverger G, et al. Clinical staging, primary chemotherapy and
involved field radiotherapy in childhood Hodgkin’s disease. Eur Paediatr Haematol
Oncol. 1985;2:65–70.
18. Dionet C, Oberlin O, Habrand JL, et al. Initial chemotherapy and low-dose radiation in
limited fields in childhood Hodgkin’s disease: results of a joint cooperative study by the
French Society of Pediatric Oncology (SFOP) and Hôpital Saint-Louis, Paris. Int J
Radiat Oncol Biol Phys. 1988;15(2):341–346.
19. Jenkin D, Doy le J, Berry M, et al. Hodgkin’s disease in children: treatment with MOPP
and low-dose, extended field irradiation without laparotomy. Late results and toxicity.
Med Pediatr Oncol. 1990;18(4):265–272.
20. Cleary SF, Link MP, Donaldson SS. Hodgkin’s disease in the very y oung. Int J Radiat
Oncol Biol Phys. 1994;28(1):77–83.
21. Kung FH. Hodgkin’s disease in children 4 y ears of age or y ounger. Cancer.
1991;67(5):1428–1430.
22. Mauch P, Tarbell N, Weinstein H, et al. Stage IA and IIA supradiaphragmatic Hodgkin’s
disease: prognostic factors in surgically staged patients treated with mantle and
paraaortic irradiation. J Clin Oncol. 1988;6(10):1576–1583.
23. Jox A, Zander T, Diehl V, et al. Clonal relapse in Hodgkin’s disease. N Engl J Med.
1997;337(7):499.
24. Kanzler H, Kuppers R, Hansmann ML, et al. Hodgkin and Reed–Sternberg cells in
Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from
(crippled) germinal center B cells. J Exp Med. 1996;184(4):1495–1505.
25. Fiumara P, Snell V, Li Y, et al. Functional expression of receptor activator of nuclear
factor kappaB in Hodgkin disease cell lines. Blood. 2001;98(9):2784–2790.
26. Gupta RK, Patel K, Bodmer WF, et al. Mutation of p53 in primary biopsy material and
cell lines from Hodgkin disease. Proc Natl Acad Sci U S A. 1993;90(7):2817–2821.
27. Page 170 Ambinder RF, Browning PJ, Lorenzana I, et al. Epstein–Barr virus and
childhood Hodgkin’s disease in Honduras and the United States. Blood. 1993;81(2):462–
467.
28. Weiss LM, Movahed LA, Warnke RA, et al. Detection of Epstein–Barr viral genomes in
Reed–Sternberg cells of Hodgkin’s disease. N Engl J Med. 1989;320(8):502–506.
29. Gupta RK, Whelan JS, Lister TA, et al. Direct sequence analy sis of the t(14;18)
chromosomal translocation in Hodgkin’s disease. Blood. 1992;79(8):2084–2088.
30. Hjalgrim H, Smedby KE, Rostgaard K, et al. Infectious mononucleosis, childhood social
environment, and risk of Hodgkin ly mphoma. Cancer Res. 2007;67(5):2382–2388.
31. Stein H, Hummel M, Durkop H, et al. Biology of Hodgkin’s disease. In: Canellos GLT,
Lister TA, Sklar JL, et al., eds. The Lymphomas. Philadelphia, PA: W.B. Saunders;
1998:287–304.
32. Gruss HJ, Pinto A, Duy ster J, et al. Hodgkin’s disease: a tumor with disturbed
immunological pathway s. Immunol Today. 1997;18(4):156–163.
33. Schwartz RS. Hodgkin’s disease: time for a change. N Engl J Med. 1997;337(7):495–496.
34. Marafioti T, Hummel M, Anagnostopoulos I, et al. Origin of nodular ly mphocy te–
predominant Hodgkin’s disease from a clonal expansion of highly mutated germinal-
center B cells. N Engl J Med. 1997;337(7):453–458.
35. Ohno T, Stribley JA, Wu G, et al. Clonality in nodular ly mphocy te-predominant
Hodgkin’s disease. N Engl J Med. 1997;337(7):459–465.
36. Jaffe ES. The 2008 WHO classification of ly mphomas: implications for clinical practice
and translational research. Hematology Am Soc Hematol Educ Program. 2009;523–31.
37. Barros MH, Zalcberg IR, Hassan R. Prognostic impact of CD15 expression and
proliferative index in the outcome of children with classical Hodgkin ly mphoma. Pediatr
Blood Cancer. 2008;50(2):428–429.
38. Dinand V, Malik A, Unni R, et al. Proliferative index and CD15 expression in pediatric
classical Hodgkin ly mphoma. Pediatr Blood Cancer. 2008;50(2):280–283.
39. Tan KL, Scott DW, Hong F, et al. Tumor-associated macrophages predict inferior
outcomes in classic Hodgkin ly mphoma: a correlative study from the E2496 Intergroup
trial. Blood. 2012;120(16):3280–7.
40. Klein JL, Nguy en TT, Bien-Willner GA, et al. CD163 immunohistochemistry is superior
to CD68 in predicting outcome in classical Hodgkin ly mphoma. Am J Clin Pathol.
2014;141(3):381–7.
41. Gupta S, Yeh S, Chami R, et al. The prognostic impact of tumour-associated
macrophages and Reed–Sternberg cells in paediatric Hodgkin ly mphoma. Eur J Cancer.
2013;49(15):3255–61.
42. Tarbell NJ, Gelber RD, Weinstein HJ, et al. Sex differences in risk of second malignant
tumours after Hodgkin’s disease in childhood. Lancet. 1993;341(8858):1428–1432.
43. Spitz MR, Sider JG, Johnson CC, et al. Ethnic patterns of Hodgkin’s disease incidence
among children and adolescents in the United States, 1973–82. J Natl Cancer Inst.
1986;76(2):235–239.
44. MacMahon B. Epidemiological evidence on the nature of Hodgkin’s disease. Cancer.
1957;10:1045–1054.
45. Trippett T, Mottl A, Oberlin O, et al. Hodgkin ly mphoma in adolescents. In: Bley er A,
Barr R, Albritton K, et al., eds. Cancer in Adolescents and Young Adults. Düsseldorf,
Germany : Springer-Verlag GmbH & Co; 2007:111–125.
46. Vianna NJ, Polan AK. Epidemiologic evidence for transmission of Hodgkin’s disease. N
Engl J Med. 1973;289(10):499–502.
47. Razzouk BI, Gan YJ, Mendonca C, et al. Epstein–Barr virus in pediatric Hodgkin disease:
age and histioty pe are more predictive than geographic region. Med Pediatr Oncol.
1997;28(4):248–254.
48. Herling M, Rassidakis GZ, Vassilakopoulos TP, et al. Impact of LMP-1 expression on
clinical outcome in age-defined subgroups of patients with classical Hodgkin ly mphoma.
Blood. 2006;107(3):1240.
49. Gandhi MK, Lambley E, Duraiswamy J, et al. Expression of LAG-3 by tumor-
infiltrating ly mphocy tes is coincident with the suppression of latent membrane antigen-
specific CD8+ T-cell function in Hodgkin ly mphoma patients. Blood. 2006;108(7):2280–
2289.
50. Claviez A, Tiemann M, Luders H, et al. Impact of latent Epstein–Barr virus infection on
outcome in children and adolescents with Hodgkin’s ly mphoma. J Clin Oncol.
2005;23(18):4048–4056.
51. Jarrett RF, Stark GL, White J, et al. Impact of tumor Epstein–Barr virus status on
presenting features and outcome in age-defined subgroups of patients with classic
Hodgkin ly mphoma: a population-based study. Blood. 2005;106(7):2444–2451.
52. Herling M, Rassidakis GZ, Medeiros LJ, et al. Expression of Epstein–Barr virus latent
membrane protein-1 in Hodgkin and Reed–Sternberg cells of classical Hodgkin’s
ly mphoma: associations with presenting features, serum interleukin 10 levels, and
clinical outcome. Clin Cancer Res. 2003;9(6):2114–2120.
53. Barros MH, Vera-Lozada G, Soares FA, et al. Tumor microenvironment composition in
pediatric classical Hodgkin ly mphoma is modulated by age and Epstein–Barr virus
infection. Int J Cancer. 2012;131(5):1142–52.
54. Robertson SJ, Lowman JT, Grufferman S, et al. Familial Hodgkin’s disease. A clinical and
laboratory investigation. Cancer. 1987;59(7):1314–1319.
55. Mack TM, Cozen W, Shibata DK, et al. Concordance for Hodgkin’s disease in identical
twins suggesting genetic susceptibility to the y oung-adult form of the disease. N Engl J
Med. 1995;332(7):413–418.
56. Linabery AM, Erhardt EB, Richardson MR, et al. Family history of cancer and risk of
pediatric and adolescent Hodgkin ly mphoma: a Children’s Oncology Group study. Int J
Cancer. 2015;137(9):2163–74.
57. Watanabe N, De Rosa SC, Cmelak A, et al. Long-term depletion of naive T cells in
patients treated for Hodgkin’s disease. Blood. 1997;90(9):3662–3672.
58. Filipovich AH, Mathur A, Kamat D, et al. Primary immunodeficiencies: genetic risk
factors for ly mphoma. Cancer Res. 1992;52(suppl 19):5465s–5467s.
59. Rubio R. Hodgkin’s disease associated with human immunodeficiency virus infection. A
clinical study of 46 cases. Cancer. 1994;73(9):2400–2407.
60. Mauch PM, Kalish LA, Kadin M, et al. Patterns of presentation of Hodgkin disease.
Implications for etiology and pathogenesis. Cancer. 1993;71(6):2062–2071.
61. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the
evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin
Oncol. 1989;7(11):1630–1636.
62. Jackson H, Parker F. Hodgkin’s disease II: pathology. N Engl J Med. 1994:35.
63. Ferry JA, Harris NL. The pathology of Hodgkin’s disease: what’s new? Semin Radiat
Oncol. 1996;6(3):121–130.
64. Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al. Ly mphocy te-predominant
Hodgkin’s ly mphoma in children: therapeutic abstention after initial ly mph node
resection—a study of the French Society of Pediatric Oncology. J Clin Oncol.
2003;21(15):2948–2952.
65. Punnett A, Tsang R, Hodgson DC. Hodgkin ly mphoma across the age spectrum:
epidemiology, therapy, and late effects. Semin Radiat Oncol. 2010;20(1):30–44.
66. Pui CH, Ip SH, Thompson E, et al. High serum interleukin-2 receptor levels correlate
with a poor prognosis in children with Hodgkin’s disease. Leukemia. 1989;3(7):481–484.
67. Gause A, Pohl C, Tschiersch A, et al. Clinical significance of soluble CD30 antigen in the
sera of patients with untreated Hodgkin’s disease. Blood. 1991;77(9):1983–1988.
68. Wieland A, Kerbl R, Berghold A, et al. C-reactive protein (CRP) as tumor marker in
pediatric and adolescent patients with Hodgkin disease. Med Pediatr Oncol.
2003;41(1):21–25.
69. Mahoney DH Jr, Schreuders LC, Gresik MV, et al. Role of staging bone marrow
examination in children with Hodgkin disease. Med Pediatr Oncol. 1998;30(3):175–177.
70. Purz S, Mauz-Körholz C, Körholz D, et al. [18F]Fluorodeoxy glucose positron emission
tomography for detection of bone marrow involvement in children and adolescents with
Hodgkin’s ly mphoma. J Clin Oncol. 2011;29(26):3523–8.
71. Castellino RA, Blank N, Hoppe RT, et al. Hodgkin disease: contributions of chest CT in the
initial staging evaluation. Radiology. 1986;160(3):603–605.
72. Hanna SL, Fletcher BD, Boulden TF, et al. MR imaging of infradiaphragmatic
ly mphadenopathy in children and adolescents with Hodgkin disease: comparison with
ly mphography and CT. J Magn Reson Imaging. 1993;3(3):461–470.
73. Bar-Shalom R, Yefremov N, Haim N, et al. Camera-based FDG PET and 67Ga SPECT
in evaluation of ly mphoma: comparative study. Radiology. 2003;227(2):353–360.
74. Wirth A, Sey mour JF, Hicks RJ, et al. Fluorine-18 fluorodeoxy glucose positron emission
tomography, gallium-67 scintigraphy, and conventional staging for Hodgkin’s disease and
non-Hodgkin’s ly mphoma. Am J Med. 2002;112(4):262–268.
75. Page 171 Mody RJ, Bui C, Hutchinson RJ, et al. Comparison of (18)F flurodeoxy glucose
PET with Ga-67 scintigraphy and conventional imaging modalities in pediatric
ly mphoma. Leuk Lymphoma. 2007;48(4):6999–7007.
76. Jadvar H, Connolly L, Shulkin B, et al. Positron-emission tomography in pediatrics. In:
Leonard M, Freeman MD, eds. Nuclear Medicine Annual 2000. Philadelphia, PA:
Lippincott Williams & Wilkins; 2000.
77. Smith R, Chen Q, Hudson M. Prognostic factors in pediatric Hodgkin’s disease. Int J
Radiat Oncol Biol Phys. 2001;51(3):199.
78. Maity A, Goldwein JW, Lange B, et al. Mediastinal masses in children with Hodgkin’s
disease. An analy sis of the Children’s Hospital of Philadelphia and the Hospital of the
University of Pennsy lvania experience. Cancer. 1992;69(11):2755–2760.
79. Ruhl U, Albrecht MR, Lueders H, et al. The German multinational GPOH-HD 95 trial:
treatment results and analy sis of failures in pediatric Hodgkin’s disease using combination
chemotherapy with and without radiation. Int J Radiat Oncol Biol Phys. 2004;60:S131.
80. Stefan DC, Stones D, Dippenaar A. Ethnicity and characteristics of Hodgkin ly mphoma
in children. Pediatr Blood Cancer. 2009;52(2):182–185.
81. Metzger ML, Castellino SM, Hudson MM, et al. Effect of race on the outcome of
pediatric patients with Hodgkin’s ly mphoma. J Clin Oncol. 2008;26(8):1282–1288.
82. Crnkovich MJ, Leopold K, Hoppe RT, et al. Stage I to IIB Hodgkin’s disease: the combined
experience at Stanford University and the Joint Center for Radiation Therapy. J Clin
Oncol. 1987;5(7):1041–1049.
83. Pui CH, Ip SH, Thompson E, et al. Increased serum CD8 antigen level in childhood
Hodgkin’s disease relates to advanced stage and poor treatment outcome. Blood.
1989;73(1):209–213.
84. Christiansen I, Sundstrom C, Enblad G, et al. Soluble vascular cell adhesion molecule-1
(sVCAM-1) is an independent prognostic marker in Hodgkin’s disease. Br J Haematol.
1998;102(3):701–709.
85. Warzocha K, Bienvenu J, Ribeiro P, et al. Plasma levels of tumour necrosis factor and its
soluble receptors correlate with clinical features and outcome of Hodgkin’s disease
patients. Br J Cancer. 1998;77(12):2357–2362.
86. Nadali G, Tavecchia L, Zanolin E, et al. Serum level of the soluble form of the CD30
molecule identifies patients with Hodgkin’s disease at high risk of unfavorable outcome.
Blood. 1998;91(8):3011–3016.
87. Chronowski GM, Wilder RB, Tucker SL, et al. An elevated serum beta-2-microglobulin
level is an adverse prognostic factor for overall survival in patients with early -stage
Hodgkin disease. Cancer. 2002;95(12):2534–2538.
88. Bohlen H, Kessler M, Sextro M, et al. Poor clinical outcome of patients with Hodgkin’s
disease and elevated interleukin-10 serum levels. Clinical significance of interleukin-10
serum levels for Hodgkin’s disease. Ann Hematol. 2000;79(3):110–113.
89. Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal
the oncogenome of primary Hodgkin and Reed–Sternberg cells. Blood.
2015;125(7):1061–72.
90. Dukers DF, Meijer CJ, ten Berge RL, et al. High numbers of active caspase 3–positive
Reed–Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease
predict favorable clinical outcome. Blood. 2002;100(1):36–42.
91. Mainou-Fowler T, Angus B, Miller S, et al. Micro-vessel density and the expression of
vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth
factor (PdEGF) in classical Hodgkin ly mphoma (HL). Leuk Lymphoma. 2006;47(2):223–
230.
92. Doussis-Anagnostopoulou IA, Talks KL, Turley H, et al. Vascular endothelial growth
factor (VEGF) is expressed by neoplastic Hodgkin–Reed–Sternberg cells in Hodgkin’s
disease. J Pathol. 2002;197(5):677–683.
93. Giles FJ, Vose JM, Do KA, et al. Clinical relevance of circulating angiogenic factors in
patients with non-Hodgkin’s ly mphoma or Hodgkin’s ly mphoma. Leuk Res.
2004;28(6):595–604.
94. Ben Arush MW, Ben Barak A, Maurice S, et al. Serum VEGF as a significant marker of
treatment response in Hodgkin ly mphoma. Pediatr Hematol Oncol. 2007;24(2):111–115.
95. Montalban C, Garcia JF, Abraira V, et al. Influence of biologic markers on outcome of
Hodgkin’s ly mphoma: a study by the Spanish Hodgkin’s Ly mphoma Study Group. J Clin
Oncol. 2004;22(9):1664–1673.
96. Casasnovas R, Mounier N, Brice P, et al. Plasma cy tokine and soluble receptor signature
predicts outcome of patients with classical Hodgkin’s ly mphoma: a study from Groupe
d’Etude des Ly mphomes de L’Adulte. J Clin Oncol. 2007;25(13):1732–1740.
97. von Wasielewski S, Franklin J, Fischer R, et al. Nodular sclerosing Hodgkin disease: new
grading predicts prognosis in intermediate and advanced stages. Blood.
2003;101(10):4063–4069.
98. Shankar AG, Ashley S, Radford M, et al. Does histology influence outcome in childhood
Hodgkin’s disease? Results from the United Kingdom Children’s Cancer Study Group. J
Clin Oncol. 1997;15(7):2622–2630.
99. Carde P, Koscielny S, Franklin J, et al. Early response to chemotherapy : a surrogate for
final outcome of Hodgkin’s disease patients that should influence initial treatment length
and intensity ? Ann Oncol. 2002;13(suppl 1):86–91.
100. Kobe C, Dietlein M, Franklin J, et al. Positron emission tomography has a high negative
predictive value for progression or early relapse for patients with residual disease after
first-line chemotherapy in advanced-stage Hodgkin ly mphoma. Blood.
2008;112(10):3989–3994.
101. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-
guided radiotherapy in patients with advanced stage Hodgkin’s ly mphoma (HD15 trial): a
randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791–
1799.
102. Kriz J, Reinartz G, Dietlein M, et al. Relapse analy sis of irradiated patients within the
HD15 trial of the German Hodgkin Study Group. Int J Radiat Oncol Biol Phys.
2015;92(1):46–53.
103. Jabbour E, Hosing C, Ay ers G, et al. Pretransplant positive positron emission
tomography /gallium scans predict poor outcome in patients with recurrent/refractory
Hodgkin ly mphoma. Cancer. 2007;109(12):2481–2489.
104. Schwartz CL, Friedman DL, McCarten K, et al. Predictors of early response and event-
free survival in Hodgkin ly mphoma (HL): PET versus CT imaging [abstract]. J Clin
Oncol 2011;29:8006.
105. Bazzeh F, Rihani R, Howard S, et al. Comparing adult and pediatric Hodgkin ly mphoma
in the surveillance, epidemiology, and end results program, 1988–2005: an analy sis of
21,734 cases. Leuk Lymphoma. 2010;51:2198–2207.
106. Donaldson SS, Whitaker SJ, Plowman PN, et al. Stage I–II pediatric Hodgkin’s disease:
long-term follow-up demonstrates equivalent survival rates following different
management schemes. J Clin Oncol. 1990;8(7):1128–1137.
107. Schellong G, Bramswig JH, Hornig-Franz I. Treatment of children with Hodgkin’s
disease: results of the German Pediatric Oncology Group. Ann Oncol. 1992;3(suppl
4):73–76.
108. DeVita V, Mauch P, Harris NL. Hodgkin’s disease. In: DeVita VT Jr, Hellman S,
Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA:
Lippincott–Raven Publishers; 1997:2242–2283.
109. Longo DL, Young RC, Wesley M, et al. Twenty y ears of MOPP therapy for Hodgkin’s
disease. J Clin Oncol. 1986;4(9):1295–1306.
110. Horning SJ, Hoppe RT, Kaplan HS, et al. Female reproductive potential after treatment
for Hodgkin’s disease. N Engl J Med. 1981;304(23):1377–1382.
111. Fry er CJ, Hutchinson RJ, Krailo M, et al. Efficacy and toxicity of 12 courses of ABVD
chemotherapy followed by low-dose regional radiation in advanced Hodgkin’s disease in
children: a report from the Children’s Cancer Study Group. J Clin Oncol.
1990;8(12):1971–1980.
112. Hutchinson R, Krailo M, Fry er C. Prognostic factor analy sis in advanced Hodgkin’s
disease (stages III and IV). Results of the CCG 521 trial. Med Pediatr Oncol. 1993;61.
113. Santoro A, Bonadonna G, Valagussa P, et al. Long-term results of combined
chemotherapy –radiotherapy approach in Hodgkin’s disease: superiority of ABVD plus
radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987;5(1):27–37.
114. Bonadonna G, Valagussa P, Santoro A. Alternating non–cross-resistant combination
chemotherapy or MOPP in stage IV Hodgkin’s disease. A report of 8-y ear results. Ann
Intern Med. 1986;104(6):739–746.
115. LaMonte CS, Yeh SD, Straus DJ. Long-term follow-up of cardiac function in patients
with Hodgkin’s disease treated with mediastinal irradiation and combination
chemotherapy including doxorubicin. Cancer Treat Rep. 1986;70(4):439–444.
116. Nachman JB, Sposto R, Herzog P, et al. Randomized comparison of low-dose involved-
field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve
a complete response to chemotherapy. J Clin Oncol. 2002;20(18):3765–3771.
117. Page 172 Weiner MA, Leventhal B, Brecher ML, et al. Randomized study of intensive
MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of
stages IIB, IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: a Pediatric
Oncology Group study. J Clin Oncol. 1997;15(8):2769–2779.
118. Donaldson SS, Lamborn KR. Radiation in pediatric Hodgkin’s disease. J Clin Oncol.
1998;16(1):391–393.
119. Wolden SL, Chen L, Kelly KM, et al. Long-term results of CCG 5942: a randomized
comparison of chemotherapy with and without radiotherapy for children with Hodgkin’s
ly mphoma--a report from the Children’s Oncology Group. J Clin Oncol.
2012;30(26):3174–3180.
120. Hudson MM, Poquette CA, Lee J, et al. Increased mortality after successful treatment
for Hodgkin’s disease. J Clin Oncol. 1998;16(11):3592–3600.
121. Wolden SL, Lamborn KR, Cleary SF, et al. Second cancers following pediatric Hodgkin’s
disease. J Clin Oncol. 1998;16(2):536–544.
122. Ruhl U, Albrecht M, Dieckmann K, et al. Response-adapted radiotherapy in the
treatment of pediatric Hodgkin’s disease: an interim report at 5 y ears of the German
GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys. 2001;51(5):1209–1218.
123. Dörffel W, Rühl U, Lüders H, et al. Treatment of children and adolescents with Hodgkin
ly mphoma without radiotherapy for patients in complete remission after chemotherapy :
final results of the multinational trial GPOH-HD95. J Clin Oncol. 2013;31(12):1562–
1568.
124. Mauz-Korholz C, Hasenclever D, Dorffel W, et al. Procarbazine-free OEPA-COPDAC
chemotherapy in boy s and standard OPPA-COPP in girls have comparable
effectiveness in pediatric Hodgkin’s ly mphoma: the GPOH-HD-2002 study. J Clin Oncol.
2010;28:3680–3686.
125. Kung FH, Schwartz CL, Ferree CR, et al. POG 8625: a randomized trial comparing
chemotherapy with chemoradiotherapy for children and adolescents with Stages I, IIA,
IIIA1 Hodgkin Disease: a report from the Children’s Oncology Group. J Pediatr Hematol
Oncol. 2006;28(6):362–368.
126. Donaldson SS, Hudson MM, Lamborn KR, et al. VAMP and low-dose, involved-field
radiation for children and adolescents with favorable, early -stage Hodgkin’s disease:
results of a prospective clinical trial. J Clin Oncol. 2002;20(14):3081–3087.
127. Oberlin O, Leverger G, Pacquement H, et al. Low-dose radiation therapy and reduced
chemotherapy in childhood Hodgkin’s disease: the experience of the French Society of
Pediatric Oncology. J Clin Oncol. 1992;10(10):1602–1608.
128. Landman-Parker J, Pacquement H, Leblanc T, et al. Localized childhood Hodgkin’s
disease: response-adapted chemotherapy with etoposide, bleomy cin, vinblastine, and
prednisone before low-dose radiation therapy. Results of the French Society of Pediatric
Oncology Study MDH90. J Clin Oncol. 2000;18(7):1500–1507.
129. Vecchi V, Pileri S, Burnelli R, et al. Treatment of pediatric Hodgkin disease tailored to
stage, mediastinal mass, and age. An Italian (AIEOP) multicenter study on 215 patients.
Cancer. 1993;72(6):2049–2057.
130. Friedmann AM, Hudson MM, Weinstein HJ, et al. Treatment of unfavorable childhood
Hodgkin’s disease with VEPA and low-dose, involved-field radiation. J Clin Oncol.
2002;20(14):3088–3094.
131. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant
ly mphoma. J Clin Oncol. 2007;25(5):579–586.
132. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for
response assessment of ly mphoma: consensus of the Imaging Subcommittee of
International Harmonization Project in Ly mphoma. J Clin Oncol. 2007;25(5):571–578.
133. Brepoels L, Stroobants S, De Wever W, et al. Hodgkin ly mphoma: response assessment
by revised International Workshop Criteria. Leuk Lymphoma. 2007;48(8):1539–1547.
134. Dieckmann K, Potter R, Hofmann J, et al. Does bulky disease at diagnosis influence
outcome in childhood Hodgkin’s disease and require higher radiation doses? Results from
the German–Austrian Pediatric Multicenter Trial DAL-HD-90. Int J Radiat Oncol Biol
Phys. 2003;56(3):644–652.
135. Donaldson SS, Link MP, Weinstein HJ, et al. Final results of a prospective clinical trial
with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin’s
disease. J Clin Oncol. 2007;25:332–337.
136. Metzger ML, Weinstein HJ, Hudson MM, et al. Association between radiotherapy vs no
radiotherapy based on early response to VAMP chemotherapy and survival among
children with favorable-risk Hodgkin ly mphoma. JAMA. 2012;307(24):2609–2616.
137. Tebbi CK, Mendenhall N, London WB, et al. Treatment of stage IA, IIA, IIIA1 pediatric
Hodgkin disease with doxorubicin, bleomy cin, vincristine, and etoposide (DBVE) and
radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer.
2006;46(2):198–202.
138. Tebbi CK, Mendenhall NP, London WB, et al. Response- dependent and reduced
treatment in lower risk Hodgkin ly mphoma in children and adolescents, results of P9426:
a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2012;59(7):1259–
65.
139. Castellino S, Keller F, Voss S, et al. Outcomes and patterns of failure in
children/adolescents with low risk Hodgkin ly mphoma (HL) who are FDG-PET (PET3)
positive after AVPC therapy. Kiln Padiatr. 2014;226:103.
140. Schwartz C, Constine L, Doojduen V, et al. A risk-adapted response-based approach using
ABVE-PC for children and adolescents with intermediate and high-risk Hodgkin’s
ly mphoma; the results of P9425. Blood. 2009;114(10):2051–9.
141. Hudson MM, Krasin M, Link MP, et al. Risk-adapted, combined-modality therapy with
VAMP/COP and response-based, involved-field radiation for unfavorable pediatric
Hodgkin’s disease. J Clin Oncol. 2004;22(22):4541–4550.
142. Friedman DL, Chen L, Wolden S, et al. Dose-intensive response-based chemotherapy
and radiation therapy for children and adolescents with newly diagnosed intermediate-
risk hodgkin ly mphoma: a report from the Children’s Oncology Group Study
AHOD0031. J Clin Oncol. 2014;32(32):3651–3658.
143. Dharmarajan KV, Friedman DL, Schwartz CL, et al. Patterns of relapse from a phase 3
Study of response-based therapy for intermediate-risk Hodgkin ly mphoma
(AHOD0031): a report from the Children’s Oncology Group. Int J Radiat Oncol Biol
Phys. 2015;92(1):60–66.
144. Kelly KM, Sposto R, Hutchinson R, et al. BEACOPP chemotherapy is a highly effective
regimen in children and adolescents with high-risk Hodgkin ly mphoma: a report from the
Children’s Oncology Group. Blood. 2011;117:2596–2603.
145. Yahalom J. Management of relapsed and refractory Hodgkin’s disease. Semin Radiat
Oncol. 1996;6(3):210–224.
146. Yahalom J. Do not miss a second (and possibly last) chance to cure Hodgkin’s disease. Int
J Radiat Oncol Biol Phys. 1997;39(3):595–597.
147. Harker-Murray PD, Drachtman RA, Hodgson DC, et al. Stratification of treatment
intensity in relapsed pediatric Hodgkin ly mphoma. Pediatr Blood Cancer. 2014;61:579–
586.
148. Constine LS, Rapoport AP. Hodgkin’s disease, bone marrow transplantation, and involved
field radiation therapy : coming full circle from 1902 to 1996. Int J Radiat Oncol Biol
Phys. 1996;36(1):253–255.
149. Benekli M, Smiley SL, Younis T, et al. Intensive conditioning regimen of etoposide (VP-
16), cy clophosphamide, and carmustine (VCB) followed by autologous hematopoietic
stem cell transplantation for relapsed and refractory Hodgkin’s ly mphoma. Bone Marrow
Transplant. 2008;41(7):613–619.
150. Engelhardt BG, Holland DW, Brandt SJ, et al. High-dose chemotherapy followed by
autologous stem cell transplantation for relapsed or refractory Hodgkin ly mphoma:
prognostic features and outcomes. Leuk Lymphoma. 2007;48(9):1728–1735.
151. Williams CD, Goldstone AH, Pearce R, et al. Autologous bone marrow transplantation
for pediatric Hodgkin’s disease: a case-matched comparison with adult patients by the
European Bone Marrow Transplant Group Ly mphoma Registry. J Clin Oncol.
1993;11(11):2243–2249.
152. Claviez A, Canals C, Dierick X, et al. Allogeneic hematopoietic stem cell transplantation
in children and adolescents with recurrent and refractory Hodgkin’s ly mphoma: an
analy sis of the European Group for Blood and Marrow Transplantation. Blood.
2009;114(10):2060–2067.
153. Stoneham S, Ashley S, Pinkerton R, et al. Hodgkin’s ly mphoma in children aged 5 y ears
or less—the United Kingdom experience. Eur J Cancer. 2007;43(9):1415–1421.
154. Bradley M, Cairo M. Stem cell transplantation for pediatric ly mphoma; past, present,
and future. Bone Marrow Transplant. 2008;41:149–158.
155. Page 173 Baker KS, Gordon BG, Gross TG, et al. Autologous hematopoietic stem-cell
transplantation for relapsed or refractory Hodgkin’s disease in children and adolescents. J
Clin Oncol. 1999;17(3):825–831.
156. Wimmer RS, Chauvenet AR, London WB, et al. APE chemotherapy for children with
relapsed Hodgkin disease: a Pediatric Oncology Group trial. Pediatr Blood Cancer.
2006;46(3):320–324.
157. Uematsu M, Tarbell NJ, Silver B, et al. Wide-field radiation therapy with or without
chemotherapy for patients with Hodgkin disease in relapse after initial combination
chemotherapy. Cancer. 1993;72(1):207–212.
158. Wirth A, Corry J, Laidlaw C, et al. Salvage radiotherapy for Hodgkin’s disease following
chemotherapy failure. Int J Radiat Oncol Biol Phys. 1997;39(3):599–607.
159. Dhakal S, Biswas T, Liesveld J, et al. Patterns and timing of initial relapse in patients
subsequently undergoing transplantation for Hodgkin’s ly mphoma. Int J Radiat Oncol
Biol Phys. 2009;75(1):188–192.
160. Shahidi M, Kamangari N, Ashley S, et al. Site of relapse after chemotherapy alone for
stage I and II Hodgkin’s disease. Radiother Oncol. 2006;78(1):1–5.
161. Hancock SL, Hoppe RT. Long-term complications of treatment and causes of mortality
after Hodgkin’s disease. Semin Radiat Oncol. 1996;6(3):225–242.
162. Poen JC, Hoppe RT, Horning SJ. High-dose therapy and autologous bone marrow
transplantation for relapsed/refractory Hodgkin’s disease: the impact of involved field
radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys.
1996;36(1):3–12.
163. Trippett TM, Schwartz CL, Guillerman RP, et al. Ifosfamide and vinorelbine is an
effective reinduction regimen in children with refractory /relapsed Hodgkin ly mphoma,
AHOD00P1: a children’s oncology group report. Pediatr Blood Cancer. 2015;62(1):60–4.
164. Cole PD, Schwartz CL, Drachtman RA, et al. Phase II study of weekly gemcitabine and
vinorelbine for children with recurrent or refractory Hodgkin’s disease: a children’s
oncology group report. J Clin Oncol. 2009;27:1456–1461.
165. Robinson SP, Goldstone AH, Mackinnon S, et al. Chemoresistant or aggressive
ly mphoma predicts for a poor outcome following reduced-intensity allogeneic
progenitor cell transplantation: an analy sis from the Ly mphoma Working Party of the
European Group for Blood and Bone Marrow Transplantation. Blood.
2002;100(13):4310–4316.
166. Kelly KM, Hodgson DC, Appel B, et al. Children’s Oncology Group’s 2013 Blueprint for
Research: Hodgkin Ly mphoma. Pediatr Blood Cancer. 2013;60:972–978.
167. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab
vedotin for patients with relapsed or refractory Hodgkin’s ly mphoma. J Clin Oncol.
2012;30(18):2183–2189.
168. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed
CD30-positive ly mphomas. N Engl J Med. 2010;363(19):1812–1821.
169. Dieckmann K, Potter R, Wagner W, et al. Up-front centralized data review and
individualized treatment proposals in a multicenter pediatric Hodgkin’s disease trial with
71 participating hospitals: the experience of the German–Austrian pediatric multicenter
trial DAL-HD-90. Radiother Oncol. 2002;62(2):191–200.
170. Dharmarajan KV, Friedman DL, FitzGerald TJ, et al. Radiotherapy quality assurance
report from children’s oncology group AHOD0031. Int J Radiat Oncol Biol Phys.
2015;91(5):1065–1071.
171. Kaplan HS, Rosenberg SA. The treatment of Hodgkin’s disease. Med Clin North Am.
1966;50(6):1591–1610.
172. Gottdiener JS, Katin MJ, Borer JS, et al. Late cardiac effects of therapeutic mediastinal
irradiation. Assessment by echocardiography and radionuclide angiography. N Engl J
Med. 1983;308(10):569–572.
173. Hodgson DC, Dieckmann K, Terezakis S, et al. Implementation of contemporary
radiation therapy planning concepts for pediatric Hodgkin ly mphoma: guidelines from
the International Ly mphoma Radiation Oncology Group. Pract Radiat Oncol.
2015;5(2):85–92.
174. Girinsky T, van der Maazen R, Specht L, et al. Involved-node radiotherapy (INRT) in
patients with early Hodgkin ly mphoma: concepts and guidelines. Radiother Oncol.
2006;79(3):270–277.
175. Eich HT, Muller RP, Engenhart-Cabillic R, et al. Involved-node radiotherapy in early -
stage Hodgkin’s ly mphoma. Definition and guidelines of the German Hodgkin Study
Group (GHSG). Strahlenther Onkol. 2008;184(8):406–410.
176. Senan S, Piet A, Lagerwaard F. Involved-node radiotherapy to the mediastinum.
Radiother Oncol. 2007;82(1):108–109.
177. Girinsky T, Specht L, Ghalibafian M, et al. The conundrum of Hodgkin ly mphoma nodes:
to be or not to be included in the involved node radiation fields. The EORTC-GELA
ly mphoma group guidelines. Radiother Oncol. 2008;88(2):202–210.
178. Girinsky T, Ghalibafian M, Bonniaud G, et al. Is FDG-PET scan in patients with early
stage Hodgkin ly mphoma of any value in the implementation of the involved-node
radiotherapy concept and dose painting? Radiother Oncol. 2007;85(2):178–186.
179. Campbell BA, Voss N, Pickles T, et al. Involved-nodal radiation therapy as a component
of combination therapy for limited-stage Hodgkin’s ly mphoma: a question of field size. J
Clin Oncol. 2008;26(32):5170–5174.
180. Lee YK, Cook G, Flower MA, et al. Addition of 18F-FDG-PET scans to radiotherapy
planning of thoracic ly mphoma. Radiother Oncol. 2004;73(3):277–283.
181. Hutchings M, Loft A, Hansen M, et al. Clinical impact of FDG-PET/CT in the planning of
radiotherapy for early -stage Hodgkin ly mphoma. Eur J Haematol. 2007;78(3):206–212.
182. Robertson VL, Anderson CS, Keller FG, et al. Role of FDG-PET in the definition of
involved-field radiation therapy and management for pediatric Hodgkin’s ly mphoma. Int
J Radiat Oncol Biol Phys. 2011;80(2):324–332.
183. Metwally H, Courbon F, David I, et al. Coregistration of prechemotherapy PET-CT for
planning pediatric Hodgkin’s disease radiotherapy significantly diminishes interobserver
variability of clinical target volume definition. Int J Radiat Oncol Biol Phys.
2011;80(3):793–799.
184. Plowman PN, Cooke K, Walsh N. Indications for tomotherapy /intensity modulated
radiation therapy in pediatric radiotherapy extracranial disease. Br J Radiol.
2008;81:872–880.
185. Hall EJ. Intensity -modulated radiation therapy, protons, and the risk of second cancers.
Int J Radiat Oncol Biol Phys. 2006;65(1):1–7.
186. Goodman KA, Toner S, Hunt M, et al. Intensity -modulated radiotherapy for ly mphoma
involving the mediastinum. Int J Radiat Oncol Biol Phys. 2005;62(1):198–206.
187. Yorke ED, Jackson A, Rosenzweig KE, et al. Dose-volume factors contributing to the
incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with
three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys.
2002;54(2):329–339.
188. Nieder C, Schill S, Kneschaurek P, et al. Comparison of three different mediastinal
radiotherapy techniques in female patients: impact on heart sparing and dose to the
breasts. Radiother Oncol. 2007;82(3):301–307.
189. Filippi AR, Ciammella P, Piva C, et al. Involved-site image-guided intensity modulated
versus 3D conformal radiation therapy in early stage supradiaphragmatic Hodgkin
ly mphoma. Int J Radiat Oncol Biol Phys. 2014;89(2):370–375.
190. Andolino DL, Hoene T, Xiao L, et al. Dosimetric comparison of involved-field three-
dimensional conformal photon radiotherapy and breast-sparing proton therapy for the
treatment of Hodgkin’s ly mphoma in female pediatric patients. Int J Radiat Oncol Biol
Phys. 2011;81(4):e667–e671.
191. Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node proton therapy in combined
modality therapy for Hodgkin ly mphoma: results of a phase 2 study. Int J Radiat Oncol
Biol Phys. 2014;89(5):1053–1059.
192. Coia LR, Hanks GE. Complications from large field intermediate dose
infradiaphragmatic radiation: an analy sis of the patterns of care outcome studies for
Hodgkin’s disease and seminoma. Int J Radiat Oncol Biol Phys. 1988;15(1):29–35.
193. Kinzie JJ, Hanks GE, MacLean CJ, et al. Patterns of care study : Hodgkin’s disease relapse
rates and adequacy of portals. Cancer. 1983;52(12):2223–2226.
194. Green DM, Gingell RL. Regarding cardiac function and morbidity in long-term survivors
of Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 1998;41(4):971.
195. Tarbell N, Mauch P, Hellman S. Pulmonary complications of Hodgkin’s disease
treatment: radiation pneumonitis, fibrosis, and the effect of cy totoxic drugs. In: Lacher
MJ, Redman JR, eds. Hodgkin’s Disease: The Consequences of Survival. Philadelphia,
PA: Lea & Febiger; 1990.
196. Page 174 Mertens AC, Yasui Y, Liu Y, et al. Pulmonary complications in survivors of
childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study.
Cancer. 2002;95(11):2431–2441.
197. Adams MJ, Hardenbergh PH, Constine LS, et al. Radiation-associated cardiovascular
disease. Crit Rev Oncol Hematol. 2003;45(1):55–75.
198. Green DM, Hy land A, Chung CS, et al. Cancer and cardiac mortality among 15-y ear
survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol.
1999;17(10):3207–3215.
199. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s
disease in children and adolescents. J Clin Oncol. 1993;11(7):1208–1215.
200. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thy roid in survivors of
Hodgkin’s disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol
Metab. 2000;85(9):3227–3232.
201. Constine LS, Donaldson SS, McDougall IR, et al. Thy roid dy sfunction after radiotherapy
in children with Hodgkin’s disease. Cancer. 1984;53(4):878–883.
202. Le Floch O, Donaldson SS, Kaplan HS. Pregnancy following oophoropexy and total
nodal irradiation in women with Hodgkin’s disease. Cancer. 1976;38(6):2263–2268.
203. Anselmo AP, Cartoni C, Bellantuono P, et al. Risk of infertility in patients with Hodgkin’s
disease treated with ABVD vs MOPP vs ABVD/MOPP. Haematologica. 1990;75(2):155–
158.
204. Bramswig JH, Heimes U, Heiermann E, et al. The effects of different cumulative doses
of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin’s
disease during childhood or adolescence. Cancer. 1990;65(6):1298–1302.
205. By rne J, Fears TR, Gail MH, et al. Early menopause in long-term survivors of cancer
during adolescence. Am J Obstet Gynecol. 1992;166(3):788–793.
206. da Cunha MF, Meistrich ML, Fuller LM, et al. Recovery of spermatogenesis after
treatment for Hodgkin’s disease: limiting dose of MOPP chemotherapy. J Clin Oncol.
1984;2(6):571–577.
207. Green DM, Hall B. Pregnancy outcome following treatment during childhood or
adolescence for Hodgkin’s disease. Pediatr Hematol Oncol. 1988;5(4):269–277.
208. Pedrick TJ, Hoppe RT. Recovery of spermatogenesis following pelvic irradiation for
Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 1986;12(1):117–121.
209. Ortin TT, Shostak CA, Donaldson SS. Gonadal status and reproductive function following
treatment for Hodgkin’s disease in childhood: the Stanford experience. Int J Radiat Oncol
Biol Phys. 1990;19(4):873–880.
210. Hudson MM, Greenwald C, Thompson E, et al. Efficacy and toxicity of multiagent
chemotherapy and low-dose involved-field radiotherapy in children and adolescents
with Hodgkin’s disease. J Clin Oncol. 1993;11(1):100–108.
211. Jules-Ely see K, Stover DE, Yahalom J, et al. Pulmonary complications in ly mphoma
patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev
Respir Dis. 1992;146(2):485–491.
212. Marina NM, Greenwald CA, Fairclough DL, et al. Serial pulmonary function studies in
children treated for newly diagnosed Hodgkin’s disease with mantle radiotherapy plus
cy cles of cy clophosphamide, vincristine, and procarbazine alternating with cy cles of
doxorubicin, bleomy cin, vinblastine, and dacarbazine. Cancer. 1995;75(7):1706–1711.
213. Mefferd JM, Donaldson SS, Link MP. Pediatric Hodgkin’s disease: pulmonary, cardiac,
and thy roid function following combined modality therapy. Int J Radiat Oncol Biol Phys.
1989;16(3):679–685.
214. Koh ES, Sun A, Tran TH, et al. Clinical dose-volume histogram analy sis in predicting
radiation pneumonitis in Hodgkin’s ly mphoma. Int J Radiat Oncol Biol Phys.
2006;66:223–228.
215. Scholz KH, Herrmann C, Tebbe U, et al. My ocardial infarction in y oung patients with
Hodgkin’s disease: potential pathogenic role of radiotherapy, chemotherapy, and
splenectomy. Clin Invest. 1993;71(1):57–64.
216. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for
acute ly mphoblastic leukemia in childhood. N Engl J Med. 1991;324(12):808–815.
217. Andersson A, Naslund U, Tavelin B, et al. Long-term risk of cardiovascular disease in
Hodgkin ly mphoma survivors—retrospective cohort analy ses and a concept of
prospective intervention. Int J Cancer. 2009;124(8):1914–1917.
218. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of
Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol. 2004;22(15):3139–3148.
219. Kinsella TJ, Trivette G, Rowland J, et al. Long-term follow-up of testicular function
following radiation therapy for early -stage Hodgkin’s disease. J Clin Oncol.
1989;7(6):718–724.
220. Hobbie WL, Ginsberg JP, Ogle SK, et al. Fertility in males treated for Hodgkins disease
with COPP/ABV hy brid. Pediatr Blood Cancer. 2005;44(2):193–196.
221. Viviani S, Santoro A, Ragni G, et al. Gonadal toxicity after combination chemotherapy
for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol.
1985;21(5):601–605.
222. Haukvik UK, Dieset I, Bioro T, et al. Treatment-related premature ovarian failure as a
long-term complication after Hodgkin’s ly mphoma. Ann Oncol. 2006;17(9):1428–1433.
223. Behringer K, Breuer K, Reineke T, et al. Secondary amenorrhea after Hodgkin’s
ly mphoma is influenced by age at treatment, stage of disease, chemotherapy regimen,
and the use of oral contraceptives during therapy : a report from the German Hodgkin’s
Ly mphoma Study Group. J Clin Oncol. 2005;23:7555–7564.
224. Hodgson DC, Pintilie M, Gitterman L, et al. Fertility among female Hodgkin ly mphoma
survivors attempting pregnancy following ABVD chemotherapy. Hematol Oncol.
2007;25:11–15.
225. Wolden SL, Hancock SL, Carlson RW, et al. Management of breast cancer after
Hodgkin’s disease. J Clin Oncol. 2000;18(4):765–772.
226. van Leeuwen FE, Klokman WJ, Veer MB, et al. Long-term risk of second malignancy in
survivors of Hodgkin’s disease treated during adolescence or y oung adulthood. J Clin
Oncol. 2000;18(3):487–497.
227. Schellong G, Riepenhausen M, Creutzig U, et al. Low risk of secondary leukemias after
chemotherapy without mechlorethamine in childhood Hodgkin’s disease. German–
Austrian Pediatric Hodgkin’s Disease Group. J Clin Oncol. 1997;15(6):2247–2253.
228. Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent malignant neoplasms among
1,641 Hodgkin’s diseasepatients diagnosed in childhood and adolescence: a population-
based cohort study in the five Nordic countries. J Clin Oncol. 1996;14(5):1442–1446.
229. Metay er C, Ly nch CF, Clarke EA, et al. Second cancers among long-term survivors of
Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol.
2000;18(12):2435–2443.
230. Green DM, Hy land A, Barcos MP, et al. Second malignant neoplasms after treatment
for Hodgkin’s disease in childhood or adolescence. J Clin Oncol. 2000;18(7):1492–1499.
231. Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second neoplasms after
childhood Hodgkin’s disease. N Engl J Med. 1996;334(12):745–751.
232. Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malignancy after Hodgkin’s
disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol.
2000;18(3):498–509.
233. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and
chemotherapy among y oung women with Hodgkin disease. JAMA. 2003;290(4):465–
475.
234. Gilbert ES, Stovall M, Gospodarowicz M, et al. Lung cancer after treatment for Hodgkin’s
disease: focus on radiation effects. Radiat Res. 2003;159(2):161–173.
235. Basu SK, Schwartz C, Fisher SG, et al. Unilateral and bilateral breast cancer in women
surviving pediatric Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 2008;72(1):34–40.
236. Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated
for Hodgkin’s disease: associations with gender and radiation dose. Int J Radiat Oncol Biol
Phys. 2008;72:24–33.
237. Robison LL, Green DM, Hudson M, et al. Long-term outcomes of adult survivors of
childhood cancer. Cancer. 2005;104:2557–2564.
238. Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for y oung
women treated for Hodgkin ly mphoma. J Natl Cancer Inst. 2005;97:1428–1437.
239. Mertens AC, Mithy PA, Radloff G, et al. XRCC1 and glutathione-S-transferase gene
poly morphisms and susceptibility to radiotherapy -related malignancies in survivors of
Hodgkin disease. Cancer. 2004;101(6):1463–1472.
240. Bierman PJ, Vose JM, Leichner PK, et al. Yttrium 90–labeled antiferritin followed by
high-dose chemotherapy and autologous bone marrow transplantation for poor-prognosis
Hodgkin’s disease. J Clin Oncol. 1993;11(4):698–703.
241. Rooney CM, Smith CA, Ng CY, et al. Use of gene-modified virus-specific T
ly mphocy tes to control Epstein–Barr virus–related ly mphoproliferation. Lancet.
1995;345(8941):9–13.
CH A P TER 8
Non-Hodgkin Lymphoma
Mary S. Huang, Nancy J. Tarbell, and Howard J. Weinstein
Page 175Malignant ly mphoma was described by Hodgkin in 1832 (1) and was distinguished
from leukemia by Virchow in 1845 (2). Progress in treating children with non-Hodgkin
ly mphoma (NHL) mirrors the recognition of the sy stemic spread of the disease and
underly ing biology. Response to therapy and overall prognosis depend on the underly ing
histologic subty pe, primary site, and the extent of disease (3,4). Historically, local therapy
resulted in an overall survival of 10–30% (4). Multiagent protocols including sy stemic therapy
result in overall survivals of 70–95% (5).
Childhood NHL is distinguished from adult NHL by differing frequencies of
histopathologic ty pes and by the greater frequency of extranodal presentations (6,7). The
pediatric NHLs are mostly (>95%) high grade and include the following four major
subty pes: B- and T-ly mphoblastic ly mphoma, Burkitt ly mphoma, diffuse large B-cell
ly mphoma, and anaplastic large-cell ly mphoma (ALCL) (Fig. 8.1 ). Many of these high-
grade ly mphomas disseminate noncontiguously, evolve into a leukemic phase, and may
involve the central nervous sy stem (CNS) (7). The more common low-grade ly mphomas
seen in adults, such as follicular and marginal zone ly mphomas, are rare in children (6).
Figure 8.1 Denis Parsons Burkitt
(1911–1993) was the son of an engineer. A
Protestant raised in Northern Ireland, he
lost an eye in a fight as a schoolboy. He
graduated as a physician in 1935 and
trained in surgery but had difficulty in
obtaining surgical positions because of his
visual loss. Eventually, he was posted as
an Army physician in Africa and
subsequently worked as a missionary
physician. He characterized a previously
undescribed aggressive head and neck
cancer of childhood. Michael Epstein
attended one of Burkitt’s lectures in
England, suspected a viral origin, and
requested a tissue sample. Epstein and
Yvonne M. Barr isolated the virus
(Epstein–Barr virus). Burkitt also
described the crucial influence of dietary
fiber on health and disease.
Figure:
Denis Parsons Burkitt (1911–1993) was the son of an engineer. A Protestant raised in
Northern Ireland, he lost an eye in a fight as a schoolboy. He graduated as a physician in 1935
and trained in surgery but had difficulty in obtaining surgical positions because of his visual
loss. Eventually, he was posted as an Army physician in Africa and subsequently worked as a
missionary physician. He characterized a previously undescribed aggressive head and neck
cancer of childhood. Michael Epstein attended one of Burkitt’s lectures in England, suspected
a viral origin, and requested a tissue sample. Epstein and Yvonne M. Barr isolated the virus
(Epstein–Barr virus). Burkitt also described the crucial influence of dietary fiber on health and
disease.
EPIDEMIOLOGY AND ETIOLOGY
The ly mphomas are the third most common malignancy in children below 15 y ears of age.
They are rare under the age of 3 y ears, peaking in incidence from age 7 to 11 y ears. There is
approximately a 3:1 male:female ratio (3,4). Ly mphomas account for approximately 10% of
all childhood cancers: 60% are NHL and 40% are Hodgkin disease (8). There is geographic
variation in the incidence of the NHLs. For example, in equatorial Africa, Burkitt ly mphoma
accounts for almost 50% of all childhood cancers. In this setting, endemic Burkitt ly mphoma
is invariably positive for Epstein–Barr virus (EBV), in contrast to about 10% of cases of
sporadic Burkitt ly mphoma. However, both endemic and sporadic cases of Burkitt ly mphoma
have the same chromosomal translocations involving one of the loci encoding
immunoglobulin heavy or light chains and the c-my c oncogene. The exact role of EBV in the
pathogenesis of Burkitt ly mphoma and other malignancies is unknown. NHL occurs in
association with congenital immunodeficiency sy ndromes such as X-linked
ly mphoproliferative sy ndrome, ataxia telangiectasia, Wiskott–Aldrich sy ndrome, and
common variable immune deficiency disease, presumably caused by host defects in
immunoregulation or gene rearrangement (9,10). Immunosuppressive therapy and acquired
immunologic disorders including HIV also increase the risk of developing NHL (10). These
are predominantly diffuse large B cell or Burkitt subty pes. Screening for HIV and other
immunodeficiencies should be considered for all children with NHL, especially for those with
B-cell ly mphomas.
CLINICAL PRESENTATION
Page 176Several subty pes of NHL in children are associated with distinct clinical
manifestations and sites of disease (Table 8.1 ). Sy mptoms leading to diagnosis usually are
of short duration. Approximately 25% of children with NHL have an anterior mediastinal
mass (usually T ly mphoblastic or diffuse large B cell) and present with wheezing, stridor, and
cough progressing to dy spnea. The majority of these patients are adolescents, and their
presentation may pose a medical emergency (11). Patients with large anterior mediastinal
masses are at risk of cardiac or respiratory arrest during general anesthesia or deep sedation.
A careful workup including a chest computed tomography (CT) scan with airway
measurements is essential (12) before attempting any procedures. The least invasive
procedure (e.g., biopsy of a peripheral ly mph node) should be carried out. If these
procedures are not successful in providing a diagnosis, then a CT-guided needle biopsy of the
mediastinal mass should be considered (13). In some clinical situations (e.g., orthopnea or
significant airway narrowing), preoperative or preprocedure steroids should be considered
for up to 48 hours. The use of steroids has largely replaced localized irradiation in this setting.
Primary gastrointestinal involvement occurs in about 30% (usually Burkitt histology ),
commonly presenting as an abdominal mass with ascites, an “acute abdomen” from an
intussusception, or rarely a malnutrition sy ndrome with colitis sy mptoms (14). The majority
of children with Burkitt ly mphoma presenting with an ileal–cecal intussusception have limited
gastrointestinal involvement that is amenable to complete surgical resection (Murphy stage 2
or group A). In 20–30% of children, the head and neck region, including the Waldey er ring or
cervical ly mph nodes, is the site of origin. The remainder of patients have miscellaneous
primary sites, including bone, breast, skin, epidural space, or noncervical ly mph nodes.
Involvement of the bone marrow at diagnosis occurs in 10–30% of patients with Burkitt and
ly mphoblastic ly mphomas. Overt CNS involvement at diagnosis is not common but is mostly
seen in children with advanced-stage Burkitt and ly mphoblastic ly mphomas. Children who
develop Burkitt ly mphoma in endemic areas of the world often have a mass in the head or
neck region (especially jaw) in contrast to the abdominal presentation ty pical of nonendemic
Burkitt ly mphoma.
Page 177Originally, the Ann Arbor staging sy stem for the Hodgkin disease was used for NHL
(see Table 7.1 ) (15). The usefulness of this sy stem in pediatric NHL is limited, and an
alternative staging sy stem proposed by Murphy et al. has been widely accepted (Table
8.2 ). This sy stem recognizes ty pical patterns of disease presentation and has greater
prognostic utility than the Ann Arbor sy stem. In Burkitt ly mphoma and large B-cell
ly mphomas, another staging sy stem developed by Patte et al. (17) is also used (Table
8.3 ). It classifies patients according to tumor burden and surgical resection.
Table 8.2 Murphy and St. Jude Children’s Research Hospital Staging System for
Childhood NHL
Table 8.3 Clinical Staging of B-Cell Lymphomas
The current most widely accepted histologic classification sy stem is the World Health
Organization (WHO) classification that was updated most recently in 2008 (18,19). This
sy stem has been validated as highly reproducible in international studies and has evolved to
incorporate histology as well as immunohistochemistry, gene expression profiling, and
cy togenetic, molecular, and clinical features.
As previously discussed, over 95% of the pediatric NHLs are high grade and fall into
four major histologic subty pes (ly mphoblastic ly mphoma, Burkitt ly mphoma, diffuse large
B-cell ly mphoma, and ALCL). T- and B-cell ly mphoblastic ly mphomas comprise about 30%
of NHL in childhood; T cell is the more common ty pe. Mature B-cell ly mphoma includes
Burkitt ly mphoma (35–40% of cases) as well as diffuse large B-cell ly mphoma (DLBCL)
and primary mediastinal large B-cell ly mphoma (PMBL). Together, the latter two comprise
approximately 20% of NHL in childhood. In the current WHO classification, PMBL is
considered distinct from other DLBCLs based upon its unique clinical, histologic, and
molecular features. Other mature B-cell ly mphomas, including pediatric marginal zone
ly mphoma, pediatric follicular ly mphoma, and MALT ly mphoma, are also recognized as
distinct entities that rarely occur in childhood. Within the category of mature T-cell
ly mphoma, ALCL accounts for approximately 10% of NHL in childhood.
Page 178B-cell ly mphoblastic ly mphoma consists of cells with round or convoluted
nuclei, fine chromatin, inconspicuous nuclei, and scant, faintly basophilic cy toplasm. In B-
cell ly mphoblastic ly mphoma, the tumor cells characteristically express TdT, CD10, CD19,
and CD79a, which is identical to the most common immunophenoty pe of B-acute
ly mphoblastic leukemia (ALL) in childhood (20). The T-cell ly mphoblastic ly mphomas are
also TdT positive, but express a combination of T-cell antigens (CD2, CD3, CD4, CD5, and
CD8) similar to that of T-cell ALL. T-cell ly mphoblastic ly mphomas share many clinical and
biologic features with T-cell ALL (21). When the bone marrow is involved with ly mphoblasts
(>25%), the distinction between ly mphoma and leukemia becomes difficult. Subtle distinct
biologic differences between the blasts in T-ly mphoblastic leukemia and ly mphoma are being
recognized with newer molecular assay s (22).
Burkitt ly mphoma tumor cells are monomorphic, medium-sized cells with round nuclei,
multiple nucleoli, and basophilic cy toplasm. A “starry -sky ” pattern is the result of benign
macrophages that have ingested apoptotic tumor cells. Cells ty pically express sIgM, CD19,
CD20, CD22, CD79a, and CD10 (18). Most, but not all cases, have a cy togenetic abnormality
involving the MYC gene at band 8q24.
Diffuse large B-cell ly mphoma consists of tumor cells that are larger than ly mphocy tes
with vesicular nuclei, basophilic cy toplasm, and a moderate-to-high proliferation fraction
(19). The nuclear size is equal to or greater than that of a normal macrophage. DLBCL can
be subdivided into several subclasses based on either immunophenoty ping or DNA
microarray s (18). These large B-cell ly mphomas ty pically express CD19, CD20, and CD22,
and 50–75% express cy toplasmic or surface immunoglobulin. PMBLs in addition to
presenting in the mediastinum are ty pically associated with compartmentalizing alveolar
fibrosis and, in contrast to other DLBCLs, ty pically do not express immunoglobulin.
Alterations of oncogenes involved in adult DLBCL such as BCL6 and BCL2 are very rare in
children with DLBCL, whereas rearrangement of the MYC oncogene is more common in
pediatric compared to adult DLBCL (23,24).
Pediatric follicular ly mphoma is an interesting entity that was initially noted for
clinically indolent behavior, and limited disease at diagnosis, ty pically stage I. It occurs, as
well, in y oung adults and, in contrast to conventional adult follicular ly mphoma, is
characterized by a high proliferation index (>30% Ki67 fraction) and absence of BCL-2 gene
abnormalities (25).
ALCL consists of ly mphoid cells that are usually large with abundant cy toplasm and
pleomorphic, often horseshoe-shaped nuclei. The cells are CD30 positive, and the majority of
pediatric cases are also positive for the anaplastic ly mphoma kinase (ALK) protein and have
the chromosomal translocation t(2;5)(p23;q35) involving the nucleophosmin (NPM) and ALK
genes (18).
Figure: Murphy and St. Jude Children’s
Research Hospital Staging System for
Childhood NHL
Figure: Clinical Staging of B-Cell
Lymphomas
PROGNOSTIC FACTORS
The most prominent prognostic determinant in childhood NHL is the clinical stage. Tumor
burden, as measured in part by serum LDH, has been predictive of outcome in some series,
especially for Burkitt ly mphoma (17,26,27). In general, patients with localized Murphy stage
I and II ly mphomas have a better prognosis than those with more extensive stage III and IV
ly mphomas. However, stratified therapy has resulted in excellent outcomes for both low- and
high-stage disease. Site of involvement has also been prognostic. For example, presentation of
PMBLs has been recognized as having significantly higher risk for relapse than other DLBCLs
(17,28). In the past, bone marrow involvement was associated with a poor prognosis, but with
intensive chemotherapy it is no longer an adverse prognostic factor (17,26,27). Before the use
of preventive CNS therapy, CNS relapse developed in 30–40% of children with stage III and
IV Burkitt and ly mphoblastic ly mphomas. CNS relapses were also noted, albeit in a much
lower percentage, in children who had head and neck primary sites of other NHLs (29,30).
Overt CNS involvement at diagnosis is rare and is associated with a poorer prognosis. In this
situation, intrathecal (IT) chemotherapy and cranial irradiation may be indicated (27,31).
SELECTION OF THERAPY
Chemotherapy
Because of the high likelihood of disseminated
disease at presentation, all children with the high-
grade subty pes of NHL, regardless of stage,
receive sy stemic, combination chemotherapy.
The four major histologic subty pes of childhood
NHL respond to a wide range of drugs including
steroids, anthracy clines, vinca alkaloids,
topoisomerase 2 inhibitors, and alky lating agents,
but different combinations and schedules are
optimal for particular histologies. Tables 8.4 Table 8.4 Low-Stage/Low-Risk
and 8.5 list some of the commonly used Patients
regimens and treatment outcomes.
For limited-stage ly mphoblastic ly mphoma, treatment with the use of ALL therapy is
effective, with approximately 85–90% disease-free survival (20,31). The use of more
intensive ALL chemotherapy regimens has also resulted in excellent outcomes for most
children with advanced-stage disease (disease-free survival of 80–85%) (30,31). Similar to
the case with ALL patients, there is evidence that poor initial response to treatment, most
notably steroids, appears to confer a worse prognosis with event-free survival (EFS) only in
the 50% range (31). The least toxic and most effective method of CNS prophy laxis for these
patients remains unclear. Both cranial irradiation and IT methotrexate have been very
effective but are associated with neurocognitive late effects. Data from recent studies
indicate that intensive IT methotrexate with or without sy stemic high-dose methotrexate is
adequate therapy to prevent CNS relapse (30,38). In many settings, patients with B- or T-
ly mphoblastic ly mphoma are eligible to participate in trials for B- or T-ALL, respectively,
thereby allowing for new agents or treatment strategies to be tested in this group of patients.
Page 179For the purposes of treatment,
high-grade mature B-cell ly mphomas have been
treated similarly. Burkitt ly mphoma, in contrast
to DLBCL, is much more likely to involve the
bone marrow and CNS and much more likely to
be complicated with a tumor ly sis sy ndrome.
Although histologically and clinically
distinct, both Burkitt ly mphoma and DLBCL
respond well to treatments as outlined below. For
low-stage Burkitt ly mphoma as well as DLBCL,
short-duration therapy with cy clophosphamide,
doxorubicin, vincristine (Oncovin), and
prednisone (CHOP) or cy clophosphamide,
vincristine (Oncovin), prednisolone, and Table 8.5 Advanced-Stage/High-Risk
doxorubicin (Adriamy cin) (COPAD) results in Patients
excellent relapse-free survivals of 90–98% and
85–90% (26,31,32), respectively. For higher-stage and higher-risk groups, the ly mphoma
malignant B ty pe (LMB)-96 protocol, a multiagent intensive chemotherapy regimen for B-
cell ly mphoma, has resulted in greater than 90% 4-y ear EFS. LMB-96 includes 3–5 months
of intensive cy cles of cy clophosphamide, vincristine, prednisone, high-dose methotrexate,
doxorubicin, cy tosine arabinoside (AraC), and etoposide (17,27). Promising results from pilot
trials show safety and efficacy of rituximab, CD20 targeted therapy, on an LMB therapy
backbone (39,40). A randomized trial with the addition of rituximab on standard therapy is
currently in progress.
As noted previously, within the high-grade mature B-cell ly mphoma group, PMBL
stands out clinically, with significantly inferior EFS, in the less than 70% range, using LMB
therapy (28). With the adriamy cin, prednisone, vincristine (oncovin), 6-mercaptopurine, and
methotrexate (APO) protocol, which does not include an alky lating agent but features
intensive doxorubicin, durable EFS of approximately 70% has also been seen (33). This
regimen has never been directly compared to an LMB approach. As a clinical entity, PMBL
ty pically affects adolescents and y oung adults with peak incidence in the third and fourth
decades. As such, the majority of patients and clinical trials have been pursued in patients
greater than 18 y ears of age. In contrast to pediatric follicular ly mphoma, we do not know
that PMBL in y ounger patients behaves in a distinct way. It may be reasonable to extrapolate
from adult experience with this tumor in planning treatment for adolescent patients. Good
results have been reported with rituximab containing regimens, including Rituximab+CHOP
(34,41) and DA-Epoch-R (dose-adjusted etoposide, doxorubicin, cy clophosphamide,
vincristine, prednisone, and rituximab) (35). The latter regimen is notable for substantial
potential cumulative exposure to anthracy cline. A current randomized trial in adults is
comparing these two regimens. In future, it may be beneficial to include adolescents with this
disease in collaborative trials with y oung adult patients to optimize therapy and characterize
the disease more fully.
Rare low-grade mature B-cell ly mphomas, pediatric follicular ly mphoma, pediatric
marginal zone ly mphoma, and MALT ly mphoma occur in childhood. For the former two
presenting with low-stage disease, many patients have done well with resection and
observation only (25,42). For ocular MALT ly mphoma, treatment has consisted of resection
followed by radiation therapy without adjuvant chemotherapy (43). Efforts to collect clinical
information and pathologic specimens to further characterize these rare pediatric ly mphomas
and determine best approaches are in progress.
For early -stage ALCL, CHOP is effective therapy (32). The APO regimen has also
been effective for higher-stage ALCL in children (disease-free survival 70–75%) (33). Other
regimens for ALCL have been modeled after B-cell protocols and report similar results (36).
Although vinblastine has been shown to be particularly effective as a single agent in ALCL
(44,45), recent efforts to bring this agent forward into frontline therapy did not show
significant benefit (37). Current trials attempt to incorporate therapies that target CD30 or ALK
mutations in this disease. The optimal strategy to incorporate new agents into existing
regimens remains unclear.
Page 180In recent y ears, outcomes for pediatric patients with NHL have improved
dramatically. Optimal combinations of agents, intensity, and duration of therapy have evolved
for disease groups. In the future, we anticipate further stratification of treatment regimens
and, as noted above, the addition of disease-specific agents, such as rituximab, in mature B-
cell ly mphomas or agents targeting ALK and CD30 in ALCL.
Figure: Low-Stage/Low-Risk Patients
Figure: Advanced-Stage/High-Risk Patients
RADIOTHERAPEUTIC MANAGEMENT
The role of radiotherapy in the management of all childhood NHL has decreased as sy stemic
chemotherapeutic regimens have become more effective (5). As the overall survival
improved for children with all stages and subty pes of NHL, studies designed to assess the
need for regional radiation therapy followed. This has evolved on a background of significant
concerns for late effects of treatment, including neurocognitive effects of low-dose CNS
radiation as well as the risk for second malignancy, and cardiac and pulmonary toxicity in
patients receiving radiation therapy to the mediastinum and neck combined with
chemotherapy (46). Increasing reports demonstrate successful local and sy stemic control
with chemotherapy alone for children with NHL regardless of histology and stage (5).
As previously discussed, prophy lactic CNS treatment is needed in the majority of
children with NHL, thereby reducing the otherwise high risk of CNS relapse. The approach
for all ly mphoblastic histologies includes sy stemic and IT chemotherapy. It has become
evident that there is no benefit to adding radiation therapy for CNS prophy laxis in Burkitt
ly mphoma (29), (38). The current CNS preventive regimens for advanced-stage
ly mphoblastic ly mphoma include either cranial irradiation and IT chemotherapy or IT
chemotherapy and sy stemic chemotherapy only. The Berlin–Frankfurt–Munster (BFM)
group safely reduced the dosage of cranial radiation therapy to 12 Gy for ly mphoblastic
ly mphoma and eliminated it entirely from BFM-95 without increasing the CNS relapse rate
(30). Cranial irradiation (12–18 Gy ) is still warranted for the rare patient with ly mphoblastic
ly mphoma with initial CNS disease or a CNS relapse. Patients with cranial nerve palsies at
diagnosis, independent of cerebrospinal fluid findings, are treated in a similar fashion as
children with initial CNS ly mphoma.
The current indications for radiation therapy to involved sites of disease outside the CNS
in pediatric NHL have become somewhat limited. Involved-field radiation is considered for
patients who do not attain a complete remission after induction chemotherapy. This situation is
relatively rare, but more common in PMBL. Given the increased rate of local failure
compared to other pediatric NHLs, the role of involved-field radiation remains a topic of
some debate. Adult data suggest that with the addition of rituximab to prior regimens, the
number of patients who require involved-field radiation in PMBL patients may decrease
(34,35,47).
As noted previously, rarely, low-grade mature B-cell ly mphoma, such as pediatric
follicular ly mphoma, pediatric marginal zone ly mphoma, and ocular MALT ly mphoma,
occur. Limited data are available as to the best therapy for these patients. Historically, ocular
MALT in pediatrics has been approached as adult cases, with low-dose superficial radiation
therapy (43). No role for radiation therapy in low-stage pediatric follicular ly mphoma or
pediatric marginal zone ly mphoma has been established.
Involved-field radiation may also be considered for palliation of pain or mass effect, and
consolidation to regions of local disease before or after bone marrow transplantation in
patients with recurrent disease. Care should be taken to use modest fractionation schedules
and to avoid exceeding normal tissue tolerance dosages because patients may be eligible for
subsequent bone marrow transplantation necessitating total body irradiation (TBI) as a
component of the preparative regimen.
Children with refractory or relapsed NHL can experience prolonged disease-free
survival after treatment with high-dose chemotherapy or high-dose chemoradiotherapy
followed by autologous or allogeneic bone marrow transplant (48,49,50). When TBI is a
component of the preparatory regimen, fractionated courses to total dosages of 12–14 Gy are
common (see Chapter 2 ). Disease recurrence rather than the morbidity of transplant is
the predominant cause of failure in this setting. The strategy of irradiating the local sites of
initial disease recurrence before or after transplant, whether or not TBI is used, can be
considered (48). Dosages to these sites (usually at least 20 Gy ) are constrained by normal
tissue tolerances.
Historically, emergency radiation therapy for superior vena cava sy ndrome, acute
airway compromise, or spinal cord compression has been used to provide rapid sy mptom
relief. The response is particularly dramatic with ly mphoblastic ly mphoma and sy mptoms
are usually improved within 48 hours of treatment. Usually 1.5–2 Gy per fraction for a total
dosage of 6–7.5 Gy is adequate to relieve sy mptoms. Hy perfractionated regimens (1.2–1.5
Gy per fraction twice a day for a total dosage of 6–10 Gy ) can also be used. Sy stemic
steroids, particularly in the case of mediastinal mass, are more commonly used and
generally are equally effective. On rare occasions, emergency radiation therapy or
treatment with steroids is appropriate in the absence of a histologic diagnosis. Despite the
rapid response with either, this can be done without significantly compromising tissue
diagnosis if sampling can occur within 48 hours of treatment (13).
SURGICAL MANAGEMENT
Although surgical biopsy may be critical in the diagnosis of NHL, the role of surgery is
otherwise limited. It should be performed on patients in whom there is good reason to believe
that total resection can be achieved, such as in limited abdominal disease. As well, in patients
with rare low-grade ly mphoma, such as pediatric follicular ly mphoma or marginal zone
ly mphoma, complete surgical resection of stage I disease may be curative and eliminate the
need for any adjuvant therapy (42).
RESULTS OF THERAPY
Before 1975, when therapy was directed to the identifiable gross tumor, few children
survived. The small number of patients who did survive had favorable presentations, including
limited resectable abdominal disease or involvement of a single nodal region or extranodal
site. With current intensive multiagent regimens, survival is generally excellent for all
patients, including those with disseminated disease and adverse prognostic factors such as
bone marrow involvement, CNS involvement, and high-serum LDH. Most relapses occur
within 12 months of diagnosis for Burkitt ly mphomas and within the first 2–4 y ears for the
other histologic subty pes. Late relapse has been reported with ALCL and B-ly mphoblastic
ly mphoma.
Page 181Children with stage I to II disease have 2-y ear disease-free survival rates of
85–98% (5,31,32). Children with stage III disease have an 85–90% 2-y ear disease-free
survival. Those with stage IV disease and marrow involvement have an 85–90% disease-free
survival, and those with CNS disease (Burkitt ly mphoma) have an 80% EFS. Patients with
PMBL have had significantly worse EFS at 60–70% (27,28).
Patients undergoing transplantation early in their disease course (i.e., after first relapse
or second complete remission) have 2-y ear disease-free survival approaching 50%, whereas
those with refractory disease or early relapse fare less well (48,49,50).
With improvements in survival in many groups of patients, recent efforts have focused
on maintaining excellent EFS with reduced late toxicity. Incorporating more specific targeted
therapies for patients with less favorable subgroups, notably PMBL, may be helpful as a
focus of future development.
REFERENCES
1. Hodgkin T. On some morbid appearances of the absorbent gland and spleen. Med Chir
Trans. 1832;17:68–114.
2. Virchow R. Weisses Blut. In: Froriep’s neue Notizen, ed. Neue Notizen aus dem Gebete
der Natur und Heilkunde. Vol. 36. Berlin; 1845:151–156.
3. Sandlund JT, Downing JR, Crist WM. Non-Hodgkin’s ly mphoma in childhood. N Engl J
Med. 1996;334:1238–1248.
4. Lemerle M, Gerard-Marchant R, Sancho H, et al. Natural history of non-Hodgkin’s
malignant ly mphomata in children: a retrospective study of 190 cases. Br J Cancer.
1975;31:324–331.
5. Minard-Colin, V, Grugieres, L, Reiter A, et al. Non-Hodgkin ly mphoma in children and
adolescents: progress through effective collaboration, current knowledge, and challenges
ahead. J Clin Oncol. 2015;33(27):2963–2974.
6. Frizzera G, Murphy SB. Follicular (nodular) ly mphoma in childhood: a rare clinical-
pathological entity. Report of eight cases from four cancer centers. Cancer.
1979;44:2218–2235.
7. Murphy SB. Classification, staging and end results of treatment of childhood non-
Hodgkin’s ly mphomas: dissimilarities from ly mphomas in adults. Semin Oncol.
1980;7:332–339.
8. Young JL Jr, Ries LG, Silverberg E, et al. Cancer incidence, survival, and mortality for
children y ounger than age 15 y ears. Cancer. 1986;58:598–602.
9. Tay lor AM, Metcalfe JA, Thick J, et al. Leukemia and ly mphoma in ataxia
telangiectasia. Blood. 1996;87:423–438.
10. Rey nolds P, Saunders L, Lavefsky M, et al. The spectrum of acquired
immunodeficiency sy ndrome (AIDS) associated malignancies in San Francisco, 1980–
1987. Am J Epidemiol. 1993;137:19–30.
11. Weinstein H, Vance Z, Jaffe N, et al. Improved prognosis for patients with mediastinal
ly mphoblastic ly mphoma. Blood. 1979;53:687–694.
12. Shamberger RC, Holzman RS, Griscom NT, et al. Prospective evaluation by computed
tomography and pulmonary function tests of children with mediastinal masses. Surgery.
1995;118:468–471.
13. Loeffler JS, Leopold KA, Recht A, et al. Emergency prebiopsy radiation for mediastinal
masses: impact on subsequent pathologic diagnosis and outcome. J Clin Oncol.
1986;4:716–721.
14. Magrath IT, Shiramizu B. Biology and treatment of small non-cleaved cell ly mphoma.
Oncology (Wiliston Park). 1989;3:41–53.
15. Cheson, BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation,
staging and response assessment of Hodgkins and non-Hodgkin Ly mphoma: the Lugano
classification. J Clin Oncol. 2014;32(27):3059–3068
16. Bhojwani D, McCarville MB, Choi JK, et al. The role of FDG-PET/ CT in the evaluation
of residual disease in paediatric non-Hodgkin ly mphoma. Br J Haematol.
2015;168(6):845–853
17. Patte P, Auperin A, Gerrard M, et al. Results of the randomized international
FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin ly mphoma in children and
adolescents: it is possible to reduce treatment for the early responding patients. Blood.
2007;109:2773–2780.
18. Jaffe ES, Harris NL, Stein H, et al. Classification of ly mphoid neoplasms: the
microscope as a tool for disease discovery. Blood. 2008;112:4384–4399.
19. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues. 4th ed. Geneva, Switzerland: WHO Press; 2008.
20. Neth O, Seidemann K, Jansen P, et al. Precursor B-cell ly mphoblastic ly mphoma in
childhood and adolescence: clinical features, treatment and results in trials NHL-BFM 86
and 90. Med Pediatr Oncol. 2000;35(1):20–27.
21. Head DR, Behm FG. Acute ly mphoblastic leukemia and the ly mphoblastic ly mphomas
of childhood. Semin Diagn Pathol. 1995;12(4):325–334.
22. Raetz EA, Perkins SL, Bhojwani D, et al. Gene expression profiling reveals intrinsic
differences between T-cell acute ly mphoblastic leukemia and T-cell ly mphoblastic
ly mphoma. Pediatr Blood Cancer. 2006;47:130–140.
23. Heerema NA, Bernheim A, Lim MS, et al. State of the art and future needs in
cy togenetic/molecular genetics/array s in childhood ly mphoma: summary report of
workshop at the First International Sy mposium on Childhood and Adolescent Non-
Hodgkin ly mphoma, April 9, 2003, NYC, NY. Pediatr Blood Cancer. 2005;45:616–622.
24. Dave BJ, Weisenburger DD, Higgins CM, et al. Cy togenetics and fluorescence in situ
hy bridization studies of diffuse large B-cell ly mphoma in children and y oung adults.
Cancer Genet Cytogenet. 2004;153:115–121.
25. Louissaint A Jr, Ackerman AM, Dias-Santagata D, et al. Pediatric-ty pe nodal follicular
ly mphoma: an indolent clonal proliferation in children adn adults with high proliferation
index and no BCL2 rearrangement. Blood. 2012;120(12):2395–2404.
26. Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of
COPAD chemotherapy in children and adolescents with resected localized B-cell non-
Hodgkin’s ly mphoma: results of the FAB/LMB 96 international study. Br J Haematol.
2008;141:840–847.
27. Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of
high-risk central nervous sy stem B non-Hodgkin ly mphoma and B acute ly mphoblastic
leukemia in children and adolescents. Blood. 2007;109:2736–2743.
28. Gerrard M, Waxman IM, Sposto R, et al. Outcome and pathologic classification of
children and adolescents with mediastinal large B-cell ly mphoma treated with
FAB/LMB96 mature B-NHL therapy. Blood. 2013;121(2):278–285.
29. Murphy SB, Bley er WA. Cranial irradiation is not necessary for central-nervous-sy stem
prophy laxis in pediatric non Hodgkin’s ly mphoma. Int J Radiat Oncol Biol Phys.
1987;13:467–468.
30. Burkhardt B, Woessmann W, Zimmermann M, et al. Impact of cranial radiotherapy on
central nervous sy stem prophy laxis in children and adolescents with central nervous
sy stem—negative stage III or IV ly mphoblastic ly mphoma. J Clin Oncol.
2006;24(3):491–499.
31. Moricke A, Reiter A, Zimmerman M, et al. Risk-adjusted therapy of acute
ly mphoblastic leukemia can decrease treatment burden and improve survival: treatment
results of 2160 unselected pediatric and adolescent patients enrolled in the trial ALL-
BFM 95. Blood. 2008;111:4477–4489.
32. Page 182 Link MP, Devidas M, Murphy SB, et al. Favorable treatment outcome of
children with early stage large B-cell and anaplastic large cell ly mphomas. J Clin Oncol.
2004; ASCO Annu Meeting Proc. 2004;22(14S):8500.
33. Laver JH, Mahmoud H, Pick TE, et al. Results of a randomized phase III trial in children
and adolescents with advanced stage diffuse large cell non-Hodgkin’s ly mphoma: a
Pediatric Oncology Group study. Leuk Lymphoma. 2001;42:399–405.
34. Vassilakopoulos TP, Gerassimos AP, Katsigiannis A, et al. Rituximab, cy clophosphamide,
doxorubicin, vincristine and prenisone with or without radiotherapy in primary
mediastinal large b-cell ly mphoma: the emerging standard of care. Oncologist.
2012;17:239–249.
35. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH- rituximab therapy in
primary mediastinal B-cell ly phoma. N Engl J Med. 2013;368(15):1408–1416.
36. Brugières L, Le Deley M-C, Rosolen A, et al. The impact of the methotrexate
administration schedule and dose on the treatment of children and adolescents with
anaplastic large cell ly mphoma: results of a randomized trial of the EICNHL group. J
Clin Oncol. 2009;27(6):897–903.
37. Pfrendschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus
rituximab versus CHOP-like chemotherapy alone in y oung patients with good-prognosis
diffuse large-B-cell ly mphoma: a randomized controlled trial by the MabThera
International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379–391.
38. Mandell LR, Wollner N, Fuks Z. Is cranial radiation necessary for CNS prophy laxis in
pediatric NHL? Int J Radiat Oncol Biol Phys. 1987;13:359–363.
39. Goldman S, Smith L, Anderson JR, et al. Rituximab and FAB/LMB96 chemotherapy in
children with Stage III/IV B-cell non-Hodgkin ly mphoma: a Children’s Oncology Group
report. Leukemia. 2013;27(5):1174–1177.
40. Goldman S, Smith L, Galardy P, et al. Rituximab with chemotherapy in children and
adolescents with central nervous sy stem and/or bone marrow-positive Burkitt
ly mphoma/Leukaemia: a Children’s Oncology Group Report. Br J Haematol.
2014;167:394–401.
41. Stefanovic A, Lossos IS. Extranodal marginal zone ly mphoma of the ocular adnexa.
Blood. 2009;114(3):501–510.
42. Attarbaschi A, Beishuizen A, Mann G, et al. Children and adolescents with follicular
ly mphoma have an excellent prognosis with either limited chemotherapy or with a
“Watch and wait” strategy after complete resection. Ann Hematol. 2013;92(11):1537–
1541.
43. Brugieres L, Quartier P, Le Deley MC, et al. Relapses of childhood anaplastic large-cell
ly mphoma: treatment results in a series of 41 children—a report from the French
Society of Pediatric Oncology. Ann Oncol. 2000;11:53–58.
44. Garner R, Li Y, Gray B, et al. Long-term disease control of refractory anaplastic large
cell ly mphoma with vinblastine. J Pediatr Hematol Oncol. 2009;31(2):145–147.
45. Alexander S, Kdraveka JM, Weitzman S, et al. Advanced stage anaplastic large cell
ly mphoma in children and adolescents: results of ANHL0131, a randomized phase III
trial of APO versus a modified regimen with vinblastine: a report from the chidlren’s
oncology group. Pediatr Blood Cancer. 2014;61(12):2236–2242.
46. Bluhm E, Ronckers C, Hay ashi RJ, et al. Cause-specific mortality and second cancer
incidence after non-Hodgkin ly mphoma: a report from the Childhood Cancer Survivor
Study. Blood. 2008;111(81):4014–4021.
47. Giri S, Bhatt VR, Pathak R, et al. Role of radiation therpay in primary mediastinal large
B-cell ly mphoma in rituximab era: a US population-based analy sis. Am J. Hematol.
2015;90(11):1052–1054.
48. Armitage JO. Bone marrow transplantation in the treatment of patients with ly mphoma.
Blood. 1989;73:1749–1758.
49. Kobrinsky NL, Sposto R, Shah NR, et al. Outcomes of treatment of children and
adolescents with recurrent non-Hodgkin’s ly mphoma and Hodgkin’s disease with
dexamethasone, etoposide, cisplatin, cy tarabine, and L-asparaginase, maintenance
chemotherapy, and transplantation: Children’s Cancer Group Study CCG-5912. J Clin
Oncol. 2001;19:2390–2396.
50. Harris RE, Termuhlen AM, Smith LM, et al. Autologous peripheral blood stem cell
transplantation in children with refractory or relapsed ly mphoma: results of Children’s
Oncology Group study A5962. Biol Blood Marrow Transplant. 2011;17(2):249–258.
CH A P TER 9
Ewing Sarcoma
Karen J. Marcus, Torunn I. Yock, and Nancy J. Tarbell
Page 183James Ewing (1866–1943) first described the bone tumor that bears his name in
1921 (1). He observed that the malignancy was most common in teenagers, occurred in the
metaphy seal and diaphy seal region of long bones or in the flat bones, was associated with
pain and often fever, had a histologic appearance of highly vascular sheets of small round
cells, and was quite sensitive to radiation (Fig. 9.1 ) (2).
Figure 9.1 A: In the fourth edition of his textbook Neoplastic Diseases: A Textbook on
Tumors (1940), James Ewing of the Memorial Hospital, New York, described a “diffuse
endothelioma of radius, diffuse absorption without destruction of shaft, spontaneous fracture,
wide invasion of muscle, duration 1 year.” Ewing wrote that “the first indication is for
treatment by radiation in full doses, and over considerable periods. This recommendation is
based on the reported cure of certain cases … by radiation alone, and on the clinical
disappearance of the disease by variable periods in many more cases. The response to
radiation also confirms the diagnosis. The danger of metastases occurring while this
treatment is in progress is probably negligible, since the tumor tissue generally undergoes
rapid liquefaction and necrosis.” B: Ewing illustrated the excellent response of the tumor to
radiotherapy.
Ewing sarcoma consists of monomorphic sheets of small, round malignant cells with
hy perchromatic nuclei and little cy toplasm. There is a dearth of associated stroma. Cells
usually are periodic acid–Schiff (PAS) positive, indicating the presence of gly cogen granules.
Gly cogen in the tumor cells and the demonstration of the MIC2 gene product on the tumor
cell membrane help identify Ewing sarcoma (4,5). The tumor cells are also uniformly
vimentin positive and often cy tokeratin positive, indicating origin from epithelial and neuronal
elements (6).
Sarcomas are subdivided into two classes; the first class is composed of tumors
display ing complex kary oty pic abnormalities with no distinct pattern, and the second class
includes tumors associated with particular chromosomal translocations that result in specific
fusion genes. The Ewing sarcoma family is in the second class of sarcomas. Ewing sarcoma
and primitive neuroectodermal tumor (PNET) have been linked to the specific chromosomal
abnormalities involving a reciprocal translocation between chromosomes 11 and 22: t(11;22)
(q24;q12).
Advances in cy togenetic and molecular science provide insights into these abnormalities.
The key diagnostic feature in the Ewing sarcoma family is the detection of the translocation
involving the EWSR1 gene located on chromosome 22 band q12 and one of several partner
chromosomes (5). The EWSR1 gene is a member of the TET family of RNA-binding
proteins. Ty pically in Ewing sarcoma, the amino terminus of the EWSR1 gene is juxtaposed
with the carboxy -terminus of another gene. This genetic rearrangement is detectable in 86–
90% of tumors. Approximately 5–10% of Ewing sarcomas do not contain t(11;22) but instead
have a translocation between chromosomes 21 and 22: t(21;22) (q21;q12). However, this
alternate rearrangement has molecular consequences similar to those of t(11;22) (7).
The 11;22 translocation juxtaposes the EWS gene with the FLI gene, a member of the
ETS transcription factor family. The 21;22 translocation juxtaposes the EWS gene to another
ETS family member, ERG. There are structural similarities between these two translocations,
suggesting that they bind to similar DNA target sites. The EWS–FLI1 fusion was the first
sarcoma gene to be cloned (8). EWS–FLI can produce malignant transformation of some, but
not all, cell lines. The EWS/FLI gene appears to act as a transcription factor. Its mechanism of
action appears to be a modulation of transcription of target genes. Ewing sarcoma and PNET
translocation seem to fall in a developing class of tumor-associated chromosomal
translocations that form chimeric transcription factors (7). The formation of aberrant
transcription factors is associated with many human malignancies. We may conclude that the
probable mechanism of carcinogenesis in Ewing sarcoma is a translocation that produces an
aberrant transcription factor. These factors can cause deregulation of pathway s, resulting in
tumorigenesis. Using retroviral sy stems to biologically screen cDNA from cells transformed
by EWS/FLI1, platelet-derived growth factor-C (PDGF-C) has been identified as the target of
EWS/ETS transcriptional deregulation (9). Therefore, Ewing sarcoma cy togenetics may help
us to understand oncogenic mechanisms.
The EWS gene is a member of the ETS family of transcription factors defined by the
ETS domain. The FLI1 gene appears to be involved in early hematopoietic, vascular, and
perhaps neuroectodermal development (10). Evidence suggests that EWS–FLI1 fusion protein
is the key oncogenic lesion in Ewing sarcoma. EWS–FLI1 acts as the dominant oncogene
(11). The transcription factor resulting from the translocation replaces the EWS RNA-binding
domain by the FLI1–ETS domain with the resulting aberrant transcriptional effects. A number
of genes have been identified as direct or indirect regulatory targets of the aberrant protein
produced by the EWS–FLI1 translocation (9,12). A major hurdle in the attempts to generate
model sy stems of the Ewing family of tumors is the toxicity of the fusion gene. The identity
of the cells from which Ewing tumors originate has remained elusive. The observation of the
t(11;22) translocation leading to the EWS–FLI1 expression suggests the existence of a primary
cell transformed by EWS–FLI1. Evidence from a genetically defined EWS–FLI1 model
sy stem suggests a mesenchy mal origin of these tumors (13). Recent publications have shown
that the t(11;22) breakpoint location and therefore the exact amino acid composition of the
resultant EWS–FLI fusion oncoproteins might have prognostic relevance (13,14,15,16).
Despite some suggestion that the breakpoint location is prognostic, two recent large series
have shown that the EWSR1-ETS translocation breakpoint site is not an adverse prognostic
factor (14,15).
CLINICAL PRESENTATION
Pain is the most common presenting sy mptom, noted in approximately 90% of cases. Local
swelling or mass effect related to the bone tumor is apparent in a majority of children. A
distinct soft tissue mass can be appreciated clinically in one-third of cases. Significant
limitation of movement has been described in 25% of presentations. Neurologic sy mptoms or
signs occur in 15% of children, either as spinal cord compression or as peripheral nerve
compression. The latter is most often apparent with lesions of the pelvis or about the knee.
Fever is present in 10% of cases and has been related to tumor size and metastatic disease at
diagnosis.
The diagnostic evaluation of the patient with
Ewing sarcoma is shown in Table 9.1 .
Laboratory findings may include high leukocy te
count, a nonspecific finding indicative of tumor
bulk or extensive disease. A high leukocy te count
has been related to increased risk of tumor
recurrence (16,17). Pretreatment serum lactate
dehy drogenase (LDH) is of prognostic
significance, and the degree of LDH elevation
has been related to tumor volume (17).
Currently, FDG-PET and FDG-PET/CT are
optional staging modalities. However, they have
demonstrated high sensitivity and specificity in
Ewing sarcoma and may provide additional Table 9.1 Clinical Evaluation of the
information that alters therapy planning. Positron Patient with Ewing Sarcoma
emission tomography (PET) using fluorine-18
fluoro-deoxy glucose is being studied for detection of osseous metastases in bone tumors and
appears to be a sensitive and specific modality in Ewing sarcoma and PNET.
Page 185The diagnostic features of Ewing sarcoma are radiographically defined as a
permeative, destructive lesion of bone. In long bones, the tumor most often presents along the
metaphy seal region or within the diaphy sis (i.e., at the midshaft level). The periosteum often
is displaced by the underly ing tumor, resulting in the clinical sign of Codman triangle,
representing a bone expansile lesion. Although bone expansion is common, new bone
formation bey ond the periosteal margin is rare. An associated soft tissue mass is ty pical,
occurring in more than 50% of long bone neoplasms (18,19). Both computed tomography
(CT) and magnetic resonance imaging (MRI) appear necessary for most sites and are
complementary. Using both studies has added substantially to the determination of disease
extent, identify ing extraosseous involvement, and the degree of marrow infiltration linearly
(Fig. 9.2 ). CT has been valuable in outlining the bone and soft tissue extent of central
Ewing sarcoma. Better definition of tumor extent by CT scans is credited with improvement
in control of pelvic Ewing sarcoma (20). MRI has added to this definition of tumor (Fig.
9.3 ) (21). Radionuclide bone scan may also be of value, although it may exaggerate the
linear tumor extent. PET/CT is useful in combination with MRI for active tumor definition.
MRI may show edema. Whether direct microscopic extension of tumor is associated with the
edema is unknown at present.
Figure 9.2 Ewing sarcoma of the left radius (A) with (B) extensive infiltration of the
surrounding soft tissue.
Figure 9.3 A: Ewing sarcoma of the tibia seen on a plain radiograph shows cortical
disruption, “onion skinning,” and a suggestion of soft tissue involvement. B, C: Coronal and
axial magnetic resonance imaging show extensive soft tissue infiltration.
Approximately 53% of Ewing sarcomas have a primary site in an extremity, and 47%
have central primaries. Ewing sarcoma presents in the proximal extremities in 20–30% and
distal extremities in 30–40% of cases (22,23,24). Metastases are present at diagnosis in
approximately 20–25% of patients.
Primary lesions of the rib are associated with direct pleural extension and significant
extraosseous soft tissue mass in a majority of cases (25,26). The original description of
thoracopulmonary malignant tumors by Askin et al. (27) in 1979 characterized small round
cell tumors in this location as a separate clinicopathologic entity, often called Askin tumor. He
described a female predominance and a short median survival (8 months). These tumors tend
to have a large soft tissue component that can displace most of one lung with or without much
rib involvement. This patient group has special management issues (28,29).
Page 186The frequency of overt metastasis is estimated at 25–30% for pelvic primaries
and less than 10% for tumors of the extremities or ribs. The sites of metastatic disease at
diagnosis parallel the distribution noted with treatment failure, most often involving the lungs
(40%) or bones (40%), with less common disease involving the bone marrow, ly mph nodes,
soft tissue, visceral sites, or, rarely, the central nervous sy stem (30). No formal staging
sy stem has been recognized for Ewing sarcoma. The disease factors most recognized as
prognostically significant include the bone of origin or primary site, older age, tumor size,
presence or degree of soft tissue extension, and identification of hematogenous metastasis at
diagnosis (Table 9.2 ). Smaller tumors (less
than 200 mL in volume) and distal extremity
tumors tend to be favorable (24,31). At present,
the most important prognostic factor at diagnosis
appears to be the presence of metastasis (32,33).
Reports suggest that the response to initial
chemotherapy is significant as well (34).
Table 9.2 Prognostic Factors in Ewing
Sarcoma
Figure: Clinical Evaluation of the Patient
with Ewing Sarcoma
Figure:
Ewing sarcoma of the left radius (A) with (B) extensive infiltration of the surrounding soft
tissue.
Figure:
A: Ewing sarcoma of the tibia seen on a plain radiograph shows cortical disruption, “onion
skinning,” and a suggestion of soft tissue involvement. B, C: Coronal and axial magnetic
resonance imaging show extensive soft tissue infiltration.
Figure: Prognostic Factors in Ewing Sarcoma
SELECTION OF TREATMENT
Local Control
The relative roles of surgery and radiation therapy for local treatment of Ewing sarcoma
have long been debated. In 1953, Wang and Schulz (35) reported 5-y ear survival in 6 of 36
children treated with wide-field irradiation, as compared with 1 of the 14 treated by primary
surgical resection. Using 50 Gy to the entire bone, Phillips and Sheline documented survival in
5 of 21 cases in 1969 (36). After these reports, Ewing sarcoma was generally treated with
radiation therapy except for small tumors in expendable bones. Reviews have indicated an
overall rate of local tumor control of 75% to almost 95% after primary radiation therapy
(3,32,37,38,39,40,41).
Historically, the use of radiation therapy had been the local treatment of choice.
However, the role of surgery has increased because of several developments. These
important developments include the recognition that the local failure rate of radiotherapy for
Ewing sarcoma ranges from 9% to 25%. In addition, the development of innovative surgical
techniques allowing preservation of limb and structural bone function has promoted surgery
as an alternative to radiation. The routine use of cy toreductive chemotherapy, as discussed
later in this chapter, often produces a significant decrease in the soft tissue component,
rendering tumors more readily resectable. In addition, the concern over second malignancies
from radiation therapy has prompted the reevaluation of the role of surgery as well (42).
However, the data concerning local control with radiation therapy alone are difficult to
interpret. Difficulties in assessing response to radiation therapy are evident in the slow rate of
resolution of CT, MRI, and radionuclide bone scan findings after irradiation. The significance
of residual soft tissue abnormalities and persistent areas of increased uptake on technetium
scans is uncertain (22,23,34,43). In patients who have hematologic metastasis, the implication
of residual recurrent tumor at the primary site confirmed by biopsy or autopsy is uncertain
because of the possibility of reseeding from the primary tumor (20,44).
Page 187Several other fundamental factors make it difficult to interpret the data
comparing surgery and radiotherapy for local treatment. The local recurrence rate after
radiation is strongly correlated with the primary tumor site. Local failure of extremity lesions
is of the order of 5–10%, compared with a local failure rate for pelvic lesions of 15–70%.
Local recurrence after radiation therapy of pelvic lesions is expected to improve with
improved tumor imaging and the widespread use of computerized radiotherapy treatment
planning. Therefore, old data may be of more limited use in contemporary management. It
should be noted that tumor size affects local control. Local control for tumors more than 8 cm
in diameter is on the order of 80%, compared with 90% for those less than 8 cm in diameter.
The fact that larger tumors are more likely to be treated with radiation instead of surgery
influences the clinical results of these modalities.
Some patients are treated with a combination of surgery and radiation therapy. Several
factors make it difficult to interpret this data. These include the important effect of quality of
radiotherapy on local control. In many “surgical” series, the comparison is not surgery with
radiotherapy but rather radiotherapy compared with radiotherapy and surgery. This is
analogous to the treatment of many other solid tumors with radiation therapy with resection.
Many surgical series include patients who are at lower risk. They include people who
have undergone ray resection of the hands and feet, removal of the wing of the ileum, lower
sacrum (lower than the S3 bone), ribs, clavicle, or body of the scapula. One must also
consider the relative functional deficits that will be experienced during high-dose irradiation,
surgery alone, and surgery with irradiation. In this context, when selecting local treatment for
childhood Ewing sarcoma, one must consider the rehabilitation capacity and the
psy chological adjustment of the patient with these local treatments (25,45,46).
Fundamentally, when attempting to compare surgery with radiation therapy in the
management of Ewing sarcoma, there is the problem of case selection. Studies are not
strictly comparable, so surgery and radiation can be seen not as competitive but as
complementary. However, one additional matter must be considered in comparing radiation
therapy with surgery : the risk of second malignant neoplasms. As we will describe later in this
chapter, radiation and alky lating agents combine to increase the risk of second malignant
neoplasms after the treatment of Ewing sarcoma. Studies indicate that the relative risk of
sarcomas in the treatment field is related to the radiotherapy dosage and the extent of
exposure to alky lating agents.
In an attempt to eliminate selection bias and evaluate local control modalities, Dubois et
al. (47) reported on 979 patients with localized Ewing sarcoma treated on three consecutive
randomized trials in the Children’s Oncology Group. The patients received similar
chemotherapy regimens. Although local control was not randomized, the authors used logistic
regression to generated propensity scores which indicated the probability that each patient
would have been selected to receive radiotherapy, surgery, or combined radiotherapy and
surgery. The potential covariates assessed were age, sex, tumor site, tumor size, clinical trial,
and y ear of study entry. Tumor size was eliminated from the final model as tumor size was
not available for all patients. On multivariate analy sis, compared with surgery, radiation had a
higher risk of local failure (HR, 2.41; 95% CI, 1.24–4.68). However, there were no significant
differences in EFS (HR, 1.42; 95% CI, 0.94–2.14), overall survival (HR, 1.37; 95% CI, 0.83–
2.26), or distant failure (HR, 1.13; 95% CI, 0.70–1.84) between local control groups.
The relative functional deficits that will be experienced during high-dose irradiation,
surgery alone, and surgery with irradiation must also be considered. In this context, when one
is selecting local treatment for childhood Ewing sarcoma, the patient’s rehabilitation capacity
and psy chological adjustment should be considered (4,40,48).
Surgery
The role of surgical resection in combined-modality treatment was addressed by the
Memorial Sloan–Kettering Cancer Center (23,49). With overall disease-free survival
approaching 80% at 3.5 y ears, Rosen et al. (50) described local treatment failure in 34 (21%)
patients after radiation therapy and aggressive multiagent chemotherapy, compared with 0 of
33 patients who underwent surgical resection in addition to chemotherapy. In an influential
review of the May o Clinic experience with Ewing sarcoma, Wilkins et al. (51) related a
significant impact of surgical resection on overall survival: 74% at 5 y ears, compared with
27% in patients treated without surgery. Other reports have also described improvement in
local control with the addition of surgery (22,25,40,45,52,53,54). However, the studies
reflected selected surgical intervention. For example, in a review by Wilkins et al. (51) of 27
children with microscopically complete resection in a total series of 65 cases, the analy sis
included 11 patients treated with radiotherapy and no adjuvant chemotherapy. These 11
patients were included in the analy sis of the “nonoperated group” and were compared with
the patients receiving surgery plus chemotherapy, clearly biasing the results to favor the
surgical group. In a more balanced comparison, Brown et al. (22) described improvement in
local control with surgery in extremity lesions. There were local recurrences in 0 of 5
resected cases, compared with 3 of 15 patients treated with primary radiation therapy. Brown
et al.’s analy sis pointed out the selected use of surgery in 35 of 67 patients, clearly selecting
cases with distal and smaller lesions for surgery.
Treatment results after surgical resection when combined with chemotherapy have been
excellent, even considering the selection factors inherent in surgical subsets. In cases with
complete or good partial response to preoperative chemotherapy, Hay es et al. (55) described
disease-free survival in 11 of 11 cases with negative operative margins and no added
irradiation. Most other series addressing the impact of surgery have incorporated
postoperative radiation therapy, often at reduced dosage levels (48,50,51,54,56). The addition
of surgery for “dispensable bones” (e.g., fibula, rib, smaller lesions of the hands or feet) often
is considered a significant addition to therapy with little attendant functional deficit, although
excellent results have also been reported with irradiation (44). Options for surgical
management have also been considered primarily in the very y oung population, in whom
radiation late effects would be more significant (56,57,58,59).
Page 188Appropriate comparison of surgical results for Ewing sarcoma entails attention
to the adequacy of radiation therapy in the control arm (23,43). The German Cooperative
Ewing’s sarcoma Study (CESS) reported a significant difference in local control and survival
favoring the cases operated on in the CESS-81 trial (20,40,56). On review, the high rate of
local failure in the radiation therapy group was attributed to a substantial number of cases
with inadequate irradiation volume. In fact, a report by Sauer et al. (56), on the same cohort,
showed equivalent results of surgery or radiation therapy in small lesions. In addition, the
CESS initiated a quality assurance program in 1984. The results of the subsequent study
(CESS-86) demonstrate a marked improvement in local control with irradiation compared to
the previous trial. From 1986 to 1991, 177 patients with localized Ewing sarcoma were treated
with chemotherapy plus radical surgery or surgery plus radiation (45 Gy ) or irradiation alone
(60 Gy total), with a central treatment planning review for quality assurance. Results are now
comparable to those of the surgery group (3-y ear relapse-free survival 67% after irradiation,
65% after surgery, and 62% after resection plus irradiation) (37,41,43,52,60,61). If the
functional results are similar, the potential for second malignancies in patients treated with
irradiation for Ewing sarcoma would favor surgery as the treatment of choice for small
extremity lesions, dispensable bones, or very y oung children. High-risk lesions may benefit
from combined surgery and radiation (37,62).
Chemotherapy
Early studies established the role of chemotherapy in primary management of Ewing
sarcoma (17,51,63). Multiagent regimens incorporating vincristine, actinomy cin D,
cy clophosphamide, and adriamy cin (VACA) resulted in overall survival rates of 50–75% for
patients without metastasis at diagnosis (17,22,39,55,64). The Intergroup Ewing’s sarcoma
Study (IESS) I (1973–1978) demonstrated the importance of combining alky lating agents and
anthracy clines. The IESS-II (1978–1982) showed that early and intensive chemotherapy
combined with local treatment of the primary tumor was beneficial (17,38,65,66).
The 5-y ear relapse-free survival and overall survival improved from IESS-I to IESS-II.
The local control rate improved as well, with a local failure rate of 15% on IESS-I and 9% on
IESS-II.
CESS-81 was conducted from 1981 to 1985 (40,60,67,68). Patients received VACA for
two cy cles followed by local therapy and two additional cy cles of the four-drug
chemotherapy program. The result of this study of local therapy, which was not randomized,
showed a 5-y ear relapse-free survival of 54% for the patients treated with surgery only, 68%
for those treated with surgery and postoperative irradiation, and 43% for those treated with
radiotherapy alone. The local failure rate was strikingly different: 6% for surgery alone, 17%
for surgery and postoperative irradiation, and 50% for radiotherapy alone. The high local
failure rate in the radiotherapy alone arm was clearly secondary to major radiotherapy
volume deviations. Midway through the trial, central review of radiotherapy was instituted
resulting in a decline in local failure.
The response of the primary tumor to chemotherapy as an important prognostic factor
has been demonstrated in patients undergoing surgery after initial chemotherapy (69). Picci
et al. (59) studied 118 patients between 1983 and 1993 and graded the surgical specimens
from grade I to III, with grade I having gross visible tumor, grade II microscopic tumor, and
grade III specimens with total necrosis. The 5-y ear disease-free survival ranged from 34%
for grade I to 95% in the grade III group (59). Others have confirmed that tumor necrosis
after induction chemotherapy carries a favorable prognosis (32,69).
The proportion of patients with distant metastasis is another measure of
chemotherapeutic responsiveness. Marcus et al. (21) analy zed the impact of tumor size on
survival; the dominant pattern of failure for large tumors remained distant metastasis despite
aggressive chemotherapy. Jurgens et al. (40) described distant metastasis in 29% of the CESS-
81 cases; isolated distant metastasis occurred in 10%. The updated results of IESS-II
demonstrated a 63% survival at 5 y ears, with 25% of patients developing distant metastases
only (66).
The substitution of ifosfamide for cy clophosphamide was tested in the CESS-86, which
included 177 patients from 1986 to 1991 (20,40,60,67,68,70,71). Patients whose primary
tumors were judged to be smaller than 100 cm 3 received induction VACA. Those with larger
tumors received vincristine, actinomy cin, ifosfamide, and adriamy cin (VAIA). Local
therapy, at the discretion of the treating phy sician, was given at week 10. This was followed
by four courses of VACA for the smaller tumors and four courses of VAIA for the larger
tumors. When a curative resection was conducted, no additional radiation was given if there
were no significant risk factors for local recurrence, such as positive margins. However, if the
operative bed was at risk for local persistence of tumor, patients were randomized to once or
twice per day postoperative irradiation. For patients in whom a curative resection was
possible but there was only small residual disease after induction chemotherapy, surgery was
not performed and patients were randomized to once- or twice-a-day radiation. When a
tumor resection was not undertaken and there was substantial tumor, patients were
randomized to receive either 45 Gy of conventional irradiation once per day to a larger field
with a 15-Gy cone-down boost to a total of 60 Gy or 44.8 Gy of twice-daily radiation to a
larger field followed by a 16-Gy boost with twice-daily irradiation.
In CESS-86, 22% of the patients were treated locally with surgery, 53% with surgery and
radiation, and 25% with radiation alone. Although the patients treated with surgery alone had
a low rate of local failure, they had a higher rate of distant metastases. Local treatment did
not influence survival. In addition, there appeared to be no difference between once- and
twice-daily irradiation. Tumor volume greater than 200 mL and poor histologic response to
chemotherapy had a negative effect on outcome by both univariate and multivariate
analy ses (70).
The impact of local therapy modality for the 1058 patients enrolled in the CESS and the
European Intergroup Cooperative Ewing’s sarcoma Study (EICESS) trials was reported. After
induction chemotherapy patients with resectable tumors had excellent local control, with a
local relapse rate of 7.5%. Comparable local control was achieved in patients given
preoperative radiotherapy in the EICESS-92 trial to patients for whom there was a high
likelihood of close resection margins or in whom further tumor reduction was expected to
allow function-preserving surgery. For patients treated with definitive radiotherapy, local
relapse was 26%, significantly higher than for those able to undergo resection; however, this
cohort represented a negatively selected group of patients with unfavorable tumor sites.
Page 189The sy nergistic effectiveness of etoposide in combination with alky lators was
studied in the Children’s Cancer Group (CCG) Study 7881 and Pediatric Oncology Group
(POG) Study 8850 (71). This trial evaluated the use of VACA with and without ifosfamide and
etoposide to treat newly diagnosed Ewing sarcoma or PNETs. This phase III randomized trial
was open from 1983 to 1994. Patients were randomly assigned to receive 49 weeks of
standard chemotherapy with VACA or the experimental treatment, which alternated VACA
with the ifosfamide–etoposide combination. The trial demonstrated, in terms of both
increased survival and overall survival, the superiority of six-drug chemotherapy to four-drug
chemotherapy for localized disease (Table 9.3 ). There was an improvement in local
control for patients with localized pelvic Ewing sarcoma who received the ifosfamide–
etoposide combination (72). This improvement was irrespective of the local control modality
used. However, no benefit was attributable to six-drug chemotherapy for patients with
metastatic disease.
Intensification of chemotherapy to improve the outcome of patients with Ewing sarcoma
and PNET was tested in two trials. These two sequential prospective randomized trials tested
the hy pothesis that intensification of chemotherapy can improve the outcome over standard-
dose chemotherapy in patients with nonmetastatic tumor. The first such trial was open from
1995 to 1998, and the second from 2001 to 2005. Both trials used interval compression as the
method of dosage intensification and were limited to patients with newly diagnosed localized
disease. The analy ses of these studies included event-free and overall survival, toxicity, and
the relationship between the intensification achieved and outcome. The first trial failed to
show an improvement with dose intensification (73). However, the second trial, which
accrued 564 eligible patients randomized to either every -3-week or every -2-week
chemotherapy cy cles, demonstrated superior event-free and overall survival for the every -
2-week regimen (74). The differences for both event-free and overall survival were
statistically significant.
For patients with nonmetastatic Ewing sarcoma, the intergroup prospective randomized
trial discussed previously demonstrated that the regimen of alternating
vincristine/doxorubicin/cy clophosphamide and ifosphamide/etoposide was superior to the
vincristine/doxorubicin/cy clophosphamide alone. Following this trial, the interval compression
administration of chemotherapy demonstrated superiority to standard chemotherapy
delivery. The compressed alternating regimen became the current standard in North
America. Trials are ongoing to test the addition of other agents to this now standard regimen.
In the management of metastatic disease at presentation, little progress appears to have
been made during serial studies. For example, in IESS-I patients with metastatic disease were
treated with VACA for a 5-y ear survival of 30%.
In IESS-II drugs were VACA plus 5-fluorouracil,
and the 5-y ear survival was 28%. In the
aforementioned CCG–POG trial recently
completed, the 2-y ear survival was 22%.
Radiotherapeutic Management
The role of radiation therapy in primary
management of Ewing sarcoma is generally
evaluated in each patient with a team including
surgeons, medical oncologists, and radiation
oncologists. As previously discussed, there is
controversy concerning the relative advantages
of irradiation and surgery with preoperative or
postoperative irradiation (21,43,52,61,75).
Volume
Local control of tumor with irradiation improved
after the general acceptance of a target volume
encompassing the entire medullary cavity to
Table 9.3 National Cancer Institute
moderately high dosage levels (30,76). Suit (77)
Protocol INT-0091 (Children’s Cancer
summarized the experience of the 1950s and
Group Study 7881 and Pediatric
1960s in recommending irradiation to the entire
Oncology Group Study 8850)
involved bone with a higher-dose boost to the
primary tumor site. He noted few instances of
marginal or distant intramedullary recurrence with such treatment. However, subsequent
studies have reported irradiation results based largely on treatment techniques that have not
included the opposite epiphy sis, noting no marginal recurrences despite high variable rates of
local tumor control (21,52,78).
Page 190The importance of adequate treatment volume and radiation quality cannot be
overemphasized. The results of the CESS-81 study indicated an excessive rate of local
recurrence attributed to poor quality control for radiation therapy. Protocol modification to
include central planning for radiation therapy diminished the frequency of local failure
(56,78).
Brown et al. (22) analy zed the sites of local recurrence, describing consistent failure in
the primary tumor volume for patients with lesions of the extremities and pelvis. Marginal
failures occurred infrequently, limited to patients with rib primaries. In a study reducing
treatment volume and dosage, Hay es et al. (55) found a high rate of local recurrence (25%
isolated, 35% overall). However, treatment failures were localized within the primary target
volume in 13 of 14 instances using a limited, postchemotherapy tumor extent to define the
soft tissue component of the irradiation fields.
Data addressed the efficacy of diminished treatment volumes (31,79). Local or tailored
fields encompassing the primary tumor with a 3- to 5-cm margin rather than the whole bone
have been studied (Fig. 9.4 ). Marcus (31) reported excellent local control using tailored
fields, noting the ability to spare a component of the long bones in tumors less than 8 cm in
diameter, whereas full-bone irradiation is often needed to achieve a 4-cm margin around
larger tumors. Despite the higher overall rates of local failure in the St. Jude Children’s
Research Hospital study, Hay es et al. (55) also noted local control in 12 of 14 patients with
lesions less than 9 cm in diameter using smaller target volumes.
Figure 9.4 Changes in treatment volume for Ewing sarcoma. A: Field encompassing the
entire length of the medullary cavity for a tumor involving the proximal left humerus. B:
Tailored field encompassing only the proximal aspect of the leg for a limited tumor of the left
tibia; there is a 5-cm distal margin beyond known bone involvement as demonstrated by all
imaging procedures. In recent years, national protocols have called for a 2- to 3-cm margin.
An important study in the determination of the proper field size for the irradiation of
localized Ewing sarcoma was POG-8346. Between 1983 and 1988, 184 children were studied.
Of this group, 179 were truly eligible for the study ; 79% had localized disease, and 21% had
metastases. Induction treatment was cy clophosphamide and adriamy cin followed by local
treatment with either surgery or radiation therapy. This was followed by actinomy cin D and
vincristine. Patients treated to the local site with radiation therapy were randomized to receive
whole-bone irradiation to 39.6 Gy with a 16.2-Gy boost or involved-field irradiation to 55.8
Gy. For the 104 patients with localized disease who were irradiated, the 5-y ear event-free
survival was 42%, with no difference in event-free survival between those randomized to
receive large or small fields. The local control rate was only 45% for those not treated
according to the protocol-specified volume (80).
The current recommendations for treatment volume mandate the use of MRI whenever
possible to identify the tumor extent. The entire bony abnormality and soft tissue mass are
included, identified at diagnosis before either surgery or chemotherapy as the gross tumor
volume (GTV), with a 1-cm margin added to cover potential occult tumor. An additional
margin, generally determined by the institution, is then added. This results in the planning
target volume (PTV) to account for daily setup, patient movement, and an additional margin
for dosimetric considerations. The exception to this method is the case of a large soft tissue
mass that protrudes into a body cavity at diagnosis and is responding to chemotherapy and
allowing normal tissues to move back to their normal position. In this circumstance, the initial
GTV excludes the prechemotherapy volume if that volume previously extended into the
body cavity. The volume of infiltrative soft tissue disease is not modified. The entire original
bony abnormality is alway s treated.
Page 191In postoperative irradiation, the appropriate target volume has not been
adequately defined. Based on the data supporting local volume for primary radiation therapy,
one would recommend treatment to the preoperative tumor bed with adequate margins, later
reducing the treatment fields to documented sites of tumor residual in incompletely resected
lesions. In all cases with residual tumor in the operative specimen, encompassing the surgical
incision appears to be important.
Dosage
Early reports established the efficacy of radiation dosages of 50–60 Gy at 180–200 cGy per
fraction, describing better local control than is achieved with a total dosage of less than 45 Gy
(6,81). Dosage recommendations have included 40–45 Gy to the entire medullary cavity,
with a boost to the primary site to cumulative levels of 55–60 Gy (77).
The IESS-I results indicated no dose–response relationship between 40 and 68 Gy. Using
50 Gy in 25 fractions, the National Cancer Institute reported clinically apparent local
recurrence in 20% of cases (39). Whether the lower frequency of local recurrence in the
IESS and selected single-institution series using 60 Gy reflects a dose–response relationship is
uncertain based on available data (43,49).
Alterations in total dosage and the time–dose relationship were found in University of
Florida research using hy perfractionated irradiation (31,82,83). Patients were treated with
120 cGy twice daily to 36 Gy for initial target volumes encompassing the primary tumor in
4-cm margins. Subsequent reduced fields were used to cumulative levels of 50.4 Gy (with
total resolution of the soft tissue component by preirradiation chemotherapy ) and 55.2 Gy
(with no response to chemotherapy ). For patients with a lesion less than 8 cm in diameter,
local recurrence was documented in only 1 of 11 children (84). In a review of the University
of Florida series of patients treated between 1969 and 1987, those with tumors 8 cm or
smaller treated with twice-daily irradiation had a local control rate of 88%, compared with
92% for once-daily radiation. However, for those with tumors larger than 8 cm, the local
control rate for twice-daily radiation was 88%, compared with 58% for once-daily
irradiation. Evaluation of this data must be tempered by the previously cited randomized trial
of CESS, which did not show a benefit to multiple-daily -fraction irradiation (40,60). With
larger lesions, some have used more aggressive sy stemic therapy and total-body irradiation
(TBI; 400 cGy twice daily ) with reported improved local and overall disease control (21).
The current dosage recommendations are 55.8 Gy for gross residual disease and 50.4
Gy for microscopic disease. Lesions of the vertebral body are treated with 45 Gy. Standard,
once-per-day fractionation is generally used. No dosage modifications are recommended for
smaller tumors, although normal tissues should be protected whenever possible. The shielding
of critical structures must also be weighed against the possibility of underdosing known tumor-
bearing tissue.
Chemotherapy influences local control.
Aforementioned studies suggested a local control
benefit from the addition of adriamy cin, and
more recent reports address the prognostic
implications of the histologic response of the
primary tumor to chemotherapy. The recent
randomized trial CCG-7881 and POG-8850
showed a local control benefit of VACA with
ifosfamide and etoposide compared with VACA
alone (Table 9.4 ) (71). It is likely that along
with improved imaging (MRI and functional
MRI) for tumor identification, improvements in
chemotherapy will increase local control of the Table 9.4 Influence of Chemotherapy
primary tumor. on Local Control of Ewing Sarcoma in
CCG-7881 and POG-8850
Technique
Radiation delivery techniques have dramatically improved over the y ears. Currently, the
standard of care around the country is three-dimensional (3D) CT and MRI-aided radiation
planning. The improved imaging and its incorporation into the planning process for radiation
treatments have allowed increased sparing of normal tissues and better dose localization into
the tumor. The imaging studies of CT, MRI, and PET scanning can be used and often
registered to the planning CT scan to better delineate the gross target volume and clinical
target volumes. Currently, 3D conformal radiotherapy (3DCRT) and intensity -modulated
radiotherapy (IMRT) are widely available and considered the standard of care for these
tumors when they require radiation therapy. However, another major advance with
tremendous promise is proton radiation, which will be used more commonly as more
facilities open over the next decade.
Sophisticated radiation therapy techniques will achieve maximal local tumor control
while minimizing treatment-related complications. For extremity lesions, sparing a strip of
linear soft tissue is fundamental. Avoiding circumferential irradiation decreases the likelihood
of significant late fibrosis and edema (43,85). To achieve adequate coverage, treatment plans
incorporating oblique opposed fields or angled pairs with compensating wedges may be
necessary. Conventional opposed anterior-posterior or lateral field configurations may be
ideal if adequate soft tissue can be spared. Immobilizing casts or molds are important for
daily reproducibility and accuracy during treatment (see Chapter 22 ).
Page 192Large extremity lesions often necessitate irradiation of the adjacent joint. With
the same attention to normal tissue sparing, the major late problem associated with joint
irradiation appears to be greater growth alterations if both epiphy ses of the joint are included,
particularly at the knee (41,85).
Lesions of the distal extremities, including the ankle, feet, and hands, present
individualized problems regarding treatment planning. The use of tissue compensation,
immobilizing devices, and detailed attention to dosimetry are critical to achieving excellent
tumor control and functional integrity (23,81). The use of a water bath to achieve dosage
homogeneity has been suggested. Alternatively, a single-photon beam incident on the
contralateral surface of the hand or foot may be combined with an ipsilateral electron field.
For pelvic lesions, techniques to avoid full-dose irradiation of the bladder often are
possible with oblique or multifield configurations. Carefully including the soft tissue extent,
often more impressive on CT or MRI studies, will ensure maximal tumor control. For
vertebral Ewing sarcoma, uniform irradiation of the adjacent vertebrae will minimize late
effects. The use of weighted opposed anterior–posterior fields or a wedged-pair technique
generally ensures adequate coverage of the vertebrae, of necessity including the spinal canal.
Rib lesions (Askin tumor) are generally large tumors, often with extension to the pleural
surfaces. This site warrants special consideration because it is often associated with a large
soft tissue component (68). The surgeon must not attempt to remove the tumor initially before
chemotherapy. After biopsy, chemotherapy should be given for large lesions because it
induces tumor shrinkage (29,86). In thoracic rib and soft tissue primaries, the
postchemotherapy volume appears adequate to define the irradiation volume. If resection is
done first, margins may be positive and may necessitate a much larger volume of irradiation.
The radiation volume often is limited by organ toxicity such as the heart in left sided lesions.
Resection after chemotherapy may be adequate if operative margins are clearly negative
after nearly complete response to chemotherapy. If the resection margins are positive or the
tumor is incompletely resected, local irradiation is indicated to increase the likelihood of local
tumor control (22,26,28,55,86). Inclusion of the pleural cavity in patients with cy tologically
positive effusions has been recommended because the pattern of failure as described by
Askin et al. (27) included the pleura in a significant number of cases. There is also a risk of
pleural relapse in patients with Askin tumor and no initial pleural effusion. Some clinicians
attempt to treat the pleural surface but spare the lung by using external beam electrons. An
alternative technique is intrapleural radioisotope application. A small amount of dy e is placed
in the pleural cavity with saline and the patient is rotated. Free flow is confirmed by
fluoroscopy. As an alternative, a tracer amount of radioactivity may be used to confirm free
flow in the pleural space with a gamma camera. After free flow is confirmed, a therapeutic
dose of 32P is instilled to irradiate the pleural surface. The patient is turned periodically to
distribute the isotope (86). The treatment of the entire pleural surface in the absence of a
positive pleural effusion is controversial.
There is a limited experience with brachy therapy for Ewing sarcoma. Potter et al. (87)
described six patients treated with chemotherapy, external beam irradiation, and
intraoperative high-dose rate brachy therapy for close surgical resection margins. All six
children are alive and well.
Improvements in imaging modalities, particularly the routine use of MRI scans to assess
tumor extent, provide more accurate target definition. Technologic advances in radiation
therapy treatment delivery will also allow greater sparing of normal tissue without
compromising tumor treatment. Such technologic advances may include the use of intensity -
modulated radiation therapy and the use of protons.
Proton radiation is similar in quality as photon radiation, which means that it causes
ionizing events in cells and causes DNA damage that is believed to be the lethal event in tumor
cells. However, it has the advantage over photon radiotherapy (IMRT or 3DCRT) in that it
better localizes the dose to the tumor with better sparing of the normal surrounding tissues.
Dose to normal tissues is decreased by a factor of 2 or more in many cases. Protons deliver
maximum dose at a finite range, in contrast to photons that have infinite range with dose
decreasing exponentially with depth. When treating a tumor at some depth in tissue, protons
enter the tissue with a decreased entrance dose compared with photons, and then deposit a
higher dose in the tumor. Protons have no exit dose bey ond the tumor being targeted (88).
Photons entail both an entrance dose and an exit dose to normal tissues in the process of
targeting a tumor. The result is similar dose distribution to the tumor itself but decreased dose
to normal tissue (89,90). This technique therefore should result in reduced acute and long-
term side effects including a reduction in second malignancy risk. Protocols are open at some
proton centers in the United States and these centers use protons instead of photons to treat the
patients with the endpoints of morbidity and side effects (Fig. 9.5A, B ).
Figure 9.5 A, B: Example of a teenage boy with a pelvic Ewing sarcoma planned with
proton radiotherapy. Note sparing of even low dose to most of the bladder, rectum, small
bowel, and contralateral hip.
Current experience with Ewing sarcoma indicates 5-y ear disease-free survival in 50–75% of
patients with localized disease at diagnosis (17,25,54,66). There have been late relapses, and
the 10-y ear survival is decidedly worse than the 5-y ear survival. A limited number of single-
institution reports indicate higher disease-free survival (21,40,50). Survival clearly parallels
initial disease extent (38). Disease-free survival greater than 75% has been documented for
limited volume Ewing sarcoma involving the distal extremities. Survival rates of only 25–35%
are achieved with large central lesions (22,38,40,54).
Overall functional results after treatment of Ewing sarcoma have correlated closely with
the degree of attention to detailed local management. Selection of primary surgery for
lesions permitting function-preserving resection with negative or microscopically positive
margins may decrease late effects of high-dose irradiation, particularly in prepubertal
y oungsters (25,53,54).
With appropriate radiation therapy, patients treated for Ewing sarcoma of the extremities
had excellent functional results in more than 60% of cases. The NCI late effects review noted
minor alterations in leg length or minimal sy mptoms of soft tissue change in another 20% of
cases (83). Significant treatment-related morbidity occurred in 20% of the NCI cases and
was related primarily to larger primary lesions. Significantly higher morbidities have been
reported in series combining sy stemic chemotherapy with dosages greater than 60 Gy
(22,54,85). In a limited number of patients treated with 70 Gy to the primary site, severe
functional deterioration was reported in 26% of patients (50).
Page 194The risk of fracture after treatment has also been related to total dosage.
Fracture appears to correlate more directly with the extent of cortical disruption at the time of
biopsy, in addition to tumor size and y ounger age at presentation (17,20,53,57).
Limited changes have been reported after primary irradiation of tumors of the upper
extremities. Some degree of hip dy sfunction and potential growth disturbances are
documented in long-term follow-up of patients with pelvic Ewing sarcoma. Combined
cy clophosphamide-irradiation cy stopathy has also been noted in such cases (22,41). One of
the primary concerns regarding irradiation is the impact on bone growth. Morphologic
changes of the irradiated epiphy sis have been reviewed in the NCI series (85). Quantitatively,
reduction and subsequent growth relates to the sites of epiphy seal irradiation and the age at
treatment. Overall functional results are less favorable in very y oung children (41,85) (see
Chapter 19 ).
The high incidence of secondary tumors in Ewing sarcoma was originally suggested in
the combined reporting of the Late Effect Study Group (LESG), assessing the frequency of
secondary bone sarcomas in 9170 children surviving more than 2 y ears after treatment for
cancer. The rate of carcinogenesis in patients with Ewing sarcoma was second only to that in
patients with retinoblastoma in this study. There was a sharp dose–response relationship after
dosages to the bone of more than 60 Gy. With the current standard in Ewing sarcoma of 45–
55 Gy, this risk of second tumors appears to be less than in the original reports. In contrast to
the 22% actuarial risk of second tumors reported by LESG (96), more recent data
demonstrate a cumulative incidence of 9.2% for any second malignancy and 6.5% for
secondary sarcoma (46). Here again, a dose–response relationship was demonstrated, with
no secondary sarcomas seen with a dosage of less than 48 Gy. The risk of secondary
leukemia may be greater with high-dose regimens as well (98).
In an overall review of second
malignancies after treatment for Ewing sarcoma
in CESS-81 and CESS-86, the addition of
radiotherapy to surgery or treatment with
radiotherapy alone was associated with a higher
cumulative risk of second malignancies (Table
9.5 ) (99). The Childhood Cancer Survivor
Study, a retrospective study of 13,581 children
diagnosed with cancer before age 21 and
surviving at least 5 y ears, reported a 5%
cumulative incidence of secondary
malignancies at 25 y ears for the entire cohort
(42). The incidence continued to increase over
the follow-up period. Survivors of Ewing
sarcoma were at higher risk of developing Table 9.5 Second Malignancies in
second malignant tumors than others in the Patients Treated in the German
cohort. Other factors in addition to radiotherapy Cooperative Ewing Sarcoma Studies
were found to play a role in the development of CESS-81 and CESS-86
a second malignant tumor. The use of
anthracy cline increased the risk of soft tissue sarcoma, and the use of alky lators increased the
risk of secondary bone tumors. Although children treated for Ewing sarcoma and PNET must
be followed up over the long term, the success in treatment should not be overshadowed by
these adverse sequelae.
Figure: Second Malignancies in Patients
Treated in the German Cooperative Ewing
Sarcoma Studies CESS-81 and CESS-86
REFERENCES
Page 197Osteosarcoma is the most common primary malignant bone tumor in children. The
tumor derives from bone forming mesenchy me (1,2,3,4,5,6,7,8,9,10,11) (Fig. 10.1A &
B ). The incidence is one to three new cases per million per y ear (6). The majority of
cases occur in the second decade of life with a male predominance. There is a bimodal
distribution with a second smaller peak of incidence at age >60 y ears (Fig. 10.2 ) (6,12).
Figure 10.1 A & B: Histopathology of osteosarcoma: low power (A) and high power (B).
Figure 10.2 Osteosarcoma incidence per million people per year by age based on SEER
data. The peak for older people is associated with Paget disease. (Reproduced from Mirabello
L, Troisi R, Savage S. Osteosarcoma incidence and survival rates from 1973 to 2004: data
from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009;115:1533, with
permission.)
Inactivation of the retinoblastoma (Rb) and P53 pathway s appears to be a central event
in the genesis of osteosarcoma. Rb is a tumor suppressor gene that is discussed in detail in
Chapter 5 . Abnormalities (70–80% allelic loss, 10–20% rearrangements, 20–30% point
mutations) in the p53 locus on the short arm of chromosome 17 have been noted in up to 50%
of cases (13). Patients with a germline mutation of p53 are at very high risk of osteosarcoma
(14). Genetic studies on human, canine, and murine osteosarcomas have revealed mutation
of c-kit (15) and TP53 (16) genes, overexpression of urokinase plasminogen activator/uPA
receptor (17), CRM1 (18), Ezrin (19), alpha V integrin and vascular endothelial growth factor
(20), runt-related transcription factor Runx2 (21) and URG4 gene (associated with cell
proliferation) (22), increased phosphory lation of cJun, JNK, and ERK1/2 (23), and expression
of cy clooxy genase (COX-2) (24) and somatostatin receptors (25). Some of these genetic
alterations may have oncogenic or prognostic significance and may also be potential
therapeutic targets. High-resolution array comparative genomic hy bridization in combination
with interphase fluorescence in-situ hy bridization has been shown to detect chromosomal
instability and genomic imbalance that have been correlated to response to chemotherapy
(26).
Second malignant neoplasms can occur in patients with osteosarcoma treated with
surgery alone or with surgery and chemotherapy, perhaps as a result of these genetic
abnormalities (27,28,29). Osteosarcoma may develop in long-term survivors of heritable Rb.
These secondary osteosarcomas may arise in or outside the irradiated field and in children
treated without radiotherapy (see Chapters 5 and 20 ).
Figure:
A & B: Histopathology of osteosarcoma: low power (A) and high power (B).
Figure:
Osteosarcoma incidence per million people per year by age based on SEER data. The peak for
older people is associated with Paget disease.
(Reproduced from Mirabello L, Troisi R, Savage S. Osteosarcoma incidence and survival rates
from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program.
Cancer. 2009;115:1533, with permission.)
SIGNS, SYMPTOMS, EVALUATION, AND STAGING
Page 198Osteosarcoma usually occurs in the metaphy ses of the long bones, especially
around the knee joint. The bones most commonly involved are the femur (approximately
40% of cases), tibia (15%), and humerus (15%) (Fig. 10.3 ) (1,3,6,7,30). The usual clinical
presentation is swelling or pain. A few patients present with a pathologic fracture and may be
associated with a poorer overall survival and disease-free interval (31).
On conventional radiographs, the tumor has a ty pical appearance. There are poorly
defined margins, interrupted periosteal new bone, and soft tissue invasion. Where the bony
cortex is penetrated at the edge of a tumor, there may be a periosteal elevation and vertical
spicule formation (Codman triangle) (3,7,30). Computed tomography (CT) and magnetic
resonance imaging (MRI) help delineate the intramedullary extent of tumor as it tracks along
the marrow cavity and the soft tissue extent of tumor (7,32) (Fig. 10.4 ). The bone scan has
nearly 100% sensitivity for the presence of malignant bone tumor, although the specificity is
less. On the bone scan, one may observe osteoblastic activity in the shaft of the long bone
proximal to the primary tumor. This may represent reactive change and not indicate the
presence of malignancy (7). Thallium scintigraphy has been used for tumor localization;
however, whole-body fluorine-18-flurordeoxy glucose positron emission tomography (FDG-
PET) in combination with CT scans has been shown to have a role in tumor assessment,
staging, and restaging for patients with osteosarcoma (33,34). A surgeon may order an
angiogram to determine tumor vascularity, detect vascular displacement, determine the
relationship between vessels and the tumor, and identify vascular anomalies. The most
common sites of distant metastases are the lungs and bones (3,4,30,32, 35,36,37). To evaluate
pulmonary metastases, a plain chest radiograph is used to identify chest nodules or
cannonball lesions. A chest CT can be used to assess the presence or absence of small nodules
(33,37).
Page 199If we are to improve the treatment of osteosarcoma, it will be important to
adapt therapy to the individual patient’s prognostic factors (38). The conventional means of
doing this is a staging sy stem. The presence or absence of metastases and the use of histologic
subty ping do help predict prognosis (Table
10.1 , Fig. 10.5 ). A variety of factors have
been investigated as potential prognostic factors.
As will be discussed later in this chapter,
histologic response to neoadjuvant
chemotherapy is useful in predicting outcome.
However, information of this ty pe is available
only after chemotherapy and surgery. Clinical
features with predictive value in determining
outcome include the duration of presenting
sy mptoms (shorter is worse), tumor size (larger
is worse), location of the primary tumor (head,
spine, rib, and pelvic sites are worse), and weight
loss of >10 lb. The primary tumor size seems
strongly predictive of outcome and may be Figure 10.3 Skeletal distribution of
calculated as either absolute tumor length (>10 primary osteosarcomas in patients
cm), relative tumor length given as the treated on the Neoadjuvant Cooperative
proportion of tumor length to the overall length Osteosarcoma Study Group protocols of
of the involved bone (more than one-third of the the Cooperative German–Austrian–Swiss
involved bone), or absolute tumor volume (>70 Osteosarcoma Study Group. (Modified
or 150 cm 3) (40,44). from Bielack S, Kempf-Bielack B, Delling
G, et al. Prognostic factors in high-grade
osteosarcoma of the extremities or
trunk: an analysis of 1702 patients
treated on Neoadjuvant Cooperative
Osteosarcoma Study Group protocols. J
Clin Oncol. 2002;20:776–790, with
permission.)
Figure 10.4 An 18-year-old right-
handed high-school senior presented to
medical attention when his tennis game
and weight-lifting activities were
inhibited by pain in his left shoulder.
Diagnostic images showed a mixed
sclerotic and lytic mass in the proximal
left humerus. Incisional biopsy made the
diagnosis of osteosarcoma. The patient
was treated with induction
chemotherapy in the hope of producing a
substantial tumor response eventually
leading to limb-sparing surgery.
Unfortunately, within 2 years of the initial
diagnosis, widespread pulmonary
metastases developed, refractory to
chemotherapy, which led to the patient’s
death.
There is no widely used staging sy stem for osteosarcoma. Some clinicians simply
separate patients into two groups: those with localized disease and those with metastatic
disease. The sy stem developed by Enneking and adopted by the Musculoskeletal Tumor
Society is used by some orthopedic oncologists. In general, there are few low-grade
osteosarcomas; therefore, in this sy stem, most tumors are stage II or III (Table 10.2 ). One
study from the European Osteosarcoma
Intergroup (EOI) suggested that patients with
chondroblastic tumors had a slightly superior
survival to those with other histologies; however,
the SEER data suggest that the conventional
osteosarcoma subty pes have similar 5-y ear
overall survival rates (12,45).
Page 201The Cooperative German–
Austrian–Swiss Osteosarcoma Study Group
(COSS) has provided an extensive evaluation of
prognostic factors in high-grade osteosarcoma of
the extremities or trunk. In an evaluation of 1702
patients treated on neoadjuvant osteosarcoma Table 10.2 The Enneking Staging
protocols, the investigators found that the long- System for Osteosarcoma
term survival of patients with limb primaries was
superior to that of those with axial primaries, patients who presented without metastases had
higher survival rates than those who presented with metastases, patients with extremity
sarcomas occupy ing less than one-third of the bone had higher survival rates than those with
sarcomas occupy ing more than one-third of the bone, and distal extremity tumors had a
superior outcome to proximal tumors. The response to chemotherapy (i.e., the amount of
tumor necrosis at the time of resection in a setting of neoadjuvant chemotherapy ) also was a
highly important predictor of outcome along with the extent of surgical resection (Table
10.3 ) (46,48).
Surgery
Local Disease
The biopsy site should be selected to allow access to the infiltrating edge of the tumor. In
general, either minimal or no cortical bone should be removed in order to reduce the risk of
pathologic fracture (41,49,50,51,52).
The classical definitive operative procedure is an amputation above the region of the
affected bone or a disarticulation at the joint above the lesion. Traditional teaching is that if
one resects the bone bey ond the site defined by all radiographs as the most proximal extent of
disease and if the margins are pathologically negative, the chance of stump recurrence is
negligible (50,51). In recent y ears, surgical treatment for local osteosarcoma has changed.
New limb salvage procedures have been performed with gratify ing results (53,54).
Limb-sparing operations may be selected if there is no evidence of neurologic or
vascular compromise by the local tumor, if the surgeon believes that he or she can obtain an
adequate margin around the primary osteosarcoma, and if there is a plan for reconstruction
that will provide better function than amputation. Relative contraindications to limb sparing
include the presence of a pathologic fracture, a poor response to neoadjuvant chemotherapy,
or skeletal immaturity that will lead to significant limb growth discrepancies (55,56).
What is an adequate surgical margin for local management of osteosarcoma? A radical
margin entails removal of the entire bone of origin with accompany ing soft tissue
involvement, as is achieved by a hip disarticulation for a distal femoral tumor. A wide margin
is defined as excision of the tumor with a cuff of surrounding normal tissue, and a marginal
margin entails excision of the tumor and its surrounding reactive pseudocapsule. Local control
is improved by the adequacy of the surgical margin and a good response to neoadjuvant
chemotherapy (57). It is generally accepted that limb-sparing surgery has a slightly greater
risk of local tumor recurrence than does amputation. Amputation has a slightly greater risk of
local recurrence than does disarticulation (Table 10.4 ). A good chemotherapeutic response
may allow the surgeon to have a tighter margin on the primary tumor and exclude more
normal tissue from the resection. However, to know before surgery whether a marginal
excision is reasonable, one must have an idea of what tumor response was achieved by
chemotherapy. Unfortunately, no single imaging study can reliably provide this information,
although plain radiographs, CT, bone scan, MRI, and FDG-PET scan can be used (55,59).
By un et al. (60) report that the incorporation of serial dual phase 18F-FDG-PET (at 60 and
150 minutes) after one cy cle of neoadjuvant chemotherapy can predict histologic response
with an accuracy of >70%.
Page 202The reconstruction technique
elected after limb-sparing procedures depends
on the location of the osteosarcoma, whether
there is joint involvement, the extent of bone and
soft tissue resection, the patient’s age, the
functional demands of the patient and the family,
and the prospects for rehabilitation. When the
excision is intra-articular (within or involving a
joint), reconstruction options include custom
segmental total joint replacement, whole
segment osteoarticular allograft (i.e., from a
cadaveric donor), allograft–prosthetic composite Table 10.4 Local Recurrence Rates
reconstruction, arthrodesis (surgical fixation of a for Osteosarcoma as a Function of the
joint; artificial anky losis) with autologous or Extent of Surgery
allogeneic bone, or arthrodesis with a porous
prosthesis allowing host bone ingrowth and bone graft. If a joint is not involved, one can
reconstruct with autologous or allogeneic bone, a prosthesis, or a segmental prosthetic spacer.
Rotation-plasty is also an option in certain situations (2,61,62,63).
It is gratify ing that, in modern pediatric oncology practice, the child with osteosarcoma
may be offered limb-sparing options for local treatment bey ond the traditional amputation or
hip disarticulation. The previous discussion has cited indications and relative contraindications
to limb-sparing surgery, the risk of local recurrence after various forms of surgery, options
for reconstruction after tumor resection, and the need for adequate surgical margins.
Although limb function after limb-sparing surgery is generally good in many patients, limb-
sparing surgery is not for every one faced with osteosarcoma. Case selection by a skilled
orthopedic oncologist, invocation of sound oncologic principles, and adequate rehabilitative
services postoperatively are necessary to achieve the best possible function and cancer
control.
Metastatic Disease
Surgery also play s a role in treating
osteosarcoma metastatic to the lung. Some
patients present with a primary tumor along with
limited pulmonary involvement. Aggressive
multiagent chemotherapy, surgical management
of the primary tumor, and thoracotomy for
resection of pulmonary metastases appear to
have significantly increased survival in cases
that seemed hopeless (Table 10.5 ) (44,64).
The most common sites of metastases in the
relapse of initially localized osteosarcoma are
lung and bone (Fig. 10.6 ). When tumor
relapses in the lung, surgical resection of
pulmonary nodules may result in a prolonged
disease-free interval and, together with
aggressive chemotherapy, a small potential for
cure (4,28,35,36,50,65,66). In some patients,
repeated thoracotomies appear to have
prolonged survival in the face of multiple
episodes of pulmonary metastases (41). By
diagnosing pulmonary recurrences earlier and
with limited tumor bulk, thoracic CT may either
Table 10.5 Factors Predicting Event-
open the possibility for a beneficial effect of
Free Survival in Patients with Primary
surgery, create a lead-time bias but still requires
Metastatic Osteosarcoma in the
improved specificity and sensitivity (67,68).
German–Swiss–Austrian Cooperative
Osteosarcoma Study Group Clinical
Trials
Page 203
Figure 10.6 John Hunter (1728–1793) was an extraordinary surgeon, anatomist, teacher,
and collector. His magnificent collection of scientific specimens was purchased by
Parliament and placed in the custody of the Company of Surgeons, renamed the Royal
College of Surgeons in 1800. These illustrations of osteosarcoma, taken from the Hunterian
Museum, Lincoln’s Inn Fields, London, appear by permission of the president and council of
the Royal College of Surgeons of England. In November 1786, Hunter encountered a patient
with “a hard swelling of the lower part of the thigh, as it were beginning from the knee …
the part began evidently to enlarge … and was attended with more pain as it enlarged …
and the pain was now exhausting him much.” An amputation was done. Hunter described an
“osteoid sarcoma” of the distal femur (A) and also noted the intramedullary spread of the
tumor: “A short distance below the site of amputation there is a second hemispherical tumor
in the medullary canal … above the main growth, the disease having extended within the
canal, in this case, for an unusual distance beyond the limits of the external swelling.” Four
weeks after the amputation, the patient “began to complain of a difficulty in breathing, but
not attended with the least pain … he began to lose his flesh and sink gradually, his breathing
being more and more difficult … he died; living only 7 weeks after the operation.” On
autopsy, “bony tumors were found in the cellular membrane of the lungs, upon the
pericardium, and some very large ones of the pleura, adhering to the ribs, and upon the
anterior surface of the vertebrae of the back” (B & C). Hunter noted that “when the leg was
amputated he had not the least symptom of any disease in the chest” but deduced that the
lung metastases “had taken place a considerable time before the symptoms took place.” As
for the osteoid appearance of the tumor, Hunter wrote that “one can figure to themselves a
reason why the tumor which formed on the outer surface of the thigh-bone might become
bony, because it might acquire that disposition from the bone it surrounded but, from these
tumours formed in the chest becoming bone, shows it was the nature of the tumours
themselves.” The remaining figure (D) is “the osseous part of an osteosarcomatous tumor”
from “the rib of a Horse” from Hunter’s collection. (Descriptions of this material are found in
Descriptive catalog of the pathological series in the Hunterian Museum of the Royal College
of Surgeons of England. Edinburgh and London: E. & S. Livingstone, 1972; Part I:133–138; Part
II:75–77. Biographical material is from Allen E. Hunterian Museum [pamphlet], Royal College
of Surgeons, 1974.)
Several variables must be considered when one uses metastasectomy for pulmonary
metastases. These include the aggressiveness of the proposed operation, whether they are
unilateral or bilateral, the interval between the development of the metastases and the
treatment of the primary, the extent of vascular invasion, the presence or absence of hilar
ly mph node involvement, and whether additional salvage chemotherapy is available after
surgery (44,55,69). Thoracoscopic assisted procedures may be hampered by limited ability
to palpate the tissues for complete assessment of the lung tissues (70).
Bielack et al. (44) reviewed the outcomes of 249 consecutive patients with second and
subsequent recurrences of osteosarcoma. With mainly chemotherapy and surgery, the 5-
y ear overall and event-free survival rates were 32% and 18% for second, 26% and 0% for
third, 28% and 13% for fourth, and 53% and 0% for fifth recurrences, respectively. The role
of the bony metastasectomy is not well defined, undoubtedly because the occurrence of
bony metastases in the setting of potentially salvageable osteosarcoma is far less common
than that of pulmonary metastases (55).
Page 207Some patients with unresectable osteosarcomas are treated with conventional
external beam irradiation. The COSS described a series of patients with osteosarcoma of the
spine who were treated with intralesional or marginal resections and also received photon
irradiation, neutron beam treatment, or samarium. In the analy sis of patients who underwent
either incomplete surgery or no surgery, 7 received postoperative irradiation and 10 did not.
The seven patients who received irradiation had a slightly higher long-term survival than
those who did not, 50% versus 10%, respectively (p = 0.059) (95).
In 2003, COSS investigators described a group of patients with pelvic osteosarcomas
treated between 1979 and 1998. Of 30 patients with intralesional surgery or no primary
surgery, 11 received radiotherapy (65–68 Gy with photons, two were treated with neutrons,
and one also received 153Sm). The 5-y ear overall survival of the irradiated patients (16%)
was superior to that of those not irradiated (0%, p = 0.0033) (58).
Machak et al. (96) reported a retrospective review of 31 patients with limb osteosarcoma
who refused definitive surgery and were treated with cis-platinum, doxorubicin (IV or IA), or
both. All patients received 40–68 Gy at 2.5–3 Gy per fraction, one fraction per day, or 1.25–
1.5 Gy twice daily. With a median follow-up of 39 months, the predicted 5-y ear overall
survival was 61%. Local progression-free survival was 56% (40% for 50 Gy or less, 77% for
more than 50 Gy ). There were five fractures, one skin necrosis, and one osteomy elitis. It is
conceivable that use of neoadjuvant radiotherapy with chemotherapy increased the
proportion of good responders of the time of surgery.
Hirano et al. (61) from Nagasaki University sandwiched 30 Gy (2–3 Gy per fraction) in
the midst of preoperative chemotherapy in 15 patients with osteosarcoma. Histology of the
resected specimens showed a tumoricidal effect in nine patients and a lesser effect in three.
Wagner et al. (78) used a combination of short-course preoperative irradiation (19.8
Gy ), surgical resection, intraoperative 90Y plaque brachy therapy to at-risk areas of the dura
when applicable, and postoperative irradiation with sequential cone-downs to 50.4–58.2 Gy
(total 70.2–77.4 Gy ) to treat bone tumors mainly involving the spine and pelvis. For patients
with osteosarcoma, the 5-y ear local control, disease-free survival and overall survival were,
respectively, 75%, 50%, and 67%.
Dincbas et al. (97) showed that preoperative radiation therapy (usually 35 Gy in 10
fractions) and preoperative chemotherapy (three courses) allowed successful limb-sparing
surgery in 44 out of 46 patients. Tumor necrosis rate was >90% in 87% of patients, and 5-
y ear local control rate was 97.5%. The overall 5-y ear survival rate was 44%.
Maxilla and Mandible
Some surgeons believe that a wide surgical excision of osteosarcoma of the maxilla or
mandible is risky because of the functional consequences. Local recurrence and death after
intralesional resection or resection with a positive margin are ty pical (98,99). Chambers and
Mahoney reported 33 patients treated with preoperative brachy therapy. Implantation was
accomplished by drilling holes in the mandible and placing radium needles. The dosage was
100–160 Gy. Wide surgical excision of the involved hemimandible and adjacent soft tissue
was performed 2–4 weeks after irradiation. Out of 11 children, 10 were long-term survivors
with follow-up from 4 to 15 y ears (100). Suit reported additional three cases (two of the
mandible and one of the maxilla) locally controlled with a similar technique (49,101). Heroic
brachy therapy is rarely necessary in modern practice. With radical surgical resection of the
tumor, followed by reconstruction, local control of facial bone osteosarcoma is to be
expected (102).
Lung
Historically, the propensity of osteosarcoma to metastasize to the lungs stimulated interest in
the use of prophy lactic lung irradiation (Table 10.8 ). The fundamental problem with
thoracic irradiation is that pulmonary tolerance may be exceeded before necessary
tumoricidal dosages are achieved (108). Abbatucci et al. (109), working from radiobiologic
principles, showed that the exponential kill of clonogenic cells produced by fractionated
radiotherapy, in principle, could eradicate subclinical metastases in a highly oxy genated lung.
Visible tumor deposits, detectable on chest radiograph, measure 6–10 mm in diameter and
contain 108–109 cells. If one assumes that the dosage needed to reduce the number of viable
clonogenic cells in a tumor to 10% (D10) is 4 Gy for osteosarcoma, then 20 Gy of
fractionated irradiation should be able to prevent the growth of metastases containing 104 or
105 cells. However, more recent experiments on canine osteosarcoma cell lines showed that
the cells were relatively radio-resistant with a survival fraction at 2 Gy to be 0.62 and a mean
alpha–beta ratio of 3.5 (105). Breur (110,111) analy zed 13 patients with microscopic
pulmonary metastasis and extrapolated backward in time, showed that about 1 in 4 patients
with subclinical metastasis had tumors containing about 105 cells. In principle, these small
metastatic deposits would be curable by adjuvant pulmonary irradiation. This argument has
been criticized by Baeza et al. (112).
Table 10.8 Prophylactic Lung Irradiation in the Treatment of Osteogenic Sarcoma
Chemotherapy
For many y ears, it was accepted that the long-term survival of patients with osteosarcoma
treated with radical surgical ablation alone was approximately 20%. A 1978 M. D. Anderson
Cancer Center trial used cy clophosphamide, vincristine, melphalan, and doxorubicin and
achieved a 2-y ear survival rate of 50% (133). Subsequent pediatric trials from M. D.
Anderson used the T7 protocol of preoperative intra-arterial cis-platinum, surgery, and
postoperative programs of doxorubicin, methotrexate, cis-platinum, and cy clophosphamide in
various combinations. Patients undergoing limb salvage had a 58% 110-month disease-free
survival. Patients undergoing amputation had a 54% disease-free survival (difference not
significant). Optimum survival (80%) was found in patients with more than 90% tumor
necrosis, induced by the preoperative chemotherapy, at the time of amputation. Survival was
also correlated with smaller primary tumor volumes (134). Patients with a poor histologic
response had a 33% disease-free survival rate (48,135).
In a separate report from the M. D. Anderson group covering the y ears 1979–1982,
reporting 37 patients of the age of 16 y ears or older with extremity lesions, preoperative
doxorubicin and intra-arterial cis-platinum were followed postoperatively by the same drugs.
Patients who suffered cis-platinum toxicity received dacarbazine as a substitute (136).
Based on these results, the T7 protocol was modified by the use of cis-platinum,
doxorubicin, bleomy cin, cy clophosphamide, and dactinomy cin in the postoperative period.
This was called the T10 protocol (135). Sixty additional patients, treated from 1983 to 1988,
received intensified preoperative intra-arterial cis-platinum. Postoperatively, complete
responders received doxorubicin and cis-platinum (or dacarbazine), and partial or poor
responders were changed to an alternating program of methotrexate, doxorubicin, or
dacarbazine, and bleomy cin, cy clophosphamide or actinomy cin. Patients treated from 1979
to 1982 had a 54% 5-y ear disease-free survival. Those treated from 1983 to 1988 had a 69%
3-y ear disease-free survival (134).
In an attempt to confirm the preliminary good results of the T10 protocol, the Children’s
Cancer Group (CCG) undertook a single-arm trial of neoadjuvant chemotherapy that based
the postoperative therapy on the histologic response of the preoperative chemotherapy. The
protocol, CCG-782, accrued 268 patients with nonmetastatic osteosarcoma of the extremity
between 1983 and 1986. Preoperative chemotherapy consisted of four courses of high-dose
methotrexate and one course of bleomy cin, cy clophosphamide, and dactinomy cin. Good
histologic responders (i.e., those with less than 5% residual viable tumor) were treated
postoperatively with methotrexate, bleomy cin, cy clophosphamide, dactinomy cin, and
doxorubicin. Poor histologic responders were treated with bleomy cin, cy clophosphamide,
dactinomy cin, doxorubicin, and cis-platinum. The 8-y ear event-free survival was 53%. The
overall survival rate was 60%. Good histologic responders had an 8-y ear postoperative event-
free survival rate of 81% and a survival rate of 87%, whereas those with a poor histologic
response had an 8-y ear postoperative event-free survival of 46% and a survival rate of 52%
(88).
Pratt et al. (137) from St. Jude Children’s Research Hospital, in studies open from 1973 to
1981, reported 76 patients who received doxorubicin, cy clophosphamide, and methotrexate at
two different dosage levels after amputation. The actuarial 10-y ear survival was 46% and
56% for two chemotherapy protocols, compared with 18–25% for historic controls who
received ineffective or no chemotherapy after amputation (p < 0.001).
Sequential chemotherapy trials were conducted at New York’s Memorial Sloan-Kettering
Cancer Center from 1976 to 1986. Patients received preoperative high-dose methotrexate
with leucovorin rescue (some patients were randomized to additionally receive vincristine)
and postoperative cy clophosphamide, bleomy cin, doxorubicin, and actinomy cin D. In recent
y ears, patients who had a poor response to methotrexate received doxorubicin and cis-
platinum. The 10-y ear survival of 279 patients was 73%. As in the M. D. Anderson studies
and other series, histologic response of the primary tumor to neoadjuvant chemotherapy was
an important predictor of survival (83,85,90,103,136,138,139,140,141,142).
Page 211The apparent successes of adjuvant chemotherapy trials were challenged by a
research team at the May o Clinic. This group suggested that there might be a change in the
natural history of osteosarcoma. Whereas the May o Clinic noted a 20% survival rate from
ablative surgery in patients treated from 1963 to 1965, a comparable group treated from 1972
to 1974 without chemotherapy had a 50% overall survival rate (38). A randomized
prospective trial reported by the May o Clinic Group showed that high-dose methotrexate as
adjuvant therapy, in comparison to no chemotherapy, offered no benefit: survival in both
groups was 52% (136,143,144,145).
Two randomized prospective trials attempted to resolve the argument over the value of
adjuvant chemotherapy. The University of California at Los Angeles (UCLA) trial
randomized 59 patients with nonmetastatic osteosarcoma. All patients received preoperative
doxorubicin. Thirty -two patients were randomized to receive adjuvant postoperative high-
dose methotrexate, doxorubicin, bleomy cin, cy clophosphamide, and actinomy cin D.
Twenty - seven patients received no adjuvant chemotherapy. Of the patients who received
adjuvant chemotherapy, 55% remained disease free at a median of 2 y ears after excision of
the primary tumor. Of the patients who received no adjuvant chemotherapy, only 20%
remained free of disease (p < 0.01). Of 18 control patients treated before the trial, the overall
disease-free survival was not significantly different from that of the 27 randomized control
patients treated without chemotherapy from 1981 to 1984. Overall survival for randomized
patients did not differ significantly between the two arms (140). When the larger group of
patients who chose their therapy was combined with the randomized group, there was a
significant overall survival benefit favoring chemotherapy at 6 y ears.
Link et al. (85,146,147,148) reported a randomized chemotherapy trial involving 36
patients. At 2 y ears, the actuarial relapse-free survival was 17% in the control group and 66%
in the group receiving adjuvant cy clophosphamide, bleomy cin, actinomy cin, methotrexate
with leucovorin rescue, doxorubicin, and cis-platinum (p < 0.001). A similar benefit to
chemotherapy was observed among 77 patients who declined to undergo randomization but
elected observation or chemotherapy.
The long-term results of the COSS-86 protocol included 171 eligible patients; 128 patients
were stratified into the high-risk group. “Low risk” was defined as a tumor length of less than
one-third of the involved bone, less than 20% chondroid brown substance in the biopsy
specimen, and more than 20% reduction of early - or late-phase activity in sequential bone
scans. Other patients were considered to be at high risk. Doxorubicin, high-dose methotrexate,
and cis-platinum were given to all patients. Patients who met one of the high-risk criteria
received early sy stemic treatment intensification with ifosfamide added as a fourth agent.
Postoperatively, the high-risk patients received cis-platinum intra-arterially or intravenously.
In the total group of 171 patients, which included the high- and low-risk patients, overall event-
free survival rates at 10 y ears were 72% and 66%, respectively. No benefit from intra-
arterial cis-platinum was seen (93).
A randomized trial of two chemotherapy regimens in operable osteosarcoma was
conducted by the European Osteosarcoma Intergroup and reported in the Lancet in 1997.
Patients with operable, nonmetastatic osteosarcoma were randomly assigned to receive
doxorubicin and cis-platinum preoperatively or alternatively vincristine, methotrexate, and
doxorubicin preoperatively and bleomy cin, cy clophosphamide, dactinomy cin, vincristine,
methotrexate, doxorubicin, and cis-platinum postoperatively. Of the 407 randomized patients,
391 were eligible and were followed up for at least 4 y ears. The proportion showing more
than 90% tumor necrosis in response to preoperative chemotherapy was about 29% in both
regimens and was a strong predictor for survival. Overall survival was 65% at 3 y ears and
55% at 5 y ears in both groups. Thus, there was no difference between the two-drug and
multidrug regimens. The two-drug regimen was shorter in duration and better tolerated (87).
A trial by the Children’s Oncology Group (COG) randomized patients to one of four
arms: a three-drug regimen (cis-platinum, doxorubicin, methotrexate), a four-drug regimen
(cis-platinum, doxorubicin, methotrexate, ifosfamide), the three-drug regimen plus muramy l
tripeptide (MTP), and the four-drug regimen plus MTP (94). The addition of ifosfamide did
not enhance event-free survival or overall survival. The addition of MTP significantly
improved 6-y ear overall survival (from 70% to 78%) and resulted in a trend toward better
event-free survival. COG, COSS, EORTC/the Medical Research Council (MRC), and
Scandinavian Sarcoma Group (SSG) have completed a Phase III trial to optimize treatment
strategies for resectable osteosarcoma based on histologic response to preoperative
chemotherapy. The induction chemotherapy was with methotrexate, doxorubicin, and cis-
platinum (MAP). Randomization occurs after surgery and assessment of histologic response.
Patients with good histologic response are randomized to receive either MAP or MAP +
ifosfamide (MAPifn) and etoposide. Patients with poor histologic response are randomized to
receive either MAP or MAP + pegy lated interferon alfa-2b (MAPIE). Results of this study
are not available y et. Additional completed efforts to evaluate trastuzumab or inhaled GM-
CSF in patients with metastatic osteosarcoma have not provided any survival benefit
(149,150).
In Table 10.7 , we summarize studies by several cooperative groups. The data
indicate that surgery plus modern chemotherapy should achieve a 60–70% 5-y ear event-free
survival (Figs. 10.7 and 10.8 ). It is not clear that neoadjuvant chemotherapy is superior
to postoperative chemotherapy.
Figure 10.7 A Kaplan–Meier survival curve for patients in two consecutive trials of the
European Osteosarcoma Intergroup shows improved survival for patients with at least 90%
necrosis after preoperative chemotherapy (p < 0.01 with one degree of freedom). (From
Hauben EI, Weeden S, Pringle J, et al. Does the histological subtype of high-grade central
osteosarcoma influence the response to treatment with chemotherapy and does it affect
overall survival? A study on 570 patients of two consecutive trials of the European
Osteosarcoma Intergroup. Eur J Cancer. 2002;38(9):1218–1225, with permission.)
Figure 10.8 Overall survival for patients with localized disease, compared with those with
metastases at diagnosis, in patients treated on Cooperative German–Austrian–Swiss
Osteosarcoma Group protocols. (From Bielack S, Kempf-Bielack B, Delling G, et al.
Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of
1702 patients treated on Neoadjuvant Cooperative Osteosarcoma Study Group protocols. J
Clin Oncol. 2002;20:776–790, with permission.)
Figure: Local Recurrence Rates for
Osteosarcoma as a Function of the Extent of
Surgery
Figure: Factors Predicting Event-Free
Survival in Patients with Primary Metastatic
Osteosarcoma in the German–Swiss–
Austrian Cooperative Osteosarcoma Study
Group Clinical Trials
Figure:
John Hunter (1728–1793) was an extraordinary surgeon, anatomist, teacher, and collector.
His magnificent collection of scientific specimens was purchased by Parliament and placed
in the custody of the Company of Surgeons, renamed the Royal College of Surgeons in 1800.
These illustrations of osteosarcoma, taken from the Hunterian Museum, Lincoln’s Inn Fields,
London, appear by permission of the president and council of the Royal College of Surgeons of
England. In November 1786, Hunter encountered a patient with “a hard swelling of the lower
part of the thigh, as it were beginning from the knee … the part began evidently to enlarge
… and was attended with more pain as it enlarged … and the pain was now exhausting him
much.” An amputation was done. Hunter described an “osteoid sarcoma” of the distal femur
(A) and also noted the intramedullary spread of the tumor: “A short distance below the site
of amputation there is a second hemispherical tumor in the medullary canal … above the
main growth, the disease having extended within the canal, in this case, for an unusual
distance beyond the limits of the external swelling.” Four weeks after the amputation, the
patient “began to complain of a difficulty in breathing, but not attended with the least pain
… he began to lose his flesh and sink gradually, his breathing being more and more difficult
… he died; living only 7 weeks after the operation.” On autopsy, “bony tumors were found in
the cellular membrane of the lungs, upon the pericardium, and some very large ones of the
pleura, adhering to the ribs, and upon the anterior surface of the vertebrae of the back” (B &
C). Hunter noted that “when the leg was amputated he had not the least symptom of any
disease in the chest” but deduced that the lung metastases “had taken place a considerable
time before the symptoms took place.” As for the osteoid appearance of the tumor, Hunter
wrote that “one can figure to themselves a reason why the tumor which formed on the outer
surface of the thigh-bone might become bony, because it might acquire that disposition from
the bone it surrounded but, from these tumours formed in the chest becoming bone, shows it
was the nature of the tumours themselves.” The remaining figure (D) is “the osseous part of
an osteosarcomatous tumor” from “the rib of a Horse” from Hunter’s collection.
(Descriptions of this material are found in Descriptive catalog of the pathological series in the
Hunterian Museum of the Royal College of Surgeons of England. Edinburgh and London: E. & S.
Livingstone, 1972; Part I:133–138; Part II:75–77. Biographical material is from Allen E.
Hunterian Museum [pamphlet], Royal College of Surgeons, 1974.)
Figure: The Cade Technique: Management
of Osteosarcoma with Primary Irradiation or
Primary Irradiation and Selected Delayed
Amputation (Excluding Parosteal Tumors)
Figure: Significant Recent Cooperative
Group Trials Addressing the Management of
Localized Osteosarcoma
Figure: Prophylactic Lung Irradiation in the
Treatment of Osteogenic Sarcoma
Figure:
A Kaplan–Meier survival curve for patients in two consecutive trials of the European
Osteosarcoma Intergroup shows improved survival for patients with at least 90% necrosis
after preoperative chemotherapy (p < 0.01 with one degree of freedom).
(From Hauben EI, Weeden S, Pringle J, et al. Does the histological subtype of high-grade
central osteosarcoma influence the response to treatment with chemotherapy and does it
affect overall survival? A study on 570 patients of two consecutive trials of the European
Osteosarcoma Intergroup. Eur J Cancer. 2002;38(9):1218–1225, with permission.)
Figure:
Overall survival for patients with localized disease, compared with those with metastases at
diagnosis, in patients treated on Cooperative German–Austrian–Swiss Osteosarcoma Group
protocols.
Dosage
Osteosarcoma has a reputation of being radio-resistant. This reputation is unjustified. Because
radiotherapy was formerly used to treat bulky tumors, it is no surprise that local failures were
common. The D0 values of human and rodent osteosarcoma cell lines are reported to be
similar to those of most other mammalian tumors, perhaps with a higher D0 (77,151).
Page 213Canine osteosarcoma has been treated with a variety of dosage and
fractionation schemes including 8 Gy three times at 0, 7, and 21 day s and 8 Gy four times at
0, 7, 14, and 21 day s. Radiotherapy is generally used to palliate the dog’s pain and
dy sfunction. High response rates are achieved, albeit with short follow-up, because most
animals are euthanized for metastatic disease (77).
In a dose–response study of patients treated with the Cade technique, Gaitan–Yanguas
produced uniform tumor sterilization with dosages of 80–100 Gy and alway s found persistent
tumor at 50 Gy or less (74). Phillips and Sheline (77) found viable tumor in 1 of 10 patients
receiving less than 100 Gy and in 2 of 7 patients receiving at least 100 Gy (77).
Lombardi et al. (152) administered 36 Gy at 6 Gy per fraction, with three fractions per
week for 2 weeks to 21 osteosarcoma sites irradiated for palliation in 14 patients. There was a
clinical response (disappearance of pain, decrease in tumor size, improvement in function) or
radiologic response at 18 of the 21 sites. Of eight primary sites irradiated because of
sy nchronous metastases, all showed a clinical or radiographic response. In five patients,
radiotherapy was given where preoperative chemotherapy had not rendered the patient
suitable for limb-sparing surgery. Surgery after radiotherapy revealed 95–100% tumor
necrosis in all cases. Limb-sparing surgery was performed in three of five cases, but because
of infectious complications related to soft tissue damage, all limbs were amputated
eventually.
Caceres et al. (138) from Peru gave 60 Gy in 6 weeks to 15 patients in conjunction with
chemotherapy. Post radiotherapy biopsy showed no evidence of active tumor in 12 of 15
(80%) patients. The whole specimen was studied, because of amputation or autopsy, in five
patients. No viable tumor was found. Complications were common, including pathologic
fracture, soft tissue fibrosis or necrosis, local infection, and moist desquamation. The degree
of tumor necrosis seen by Caceres et al. (72) is inconsistent with an earlier report from the
same group of less impressive tumor destruction after 80–120 Gy at 10–12 Gy per fraction
(Table 10.6 ). If radiotherapy is to be used alone as definitive treatment for a small (less
than 5 cm) osteosarcoma in an unresectable location such as the base of skull or vertebral
body, or if a patient refuses surgery, the dosage should be as high as normal tissue tolerance
allows, that is, 60–75 Gy at conventional fractionation with progressive shrinking-field
technique (153,154).
When radiotherapy is used for prophy lactic treatment of the lungs, the dosage is 13.5–
19.5 Gy at 1.5 Gy per fraction. These dosages generally have been reported without lung
correction factors being applied (35,106,107,155).
Volume
The treatment volume is determined by plain radiographs, bone scan, CT, MRI, and FDG-
PET scans if available. It is customary to define the tumor volume based on the largest
volume of these studies (the “worst-case volume”). A margin is then allowed.
Prophy lactic WLI is directed to the entire substance of the lung. Particular attention must
be paid to coverage of the apices of the lung and to the areas of the lung that curve over the
surfaces of the diaphragms, which can be identified with CT-based radiation planning.
Technique
An immobilization device is generally needed. The field should be contoured specifically to
the anatomic problem for the individual patient. In most cases, multiple fields are used. To
maintain a functional limb after irradiation, a strip of skin should be spared, and one should
avoid high-dose irradiation to the full width of the joint.
Some investigators have attempted to improve the local control rates of osteosarcoma by
altering tumor and normal tissue oxy genation. Of historical interest, the tourniquet technique
attempted to produce anoxia in both tumor and normal limb tissues to remove any advantage
the tumor might gain from hy poxic areas. Using this technique, patients received fractionated
irradiation up to total dosages of 75–160 Gy. In patients who were long-term survivors, the
functional result was poor (79,141). One group reported local response rates of
approximately 70% and reasonable limb function with tourniquet anoxia and high-dose-per-
fraction treatment (i.e., three doses of 25 Gy ). Radiation treatment under hy perbaric oxy gen
conditions was also investigated (79). A group of investigators from Stanford University
reported a series of patients who had unresectable osteosarcomas or who refused amputation,
treated with 42–48 Gy at 6 Gy per fraction, one fraction every 5 day s, and pulsed 5′ -
bromodeoxy uridine infused as a radiosensitizer (156). Local control was achieved in seven of
nine patients, four of whom were long-term survivors. Significant soft tissue injury occurred
in five patients (82).
Neutron Therapy
Neutrons are a form of high linear energy transfer radiation. They offer several advantages
over conventional photon or electron radiotherapy. First, neutrons are better able to kill
hy poxic cells than photons. The oxy gen enhancement ratio for neutrons is of the order of 1.6,
compared with 2.5–3.0 for photons. Second, repair of radiation-induced sub-lethal and
potentially lethal damage is less readily accomplished after neutron irradiation than after
conventional irradiation. Thirdly, neutrons are toxic throughout the phases of the cell cy cle
(M, G1, S, G2), whereas photons are more toxic in late G2/M (157,158).
Kubota et al. (151) compared the biologic effects of 13-MeV neutrons with those of
137Cs gamma ray s in MG-63 human osteosarcoma cells in plateau phase growth and in
multicellular spheroids. The relative biologic effectiveness varied slightly with the
measurement technique but was in the range of 1.9–2.29. If one accepts the assertion that
osteosarcomas are rapidly growing tumors with areas of necrosis and potentially hy poxic
areas, then one might conclude that these tumors would be more effectively irradiated by
neutrons.
There is a small clinical experience with the use of neutrons for local control of
osteosarcomas. Many of the patients treated had inoperable tumors or refused amputations
(159). The results of neutron treatment are shown in Table 10.9 . The 77 patients cited have
an overall local control rate of 44 of 77 (58%). Clearly, there are risks from combining the
results of 11 series to draw a conclusion. The local control rates of the individual series range
from 0% to 100%, and these series include patients with tumors at a variety of locations.
Dense fibrotic reactions can occur after neutron treatment, leading to severe complications
and, in some patients, to amputation (163,164). For a patient with osteosarcoma who refuses
definitive surgery or is medically or technically inoperable, it is reasonable to consider the
use of neutrons. However, part of the informed consent for such treatment must include a
discussion of the potential for serious late ill effects of such treatment.
Page 214
Table 10.9 Literature Review of the Local Control Rates for Osteosarcomas after
Neutron Therapy
Figure 10.9 Proton radiation dose distributions for a large pelvic osteosarcoma. Note the
sparing of most pelvic organs and the contralateral pelvic bones (bone marrow).
Radioisotope Therapy
Bone-seeking radiopharmaceuticals are at an early stage of investigation in the treatment of
osteoblastic osteosarcoma. The uptake of radiopharmaceuticals in adult skeletal metastatic
lesions such as breast and prostate cancer results from an osteoblastic response in the normal
bones surrounding the metastases. However, osteosarcoma often produces bone matrix within
the target. A radioisotope that hones into bone and gives off radioactivity for a sufficiently
long period of time may produce a therapeutic benefit.
Samarium-153 ethy lene diamine tetramethy lene phosphonate is a bone-seeking
radiopharmaceutical. It is produced by neutron capture from 153Sm to y ield a radioisotope
of high purity that has both a medium-energy beta emission for therapeutic purposes and
gamma emission, which is useful for conventional gamma camera scintigraphic imaging.
Compared with technetium-99m methy lene diphosphonate preparations, which are used for
routine bone imaging, 153Sm has comparable or better bone–blood and bone–muscle ratios.
Because of these favorable bone-seeking characteristics, 153Sm has been used for palliative
treatment of bone metastases (173).
Page 216In pilot studies of the use of 153Sm to irradiate patients with osteosarcoma and
bone metastases, all patients receiving high-dose samarium experienced severe
pancy topenia: some requiring transfusions and even stem cell infusion. It appears that
samarium treatment can reduce bone pain in some patients, albeit with significant toxicity.
There also appears to be one long-term survivor, a patient with a large pelvic osteosarcoma
and multiple primary pulmonary metastases who was treated with external beam
radiotherapy to the pelvic lesion, multiagent chemotherapy, and samarium
(174,175,176,177).
Fourteen patients with metastatic, unresectable, progressive, and/or recurrent
osteosarcoma received high-dose 153Sm (30 mCi/kg) and gemcitabine chemotherapy and
peripheral stem cell rescue (178). Indicator lesions were improved on imaging in 8 of 14
patients, and alkaline phosphatase decreased in 6 of 8 patients. The investigators noted
temporary ly mphopenia but did not find significant nephrotoxicity or hemorrhagic cy stitis.
One patient with multiple lung metastases developed life-threatening pulmonary hemorrhage.
223Ra is a bone-seeking alpha particle emitting radioisotope that has been used for
osteoblastic lesions from prostate cancer and now is being evaluated metastatic osteosarcoma
and possesses characteristics similar to calcium (179,180).
Palliation
It is reasonable to consider radiotherapy to
palliate painful bony sites and treat spinal cord
compression (Fig. 10.10 ) (65,80,153,181).
Unfortunately, the literature documenting the
palliative efficacy of radiotherapy in
osteosarcoma is sparse. The 1964 report by Lee
and MacKenzie of the Westminster Hospital,
London, describes the results with the
administration of 7000–8000 R with a 2-MeV
Van de Graaff electrostatic generator. The
authors note “clinical response of the tumor was
very variable. Sometimes, there was apparent
worsening: there might be sudden increase in the
size of the tumor, with more pain. Such changes
might be the result of hemorrhage, or fracture,
or disintegration of bone. More often, there was
a gradual reduction of pain and swelling, starting
after some 2000 R (sometimes much later) and
continuing for several weeks after completion of
treatment” (80). In 1975, de Moor (182) from
Johannesburg described the use of radiation for
palliation and noted that “pain relief or reduction
in swelling was experienced generally, and often
within the first 2–3 weeks of treatment” (Fig.
10.10 ).
The series of Beck et al. (183) from the
University of California at San Francisco Figure 10.10 When osteosarcoma
included 44 patients with adequate information metastasizes to bone, radiotherapy may
“to assess whether the treatment represented be used for palliation. This 9-year-old boy
even a short-term subjective gain for the patient. presented with osteosarcoma of the left
In 19 patients (43%), there was definite
palliation. Twenty - five patients (57%) had either femur. Bone metastases were diagnosed
no change or worsening of sy mptoms. Those a year and a half after the primary tumor
who survived experienced relief only after was identified. When the child
surgery.” These authors used conventionally complained of pain in the spine, both MRI
fractionated radiation with total dosages ranging and bone scan identified metastatic
from 50 to 80 Gy. In contrast, Lombardi et al. disease in conjunction with pulmonary
(152) administered 6 Gy three times per week metastasis. For spinal cord compression,
for a total of 36 Gy in six fractions over 2 weeks. palliative radiation therapy was
In 14 patients with 21 evaluable sites, there was a administered.
clinical response in 18%.
Machak et al. (96) reported on 31 patients treated with curative intent with
chemotherapy ; they reported “a clinical response and limb function restoration” in 24 of the
31 (77%) patients but a good imaging and biochemical response in only 11. Of the 20
nonresponders, 15 (75%) improved after radiotherapy, supporting a palliative role for
radiotherapy.
Mahajan et al. (34) reported a series of 39 patients with metastatic and/or recurrent
osteosarcoma who were treated with radiation therapy (median dose 30 Gy in 10 fractions)
and concurrent chemotherapy (most commonly ifosfamide or methotrexate). Subjective
improvement occurred in 76% of painful sites. Sustained reduction of standard uptake vales in
positron emission tomography (PET)-CT scans or bone scans occurred in 72% of the patients.
In this report, the actuarial 4-y ear survival from the development of metastasis was 39%.
Thus, a substantial number of patients could have their painful bony sites palliated with a
combination of short-course radiation and concurrent chemotherapy.
Treatment
The primary treatment for chordomas is surgery. Postoperative radiation therapy is
generally necessary to reduce recurrence. In adults, the results of proton therapy appear
better than that of photon therapy, probably because of the higher radiation dose delivered. In
children, a small series reported 60% local
control after passive-scattered proton therapy to
doses ranging from 50.4 to 78.6 CGE (185).
Another small series using scanning proton
therapy to 74 CGE reported no recurrence after
a median follow-up time of 36 months (186).
Late side effects including neurologic deficits
and pituitary insufficiency have been reported in
up to 30% of the patients. A small series of
children and y oung adults with skull base
chordomas treated with carbon ion radiotherapy
has been reported (187). With a median follow-
up of 49 months, one out of seven patients with
chordomas recurred. Rombi et al. (188) reported
their experience on 26 children with skull base
tumors treated with proton therapy at the Paul
Scherrer Institute. Nineteen patients had
chordoma and 5-y ear local control and overall
survival rates were 81% and 89%, respectively,
after a mean dose of 74 Gy RBE. The value of
chemotherapy is unclear; however, some groups
have reported stability of disease with imatinib
and sorafenib (189,190,191). Brachy ury, a
nuclear transcription factor, is a strong mediator
of the epithelial to mesenchy mal transition and is
overexpressed in chordoma. A recombinant
vaccine encoding brachy ury activates human T
cells. This vaccine is being tested in a phase 1
study in patients with progressive chordoma with
encouraging preliminary results (192).
Page 218Surgery is also the primary Figure 10.11 Histopathology of
treatment for chondrosarcomas. Completely chordoma. Note the physaliferous cells
resected grade I chondrosarcomas do not need (A) and the triad of positive
adjuvant treatment. Postoperative radiation immunohistochemical stains for keratins,
therapy is usually offered to patient with higher- EMA (B), and S-100 (C) proteins.
grade or more malignant chondrosarcomas such
as mesenchy mal chondrosarcomas. For skull base chondrosarcomas treated with protons
(scattered or scanning), the local control rates were 70–100% (185,186), and with carbon ion
therapy the local control rate was reported as 100% (187). Mesenchy mal chondrosarcoma is
considered a malignant sarcoma in children. The Cooperative Soft Tissue Sarcoma (CWS)
and Osteosarcoma (COSS) Study Groups of the German Society of Pediatric Oncology and
Hematology (GPOH) reported the result on 50 children and adolescents (median age 16.6
y ears) (193). All tumors were resected; 13 patients received chemotherapy and 6 patients
received radiation therapy. The actuarial 10-y ear event-free and overall survival rates were,
respectively, 53% and 67%. Seven of eight patients whose tumors were completely resected
versus four of seven patients whose tumors were incompletely resected survived disease
free. One patient with local recurrence was salvaged after further surgery and radiation
therapy.
Figure: Literature Review of the Local
Control Rates for Osteosarcomas after
Neutron Therapy
Figure:
Proton radiation dose distributions for a large pelvic osteosarcoma. Note the sparing of most
pelvic organs and the contralateral pelvic bones (bone marrow).
Figure:
When osteosarcoma metastasizes to bone, radiotherapy may be used for palliation. This 9-
year-old boy presented with osteosarcoma of the left femur. Bone metastases were
diagnosed a year and a half after the primary tumor was identified. When the child
complained of pain in the spine, both MRI and bone scan identified metastatic disease in
conjunction with pulmonary metastasis. For spinal cord compression, palliative radiation
therapy was administered.
Figure:
Histopathology of chordoma. Note the physaliferous cells (A) and the triad of positive
immunohistochemical stains for keratins, EMA (B), and S-100 (C) proteins.
REFERENCES
Page 223Rhabdomy osarcoma (RMS) is a highly malignant neoplasm that arises from
embry onal mesenchy me with the potential for differentiating into striated muscle. Although
the cells show differentiation along rhabdomy oblastic lines, RMS is not limited to cells with
recognizable muscle cross-striations (1,2). Weber initially described RMS in 1854, but
progress in our understanding of this complex neoplasm accelerated with Stout’s landmark
descriptive series in 1946 and the delineation by Horn and Enterline in 1958 of the four
classical forms of RMS (3,4,5). RMS can arise almost any where in the body, is locally
invasive, and rapidly disseminates early in its course. Near the beginning of the 20th century,
the only cures were accomplished with radical surgery in the few fortunate children without
metastases. Significant disfigurement and loss of function were common sequelae. High-dose
radiation therapy (RT) increased the potential for local control but caused a different set of
morbidities (6,7). As chemotherapy has become increasingly effective in eliminating
micrometastatic disease and assisting in local control, the need for aggressive surgery and
large-volume irradiation has diminished, although surgery and RT still play pivotal roles in the
curative treatment of RMS (8). Overall survival rates have concomitantly increased from 15–
25% to more than 70% (9,10,11,12).
RMS is a rare tumor with clinical and biologic heterogeneity. Consequently, multi-
institutional trials were necessary to develop and refine treatment approaches. North
American investigators of the Intergroup Rhabdomy osarcoma Study Group (IRSG) have
play ed an important role in this progress, now in its seventh generation of protocols. The
difficulty of this undertaking is clear in view of the my riad sites, stages, and histologies of
RMS which are associated with different natural histories and prognoses (13). Bey ond this,
advances in imaging, changes in end points, and the need for mature data all increased the
difficulty in conducting and comparing randomized, controlled clinical studies of patients with
RMS. With this view, the IRSG was established through the collaboration of three
multidisciplinary cancer treatment study groups (Cancer and Leukemia Group B, Children’s
Cancer Study Group, and the Pediatric Branch of the Southwest Oncology Group, which later
became the Pediatric Oncology Group). Intergroup Rhabdomy osarcoma Study I (IRS-I) was
open for patient entry from 1972 to 1978 (9). With an overall 5-y ear survival rate of 55% in
IRS-I, IRS-II was designed to improve survival for the patient subgroups with poor outcomes
and to refine treatment for the remaining patients (10). IRS-II ran from 1978 to 1984, IRS-III
from 1984 to 1991, IRS-IV from 1991 to 1997; and IRS-V from 1997 to 2005–2006. Although
the previous generations of IRS studies were based on a surgically oriented clinical grouping
sy stem dependent on the tumor that remained after initial surgery, IRS-IV and IRS-V were
based on a more biologically oriented staging sy stem, discussed later in this chapter. These
studies, each based on the results of its predecessor, have provided a database of over 4000
patients. The IRSG studies are now conducted through the Children’s Oncology Group (COG),
the United States-based cooperative research network that formed from the merger of the
Pediatric Oncology Group and the Children’s Cancer Study Group. The first generation of
studies, ARST0331 (low risk), ARST0531 (intermediate risk), and ARST0431 (high risk),
opened in 2005–2006, upon the completion of IRS-V. They were closed in 2012, 2014, and
2010, respectively. New studies are in development for intermediate- and high-risk patients
and patients with relapsed disease. Due to the excellent outcome seen on ARST0331 in low-
risk patients, there is currently not a plan to continue to perform clinical investigations in this
very favorable group of patients (14).
Other multi-institutional group studies have also provided important data (15,16,17,18).
Of particular note are the European-based International Society of Pediatric Oncology
(SIOP) and the United Kingdom-based Children’s Solid Tumor Group (CSTG) (16,17,18).
Finally, many single-institution studies have also been quite informative regarding RMS
(7,8,19,20). Progress in treating RMS is exemplified by the improvement in overall 5-y ear
survival in the IRS studies: 56% in IRS-I, 63% in IRS-II, 71% in IRS-III (Fig. 11.1 )
(9,10,11,12,21,22). Overall survival was 86% in IRS-IV, and in IRS-V, it was 97% for low-risk
patients and 79% for the intermediate-risk patients (23).
Page 224
Figure 11.1 Improvement in 5-year survival of children with RMS treated on the IRS
trials. (From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D,
eds. Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer;
2015.)
Figure:
Improvement in 5-year survival of children with RMS treated on the IRS trials.
(From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds.
Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer; 2015.)
EPIDEMIOLOGY
RMS accounts for about 3.5% of all malignant disease in children y ounger than 15 y ears of
age and 2% of cancer cases among adolescents and y oung adults 15–19 y ears old (24,25).
RMS is the most common soft tissue sarcoma of childhood, representing about half of this
otherwise very heterogeneous group of tumors. The annual incidence of RMS is 4.4 per
million in white children and 1.3 per million in black children. There is a slight male
predominance (1.4:1). Seventy percent of cases occur before the age of 10 y ears, with a
peak incidence at 2–5 y ears of age (Fig. 11.2 ). Congenital anomalies have been identified
in as many as one-third of children with RMS, most commonly involving the gastrointestinal,
genitourinary, cardiovascular, and central nervous sy stems (26).
Figure 11.2 Clinical features of RMS from IRS-I, IRS-II, and IRS-III pooled data. A: Age at
presentation; site of primary tumor (B); clinical group (C); histology (D). (Modified from
Wexler LH, Skapek, SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds.
Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer; 2015.)
Although the majority of cases of RMS occur sporadically, a proportion are associated
with genetic conditions, including the Li–Fraumeni sy ndrome (in which germline mutations of
p53 exist), neurofibromatosis ty pe 1, Costello sy ndrome, Noonan sy ndrome, and Beckwith–
Wiedemann sy ndrome (27,28,29,30). With greater recognition that rhabdomy osarcoma is a
cancer seen in patients with Li–Fraumeni sy ndrome and more frequent testing, this sy ndrome
is being increasingly recognized as an important cause of RMS, particularly embry onal RMS
(31). Some centers are now routinely referring children diagnosed with rhabdomy osarcoma
for genetic counseling and consideration of testing, as Li–Fraumeni sy ndrome has far-
reaching implications for both the child and other affected family members.
Figure:
Clinical features of RMS from IRS-I, IRS-II, and IRS-III pooled data. A: Age at presentation; site
of primary tumor (B); clinical group (C); histology (D).
(Modified from Wexler LH, Skapek, SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack
D, eds. Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer;
2015.)
BIOLOGY
Although the origin and genetics of RMS remain unclear, clinical observations can provide
direction for additional understanding of this tumor. If we can determine the tumor
characteristics that predict radiochemotherapy responsiveness or, conversely, tumor
resistance to therapy and a propensity to disseminate, then we can select the patients in whom
more or less toxic therapy should be used. Moreover, we may devise novel biologic
maneuvers to treat such tumors that minimize normal tissue damage. Reducing the toxicity of
therapy becomes increasingly important as the cure rate continues to improve. Areas in
which progress has been made include the genetic control of my ogenesis, tumor suppressor
genes, and molecular diagnostics (32,33).
Cytogenetics
There are two major histologic subty pes of rhabdomy osarcoma, alveolar and embry onal.
Alveolar RMS is usually characterized by one of two translocations, both of which involve the
FKHR gene on chromosome 13 (32,33). The most common translocation, t(2;13)(p35;q14),
fuses the PAX3 gene, a transcription regulator, to the FKHR transcription factor. This
translocation is present in about 60% of children with alveolar RMS. The less common
translocation, t(1;13)(p36;q14), fuses the PAX7 transcription regulator to FKHR and is
involved in about 20% of cases. This latter translocation seems to occur in y ounger patients
and to be associated with a higher event-free survival rate than the PAX3 gene
rearrangement. Approximately 20% of alveolar RMS do not have either translocation, and
there is evidence that these fusion-negative tumors behave more like embry onal RMS
clinically, with a better outcome than fusion-positive alveolar tumors (34). The specific
translocations (or lack thereof) do not appear to correlate well with histologic features (35). In
the future, monitoring for these fusion products with sensitive techniques such as reverse
transcriptase poly merase chain reaction may be useful for detecting minimal residual
disease during or after treatment and for guiding therapy (36,37).
Page 225Embry onal RMS is often characterized by loss of heterozy gosity at 11p15.5,
suggesting the presence of a tumor suppressor gene (38).
Genomic amplification also differs in alveolar and embry onal RMS. It is rare in
embry onal RMS, whereas gains of whole chromosomes (particularly of chromosomes 2, 8,
12, and 13) and hy perdiploidy are common (39,40,41,42). In alveolar RMS, gene
amplification is common, as is near-tetraploidy.
Proto-oncogenes
The myc gene can contribute to uncontrolled cell proliferation via several pathway s including
insertion mutations, translocations, retroviral transductions, and amplification. Two reports
involving 20 patients showed that 50% of those with alveolar RMS had n-myc amplification, in
contrast to its uniform absence in patients with embry onal RMS (44,45). Impressively, among
the patients with alveolar RMS, n-myc amplification predicted a fatal outcome.
Page 226RMS occurs in any anatomic location where there is skeletal muscle and in some
locations where skeletal muscle is not normally found (Fig. 11.2 ) (10). The most common
locations are the genitourinary sites and the head and neck. Genitourinary sites include the
bladder, prostate, vagina, uterus, urethra, and paratesticular region. Head and neck lesions are
divided into parameningeal sites (nasophary nx, nasal cavity, paranasal sinuses, middle ear
and mastoid region, infratemporal fossa, and ptery gopalatine and paraphary ngeal areas) and
other head and neck sites (parotid region, cheek, masseter muscle, oral cavity, orophary nx,
lary nx, hy pophary nx, scalp, face, and pinna) (49).
RMS commonly presents as a mass with poorly defined margins, but specific
presentations relate to the primary disease site. A mass in the genitourinary sy stem may
cause urinary tract or rectal obstruction. On occasion, the mass may protrude from the
cervix, vagina, or urethra. When the protruding tumor has the gross appearance of a cluster
of grapes, it is called botry oid (grapelike) sarcoma. Prostate and bladder RMS may also have
a botry oid appearance and protrude into the lumen of the bladder. Hematuria, urinary
frequency, or retention with subsequent renal failure may occur. Paratesticular RMS presents
with a mass and may be confused with a hy drocele, incarcerated hernia, or testicular torsion.
In the extremities, RMS often is palpable and causes pain or limits motion. Parameningeal
RMS may present with airway obstruction or a palpable mass. As the tumor grows, it can
erode the base of the skull and cause cranial nerve palsies. Penetration into the brain can
occur and mimic an intracranial mass, with headache, vomiting, and diplopia. RMS of the
cheek or lary nx causes obstruction of the aerodigestive track or a discernible mass; other
sy mptoms or signs referable to the head and neck include hoarseness, poly ps, decreased
hearing, persistent otitis, otorrhea, rhinorrhea, nasal congestion or obstruction, and headache.
Patients with orbital RMS usually present with proptosis, discoloration, or limitation of
extraocular motion. RMS of the trunk can present as a mass simulating a hernia or hematoma,
or causing a classical superior vena cava sy ndrome. In the retroperitoneum, RMS can cause
gastrointestinal discomfort or other mass-related sy mptoms.
Diagnostic Evaluation
The history and phy sical examination should focus on the extent of local disease and the
possible presence of metastases. RMS may extend locally and infiltrate along fascial planes
and into surrounding tissues. Tumor margins are often indistinct. Depending on the site, the
local tumor generally is imaged by some combination of computed tomography (CT) or
magnetic resonance imaging (MRI). Genitourinary RMS often is investigated initially by
ultrasound and barium enema, and voiding cy stourethrogram, cy stoscopy, or pelvic
examination under anesthesia occasionally is indicated. The draining ly mphatics, particularly
in genitourinary and extremity primary sites, are evaluated with CT and often surgery
(50,51). The most common sites of metastases are lung, bone, bone marrow, and locoregional
ly mph nodes (22). Chest CT is the optimal imaging method for lung metastases. A nuclear
medicine bone scan is performed to detect bony metastases but is not reliable in determining
skull base involvement in parameningeal tumors, which is evaluated with CT or MRI. Bone
marrow aspirate and biopsy are performed, and examination of cerebrospinal fluid (CSF)
cy tology is indicated if the tumor is in a parameningeal site (52). MRI is used to evaluate
spinal cord–related sy mptoms. Positron emission tomography (PET) scan is also being used
with increasing frequency and is effective at detecting regional ly mph node involvement and
identify ing distant metastases (53). A recent retrospective review of over 1600 children with
RMS enrolled in Intergroup studies from 1991 to 2004 suggests that about one-third of patients
(those with localized noninvasive embry onal tumors) do not need to undergo bone marrow
and bone scan examinations at diagnosis (54).
Prognostic Features
Histology
Most RMS are soft, fleshy tumors with variation in the extent of both invasion and necrosis.
Immunohistochemical stains, including antidesmin, antivimentin, and anti–muscle-specific
actin, are used routinely to help ascertain the muscle origin of the tumor cells, and the
detection of the muscle regulatory gene MyoD1 may be even more sensitive than desmin
(55).
Four histologic subty pes of RMS are classically described: embry onal, alveolar,
pleomorphic, and mixed (Fig. 11.2 ). However, the lack of agreement in classification
among pathologists and the need to develop a single sy stem that is prognostic prompted
formation of an international panel to devise a new sy stem, the International Classification of
Rhabdomy osarcoma (Table 11.1 ) (56,57,58). Classification on the basis of histologic
features remains a challenge and current COG clinical trials utilize central pathologic review
to ensure uniform pathologic diagnosis since stratification schema and guidelines vary by
histology (59).
Unfavorable: Alveolar
About 20% of children with RMS have the alveolar subty pe that is more common in
adolescents and in tumors involving the extremities, trunk, and perianal and perineal regions.
The alveolar form resembles developing skeletal muscle in the 10- to 20-week-old fetus. The
cells are round, with scanty eosinophilic cy toplasm that is occasionally vacuolated. Cross-
striations are quite rare. The name alveolar is derived from the pattern produced by the
tendency of cells to line connective tissue septa reminiscent of alveoli. Variable arrangement
of trabeculae may cause the tumor cells to be arranged in strands, clefts, sheets, or clusters
(1). The characteristic translocations are discussed in the “Biology ” section earlier in this
chapter. A “solid” variant has been identified, which grows as solid masses of closely
aggregated cells with little or no discernible alveolar arrangement.
Stage
RMS has been staged according to multiple sy stems developed in different institutions or
multi-institutional groups. With the advent of IRS-III, a pretreatment staging sy stem was
developed based on the tumor, node, and metastasis (TNM) sy stem used by the SIOP, which
reflected the disease characteristics at diagnosis (Table 11.2 ). IRS-IV, IRS-V, and the
current COG trials have used this TNM staging sy stem, which incorporates tumor size and
invasiveness (a or b, T1 or T2, respectively ), nodal status, presence of metastasis, and tumor
site. Essentially, stage 1 tumors are in favorable sites. Stage 2 tumors are in unfavorable sites
but are small (less than 5 cm) with negative ly mph nodes. Stage 3 tumors are in unfavorable
sites and are large or with positive ly mph nodes. Stage 4 tumors are at any site, with
hematogenous metastasis. This staging sy stem has been validated with respect to its
relationship to patient outcome (60).
Table 11.2 Tumor, Node, Metastasis Pretreatment Staging Classification
Page 228Group
Implicit in the discussion of the grouping and
staging sy stems is the importance of accurate
identification of prognostic variables. Most of
these variables are interrelated. A wealth of data
support the relevance of the clinical group of the
patient, which in essence is the postsurgical
disease extent at the time chemotherapy is
initiated. The clinicopathologic grouping sy stem
has been used since the first IRS studies (Table
11.3 , Fig. 11.2 ). The clinical group reflects
the absence of microscopic disease (group I,
13% of patients) or presence of microscopic Table 11.3 The IRS Grouping System
disease (group II, 20% of patients), gross disease
(group III, 48% of patients), or metastatic disease (group IV, 18% of patients) (11,21).
Clearly, the clinical group also reflects the disease site (ease of resection) and the biologic
invasiveness of the tumor. Because therapeutic decisions made before study entry affected
the assigned group, this sy stem did not accurately reflect the biology of RMS (60,61,62).
Moreover, the emphasis on surgical reduction of tumor bulk implicit in this sy stem led
surgeons to perform unnecessarily morbid surgeries at inappropriate times. In addition, the
surgical approach was not uniformly applied, which obfuscated interpretation of results (61).
However, data from all of the IRS studies support the utility of the grouping sy stem, and it
continues to be used in conjunction with stage and with careful surgical guidelines in the
current trials that are specific to site of disease (Fig. 11.3 ) (9,10,11,21).
Figure 11.3 Survival by clinical group for all patients treated in IRS-IV. Improved outcome
was seen in group II compared with group I and presumably due to undertreatment of select
patients with group I disease. (From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma.
In: Pizzo P, Poplack D, eds. Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia,
PA: Wolters Kluwer; 2015.)
Primary Site
The primary site is a strong determinant of outcome, as verified by data from IRS-II and
IRS-III (Fig. 11.4 ) (9,10,11,21). This relates, at least in part, to the association of site with
other tumor and treatment variables. The primary site generally determines the ability to
surgically remove the tumor, which in turn determines the IRS grouping (9). Surgical
removal also relates to tumor invasiveness and the morbidity that would attend resection.
Most orbital lesions are in group III (73.5% in IRS-I, IRS-II, and IRS-III); this is also true for
parameningeal lesions (which are never in group I) and genitourinary bladder or prostate
lesions (52,63). Conversely, most genitourinary nonbladder and nonprostate tumors are in
group I, and most extremity tumors are in group I or II or are metastatic (group IV) at
diagnosis. Other factors are also relevant to the association of primary site with prognosis. For
example, the tumor location determines the presenting signs and sy mptoms, which are often
related to the rapidity of diagnosis. Tumor size (up to 5 cm vs. more than 5 cm) is associated
with survival time (p < 0.001) by multivariate analy sis, and local failure in the group III
patients from D9803 was 25% for tumors ≥5cm and 10% for those <5cm (58,64). Size is also
related to tumor site through presenting sy mptoms and signs. Primary site influences the
propensity for ly mphatic spread (Table 11.4 ) (50,65). Whereas genitourinary, abdominal
or pelvic, and extremity tumors commonly involve regional ly mph nodes, tumors in the head
and neck, trunk, and female genital organs do so less commonly. However, the frequency of
ly mph node involvement is almost certainly underestimated by IRS data because the
assessment of nodal status has not been sy stematic. Data from Stanford and Memorial Sloan–
Kettering support the prognostic significance of ly mph node involvement. Pedrick et al. (20)
showed that 88% of patients presenting with involved nodes had primary tumors that were
invasive and extended bey ond the site or organ of origin. The more current IRS studies should
provide more consistent documentation of ly mph node status with improvements in imaging
techniques and careful surgical guidelines.
Page 229
Figure 11.4 Event-free survival of patients treated on Intergroup Rhabdomyosarcoma
Study IV by stage and site. A: For patients with nonmetastatic “favorable” site tumors (stage
1), the best outcome was seen for orbital primary tumors. B: For patients with
nonmetastatic unfavorable site tumors (stage 2 or 3), the best outcome was for those with
genitourinary (bladder–prostate) tumors, whereas those with extremity tumors had an
inferior outcome. GU B/P, genitourinary tract (bladder or prostate); GU non-B/P,
genitourinary tract (nonbladder, nonprostate). (From Wexler L, Skapek SX, Helman LJ.
Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds. Principles and Practice of Pediatric Oncology.
7th ed. Philadelphia, PA: Wolters Kluwer; 2016.)
Table 11.4 Lymph Node Metastasis by Primary Site for 592 Patients with Visibly
Resected Diseasea from IRS-I and IRS-II aMicroscopic or no residual disease. -->
Other Factors
A variety of other factors have prognostic significance, some of which are general and others
specific to certain tumor subgroups. IRS data showed that ly mphocy te count, patient sex, and
age are prognostic (21). Although y ounger age is associated with a better outcome, the
specific subgroup of children y ounger than 1 y ear of age with alveolar histology has a
significantly poorer survival than do older children, a finding not seen for infants with the
embry onal subty pe (66,67,68). Some site-specific variables influence outcome. In the head
and neck, risk factors that predict tumor access to the cranial subarachnoid space (skull base
erosion, cranial nerve palsy, intracranial extension) decrease the likelihood of disease-free
survival (51% vs. 81% if no risk factors) (52,69,70). In extremity sites, the presence of ly mph
node involvement is strongly associated with a high incidence of relapse in metastatic sites
and inferior survival. In contrast to many other childhood cancers, early response to
chemotherapy has had a conflicting correlation with long-term disease-free control. Two
large analy ses of the most recent COG trials failed to show improved survival in patients with
a CR or PR after induction chemotherapy ; however, a correlation was seen in the German
cooperative group soft tissue sarcoma trials (15,71,72,73,74). Further, PET response after
induction chemotherapy in RMS has been shown to correlate with local control rates,
suggesting that chemotherapeutic response play s a role in local control (75,76). More
recently, two studies from the United States and Germany showed that for embry onal
parameningeal tumors, response to chemotherapy was linked to local control and event-free
survival, suggesting that response may only be prognostic for specific sites and/or histology
(15,71,73,74,77,78).
Figure: International Classification of
Rhabdomyosarcoma
Figure: Tumor, Node, Metastasis
Pretreatment Staging Classification
Figure: The IRS Grouping System
Figure:
Survival by clinical group for all patients treated in IRS-IV. Improved outcome was seen in
group II compared with group I and presumably due to undertreatment of select patients
with group I disease.
(From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds.
Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer; 2015.)
Figure:
Event-free survival of patients treated on Intergroup Rhabdomyosarcoma Study IV by stage
and site. A: For patients with nonmetastatic “favorable” site tumors (stage 1), the best
outcome was seen for orbital primary tumors. B: For patients with nonmetastatic
unfavorable site tumors (stage 2 or 3), the best outcome was for those with genitourinary
(bladder–prostate) tumors, whereas those with extremity tumors had an inferior outcome.
GU B/P, genitourinary tract (bladder or prostate); GU non-B/P, genitourinary tract
(nonbladder, nonprostate).
(From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds.
Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer; 2016.)
Figure: Lymph Node Metastasis by Primary
Site for 592 Patients with Visibly Resected
Diseasea from IRS-I and IRS-II
aMicroscopic or no residual disease.
GENERAL PRINCIPLES OF THERAPY
Page 230Currently, the COG studies stratify patients into three risk groups (low, intermediate,
and high) on the basis of known prognostic factors and historical outcome (13). The prognostic
features incorporated into the risk classification scheme include histology, stage (which in turn
incorporates site, tumor size, invasiveness, node status, and metastases), and clinical group.
General definitions of the risk groups are as follows:
Low risk: Patients with localized embry onal RMS occurring at favorable sites (stage 1)
and patients with embry onal RMS occurring at unfavorable sites with either completely
resected disease (group I) or microscopic residual disease (group II)
Page 231Intermediate risk: Patients with embry onal RMS occurring at unfavorable sites
with gross residual disease (group III) and patients with nonmetastatic alveolar RMS at
any site
High risk: Patients with metastatic RMS (group IV, stage 4)
Clearly, this scheme will continue to evolve as treatments improve and new data emerge
regarding particular subsets of patients and biologically based prognostic features. The overall
goals are to reduce long-term toxicities in patients with a high likelihood of cure and to
develop superior and innovative therapies for patients who continue to fare poorly with
modern treatment regimens.
The therapeutic struggle for clinicians managing children with RMS, to cure while
minimizing functional and cosmetic deficits, is heightened by the difficulty in eradicating both
local and sy stemic disease. The spectrum of locations and histologies complicates
determination of treatment strategies through differences in the propensity for local and
sy stemic control and treatment sequelae. It is clear that multidisciplinary therapy is
necessary. Aggressive surgery and RT alone have been curative in fewer than 25% of
children, with the exception of patients with orbital or genitourinary primary sites (18,79).
Conversely, chemotherapy alone is associated with high local failure rates, a lesson learned
by attempts to manage orbital or genitourinary tumors without radiation (18,80). The
judicious use of chemotherapy to eradicate micrometastatic disease and reduce the extent of
local disease and RT to increase the potential for local control has led to a decrease in
aggressive surgery except in selected situations (8). The current challenge is to develop
approaches to additionally enhance the complementary actions of all three treatment
modalities in terms of intensity and sequence.
Surgery
Before the advent of radiation therapy and chemotherapy, complete resection of RMS was
the clear goal of surgical treatment. This often involved radical surgeries such as pelvic
exenteration, radical prostatectomy, cy stectomy, amputations, and orbital exenteration. Even
so, less than 10% of children were amenable to complete resection and curable because of
the absence of metastatic disease. Bey ond this, most of these children had severely
compromised quality of life functionally, cosmetically, and psy chologically. Select sites that
were more often curable by aggressive surgery included the orbit and bladder. Combined
analy sis of patients with nonmetastatic disease from IRS-I, IRS-II, and IRS-III showed that
only 16% of children had disease amenable to complete resection (group I) and 20% had
tumors for which removal of gross disease (group II) was possible (Fig. 11.5 ). In general,
achievement of local control with organ preservation is the appropriate goal. This is
accomplished with appropriate combined modality therapy. Aggressive surgery remains
appropriate in certain situations, such as for salvage therapy.
Figure 11.5 Axial (A) and sagittal (B) images of a 10-month-old boy with a group III
rhabdomyosarcoma of the bladder/prostate. The tumor displaces the bowel and causes
urinary obstruction resulting in hydronephrosis.
Reoperation for microscopic residual disease after an initial excision, or when the first
operation was performed without knowledge of the ty pe of neoplasm involved, may be
indicated before additional management. Reoperation after chemotherapy as a second-look
procedure provides an attractive option for select cases. Many of these patients have had a
“pathologic” complete response and have survival similar to that of patients who had an initial
complete resection.
Page 232The role of ly mph node dissection as a component of surgical therapy
continues to evolve. Advances in imaging may improve radiographic detection of involved
ly mph nodes. Current guidelines are site specific because of the variability in the frequency
of ly mph node involvement and outcome data relating to its significance. Genitourinary and
extremity RMS have a high incidence of ly mph node metastases (Table 11.4 ) (50). The
high frequency of nodal spread for extremity tumors, often without clinical or radiographic
evidence of involvement, has both prognostic and therapeutic implications (81,82). Currently,
COG guidelines include surgical evaluation of ly mph nodes for RMS of the extremity and for
males who are older than 10 y ears of age with paratesticular tumors. Sentinel ly mph node
biopsy continues to be explored as an alternative to formal ly mph node dissection (83). This
topic is considered further in later sections because considerations are site specific.
Overall, the extent and timing of surgical excision depend on the site of tumor and
overall treatment strategy, balancing cure with functional outcome.
Chemotherapy
Before the 1960s, the role of chemotherapy in RMS was for the treatment of metastatic
disease. Several investigators reported responses to vincristine and actinomy cin used alone
(VA) or in combination with cy clophosphamide (VAC) (79). Various groups then began to
report that the adjuvant administration of chemotherapy for totally or subtotally resected
localized disease contributed to an increase in survival probability from 10–40% to 60–80%
(84). Hey n et al. (8) randomized 32 children with completely resected RMS to adjuvant
therapy with VA or no adjuvant therapy. There were eight deaths among the 15 children in
the control group and two deaths in the 17 treated children. All children with microscopic
residual disease received chemotherapy, and survival rates were excellent.
With the widespread adoption of chemotherapy as part of the therapy of RMS, several
trials were undertaken to establish the optimum drug combinations. IRS-I tested whether VAC
was superior to VA in group II disease and whether pulse VAC plus adriamy cin was superior
to pulse VAC alone in groups II and III (Table 11.5 ). The study found no benefit to
cy clophosphamide in group II disease, and no benefit to the addition of adriamy cin in groups
III and IV (9).
Table 11.5 Design and Results of IRS-I, 1972–1978 (686 Patients)
IRS-II built on the results of IRS-I (Table 11.6 ) (10). Patients in group I received VAC
or VA. Disease-free survival was similar. IRS-II showed no benefit to pulse VAC compared
with cy clic sequential VA for group II. In groups III and IV, pulse VAC was better than a VAC
and adriamy cin combination but not statistically significantly better.
IRS-III (1984–1991) separated patients by histology into either a favorable (embry onal)
or unfavorable (alveolar, anaplastic, and monomorphous) histology. Results based on
subgroup are detailed in Table 11.7 . Several drug pairs (adriamy cin with imidazole
carboxamide [DTIC], actinomy cin D with VP-16, and actinomy cin D with DTIC) appear to
have been associated with gain in survival (11).
Table 11.7 Therapy and Outcomes According to Specific Patient Subgroups in IRS-III,
1984–1991 (1032 Patients)
IRS-IV (1991–1997) used the new staging sy stem to assign drug therapy. Patients with
group I paratesticular tumors and group I or II orbital tumors were treated with VA, and all
other nonmetastatic patients except those with preexisting renal abnormalities were
randomized to receive one of three chemotherapy regimens: VAC; vincristine, actinomy cin
D, and ifosfamide (VAI); or vincristine, ifosfamide, and etoposide (VIE) (12). Patients with
group III tumors were also randomized to receive conventional RT or hy perfractionated RT.
VAC, VAI, and VIE were equally effective, and overall the patients with embry onal tumors
who received three-drug therapy benefited in comparison to those in IRS-III, where just VA
was given. For patients with metastatic tumors, a pilot IRS study looked at the activity of
ifosfamide and doxorubicin in an up-front window and found a response rate of 63%
(complete and partial responses) (85). Subsequently, a full randomized IRS trial in 128
patients compared two up-front treatment windows, vincristine and melphalan (VM) and
ifosfamide and etoposide (IE), and later therapy consisted of VAC or VAC with the window
therapy included if the patient had an initial response (86). Initial response rates were
comparable (VM 74% vs. IE 79%), but 3-y ear failure-free survival (FFS) and overall
survival (OS) rates were superior in the patients who received the IE-containing regimen (FFS
33% vs. 19%, OS 55% vs. 27%).
Page 234IRS-V used a risk stratification schema very similar to the current sy stem
outlined above to assign patients to three risk groups (13). VA or VAC was used in a
nonrandomized fashion in the low-risk patients. VA was given to patients with tumors in
favorable sites with group I or group II disease, to patients with small, group I tumors in
unfavorable sites, and to all patients with orbital tumors (including group III). All other
patients meeting the low-risk criteria received VAC. All of the low-risk patients had
embry onal histology or one of its variants. For intermediate-risk patients, the gold standard
VAC therapy was compared in a randomized trial to VAC alternating with vincristine,
topotecan, and cy clophosphamide (VTC). This group included patients less than 10 y ears of
age with metastatic disease and embry onal histology. Previous studies in both untreated and
relapsed patients have shown topotecan to be a very active agent, particularly for patients
with alveolar histology. The results of this trial showed that there was no benefit to the addition
of topotecan (87). For high-risk patients with metastatic disease who have historically had
poor outcomes with standard VAC therapy, the combination of irinotecan and vincristine was
tested in an up-front window and then incorporated into subsequent therapy with VAC for
patients who responded (88). Irinotecan has demonstrated significant antitumor activity for
patients with both metastatic and relapsed RMS, though it is more active when given in
combination with vincristine than as a single agent (89,90,91).
The most recent clinical trial for intermediate-risk patients, ARST0531, compared
standard VAC with alternating cy cles of VAC and vincristine/irinotecan (VI) (92). The
preliminary report indicates that there is no difference in event-free survival between the two
arms. Given the significant reduction in cumulative alky lating exposure in the VAC/VI arm,
this has been recently adopted nationally as the best standard therapy for patients with
intermediate-risk disease.
The most recent low-risk trial (ARST0331) used VAC in a nonrandomized manner for all
patients (14). The cy clophosphamide dose was relatively low at 1.2 g/m 2 per cy cle. Four
cy cles were given initially with radiation administered at week 13 for patients with
microscopic, locoregional, or gross residual disease. Patients received an additional 4 or 12
courses of VA depending on which low-risk subset they were in. The goal was to increase
treatment efficacy by adding in a low cumulative dose of alky lating agent for the lowest-risk
patients while shortening the duration of treatment for these patients, and to decrease the risks
of both acute and long-term toxicities of treatment (in particular, infertility ) for the higher-risk
subset by decreasing the cumulative exposure to cy clophosphamide. This trial treated 271
low-risk patients. The 3-y ear FFS rate was 89% and the OS rate was 98%. Thus, shorter
duration of therapy did not appear to compromise outcome in these patients. Two recent high-
risk trials (ARST0431 and ARST08P1) have tested dose intensification of chemotherapy
delivered every 2 weeks instead of every 3 weeks in the small subset of patients with
metastatic disease, who continue to have a poor outcome despite the overall improvements in
survival made in nonmetastatic patients over the past few decades. ARST0431 used
alternating cy cles of vincristine, doxorubicin, cy clophosphamide with ifosfamide and
etoposide (93). This trial was based on intriguing results from the comparison of a single
institution trial to IRS-IV outcomes (94). The subsequent pilot study, ARST08P1, built on this,
using a similar intensive chemotherapy backbone, and then testing the addition of two newer
agents, temozolamide and cixutimumab, in separate arms. Final results from these trials are
not y et available.
The challenge remains to identify the drug combinations with the most favorable
therapeutic ratio when used in combination with the other modalities, and to develop
innovative therapies for the subset of patients who continue to fare poorly despite the
advances in therapy that have been made over the past few decades.
Radiation Therapy
The goal of RT today is to provide local and regional control, with or without surgery, in
conjunction with chemotherapy. The optimal multimodal strategy would coordinate RT with
these other therapies so as not to impair surgical healing or drug administration. Therefore,
major considerations would include the primary site of the tumor, the extent of surgery, the
interaction of RT with chemotherapeutic agents, and any emergent contingencies. An
analy sis of IRS-II data for group III patients underscores the difficulty that still exists in
obtaining local and regional control (95).
The responsiveness of RMS to RT was established in the 1940s and 1950s (96). Fifty to 65
Gy was thought to be necessary to achieve local control of the primary tumor regardless of
the nature of the surgical procedure. In the setting of postoperative microscopic residual
disease, these doses were demonstrated to achieve local control in 90% of cases
(84,97,98,99). Because RMS was known to extensively infiltrate tissues, large radiation
volumes initially were used, as was appropriate and standard for other soft tissue sarcomas.
As the efficacy of chemotherapy for micrometastatic disease became established and the
risk of normal tissue damage caused by combined-modality therapy was recognized,
investigators considered whether equivalent local control rates could be obtained with lower
radiation doses and volumes (98). Bey ond this, the need for any RT after wide local tumor
resection with negative margins was questioned. The IRS studies attempted to sy stematically
examine the issues of RT dosage and volume within the limits imposed by the many
chemotherapy questions that were also asked.
IRS-I patients in group I were randomized to receive postoperative RT or no RT, whereas
all other patients were irradiated (Table 11.5 ) (9). The dose was adjusted to the patient’s
age and ranged from 40 to 60 Gy. Daily fractions were 1.5–2 Gy, and RT was administered
immediately after surgery for group I patients and after 6 weeks of chemotherapy for groups
III and IV. At 5 y ears, approximately 80% of the patients in both group I study arms were
without evidence of disease. Overall survival for patients with group I RMS did not differ
significantly with RT. For this reason, RT was omitted for group I favorable histology cases for
IRS-II. In IRS-I, the dose given for local control was related to patient age and tumor size.
Dose response relationships were examined. A 32% local recurrence rate was seen after
doses less than 40 Gy and a 12% local recurrence rate was seen after doses greater than 40
Gy in the subgroup of children older than 6 y ears; however, this difference was not
statistically significant. IRS-I found no dose–response relationship when patients were
stratified solely by clinical group. The treatment volume was also analy zed for its impact on
local failure. Patients who received RT to less than the entire muscle bundle were compared
with those whose RT encompassed the entire bundle. In patients y ounger than 6 y ears, local
control rates were 84% versus 92%, respectively, and in older children rates were 91% versus
85%; however, these differences were not significant. RT to clinically uninvolved ly mph
nodes was not encouraged, whereas it was recommended for involved nodal regions. Local
control was better in genitourinary sites than in the extremity.
Page 235In IRS-II, the RT guidelines were modified based on IRS-I results (Table
11.6 ). Minimum tumor doses were 40 and 45 Gy for y ounger children (less than 6 y ears
of age) and older children, respectively, but tumors larger than 5 cm received 50–55 Gy
(100). Analy ses of local and regional failure have been performed for IRS-II, with local
failure defined as initial failure to achieve complete response or local relapse after an initial
response (10,95,100). Group I patients with an unfavorable alveolar histology had a
significantly higher frequency of locoregional recurrence than those with favorable histology.
Although the frequency of local failure was only 10% in group II, it was at 20% for group III
(excluding “special pelvic” sites) and 41% for group IV. When local relapse was analy zed as
a percentage of all relapses, it accounted for 46% of relapses in group I (despite “complete”
surgical removal of tumor) and 36%, 53%, and 20% of relapses in groups II, III, and IV,
respectively (10,95). Moreover, the local relapse rate was greater and survival rate inferior
for patients with unfavorable versus favorable histology (41% vs. 13%) and for lesions larger
than 5 cm versus smaller than 5 cm (34% vs. 23%). The predominant pattern of relapse for
group III tumors was locoregional (101). Those with ly mphatic involvement at diagnosis had
a significantly greater risk of relapse (101). The impact of radiation dose on local control was
suggested by an analy sis by Wharam et al. (49) for patients with nonparameningeal head and
neck tumors. An increased relapse rate occurred when a dose less than 40 Gy was delivered.
However, these data must be interpreted with caution, as this study was not randomized to
compare dose. Local control for all patients receiving more than 40 Gy was 93%.
In IRS-III, which accrued 1062 patients between 1984 and 1991, therapy was stratified
not only by clinical group but also by histology (with unfavorable ty pes comprising those with
alveolar, anaplastic, and monomorphous cells or patterns) and primary site (Table 11.7 )
(11). Postoperative RT was administered to all patients except those in group I with favorable
histology tumors and those in group III with special pelvic sites in complete pathologic
remission after primary chemotherapy. The RT dose for groups I and II patients was 41.4 Gy.
For patients with gross residual disease, the dose depended on patient age and tumor size: 41.4
Gy was given for children y ounger than 6 y ears with tumors smaller than 5 cm, 50.4 Gy was
given for children older than 6 y ears with tumors greater than or equal to 5 cm, and an
intermediate dose of 45 Gy was given for children who were either older or had larger
tumors, but not both. The overall survival at 5 y ears was 71%, superior to that in IRS-II (63%)
and IRS-I (55%) (11). An update of patients in group I with alveolar or undifferentiated
histology confirmed a benefit to the addition of RT for this cohort (102). For group III patients,
the rates were 73%, 65%, and 52%, respectively. Although local control rates of 90% were
achieved for patients in groups I and II, local recurrence in patients with group III disease
remained unacceptably high, as in IRS-II.
IRS-IV accrued 1011 patients between 1991 and 1997 and used the pretreatment TNM
staging sy stem to assign chemotherapy and the clinical grouping sy stem to assign
radiotherapy (12). Group II patients did especially well (Table 11.8 ). Because of the
unsatisfactory local control rates for patients with gross residual disease (group III) in IRS-II
and IRS-III and because of the normal tissue toxicities associated with radiation doses higher
than those used in the previous studies, hy perfractionated RT was tested in patients on IRS-IV
with group III disease (1.1 Gy twice daily to 59.4 Gy vs. 1.8 Gy daily to 50.4 Gy ) (103).
Although feasible, no advantage to hy perfractionation was demonstrated. There was no
difference in failure-free survival or overall survival between conventional RT and
hy perfractionated RT (by actual treatment received and when analy zed by age, gender,
tumor site, tumor invasiveness, ly mph node status, histologic features, stage, or tumor site
[Table 11.9] ).
Table 11.8 Outcome for Patient with Group II Tumors According to Histology, Primary
Site, and IRS Study
Table 11.9 Estimated Cumulative Incidence at 5 Years of Local, Regional, and Distant
Failure by Primary Site and Therapy for Patients Who Received Their Randomized
Therapy on IRS-IV
IRS-V looked prospectively at using lower doses of RT for patients with favorable
histology ; 36 Gy for patients with microscopic residual disease and no regional node
involvement, 45 Gy for patients with orbital tumors and gross residual disease, and 36–41.4
Gy for patients with superficial head and neck tumors, biliary tumors, and vulvar or uterine
tumors who undergo second-look surgery and have either negative margins or microscopic
residual tumor. All patients with alveolar group I tumors received 36 Gy to the primary site.
For intermediate-risk patients, IRS-V sought to determine the rate of local failure in patients
with gross residual tumor at diagnosis who, after second-look surgery, had response-adjusted
radiation dosage reduction (to 36 Gy for complete response and to 41.4 Gy for microscopic
residual). It also aimed to determine whether preoperative RT followed by second-look
surgery for patients with group III disease and poor response to induction chemotherapy was
feasible. Results of this study should be available soon.
The SIOP has taken a slightly different approach to the management of pediatric RMS.
They have investigated the omission or modification of local therapies based on response to
sy stemic therapy in attempt to decrease late toxicities (17,18,104). The SIOP MMT 89 trial
omitted RT or surgery for patients achieving a complete response to chemotherapy (104).
Overall survival and event-free survival were 71% and 57%, respectively. Local failure
represented the main cause of relapse. The salvage rate after local failure was high, but
prolonged follow-up is necessary to confirm durable disease control.
The most recent COG RMS trials, ARST0331 (closed in 2012) and ARST0531 (closed in
2014), enrolled patients with low-risk RMS and intermediate-risk RMS, respectively. These
trials required volume-based planning, but included the use of multiple radiation modalities
including photons, electrons, protons, and brachy therapy. Radiation was omitted only for
patients with group I favorable histology disease. Microscopic residual disease after surgery
was treated to a dose of 36 Gy and nodal disease was treated to 41.4 Gy. The dose for group
III orbital tumors was 45 Gy ; all other group III tumors receive 50.4 Gy. The gross tumor
volume (GTV) was defined as the prechemotherapy volume. A margin of 1 cm around the
GTV was recommended to define the clinical tumor volume (CTV). Nodal disease was also
included in the CTV. A volume reduction after 36 Gy was permitted for those patients
receiving 50.4 Gy who had had a substantial reduction in tumor size following sy stemic
treatment. The volume reduction was encouraged for noninvasive or “pushing” tumors, but
not for invasive tumors.
Page 237Three-y ear outcomes for ARST0331 were recently published showing a local
control rate of 92.4% for all patients (14). For patients with stage 1/2 group IIA tumors, the 3-
y ear local failure rate was 8.1% while those with group III orbital tumors had a local failure
rate of 11.5%. The isolated local failure rate was 6.7%. The 3-y ear outcomes for ARST0531
will be available in the near future. Enrollment of all patients on available protocols is
encouraged. Until the next-generation COG trials are open for enrollment, these parameters
will continue to provide the most useful guidelines for RT. However, recent reports indicating
higher than anticipated relapse rates for orbital RMS have prompted discussions regarding
higher doses for orbital RMS, particularly for patients that do not achieve a complete
response. In addition, tumor size greater than 5 cm predicts for increased local relapse and
dose higher than 50.4 Gy are being considered.
Figure:
Axial (A) and sagittal (B) images of a 10-month-old boy with a group III rhabdomyosarcoma
of the bladder/prostate. The tumor displaces the bowel and causes urinary obstruction
resulting in hydronephrosis.
Figure: Design and Results of IRS-I, 1972–
1978 (686 Patients)
Figure: Design and Results of IRS-II, 1978–
1984 (1003 Patients)
Figure: Therapy and Outcomes According to
Specific Patient Subgroups in IRS-III, 1984–
1991 (1032 Patients)
Figure: Outcome for Patient with Group II
Tumors According to Histology, Primary
Site, and IRS Study
Figure: Estimated Cumulative Incidence at 5
Years of Local, Regional, and Distant Failure
by Primary Site and Therapy for Patients
Who Received Their Randomized Therapy
on IRS-IV
SPECIFIC SITES
Paratesticular
Paratesticular RMS is less common than bladder/prostate RMS, accounting for approximately
one-third of GU RMS and 7% of all RMS (121,122). Intrascrotal paratesticular RMS usually
arises in the distal area of the spermatic cord and may invade the testis or surrounding tissues,
although primary RMS of the epididy mis or tunics can also occur (79,121). Patients generally
present with a painless scrotal mass. Scrotal ultrasound is generally the first diagnostic test that
confirms a mass in the scrotum that does not illuminate. Biopsy should not be performed and
the scrotum should not be violated. An orchiectomy is performed through an inguinal incision,
with a high ligation of the spermatic cord at the level of the inguinal ring. Paratesticular RMS
has a relatively high rate of spread to the ly mphatics, first to the para-aortic nodes, following
the course of the spermatic cord into the renal hilar retroperitoneal space. Histologically,
nearly all paratesticular RMS are of the embry onal subty pe (122). Thin slice CT scan of the
abdomen and pelvis is recommended to evaluate ly mphatics.
IRS-I and IRS-II (1973–1983) enrolled 150 patients with paratesticular RMS (122). The
majority had group I disease (n = 57) and only 14 had metastatic disease. Ninety -seven
percent had embry onal histologic subty pe. Patients with group I disease were significantly
y ounger. The 3-y ear overall survival rates by group were 98%, 90%, and 64% for group I,
group II, and group IV, respectively. There were only four group III patients. Considering the
relatively high risk of nodal involvement, surgical evaluation of ly mph nodes was performed
for most patients. Eighty -one percent of patients underwent exploratory laparotomy and
inspection and/or pathologic examination of retroperitoneal ly mph nodes; 67% of patients
underwent retroperitoneal ly mph node dissection (RPLND). Radiation therapy was delivered
to patients with group II and group III disease, while six group I patients received radiation.
Doses and volumes varied (hemiscrotum for scrotal violation, 19/20 patients with involved
RPLN received nodal RT). The results revealed the excellent prognosis for this subset of
patients, confirmed that unilateral RPLND was adequate and bilateral RPLND was not
necessary, and also indicated age as an important prognostic factor. In the most recent COG
ARST0331 study, EFS and OS for paratesticular RMS were 93% and 99%, respectively,
maintaining a similar strategy but with lower cy clophosphamide dosing to improve fertility
preservation (14).
One topic of substantial controversy over the past several y ears has been the necessity
of surgical evaluation of RPLN. IRS-III (1984–1991) required ipsilateral RPLND for all
patients, but IRS-IV (1991–1997) examined the use of CT scan of the abdomen and pelvis for
evaluation of ly mphatics in lieu of RPLND (123). The use of CT for staging led to a
significant change in the distribution of patients with group I and group II disease in these
trials. Sixty -eight percent of patients enrolled on IRS-III had group I disease versus 81% on
IRS-IV. This was a result of CT scan failing to detect ly mphatic involvement. As a result,
failure-free survival for patients with group I disease was inferior on IRS-IV, 81% at 3 y ears.
Failure-free survival was 96% on IRS-III. IRS-IV as well as the Italian and German
Cooperative Group discovered the high risk of nodal involvement for children over the age of
10 y ears (123,124). The IRS concluded that children over 10 y ears of age experienced a
superior failure-free survival (100%) on IRS-III compared to IRS-IV (68%) due to
recognized group II disease, likely as a result of receiving intensified chemotherapy and
RPLN radiation. In contrast, the Italian and German Cooperative Group performed RPLND
following negative CT scan and found only one patient to have positive ly mph nodes; 13 of
these patients were older than 10 y ears of age (124).
Page 239CT has been used to detect gross nodal involvement but may fail to
demonstrate microscopic infiltration in some patients. Consequently, it has been the practice
in the United States to perform a unilateral (trans-abdominal) nerve-sparing retroperitoneal
ly mph node dissection. Twenty -six percent of patients in IRS-I and IRS-II had retroperitoneal
ly mph node involvement at diagnosis, and 16% had positive ipsilateral inguinal nodes; contra-
lateral nodal involvement is rare (50,65). A similar percentage of patients in IRS-III had nodal
disease (125). Patients with group II disease on the basis of positive nodes receive RT to the
nodal areas in the IRS studies, in contrast to patients with negative ly mph node dissections.
Currently, on the open COG trials, ipsilateral RPLND is required for males diagnosed
with paratesticular RMS over the age of 10 y ears and any patient with suspicious ly mph
nodes by CT scan. Potential complications of RPLND include bowel, obstruction,
ly mphedema, and nerve damage (126). Nerve sparing techniques should be utilized for
RPLND. Laparoscopic RPLND has been explored as a minimally invasive technique to
evaluate ly mph nodes for paratesticular RMS and is the preferred surgical approach at some
institutions (127). If a trans-scrotal biopsy is performed instead of the inguinal approach, then
the patient is considered to have group II disease. Resection of the violated scrotal tissue is
recommended and radiation and/or hemiscrotectomy should be considered (51). The contra-
lateral testicle can be transposed laterally into the thigh before irradiation and later
reimplanted into the scrotum. The Italian and German Cooperative Group reported no local
relapses for 24 patients initially managed with trans-scrotal biopsy who were downstaged to
group I with re-excision (124). These patients received only chemotherapy, suggesting that
chemotherapy was sufficient to eradicate this microscopic disease.
Page 240The most common use of RT for paratesticular RMS is for nodal disease. All
patients with nodal disease should receive RT regardless of response. Currently on the COG
studies, gross nodal disease present after surgery receives a dose of 50.4 Gy. This may be
reduced to 41.4 Gy for microscopic disease if there is pathologic confirmation of tumor
response. Ly mph nodes follow the vessels and are generally present within 2 cm of the
vessels. Vessels and any involved ly mph nodes should be contoured. Anterior and posterior
opposed fields are generally used. Structures that are at risk in close proximity include bowel,
kidney s, bladder, and bony structures.
Page 241
Figure 11.7 Depicts a brachytherapy plan for a vaginal rhabdomyosarcoma. This 3-year-
old girl relapsed after chemotherapy alone. Prescription dose delivered was 60 Gy. A: Axial
CT treatment planning image showing percent isodose prescription lines. This plan
demonstrates rapid fall off allowing for sparing of the pelvic growth and femoral growth
plates as well. B: A multiplanar view. C, D: Sagittal DRRs with and overlay of treatment
volumes, normal structures, isodose lines. (Courtesy of Christine Haie-Mader, MD.)
Parameningeal
Parameningeal (PM) RMS accounts for approximately 15% of pediatric RMS and 40–50% of
head and neck RMS (11). They arise in sites adjacent to the meninges, as the name implies,
and have the potential to extend into the brain and spread through the CSF. The four main
subsites of PM RMS include the middle ear, nasal cavity /paranasal sinuses, nasophary nx, and
infratemporal fossa/ptery gopalatine fossa/paraphary ngeal area. Middle ear tumors originate
medially to the ty mpanic membrane. They may extend anteriorly and laterally and present
as a palpable mass in the region of the parotid, break through the ty mpanic membrane into
the external ear canal, or spread through the posterior mastoid to the posterior cranial fossa.
The three paranasal sinuses include the ethmoid, maxillary, and sphenoid sinuses. They
surround the nasal cavity and the true site of origin is often difficult to determine. These
tumors can invade the orbit or extend through the basal of skull in the region of the cavernous
sinus to the temporal lobes or through the cribiform plate to the frontal lobes. The
nasophary nx is located superiorly to the phary nx and is bounded by the nasal septum/nasal
cavity, sphenoid sinus, phary ngeal walls, and soft palate. Invasion of the base of the skull is not
infrequent and may involve the cavernous sinus causing cranial nerve palsies. Although
ly mph node involvement can occur, modern series report fewer than 20% of PM RMS as
having positive ly mph nodes (50,144). Approximately 80% of these tumors are of embry onal
histology ; the remaining 20% are alveolar. Meningeal penetration and leptomeningeal tumor
cell seeding should be assessed in patients diagnosed with PM RMS. Because PM RMS can
invade locations such as the orbit and parotid gland, it is sometime unclear if the site of origin
is truly PM. When this distinction is not clear, the tumor should be considered PM as this
dictates more aggressive therapy and invasion from more favorable sites into the sinuses,
middle ear, or paraphary ngeal space is less likely.
Page 243Complete surgical resection of the primary with a satisfactory cosmetic and
functional outcome is rarely possible; the vast majority of patients with PM RMS have group
III or group IV disease. The role of surgery is generally confined to establishing a diagnosis
with a biopsy or a subtotal excision. Cervical ly mph node dissection (radical neck dissection)
is rarely appropriate because of the associated morbidity and the low frequency of
subclinical nodal involvement; conversely, suspicious nodes should be surgically evaluated.
Before the use of chemotherapy, fewer than 20% of patients survived despite aggressive
surgery and radiation (84). For patients with PM RMS, the volume and timing of RT are
critical. The radiation volumes for PM tumors have been modified over the y ears as a result
of the lessons learned through the IRS studies (145).
IRS-I (1972–1977) enrolled 57 patients with PM RMS (146). Thirty -five percent had
evidence of meningeal involvement within 12 months of diagnosis. This was almost
universally fatal, as 90% of these patients died of their disease. RT on this protocol was
delivered to the tumor plus a 2-cm margin at week 6. Poor outcomes led to a revision of the
IRS-I protocol in 1977 near its conclusion and helped form guidelines for IRS-II. Patients
considered at high risk of meningeal dissemination defined as those with intracranial
extension, cranial nerve palsy, skull base erosion, or positive CSF received whole brain or
craniospinal radiation (69). Intrathecal chemotherapy with three agents was also advised.
Additionally, the timing of RT was changed with whole brain RT delivered week 0 and spinal
RT at week 6. After the conclusion of IRS-II, patients treated with intensive chemotherapy
and craniospinal radiation were compared to those treated with less intensive therapy and
without spinal irradiation (145). The risk of meningeal dissemination did not differ and
radiation to the spine was not advised on IRS-III (69).
In IRS-III, if there was no evidence of intracranial extension, CSF cy tology was
negative, and bone erosion or cranial nerve palsies were absent, then the primary lesion was
irradiated with a 5-cm margin, including treatment of the adjacent meninges. Patients not
meeting these criteria received intrathecal chemotherapy. If the CT or MRI demonstrated in-
continuity intracranial extension of the primary tumor, but the CSF cy tology was negative,
prophy lactic whole brain RT without spinal RT was given along with treatment to the primary
tumor. Finally, for positive CSF cy tology, craniospinal irradiation was given. Results are as
follows: 69% 5-y ear progression-free survival, 15% local failure for group III patients, and a
4.7% incidence of contiguous CNS relapse (52,147). IRS-IV reduced the radiation margin to 2
cm, and only patients with diffuse intracranial meningeal extension or multiple sites of brain
parenchy mal disease were treated to the entire cranial cavity (147). RT was given at the
beginning of the treatment course when there was clear evidence of intracranial extension,
defined as positive CSF cy tology results or any imaging evidence (by MRI) that tumor
touches, displaces, invades, distorts, or otherwise causes a signal abnormality of the dura.
Otherwise, chemotherapy was given first, with RT given at week 12. RT was omitted only for
patients with completely resected, favorable histology tumors with negative nodes.
Intrathecal chemotherapy and craniospinal irradiation were no longer used. The extent of
surgery was determined by the potential cosmetic and functional outcome, and second-look
procedures were allowed (148). IRS-V adopted the same guidelines for radiation. A review of
radiation timing for high-risk parameningeal patients with intracranial extension was carried
out comparing children from IRS-IV where intracranial extension mandated radiation at day
0 with children from IRS-V where radiation was given at week 12 (excluding those with
cranial nerve palsy or cranial base bony erosion) (149). Local control for all parameningeal
patients was 19% in both studies. Timing of RT did not affect outcomes for those with
intracranial extension (LF 21% vs. 15% p = 0.27) and therefore early irradiation is no longer
recommended for these patients.
For all of the above IRS studies, the prechemotherapy volume has been used to define
the GTV. There has been interest in evaluating a lower dose of radiation to the
prechemotherapy volume and then coning down to the postchemotherapy volume in attempt
to decrease toxicity. The underly ing principle supporting this theory is that areas of disease no
longer seen radiographically represents microscopic disease and thus should be controlled
with a dose of radiation for microscopic disease (36 Gy ). At the University of Pennsy lvania,
it has been their practice since 1992 to cone down to the postchemotherapy volume. They
reported favorable results for patients treated in this manner (150). ARST0531 defined the
CTV as the GTV plus 1 cm and continued to define the tumor volume as the
prechemotherapy volume, but allowed for a cone down to the postchemotherapy volume
after 36 Gy. All radiation started at week 4 to allow time for more complex planning and CT
planning is required. Figure 11.9 demonstrates target volume decrease following 36 Gy
for a patient with a parameningeal tumor and a good response to chemotherapy.
Figure 11.9 High-definition volume rendering. Treatment volumes for parameningeal
rhabdomyosarcoma. Recommendations on the current COG protocols are for treatment of
the prechemotherapy tumor volume (GTV) plus 1 cm to form the CTV. A: Although all IRS and
the current COG studies recommend the use of the prechemotherapy volume,
postchemotherapy volumes with a margin of 1 cm may be used for a cone down (although
not encouraged for invasive tumors) and have been explored in institutional studies as well as
European studies. B: The postchemotherapy volume plus 1 cm (after 4 weeks of
chemotherapy). Red, CTV; dark blue, parotid glands; cyan, optic nerves; green, cochlea;
yellow, hypothalamus and pituitary. (Courtesy of Fovia, Inc., and Justin Lee.)
There is often reluctance to adhere to radiation guidelines for very y oung children. The
SIOP demonstrated the significant value of RT for these patients (144). RT should not be
omitted, and the COG encourages adherence to RT guidelines even for patients less than 24
months of age (120). In all cases, the radiation oncologist should be involved at diagnosis to
allow for evaluation of tumor prior to chemotherapy and to allow adequate time for
treatment planning. Advanced techniques including IMRT and proton radiation can provide
improved sparing of normal tissues in this complex site (151). The Massachusetts General
Hospital has recently published its results for 57 pediatric rhabdomy osarcoma patients, the
most common site was parameningeal (n = 27), treated with proton therapy on a prospective
trial control (5-y ear OS and LC of 78% and 81%, respectively ) was found to be comparable
to the literature and very low rates of toxicity (120). Figure 11.10 shows a proton plan for
a 5-y ear-old boy with a PM RMS of the left infratemporal fossa.
Figure 11.10 Coronal (A) and axial (B) images for a proton plan for treatment for a
parameningeal rhabdomyosarcoma. C: Dose–volume histogram for proton plan for
parameningeal rhabdomyosarcoma. Advanced planning techniques are particularly useful for
sparing normal tissues in this region.
Page 244Orbit
Orbital RMS comprises approximately 10% of pediatric RMS (21). Because of the
accessibility of the orbit to examination and the sensitivity of ocular function to mass effect,
orbital RMS often is diagnosed early. Ey elid swelling and globe displacement are common
presenting signs. Orbital exenteration was the standard treatment until the mid-1960s, but local
disease control was rarely achieved. In the late 1960s, Cassady and coworkers observed that
RT afforded local control in five of five patients after a biopsy (7,152). RT has now assumed a
major role in the treatment of orbital RMS. Approximately two-thirds of orbital RMS are
group III. Treatment generally consists of biopsy, chemotherapy, and RT. The volume need
not include the entire orbit if the tumor is small. In the IRS study, local control has been 94%
with RT and is increased to 98% with surgical salvage (99). Of note, orbital RMS can also
invade meninges via erosion of the superior orbital fissure. An analy sis of IRS data suggested
a relationship of histology to outcome. For the 84% with embry onal histology, the 5-y ear
survival was 94%. However, for the 10% of children with alveolar RMS, this rate was 74%,
and all five infants with alveolar disease died (63). The most recent COG protocols dictated a
prescription dose of 45 Gy for both embry onal and alveolar RMS. However, patients with
alveolar orbital RMS (group III) were considered to be at intermediate risk and received
more intensified chemotherapy on ARST0531, while patients with embry onal orbital RMS
were treated on the favorable-risk protocol ARST0331. Because of the favorable outcome of
patients with orbital RMS and substantial late toxicity, the SIOP attempted to use
chemotherapy alone (153). Local control was compromised by this strategy. An international
workshop evaluating a total of 306 patients from four large cooperative groups found no
difference in overall survival based on delivery of RT at diagnosis, but a significant difference
in local control rates (82% with RT vs. 53% without RT) (154).
In a similar effort to reduce toxicity, the COG has varied the radiation and
cy clophosphamide dosing, to varied effect. Local control in IRS-III was 84% at 5 y ears with
VA chemotherapy and 45–50.4 Gy of radiation. This increased to 96% in IRS-IV with the
addition of cy clophosphamide and increased radiation doses to 50.4–59.4 Gy. In an effort to
reduce toxicity, the subsequent Intergroup D9602 trial reduced the radiation dose to 45 Gy
and omitted cy clophosphamide, but local control dropped to 86%. The most recent COG
ARST0331 trial kept the 45 Gy radiation dose, but added back cy clophosphamide at a lower
dose, achieving a 5-y ear local control rate of 89% (155). In ARST0331, the local control rate
for those 15 patients with a CR at week 12 was 100%, compared with 81% for those with a PR
or SD. Therefore, the optimum combination of chemotherapy and radiation dose is y et to be
determined, but dose escalation above 45 Gy should be considered for patients with a poor
response to chemotherapy and/or gross residual disease in the orbit following chemotherapy.
Page 245The functional and cosmetic late adverse effects of orbital irradiation are
considerable because of the close proximity of several critical structures. Three-dimensional
planning should alway s be utilized. The RT plan should be designed to deliver 45 Gy to the
tumor volume while taking into consideration the doses delivered to the lens, lacrimal gland,
cornea, retina, optic nerve, bony structures, and brain (156). Treatment with the ey e open to
avoid the bolus effect of the lids, unless the lids are involved, may be preferred. Advance
photon techniques should be considered. Proton therapy allows for substantial sparing of
normal tissues for patients with this disease and may help decrease late effects in the orbit
(Fig. 11.11 ) (120,157,158).
Figure 11.11 Proton treatment for an orbital rhabdomyosarcoma. A: A multiplanar view
of a large orbital rhabdomyosarcoma involving the superior orbit and invading lacrimal
gland. B: Axial view of proton plan. C: Dose–volume histogram.
Trunk
Truncal sites include the chest wall, paraspinal area, and abdominal wall, and diaphragm in
decreasing order of frequency. Scapular and buttock lesions are considered to be extensions
of the extremity, and retroperitoneal and perineal tumors are considered separately. An early
IRS report focused on 30 children with soft tissue sarcoma of the trunk (162). Ten of the 14
children with chest wall primaries had group I or group III disease, and five were long-term
survivors. None of the four children with metastases at diagnosis survived. Improvements in
outcomes were seen in IRS-IV. Five-y ear failure-free and overall survival was 68% and
78%, respectively (compared with 30% and 40%, respectively, for IRS-I) (163). A recent
report from the Children’s Oncology Group reported overall outcomes on the impact of
surgical excision for chest wall cases. They found no difference in failure-free or overall
survival based on the degree of resection.
Page 247Paraspinal tumors were rare (3.3%) in IRS-I and IRS-II. They tended to be
greater than 5 cm in diameter, often invaded the spinal extradural space, and were
commonly of an undifferentiated or extraosseous Ewing subty pe. Survival at 5 y ears was
approximately 50% in both studies (164). Local and distant relapses were common, and
patients with embry onal subty pes fared no better than others.
RMS of the diaphragm is ty pically unresectable and/or metastatic at diagnosis. A total of
only 15 patients were enrolled on IRS studies I–IV (165). Although complete remission was
achieved in 10 patients (67%), only 5 (33%) were alive without disease at a median follow-up
of 9 y ears.
Current guidelines include as wide a surgical resection as is feasible, either at diagnosis
or after chemoradiotherapy as a second look. For patients with an initial excision that was less
aggressive than feasible or of an uncertain nature, a re-excision should be considered. RT is
given to all patients except those with completely excised small, favorable histology tumors
and uninvolved ly mph nodes. RT fields encompass the original disease extent, and
chemotherapy is alway s used (162,164).
Retroperitoneal
Retroperitoneal tumors comprise 11% of RMS. Children usually present with abdominal pain,
back or lower extremity pain, and/or an abdominal mass (166). Median age at diagnosis is
approximately 6 y ears. The majority of patients have embry onal subty pe, but alveolar
histologic subty pe is seen (167). Retroperitoneal tumors are larger and have a higher rate of
distant metastases at diagnosis compared to tumors of other sites likely due to the ability of
tumors to grow in the abdominal or pelvic cavity without causing sy mptoms. They often
compress or invade abdominal or pelvic organs and/or major vessels and are usually not
amenable to up-front resection. In addition, ly mph node involvement is common (23% in
IRS-I and IRS-II; 28% in IRS-IV) (50). Delivery of RT is also problematic due to the size and
proximity of normal organs. In the IRS-I and IRS-II, advised RT was not delivered in 39%
(166). This very high number of RT protocol violations was attributed to the difficulty in
delivering the prescribed dose while respecting normal tissue tolerance. IRS-IV, similarly, had
a high number of protocol violations for this subsite (167). All these factors combine to render
the prognosis for retroperitoneal RMS worse than for most other sites. Five-y ear survival was
approximately 40% in IRS-II and 4-y ear survival was 60% in IRS-III (168). IRS-IV
demonstrated improved outcomes reporting estimated failure-free and overall survival at 5
y ears of 70% and 75%, respectively, for tumors of the retroperitoneum and non-GU pelvis
tumors (167). Locoregional recurrence continues to be problematic in this disease.
Embry onal subty pe and age less than 10 y ears were found to predict improved prognosis in
IRS-IV (167). Debulking of more than 50% of tumor may improve outcomes, but it is also
possible that debulking merely appears to improve outcome due to selection bias (smaller
tumors are amenable to debulking) (168). A debulking procedure should be strongly
considered if feasible (167). In addition, gastrointestinal toxicity is frequently encountered in
long-term survivors (169). Guidelines are essentially the same as those noted previously for
truncal tumors. Because of normal tissue tolerance, RT usually involves multiple reductions in
field size. CT planning should be used. IMRT may be of benefit. Proton radiation using fields
entering from posterior may be useful for sparing structures anterior to the tumor volume for
selected cases.
Perineal
Perineal tumors are rare (2% of RMS) and carry a poor prognosis (170,171). These tumors
include non–genitourinary tumors of the perineal and perianal tissue located outside of the
pelvis and between the pubic sy mphy sis and coccy x. Tumors of this region are more often of
alveolar histology than embry onal and ly mph node metastases are common (170,171). The
3-y ear survival reported for IRS-I and IRS-II combined was 59%, which was somewhat
inferior to that of patients with disease in other sites (64% for other sites) (21,170). The 5-y ear
failure-free and overall survival rates for IRS-I to IRS-IV reported collectively was only 45%
and 49%, respectively (172). When extent of disease was controlled for, only age less than 10
y ears predicted for an improved outcome. Based on the high incidence of ly mph node
involvement, the authors recommended surgical evaluation of both the iliac and inguinal
ly mphatics for accurate staging and to determine radiation fields. A recent analy sis of 29
patients from Japan and 14 patients from the United States also reported poor outcomes for
these patients (75,171). The approach to these patients also entails a resection as complete as
functionally acceptable, followed by chemotherapy and RT as appropriate. Figure 11.12
demonstrates an IMRT plan for a child with perineal RMS involving regional ly mph nodes.
Figure 11.12 Axial (A) and coronal (B) images of an intensity-modulated photon therapy
plan for a child with a perineal rhabdomyosarcoma with nodal involvement. (Courtesy of
Arthur Liu, MD.)
Hepatobiliary Tree
Hepatobiliary RMS is rare, often of botry oid subty pe, and generally occurs in very y oung
children. The common bile duct, the common, right, or left hepatic duct, and the ampulla of
Vater may be sites for RMS. A recent IRS report reviewed the experience of the 25 patients in
IRS-I to IRS-IV with RMS of the biliary tract (173). The majority of patients presented with
intermittent obstructive jaundice with or without abdominal distention, fever, pain, and loss of
appetite. Imaging was inadequate for the identification of regional metastases. Despite
aggressive surgery, gross total resection at diagnosis was possible in only six cases, two of
which had negative surgical margins. However, the 5-y ear survival rate was 78%, and much
of the mortality was related to infectious complications associated with external biliary
drains. The biliary tract is considered a favorable site, and current recommendations include
conservative surgery (without bile drainage) to establish an accurate diagnosis and determine
the extent of regional disease, followed by chemotherapy and RT. Delivery of RT may be
challenging given y oung age and volume and dose tolerances of the liver and kidney s. Proton
therapy may be of benefit, particularly for large tumors and when constraints cannot be met
with other RT modalities (Fig. 11.13 ).
Page 248
Figure 11.13 Axial images for a proton (A) versus an intensity-modulated photon plan (B)
for a 3-year-old child with biliary rhabdomyosarcoma. The properties of proton radiation
allow for increased sparing of liver and kidneys as seen in images and dose–volume
histograms (C, D).
Unfortunately, the prognosis for most patients with recurrent RMS is poor, although there is a
subset of patients with favorable salvage rates (176). These patients are those with favorable
histology who initially presented with stage 1 or group I disease and whose recurrence is local
or regional. The 5-y ear survival rates are 50–70% for this group, whereas most other children
have an extremely poor prognosis. Despite the poor long-term outlook for patients with
recurrent disease, many can still achieve a durable second remission with salvage therapy,
and there are several active chemotherapy regimens, including ifosfamide with etoposide
and cy clophosphamide with topotecan (177,178). The COG recently investigated a risk-based
approach to salvage treatment in which favorable-risk patients were treated with doxorubicin
and cy clophosphamide alternating with ifosfamide and etoposide, ARST0121 (179).
Unfavorable-risk patients with measurable disease received vincristine and irinotecan (with a
randomization to two different drug administration schedules), followed by the alternating
schedule, or the aforementioned regimen with the addition of a new agent, tirapazamine, for
patients without measurable disease. This trial found no difference in efficacy between the
two irinotecan schedules. A more recent trial, ARST0921, studied the addition of temsirolimus
and bevacizumab (in two separate arms), to the active chemotherapy combination of
vinorelbine and cy clophosphamide. The final results of this trial have not y et been published.
RT is often used for local control or palliative treatment, and aggressive surgery may
improve outcomes in the setting of recurrent disease, particularly for patients with orbital and
genitourinary tumors. Unfortunately, high-dose cy totoxic therapy with bone marrow rescue
has not proven to be effective for patients with metastatic or recurrent disease (180).
FUTURE DIRECTIONS
While it is clear that there has been tremendous progress over the last several decades,
largely attributable to the efforts and dedication of cooperative groups, phy sicians, patients,
and families, we must continue to improve outcomes for children diagnosed with RMS.
Advances in radiology and technical advances in radiation oncology should allow for better
detection of involved areas of disease and avoidance of healthy tissues while assuring
adequate delivery of radiation. Molecular profiles will indicate which patients may have
more biologically aggressive disease and are likely to play a larger role in determining what
patients may benefit from intensified treatment and/or new targeted agents. Continued
improvements in sy stemic therapy may allow us to avoid RT in some patients, while adding
to the benefit for others in whom local control comes to be of increased importance due to
eradication of sy stemic metastatic disease. We are optimistic that developments in radiation
oncology along with advances in the cancer disciplines of surgery and medicine will allow
for increased survival as well as an improvement in the quality of life for our pediatric
cancer survivors.
REFERENCES
1. Newton WA Jr, Soule EH, Hamoudi AB, et al. Histopathology of childhood sarcomas,
Intergroup Rhabdomy osarcoma Studies I and II: clinicopathologic correlation. J Clin
Oncol. 1988;6(1):67–75.
2. Parham DM, Webber B, Holt H, et al. Immunohistochemical study of childhood
rhabdomy osarcomas and related neoplasms–results of an Intergroup
Rhabdomy osarcoma study project. Cancer. 1991;67(12):3072–3080.
3. Weber C. Anatomische untersuchung einer hy pertrophische zunge nebst bemerkungen
ueber die neubilding quergestreifter muskelfasem. Virchows Arch A Pathol Anat.
1854;7:115–121.
4. Stout AP. Rhabdomy osarcoma of the skeletal muscles. Ann Surg. 1946;123(3):447–472.
5. Horn RC Jr, Enterline HT. Rhabdomy osarcoma: a clinicopathological study and
classification of 39 cases. Cancer. 1958;11(1):181–199.
6. Paulino AC. Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat
Oncol Biol Phys. 2004;60(1):265–274.
7. Cassady JR, Sagerman RH, Tretter P, Ellsworth RM. Radiation therapy for
rhabdomy osarcoma. Radiology. 1968;91(1):116–120.
8. Hey n RM, Holland R, Newton WA Jr, et al. The role of combined chemotherapy in the
treatment of rhabdomy osarcoma in children. Cancer. 1974;34(6):2128–2142.
9. Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup Rhabdomy osarcoma
Study -I—a final report. Cancer. 1988;61(2):209–220.
10. Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup Rhabdomy osarcoma
Study -II. Cancer. 1993;71(5):1904–1922.
11. Crist W, Gehan EA, Ragab AH, et al. The Third Intergroup Rhabdomy osarcoma Study. J
Clin Oncol. 1995;13(3):610–630.
12. Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomy osarcoma study -IV: results
for patients with nonmetastatic disease. J Clin Oncol. 2001;19(12):3091–3102.
13. Page 250 Raney RB, Anderson JR, Barr FG, et al. Rhabdomy osarcoma and
undifferentiated sarcoma in the first two decades of life: a selective review of intergroup
rhabdomy osarcoma study group experience and rationale for Intergroup
Rhabdomy osarcoma Study V. J Pediatr Hemato Oncol. 2001;23(4):215–220.
14. Walterhouse DO, Pappo AS, Meza JL, et al: Shorter-duration therapy using vincristine,
dactinomy cin, and lower-dose cy clophosphamide with or without radiotherapy for
patients with newly diagnosed low-risk rhabdomy osarcoma: a report from the Soft
Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol.
2014;32(31):3547-52.
15. Koscielniak E, Jurgens H, Winkler K, et al. Treatment of soft tissue sarcoma in childhood
and adolescence—a report of the German Cooperative Soft Tissue Sarcoma Study.
Cancer. 1992;70(10):2557–2567.
16. Kingston JE, McElwain TJ, Malpas JS. Childhood rhabdomy osarcoma: experience of the
Children’s Solid Tumour Group. Br J Cancer. 1983;48(2):195–207.
17. Flamant F, Rodary C, Rey A, et al. Treatment of non-metastatic rhabdomy osarcomas in
childhood and adolescence—results of the second study of the International Society of
Paediatric Oncology : MMT84. Eur J Cancer. 1998;34(7):1050–1062.
18. Flamant F, Rodary C, Voute PA, Otten J. Primary chemotherapy in the treatment of
rhabdomy osarcoma in children: trial of the International Society of Pediatric Oncology
(SIOP) preliminary results. Radiother Oncol. 1985;3(3):227–236.
19. Mandell L, Ghavimi F, Peretz T, et al. Radiocurability of microscopic disease in
childhood rhabdomy osarcoma with radiation doses less than 4,000 cGy. J Clin Oncol.
1990;8(9):1536–1542.
20. Pedrick TJ, Donaldson SS, Cox RS. Rhabdomy osarcoma: the Stanford experience using a
TNM staging sy stem. J Clin Oncol. 1986;4(3):370–378.
21. Crist WM, Garnsey L, Beltangady MS, et al. Prognosis in children with
rhabdomy osarcoma: a report of the intergroup rhabdomy osarcoma studies I and II.
Intergroup Rhabdomy osarcoma Committee. J Clin Oncol. 1990;8(3):443–452.
22. Breneman JC, Ly den E, Pappo AS, et al. Prognostic factors and clinical outcomes in
children and adolescents with metastatic rhabdomy osarcoma—a report from the
Intergroup Rhabdomy osarcoma Study IV. J Clin Oncol. 2003;21(1):78–84.
23. Qualman SJ, Coffin CM, Newton WA, et al: Intergroup Rhabdomy osarcoma Study :
Update for Pathologists. Pediatric and Developmental Pathology. 1998;1(6):550-61.
24. Gurney JG, Severson RK, Davis S, et al. Incidence of cancer in children in the United
States. Sex-, race-, and 1-y ear age-specific rates by histologic ty pe. Cancer.
1995;75(8):2186–2195.
25. Stat bite: age-specific cancer incidence among children under 15. J Natl Cancer Inst.
1999;91(24):2076.
26. Ruy mann FB, Maddux HR, Ragab A, et al. Congenital anomalies associated with
rhabdomy osarcoma: an autopsy study of 115 cases—a report from the Intergroup
Rhabdomy osarcoma Study Committee (representing the Children’s Cancer Study Group,
the Pediatric Oncology Group, the United Kingdom Children’s Cancer Study Group, and
the Pediatric Intergroup Statistical Center). Med Pediatr Oncol. 1988;16(1):33–39.
27. Birch JM, Hartley AL, Blair V, et al. Cancer in the families of children with soft tissue
sarcoma. Cancer. 1990;66(10):2239–2248.
28. McKeen EA, Bodurtha J, Meadows AT, et al. Rhabdomy osarcoma complicating multiple
neurofibromatosis. J Pediatr. 1978;93(6):992–993.
29. Moschovi M, Touliatou V, Papadopoulou A, et al. Rhabdomy osarcoma in a patient with
Noonan sy ndrome phenoty pe and review of the literature. J Pediatr Hematol Oncol.
2007;29(5):341–344.
30. Gripp KW. Tumor predisposition in Costello sy ndrome. Am J Med Genet.
2005;137C(1):72–77.
31. Lupo PJ, Dany sh HE, Plon SE, et al: Family history of cancer and childhood
rhabdomy osarcoma: a report from the Children’s Oncology Group and the Utah
Population Database. Cancer medicine. 2015;4(5):781-90.
32. Constine LS, Marcus RB Jr, Halperin EC. The future of therapy for childhood
rhabdomy osarcoma: clues from molecular biology. Int J Radiat Oncol Biol Phys.
1995;32(4):1245–1249; discussion 1263.
33. Pappo AS, Shapiro DN, Crist WM, et al. Biology and therapy of pediatric
rhabdomy osarcoma. J Clin Oncol. 1995;13(8):2123–2139.
34. Williamson D, Missiaglia E, de Rey nies A, et al: Fusion gene-negative alveolar
rhabdomy osarcoma is clinically and molecularly indistinguishable from embry onal
rhabdomy osarcoma. J Clin Oncol. 2010;28(13):2151-8.
35. Parham DM, Qualman SJ, Teot L, et al. Correlation between histology and PAX/FKHR
fusion status in alveolar rhabdomy osarcoma: a report from the Children’s Oncology
Group. Am J Surg Pathol. 2007;31(6):895–901.
36. Edwards RH, Chatten J, Xiong QB, et al. Detection of gene fusions in
rhabdomy osarcoma by reverse transcriptase-poly merase chain reaction assay of
archival samples. Diagn Mol Pathol. 1997;6(2):91–97.
37. Kelly KM, Womer RB, Barr FG. Minimal disease detection in patients with alveolar
rhabdomy osarcoma using a reverse transcriptase-poly merase chain reaction method.
Cancer. 1996;78(6):1320–1327.
38. Merlino G, Helman LJ. Rhabdomy osarcoma—working out the pathway s. Oncogene.
1999;18(38):5340–5348.
39. Weber-Hall S, Anderson J, McManus A, et al. Gains, losses, and amplification of
genomic material in rhabdomy osarcoma analy zed by comparative genomic
hy bridization. Cancer Res. 1996;56(14):3220–3224.
40. Shapiro DN, Parham DM, Douglass EC, et al. Relationship of tumor-cell ploidy to
histologic subty pe and treatment outcome in children and adolescents with unresectable
rhabdomy osarcoma. J Clin Oncol. 1991;9(1):159–166.
41. Pappo AS, Crist WM, Kuttesch J, et al. Tumor-cell DNA content predicts outcome in
children and adolescents with clinical group III embry onal rhabdomy osarcoma—the
Intergroup Rhabdomy osarcoma Study Committee of the Children’s Cancer Group and
the Pediatric Oncology Group. J Clin Oncol. 1993;11(10):1901–1905.
42. De Zen L, Sommaggio A, d’Amore ES, et al. Clinical relevance of DNA ploidy and
proliferative activity in childhood rhabdomy osarcoma: a retrospective analy sis of
patients enrolled onto the Italian Cooperative Rhabdomy osarcoma Study RMS88. J Clin
Oncol. 1997;15(3):1198–1205.
43. Dias P, Parham DM, Shapiro DN, et al. My ogenic regulatory protein (My oD1)
expression in childhood solid tumors: diagnostic utility in rhabdomy osarcoma. Am J
Pathol. 1990;137(6):1283–1291.
44. Dias P, Kumar P, Marsden HB, et al. N-my c gene is amplified in alveolar
rhabdomy osarcomas (RMS) but not in embry onal RMS. Int J Cancer. 1990;45(4):593–
596.
45. Driman D, Thorner PS, Greenberg ML, et al. MYCN gene amplification in
rhabdomy osarcoma. Cancer. 1994;73(8):2231–2237.
46. Felix CA, Kappel CC, Mitsudomi T, et al. Frequency and diversity of p53 mutations in
childhood rhabdomy osarcoma. Cancer Res. 1992;52(8):2243–2247.
47. Hettmer S, Archer NM, Somers GR, et al: Anaplastic rhabdomy osarcoma in TP53
germline mutation carriers. Cancer. 2014;120(7):1068-75.
48. Qualman S, Cancer 2008.
49. Wharam MD, Beltangady MS, Hey n RM, et al. Pediatric orofacial and
lary ngophary ngeal rhabdomy osarcoma—an Intergroup Rhabdomy osarcoma Study
report. Arch Otolaryngol Head Neck Surg. 1987;113(11):1225–1227.
50. Lawrence W Jr, Hay s DM, Hey n R, et al. Ly mphatic metastases with childhood
rhabdomy osarcoma—a report from the Intergroup Rhabdomy osarcoma Study. Cancer.
1987;60(4):910–915.
51. Breneman JC. Genitourinary Rhabdomy osarcoma. Semin Radiat Oncol. 1997;7(3):217–
224.
52. Wharam MD Jr. Rhabdomy osarcoma of parameningeal sites. Semin Radiat Oncol.
1997;7(3):212–216.
53. Volker T, Denecke T, Steffen I, et al. Positron emission tomography for staging of
pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol.
2007;25(34):5435–5441.
54. Weiss AR, Ly den ER, Anderson JR, et al: Histologic and clinical characteristics can guide
staging evaluations for children and adolescents with rhabdomy osarcoma: a report from
the Children’s Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol.
2013;31(26):3226-32.
55. Parham DM, Kelly DR, Donnelly WH, et al. Immunohistochemical and ultrastructural
spectrum of hepatic sarcomas of childhood: evidence for a common histogenesis. Mod
Pathol. 1991;4(5):648–653.
56. Page 251 Parham DM. Pathologic classification of rhabdomy osarcomas and
correlations with molecular studies. Mod Pathol. 2001;14(5):506–514.
57. Asmar L, Gehan EA, Newton WA, et al. Agreement among and within groups of
pathologists in the classification of rhabdomy osarcoma and related childhood sarcomas.
Report of an international study of four pathology classifications. Cancer.
1994;74(9):2579–2588.
58. Newton WA Jr, Gehan EA, Webber BL, et al. Classification of rhabdomy osarcomas and
related sarcomas—pathologic aspects and proposal for a new classification—an
Intergroup Rhabdomy osarcoma Study. Cancer. 1995;76(6):1073–1085.
59. Parham DM, Ellison DA. Rhabdomy osarcomas in adults and children: an update. Arch
Pathol Lab Med. 2006;130(10):1454–1465.
60. Rodary C, Gehan EA, Flamant F, et al. Prognostic factors in 951 nonmetastatic
rhabdomy osarcoma in children: a report from the International Rhabdomy osarcoma
Workshop. Med Pediatr Oncol. 1991;19(2):89–95.
61. Donaldson SS, Belli JA. A rational clinical staging sy stem for childhood
rhabdomy osarcoma. J Clin Oncol. 1984;2(2):135–139.
62. Lawrence W Jr, Anderson JR, Gehan EA, et al. Pretreatment TNM staging of childhood
rhabdomy osarcoma: a report of the Intergroup Rhabdomy osarcoma Study Group.
Children’s Cancer Study Group. Pediatric Oncology Group. Cancer. 1997;80(6):1165–
1170.
63. Kodet R, Newton WA Jr, Hamoudi AB, et al. Orbital rhabdomy osarcomas and related
tumors in childhood: relationship of morphology to prognosis—an Intergroup
Rhabdomy osarcoma study. Med Pediatr Oncol. 1997;29(1):51–60.
64. Rodeberg DA, Wharam MD, Ly den ER, et al: Delay ed primary excision with
subsequent modification of radiotherapy dose for intermediate-risk rhabdomy osarcoma:
a report from the Children’s Oncology Group Soft Tissue Sarcoma Committee.
International journal of cancer. 2015;137:204-11.
65. Lawrence W Jr, Hay s DM, Moon TE. Ly mphatic metastasis with childhood
rhabdomy osarcoma. Cancer. 1977;39(2):556–559.
66. La Quaglia MP, Heller G, Ghavimi F, et al. The effect of age at diagnosis on outcome in
rhabdomy osarcoma. Cancer. 1994;73(1):109–117.
67. Ragab AH, Hey n R, Tefft M, et al. Infants y ounger than 1 y ear of age with
rhabdomy osarcoma. Cancer. 1986;58(12):2606–2610.
68. Salloum E, Flamant F, Rey A, et al. Rhabdomy osarcoma in infants under one y ear of
age: experience of the Institut Gustave-Roussy. Med Pediatr Oncol. 1989;17(5):424–428.
69. Raney RB Jr, Tefft M, Newton WA, et al. Improved prognosis with intensive treatment of
children with cranial soft tissue sarcomas arising in nonorbital parameningeal sites—a
report from the Intergroup Rhabdomy osarcoma Study. Cancer. 1987;59(1):147–155.
70. Mandell LR, Massey V, Ghavimi F. The influence of extensive bone erosion on local
control in non-orbital rhabdomy osarcoma of the head and neck. Int J Radiat Oncol Biol
Phys. 1989;17(3):649–653.
71. Koscielniak E, Harms D, Henze G, et al: Results of treatment for soft tissue sarcoma in
childhood and adolescence: a final report of the German Cooperative Soft Tissue
Sarcoma Study CWS-86. Journal of clinical oncology : official journal of the American
Society of Clinical Oncology. 1999;17(12):3706-19.
72. Burke M, Anderson JR, Kao SC, et al. Assessment of response to induction therapy and
its influence on 5-y ear failure-free survival in group III rhabdomy osarcoma: the
Intergroup Rhabdomy osarcoma Study -IV experience—a report from the Soft Tissue
Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol. 2007;25(31):4909–
4913.
73. Rosenberg, 2014 #7.
74. Dantonello TM, Int-Veen C, Harms D, et al: Cooperative trial CWS-91 for localized soft
tissue sarcoma in children, adolescents, and y oung adults. Journal of clinical oncology :
official journal of the American Society of Clinical Oncology. 2009;27:1446-55.
75. Casey DL, Wexler LH, Fox JJ, et al: Predicting outcome in patients with
rhabdomy osarcoma: role of [(18)f]fluorodeoxy glucose positron emission tomography.
International journal of radiation oncology, biology, physics. 2014;90:1136-42.
76. Dharmarajan KV, Wexler LH, Gavane S, et al: Positron emission tomography (PET)
evaluation after initial chemotherapy and radiation therapy predicts local control in
rhabdomy osarcoma. International journal of radiation oncology, biology, physics.
2012;84:996-1002.
77. Dantonello TM, Stark M, Timmermann B, et al: Tumour volume reduction after
neoadjuvant chemotherapy impacts outcome in localised embry onal
rhabdomy osarcoma. Pediatric blood & cancer. 2015;62:16-23.
78. Ladra MM, Szy monifka JD, Mahajan A, et al: Preliminary results of a phase II trial of
proton radiotherapy for pediatric rhabdomy osarcoma. J Clin Oncol. 2014;32(33):3762-
70.
79. Maurer HM. Rhabdomy osarcoma in childhood and adolescence. Curr Probl Cancer.
1978;2(9):1–36.
80. Hay s DM, Raney RB, Wharam MD, et al. Children with vesical rhabdomy osarcoma
(RMS) treated by partial cy stectomy with neoadjuvant or adjuvant chemotherapy, with
or without radiotherapy —A report from the Intergroup Rhabdomy osarcoma Study (IRS)
Committee. J Pediatr Hematol Oncol. 1995;17(1):46–52.
81. Mandell L, Ghavimi F, LaQuaglia M, Exelby P. Prognostic significance of regional
ly mph node involvement in childhood extremity rhabdomy osarcoma. Med Pediatr
Oncol. 1990;18(6):466–471.
82. Neville HL, Andrassy RJ, Lobe TE, et al. Preoperative staging, prognostic factors, and
outcome for extremity rhabdomy osarcoma: a preliminary report from the Intergroup
Rhabdomy osarcoma Study IV (1991–1997). J Pediatr Surg. 2000;35(2):317–321.
83. Kay ton ML, Delgado R, Busam K, et al. Experience with 31 sentinel ly mph node
biopsies for sarcomas and carcinomas in pediatric patients. Cancer. 2008;112(9):2052–
2059.
84. Donaldson SS, Castro JR, Wilbur JR, et al. Rhabdomy osarcoma of head and neck in
children—combination treatment by surgery, irradiation, and chemotherapy. Cancer.
1973;31(1):26–35.
85. Sandler E, Ly den E, Ruy mann F, et al. Efficacy of ifosfamide and doxorubicin given as
a phase II “window” in children with newly diagnosed metastatic rhabdomy osarcoma: a
report from the Intergroup Rhabdomy osarcoma Study Group. Med Pediatr Oncol.
2001;37(5):442–448.
86. Breitfeld PP, Ly den E, Raney RB, et al. Ifosfamide and etoposide are superior to
vincristine and melphalan for pediatric metastatic rhabdomy osarcoma when
administered with irradiation and combination chemotherapy : a report from the
Intergroup Rhabdomy osarcoma Study Group. J Pediatr Hematol Oncol.
2001;23(4):225–233.
87. Arndt CA, Hawkins DS, Stoner JA, et al. Randomized phase III trial comparing
vincristine, actinomy cin, cy clophosphamide (VAC) with VAC/V
topotecan/cy clophosphamide (TC) for intermediate risk rhabdomy osarcoma (IRRMS).
D9803, COG study. [Abstract] J Clin Oncol. 2007;25(suppl 18):A-9509, 528s.
88. Pappo AS, Ly den E, Breitfeld P, et al. Two consecutive phase II window trials of
irinotecan alone or in combination with vincristine for the treatment of metastatic
rhabdomy osarcoma: the Children’s Oncology Group. J Clin Oncol. 2007;25(4):362–369.
89. Furman WL, Stewart CF, Poquette CA, et al. Direct translation of a protracted irinotecan
schedule from a xenograft model to a phase I trial in children. J Clin Oncol.
1999;17(6):1815–1824.
90. Rodriguez-Galindo C, Crews KR, Stewart CF, et al. Phase I study of the combination of
topotecan and irinotecan in children with refractory solid tumors. Cancer Chemother
Pharmacol. 2006;57(1):15–24.
91. Cosetti M, Wexler LH, Calleja E, et al. Irinotecan for pediatric solid tumors: the
Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol. 2002;24(2):101–105.
92. Hawkins DS, Gupta AA, Rudzinski ER: What is new in the biology and treatment of
pediatric rhabdomy osarcoma? Current Opinion in Pediatrics. 2014;26(1):50-6.
93. Weigel BJ, Ly den E, Anderson JR, et al: Intensive Multiagent Therapy, Including Dose-
Compressed Cy cles of Ifosfamide/Etoposide and
Vincristine/Doxorubicin/Cy clophosphamide, Irinotecan, and Radiation, in Patients With
High-Risk Rhabdomy osarcoma: A Report From the Children’s Oncology Group. Journal
of clinical oncology: official journal of the American Society of Clinical Oncology.
2016;34:117-22.
94. Arndt CA, Hawkins DS, Mey er WH, et al. Comparison of results of a pilot study of
alternating vincristine/doxorubicin/cy clophosphamide and etoposide/ifosfamide with
IRS-IV in intermediate risk rhabdomy osarcoma: a report from the Children’s Oncology
Group. Pediatr Blood Cancer. 2008;50(1):33–36.
95. Wharam MD, Hanfelt JJ, Tefft MC, et al. Radiation therapy for rhabdomy osarcoma:
local failure risk for Clinical Group III patients on Intergroup Rhabdomy osarcoma Study
II. Int J Radiat Oncol Biol Phys. 1997;38(4):797–804.
96. Page 252 Stobbe GD, Dargeon HW. Embry onal rhabdomy osarcoma of the head and
neck in children and adolescents. Cancer. 1950;3(5):826–836.
97. Regine WF, Fontanesi J, Kumar P, et al. Local tumor control in rhabdomy osarcoma
following low-dose irradiation: comparison of group II and select group III patients. Int J
Radiat Oncol Biol Phys. 1995;31(3):485–491.
98. Tefft M, Lindberg RD, Gehan EA. Radiation therapy combined with sy stemic
chemotherapy of rhabdomy osarcoma in children: local control in patients enrolled in the
Intergroup Rhabdomy osarcoma Study. Natl Cancer Inst Monogr. 1981(56):75–81.
99. Wharam M, Beltangady M, Hay s D, et al. Localized orbital rhabdomy osarcoma. An
interim report of the Intergroup Rhabdomy osarcoma Study Committee. Ophthalmology.
1987;94(3):251–254.
100. Maurer HM. The Intergroup Rhabdomy osarcoma Study II: objectives and study design.
J Pediatr Surg. 1980;15(3):371–372.
101. Wharam MD, Meza J, Anderson J, et al. Failure pattern and factors predictive of local
failure in rhabdomy osarcoma: a report of group III patients on the third Intergroup
Rhabdomy osarcoma Study. J Clin Oncol. 2004;22(10):1902–1908.
102. Wolden SL, Anderson JR, Crist WM, et al. Indications for radiotherapy and
chemotherapy after complete resection in rhabdomy osarcoma: a report from the
Intergroup Rhabdomy osarcoma Studies I to III. J Clin Oncol. 1999;17(11):3468–3475.
103. Donaldson SS, Meza J, Breneman JC, et al. Results from the IRS-IV randomized trial of
hy perfractionated radiotherapy in children with rhabdomy osarcoma—a report from the
IRSG. Int J Radiat Oncol Biol Phys. 2001;51(3):718–728.
104. Stevens MC, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomy osarcoma in
childhood and adolescence: third study of the International Society of Paediatric
Oncology —SIOP Malignant Mesenchy mal Tumor 89. J Clin Oncol. 2005;23(12):2618–
2628.
105. Hay s DM, Raney RB Jr, Lawrence W Jr, et al. Primary chemotherapy in the treatment
of children with bladder—prostate tumors in the Intergroup Rhabdomy osarcoma Study
(IRS-II). J Pediatr Surg. 1982;17(6):812–820.
106. Scholtmeijer RJ, Tromp CG, Hazebroek FW. Embry onal rhabdomy osarcoma of the
urogenital tract in childhood. Eur Urol. 1983;9(2):69–74.
107. LaQuaglia M. Genitourinary rhabdomy osarcoma in children. Urol Clin North Am.
1991;18(3):575–580.
108. Tefft M, Jaffe N. Proceedings: sarcoma of the bladder and prostate in children. Rationale
for the role of radiation therapy based on a review of the literature and a report of
fourteen additional patients. Cancer. 1973;32(5):1161–1177.
109. Klem ML, Grewal RK, Wexler LH, et al. PET for staging in rhabdomy osarcoma: an
evaluation of PET as an adjunct to current staging tools. J Pediatr Hematol Oncol.
2007;29(1):9–14.
110. Ferrer FA, Isakoff M, Koy le MA. Bladder/prostate rhabdomy osarcoma: past, present
and future. J Urol. 2006;176(4 Pt 1):1283–1291.
111. Hay s DM, Raney RB Jr, Lawrence W Jr, et al. Bladder and prostatic tumors in the
intergroup Rhabdomy osarcoma study (IRS-I): results of therapy. Cancer.
1982;50(8):1472–1482.
112. Hay s DM, Lawrence W Jr, Crist WM, et al. Partial cy stectomy in the management of
rhabdomy osarcoma of the bladder: a report from the Intergroup Rhabdomy osarcoma
Study. J Pediatr Surg. 1990;25(7):719–723.
113. Voute PA, Vos A, de Kraker J, Behrendt H. Rhabdomy osarcomas: chemotherapy and
limited supplementary treatment program to avoid mutilation. Natl Cancer Inst Monogr.
1981(56):121–125.
114. Tefft M, Hay s D, Raney RB Jr, et al. Radiation to regional nodes for rhabdomy osarcoma
of the genitourinary tract in children: is it necessary ? A report from the Intergroup
Rhabdomy osarcoma Study No. 1 (IRS-1). Cancer. 1980;45(12):3065–3068.
115. Raney RB Jr, Gehan EA, Hay s DM, et al. Primary chemotherapy with or without
radiation therapy and/or surgery for children with localized sarcoma of the bladder,
prostate, vagina, uterus, and cervix—a comparison of the results in Intergroup
Rhabdomy osarcoma Studies I and II. Cancer. 1990;66(10):2072–2081.
116. Hey n R, Newton WA, Raney RB, et al. Preservation of the bladder in patients with
rhabdomy osarcoma. J Clin Oncol. 1997;15(1):69–75.
117. Arndt CA, Hammond S, Rodeberg D, Qualman S. Significance of persistent mature
rhabdomy oblasts in bladder/prostate rhabdomy osarcoma: results from IRS IV. J Pediatr
Hematol Oncol. 2006;28(9):563–567.
118. Leuschner I, Harms D, Mattke A, et al. Rhabdomy osarcoma of the urinary bladder and
vagina: a clinicopathologic study with emphasis on recurrent disease: a report from the
Kiel Pediatric Tumor Registry and the German CWS Study. Am J Surg Pathol.
2001;25(7):856–864.
119. Arndt C, Rodeberg D, Breitfeld PP, et al. Does bladder preservation (as a surgical
principle) lead to retaining bladder function in bladder/prostate rhabdomy osarcoma?
Results from intergroup rhabdomy osarcoma study iv. J Urol. 2004;171(6 Pt 1):2396–
2403.
120. Ladra MM, Edgington SK, Mahajan A, et al: A dosimetric comparison of proton and
intensity modulated radiation therapy in pediatric rhabdomy osarcoma patients enrolled
on a prospective phase II proton study. Radiother Oncol. 2014;113:77-83.
121. Raney RB Jr, Hay s DM, Lawrence W Jr, et al. Paratesticular rhabdomy osarcoma in
childhood. Cancer. 1978;42(2):729–736.
122. Raney RB Jr, Tefft M, Lawrence W Jr, et al. Paratesticular sarcoma in childhood and
adolescence—a report from the Intergroup Rhabdomy osarcoma Studies I and II, 1973–
1983. Cancer. 1987;60(9):2337–2343.
123. Wiener ES, Anderson JR, Ojimba JI, et al. Controversies in the management of
paratesticular rhabdomy osarcoma: is staging retroperitoneal ly mph node dissection
necessary for adolescents with resected paratesticular rhabdomy osarcoma? Semin
Pediatr Surg. 2001;10(3):146–152.
124. Ferrari A, Bisogno G, Casanova M, et al. Paratesticular rhabdomy osarcoma: report
from the Italian and German Cooperative Group. J Clin Oncol. 2002;20(2):449–455.
125. Wiener ES, Lawrence W, Hay s D, et al. Retroperitoneal node biopsy in paratesticular
rhabdomy osarcoma. J Pediatr Surg. 1994;29(2):171–177; discussion 178.
126. Hey n R, Raney RB Jr, Hay s DM, et al. Late effects of therapy in patients with
paratesticular rhabdomy osarcoma. Intergroup Rhabdomy osarcoma Study Committee. J
Clin Oncol. 1992;10(4):614–623.
127. Skolarus TA, Bhay ani SB, Chiang HC, et al. Laparoscopic retroperitoneal ly mph node
dissection for low-stage testicular cancer. J Endourol. 2008;22(7):1485–1489.
128. Andrassy RJ, Hay s DM, Raney RB, et al. Conservative surgical management of vaginal
and vulvar pediatric rhabdomy osarcoma: a report from the Intergroup
Rhabdomy osarcoma Study III. J Pediatr Surg. 1995;30(7):1034–1036; discussion 1036–
1037.
129. Hay s DM, Shimada H, Raney RB Jr, et al. Clinical staging and treatment results in
rhabdomy osarcoma of the female genital tract among children and adolescents. Cancer.
1988;61(9):1893–1903.
130. Friedman M, Peretz BA, Nissenbaum M, Paldi E. Modern treatment of vaginal
embry onal rhabdomy osarcoma. Obstet Gynecol Surv. 1986;41(10):614–618.
131. Andrassy RJ, Wiener ES, Raney RB, et al. Progress in the surgical management of
vaginal rhabdomy osarcoma: a 25-y ear review from the Intergroup
Rhabdomy osarcoma Study Group. J Pediatr Surg. 1999;34(5):731–734; discussion 734–
735.
132. Arndt CA, Donaldson SS, Anderson JR, et al. What constitutes optimal therapy for
patients with rhabdomy osarcoma of the female genital tract? Cancer. 2001;91(12):2454–
2468.
133. Walterhouse DO, Meza JL, Breneman JC, et al: Local control and outcome in children
with localized vaginal rhabdomy osarcoma: a report from the Soft Tissue Sarcoma
committee of the Children’s Oncology Group. Pediatric blood & cancer. 2011;57:76-83.
134. Magne N, Oberlin O, Martelli H, et al. Vulval and vaginal rhabdomy osarcoma in
children: update and reappraisal of Institut Gustave Roussy brachy therapy experience.
Int J Radiat Oncol Biol Phys. 2008;72(3):878–883.
135. Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles
in mid-life: implications for forecasting menopause. Hum Reprod. 1992;7(10):1342–
1346.
136. Hay s DM, Shimada H, Raney RB Jr, et al. Sarcomas of the vagina and uterus: the
Intergroup Rhabdomy osarcoma Study. J Pediatr Surg. 1985;20(6):718–724.
137. Page 253 Brand E, Berek JS, Nieberg RK, et al. Rhabdomy osarcoma of the uterine
cervix. Sarcoma botry oides. Cancer. 1987;60(7):1552–1560.
138. Martelli H, Oberlin O, Rey A, et al. Conservative treatment for girls with nonmetastatic
rhabdomy osarcoma of the genital tract: a report from the Study Committee of the
International Society of Pediatric Oncology. J Clin Oncol. 1999;17(7):2117–2122.
139. Lawrence W Jr, Hay s DM, Hey n R, et al. Surgical lessons from the Intergroup
Rhabdomy osarcoma Study (IRS) pertaining to extremity tumors. World J Surg.
1988;12(5):676–684.
140. Neville HL, Raney RB, Andrassy RJ, Cooley DA. Multidisciplinary management of
pediatric soft-tissue sarcoma. Oncology (Williston Park). 2000;14(10):1471–1481;
discussion 1482–1476, 1489–1490.
141. Oberlin O, Rey A, Brown KL, et al: Prognostic Factors for Outcome in Localized
Extremity Rhabdomy osarcoma. Pooled Analy sis from Four International Cooperative
Groups. Pediatric blood & cancer. 2015;62:2125-31.
142. Ben Arush MW, Bar Shalom R, Postovsky S, et al. Assessing the use of FDG-PET in the
detection of regional and metastatic nodes in alveolar rhabdomy osarcoma of
extremities. J Pediatr Hematol Oncol. 2006;28(7):440–445.
143. Neville HL, Andrassy RJ, Lally KP, et al. Ly mphatic mapping with sentinel node biopsy
in pediatric patients. J Pediatr Surg. 2000;35(6):961–964.
144. Defachelles AS, Rey A, Oberlin O, et al. Treatment of nonmetastatic cranial
parameningeal rhabdomy osarcoma in children y ounger than 3 y ears old: results from
international society of pediatric oncology studies MMT 89 and 95. J Clin Oncol.
2009;27(8):1310–1315.
145. Raney RB, Meza J, Anderson JR, et al. Treatment of children and adolescents with
localized parameningeal sarcoma: experience of the Intergroup Rhabdomy osarcoma
Study Group protocols IRS-II through -IV, 1978–1997. Med Pediatr Oncol.
2002;38(1):22–32.
146. Tefft M, Fernandez C, Donaldson M, et al. Incidence of meningeal involvement by
rhabdomy osarcoma of the head and neck in children: a report of the Intergroup
Rhabdomy osarcoma Study (IRS). Cancer. 1978;42(1):253–258.
147. Raney RB. Soft-tissue sarcoma in childhood and adolescence. Curr Oncol Rep.
2002;4(4):291–298.
148. Blatt J, Sny derman C, Wollman MR, et al. Delay ed resection in the management of non-
orbital rhabdomy osarcoma of the head and neck in childhood. Med Pediatr Oncol.
1997;28(4):294–298.
149. Spalding AC, Hawkins DS, Donaldson SS, et al: The effect of radiation timing on patients
with high-risk features of parameningeal rhabdomy osarcoma: an analy sis of IRS-IV and
D9803. International journal of radiation oncology, biology, physics. 2013;87(3):512-6.
150. Chen C, Shu HK, Goldwein JW, et al. Volumetric considerations in radiotherapy for
pediatric parameningeal rhabdomy osarcomas. Int J Radiat Oncol Biol Phys.
2003;55(5):1294–1299.
151. Kozak KR, Adams J, Krejcarek SJ, et al. A dosimetric comparison of proton and
intensity -modulated photon radiotherapy for pediatric parameningeal
rhabdomy osarcomas. Int J Radiat Oncol Biol Phys. 2009;74(1):179–186.
152. Sagerman RH, Cassady JR, Tretter P. Radiation therapy for rhabdomy osarcoma of the
orbit. Trans Am Acad Ophthalmol Otolaryngol. 1968;72(6):849–854.
153. Rousseau P, Flamant F, Quintana E, et al. Primary chemotherapy in
rhabdomy osarcomas and other malignant mesenchy mal tumors of the orbit: results of
the International Society of Pediatric Oncology MMT 84 Study. J Clin Oncol.
1994;12(3):516–521.
154. Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomy osarcoma: survival
and late effects of treatment--results of an international workshop. J Clin Oncol.
2001;19(1):197–204.
155. Meza, 2013 #21.
156. Hey n R, Ragab A, Raney RB Jr, et al. Late effects of therapy in orbital
rhabdomy osarcoma in children—a report from the Intergroup Rhabdomy osarcoma
Study. Cancer. 1986;57(9):1738–1743.
157. Yock T, Schneider R, Friedmann A, et al. Proton radiotherapy for orbital
rhabdomy osarcoma: clinical outcome and a dosimetric comparison with photons. Int J
Radiat Oncol Biol Phys. 2005;63(4):1161–1168.
158. Hug EB, Adams J, Fitzek M, et al. Fractionated, three-dimensional, planning-assisted
proton-radiation therapy for orbital rhabdomy osarcoma: a novel technique. Int J Radiat
Oncol Biol Phys. 2000;47(4):979–984.
159. Pappo AS, Meza JL, Donaldson SS, et al. Treatment of localized nonorbital,
nonparameningeal head and neck rhabdomy osarcoma: lessons learned from intergroup
rhabdomy osarcoma studies III and IV. J Clin Oncol. 2003;21(4):638–645.
160. Wolden SL, Wexler LH, Kraus DH, et al. Intensity -modulated radiotherapy for head-
and-neck rhabdomy osarcoma. Int J Radiat Oncol Biol Phys. 2005;61(5):1432–1438.
161. Curtis AE, Okcu MF, Chintagumpala M, et al. Local control after intensity -modulated
radiotherapy for head-and-neck rhabdomy osarcoma. Int J Radiat Oncol Biol Phys.
2009;73(1):173–177.
162. Raney RB Jr, Ragab AH, Ruy mann FB, et al. Soft-tissue sarcoma of the trunk in
childhood. Results of the intergroup rhabdomy osarcoma study. Cancer.
1982;49(12):2612–2616.
163. Hay es-Jordan A, Stoner JA, Anderson JR, et al. The impact of surgical excision in chest
wall rhabdomy osarcoma: a report from the Children’s Oncology Group. J Pediatr Surg.
2008;43(5):831–836.
164. Ortega JA, Wharam M, Gehan EA, et al. Clinical features and results of therapy for
children with paraspinal soft tissue sarcoma: a report of the Intergroup
Rhabdomy osarcoma Study. J Clin Oncol. 1991;9(5):796–801.
165. Raney RB, Anderson JR, Andrassy RJ, et al. Soft-tissue sarcomas of the diaphragm: a
report from the Intergroup Rhabdomy osarcoma Study Group from 1972 to 1997. J
Pediatr Hematol Oncol. 2000;22(6):510–514.
166. Crist WM, Raney RB, Tefft M, et al. Soft tissue sarcomas arising in the retroperitoneal
space in children—a report from the Intergroup Rhabdomy osarcoma Study (IRS)
Committee. Cancer. 1985;56(8):2125–2132.
167. Raney RB, Stoner JA, Walterhouse DO, et al. Results of treatment of fifty -six patients
with localized retroperitoneal and pelvic rhabdomy osarcoma: a report from The
Intergroup Rhabdomy osarcoma Study -IV, 1991–1997. Pediatr Blood Cancer.
2004;42(7):618–625.
168. Blakely ML, Lobe TE, Anderson JR, et al. Does debulking improve survival rate in
advanced-stage retroperitoneal embry onal rhabdomy osarcoma? J Pediatr Surg.
1999;34(5):736–741; discussion 741–742.
169. Ransom JL, Pratt CB, Hustu HO, et al. Retroperitoneal rhabdomy osarcoma in children—
results of multimodality therapy. Cancer. 1980;45(5):845–850.
170. Raney RB Jr, Crist W, Hay s D, et al. Soft tissue sarcoma of the perineal region in
childhood—a report from the Intergroup Rhabdomy osarcoma Studies I and II, 1972
through 1984. Cancer. 1990;65(12):2787–2792.
171. Okamura K, Yamamoto H, Ishimaru Y, et al. Clinical characteristics and surgical
treatment of perianal and perineal rhabdomy osarcoma: analy sis of Japanese patients
and comparison with IRSG reports. Pediatr Surg Int. 2006;22(2):129–134.
172. Blakely ML, Andrassy RJ, Raney RB, et al. Prognostic factors and surgical treatment
guidelines for children with rhabdomy osarcoma of the perineum or anus: a report of
Intergroup Rhabdomy osarcoma Studies I through IV, 1972 through 1997. J Pediatr Surg.
2003;38(3):347–353.
173. Spunt SL, Lobe TE, Pappo AS, et al. Aggressive surgery is unwarranted for biliary tract
rhabdomy osarcoma. J Pediatr Surg. 2000;35(2):309–316.
174. Rodeberg D, Arndt C, Breneman J, et al. Characteristics and outcomes of
rhabdomy osarcoma patients with isolated lung metastases from IRS-IV. J Pediatr Surg.
2005;40(1):256–262.
175. Hay es-Jordan A, Doherty DK, West SD, et al. Outcome after surgical resection of
recurrent rhabdomy osarcoma. J Pediatr Surg. 2006;41(4):633–638; discussion 633–638.
176. Pappo AS, Anderson JR, Crist WM, et al. Survival after relapse in children and
adolescents with rhabdomy osarcoma: a report from the Intergroup Rhabdomy osarcoma
Study Group. J Clin Oncol. 1999;17(11):3487–3493.
177. Miser JS, Kinsella TJ, Triche TJ, et al. Ifosfamide with mesna uroprotection and
etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors
of children and y oung adults. J Clin Oncol. 1987;5(8):1191–1198.
178. Page 254 Say lors RL III, Stine KC, Sullivan J, et al. Cy clophosphamide plus topotecan in
children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II
study. J Clin Oncol. 2001;19(15):3463–3469.
179. Mascarenhas L, Ly den ER, Breitfeld PP, et al: Randomized phase II window trial of two
schedules of irinotecan with vincristine in patients with first relapse or progression of
rhabdomy osarcoma: a report from the Children’s Oncology Group. Journal of clinical
oncology : official journal of the American Society of Clinical Oncology. 2010;28:4658-63.
180. Weigel BJ, Breitfeld PP, Hawkins D, et al. Role of high-dose chemotherapy with
hematopoietic stem cell rescue in the treatment of metastatic or recurrent
rhabdomy osarcoma. J Pediatr Hematol Oncol. 2001;23(5):272–276.
CH A P TER 12
Soft Tissue Sarcomas Other Than
Rhabdomyosarcoma; Desmoid Tumor
Brandon R. Mancini, Kenneth B. Roberts, and Edward C. Halperin
Page 255The word sarcoma is derived from the Attic Greek word σàρκωμα or sarkoma
meaning a fleshy excrescence (1). The term was used by Galan with particular reference to
a nasal growth (2). An early English language dictionary from 1657 continued this definition
of sarcoma as a “flesh growing in the nostrils like the proud flesh in a sore” (3). In modern
usage, however, soft tissue sarcomas are defined as all malignant tumors of nonepithelial,
extraskeletal tissues including the peripheral and autonomic nervous sy stem, but excluding the
hematopoietic sy stem, glia, and supporting tissues of specific organs and viscera.
Soft tissue sarcomas constitute approximately 6.5–7% of childhood cancer. Of these,
40% are rhabdomy osarcoma and 60% are other ty pes of soft tissue sarcomas (4,5,6).
Because the distribution of the ty pes of soft tissue sarcomas in children is frequently different
from that in adults, Spunt and Pappo (7) have advocated the term nonrhabdomyosarcoma soft
tissue sarcoma (NRSTS). The United States’ Surveillance, Epidemiology, and End Results
(SEER) program provide some of the most comprehensive cancer epidemiologic data
available (8). Of the European Tumor Registries, only data published from Germany have
sufficient detail to distinguish rhabdomy osarcoma from NRSTS (9). Overall, NRSTS
comprise approximately 3–3.5% of all pediatric cancers with 550–600 new cases diagnosed
each y ear in the United States. The incidence rate over time has remained steady in the
range of 6–8 cases per million population. In Germany, the incidence rate is slightly less at
five cases per million persons. Data from SEER based on the time period 1975–1995 suggest
that NRSTS has had a propensity to dominate in older pediatric age groups (10–14 y ears and
15–19 y ears, specifically ) as part of the incidence curves for soft tissue sarcoma (STS)
leading into adulthood. There are certainly some NRSTSs that are characterized by a
pediatric predominance. But, for many of the soft tissue sarcomas, clinical features are
similar between children and adults, except that survival rates diminish for patients over age
50 y ears (10).
While the annual National Cancer Institute (NCI) report on Cancer statistics based on the
SEER database does readily distinguish among rhabdomy osarcomas and NRSTSs, pediatric
soft tissue sarcomas in the United States have been associated with improving survival over
time. For patients less than 16 y ears of age diagnosed with a soft tissue sarcoma in 1975–
1977, the adjusted 5-y ear survival was 61%. For those diagnosed in 2004–2010, there was a
statistically significant improvement in 5-y ear survival at 81% (11). But to what degree this
simply reflects an improvement in rhabdomy osarcoma management is difficult to discern.
Moreover, very few patients with NRSTSs have been enrolled in cooperative group clinical
trials. For instance, in the United States, prior to the 2006 Children’s Oncology Group (COG)
ARST0332 trial, less than 200 patients had been enrolled in only three prospective clinical
trials (12,13,14). The ARST0332 trial was open from 2007 to 2012 and accrued just 551
eligible patients over 5 y ears (15).
For most children with NRSTS, the origin or cause of the tumor is unknown. Some cases
may be traced to prior radiation exposure (see Chapter 20 ), chemical exposure,
iatrogenic or disease-caused immunosuppression, or a genetic predisposition. For example,
patients with neurofibromatosis—a set of autosomal dominant disorders of dy splastic growths
involving neural tissues often with skin manifestations—have a 7–10% lifetime risk of
developing a malignant peripheral nerve sheath tumor (MPNST). With changes in pathologic
definitions, MPNST has historically been called a neurofibrosarcoma or malignant
schwannoma. The association of sarcomas with neurofibromatosis indicates that some
sarcomas are associated with chromosomal deletions and translocations and the presence of
abnormalities of tumor suppressor genes. Homozy gous gene deletions occur in both the long
and short arms of chromosome 17 in neurofibromatosis ty pe 1. Candidate tumor suppressor
genes include 17q11 (the NF tumor suppressor gene) and p53 (17p13) (4).
Rhabdomy osarcoma and NRSTS also occur as part of the familial Li–Fraumeni sy ndrome.
More generally, in adult and pediatric soft tissue sarcomas, cy togenetic abnormalities are
common with a mixture of simple translocations or point mutations giving rise to fusion genes
or oncogenes and more complex genetic instability with a multiplicity of chromosome
aberrations (16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35) (Table 12.1 ).
Gastrointestinal stromal tumors are of particular interest, albeit rare in children, since its
associated c-kit oncogene is a successful therapeutic target with imatinib, a prototy pe ty rosine
kinase inhibitor (36). While not y et tested in pediatric NRSTS, there are a variety of other
molecular targets and associated agents under investigation in adult soft tissue sarcomas,
including platelet-derived growth factor receptor-A (sunitinib), Raf kinase (sorafenib), mTOR
(rapamy cin), vascular endothelial growth factor (bevacizumab), heat shock proteins,
hedgehog, histone deacety lase, and nucleotide excision repair (30). Within the COG, there
has been an effort to screen for actionable mutations by exon genomic transcriptional
analy sis. From a sample of 10% of the cases from the ARST0332 study using archived
formalin-fixed paraffin-embedded specimens, 33 potential mutations were found in 15
NRSTS subty pes, most involving mutations involved in Ras signaling, overlapping with
mutations in EGFR and TP53 (37). A variety of large chromosomal gains or losses were also
observed. These efforts will hopefully serve as the basis for future sy stemic therapeutics.
Page 256
Page 257The frequency of the different histologic subgroups of NRSTS of childhood varies
between reporting institutions (Table 12.2 ). These differences may be attributable to
variations in referral patterns and to the small numbers in each series. SEER represents the
best population-based description of STS subty pe distribution, location of disease, and staging
across the age spectrum despite the problem of coding errors by tumor registries. Figure
12.1 display s the results of a 2011 SEER analy sis of soft tissue sarcomas by 10-y ear-age
intervals (10). Recapitulating the distribution of NRSTS is the experience from the recent
experience from the COG ARTS 0332 trial, which includes some y oung adults; the most
common subty pes were sy novial sarcoma (27%), MPNST (11%), and undifferentiated
sarcoma (9%) (15).
Table 12.2 The Most Common Types of Childhood Nonrhabdomyosarcoma Soft Tissue
Sarcoma in Recent Clinical Seriesa aIn each series, the most common histologic types are
indicated by bold type.
Figure 12.1 A: Distribution of histologic subtypes by 10-year age groups. B: Distribution of
primary tumor sites by 10-year age groups. C: Distribution of tumor stage by 10-year age
groups. RMS, rhabdomyosarcomas; fibroblastic, fibroblastic and myofibroblastic tumors;
Fibrohistiocytic, fibrohistiocytic tumors; NST, malignant peripheral nerve sheath tumors;
Kaposi, Kaposi sarcoma; pPNET, Ewing family tumors; rhabdoid, extraneral rhabdoid tumor;
liposarcoma, liposarcomas; synovial, synovial sarcomas; blood vessel, blood vessel tumors;
ASPS, alveolar soft parts sarcoma; miscellaneous, miscellaneous/unspecified soft tissue
sarcomas including other fibromatous neoplasms. From Ferrari A, Sultan I, Huang TT, et al.,
Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance
Epidemiology and End Results Database. Pediatr Blood Cancer. 2011;57:943–949.
F RI E D RI CH V ON RE CKL I N G HAUS E N
Page 260Liposarcomas originate from primitive mesenchy mal cells rather than from
mature adipose tissue. Some have a my xoid appearance, whereas others resemble benign
lipomas. The pleomorphic ty pe may resemble fibroblastic, my oblastic, or sy novial sarcoma.
Angiosarcoma should alway s be considered high grade with an aggressive behavior, a high
rate of local recurrence, a propensity to metastasize, and a poor prognosis (66).
Leiomyosarcoma originates from smooth muscle. The well-differentiated lesions usually have
a centrally located blunt-ended nucleus (“cigar-shaped”).
Fibrosarcoma is an infiltrative, fibrous
neoplasm composed of interlocking bundles of
spindle cells (67,68). The tumor usually stains
positive for vimentin. There are two clinically
different forms of fibrosarcoma in children. One
is a lesion appearing in the first 5 y ears of life,
with a low rate of distant spread. This ty pe of
fibrosarcoma, called the congenital ty pe, is
generally treated by excision (4,40,69). In
children less than 5 y ears of age, this tumor may
also be called infantile fibrosarcoma (Fig. Figure 12.3 Example of microscopic
12.3 ). The other occurs in children older than pathology of an infantile fibrosarcoma,
5 y ears and has a more ominous prognosis with original magnification × 20. This is
behavior similar to that of adult forms (68). This another fibrous spindle-cell proliferation
classical or adult-ty pe fibrosarcoma is treated as in the example of an MFH. While
according to the principles outlined for other histologically aggressive in appearance,
NRSTSs. Infantile fibrosarcoma has a rapid when this fibrosarcoma occurs in the first
initial growth, but generally indolent behavior. several years of life, there tends to be a
Local recurrence is common, metastases are benign biologic behavior with little
rare, spontaneous regressions have been potential for metastatic spread. Local
reported, and RT is rarely used. Infantile and excision is the primary management. In
adult fibrosarcomas are histologically identical. unresectable cases, chemotherapy can
There is no routine microscopic, be used to promote regression and
immunohistochemical, or ultrastructural way of subsequent surgery.
distinguishing the two clinical ty pes (67).
Page 261Low-grade fibromyxoid sarcoma is an indolent tumor that rarely occurs in
children or y oung adults. It consists of spindle and stellate cells with uniform nuclei arranged
in a whorled pattern with alternating areas of fibrous and my xoid stroma (70). In adults
across the age spectrum, these my xofibrosarcomas may be higher grade, multifocal
involving an extremity with late recurrences outside radiation treatment fields and without
any obvious ly mphatic mode of spread (71). True MFH are pleomorphic sarcomas as noted
above, often characterized by a whorled growth pattern. They are thought to arise from
histiocy tic cells acting as facultative fibroblasts. Hemangiopericytomas arise from pericy tes,
the modified smooth muscle cell with contractile function located on the internal surface of
venous capillaries and postcapillary venules (72). The malignant mesenchymoma has two or
more cell ty pes, any of which, taken by itself, might be considered a malignant neoplasm
(73,74); however, the term is losing favor as a clinicopathologic entity, as such sarcomas can
usually be classified in other way s (75). Ectomesenchymomas are felt to be of neural crest
origin with multidirectional differentiation exhibiting combinations of neuroblastoma,
ganglioglioma, schwannoma, emby ronal rhabdomy osarcoma, benign melanocy tic
proliferation, and bone or cartilage elements. These rare tumors may have a dominant
rhabdomy osarcomatous element with clinically similar response to chemotherapy and RT
(76) (Fig. 12.4 ).
Figure 12.4 This 10-month-old boy developed a 2.5-cm superficial mass in the right
supraclavicular fossa. After ultrasound showed this to be a solid lesion, a marginal excision
was performed in February 2003. An ectomesenchymoma was diagnosed having immature
cartilage separated by bands of collagen in a myxoid background with cellular areas having
primitive ovid and spindle cells. The dominant cellular pattern had features of an embryonal
rhabdomyosarcoma. Surgical margins were positive. There was no evidence of metastasis in
an adjacent lymph node or on CT imaging. As a wider excision was not possible due to tumor
abutting clavicle, lung apex, and carotid artery, postoperative radiotherapy was indicated.
Along with VAC chemotherapy as per rhabdomyosarcoma management, the patient
received 3060 cGy in 17 fractions using a four-field technique (AP, PA, RAO, LAO fields)
facilitated by daily general anesthesia with IV propofol. Shown is the radiation treatment
plan and digital reconstructed radiographs of three of the fields. The treatment plan
minimized the volume of distal clavicle, spine, and shoulder girdle being treated to full dose.
In last follow-up at age 7 years without evidence of disease, there is negligible boney
asymmetry seen on chest X-rays correlating with normal physical examination. A: Radiation
treatment plan. B: RAO Digital Reconstructed Radiograph (DRR). C: AP DRR. D: LAO DRR. E:
Follow-up CXRs in 2003, 2006, 2009, and 2011 show relatively normal bony development
although there is some minor clavicular shortening on exam in 2015.
There are several childhood NRSTSs that have a characteristic microscopic picture, but
the cell of origin is uncertain. The epithelioid sarcoma is a tumor of the subcutaneous tissue,
tendons, and fascia, usually of the upper extremity, including the hand. There is a nodular
arrangement of plump, poly gonal to round, epithelioid cells interspersed with spindle-shaped
cells (5,77). Central degeneration or necrosis is often present. The tumor tends to spread
within fascial planes or aponeuroses and may grow along the neurovascular bundle and
encroach on large vessels or nerves. Regional ly mph node metastasis may occur in
association with high-grade tumors and tumors larger than 5 cm (78). The tumor generally
stains positive for keratin.
Alveolar soft part sarcomas have a characteristic cry stalline material seen with periodic
acid–Schiff (PAS) stain (79,80). The tumor tests positive for vimentin on
immunohistochemistry. The tumor cells ty pically have an organoid or nest-like arrangement.
Vascular invasion is alway s seen. Of 11 children with alveolar soft part sarcoma seen at St.
Jude Children’s Research Hospital (SJCRH) in a 32-y ear period, 6 had localized disease and 5
had unresectable or metastatic disease. Cy togenetic studies indicate that 17q25 abnormalities
are common (80). In 19 patients seen in Italy, 4 had metastatic disease at presentation. The 5-
y ear survival for all 19 patients was 80% (81). A slow doubling time of the tumor may
explain its very late occurrences (sometimes more than 10 y ears) (47).
P A G E 2 6 2J A M E S S . E W I N G
Ewing sarcoma is named in honor of James
S. Ewing (1866–1943), an eminent
pathologist at Cornell Medical School and
the Memorial Hospital in New York City who
described this radiosensitve small round blue
cell tumor of bone. Ewing was a major force
in the early development of radiotherapy.
Securing a major donation of radium from a
mining industry philanthropist, Ewing set the
future Memorial Sloan Kettering Cancer
Center on a firm foundation in large part
from Ewing’s efforts in cancer treatment,
pathology insights, and administrative roles.
One hypothesis of his that proved incorrect,
however, was the assertion that sarcomas
were etiologically linked to trauma.
Nevertheless, Time Magazine honored him
on its cover page in 1931 entitled “Cancer
Man Ewing” (84).
Desmoplastic small, round, blue cell tumor is a rare intraperitoneal malignancy occurring
predominantly in adolescent boy s. It is characterized by a reciprocal translocation t(11;12)
(p13;q12) associated with the EWS-WT1 gene fusion transcript. Cells often stain positive for
desmin, keratin, and neuron-specific enolase. The predominant pattern of relapse is
intraperitoneal (85). Generally, patients are treated with surgical debulking, alky lator
chemotherapy, and whole-abdomen irradiation or intra-abdominal P-32. The relapse-free
survival rate is approximately 20% (57,86,87,88). Positron emission tomography (PET)
scanning may be useful in follow-up for early diagnosis of recurrence (89). Figure 12.5
depicts a rare instance of this disease occurring outside the peritoneum.
Figure 12.5 This 12-year-old female presented with a subcutaneous mass over the left
shoulder that was marginally excised. Pathology showed a desmoplastic small, round-cell
tumor with a classical t(11;12) translocation on cytogenetics. This case represents an unusual
extra-abdominal presentation of this rare sarcoma. MRI scan showed contrast enhancement
in the surgical bed (upper panel). Reexcision, axillary node dissection, bone marrow biopsy,
and CT scans were negative for other sites of disease. The patient was treated with an Ewing
sarcoma type chemotherapy protocol with involved-field RT to 45 Gy in 25 fractions (middle
panel of axial, coronal, and sagittal CT images with superimposed radiation dose
distribution). Despite local control of the primary tumor, the patient unfortunately developed
progressive pulmonary metastases shortly after completing
vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide
chemotherapy (See bottom panel of four serial CT images showing progression of lung
metastasis over 6 months). Despite surgical excisions of lung nodules and salvage
chemotherapy, the patient ultimately succumbed to her disease.
Clear cell sarcoma is characterized by ovoid or poly gonal cells with abundant clear
cy toplasm, indistinct borders, large nucleoli, and abundant intracy toplasmic gly cogen.
Immunocy tochemistry often is positive for S-100 protein, neuron-specific enolase, and
melanocy te-associated antigen HMB-45. A specific chromosomal translocation t(12;22)
(q13;q12) involving the DNA transcription factors ATF-1 on chromosome 12 and the EWS
gene on chromosome 22 has been described in 60–75% of clear cell sarcoma cases (90,91).
A fair proportion of NRSTSs show no cellular differentiation. These are called undifferentiated
sarcomas or sarcomas not otherwise specified.
Figure: The Most Common Types of
Childhood Nonrhabdomyosarcoma Soft
Tissue Sarcoma in Recent Clinical Seriesa
aIn each series, the most common histologic types are indicated by bold type.
Figure:
A: Distribution of histologic subtypes by 10-year age groups. B: Distribution of primary tumor
sites by 10-year age groups. C: Distribution of tumor stage by 10-year age groups. RMS,
rhabdomyosarcomas; fibroblastic, fibroblastic and myofibroblastic tumors; Fibrohistiocytic,
fibrohistiocytic tumors; NST, malignant peripheral nerve sheath tumors; Kaposi, Kaposi
sarcoma; pPNET, Ewing family tumors; rhabdoid, extraneral rhabdoid tumor; liposarcoma,
liposarcomas; synovial, synovial sarcomas; blood vessel, blood vessel tumors; ASPS, alveolar
soft parts sarcoma; miscellaneous, miscellaneous/unspecified soft tissue sarcomas including
other fibromatous neoplasms.
From Ferrari A, Sultan I, Huang TT, et al., Soft tissue sarcoma across the age spectrum: a
population-based study from the Surveillance Epidemiology and End Results Database.
Pediatr Blood Cancer. 2011;57:943–949.
Figure:
The histologic appearance of a malignant fibrous histiocytoma on hematoxylin and eosin
staining, original magnification 40×. Many pathologists now categorize this lesion as a
pleomorphic sarcoma. Note the spindle-cell proliferation (long, narrow, rod-like cells) with
frequent mitoses, enlarged hyperchromatic and pleomorphic nuclei, and a storiform pattern
of growth (fascicles of cells radiating from a central point). There is also some tendency
toward a herringbone pattern in this example, characteristic of a fibrosarcoma.
Figure: Cells of Origin of
Nonrhabdomyosarcoma Soft Tissue
Sarcoma of Childhood
Figure:
Figure:
Example of microscopic pathology of an infantile fibrosarcoma, original magnification × 20.
This is another fibrous spindle-cell proliferation as in the example of an MFH. While
histologically aggressive in appearance, when this fibrosarcoma occurs in the first several
years of life, there tends to be a benign biologic behavior with little potential for metastatic
spread. Local excision is the primary management. In unresectable cases, chemotherapy
can be used to promote regression and subsequent surgery.
Figure:
This 10-month-old boy developed a 2.5-cm superficial mass in the right supraclavicular fossa.
After ultrasound showed this to be a solid lesion, a marginal excision was performed in
February 2003. An ectomesenchymoma was diagnosed having immature cartilage separated
by bands of collagen in a myxoid background with cellular areas having primitive ovid and
spindle cells. The dominant cellular pattern had features of an embryonal
rhabdomyosarcoma. Surgical margins were positive. There was no evidence of metastasis in
an adjacent lymph node or on CT imaging. As a wider excision was not possible due to tumor
abutting clavicle, lung apex, and carotid artery, postoperative radiotherapy was indicated.
Along with VAC chemotherapy as per rhabdomyosarcoma management, the patient
received 3060 cGy in 17 fractions using a four-field technique (AP, PA, RAO, LAO fields)
facilitated by daily general anesthesia with IV propofol. Shown is the radiation treatment
plan and digital reconstructed radiographs of three of the fields. The treatment plan
minimized the volume of distal clavicle, spine, and shoulder girdle being treated to full dose.
In last follow-up at age 7 years without evidence of disease, there is negligible boney
asymmetry seen on chest X-rays correlating with normal physical examination. A: Radiation
treatment plan. B: RAO Digital Reconstructed Radiograph (DRR). C: AP DRR. D: LAO DRR. E:
Follow-up CXRs in 2003, 2006, 2009, and 2011 show relatively normal bony development
although there is some minor clavicular shortening on exam in 2015.
Figure:
Figure:
Figure:
This 12-year-old female presented with a subcutaneous mass over the left shoulder that was
marginally excised. Pathology showed a desmoplastic small, round-cell tumor with a
classical t(11;12) translocation on cytogenetics. This case represents an unusual extra-
abdominal presentation of this rare sarcoma. MRI scan showed contrast enhancement in the
surgical bed (upper panel). Reexcision, axillary node dissection, bone marrow biopsy, and CT
scans were negative for other sites of disease. The patient was treated with an Ewing
sarcoma type chemotherapy protocol with involved-field RT to 45 Gy in 25 fractions (middle
panel of axial, coronal, and sagittal CT images with superimposed radiation dose
distribution). Despite local control of the primary tumor, the patient unfortunately developed
progressive pulmonary metastases shortly after completing
vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide
chemotherapy (See bottom panel of four serial CT images showing progression of lung
metastasis over 6 months). Despite surgical excisions of lung nodules and salvage
chemotherapy, the patient ultimately succumbed to her disease.
PRESENTATION, WORKUP, AND STAGING
Page 264Most NRSTSs present as a painless swelling, but may also present with signs and
sy mptoms of vascular compression, neurologic impairment from nerve compression, or
bowel dy sfunction when tumors arise from the retroperitoneum. Furthermore, the time
interval from first sy mptom to diagnosis appears to be inversely correlated with survival for
pediatric sarcomas (92).
The radiographic workup begins with a plain radiograph. One looks for evidence of soft
tissue mass, calcification, and destruction of adjacent bone. Radionuclide bone scanning is
used to assess metastatic bone involvement, activity in bone adjacent to the tumor, and active
vascular activity in the tumor itself. Arteriography is advocated for delineation of the tumor’s
blood supply, a matter of concern to the surgeon or to the direct infusional chemotherapist.
Computed tomography (CT) and magnetic resonance imaging (MRI) are the essential studies
for clear definition of tumor extent, patterns of infiltration, evaluation of adjacent bone, and
planning surgical and radiotherapeutic approaches. MRI often shows a larger area of
involvement than does CT. The evaluation for distant metastasis focuses on the most common
site, the lungs, with chest radiograph and thoracic CT scanning (59,88,93,94,95,96). Metabolic
scanning techniques, such as thallium scans and PET, are being used with increasing
frequency. PET measures glucose utilization rate in sarcomas and may be used to assess
lesion grade and to monitor neoadjuvant therapeutic response (97,98).
Page 265NRSTS in childhood may be staged by one of two sy stems. A few investigators
still use the rhabdomy osarcoma grouping sy stem, although their number is shrinking (see
Table 11.2 ). This sy stem is convenient and relies on surgical resectability as an important
prognostic factor. There is no doubt that tumor size and resectability are important in
predicting outcome in pediatric NRSTS. In fact, a retrospective analy sis of NRSTS from the
SJCRH has crudely identified three distinct risk groups: (1) grossly resected nonmetastatic
disease (89% 5-y ear survival); (2) initially unresectable, nonmetastatic disease (56% 5-y ear
survival); and (3) metastatic disease (15% 5-y ear survival) (38,99,100) (Fig. 12.6 ).
Adverse risk factors include metastatic disease, tumor size 5 cm, high-grade, positive surgical
margins, intra-abdominal primary tumor site, and omission of postoperative RT in localized
disease. Regarding tumor size as a prognostic factor in sarcoma patients (including
rhabdomy osarcoma and NRSTS), a recent report suggests that there should be an adjustment
for overall patient size (101). The authors noted, for example, that the mortality risk
associated with a patient with a body surface area of 1.75 m 2 and a 5-cm tumor was the
same as for a 0.6 m 2 child with a 2.8-cm tumor. A variation of this prognostic risk grouping
has been continued in the recently closed COG ARST0332 trial as noted below and validated
in a SEER based study (44).
Table 12.7 French Federation of Cancer Centres System of Grading Soft Tissue
Sarcomas
Comparisons between the NCI and FNCLCC sy stem show that up to one-third of cases
have grading discrepancies, but the latter sy stem may be a slightly better determinant of
prognosis, albeit not for every NRSTS subty pe (110,113). The recent COG protocol on
NRSTS has central pathology review; one of its aims will be to directly compare the POG
and the FNCLCC grading sy stems for pediatric sarcomas. Recently, Khoury et al. (114)
directly compared the POG and FNCLCC grading sy stems for pediatric NRSTSs. In this
study, 130 tumors were graded using both the POG and FNCLCC grading sy stems and it was
determined that both grading sy stems were equally effective in predicting event-free survival
(EFS). Interestingly, the POG sy stem appeared to upgrade tumors compared with the
FNCLCC sy stem and conclusion was made that the FNCLCC sy stem was superior to the POG
sy stem for tumors of intermediate grade. Furthermore, the mitotic index cutoff was noted to
be a highly relevant grading parameter needing further study in a prospective trial. To date,
the WHO or other pathology associations have not endorsed any particular grading schema.
Page 267While the clinician may rely on sarcoma grading to make treatment decisions,
one must be aware of the degree of uncertainty in pathologic diagnosis. This problem has a
bigger dimension as the pathologist is increasingly forced to evaluate smaller biopsy
specimens rather than the whole tumor, as newer treatment algorithms involve preoperative
RT or chemotherapy. With smaller specimens, there is an increasing danger of sampling
errors as necrosis, mitotic activity, differentiation, pleomorphism, and other grading aspects
have geographical variability within a particular tumor. Despite advances in molecular
biology, identification of cy togenetic or particular DNA or RNA lesions has not y et supplanted
tumor grading to aid clinical decisions for NRSTS.
Figure:
Risk stratification of nonrhabdomyosarcoma soft tissue sarcomas.
(From Spunt SL, Hill DA, Motosue AM, et al. Clinical features and outcome of initially
unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin
Oncol. 2002;20:3225–3235, with permission.)
Figure: The 2012 American Joint Committee
on Cancer Staging System for Sarcoma of
Soft Tissuea
aThis staging system does not apply to Kaposi sarcoma, fibromatosis (desmoids tumor),
infantile fibrosarcoma, or sarcomas arising in dura mater or brain, parenchymal organs, and
hollow viscera. Staging system now includes gastrointestinal stromal tumors,
dermatofibrosarcoma protuberans, angiosarcoma, and extraskeletal Ewing sarcoma.From
Compton CC, Byrd DR, Garcia-Aguilar J, et al., eds. AJCC Cancer Staging Manual.7th ed. New
York, NY: Springer; 2012, with permission from AJCC.
Figure: POG Grading System for Pediatric
Nonrhabdomyosarcoma Soft Tissue
Sarcomas
Figure: Tumor Differentiation Scores of
Sarcoma in the French Federation of Cancer
Centers System of Grading Soft Tissue
Sarcomas
Figure: French Federation of Cancer Centres
System of Grading Soft Tissue Sarcomas
SELECTION OF THERAPY
Page 268Surgery
Every biopsy should be planned to be consistent with the treatment plan. The two techniques
for biopsy are either via needle or open incisional. Needle biopsy techniques include fine-
needle aspiration (of variable accuracy and dependent on the experience of the
cy topathologist) or core needle biopsy (4). The incision for an open incisional biopsy should
be the minimum that is technically feasible and homeostasis should be secure. Incisions on
the extremity should be along the long axis (96). Muscle compartments should not be crossed;
one does not want to contaminate adjacent areas with tumor. The biopsy should be placed so
that the entire surgical tract will be removed at the time of the definitive operation.
Complete surgical excision is the mainstay of therapy. NRSTS may infiltrate widely.
Sarcomas tend to expand and infiltrate adjoining tissue spaces, producing a pseudocapsule
made up of compressed normal tissue intermingled with microscopic extensions of the tumor.
A sy stem for assessing the adequacy of surgical margins in sarcoma surgery was described
by Enneking et al. (115). An intralesional surgical margin is through tumor, with gross or
microscopic contamination. A marginal resection is through the reactive or inflammatory
zone. A wide excision is through normal tissue outside the inflammatory zone. A radical
excision is outside the anatomic compartment containing the tumor. A wide excision or
amputation often is needed to obtain the microscopic-free margin needed for control. Clinical
experience, primarily in adults, has shown that the local failure rate for simple excision of
malignant soft tissue sarcomas is 60–90% (59,88,116). This failure rate falls to 18–30% when
simple excision is replaced by radical resection, radical compartmental resection, or
amputation above the proximal joint (6,69,96,117,118,119,120). In a pediatric series, the 5-
y ear survival rate was higher for complete tumor excision than for partial excision (47). For
low-grade lesions, wide excision with negative margins may be curative as the sole treatment
(42,118). Surgical margins of at least 1.0 cm around gross tumor are preferred for optimal
local control (121). In cases of positive margin or unanticipated finding of NRSTS on
marginal excision, a re-excision should be strongly considered (122).
There are many patients for whom limb-sparing treatments may be considered and
preferred (119,120,123,124,125). Limb-sparing surgery removes a soft tissue sarcoma, while
preserving the extremity with a satisfactory functional and cosmetic result. To achieve results
comparable to those of radical procedures, most limb-sparing procedures involve the planned
use of preoperative or postoperative external beam irradiation, brachy therapy, or intra-
arterial or sy stemic chemotherapy. But regardless of adjuvant RT or chemotherapy, resection
with negative surgical margins is critical for optimal local control (126). In the presence of
planned RT, resection margins may be relatively tight within millimeters, but if surgery alone
is planned, margins greater than 1.0 cm are likely required along with an en bloc resection
bey ond any tumor pseudocapsule (127). For tumors abutting bone, stripping off the
periosteum en bloc is usually sufficient in the absence of any direct bone invasion; however,
the addition of RT in thigh sarcomas may entail a higher risk for later development of femoral
bone fractures (128). Other investigators have observed an increased risk of bone fractures as
simply a function of high radiation dose delivery and not necessarily related to periosteal
resection (129,130). Sarcomas that involve neurovascular bundles are challenging clinical
problems, in which surgical and adjuvant radiotherapeutic management must be
individualized regarding the sacrifice of blood supply or nerves.
Limb-sparing surgery is clearly not appropriate for some patients. These patients include
y oung children who may deal better with an amputation than with the limb-length
discrepancy that may occur with limb-sparing procedures, those with extremity lesions
where it is not possible to acquire adequate surgical margins and where RT may produce
major long-term complications, those with lesions that involve major vessels or nerves where
resection will severely compromise function, and those in whom a fracture has resulted from
tumor and the limb is useless and painful (117,123). Simply put, in the skeletally immature
patient, due consideration must be given to the possibility that inappropriate or incorrectly
administered RT may produce a stiff, painful, shortened, or disfigured extremity and
engender a risk of secondary malignancy. Therefore, in some situations amputation may be
preferred.
The role of regional ly mph node dissection in NRSTS is evolving. Overall, the incidence
of nodal involvement is about 4%, ranging from close to 0% for grade 1–12% for grade 3
(6,61). It is reasonable to biopsy enlarged regional nodes in high-grade primary tumors.
Certain histologic subty pes are more prone to ly mphatic spread, including epithelial and
sy novial sarcomas, while others are not. Kay ton et al. (131) has published a small series using
sentinel node biopsies in pediatric tumors suggesting its utility in NRSTSs that are at risk for
ly mphatic spread.
Surgery also play s a role in managing NRSTS in the treatment of pulmonary metastases
(132,133). With proper patient selection, long-term survival is possible for those undergoing
removal of pulmonary metastases. Preoperative evaluation with chest radiograph and
thoracic CT scanning is performed to determine the number and location of the metastases.
Tumor may be resected via a median sternotomy or lateral thoracotomy. Two studies in the
literature, both of which included adult and pediatric patients, evaluated the important
prognostic factors predicting survival after pulmonary metastasectomy. Higher survival rates
appear to be associated with complete resection of all metastases, the presence of few lesions
(i.e., 1–3), and a long disease-free interval before the development of metastases. Patients
rendered free of disease in the series of Jablons et al. (134) had a median survival of 26.8
months. A similar group in the series of Casson et al. (135) had a median survival of 28
months. It is only fair to note that there are no randomized series in the literature comparing
surgery with observation or with chemotherapy without resection. Therefore, it cannot be
proven that the apparent prolongation of survival after surgery is attributable to the surgical
therapy as opposed to good tumor biology (134). As an alternative to surgical resection of
oligometastatic disease, there is an evolving experience with high-dose ablative and
hy pofractionated stereotactic body radiosurgery (136,137,138). With some of these
radiosurgical techniques, the surgeon may be asked to assist with the placement of radio-
opaque fiducial markers into the tumor mass to facilitate precise radiation dose delivery with
minimal normal tissue exposures.
Page 269Radiotherapy
We have previously noted that the local control rate for NRSTS increases as the extent of
surgical resection increases. This is undoubtedly because more radical surgery extirpates
microscopic extension of tumor. It is well known that radiation can also sterilize microscopic
extensions of tumor (139). We may infer that radiation can be used to accomplish that which
is achieved by increasing the extent of surgery (96). The judicious combination of limited
surgery and RT should be able to achieve local control rates equivalent to those of radical
surgery, with a superior functional result in many cases. Most of the available data support
this line of reasoning (96,125,139,140,141).
POG protocol 8653 was designed to study the role of adjuvant chemotherapy in children
with resectable NRSTS (142). Local therapy was standardized to include surgery only for
patients with wide or radical margins and surgery with postoperative irradiation for marginal
excisions. Protocol guidelines were imperfectly followed. The results indicate higher local
control rates with RT for marginal excisions in high-grade tumors (143) (Table 12.8 ).
There will be situations in which radical surgery is not recommended for children or is
recommended and declined because of unacceptable functional, cosmetic, emotional, or
psy chological consequences. RT may play a crucial role for these patients by allowing more
conservative surgery with equivalent rates of local control.
Table 12.8 POG Protocol 8653: Local Control by Surgical Margins and Radiotherapy
Page 270
Table 12.9 Factors Affecting Local Relapse in NRSTS in the St. Jude Children’s Research
Hospital Retrospective Reviews
While there are considerable concerns with delivering high-dose RT to children with
NRSTS due to developmental defects and an increased risk for secondary cancers, the role of
RT for high-grade, incompletely resected, or recurrent soft tissue sarcomas in adults is well
established. There is one randomized trial of surgery alone versus surgery and postoperative
RT for extremity soft tissue sarcomas. In this small study from the NCI, 91 patients with high-
grade lesions were randomly assigned to surgery plus postoperative chemotherapy with or
without postoperative adjuvant RT. Another 50 patients with low-grade lesions were
randomized to surgery plus adjuvant RT or surgery alone (150). RT to 45 Gy in 25 fractions
was delivered to a wide field followed by a boost for an additional 18 Gy to the tumor bed.
Among the patients with high-grade lesions, there were no local recurrences in the patients
who received RT, while for patients receiving only adjuvant chemotherapy, the actuarial local
failure rate was 22% at 10 y ears of follow-up. For patients with low-grade sarcomas, the
local relapse rates were 4% versus 33% for those receiving postoperative RT and resection
alone, respectively. As half of the “low-grade” patients had my xoid liposarcoma (possibly
undergraded) or desmoid tumors (known to respond to RT), this small randomized trial is not
definitive. Indeed, other retrospective studies of low-grade soft tissue sarcomas with a wide
resection generally have very low local recurrence rates, especially for superficial tumors.
Regardless, within this NCI trial, there was no influence of postoperative RT on overall
survival for either high- or low-grade tumors.
A common conundrum occurs when anticipating that there will be positive or close
margins at the time of surgery. For patients undergoing preoperative radiotherapy who are
found to have close or positive surgical margins when they ultimately undergo surgery,
postoperative radiotherapy has historically been a consideration. Such microscopic tumor
residua in the surgical bed may still be destined to die from the prior effects of radiotherapy,
however. Recent data from the several investigators suggest that there is little benefit to this
practice of delivering a postoperative boost in fact (151,152). Another consideration when
balancing potential toxicities and local control benefit from radiotherapy is to plan on the
integration of either brachy therapy or intraoperative radiotherapy directed at the surgical
bed. Placement of afterloading hollow catheters in conjunction with surgical resection helps
to better localize radiation dose where it is needed most. This is discussed below including
later in this chapter under radiotherapy techniques.
One such adult randomized RT trial from the Memorial Sloan–Kettering Cancer Center
(MSKCC) shows a benefit for high-grade extremity sarcomas managed with surgery and
brachy therapy (153). After complete resection of either extremity or superficial trunk soft
tissue sarcoma (45 low grade, 119 high grade), patients were randomized to surgery alone
versus low-dose-rate brachy therapy using afterloaded Ir-192 to deliver a dose of 45 Gy to
the tumor bed. In patients with high-grade sarcomas, the 5-y ear local control rates were 91%
with brachy therapy compared with 70% with surgery alone. There was no benefit to
brachy therapy for the low-grade tumors. Moreover, there was no difference among the
patient groups from brachy therapy in terms of distant metastasis or disease-specific survival.
The other major phase III study in adult sarcoma patients compared preoperative versus
postoperative RT (154). The theoretical advantage of preoperative RT is a smaller volume as
well as a lower dose of RT that must be employ ed. The RT need only be directed at the gross
tumor with a several centimeter margin, rather than having to encompass the larger surgical
resection bed. In the postoperative setting, higher radiation doses are generally employ ed to
counter any potential incremental tumor hy poxia or clonogenic repopulation during the
healing phase after surgery. Thus, preoperative RT in this setting tends to employ a radiation
prescription of 50 Gy compared with 64–70 Gy in the postoperative setting. The major
disadvantage of preoperative RT is a relative impairment of wound healing with a higher risk
of dehiscence and infection. Nevertheless, the concept of preoperative RT for NRSTS has not
been extensively studied. Certainly, there could be an improvement in function and lower risk
of secondary cancers with this approach.
More specifically, this Canadian trial comparing preoperative and postoperative RT
enrolled 190 patients, most more than 50 y ears old. The trial was open from 1994 to 1997 and
included patients with limb MFH, liposarcoma, leiomy osarcoma, and other spindle-cell
sarcoma histologies. Half received 50 Gy of preoperative RT and a 16–20 Gy postoperative
boost for a positive margin. Patients in the postoperative group received 50 Gy and a 16–20
Gy boost. In a planned interim analy sis, the study was terminated early due to higher wound
complications (defined as secondary wound surgery, hospital admission for wound care, or
the need for deep packing or prolonged wound dressings within 120 day s of tumor resection)
with the preoperative as opposed to postoperative RT (35% vs. 17%) (154). In subsequent
publications, the local recurrence rate, regional or distant failure rate, progression-free
survival, and functional outcome did not differ between the groups, with local control rates of
over 90% in both treatment groups at 7 y ears of follow-up (155,156). Of interest, the
postoperative RT patients have experienced greater late toxicity, particularly with greater
functional problems due to fibrosis within the irradiated volume. There were also trends
toward more ly mphedema and joint stiffness in this group contributing to adverse functional
outcomes (157).
Page 271Investigators from the University of Florida have reported on 95 NRSTS
patients, including those who were y oung adults who had resectable disease that was
managed with either preoperative RT to a median dose of 50.4 Gy or postoperative RT to a
median dose of 61 Gy (158). Overall local control was 12% at 5 y ears. Patients with close,
defined as less than 1 cm, or positive margins had inferior local recurrences in 8 out of 30
patients (27%) compared with 4 out of 64 patients (6%) with negative margins. There were
no associations based on grade, but as this was not a randomized trial, low-grade tumors
tended to not be irradiated in comparison to high-grade tumors. Finally, all local recurrences
led to ultimate death of the patient. The COG ARST0332 trial is described in more detail
below in conjunction with chemotherapy indications, but suffice it to say that low-grade,
localized NRSTS patients were divided into two separate schema of surgery alone versus
surgery and postoperative RT based on tumor size, grade, and surgical margins.
In conclusion, acceptable indications for RT in childhood NRSTS are localized,
incompletely resected tumor with gross residual disease; palliation of metastasis (palliation of
pain or compressive sy ndromes requires 35–50 Gy ; however, conventional RT is rarely
effective for gross lung metastases) (6,117); as part of a planned limb-sparing procedure; and
after an attempt at gross total tumor removal when there is microscopic residual tumor or
positive regional ly mph nodes. More attention to preoperative RT in pediatric NRSTS is likely
to become an active area of further investigation with encouraging recent cooperative group
studies mature, as also based on the evolving experience in adult soft tissue sarcomas. For
oligometastatic disease, there is recent enthusiasm for stereotactic body radiosurgery or high-
dose, hy pofractionated conformal RT as an alternative to surgery resection (136).
Chemotherapy
The use of adjuvant chemotherapy in childhood NRSTS initially was defended on the basis of
the significant risk of metastatic disease and local recurrence in high-grade lesions,
retrospective comparisons, and the success of chemotherapy in rhabdomy osarcoma. The
most active single agents are adriamy cin and ifosfamide (159). Other active agents are
dacarbazine, actinomy cin D, vincristine, etoposide, and cy clophosphamide
(6,59,69,88,94,104,118,145, 160,161). In this section of the chapter, we will review the most
pertinent larger-scale studies.
POG 9553 was a phase II trial of vincristine, ifosfamide, and doxorubicin in unresected
or metastatic NRSTS (12). Surgery was considered at week 7 with RT thereafter. Radiation
doses were age dependent: 54 Gy if under the age of 6 y ears and 64 Gy for those older.
Pulmonary metastasis management included low-dose whole-lung RT, although this is
currently a controversial practice. Doxorubicin was withheld during RT. Results were reported
for 39 patients. The 3-y ear overall survival and progression-free survival rates (± standard
deviation) for eligible patients were 59% ± 8% and 44% ± 7%, respectively. There was
suggestion that sy novial cell sarcomas responded better to chemotherapy compared with
other histologies.
Page 272The German soft tissue sarcoma study, CWS-81, was initiated in 1981 under the
auspices of the German Society of Pediatric Oncology. This study was open to children with
rhabdomy osarcoma, undifferentiated sarcoma, EOES, sy novial sarcoma, leiomy osarcoma,
peripheral PNET, fibrosarcoma, hemangiosarcoma, neurofibrosarcoma, and liposarcoma.
For the purposes of this chapter, we will confine our discussion to the results concerning
NRSTS, exclusive of EOES and PNET. Patients with localized, completely resected disease
received vincristine, actinomy cin D, cy clophosphamide, and adriamy cin. Patients with
grossly resected tumor, microscopic residual disease, and no evidence of regional node
involvement received the same chemotherapy, but also had involved-field irradiation. These
patients were then treated with vincristine, actinomy cin D, and cy clophosphamide. Patients
with grossly resected tumor with microscopic residual disease and regional nodal
involvement, or those with incomplete resection or biopsy with gross residual disease, initially
received four-drug chemotherapy. Those who were good responders continued on this
chemotherapy and received involved-field irradiation; ultimately, the adriamy cin was
discontinued. Those who were poor initial responders received involved-field irradiation, but
ifosfamide was substituted for cy clophosphamide. Patients who had stage IV disease
received vincristine, actinomy cin D, ifosfamide, and adriamy cin. In 1984, ifosfamide was
also added for patients with stage III disease who did not respond to preoperative
chemotherapy. Detailed information is available concerning the 30 children and adolescents
with sy novial sarcomas treated on this study (163). A survival rate of 70% was observed, with
a median observation time of 34 months. Patients with sy novial sarcoma of the extremities
had a disease-free survival rate of 88%. Six of eight patients who had their tumors resected
with no residual disease are disease-free survivors, seven out of nine patients who had their
tumor resected with microscopic residual disease are disease-free survivors, six of eight
patients who have had their tumor resected with gross residual disease are disease-free
survivors, and three of five patients with metastatic disease at presentation (stage IV) are
disease-free survivors. Obviously, the German study was not a head-to-head comparison of
chemotherapy and observation, and it is not clear what the survival would have been if
patients were treated with local therapy alone.
The International Society of Pediatric Oncology (SIOP) has conducted two protocols for
NRSTS. The treatment program consisted of primary complete tumor excision, if feasible
without mutilation. For patients who were not resectable initially, neoadjuvant chemotherapy
was administered. Initial chemotherapy was ifosfamide, vincristine, and actinomy cin D.
Second-line chemotherapy on study MMT84 was cy clophosphamide and doxorubicin, and in
study MMT89 it was epirubicin, doxorubicin, carboplatin, and VM26. Patients were then taken
to surgery, if possible. RT was used for macroscopic residual tumor after surgery. For patients
who had initial primary excision, adjuvant chemotherapy was given with ifosfamide,
vincristine, and actinomy cin D. In nonmetastatic patients an initial complete excision was
obtained in 24% of patients, complete response was obtained in 30% of patients by initial
partial excision followed by chemotherapy, and a complete response was obtained in 30% of
patients by an initial biopsy, neoadjuvant chemotherapy, and second surgery. In 8% of
patients, a complete tumor response was obtained by surgery, chemotherapy, and RT, and in
another 8% of patients complete response was obtained by surgery, chemotherapy, second
surgery, and RT. Therefore, 16% of patients received RT. The overall survival rate in study
MMT84 was 73% at 5 y ears for nonmetastatic patients, and in MMT89 it was 84%. Survival
was only 15% for metastatic patients. The 5-y ear survival rate was 60% for fibrosarcoma,
leiomy osarcoma, sy novial sarcoma, and other classified sarcomas and 50% for PNET and
EOES (45,164). Very y oung patients represent a considerable challenge in which surgery is
performed with very tight margins, chemotherapy has to be attenuated due to altered
metabolism of drugs, and RT is generally avoided. A report from SIOP that included 38
patients with NRSTS treated on the MMT84 and MMT89 protocols suggested that patients less
than 1 y ear of age at diagnosis had similar survivals to older patients (75% in infants and 71%
in older children, p = 0.61) (165). Data were not specified for the subset of nonmetastatic
tumors.
(From Pratt CB, Pappo AS, Gieser P, et al. Role of adjuvant chemotherapy in the treatment
of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric
Oncology Group study. J Clin Oncol. 1999;17:1219–1226, with permission.)
Figure:
Treatment schema in COG ASRT0332 trial.
RADIOTHERAPEUTIC MANAGEMENT
RT for childhood NRSTS may be administered after biopsy but before definitive surgery
(preoperatively ), postoperatively, or intraoperatively. The arguments for preoperative
irradiation include the following. First, preoperative treatment will produce partial regression
of the tumor, and the resection may be less extensive than if the surgery had been done
initially. Second, preoperative treatment may decrease the risk of autotransplantation of the
tumor in the surgical bed and may also decrease the risk of intravascular seeding. Third, in
preoperative treatment, the clinically and radiographically demonstrable areas of risk are
treated, while other tissues are shielded (184,185). In addition, because postoperative
treatment must cover all surgically manipulated areas, the irradiated volume often is larger.
Finally, the postoperative surgical bed may be poorly vascularized. The concern regarding
tumor cell hy poxia in this setting has led to higher radiation doses being required. Results of
the Canadian randomized trial suggest an equivalence of 50 Gy preoperatively to 66–70 Gy
postoperatively (154,156).
Some of the results of preoperative RT in combined adult and pediatric series of NRSTS
from single institutions are also promising. Suit and coworkers (96,119) achieved an 88% 5-
y ear actuarial local control rate and a 66% survival with limited surgery and RT in 258
patients with extremity and head and neck primaries. These results have been echoed in other
studies (102,186). Eilber et al. (125,127) administered preoperative external beam irradiation
and intra-arterial doxorubicin (30 mg/day for 3 day s) followed by limb-sparing surgery for
extremity sarcomas. The local control rate was 96% for patients who received 35 Gy, 90–
95% for those who received 28 Gy, and 82% for those who received 17.5 Gy.
The disadvantages of preoperative therapy include a delay in the start of definitive
surgery, loss of ability to examine the whole tumor specimen for stage and grade, and loss of
the ability to surgically assess the extent of the disease. Therefore, many radiotherapists and
surgeons favor postoperative treatment. Postoperative RT must be delay ed until adequate
wound healing has occurred (96,119). A retrospective review comparing preoperative and
postoperative external beam irradiation from the University of Minnesota for adults with
NRSTS found no significant difference in overall or relapse-free survival or local control.
However, wound complications were more common in preoperative RT patients (31% vs.
8%, p = 0.0014) (184). Several other centers have performed retrospective comparisons of
preoperative and postoperative irradiation in series of largely adult patients. Some studies
favor preoperative treatment (96,187); others do not (117,188). The aforementioned
randomized trial of preoperative versus postoperative RT conducted at the Princess Margaret
Hospital for adult patients with soft tissue sarcomas presents the best data supporting
preoperative RT (154,155,156,157). While there were more problems with wound healing
after RT as compared with postoperative RT (35% vs. 17%, p = 0.01), proper selection of
patients and surgical attention to avoiding tension on the surgical wound may help mitigate this
problem. Preoperative RT uses lower radiation doses (50 Gy vs. 66–70 Gy ) and smaller
treatment volumes. This translates into lower late complications with fibrosis, ly mphedema,
and joint stiffness. And importantly, the local and distant control of disease is equivalent with
the two approaches of preoperative versus postoperative RT.
Page 276Most agree that wound complications are higher with preoperative treatment
(187,188). When the therapeutic plan includes external beam radiotherapy (EBRT) and
surgery for the local treatment of NRSTS, it is generally preferable to completely excise
small lesions and treat with postoperative irradiation when indicated. Small, low-grade lesions
resected with good surgical margins may be observed. Resected tumors with high-risk
features, including large-size, high-grade, or positive surgical margins should be considered
for postoperative RT. High-grade tumors that have been cleanly resected have controversial
indications for postoperative RT due to the concerns about late effects. As noted above, the
COG ARST 0332 trial allocated small, high-grade, negative-margin tumors to surgery alone,
while in adult practice some of these patients might be treated with adjuvant radiotherapy.
Positive surgical margins (group II disease) are a clear indication for postoperative RT.
Paulino published a series of 83 NRSTS patients managed at the University of Iowa (50).
Overall local control rate at both 5 and 10 y ears was 66%. On multivariate analy sis, the size
of the tumor and postoperative RT were prognostic factors for local control. Twenty -five
patients had positive surgical margins. Five-y ear local control rates were significantly
improved with the use of RT, 82% versus 43%, p = 0.04. In a subset of 13 group I patients with
low-grade, small tumors, surgery alone resulted in no local recurrences. On the other end of
the spectrum of localized NRSTS, most large lesions, particularly of high grade, are better
treated with biopsy, preoperative irradiation or chemoradiation, and then excision. While the
actual evidence for postoperative radiotherapy in the pediatric setting after surgical resection
in NRSTS is sparse, there is support as nicely reviewed by Million and Donaldson (189).
Volume
Extremity NRSTSs tend to grow in a longitudinal fashion by following muscle groups.
Historically, generous proximal and distal margins bey ond the tumor volume (5–10 cm) have
been used. Because the lesions usually do not cross muscle compartments, the
circumferential margins may be more modest (120). Krasin and colleagues have reported on
a small series of 32 high-grade NRSTS cases in which 2-cm margins around gross tumor
volumes were chosen (190). Median doses for preoperative and postoperative radiotherapy
were 45 Gy and 60 Gy, respectively. The 3-y ear local recurrence rate was 4%. Local
recurrences were in the high-dose radiation volume and correlated with those patients who
had marginal resections.
A limb MRI scan, followed by a computerized treatment plan, is extremely helpful.
Peritumoral edema within a muscle compartment seen on MRI scanning has a high likelihood
of harboring microscopic tumor and should be targeted (191). The treatment of sarcomas
often is a venue for the demonstration of the benefits of intensity -modulated radiation therapy
(IMRT), three-dimensional (3D) treatment planning techniques, tissue compensators, wedges,
customized blocking, and rigid immobilization for reproducible treatments. The use of
intensity -modulated radiotherapy to better conform the high-dose radiation distribution to the
tumor region may well reduce developmental toxicities, but comes with the theoretical
problem of increased integral dose which may increase the later risk for secondary cancers
(192,193). One should avoid high-dose irradiation of the entire width of a limb in order to
avoid severe ly mphedema (radiation-induced elephantiasis) (117). Blocking should be used to
avoid the anky losis attendant to the high-dose irradiation of the full width of a joint (139).
Growth plates should be shielded when possible (although it is usually better to fully treat a
growth plate and shorten a limb rather than asy mmetrically irradiate a growth plate and
angulate a limb). There is also an evolving understanding that fractures may be minimized by
reducing the volume of bone, especially weight-bearing bones such as the femur, being
treated to high doses (129,130). The use of IMRT and proton RT is under investigation in this
regard. In nonextremity lesions, the tumor volume must be covered with as generous a
margin as is feasible. In children with NRSTS, there may be a more compelling reason to use
IMRT or protons to reduce the exposure of normal tissues. In fact, particle therapy, such as
protons, is enthusiastically under investigation and has shown preliminary benefit in Ewing
sarcoma and rhabdomy osarcomas (194,195,196). Limiting the high-dose regions to the
affected muscle compartment, while reducing dose to adjacent bone, growth plates, joints,
other muscle groups, skin, and uninvolved neurovascular bundles, may result in better
functional outcomes and less developmental toxicities. IMRT also facilitates differential
dosing or a dose gradient between gross tumor and adjacent normal tissues, which can be
important in limiting toxicities or escalating radiation dose in cases of unresectable disease.
For instance, with retroperitoneal sarcomas, investigations are underway in adults to deliver
higher preoperative doses within the target volume where a tight surgical margin is
anticipated, while potentially lowering dose to the intestines and kidney. Similar concepts are
adaptable to childhood NRSTS. The rational reduction in radial margins with these techniques
requires the technical advances of cross-sectional imaging with 3D treatment planning, an
anatomic understanding of tissues at risk, and precise immobilization and field verification.
Epithelioid sarcoma and sy novial sarcoma may metastasize to ly mph nodes in 10–20%
of cases (5,59,197,198,199,200). Some phy sicians use elective ly mph node irradiation for
these lesions, particularly high-grade tumors. Its efficacy is unknown.
Page 277Dosage
Modern radiobiologic evidence gives little credence to the assertion that NRSTSs are
inherently radioresistant. The available retrospective reviews suggest that a minimum of 40
Gy is necessary for the postoperative control of microscopic NRSTS in children (88,116). At
these dosages, however, there is a substantial chance of local failure. More aggressive
treatment is generally warranted. Several investigators favor a dosage of 50–60 Gy using a
shrinking field technique (96,117,201). In a University of Florida series for excised pediatric
NRSTS tumors, 54 Gy appeared to be an adequate total dose (143,202). Although
hy perfractionation is out of favor after a negative randomized trial in rhabdomy osarcoma
(203), some clinicians have suggested the use of twice-a-day irradiation (i.e., 1.1–1.2 Gy
twice daily to 66–72 Gy ) (67,117). In adults, however, a retrospective analy sis from the M.
D. Anderson Cancer Center suggests that cumulative doses of at least 64 Gy are optimal
(204). Another analy sis from the University of Chicago suggests 60 Gy is adequate with no
benefit to higher postoperative doses when there are negative surgical margins, but poor
lower control with lower doses (179). As previously noted, the COG ARST 0332 trial
employ ed 55.8 Gy in 31 fractions as a standard postoperative RT dose (15).
For preoperative treatment, lower radiation doses may be used on the order of 50 Gy.
The COG ARST 0322 trial used 45 Gy for a preoperative radiotherapy dose (15). The
administration of additional radiation given postoperatively if there are positive surgical
margins is now considered controversial (151). Historical experience in the POG used
different radiation dose levels depending on age, which has become a less favored concept.
POG protocol 8653 intended that unresectable (i.e., group III) tumors receive preoperative
RT to 55 Gy for children less than 6 y ears of age and 65 Gy for older children. At least six
patients—out of an unclear number of group III patients—had an insufficient response and
could not undergo planned resection (14). POG 9553 used either 54 or 64 Gy (depending on
the age of the child), following initial chemotherapy, in a prospective series of 25 children
with group III NRSTS. This preoperative management resulted in a 3-y ear overall survival
rate of 80% and progression-free survival of 60% (12). A retrospective series from St. Jude
Children’s Research Hospital of 27 patients with localized unresected NRSTS and a 33% 5-
y ear EFS included 15 patients who received preoperative RT, most often with chemotherapy ;
the RT doses ranged from 35 to 65 Gy, but these dose tallies included some component of
postoperative RT (100). As one of the larger of such series, there is no clarification of optimal
radiation doses for group III NRSTS patients such that the adult experience gives the best
guidance for the present. But as previously noted, COG ARST 0332 employ ed a preoperative
RT dose of 45 Gy, modestly less than the 50 Gy standard used for adults.
When intraoperative boosts with brachy therapy or electrons are given as part of a
combined approach, the dosage usually is 10–20 Gy. Gross residual sarcoma requires 65–72
Gy by external beam and implant (40,119,120). Some adult patients with unresectable lesions
have been treated with external beam and intravenous radiosensitizers, external beam plus
hy perthermia, combined brachy therapy and interstitial hy perthermia, or neutron beam
therapy (42,205).
The second general technique of pediatric brachy therapy for NRSTS involves
permanent interstitial implant. Low-activity iodine-125, gold-198, or palladium-103 seeds are
used. They may be placed with the use of a seed gun (a device used for their implantation),
through individual needles, or embedded in Vicry l suture material and then sewn into the
tumor bed. Although the low energy of these radioactive sources lowers the risk to visitors,
these implants often are extremely difficult to perform.
The third form of brachy therapy for pediatric NRSTS is remote afterloading. This may
be done at a low-dose rate, high-dose rate, or pulsed-dose rate (intermittent use of a high-dose
rate machine). The catheters or applicators are inserted into, or placed on, the tumor site.
They are then connected to the afterloader for remotely controlled radioactive loading. The
radioactive sources are retracted into the high-dose rate applicator’s vault during planned
interruptions. The procedure may be done in an outpatient clinic or operating room. Some
departments have specially designated rooms for this purpose. Intraoperative high-dose rate
brachy therapy is a modification of this general technique (209,210,211,212,213,214).
In the treatment of NRSTS, brachy therapy may be used as a boost after or before EBRT,
or as a form of irradiation monotherapy (100). In general, the planning volume for
brachy therapy for NRSTS is smaller than for EBRT. In brachy therapy, the volume treated
closely approximates the clinical target volume. There is no need to allow for internal organ
movement, patient movement, or setup errors. Because the dosage from the radioisotope falls
off rapidly, the volume of normal tissue irradiated outside the planning target volume is
minimized.
Page 279When brachy therapy is the sole form of irradiation to be given, surgical drain
sites usually are not implanted. In adult practice, if 45–50 Gy of external irradiation is given
as part of a course of treatment, the brachy therapy boost generally is 10–20 Gy at about 50
cGy per hour. If brachy therapy is the sole form of irradiation used in combination with
surgery, then 40–50 Gy in 4 or 5 day s is given. The role of brachy therapy in adult NRSTS has
been evaluated in several retrospective reviews, but some randomized prospective trials are
particularly noteworthy. Between 1982 and 1987, 126 patients, mostly adults, with soft tissue
sarcoma were entered into the aforementioned prospective randomized trial at MSKCC
(153,215). Patients underwent a grossly complete resection with a limb-sparing operation for
NRSTS of the extremity or superficial trunk. Intraoperatively, after the resection was
complete, patients were randomized to receive either adjuvant brachy therapy or no adjuvant
therapy. Patients who received the implant had a dosage of 42–45 Gy administered with
iridium-192 over a 4- to 6-day period. The median follow-up of this trial was 76 months. The
5-y ear actuarial local control rate for high-grade tumors was 89% for brachy therapy -treated
patients and 66% for control subjects (p = 0.0025). There was no local control benefit in the
low-grade tumor group.
The improved local control with brachy therapy in high-grade tumors did not translate
into an overall decrease in distant metastasis. Even in the high-grade tumor, freedom from
distant metastases was approximately 70% at 5 y ears in both the brachy therapy and control
arms (215,216). This trial is of interest not only because it demonstrated a benefit to adjuvant
brachy therapy but also because it showed a benefit to a form of therapy that, in contrast to
adjuvant external beam irradiation, generally does not irradiate the full surgical scar, does not
irradiate the drain site, is shorter in duration (10–14 day s of hospitalization vs. 6–7 weeks of
outpatient treatment), and is slightly less costly.
Page 280The team from MSKCC elected to explore the use of brachy therapy in low-
grade tumors in more detail because their initial randomized trial did not include a large
number of patients with low-grade NRSTS. From 1982 to 1992, they randomized 45 patients
with low-grade tumors to brachy therapy or observation. There was no benefit to
brachy therapy in terms of local recurrence (about 76% local control in each arm, p = 0.60)
or overall survival (p = 0.38). In two studies, patients with high-grade NRSTS with a negative
margin had 89% and 94% local control rates, respectively, when treated with brachy therapy,
compared with 59% and 77% in those with a positive margin. In patients with high-grade
tumors and positive margins treated with brachy therapy and external beam irradiation, the
local control rate was 90% (209,215,217). In the view of the investigators, these two
randomized trials argue in favor of adjuvant brachy therapy for resected high-grade tumors,
for surgery alone as the treatment for resected low-grade tumors smaller than 5 cm, and for
consideration of external beam for resected low-grade tumors larger than 5 cm because of
the remaining high risk of local recurrence in these tumors (i.e., 20–25%). In the early y ears
of the MSKCC trials, there was a substantially higher rate of wound complications in the
brachy therapy -treated patients than those in control subjects (44% vs. 14%, p = 0.0006). The
higher rate of complications has been alleviated by a policy of not loading patients with
radioactivity until the fifth postoperative day (216). Burmeister et al. (210), in Australia,
obtained slightly less satisfactory results with brachy therapy and external beam therapy in
patients with large high-grade sarcomas with close or positive margins. When brachy therapy
is used as the only form of RT, some of the local failures result from marginal misses
(140,208,215,218). In the Institut Gustave–Roussy series, 14 of 16 local failures were
marginal or distant from the high-dose brachy therapy region (218).
Data from approximately 100–150 children given brachy therapy for the treatment of
rhabdomy osarcoma and NRSTS have been reported. The techniques have included low-dose
rate applications, high-dose rate applications, and pulse applications. Although the local
control rate is excellent, it is clear from the retrospective reviews that careful patient selection
is essential for successful outcomes. In general, brachy therapy seems to be most appropriate
for patients who have NRSTS, microscopic small-volume residual disease at an accessible
site and for those who have responded well to chemotherapy, external beam RT, and surgery.
The American Brachy therapy Society ’s recommendations for brachy therapy for soft tissue
sarcomas offer general guidelines as to the appropriate dosage. When brachy therapy alone is
used, 45–50 Gy is administered over 4–6 day s. For patients in whom low-dose-rate
brachy therapy is used in combination with EBRT (generally 40–50 Gy ), a 15- to 25-Gy boost
is given. There are few clinical data to invoke in selecting dosages for fractionated high-dose-
rate brachy therapy. When high-dose-rate therapy is used as the sole local control modality, a
dosage of 2.5–3 Gy twice daily, to a total dosage of 30–36 Gy, may be considered (213,214).
If high-dose-rate brachy therapy is used as a boost to EBRT, then the linear quadratic model
can be used to devise a fractionated scheme that generates the equivalent to a low-dose-rate
brachy therapy dosage of 15–25 Gy (212,213).
What are we to conclude, on the basis of
these NRSTS studies, concerning the role of
brachy therapy in pediatric patients?
Brachy therapy should be considered as an
option in treating children. It has the ability to
deliver a highly localized dose while sparing
normal tissue (Fig. 12.11 ). However, in
children, brachy therapy poses problems of
inpatient management: can the child provide his
or her own feeding, bodily care, and immediate
needs while radioactive? If not, will there be an
unacceptable exposure to nursing personnel or to
the parents during the implant? Several solutions
have been proposed. One is to use a remote
afterloading brachy therapy machine. If a high-
dose-rate remote afterloader is used, the
duration of the radiation exposure is short and
personnel exposure is minimized. The drawback
is that the dose rate is so high that some of the
normal tissue-sparing benefits of brachy therapy Figure 12.11 The volume selection for
may be lost. To address this latter concern, some pediatric brachytherapy for NRSTS is
phy sicians pulse or fractionate the highly nuanced. In many cases, the
brachy therapy (i.e., use multiple exposures). As patient has been treated with induction
an alternative, one can use a remote afterloader chemotherapy or EBRT. Often one cannot
with conventional activity sources. In this way, be sure whether a partial response of
the duration of the implant is no different than gross tumor implies a complete response
with conventional afterloading. However, the of all or part of the initial occult disease
sources can be withdrawn whenever nursing volume. Consider the following
personnel or a parent enters the room for a hypothetical example: I: An NRSTS is
planned feeding, wound care, bathing the child, shown near an epithelial surface. The
and so on. A third way to deal with the particular bulky tumor’s left-to-right dimension is
problems of brachy therapy in a child is to use noted by line AB. Let us assume that the
iodine-125 instead of iridium-192. The treatment tumor is treated with induction cytotoxic
energy for iodine-125 is 28 keV, compared with therapy and that it regresses. II: The left-
380 keV for iridium-192. The lower energy of to-right dimension, demarcated in
iodine-125 reduces exposure to clinical staff and relation to line AB, has shrunk. If the
family, allows more efficacious shielding with brachytherapy volume is denoted by the
lead drapes, and reduces exposure to normal bracketed area, then the irradiated
tissue at a distance from the implant. The iodine- volume will be adequate. III: On the other
125 may be embedded in suture material or hand, assume that the tumor regressed
absorbable mesh (216). significantly but that the total left-to-
Page 281Intraoperative radiation therapy right dimension did not change. If the
(IORT) has been described for the treatment of brachytherapy volume is addressed only
NRSTS (219). There are two general forms: to the readily palpable or visible tumor,
intraoperative electron beam therapy (IO-ERT) as shown by the bracketed area, then a
and intraoperative high-dose rate brachy therapy large portion of the tumor will be missed.
(IO-HDRBT). There are three techniques for
administering IO-ERT. Historically, patients underwent surgery in the operating room and
then were transported, using specialized sterile techniques, from the operating room to the
radiation oncology department. The linear accelerator suite was draped and prepared as a
temporary operating room.
The accelerator was “docked” to a cone used to demarcate the area that the phy sicians
wanted to irradiate. A single large fraction of electrons was administered. Normal tissue was
spared by retraction and shielding. A second technique involved placing a linear accelerator
in the operating room as a dedicated IO-ERT device. Of course, this necessitated reinforcing
the weight-bearing capacity of the floor of the operating room, particularly if it was located
in an upper floor of the hospital. The accelerator was only used for its electron-generating
capabilities, so the purchase of a conventional linear accelerator with photon and electron
capabilities wasted the photon capabilities of the machine. This problem was addressed by the
third technique for IO-ERT: the development of an electron-only dedicated linear accelerator
for placement in the operating room. Such devices are now available and can be moved from
operating room to operating room. Because they generate only electrons, shielding needs for
the walls, floor, and ceiling of the operating room are minimal.
Some authorities view IO-HDRBT as an alternative to IO-ERT or an adjunct to it.
Intraoperative electrons often cannot treat inaccessible or highly contoured sites such as the
base of the skull, the pelvic sidewall, the deep pelvic area, or angled areas in the abdomen or
thorax. The IO-HDRBT device uses flexible applicators and catheters to treat almost any
surface. Retraction and shielding are used to spare critical normal structures. A single high-
activity iridium-192 source is used, and one can customize the dose distribution. However,
one is constrained by the penetration attendant to iridium-192. There is very limited clinical
experience with the use of IORT to treat childhood NRSTS. In small series of highly selected
patients, excellent local control rates have been achieved. The generally recommended
dosage, if 40–50 Gy of EBRT is used, is an IORT boost of 10–15 Gy (211,212,213,214,219).
When NRSTS in children is localized and amenable to definitive surgical excision or limited
excision plus RT, the survival probability is 60–90%. The 5-y ear EFSs in the retrospective
reviews from St. Jude Children’s Research Hospital are group I, 83% group II, 65% group IV,
approximately 9% groups I and II and less than 5 cm, 92% groups I and II and more than 5
cm, 55% (6,38). In the May o Clinic series, the 10-y ear EFS was 76%. A worse prognosis is
associated with high stage, high grade, and tumor size greater than 5 cm (48). The 5-y ear
disease-free survival for children with NRSTS of the head and neck in the M.D. Anderson
Hospital series was 75% (43). For patients with stages I–III NRSTS treated on SIOP trial
MMT84, the 5-y ear survival rate was 73% and it was 80% for trial MMT89 (45,164). A
multivariate analy sis of predictive factors for local tumor recurrence in the Roy al Marsden
series of NRSTS (adults and children) showed significant worsening of the risk for local
recurrence with retroperitoneal versus lower limb tumors, high grade versus low grade, and
inadequate surgical margins. Metastases were predicted by tumor size more than 5 cm, high
grade, local recurrence, or the presence of involved ly mph nodes (117). In POG Study
8653/8654, the 5-y ear overall survival for IRS groups I–II NRSTS was 82% and EFS was
71%, while for IRS groups III–IV disease the overall survival was 26% and EFS was 19%
(14). A retrospective review from the Rambam Medical Center, which includes desmoid
tumors in the series, showed 5-y ear overall survival of 72% for IRS group I, 75% for group
II, 90% for group III, and 40% for group IV (47). A retrospective review of sy novial
sarcoma treatment in children and adolescents treated with surgery, chemotherapy, and RT
found that progression-free survival was associated with IRS group (I, 79% II, 82% III, 38%
IV, 0%), maximum tumor diameter (less than 5 cm, 82% more than 5 cm, 56%), and
histology (monophasic, 86% biphasic, 54%) (60). A small series of childhood angiosarcomas
had a characteristically poor event-free (29%) and overall (22%) survival (66). For
fibrosarcomas, because of the difference in behavior between the congenital or infantile and
adult ty pes, survival is a function of age (y ounger than 2 y ears, 79% older than 2 y ears, 51%)
(67,224).
Page 282Locally advanced (group III) NRSTSs continue to be a challenging problem.
Preoperative chemotherapy and RT may convert a subset of these patients to having
resectable tumors, which improves local control and has some prospects for cure. The small
series from SJCRH showed a 33% 5-y ear disease-free survival with this strategy (100). More
encouragingly, within the POG 9553 protocol of ifosfamide and doxorubicin followed by
EBRT to 54 or 64 Gy, depending on age, 25 patients with group III tumors had a 60% 3-y ear
disease-free survival (12). Fifteen of these patients had sy novial cell sarcoma, thought by
some investigators to be more sensitive to chemotherapy. Similar results in a larger cohort of
200 patients were seen in the COG ARST 0332 trial, where those patients with bulky, high-
grade tumors receiving sequential preoperative chemotherapy and radiotherapy followed by
surgery where feasible had a 52% 3 y ear disease-free survival (15).
Ferrari et al. (160) published a retrospective pooled analy sis from the United States and
Europe investigating prognostic variables and treatment modalities in 304 patients with
initially unresectable, but nonmetastatic NRSTS (akin to rhabdomy osarcoma clinical group
III). This study noted that there was similar negative prognostic implication of particular
tumor characteristics compared with adult soft tissue sarcoma, with those poor prognostic
features including large tumor size, MPNST histology, older patient, and axial location of
tumor. When examining response rate to chemotherapy, a 41% response rate was recorded
(in terms of complete response and major partial response). This was 57% if minor responses
were included. In addition, it was reported that final outcome was directly correlated with
response to initial chemotherapy. Particular importance of local therapy was also emphasized
in this study, as local progression and relapse was the major cause of treatment failure and
patients able to undergo complete delay ed resection had the best outcome. From a
radiotherapy perspective, the use of radiotherapy also was directly correlated with a better
survival on multivariate analy sis. It was noted that radiotherapy improved survival after
incomplete resection, but had little or no benefit after complete surgery. However, the authors
do describe a selection bias for those patients who received radiotherapy, as these patients
were a selected subset with unfavorable features. Furthermore, the use of radiotherapy was
not homogeneous and was highly variable over time between centers included in the study.
Radiotherapy was the only local modality in 72 patients. An additional 72 patients underwent
surgery and radiotherapy with the vast majority undergoing radiotherapy postoperatively.
The median total radiation dose was 54 Gy for patients receiving RT alone or postoperative
RT for positive margins. Patients who had a complete surgical resection and who received RT
had a median radiation dose of 50 Gy. Overall, this study concluded that aggressive
multimodal treatment strategies should be pursued with effort to get patient to a complete
surgical resection. This study has also pointed out that there are histology specific predictors
of chemotherapy response seen in other studies, which in turn impact on prognosis.
Specifically, sy novial cell sarcoma is a relatively chemosensitive tumor while MPNST
tended to be more chemoresistant. Investigators at COG in designing future NRSTS studies
are contemplating using preoperative chemoradiation for locally advanced tumors in which
lower radiation doses will be justified if there is a good response to chemotherapy or in the
case of chemosensitive histologies.
Unresectable or metastatic disease carries a dismal prognosis. Unresectable NRSTSs are
rarely cured by RT with chemotherapy, and the local control rate is also poor (143). The 5-
y ear survival rate for children with stage IV NRSTS treated on SIOP trials MMT84 and
MMT89 was 15% (45,164). In an SJRCH review of metastatic NRSTS, the 2-y ear
progression-free survival was 15% (4,6,90,99).
Another University of Florida study focused on unresectable, nonmetastatic NRSTS
patients documented relatively poor results associated with radiotherapy and chemotherapy
(225). Of the 19 patients in this small study, the median radiation dose was 55.2 Gy, 12
patients received chemotherapy, and 13 patients had high-grade tumors. The 5-y ear local
control rate was only 40%. Nine of the thirteen recurrences were local only, but all
recurrences ultimately resulted in patient death, half of which never developed metastatic
disease. This study highlighted the need for more intensive therapies aimed at improving local
control for unresectable NRSTS.
COG ARST0032 approached metastatic disease based on initial tumor grade. For high-
grade tumors, patients were then divided into two groups, grossly resected versus unresected,
where they received adjuvant chemotherapy plus radiotherapy versus neoadjuvant
chemoradiotherapy, respectively. For low-grade tumors, if all disease was resected,
independent of microscopic margin status, these patients went on to observation alone. If all
disease was not resected, they entered in the high-grade arm of the algorithm where further
therapy was assigned. Results of this strategy for metastatic disease have not y et been
reported.
DESMOID TUMORS
Page 283There are a variety of childhood mesenchy mal tumors of fibroblastic and
my ofibroblastic derivation that are generally regarded as benign in the sense that these
tumors have no potential for metastasis. The group includes infantile my ofibromatosis, digital
fibromatosis, fibromatosis colli, and desmoid tumors (226). The term desmoid derives from
the Attic Greek word δέσμη or desmē meaning “package, bundle,” and in medicine has come
to refer to ligamentous or tendenous (3). In addition to the term desmoid tumor (which dates
back to an 1847 surgical treatise), these lesions are called extra-abdominal desmoid, well-
differentiated nonmetastasizing fibrosarcoma, aggressive fibromatosis, and grade 1
fibrosarcoma (desmoid) (227,228). The usual presenting complaint is a deep-seated, firm
mass arising in muscles or soft tissues (226,227,228,229). These lesions tend to extend along
fascial planes. Histologically, spindle cells with an abundant collagenous background form
interlacing bundles and infiltrate surrounding tissue. Mitoses are rare (Fig. 12.12 )
(226,229,230,231,232). Immunohistochemical staining for beta-catenin is important in the
diagnosis (233).
Figure 12.12 Desmoid tumor in a child. Note both H&E (A) and immunostaining (B) for
beta-catenin, in which nuclear staining is characteristic for this disease.
Occurring with an estimated incidence of two to four cases per million persons per y ear,
desmoid tumors have relative peaks in incidence between 6 and 15 y ears of age and between
puberty and 40 y ears of age in women. Risk factors include high-estrogen states (like
pregnancy ) and prior surgical trauma (20). A small fraction of desmoid tumors are
associated with Gardner sy ndrome. As such, there is an associated, inherited mutation in the
adenomatous polyposis coli (APC) tumor suppressor gene (20).
Desmoid tumors almost never metastasize. The goal of treatment is to obtain local
control. Desmoid tumors can occur in a wide variety of locations. For this reason, the degree
of resectability is quite variable. Tumors in an accessible site, not adjacent to vital structures,
are more amenable to gross total excision than those adjacent to major nerves or vessels. In
general, about two-thirds of desmoids can undergo gross total excision. Moreover, there is
some suggestion in the medical literature that pediatric as opposed to adult desmoid tumors
may be more aggressive (234,235). And a recent series from SJCRH suggests that the margin
of surgical resection does not predict well for ultimate local control such that the initial
surgical approach should attempt to remove all gross tumor when feasible but with primary
attention to preserving function (236). The problem of the extent of excision leads us to the
first of several controversies in the management of pediatric desmoid tumors.
What is to be done in the child who has undergone an excision but in whom there are
positive margins of resection? Several papers from the MGH argue that such patients ought to
be closely observed. In a 2001 review, Suit and Spiro (237) wrote:
Patients with primary desmoid tumors who have had grossly complete
resection, but whose surgical margins are positive on pathological examination
are exposed to a risk of no local regrowth of at least some 30–40%. This high
local control results in margin-positive patients and the fact that salvage
treatment of patients who failed locally is usually successful warrant a policy
of placing such patients on observation. This policy has been followed at the
MGH for approximately 25 years. To date, there have been no regrets and a
worthwhile number of patients have not been exposed to the risk of radiation-
induced damage to normal tissues, including tumor induction. In contrast,
margin-positive resection of recurrent desmoid tumors is an unequivocal
indication for additional treatment.
The long-term ill effects of radiation therapy in children with desmoid tumors can be
considerable. Therefore, it would be best to minimize the use of radiation wherever
possible.
Although postoperative irradiation in patients with positive margins reduces the risk of
local relapse, most patients with local relapse after surgery alone can be cured by
additional surgery and radiation therapy.
Therefore, it would be reasonable to adopt a policy of watchful waiting in accessible
sites, amenable to close follow-up. A significant number of these patients might be
locally controlled with surgery alone, even with positive margins. For those who relapse,
one could use surgery and radiation therapy to obtain local control.
The probability of local control with surgery alone is unpredictable a priori, and a wide range
of local control rates are reported (226,227,228,238,239). A consensus view is that local
control in patients with free margins is obtained in about 70% of cases. Several ty pes of
patients are at particularly high risk for local recurrence and progression. These include those
with unresectable lesions, those who have undergone resection and gross tumor has been left
behind, those who have undergone resection with large areas of clearly positive histologic
tumor margins, and those who have already suffered one or more local recurrences after
primary surgical therapy. With the exception of patients with microscopic positive margins,
the remainder should be considered for RT (Fig. 12.13 ).
Several retrospective series, combining pediatric and adult patients, have demonstrated
that fractionated external beam irradiation or external beam plus brachy therapy can locally
control approximately 75% of desmoid tumors (Tables 12.10 and 12.11 ). Complete or
partial resolution may take 2–3 y ears after completion of a course of treatment (227,256).
For some patients, “local control” means cessation of growth rather than tumor regression.
The long-term ill effects of radiation therapy for the treatment of desmoid tumors can
include fibrosis in the treated area, paresthesias that are most often associated with growth of
tumor into a nerve, limb edema, fracture associated with surgical stripping of the ostium or
curettage, skin ulcers, cellulitis, and the induction of second malignant neoplasms (Fig.
12.13 ) (232,235,248).
Figure 12.13 A right buttock desmoid
tumor was diagnosed in a 6-year-old boy.
The lesion was excised in 1979, 1980,
1982, and 1983 and recurred each time.
Postoperative irradiation (49.6 Gy) was
given after a reexcision of gross disease.
Angled photon fields were used to
minimize rectal dosage. The tumor
slowly regressed, and local control has
been maintained up to the time of this
writing (2009). There is partial atrophy of
the right buttock musculature, the bones
of the right hemipelvis are smaller than
those of the left hemipelvis, and the
patient walks with a marked limp.
Diabetes mellitus was diagnosed in 1994.
In 2002, 19 years after RT, the thin,
atrophied tissues gave way and a deep,
infected ulcer developed in the right
buttock. Plastic surgery with rotation of
vascularized flaps was needed for wound
closure.
Table 12.11 Local Control Rates in Combined Pediatric and Adult Series of
Radiotherapy with or without Surgery for the Management of Desmoid Tumors
This risk of late effects raises the question of whether one should be particularly cautious
in using radiation therapy in children with desmoid tumors. A report by Merchant et al. (235)
from SJCRH argued that desmoid tumors in pediatric patients are particularly locally
aggressive and often occur after radiation therapy. This adverse biologic behavior, in
conjunction with the associated ill effects of radiation, argues against the use of radiation
therapy in desmoid tumors. The study by Merchant et al. contains data from only 13 patients
collected over a 36-y ear period. The desmoid tumors arose from a particularly unusual set of
locations, such as the paraspinal region in five cases and the nasophary nx and ptery goid fossa
in two cases. A wide variety of treatments were used, including surgery and chemotherapy,
in addition to radiation therapy. Enzinger and Shiraki (228) and Walther et al. (260) also
reported a high risk of failure in adolescents.
Page 286On the other hand, as shown in Table 12.11 , a large number of patients have
been treated successfully with radiation therapy. Most series are a mixture of adults and
children. However, they do not report that desmoid tumors in children are more aggressive.
Therefore, it seems reasonable to use radiation therapy to treat desmoid tumors in children,
albeit with the cautions about positive margins raised earlier in this section.
Desmoids can widely infiltrate. When external beam is used, treatment portals should be
generous. Marginal relapses account for a very large number of the relapses after external
beam radiation therapy (232,248,243,249,251). MRI studies of desmoids often show an
infiltrative margin. At surgery, microscopic tumor has been found to extend bey ond the
volume defined by MRI. All available evidence from the phy sical examination, surgical
report, CT, and MRI should be integrated to determine the tumor volume. Generous margins
(about 5 cm) should then be used around this volume. Daily fractions of 1.8–2 Gy are used.
There may be a higher local recurrence rate when dosages less than 50 Gy are used. In
1984, Kiel and Suit (226) suggested that dosages greater than 60 Gy may be associated with a
greater incidence of local control and had treated some patients with 70 Gy, often using
photons and protons. Schulz–Ertner et al. (251) found no benefit of administering more than
50 Gy rather than less than 50 Gy on univariate analy sis. Zlotecki et al. (248) found no benefit
of hy perfractionated irradiation over standard fractionation. Almost all patients received 50–
56 Gy. However, Ballo et al. (257) reported a significant difference in local control between
dosages less than 50 Gy and dosages more than 50 Gy. They also found greater irradiation-
associated morbidity in patients who received dosages more than 56 Gy. Evidence indicates
that a total dosage of 50–55 Gy is appropriate and that higher dosages may increase the risk
of complications without commensurate gain in local tumor control (227,237,256).
Brachy therapy has been reported as a treatment for desmoids, either alone or with external
beam therapy, by one institution (243). The recent SJCRH series reported that seven of 16
patients receiving postoperative radiotherapy involved brachy therapy (236). However,
because of concerns about the assessment of tumor margins and their coverage, we believe
that the role of brachy therapy is limited in children with desmoids.
In y oung children with desmoids, radiation’s effects on growing bone, the risk for
subsequent soft tissue fibrosis, and the potential for secondary malignancy may prompt
consideration of alternative therapies. A large range of drugs are available for managing
desmoid tumor. There have been some efforts to use cy totoxic chemotherapy, mostly
employ ed to treat recurrent tumor after surgery and radiation. For instance, a series of six
children with fibromatosis were treated with VAC (vincristine, actinomy cin D, and
cy clophosphamide) with five having long-term control, although three subjects also received
high-dose RT (41). The POG published a prospective phase II trial of vinblastine and
methotrexate showing a response rate of 31% (261). Of a total of 27 patients, 16 had
recurrent desmoid tumor and 11 had untreated disease not amenable to either surgery or
irradiation. There have been other anecdotal reports of the use of gemcitabine, liposome-
encapsulated doxorubicin, and temozolomide.
Page 287Other medical treatments are evolving. Several reports on the pathophy siology
of desmoid tumors show expression of platelet-derived growth factor receptor (262,263),
estrogen receptor (264,265), somatostatin receptors (266), and cy clooxy genase-2 (267). In
turn, this has provided a rationale for the reported use of various “targeted therapies” either
alone or in combination. This has included imatinib mesy late (262,263), tamoxifen, or other
estrogen antagonists (264,265,268), octreotide radiolabeled with Y-90 (266), and nonsteroidal
anti-inflammatory drugs (268,269,270). A COG study formally evaluated high-dose
tamoxifen and sulindac in pediatric patients with recurrent or untreated fibromatosis (271).
Fifty -nine eligible patients were enrolled of which six (16%) had prior radiation. While no
life-threatening toxicity was reported, 12 of 30 females developed ovarian cy sts, which were
asy mptomatic in 11 of the cases and did not require stopping treatment. Response rates were
low, included four partial and one complete response (5/59 = 8%). The estimated 2-y ear
progression-free and overall survival rates were 36% and 96%, respectively. Of note, there
were three deaths due to progressive desmoid tumor which tended to be late events. Finally,
there have been anecdotal reports of responses to other agents including colchicine and
interferons.
Figure:
Desmoid tumor in a child. Note both H&E (A) and immunostaining (B) for beta-catenin, in
which nuclear staining is characteristic for this disease.
Figure: Local Control of Desmoid Tumors
with Three Forms of Therapy
Figure:
A right buttock desmoid tumor was diagnosed in a 6-year-old boy. The lesion was excised in
1979, 1980, 1982, and 1983 and recurred each time. Postoperative irradiation (49.6 Gy) was
given after a reexcision of gross disease. Angled photon fields were used to minimize rectal
dosage. The tumor slowly regressed, and local control has been maintained up to the time of
this writing (2009). There is partial atrophy of the right buttock musculature, the bones of the
right hemipelvis are smaller than those of the left hemipelvis, and the patient walks with a
marked limp. Diabetes mellitus was diagnosed in 1994. In 2002, 19 years after RT, the thin,
atrophied tissues gave way and a deep, infected ulcer developed in the right buttock. Plastic
surgery with rotation of vascularized flaps was needed for wound closure.
Figure: Local Control Rates in Combined
Pediatric and Adult Series of Radiotherapy
with or without Surgery for the Management
of Desmoid Tumors
REFERENCES
PAGE 294HISTORY
It is thought that the first description of a Wilms tumor was by Thomas F. Rance (1) in his
1814 report “Case of Fungus Haematodes in Kidnies.” In 1828, Dr Ebenezer Gairdner (2),
Fellow of the Roy al College of Phy sicians, Edinburgh, published a second case. The patient
was a 3-y ear-old girl named Agnes B. Agnes B died of a left renal tumor that weighed 5
pounds, 3 ounces. In 1879, renowned phy sician William Osler (3) described two cases of
“my osarcoma of the kidney,” one of which had tumor extension into the right heart and
pulmonary artery. Max Wilms (1867–1918), who was trained in pathology, internal medicine,
and surgery, thoroughly reviewed the pertinent literature and added seven new patients in his
1899 monograph Die Mischgeschwuelste. In addition to renal tumors, Wilms described the
histologically “mixed tumors,” of the ovary, testicle, head and neck, bladder, and other organs
(4). It was because of Wilms exceptional monograph that his name became connected with
this childhood tumor (Fig. 13.1 ) (5).
Figure 13.1 A & B: In his monograph, Die Mischgeschwulste der Niere (the mixed tumor of
the kidney), published in Leipzig in 1899, Max Wilms described, as his first illustrative case,
“Niven Tumor von einem 3 jahrien Mädchen” (“renal tumor of a 3-year-old girl”). C: Wilms
described the blastemal, epithelial (tubules), and stromal elements seen on microscopic
examination of “mixed” renal tumor.
By the mid-20th century, radiation oncologists had developed a large body of clinical
experience with Wilms tumor and began formulating opinions about the role of radiotherapy.
Ralston Paterson (6), distinguished radiation oncologist of the Christie Hospital and Holt
Radium Institute of Manchester, England, wrote in his 1948 textbook:
We feel that the most promising policy is to start treatment by radiotherapy
and not by surgery. X-ray therapy is used and consists of abdominal x-ray
baths to cover the entire tumor and any possible intra-abdominal extension.
An interval of 6 weeks to 3 months is then allowed in which the tumor mass
entirely disappears.… Two opposing fields, anterior and posterior… cover the
whole abdomen including the liver.… The essential point in the treatment of
Wilms tumor is to remember that even enormous tumors can be made operable
and that radiation followed by nephrectomy can undoubtedly obtain cure in
some cases.
Dean and Guttmann (7) expressed the predominant viewpoint of US radiation oncologists
when they wrote in their 1950 textbook:
Dean and Guttmann’s views were reinforced by Jacox and Cahill’s (8) 1850 review of
the management of Wilms tumor. They wrote:
At present we believe that nephrectomy should be performed as soon as the
diagnosis of Wilms tumor is made, irrespective of the size of the mass. In
general, preoperative irradiation is not favored, because we believe that
waiting needlessly jeopardizes the patient’s chances of survival. Ladd and
White and their confreres at the Boston Children’s Hospital have made a
serious study of the removal of these tumors by the transperitoneal route, with
a minimum of handling either for diagnosis or on the operating table, with
ligation of the renal vessels and pedicle before displacement of the tumor. The
result has been a much higher proportion free from recurrence that has
formerly been reported.
Page 295What we can see, in this brief historical review of the origins of radiotherapy
for Wilms tumor, is the divide between US radiation oncologists and their European
colleagues. The European literature favored preoperative treatment, and the US literature
favored postoperative radiation therapy. We also see the acknowledgment that wide treatment
volumes to cover the entire tumor bed are necessary. We will address these themes later in
this chapter.
Figure:
A & B: In his monograph, Die Mischgeschwulste der Niere (the mixed tumor of the kidney),
published in Leipzig in 1899, Max Wilms described, as his first illustrative case, “Niven Tumor
von einem 3 jahrien Mädchen” (“renal tumor of a 3-year-old girl”). C: Wilms described the
blastemal, epithelial (tubules), and stromal elements seen on microscopic examination of
“mixed” renal tumor.
EPIDEMIOLOGY
Wilms tumor (nephroblastoma) is an embry onic kidney tumor. It is the most common
abdominal tumor in children and represents 6% of childhood cancer. The incidence rate in
white children y ounger than 15 y ears is 8.1 new cases per million population (9). There are
approximately 470–500 new cases in the United States per y ear (10,11). Wilms tumor is
bilateral at presentation in 4–8% of cases (12,13,14).
For unilateral tumors, the median age at diagnosis is 41.5 months for boy s and 46.9
months for girls. For bilateral tumors, the median age at presentation is 29.5 months for boy s
and 32.6 months for girls (11). More than 75% of patients present before 5 y ears of age. The
male-to-female ratio is 0.92 for unilateral tumors and 0.6 for bilateral tumors (11). The
incidence rate is approximately three times higher for blacks in the United States and Africa
than for East Asians. Rates for the white populations in Europe and North America are
intermediate between those of blacks and East Asians. Children tend to present with more
advanced disease in less developed nations (11,12,13,14).
MOLECULAR BIOLOGY
Another recent COG study has demonstrated that gain of 1q is a promising biomarker for
patients with FH Wilms tumor. In a report from the NWTS that studied 212 patients from
NWTS-4, 27% of patients display ed 1q gain. The 8-y ear event-free and overall survival rates
were 76% and 93% (p = 0.002) for patients with 1q gain and 89% and 98% (p = 0.008) for
those lacking 1q gain. Gain of 1q did not correlate with tumor stage. After stratification for
tumor stage, 1q gain was associated with significantly increased risk of disease recurrence
(risk ratio 2.72, p = 0.009) (36).
Figure: Analysis for the Joint Effect of LOH
at 1p and 16q for (A) Stage I/II and (B) Stage
III/IV Favorable Histology Patients (29)
29 Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity for chromosomes 1p and 16q is
an adverse prognostic factor in favorable histology Wilms tumor: a report from the National
Wilms Tumor Study Group. J Clin Oncol. 2005;29:7312–7321.
Figure: COG Risk-Stratification Schema for
Renal Tumor Protocols
PATHOLOGY
The childhood kidney tumor pathology classification sy stems are those of the NWTS (Table
13.3 ), the International Society of Pediatric Oncology (SIOP) study (Table 13.4 ), and
COG (Table 13.5 ).
Mesoblastic Nephroma
Mesoblastic nephroma is the most common renal tumor encountered in the first month of life.
Its median age at presentation is 3 months. It is distinguished from Wilms tumor by its usually
benign behavior, a preponderance of mesenchy mal derivatives, and a lack of the malignant
epithelial components seen in Wilms. The tumor consists of spindle-shaped cells in interlacing
bundles adjacent to renal parenchy ma where there are foci of cy stic or dy splastic tubules.
The treatment of choice is nephrectomy. Local recurrence is unusual. Nonetheless, adequate
margins of resection should be obtained, although recurrence even after operative rupture or
positive margins at resection is rare. Distant metastases are also rare. The actuarial 2-y ear
survival rate is 98% (37,38,39,40).
Page 298Nodular Renal Blastemas and Nephrogenic Rests
A spectrum of “pre–Wilms tumor” entities has been described. Nodular renal blastemas are
small but visible sub-capsular nodules composed of benign embry onic rests. Nephrogenic
rests may be limited to the periphery of the renal cortex (perilobar) or randomly distributed
throughout the renal lobe (intralobar). Multifocal or diffuse nephrogenic rests are called
nephroblastomatosis.
Wilms Tumor
Wilms tumor is a triphasic embry onal neoplasm, which includes blastemal, epithelial
(tubules), and stromal elements. Each element may exhibit a variety of patterns of
aggregation or lines of differentiation (Fig. 13.2A–C ) (38,39,40). The proportion of the
three components varies from tumor to tumor. If one of the components comprises more than
two-thirds of the tumor sample, the pattern is designated according to the predominant
component. The mixed ty pe is most common (41% of Wilms tumor), followed closely by
the clinically more aggressive blastemal predominant (39%), the more indolent epithelial
predominant (18%), and the stromal predominant (1%), which behaves like the mixed ty pe
(38,39,40).
Figure 13.2 A & B: James B. Ewing, renowned for the four editions of his book Pathology
of Neoplasia (Philadelphia, PA: WB Saunders; 1942) and his identification for the tumor now
called Ewing sarcoma, also provided excellent histologic descriptions of Wilms tumor. These
slides, from Ewing’s book, show the topography of Wilms embryonal tumor of the kidney with
(A) epithelial tubules lining in masses of spindle and polyhedral cells and (B) the small round
cells of the embryonal tumor infiltrating adjacent tissue. C: Favorable histology triphasic
Wilms tumor with predominantly epithelial (tubular) differentiation (arrow).
The gross pathologic features of Wilms tumor include its general occurrence as a single
unilateral tumor, although multicentric growth and bilateral disease can occur. The tumor is
ty pically solid, lobulated, and not calcified. However, soft and cy stic areas may be
encountered.
Histopathologic studies in the NWTS identified factors that correlate with prognosis. In
the first NWTS, 88% of cases were categorized as FH, defined as having ty pical histologic
features of Wilms tumor without anaplastic or sarcomatous components (41). The frequency
of this pattern was upheld in the third NWTS, with 89% of cases categorized as FH on central
pathology review (42).
Page 299Three entities traditionally have been grouped under the general term
unfavorable histology (UH) in the NWTS: anaplastic Wilms tumor, CCSK, and RTK (39). The
latter two are no longer considered to be variants of Wilms tumor but are distinct entities (38).
Anaplasia is defined as the significant enlargement of nuclei in the stromal, epithelial, or
blastemal cell lines to at least three times the diameter of adjacent nuclei of the same cell
ty pe; hy perchromatism of these enlarged nuclei; and multiple mitotic figures. DNA indices
greater than 1.5 are associated with anaplastic histology (Fig. 13.3A & B ) (38,40,43,44).
Anaplasia was noted in 4% of all NWTS-3 entries and in 5% of patients in the SIOP studies
(38,40,43,44). Anaplastic tumors are extremely rare in infants, are uncommon before 2
y ears of age, and make up about 10% of Wilms tumors diagnosed after 5 y ears of age (40).
Anaplasia appears to be associated with greater resistance to chemotherapy rather than
greater aggressiveness of Wilms tumor. The 4-y ear survival rate in NWTS-3 for patients with
anaplastic histology was 82% but was lower in earlier studies (41,42,43,44).
Figure 13.3 Anaplastic Wilms tumor with a large dark hyperchromatic nucleus (arrow)
(A) and multipolar mitosis (arrow) (B).
Anaplastic Wilms tumor may be focal or diffuse. When this distinction was originally
drawn, the term diffuse anaplasia was applied to tumors with anaplastic nuclear changes in
more than 10% of 400 microscopic fields. Focal anaplasia was applied to the remainder of
anaplastic tumors. Using this distinction, focal anaplasia was associated with a more favorable
outcome than diffuse anaplasia in the first NWTS, but this difference did not obtain statistical
significance and was not confirmed in the second and third NWTS trials (45).
The original distinction between focal and diffuse anaplasia did not consider distribution
of tumor throughout the kidney, which might affect the likelihood of complete resection. In a
recently revised definition, focal anaplasia refers to anaplasia that is sharply localized in the
primary tumor, without significant nuclear or mitotic aty pia in the remainder of the lesion.
Diffuse anaplasia is either nonlocalized anaplasia, localized anaplasia with severe nuclear
unrest elsewhere in the tumor, anaplasia outside the tumor capsule or in metastases, or
anaplasia found in a random biopsy taken from the tumor.
Using the new criteria, and on review of patients in NWTS-3 and NWTS-4, patients with
focal anaplasia had a 4-y ear survival rate statistically significantly higher than that of patients
with diffuse anaplasia (97% vs. 50%). This difference did not exist for stage I tumors (100%
survival for focal or diffuse) but did exist for stages II (90% vs. 55%), III (100% vs. 45%),
and IV (100% vs. 4%) (40,45).
Page 300Patients with anaplastic histology Wilms tumor were treated in prospective
single-arm studies in NWTS-5. Patients with stage I anaplastic tumors were treated with
vincristine and dactinomy cin for 18 weeks without radiation therapy. Patients with stages II–
IV diffuse anaplastic histology were treated with regimen “I” chemotherapy that consisted of
vincristine, doxorubicin, cy clophosphamide, and etoposide for 24 weeks plus flank/abdominal
radiation therapy. Among 2596 patients with Wilms tumor enrolled onto NWTS-5, 281
(10.8%) had anaplastic histology. The 4-y ear event-free and overall survival rates for stage I
anaplastic histology tumors were 70% and 83%, respectively. The 4-y ear event-free and
overall survival rates in stages II, III, and IV diffuse anaplastic tumors after immediate
nephrectomy were 83% and 82%, 65% and 67%, and 33% and 33%, respectively. These
results form the basis for the COG study with augmentation of therapy for stages I, III, and
IV anaplastic tumors (46).
As we have already noted, several clinical sy ndromes are risk factors for the development of
Wilms tumor. These include aniridia, BWS (exomphalos, macroglossia, and gigantism), and
hemihy pertropia. If somatic changes of these kinds are known to exist, then routine screening
in an attempt to make the early diagnosis of Wilms tumor is appropriate (50). A phy sical
examination and periodic ultrasound are indicated. It is interesting to note that in Germany,
10% of patients with Wilms tumor are diagnosed at infant and childhood screening
examinations, conducted for known predisposing sy ndromes, and at routine well-baby
examinations (50).
Page 301The majority of children with Wilms tumor are diagnosed in response to a
medical complaint causing a visit to the doctor. The clinical presentation usually is an
abdominal mass (83%), fever (23%), or hematuria (21%). Abdominal pain (37%) may be
the result of local distention, spontaneous intralesional hemorrhage, or peritoneal rupture. In
one major series, abdominal pain correlated with poorer 5-y ear survival (51). Less common
presenting signs and sy mptoms include hy pertension, varicocele, hernia, enlarged testicle,
congestive heart failure, hy pogly cemia, Cushing sy ndrome, hy drocephalus, pleural effusion,
and an acute abdomen (52).
The presence and character of the abdominal pain, the previous medical history, and the
family history are important aspects of the medical interview. Phy sical examination is of
value in assessing abdominal status and identify ing associated congenital anomalies.
The optimum diagnostic imaging workup for Wilms tumor is a matter of controversy.
Evaluation of disease extent classically included intravenous py elogram (IVP) and chest
radiograph. Current imaging protocols largely replace the IVP with abdominal ultrasound.
Ultrasound usually allows determination of the origin of a childhood abdominal mass,
identifies a contralateral kidney, and demonstrates the presence or absence of tumor
extension into the renal vein or inferior vena cava (53).
When an abdominal mass is identified or suspected, abdominal computed tomography
(CT) is used to assess the volume of tumor
involvement in one or both kidney s, renal
function, retroperitoneal ly mph nodes, and
invasion of the collecting sy stem or renal vein;
evaluate the margin between tumor, kidney, and
surrounding structures; assess hepatic metastasis
(although many children thought to have
invasion of the liver from a right-sided Wilms
tumor are found at surgery to have hepatic
compression rather than invasion); and
demonstrate lesions in the opposite kidney, which Figure 13.6 A 5-year-old girl presented
may represent either bilateral Wilms tumor
with intermittent sharp abdominal pain,
(BWT) or nephrogenic rests (Fig. 13.6 ) (53).
nausea, vomiting, weight loss, and
The evaluation of the contralateral kidney has
hematuria. Abdominal computed
become a matter of discussion in the surgical tomography showed a 7.9- to 12.5-cm
literature. Some authorities believe that mass at the left renal region, beginning
preoperative CT and magnetic resonance immediately sub-diaphragmatically and
imaging (MRI) can be used to rule in or rule out extending to just below the aortic
BWT. Others believe that imaging is useful but bifurcation. There was a calcified rim
not definitive and that a surgical exploration of superiorly and a heterogeneous
the contralateral kidney remains essential during parenchymal enhancement. Left renal
the surgical approach to the primary tumor vein invasion and inferior vena cava
(17,50).
thrombosis were observed. On
Plain chest radiographs should be obtained exploratory laparotomy, tumor was
to determine whether pulmonary metastases are palpated in the inferior vena cava. The
present. Some centers recommend thoracic CT tumor was resected, with some tumor
to detect pulmonary metastasis that might be spillage from a weak point on Gerota
missed on chest radiograph. CT-positive, chest fascia. Tumor thrombus was removed
radiograph–negative lung metastases do occur from the inferior vena cava. Pathology
(53). There has been much uncertainty showed a favorable histology Wilms
regarding appropriate therapy for pulmonary tumor, 13.5 cm in greatest diameter,
disease documented only by CT in the presence invading through the renal capsule to the
of normal plain chest films (54). Radionuclide inked surgical margin. Rupture of the
bone scan is indicated in CCSK and renal RTK. renal capsule was identified. Tumor was
Bone scan and skeletal survey are present at the renal vein margin of the
complementary in CCSK. If only one technique tumor thrombosis with focal invasion of
is used, metastases may be missed (41,55). the vein wall. No lymph nodes were
Brain MRI is of value in RTK and, perhaps, in
Wilms tumor with overt pulmonary involvement involved. For pathologic stage III Wilms
at diagnosis. tumor, favorable histology, the child was
treated with chemotherapy and flank
irradiation. There was no evidence of
persistent or recurrent tumor 3 years
after diagnosis.
Figure:
A 5-year-old girl presented with intermittent sharp abdominal pain, nausea, vomiting, weight
loss, and hematuria. Abdominal computed tomography showed a 7.9- to 12.5-cm mass at the
left renal region, beginning immediately sub-diaphragmatically and extending to just below
the aortic bifurcation. There was a calcified rim superiorly and a heterogeneous
parenchymal enhancement. Left renal vein invasion and inferior vena cava thrombosis were
observed. On exploratory laparotomy, tumor was palpated in the inferior vena cava. The
tumor was resected, with some tumor spillage from a weak point on Gerota fascia. Tumor
thrombus was removed from the inferior vena cava. Pathology showed a favorable histology
Wilms tumor, 13.5 cm in greatest diameter, invading through the renal capsule to the inked
surgical margin. Rupture of the renal capsule was identified. Tumor was present at the renal
vein margin of the tumor thrombosis with focal invasion of the vein wall. No lymph nodes
were involved. For pathologic stage III Wilms tumor, favorable histology, the child was
treated with chemotherapy and flank irradiation. There was no evidence of persistent or
recurrent tumor 3 years after diagnosis.
STAGING
Page 302A staging sy stem for Wilms tumor was first published by Cassady et al. (56,57) in
1973, building on prognostic factors identified in a review from Garcia et al. (58). The
Cassady sy stem remains useful for determining whether y oung children with early stage
disease may be appropriate for therapy with surgery alone. For tumor confined to the kidney
and completely excised in children y ounger than 2 y ears of age at diagnosis and with tumors
that weigh less than 550 g, the prognosis is excellent. Such patients may be treated
appropriately with surgery alone and are considered to have stage I disease (57,58,59). The
absence of an inflammatory pseudocapsule, renal sinus invasion, capsular invasion, and
intrarenal vessel invasion in such patients are additional factors that mitigate against the risk of
relapse when treated with nephrectomy alone (53).
The NWTS proposed initial staging criteria to prospectively address tumor-related
factors. The first two NWTS studies were based on a sy stem of surgically identified groups
(41).
Beginning with the third NWTS trial in 1979, a new staging sy stem was adopted. Specific
disease-related parameters noted to be prognostically significant in analy ses of NWTS-1 and
NWTS-2 led to modifications of the sy stem and the change from groups to stages. A closed or
open biopsy permitted categorization as stage II (rather than group III), assuming subsequent
total tumor removal. Local spill of tumor during surgery was downstaged from group III to
stage II, reflecting data indicating that such cases had excellent tumor control even with
limited irradiation and chemotherapy in NWTS-1 and NWTS-2 (60). Also, the NWTS-3
staging sy stem upstages all previous group II cases with ly mph node metastasis to stage III,
even when all visible disease has been completely resected. The adverse impact of ly mph
node involvement, both on abdominal recurrence and on ultimate relapse-free survival, has
been documented (13,22,41,61).
For NWTS-5, the most significant change was the distinction between stages I and II.
Criteria for stage I was refined to accommodate an important subset of patients who were
being managed by nephrectomy alone. Before NWTS-5, the distinction between stages I and
II in the renal sinus was established by the hilar plane, which was an imaginary plane
connecting the most medial aspects of the upper and lower poles of the kidney. This criterion
was difficult to apply because of tumor distortion, and thus the hilar plane criterion has been
replaced with renal sinus vascular or ly mphatic invasion. This definition includes not only the
involvement of vessels within the hilar soft tissue, but of vessels located in the radial
extensions of the renal sinus into the renal parenchy ma (62,63).
The COG staging guidelines for Wilms tumor are shown in Table 13.6 . These
guidelines are essentially similar to NWTS-5 except for the fact that children with tumor
spillage are upstaged from stage II to stage III because of the higher risk for relapse with two-
drug chemotherapy alone (64).
In the SIOP Wilms tumor trial 1, investigators compared preoperative radiotherapy with
primary surgery. The staging sy stem used in this trial is shown in Table 13.7 . SIOP
subsequently began using NWTS grouping and staging, with the proviso that the NWTS
sy stems were not specifically designed for the
preoperative therapy often used by SIOP
(65,66,67,68,69,70,71). For this reason, outcomes
between NWTS and SIOP studies should not be
compared stage-for-stage. In addition, SIOP
uses a “stage II, node-negative” and “stage II,
node-positive” distinction and therefore includes
some NWTS stage III tumors in the stage II
infradiaphragmatic SIOP stage.
Table 13.7 Staging System Used in
SIOP Wilms Tumor Trial 1
Figure: Children’s Oncology Group Staging
of Wilms Tumor
Figure: Staging System Used in SIOP Wilms
Tumor Trial 1
NWTS, SIOP, AND THE MANAGEMENT OF WILMS TUMOR
The NWTS, SIOP, and the United Kingdom Children’s Cancer Study Group (UKCCSG) have
compiled a large body of information concerning the clinical management of Wilms tumor.
The most widely quoted studies are those of NWTS and SIOP.
Page 305NWTS-2 (1974–1979) explored three major questions: Can vincristine and
actinomy cin D substitute for radiotherapy in older children with group I disease? Are
adjuvant vincristine and actinomy cin D for protracted periods helpful in group I? Is the
addition of adriamy cin to actinomy cin D and vincristine of value in groups II to IV? The
study is shown schematically in Figure 13.8 (75). Flank irradiation was given in groups II–
IV disease according to the same age-dependent scale as NWTS-1. WAI was reserved for
diffuse peritoneal seeding. Lung metastases were initially treated with 14 Gy of whole-lung
irradiation (WLI), but when a 10% incidence of pneumonitis occurred, the dosage was scaled
back to 12 Gy. Study results are summarized in Table 13.9 . About 85% of the patients
were FH and 15% UH. Two-y ear survival rates were 54% for UH, 90% for FH, 54% for
ly mph node positive, and 82% for ly mph node negative. Excellent survival rates appeared to
be achievable without irradiation in group I, and adriamy cin added considerable benefit in
groups II–III FH and some benefit in groups II–III UH and group IV. The 2-y ear relapse-
free survival rate for all NWTS-2 patients was 88% for group I, 78% for group II, 70% for
group III, and 49% for group IV (17,75,77,78,79).
Figure 13.8 The design of NWTS-2. (From D’Angio GJ, Tefft M, Breslow N, et al. Radiation
therapy of Wilms’ tumor: results according to dose, field, post-operative timing and histology.
Int J Radiat Oncol Biol Phys. 1978;4:769–780, with permission.)
Table 13.9 NWTS-2 Results
The results of NWTS-4 are shown in Table 13.12 . There was no difference in the
low-risk or high-risk patients for standard or PI therapy. When one breaks down the results
based on histology, stage, standard or PI therapy, and, for the more advanced patients, short
or long course of therapy, there are, once again, no significant differences between the
various treatment groups (79). Comparing the results from NWTS-4 with those of the
UKCCSG Wilms Tumor Study 2, reported contemporaneously, we see surprisingly similar
results (Table 13.13 ) (80). The risk of local recurrence of patients enrolled in NWTS-4 is
shown in Table 13.14 .
The NWTS evaluated the frequency with which spilled tumor cells of FH produce intra-
abdominal disease recurrence. Flank irradiation but not doxorubicin reduced abdominal
relapse rates. The odds ratio for the risk of recurrence relative to no radiation was 0.35 for 10
Gy and 0.08 for 20 Gy. Tumor spillage resulted in higher relapse and significantly lower
survival among stage II patients. For stage II patients (NWTS-4), the 8-y ear event rates, with
and without spillage, respectively, were 79% and 87% for relapse-free survival (p = 0.07),
and 90% and 95% for overall survival (p = 0.04) (64).
The evidence from NWTS-4 is that PI initial chemotherapy is as effective as a longer
program. Shorter-course subsequent chemotherapy appears as effective as a longer
program. Overall survival rates are excellent, and few patients are irradiated (79).
The long-term data from NWTS-3 and NWTS-4 show no significant effects for
doxorubicin in stage II FH patients; however, for stage III patients, the relapse-free and
overall survival rates were 84% and 89% with and 74% and 83% without doxorubicin,
respectively. For stage III patients, the use of doxorubicin results in a significant reduction in
local and general recurrence without any improvement in overall survival (81).
NWTS-5 (1995–2001) treated stage I
favorable and anaplastic histology and stage II
FH with 18 weeks of actinomy cin D and
vincristine. Stage I FH in children y ounger than
24 months of age and with tumor weight less
than 550 g was treated with surgery alone.
Stages III–IV FH and stages II–IV focal
anaplastic tumors were treated with 24 weeks of
actinomy cin D, vincristine, adriamy cin, and
local irradiation and WLI as appropriate. Stages
II–IV diffuse anaplastic sarcoma and stages I–
IV CCSK were treated with cy clophosphamide,
vincristine, adriamy cin, and etoposide along with
local irradiation and WLI as appropriate. Stages
I–IV RTK was treated with carboplatin,
etoposide, cy clophosphamide, and radiotherapy.
The radiotherapy guidelines in NWTS-5 were
similar to those used in NWTS-4 except for
anaplastic tumors where a dose of 10.8 Gy was
recommended as compared with an age-
adjusted schedule used in NWTS 1-4. As a
major objective, NWTS-5 sought to evaluate the
importance of LOH for chromosome 1p and 16q Table 13.12 NWTS-4 Results
markers for prognosis. These results have been
detailed earlier in the chapter (Table 13.1 ) (29).
The outcome of 57 patients with FH tumors and peritoneal implants at the time of
nephrectomy in NWTS-4 and NWTS-5 were analy zed. Stage III tumors were seen in 74%,
and 26% had stage IV tumors. All children received multimodality therapy with three-drug
chemotherapy and irradiation. Forty -seven
patients (82%) received WAI and the radiation
dose was 10.5 Gy in 50 patients. The overall
abdominal and sy stemic tumor control rates
were 97% and 93%, respectively. The detection
of peritoneal implants was not associated with
inferior survival after this therapy. The 5-y ear
relapse-free survival rates with and without
peritoneal implants were 90% and 83%,
respectively (82).
AREN03B2
This is a renal tumors classification, biology, and banking study. The objectives are:
AREN0321
This was a study for the treatment of children with high-risk renal tumors. The primary
objectives were as follows:
Preliminary Results: A higher than expected severe toxicity rate was encountered in these
y oung children with UH tumors after treatment with these intensive multimodality treatment
regimens. Despite reductions in chemotherapy dosages and large-field RT doses in y oung
infants, severe toxicities continued to be observed and thus the study was permanently closed
in 2013. Final results are awaited. The indications and dosages of flank and WAI were
modified as shown in Table 13.15 . In a preliminary report of AREN0321, a total of 24
patients with stage IV diffuse anaplastic Wilms tumor were enrolled on the phase 2 window
with vincristine and irinotecan. The partial response rate was 79% indicating that this regimen
has high response rate in patients with diffuse anaplasia (83).
AREN0532
This was a study for the treatment of children with very low and standard risk FH Wilms
tumor. The objectives were as follows:
Preliminary Results: A total of 116 children with very low-risk Wilms tumors were treated
with nephrectomy alone on this study and their 4-y ear event-free and overall survival rates
were 90% and 100%, respectively. Tumor 11p15 methy lation status was highly predictive of
relapse (84). Among patients with stage I/II tumors with LOH at 1p and 16q, the 4-y ear
event-free survival after augmentation of therapy with DD4A was 84% compared with 75%
with regimen EE4A (85).
Page 311AREN0533
This is a study for the treatment of newly diagnosed higher risk FH Wilms tumors. The
objectives are as follows:
1. To demonstrate that patients with stage IV FH Wilms tumor with pulmonary metastases
only, who have complete resolution of the pulmonary lesions after 6 weeks of regimen
DD4A chemotherapy (vincristine, dactinomy cin, and doxorubicin) and are called rapid
complete responders (RCR), will have at least an 85% 4-y ear event-free survival after
therapy with additional chemotherapy (regimen DD4A) and without WLI.
2. To demonstrate that stage IV FH patients who do not have resolution of pulmonary
metastases by week 6, called slow incomplete responders (SIR), will have a 4-y ear
event-free survival rate of 85% with the addition of cy clophosphamide and etoposide to
a modified regimen DD4A (regimen M) and WLI.
3. To improve the 4-y ear event-free survival rate to 75% for patients with stage III or IV
FH Wilms tumor with LOH for chromosomes 1p and 16q.
4. To determine the relationship between the burden of pulmonary metastatic disease and
outcome in stage IV FH patients.
Preliminary Results: Among patients with stage III/IV tumors with LOH at 1p and 16q, the 4-
y ear event-free survival after augmentation of therapy with regimen M was 92% compared
with 66% with regimen DD4A (86). Among 296 patients with lung metastasis, 105 (39%) had
a complete response at week 6. Their 4-y ear event-free and overall survival rates were 78%
and 95%, respectively, without WLI. While these results were inferior to the event-free
survival of 85% with WLI and DD4A, the difference was not statistically significant (87).
Among patients who had a slow incomplete response at week 6, the augmentation of therapy
with regimen M and WLI resulted in a 3-y ear event-free and overall survival of 88% and
92%, respectively. These outcomes were significantly superior to the estimated event-free
survival of 75% with regimen DD4A and WLI (88).
Page 312AREN0534
This is a study for the treatment for patients with bilateral, multicentric, or bilaterally
predisposed unilateral Wilms tumor. The objectives are as follows:
1. To improve the 4-y ear event-free survival rate to 73% for patients with BWT.
2. To prevent complete removal of at least one kidney in 50% of patients with BWT by
using prenephrectomy three-drug chemotherapy induction with vincristine,
dactinomy cin, and doxorubicin.
3. To evaluate the efficacy of chemotherapy in preserving renal units in children with
diffuse hy perplastic perilobar nephrogenic rests (DHPLNR) and preventing Wilms
tumor development.
4. To facilitate partial nephrectomy in lieu of nephrectomy in 25% of children with
unilateral tumors and aniridia, BWS, hemihy pertrophy, or other overgrowth sy ndromes
by using prenephrectomy two-drug chemotherapy induction with vincristine and
dactinomy cin.
5. To have 75% of children with BWT undergo definitive surgical treatment by 12 weeks
after initiation of chemotherapy.
SIOP trial 2 (1974–1976) (Tables 13.20 and 13.21 ) was a nonrandomized study
comparing patients receiving 20 Gy of irradiation and 5 day s of actinomy cin D before
surgery with children treated with primary surgery. Tumor rupture occurred in 5% of the
preoperatively treated patients and in 20% of the other patients (p = 0.0025) (65,66,67). The
main reason for not giving preoperative therapy was small tumor size. Survival rate was only
61% in patients with larger tumors who received preoperative and postoperative irradiation.
SIOP trials 1 and 2 demonstrated that presurgical treatment with radiotherapy reduced the
number of tumor ruptures. This, in turn, reduced the need for WAI and its attendant ill effects
in y oung children (65,66,67).
SIOP trial 6 (1980–1987) adopted the prenephrectomy chemotherapy used in SIOP trial
5. All patients received actinomy cin D and vincristine. Patients who had stage I disease at the
time of surgery were randomized to receive postoperative vincristine and actinomy cin D for
17 or 38 weeks. All ly mph node-negative stage II patients received 38 weeks of vincristine
and actinomy cin D and were randomized to receive or not receive 20 Gy of involved-field
irradiation. Stage II node-positive patients and stage III patients were randomized to receive
vincristine, actinomy cin D with intensified vincristine, or the two drugs with doxorubicin
(Table 13.25 ). The stage distribution for the 396 SIOP trial 6 patients was stage I (56%),
stage II node negative (27%), and stage II node positive and stage III (17%). Tumor rupture
was found in 6% of cases (65,66,67,68,69,90).
Table 13.25 SIOP 6 Wilms Tumor Treatment Protocol
Page 315
Page 316In SIOP 9, approximately 10% of patients had completely necrotic tumors with
no viable tumor after induction chemotherapy. The 5-y ear event-free survival rate among
these patients was 98% and the only death was due to veno-occlusive disease. It was proposed
that such patients be considered for reduction in therapy after nephrectomy (71).
SIOP trial 93-01 (1993–2000): Patients were classified into three histologic groups as
shown in Table 13.4 . Because the available results show no difference between 4-week
and 8-week preoperative chemotherapy, 4 weeks has been adopted as the standard. Patients
with stage I low-grade histology received no additional therapy. Patients with stage I
intermediate- or high-grade tumors were randomized to a 4-week postoperative program of
vincristine and actinomy cin D or a 6-week program. All stage II and III patients with
intermediate-grade tumors received therapy as in SIOP trial 9. Stage II and III high-grade
tumors were treated with ifosfamide, etoposide, and carboplatin (Tables 13.30 and
13.31 ). The survival results are excellent (Tables 13.32 and 13.33 )
(65,66,67,68,69,72). In SIOP 93-01, 410 patients with stage I intermediate-risk and anaplastic
Wilms tumor after 4 weeks of chemotherapy were randomized postoperatively to no further
therapy or two additional cy cles of chemotherapy. There was no difference in 2-y ear event-
free survival between the no further therapy group (91%) compared with those who received
additional chemotherapy (89%) (72). Among 1090 patients in SIOP 93-01, 5% had tumor
progression during preoperative chemotherapy
in SIOP 93-01. These tumors were generally
smaller at diagnosis, more often stage III after
surgery and associated with higher grade
histology. They had significantly poorer event-
free and overall survival compared with those
who responded to chemotherapy (91). A
pathologic review of stage II tumors in SIOP 93-
01 revealed that there was a significantly higher
survival among patients who were stage II due to
nonviable tumor in the renal sinus or perirenal
fat compared with those with viable tumor in
these sites (100% vs. 91%). It was proposed that
the definition of stage II be revised (76).
Table 13.30 SIOP 93-01 Wilms Tumor
Treatment: Postoperative Treatment
Strategies for Unilateral Wilms Tumor
Table 13.31 SIOP 93-01 Stage IV Protocol
Page 317A summary of SIOP trials 1, 2, 5, 6, 9, and 93-01 shows that 4 weeks of
prenephrectomy chemotherapy, without irradiation, results in 56% of patients having stage I
disease at surgery. In most cases, these patients go on to receive postoperative chemotherapy
and have a survival rate of more than 90%. Stage II node-positive and stage III patients have
approximately a 61% relapse-free survival and a 75% overall survival (65,66,67,68). A
diminishing number of patients have received radiotherapy in the sequential SIOP trials. The
estimated percentages of patients who received irradiation are as follows: SIOP 1, 90%; SIOP
2, 90%; SIOP 5, 72%; SIOP 6, 34%; SIOP 9, 24% (68). If one excludes patients with
metastases, then only about 16% of SIOP patients receive irradiation (90,92).
The latest SIOP protocol 2001 treatment and radiation therapy guidelines are
summarized in Tables 13.34 , 13.35 , 13.36 , and 13.37 .
Table 13.34 SIOP 2001 Postoperative Treatment Strategies for Localized Tumors
Table 13.37 SIOP 2001 Radiation Therapy Dosage (Total Dose/Dose per Fraction)
A recent report from the SIOP 2001 protocol showed that intensification of
chemotherapy for blastemal ty pe Wilms tumors resulted in improved 5-y ear event-free
survival of 80% compared with 67% seen in SIOP93-01. There was no difference in overall
survival. The benefit of augmented therapy for improved overall survival was only seen in
stage I tumors by the addition of doxorubicin (93). In another report from SIOP 2001, the
omission of doxorubicin for children with stage II–III intermediate-risk Wilms tumors without
blastemal subty pe tumors did not result in inferior outcomes. Following treatments with and
without doxorubicin, the 2-y ear event-free survival was 93% and 88% and 5-y ear overall
survival was 97% and 96%, respectively (94).
Figure: NWTS-1 Results
Figure:
The design of NWTS-1.
(From D’Angio GJ. National Wilms’ Tumor Study. Seattle, WA: NWTS Data and Statistical
Center; 1991[Informational Bulletin #19], with permission.)
Figure: NWTS-2 Results
Figure:
The design of NWTS-2.
(From D’Angio GJ, Tefft M, Breslow N, et al. Radiation therapy of Wilms’ tumor: results
according to dose, field, post-operative timing and histology. Int J Radiat Oncol Biol Phys.
1978;4:769–780, with permission.)
Figure:
The design of NWTS-3.
(From D’Angio GJ, Evans A, Breslow N, et al. The treatment of Wilms’ tumor: results of the
Second National Wilms’ Tumor Study. Cancer. 1981;47:2302–2311, with permission.)
Figure: NWTS-3 Results
Figure: NWTS-3 Relapse Rates
Figure:
NWTS-4 simplified schema. Stage IV anaplastic tumors continued the randomization of NWTS-
3.
(From Thomas PRM. Wilms’ tumor: changing role of radiation therapy. Semin Radiat Oncol.
1997;7: 204–211, with permission.)
Figure: NWTS-4 Results
Figure: Comparing Results: NWTS-4 and UK
Children’s Cancer Study Group Wilms
Tumor Study 2
Figure: Risk of Local Recurrence in NWTS-4
Figure: COG Radiation Therapy Guidelines
Figure: COG Chemotherapy Regimens
Figure: Results of the Treatment of New
Cases of Historically Confirmed Wilms
Tumor, with More Than 2 Years of Follow-
Up, As Reported by Schweisguth and
Bamberger of the Institut Gustave Roussy in
1963
Figure: SIOP 1 Wilms Tumor Treatment
Protocol
Figure: SIOP 1 Results
Figure: SIOP 2 Wilms Tumor Treatment
Protocol
Figure: SIOP 2 Results
Figure: SIOP 5 Wilms Tumor Treatment
Protocol
Figure: SIOP 5 Results
Figure: Effect of Preoperative Treatment:
SIOP Trial 5
Figure: SIOP 6 Wilms Tumor Treatment
Protocol
Figure: SIOP 6 Results
Figure: SIOP 9 Wilms Tumor Treatment
Protocol
Figure: SIOP 9: Stage IV Protocol
Figure: SIOP 9 Results
Figure: SIOP 93-01 Wilms Tumor
Treatment: Postoperative Treatment
Strategies for Unilateral Wilms Tumor
Figure: SIOP 93-01 Stage IV Protocol
Figure: SIOP 93-01 Results
Figure: SIOP 93-01 Results
Figure: SIOP 2001 Postoperative Treatment
Strategies for Localized Tumors
Figure: SIOP 2001 Stage IV Postoperative
Treatment
Figure: SIOP 2001 Indications for
Radiotherapy
Figure: SIOP 2001 Radiation Therapy Dosage
(Total Dose/Dose per Fraction)
SELECTION OF THERAPY
Page 318Surgery
If one follows the NWTS philosophy, 90–95% of intra-abdominal tumors are resectable at
diagnosis, and surgery is the initial definitive treatment. Operative approaches have included
a vertical incision or a thoracoabdominal exposure. The current preferred approach is a wide
transverse abdominal incision and total resection generally is achievable with a
transperitoneal approach (95). The surgeon should try and accomplish the safe and complete
removal of the tumor. A thorough exploration of the abdominal cavity should be performed
and the liver and regional ly mph nodes should be examined for evidence of tumor spread.
The presence or absence of ly mph node metastases is of major importance in determining
treatment and relapse-free survival. Ly mph node sampling is necessary for accurate staging.
After the abdominal exploration is completed, radical nephrectomy is performed. The tumor
should be handled carefully throughout the procedure in order to avoid tumor spillage, as this
complication results in a significant increase in local abdominal relapse. The incidence of
operative rupture or spill ranges from 15% to 30% (41,61,64,65,66,67,68,69,70). Most cases
of operative spill are focal (limited to the operative site) rather than diffuse (contamination of
the peritoneal cavity ) (64). The risk of abdominal relapse and mortality has been significantly
greater after surgical spill (41,64,65,96,97). In cases with marginally operable tumors or with
large areas of central necrosis, preoperative radiotherapy or chemotherapy may be
preferable to attempted resection with spill. As noted earlier in this chapter, the SIOP
philosophy, using preoperative chemotherapy, has significantly reduced the risk of operative
spill and tumor rupture.
Page 319Surgical staging is important in determining treatment and prognosis. Palpation
and visual assessment of the opposite kidney and liver are routine, although, as noted earlier in
this chapter, some surgeons believe that preoperative imaging studies, particularly MRI, can
exclude contralateral kidney involvement with tumor. The prognostic importance of ly mph
node involvement has been established (Table 13.9 ) (74,98,99).
A review of NWTS-4 patients undergoing primary nephrectomy found an 11%
incidence of surgical complications (100). The most common complications of nephrectomy
are hemorrhage and small bowel obstruction. The risk factors associated with increased
surgical complications were higher local tumor stage, incorrect preoperative diagnosis,
intravascular extension, and en bloc resection of other visceral organs. Heroic attempts to
excise en bloc all or parts of adjacent organs to which the tumor appears to be adherent are
not warranted, because such procedures are associated with an increased risk of surgical
complications (100,101). Wilms tumors are generally very large and their gross appearance
at the time of surgery can be misleading in interpreting tumor extent or operability. These
tumors often compress and adhere to adjacent structures and in the majority of cases,
pathologic evidence of organ invasion is not present (101).
Page 320In NWTS-3, surgeons encountered renal vein involvement in 10% of patients.
Extension into the inferior vena cava and atrium occurs in up to 5% or more. En bloc removal
of the kidney and renal vein tumor thrombus is possible in most children, and separate
removal is possible in others. In some cases, the thrombus is “milked” from the inferior vena
cava to the renal vein before removal. With meticulous surgery, renal vein involvement does
not adversely affect prognosis (102).
Inoperability results primarily from large tumor size with direct involvement of the liver
or retroperitoneal structures. Some surgeons recommend preoperative chemotherapy to
improve the chance of resectability. Those who subscribe to the viewpoints of the SIOP
studies will be predisposed to using preoperative chemotherapy without a biopsy. For those
who feel uncomfortable with a diagnosis made by phy sical findings and diagnostic imaging,
percutaneous biopsy is indicated, and tumor resection is planned after response to
preoperative chemotherapy (100). A needle biopsy may entail general anesthesia or heavy
sedation with local anesthesia. Ultrasound or contrast-enhanced CT scans may be used to
localize the biopsy site. A proper biopsy must provide an adequate, representative specimen
(39,77). Tumor subcapsular bleeding is a possible biopsy -related complication. For this
reason, some clinicians prefer a posterior approach for the biopsy so that bleeding is more
locally confined and less likely to spill into the abdominal cavity.
In the 1930s, nephrectomy alone achieved cure in 15–30% of children (95). Recent
experience with the management of highly selected small intrarenal primary Wilms tumor
suggests that one can identify a group of patients at extremely low risk of sy stemic
micrometastasis potentially treatable with surgery alone. In a pilot study at Children’s Hospital
in Boston, eight patients y ounger than 2 y ears with unilateral, nonmetastatic, small (< 550 g
total tumor and kidney specimen weight) FH tumors (stage I) underwent nephrectomy with
no additional therapy. With mean follow-up of 5 y ears, all eight children are alive. Seven are
continuously disease-free; one developed a metachronous bilateral tumor and was treated
successfully (56,57). In NWTS-5, 75 children y ounger than 2 y ears and with stage I FH
tumors weighing < 550 g were enrolled in a prospective study and treated with nephrectomy
only. Eleven patients relapsed, among them five had recurrent disease in lung, three in the
operative bed, and three in the contralateral kidney. The 2-y ear disease-free and overall
survival rates were 87% and 100%, respectively (103). Long-term results of this study
revealed a 5-y ear relapse-free and overall survival of 84% and 98%, respectively (104).
Surgical techniques in children with Wilms tumor can impact both the tumor stage and
risk of local recurrence. In a surgical quality assessment (QA) review from the NWTS-5,
among 1305 patients who underwent nephrectomy, 117 (9%) did not have ly mph node
sampling and tumor spillage occurred in 253 patients (19%). A total of 30 patients were
deemed to have had unnecessary biopsies either preoperatively or intraoperatively leading to
local tumor spillage. This report and an earlier one from NWTS-4 have clearly demonstrated
that the absence of a ly mph node biopsy and tumor spillage were both associated with a
higher rate of abdominal relapse (97,105). A surgical QA program is presently in place in the
COG to educate surgeons regarding the value of ly mph node sampling and avoidance of
procedures that result in tumor spillage.
Radiation Therapy
In 1950, Gross and Neuhauser of Boston Children’s Hospital reported that 10 of 31 (32%)
patients treated for Wilms tumor from 1931 to 1939 appeared to be cured of their tumors,
compared with 18 of 38 (47%) cured when treated between 1940 and 1947. The authors
suspected that the difference resulted from the radiotherapy administered to 36 of the 38
patients in the later period. It was customary to irradiate children in the immediate
postoperative period (i.e., shortly after they left the operating room). Dosages of 200 R/day
were given to a total dosage of 4000–5000 R (106).
At present, approximately 70–75% of children with Wilms tumor are treated without
radiation therapy. The number rises to 80–85% if metastatic disease is excluded. The NWTS
and SIOP trials that have led to this restricted use of radiation therapy are described earlier in
this chapter. When irradiation is used, it is successful in limiting the frequency of abdominal
relapse to 0–4% of children with FH tumors (78).
Chemotherapy
In 1966, Sidney Farber reported improved results in the treatment of recurrent and metastatic
Wilms tumor. His series included 16 patients with recurrent disease and 15 with metastatic
disease at diagnosis. Patients were treated primarily with actinomy cin D and, to a limited
degree, vincristine. The 2-y ear survival rate was 58% (107).
The addition of effective chemotherapy has substantially improved the overall results in
Wilms tumor in the past two decades. The NWTS and SIOP studies that have substantially
established the indications for chemotherapy are discussed earlier in this chapter.
RADIOTHERAPEUTIC MANAGEMENT
The current guidelines for external beam radiation therapy in COG protocols are summarized
in Table 13.15 . Indications for radiation therapy in the current SIOP 2001 trial are
summarized in Tables 13.34–13.37 .
The timing of postoperative irradiation is important. Delay ed initiation of treatment
bey ond 10 day s after surgery has been related to higher risk of abdominal recurrence in
several, but not all, studies (41,42,60,75,77,78). Most relapses related to delay ed start of
therapy have been in patients with UH. A recent analy sis (NWTS-3 and NWTS-4) looked at
the influence of delay of radiation therapy on outcome in Wilms tumor in patients with stages
II–IV FH tumors. The mean delay in radiotherapy was 10.9 day s from surgery, and the
median was 9 day s; 59% of children were treated 8–12 day s postoperatively. For children
who were treated 0–9 day s postoperatively and those treated at least 10 day s postoperatively,
there was no difference in the rate of flank or abdominal recurrence. In NWTS-1 and
NWTS-2, 80% of children were treated with radiotherapy during week 1, whereas in NWTS-
3 and NWTS-4, 24% of children were treated in week 1 but 66% were treated with
radiotherapy in week 2 (108). NWTS-5 recommended that postoperative irradiation begins no
later than the ninth postoperative day. In the COG protocols, it is recommended that radiation
therapy be initiated by day 9 if possible, but no later than day 14 after nephrectomy.
Page 321Volume
The irradiation volumes for the flank, WAI, and WLI are identical in NWTS, SIOP, and COG
protocols.
Local–regional irradiation treatment fields include the tumor bed, importantly
differentiated from the renal bed to include the entire preoperative tumor extent in the
abdomen. The tumor bed is defined as the outline of the kidney and any associated tumor.
The tumor volume is established by careful review of the surgical findings, IVP, CT,
ultrasound, or MRI. The superior margin of the field is placed at the upper pole of the
kidney /tumor with an additional 1-cm margin and the inferior portal margin encompasses the
lower margin of the kidney /tumor with a 1-cm margin. The field should extend to the dome
of the diaphragm only in patients in whom the tumor is known to have extended that far
superiorly. A variable proportion of the liver is necessarily included to adequately encompass
the initial tumor extent for right-sided lesions. Medially, the target volume should encompass
the entire width of the vertebral bodies, with
adequate contralateral extension to include the
entire para-aortic ly mph node chain but exclude
the remaining kidney. The choice of the medial
margin reflects the importance of ly mph node
radiation therapy. In addition, homogeneous
irradiation of the vertebral bodies avoids one
mechanism of late scoliosis by equally affecting
growth on each side of the vertebral body.
Laterally, the treatment field tangentially
includes the abdominal wall. Parallel-opposed
anterior and posterior fields are used (Fig.
13.11 ).
For patients with preoperative
intraperitoneal tumor rupture, intraoperative
rupture with diffuse dissemination of tumor,
diffuse peritoneal implants, or massive Figure 13.11 Flank radiation therapy
abdominal disease, irradiation must address the field for a left-sided Wilms tumor. The
entire abdominal cavity. The target volume gross tumor volume (GTV) based on
includes all of the peritoneal surfaces, defined preoperative CT scan is shown in green.
superiorly by the diaphragms and inferiorly The right kidney (blue) and the diaphragm
through the lower pelvic region, generally at the (yellow) are also shown.
bottom of the obturator foramen. The
acetabulum and femoral heads are blocked (Fig. 13.12 ). Attempts to limit irradiation by
blocking the contralateral pelvic region of the peritoneal cavity have been associated with
abdominal recurrence when abdominal irradiation was appropriate (109).
WLI must be administered carefully to encompass both apices and the posterior inferior
extent of the lungs. The average field extends above the clavicles and approximately down to
T12-L1. The shoulders are excluded from the field by blocks. Care should be taken not to
irradiate the uninvolved kidney in the whole-lung field (Fig. 13.13 ).
When clinical situations call for WLI plus flank irradiation as in abdominal stage III
patients with lung metastases, it is preferred that patients be treated with one large field,
reducing off the flank at 10.5 Gy and then continue with WLI to 12 Gy. If these fields are
treated separately, field matching with appropriate gaps and feathering are important in
avoiding excessive liver irradiation in right-sided disease and avoiding irradiation of the
remaining kidney in left-sided tumors.
As stated earlier, the first two NWTS trials incorporated an age-dependent scale of dosages
ranging from 18 to 40 Gy and the results showed no apparent dose–response relationship, with
equal frequency of abdominal recurrence at dosage levels of 18–20 Gy, 20–24 Gy, and 24–
40 Gy (41,75). The NWTS-3 trial has established that doses of 10 Gy are adequate with
three-drug chemotherapy and this has been adopted in subsequent NWTS and COG protocols
(42). In patients with residual disease (>3 cm), a booster (10.8 Gy ) dose may be given for a
cumulative tumor dose of 21.6 Gy. In recent SIOP trials, local–regional radiation therapy is
given to patients who, after preoperative chemotherapy and nephrectomy, are found to have
stage II high-risk tumors or stage III. These categories comprise approximately no more than
25% of patients. The dosage to the tumor bed is 14.4–25.2 Gy, with an optional boost to
localized areas of tumor as needed (Tables 13.34 –13.37 ) (69).
The late effects of treatment of childhood cancer and the causes and frequency of treatment-
induced second malignant neoplasms (SMNs) are considered in detail in Chapters 19 and
20 . In this section, we will review the late ill effects, including induced neoplasms,
particularly associated with the treatment of Wilms tumor.
Hematologic Toxicity
Review of the data from NWTS-3 indicates clinically significant acute hematologic toxicities.
Fatal toxicities occur in a small proportion of patients. Depending on the drugs given, severe
hematologic toxicity occurs in 6–64% of patients over a 6-week course of treatment. Toxicity
and infections account for 15% of the deaths of NWTS children, producing a 1% treatment-
related mortality rate (79).
Hepatic Effects
Hepatotoxicity from Wilms tumor therapy may be indicated by an increase in transaminases
or by hy perbilirubinemia. Veno-occlusive disease consists of the clinical triad of
hepatomegaly, ascites, and icterus. In unirradiated NWTS-4 patients, the frequency of
hepatic toxicity related to actinomy cin D (serum glutamic–oxaloacetic transaminase, serum
glutamic–py ruvic transaminase elevations) rose from 2.8% in patients receiving 15 mg/kg of
standard divided-dose therapy to 3.7% in those receiving pulse intense (PI) 45 mg/kg and
14.3% in those receiving 60 mg/kg PI therapy. These data prompted replacement of the 60-
mg/kg treatment with the 45-mg/kg dosage (140). A review of cases accrued via the German
Pediatric Oncology Hematology Group to SIOP trial 9 studied 58 patients who received
chemotherapy and abdominal irradiation. Eleven of these 58 patients developed signs of
hepatotoxicity, four of them with veno-occlusive disease. There was a predominance of
children with right-sided tumors in the group with hepatic injury (9 out of 33, 27%, vs. 2 out of
24, 8%) (141). In a report from the NWTS-1 to NWTS-4, a case–control study was
conducted to determine relationships among doxorubicin, liver radiation dose, patient gender,
and the development of portal hy pertension. The 6-y ear cumulative risk for portal
hy pertension was 0.7% for right-sided tumors versus 0.1% for those with left-sided tumors (p
= 0.002). There was a significant association between minimum and maximum liver dose
(>15 Gy ) and portal hy pertension. Doxorubicin and gender were not significant (142).
Orthopedic Effects
In long-term follow-up studies of Wilms tumor survivors, scoliosis and musculoskeletal
abnormalities are more common in irradiated patients than in those not irradiated. This may
result from asy mmetric irradiation of the vertebral bodies or the paraspinal musculature.
Rate et al. (143) identified 31 children with Wilms tumor who received abdominal irradiation
between 1970 and 1984 and were followed past skeletal maturity. Ten of the children were
irradiated with orthovoltage and 21 with megavoltage. Of the children irradiated with
megavoltage, the most common orthopedic abnormalities were lower rib hy poplasia (57%)
and mild scoliosis (10–20 degrees) (48%). In the patients irradiated with orthovoltage, lower
rib hy poplasia occurred in 50%, mild scoliosis in 40%, severe scoliosis (more than 20
degrees) in 40%, and limb length inequality in 20% (143,144). Scoliosis as a late ill effect of
abdominal irradiation for Wilms tumor was confirmed by a report from the University of
Helsinki in which 21 of 24 patients (88%) had some degree of scoliosis. Most patients had
been irradiated with cobalt-60 (144,145).
Renal Effects
After unilateral nephrectomy in childhood, the
remaining kidney generally adjusts its function
and size; this is called compensatory
hy pertrophy of the kidney. One y ear after
nephrectomy for Wilms tumor, the glomerular
filtration rate (GFR) and effective renal plasma
flow are approximately 90% of normal values
for age-matched children with two normal
Table 13.38 Long-Term
kidney s. Children treated with surgery and
chemotherapy also have close to normal values. Complications of Renal Function
The addition of radiation to chemotherapy
results in a diminished renal function to approximately 73% of normal GFR (Table 13.38 )
(141,146). In a report from the NWTS, the 20-y ear cumulative risk of renal failure for
children with unilateral tumors without congenital abnormalities, BWT, male GU anomalies,
Deny s–Drash sy ndrome, and WAGR sy ndrome was <1%, 5.5%, 10.9%, 62%, and 38%,
respectively. It was recommended that patients with aniridia and GU abnormalities be
carefully monitored throughout life for signs of nephropathy or renal failure (120).
Pulmonary Effects
In a report from the NWTS, among 6500 patients from NWTS1-4 with a median follow-up of
18 y ears, the 15-y ear cumulative incidence of pulmonary disease (abnormal pulmonary
function tests or clinical sy mptoms and signs of restrictive pulmonary disease) was <0.5%
without lung RT and 4–5.5% after lung RT was delivered for primary stage IV tumors or at
relapse. There was no correlation between the incidence of pulmonary disease and WLI dose
as the majority of patients received between 12 and 14 Gy (148).
Pregnancy Outcome
There is now long-term follow-up on pregnancy outcome in irradiated women who were
treated, as children, for Wilms tumor. As Table 13.40 indicates, the risk of early or
threatened labor, malposition of the fetus, short gestation, or low birth weight appears directly
correlated with the irradiation dosage. The outcome also appears worse for those treated with
abdominal–pelvic fields and those treated with higher irradiation dosages (149,150).
Table 13.40 Pregnancy Outcome
Treatment-Induced Neoplasms
Initial reports concerning the risk of SMNs after treatment of Wilms tumor indicated that the
cumulative incidence 10 y ears after diagnosis was 1% (151,152). In an NWTS report, the 15-
y ear cumulative risk of SMN was 1.6% since Wilms tumor diagnosis. The risk of developing a
ly mphoma or leukemia was 0.4% at 8 y ears after which no cases occurred. However, the
risk of developing a solid tumor continued to rise sharply with time. Approximately 73% of
solid tumors arose within a previous irradiated field. Higher abdominal radiation dose,
doxorubicin use, and treatment for relapse were the significant factors correlated with the
development of second tumors (153). Long-term follow-up indicates that there is a risk of
acute my elocy tic leukemia in long-term survivors of Wilms tumor. This may be related to
the administration of alky lating agents and abdominal irradiation (154). In another NWTS
report on the rates and causes of mortality in Wilms tumor patients, the standardized
mortality ratio (SMR) was 24.3 within 5 y ears of diagnosis, 12.6 for the next 5 y ears, and
>3.0 thereafter. The main cause of mortality within the first 5 y ears was original disease
(91%). However, bey ond 5 y ears, the two important causes of mortality were original
disease (40%) and late effects of treatment (39%). The three common treatment-related late
effects that contributed to mortality were SMNs, congestive heart failure, and end-stage renal
disease. The risk of death particularly from treatment-related late effects remained elevated
even 20 y ears after diagnosis (155). In the British Cancer Survivor Study, the cumulative
incidence of a second primary neoplasm at 30, 40, and 50 y ears of age was 2%, 7%, and
12%, respectively. Thirty -five of 39 solid neoplasms that developed in the thoracic,
abdominal, or pelvic regions occurred within irradiated tissue. Higher doses of radiation
therapy delivered to the abdomen and pelvis was an important reason for the development of
secondary tumors (156). In another recent NWTS report, female survivors who received
WLI had nearly a 15% risk of developing invasive breast cancer by age 40 y ears. This report
highlighted the need for reevaluating current COG guidelines that recommend breast cancer
screening only for those who received >20 Gy to the chest (157).
Growth Abnormalities
Abdominal irradiation can also produce
significant reduction in sitting height and a more
modest decrease in standing height. These
effects are more pronounced the y ounger the
patient is at the time of radiotherapy (143,158).
Long-term analy sis of predicted height deficits
in children who receive flank radiation for
Wilms tumor indicates, as shown in Table
13.41 , that the y ounger a child is at the time
of flank irradiation, the greater the predicted
height deficit. Furthermore, the higher the Table 13.41 Predicted Deficit in
dosage of irradiation administered, the greater Height at Age 18 Years after Flank
the predicted height deficit. These effects are Irradiation at Selected Ages and Dosages
related to irradiation of the thoracolumbar
vertebral bodies. Abnormalities can also ensue from asy mmetric irradiation of the
paravertebral musculature, which may, over time, lead to a risk of scoliosis.
Figure: Long-Term Complications of Renal
Function
Figure: Long-Term Complications of
Cardiac Function (99)
99 Breslow N, Sharples K, Beckwith JB, et al. Prognostic factors in non-metastatic favorable
histology Wilms’ tumor—results of the Third National Wilms’ Tumor Study. Cancer.
1991;68:2345–2353.
Figure: Pregnancy Outcome
Figure: Predicted Deficit in Height at Age 18
Years after Flank Irradiation at Selected
Ages and Dosages
FUTURE DEVELOPMENTS
Page 327In spite of the tremendous progress that has been made in the management of
Wilms tumor, a significant amount of clinical and basic research is being conducted by the
NWTS and SIOP investigators to further optimize therapy in this disease. The future risk
stratification of Wilms tumors for the next generation of COG protocols will likely include two
promising biomarkers (11p15 LOH for VLRWT and 1q gain for FH tumors) in addition to the
other currently used prognostic factors including tumor histology, age, tumor weight, tumor
stage, LOH status, and tumor response to chemotherapy. Treatment strategies for the various
risk groups are currently being developed. Based on the preliminary findings of current COG
protocols, chemotherapy response at week 6 will determine the need for WLI in children with
FH tumors and lung metastasis. Regimen ‘M’ will be used for patients with higher risk tumors
including those with LOH and slow responders to chemotherapy at week 6. Vincristine and
Irinotecan will be included in the chemotherapy regimen for children with diffuse anaplastic
Wilms tumors. Safer multimodality treatment regimens are being considered for UH tumors.
The indications for and dosages of radiation therapy will likely remain the same. As discussed
above, IMRT will be recommended for WLI and whole-liver irradiation. The COG radiation
oncologists will continue research to answer some of the remaining clinical radiotherapy
questions including: RT dose response in relapsed Wilms tumor and diffuse anaplasia; RT
quality assurance review data for patients enrolled on COG protocols; RT effects on flank
relapse in stage III patients with tumor rupture; correlation of RT dose with late effects among
NWTS survivors such as infertility, SMNs, etc.; and the possible role of proton therapy to
reduce late effects in children with Wilms tumor.
Finally, it is very important for all phy sicians involved in the care of children to promote
the recruitment of childhood cancer survivors into long-term follow-up programs that are
designed to provide education and specific surveillance guidelines for the early detection and
prompt management of any potential treatment-induced sequelae. Such measures will go a
long way in preventing or ameliorating the negative impacts of such sequelae on their quality
of life. The COG long-term follow-up guidelines for survivors of childhood, adolescent, and
y oung adult cancers are updated annually and are available on the COG website
(http://www.survivorshipguidelines.org ) (159).
REFERENCES
Vascular Tumors
The most common benign lesions in children are hemangiomas and hemangioendotheliomas.
Hemangiomas are the more common and usually occur within the first 6 months of life (2).
Most hemangiomas are incidentally discovered on imaging studies. Infantile
hemangioendothelioma is a subty pe of hemangioma that is ty pically found in infants. A
female predilection is noted, with a female-to-male ratio of 4.3:1 to 2:1. Afflicted infants
generally present with abdominal distension and cutaneous hemangiomas (10% of cases) that
suggest the diagnosis. More than 50% of these infants have high-output cardiac failure at
initial presentation (2). The classical triad of hepatomegaly, anemia, and congestive heart
failure leads to the suspicion of infantile hemangioendothelioma. Kasabach–Merrit sy ndrome
with consumptive coagulopathy, thrombocy topenia, and hemorrhage is the leading cause of
morbidity and mortality seen in infantile hemangioendothelioma (3).
The natural history for hemangiomas is spontaneous regression in the first 2 y ears of
life; however, treatment is required if cardiac failure or platelet consumption occurs. Several
treatment options are available, including high-dose corticosteroids (3–5 mg/kg/day ),
interferon-alfa (3 MU/m 2/kg/day SC), aminocaproic acid, vincristine, and
cy clophosphamide; all are associated with potential severe side effects and poor outcome (4).
Focal lesions can be treated with complete surgical excision. Selective hepatic artery
embolization may not be as successful for multifocal as it is for focal lesions. Operative
ligation of the hepatic artery can be used to decrease shunting through the lesion, with
subsequent improvement in cardiac output (5). Radiation therapy is usually avoided because
angiosarcomatous degeneration may follow radiation. Rarely, liver transplantation may be
indicated for diffuse disease that is unresponsive to steroid and interferon therapy.
Mesenchymal Hamartoma
Infantile mesenchy mal hamartomas are rare benign tumors, comprising 6% of liver tumors
in children (Table 14.1 ), and can be considered more of a malformation than true tumors.
They tend to be diagnosed before the age of 2 y ears and are more common in the right lobe
of the liver. They usually present as an asy mptomatic abdominal mass after a period of rapid
growth during the first few months of life and cause compression of adjacent tissue but are
curable by resection (6). Alpha fetoprotein (AFP) levels may be variably elevated. CT scan
reveals a well-circumscribed, multilocular, heterogeneous, cy stic mass with solid septa and
stroma. Biopsy is recommended if cy sts are small or appear more solid rather than septated.
Complete surgical excision, with a rim of normal tissue (if possible), is the treatment of
choice (7).
Children with primary malignant liver tumors (PMLTs) often present with an abdominal mass
or generalized abdominal enlargement. The child may have pain localized to the right upper
quadrant, fever, anorexia, weight loss, jaundice, or vomiting. The first presentation may, on
occasion, be an acute abdominal crisis caused by tumor rupture and hemoperitoneum.
Paraneoplastic sy ndrome, such as precocious sexual development, has been associated with
PMLTs (8). Anemia and thrombocy tosis often occur. This is probably related to the ability of
HBL cells to secrete gonadotropin and interleukin-1B, which induces IL-6 production in
fibroblasts of endothelial cells (9).
Hepatoblastoma
HBL is the most common PMLT occurring in the first 20 y ears of life and accounts for 1% of
all pediatric malignancies and about 60% of PMLTs in the pediatric age group (8). Median
age at diagnosis is 16–19 months. Only 5% of the cases occur in children older than 4 y ears.
As with all PMLTs, there is a male predominance with a reported male-to-female ratio of
1.4–2.0:1. HBL has been reported to be associated with a host of conditions, including
Beckwith–Wiedemann sy ndrome, Wilms tumor, adrenal cortical tumors, fetal alcohol
sy ndrome, familial adenomatous poly posis (FAP), prematurity, low birth weight, parental
cigarette smoking, and paternal excess exposure to metals or petroleum products. The cell of
origin is thought to be a pluripotent hepatic stem cell.
HBL may be histologically classified into six patterns (Table 14.2 ). Conventional
HBLs contain fetal hepatoblasts, embry onal hepatoblasts, or a mixture of the two cell ty pes
(Figs. 14.1 and 14.2 ). Fetal-ty pe hepatoblasts recapitulate the cy toarchitecture of the
normal human fetal liver. Cells of the early fetal liver and the cells of fetal HBL are of
similar size and configuration. Both proliferate as cuboidal cells with trabeculae one- to two-
cell thick. Both display strong positivity for AFP. Both tissues also display sinusoidal
hematopoiesis and a lack of intrahepatic bile ducts. Fetal cells are slightly smaller than normal
hepatocy tes and have a low nucleocy toplasmic ratio. In contrast, embry onal hepatoblasts
have a higher nucleocy toplasm ratio than do fetal cells, and they also have a compact
basophilic cy toplasm (Fig. 14.3 ). This gives a light-microscopic impression of a higher
cell density. Small-cell undifferentiated or anaplastic HBL contains sheets and nests of
medium-sized cells, with little or no evidence of hepatoblastic differentiation. There is scant
cy toplasm and a high mitotic index. Mixed epithelial and mesenchy mal HBL is composed of
ty pical areas of fetal epithelial and embry onal ty pe cells mixed with primitive mesenchy me
and various mesenchy mally derived tissues.
It is unclear whether the recognized
histologic subty pes are related to prognosis. The
subty pes can occur together within the same
tumor in vary ing composition. Some
investigators report that in long-term survivors of
HBL, the most common histology is the
conventional ty pe, with a predominantly fetal
cell pattern (10). However, there is no uniformly
accepted definition of “predominantly ” or
“pure” fetal histology. Although conventional Table 14.2 Histologic Classification of
epithelial tumors constitute 60% of all HBLs, Hepatoblastoma
they represent 85% of HBLs in children who
have undergone complete tumor resection and
are long-term survivors. Almost no children with
anaplastic HBL survive the disease. A Pediatric
Oncology Group (POG)–Children’s Cancer
Study Group (CCSG) trial showed the distinction
between fetal HBL and other histologic subty pes
to be of prognostic importance in stage I disease
(3-y ear progression-free survival of 79% vs.
56%, p = 0.11) (11). However, not all
investigators have confirmed the prognostic
importance of histologic subty pes in all stages. Figure 14.1 Hepatoblastoma, ×20
For example, a large analy sis, the Japanese magnification. (Courtesy Dr. John
Study Group for Pediatric Liver Tumor (JPLT), Buchino.)
found no significant influence of HBL histologic
classification on outcome (12).
Liver enzy mes and bilirubin are usually normal or mildly elevated. Abdominal ultrasound
helps to establish the presence of a hepatic mass and differentiates cy stic from solid lesions.
Color Doppler ultrasound may be performed to assess tumor vascularity and evaluate
inferior vena cava for tumor thrombus (18). The technetium-90m sulfur colloid scan is of
some value in localizing the tumor to the liver and defining its boundaries. It is a sensitive test,
but not specific. CT and MRI provide superior delineation of the mass and show evidence of
multifocality (19). On nonenhanced CT, epithelial HBL is a homogeneous low-attenuation
mass. The mixed ty pe is inhomogeneous. Calcifications can be present. Contrast
enhancement of the periphery or septa may be seen. On MRI, the epithelial ty pe is
homogeneous and hy pointense on T1 and hy perintense on T2. The mixed ty pe may be more
inhomogeneous and hy pointense on T1 and T2, and hemorrhage will show high signal
intensity on T1 and T2 (Fig. 14.4 ). On CT, HCC will show solitary or multiple masses.
Calcification can occur. The tumor rim may show enhancement with contrast. On MRI, the
T1 images may be isointense or hy perintense. On T2 images, a mosaic pattern (caused by
necrosis, hemorrhage, septa, and fatty metaplasia) is common (20). The operating surgeon
may request an angiogram to obtain information about the origin and distribution of the right
and left hepatic arteries to provide additional information on the vascular supply of the tumor
(8). Routine chest radiographs and thoracic CT scans are necessary because 10–20% of
patients with HBL and 30% of patients with HCC have lung metastasis at the time of diagnosis
(9,21,22). Positron emission tomography CT with 18F-Fluorodeoxy glucose has proved to
more sensitive than MRI or CT in detecting recurrent or metastatic diseases (23,24).
Metastases to brain and bones are not uncommonly seen, especially in advanced HCC.
Figure 14.4 A–D: Hepatoblastoma is best visualized on cross-sectional imaging. It is
homogeneous and hypointense on T1 and hyperintense on T2 on magnetic resonance images.
Page 335Approximately two-thirds of children with HBL and HCC have an elevated
AFP. The clinician should note that AFP, sy nthesized by the fetal liver, is high in the normal
newborn infant but drops rapidly throughout the first several months of life. By age 1 y ear,
the serum AFP is <10 ng/mL. The clinician should be cautious as well that AFP is not alway s
elevated in HBL and HCC, and AFP may be elevated mildly in benign hamartomas, infantile
rhabdoid tumor, and fibrolamellar HCC. Absence of AFP elevation may be a poor prognostic
sign in HBL, which is often associated with small-cell (anaplastic) histology and responds
poorly to therapy. It is also elevated in germ cell tumors with y olk sac components, and some
arise in the liver. For patients with elevated AFP, it may be of value in monitoring the course
of therapy (18). Complete resection of HBL or HCC should result in a normal AFP by 2
months postoperatively. No change in an elevated AFP after surgery indicates either residual
tumor or regenerating normal liver. The diagnosis of growing tumor depends on confirmatory
imaging studies. An elevation in the AFP level during the follow-up period generally heralds a
local tumor recurrence or distant metastasis. A diagnostic tumor biopsy for all patients should
be performed before chemotherapy, regardless of their age and serum AFP level (25).
Adequate tumor samples can be obtained via percutaneous core needle biopsy, laparoscopic
core needle or wedge biopsy, and/or open core needle or wedge biopsy, depending upon
patient characteristics, the size and location of the tumor, and the team available at the
institution. Fine-needle aspiration should be avoided for diagnosis, as the material obtained is
usually insufficient to evaluate tumors in this age group.
Genomic Abnormality
Hepatoblastoma mutation frequency, as determined by whole-exome sequencing, was very
low (three variants per tumor) in children y ounger than 5 y ears (26,27). Hepatoblastoma is
primarily a disease of WNT pathway activation. The primary mechanism for WNT
pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1
mutations have been reported to be present in 70% of cases. Rare causes of WNT pathway
activation include mutations in AXIN1, AXIN2, and APC (APC seen only in cases associated
with familial adenomatosis poly posis coli) (28). The frequency of NFE2L2 mutations in
hepatoblastoma specimens was reported to be 7% in one study and 10% in another study
(26,27). These mutations render NFE2L2 insensitive to KEAP1-mediated degradation,
leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative
stress and is believed to confer resistance to chemotherapy.
A first case of pediatric hepatocellular carcinoma has been analy zed by whole-exome
sequencing showing a higher mutation rate (53 variants per tumor) and the coexistence of
CTNNB1 and NFE2L2 mutations (29). Fibrolamellar hepatocellular carcinoma, a rare
subty pe of hepatocellular carcinoma observed in older children, is characterized by an
approximately 400 kB deletion on chromosome 19 that results in production of a chimeric
RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of
the molecular chaperone DNAJ, fused in frame with PRKACA, the cataly tic domain of
protein kinase A (30).
Figure:
A–D: Hepatoblastoma is best visualized on cross-sectional imaging. It is homogeneous and
hypointense on T1 and hyperintense on T2 on magnetic resonance images.
STAGING
Figure 14.5 PRETEXT is distinct from Couinaud 8-segment (I–VIII) anatomic division of the
liver. PRETEXT defines four “Sections.” Boundaries of each section are defined by the right
and middle hepatic veins, and umbilical fissure (From López-Terrada D, Alaggio R, de Dávila
MT, et al. Towards an international pediatric liver tumor consensus classification: proceeding
of the Los Angeles COG liver tumors symposium. Mod Pathol. 2014;27:472–491).
In the German HBL Study HB94, the following six factors predicted poor prognosis (31):
Metastatic disease
Initial AFP greater than 1 × 106 ng/mL
Extrahepatic and intrahepatic vascular invasion
Multifocal disease and involvement of both liver lobes
Stage (tumor, node, metastasis [TNM])
Poor epithelial differentiation
In the SIOPEL-1 study, only metastatic disease and involvement of all four sectors of the
liver predicted poor outcome (32,33).
Figure: Staging System of Hepatoblastoma
by the Children’s Oncology Group
Figure:
PRETEXT is distinct from Couinaud 8-segment (I–VIII) anatomic division of the liver. PRETEXT
defines four “Sections.” Boundaries of each section are defined by the right and middle
hepatic veins, and umbilical fissure (From López-Terrada D, Alaggio R, de Dávila MT, et al.
Towards an international pediatric liver tumor consensus classification: proceeding of the Los
Angeles COG liver tumors symposium. Mod Pathol. 2014;27:472–491).
SELECTION OF THERAPY
Surgery
The key to successful treatment of malignant liver tumors is surgical removal, either by
tumor resection/partial hepatectomy or liver transplantation. It is also possible to achieve a
cure with a near-complete excision in conjunction with adjuvant therapy that is able to
further eliminate residual tumor. Tumor resectability is determined by tumor size, the
existence of bilobar involvement necessitating resection of more than three liver segments,
vascular invasion, or distant metastases (34).
Less than 25–50% of all HBLs are resectable at time of diagnosis. After neoadjuvant
cisplatin-based chemotherapy, the probability of resection rises to about 90% and renders
tumor free through tumor resection after initial chemotherapy (35). Tumors that are
unresectable but without overt metastasis have EFS of 60–70%, while those with metastasis
disease do poorly with approximately 20–30% EFS (36). Only 30–50% of the cases of HCC
are amenable to complete resection at presentation because of multilobar involvement or
massive tumor size (37). HCC does not respond well to chemotherapy or radiotherapy.
The timing of surgical approach is crucial. Surgeons with experience in pediatric liver
resection and transplantation should be involved early in the decision-making process. There
are three way s a surgeon is used to treating a primary liver cancer, including initial surgical
resection, delay ed surgical resection (following chemotherapy ), and orthotopic liver
transplantation. Controversy exists between COG and SIOPEL approaches to the role of
preoperative chemotherapy (initial biopsy only ) versus primary resection. In the SIOPEL-1
study, primary surgery was performed only for patients with PRETEXT group 1, and
resection was attempted for all others after four to six cy cles of cisplatin-based
chemotherapy (25). When chemotherapy is initiated without a histologic diagnosis, there is
about a 4% risk that the patient may not have HBL or HCC. Errors in diagnosis include
hemangioendothelioma, angiosarcoma, neuroblastoma, and germ cell tumor. COG favors
primary surgery and adjuvant chemotherapy, except for clearly unresectable tumors.
Preoperative chemotherapy reduces the tumor burden in the majority of HBL cases, and
children with initially unresectable HBL may be rendered resectable by preoperative
chemotherapy (38). However, 3–4% of stage 1 HBL do not require chemotherapy (well-
differentiated, pure fetal histology with low-mitotic rate) and a small subgroup of small
undifferentiated cells does not respond to current chemotherapy, thus making upfront
chemotherapy undesirable (39). It is difficult to compare the COG and European approaches,
as the 5-y ear survival of PRETEXT stage I and II patients is 90–100% on the European
studies and seems to be similar to the US studies where surgery was performed before
chemotherapy (40). The current COG trial, AHEP-0731, has now assigned patients to risk-
based and surgical guidelines and recommends up-front resection only for PRETEXT I and
II tumors (41) (Table 14.4 ).
Page 337
When the patient comes to definitive surgery, a bilateral subcostal incision allowing a
large area of exposure is often performed (35). A simple tumorectomy with adequate
margins is rarely possible. Rather, hepatic lobectomy or extended lobectomy is needed.
Intraoperative ultrasonography has been widely applied to determine the exact location of the
tumor relative to the vessels. Perioperative mortality was reported to be as high as 18–33% in
the past but is now in the order of 5–10% in specialized centers (37). Surgical complications
include severe bleeding, bile duct injury, pleural effusion, rupture of the inferior vena cava,
cardiac arrest, convulsions, and subhepatic abscess (42). Improved surgical techniques such
as vascular reconstruction, ultrasonic aspiration, and dissection under vascular exclusion and
improvements in anesthesia, blood product replacement, and postoperative intensive care
have produced the significant reduction in operative and perioperative mortality. In stage IV
disease, surgical resection of pulmonary metastases can be considered if they persist after
preoperative chemotherapy and if the primary tumor has been rendered resectable by drug
treatment (37). In patients with stage I disease at initial diagnosis that recurs with isolated
pulmonary disease, surgical resection is recommended and often result in extended or even
long-term survival (32,43).
Liver transplantation has had an increasing role in children with nonresectable tumors or
in those who show chemotherapy resistance. Otte reported the result of SIOPEL-1
(International Society of Pediatric Oncology ), which showed overall survival (OS) at 10
y ears after liver transplantation to be 85% for the seven children who received a “primary
liver transplantation” and 40% for the five children who underwent “rescue liver
transplantation” after previous partial hepatectomy (44). They reviewed the world
experience (147 cases), and the overall survival rate at 6 y ears after liver transplantation was
82% for 106 patients who received a “primary liver transplantation” and 30% for 41 patients
who underwent “rescue liver transplantation.” There is a trend for a better patient survival
after living related liver transplantation (45,46,47). D’Antiga and Czauderna recommended
early referral to a transplantation center for patients who had the following characteristics:
older patients who had multifocal tumors, high PRETEXT scores, involvement of major liver
vessels, and AFP levels <100 ng/mL (33,48). Because of rarity of this disease and to optimize
result, children with extensive primary liver cancer should be managed and treated in centers
experienced in liver transplantation. In both the nationwide survey of the outcomes of living
donor liver transplantation for hepatoblastoma in Japan and the United States, the actuarial 5-
y ear survival rates exceeded 75% (49,50). Cases with multifocal or large solitary lesions,
tumors involving all four sectors of the liver, and unifocal, centrally located tumors that
involve the main hilar structures or main hepatic veins should be referred to a transplant
surgeon (51). Increasing evidence suggests that transarterial chemoembolization is feasible in
patients with unresectable hepatoblastoma, in patients who are not candidates for liver
transplant, or both.
Chemotherapy
The most important advance in the care of children with HBL has been the discovery of
effective adjuvant chemotherapy in improving surgical and overall outcomes. Cisplatin-
based chemotherapy has been successful in the treatment of HBL with a survival rate >90%
for children with stage I and II disease (22,52,53,54,55). Chemotherapy in some cases is able
to eradicate pulmonary metastases completely and eliminate multinodular tumor foci in the
liver (56). Initial reports showed the efficacy of vincristine, cy clophosphamide, doxorubicin,
and 5-fluorouracil. Cisplatin is the most active single agent used to treat hepatoblastoma.
Doxorubicin is active as well. Carboplatin has been replaced to reduce ototoxicity ; however,
the effect and efficacy have not been compared in randomized control studies to date.
Irinotecan and etoposide, paclitaxel, gemcitabine, and bevacizumab show promising activity
but need to be studied further (57,58). Bevacizumab is associated with side effects such as
hy pertension, leukoencephalopathy, and wound healing complications that must be taken into
consideration. Chemotherapy is usually started approximately 4 weeks after surgery to allow
liver regeneration. A minimum of 2 weeks should be elapsed before administration of
cy totoxic agents. Treatment usually consisted of six cy cles of chemotherapy in 2–4 weeks
interval.
Page 338Only four international groups—the Intergroup (USA/Canada), JPLT (Japan),
GPOH (Germany /Austria), and the SIOPEL—were sufficiently large to set up independent
studies (Table 14.5 ).
In 1976, CCG trial 881 added doxorubicin and 5-fluorouracil to the three drugs used in
trial 831. Adjuvant chemotherapy was given to 24 patients who did not have measurable
disease after surgery. Of these, 83% were disease-free survivors with a median follow-up of
30 months, whereas only 12 (44%) of 27 different patients with measurable disease achieved
a response with a median duration of 18 months (61).
CCG trial 823F used cisplatin and continuous-infusion doxorubicin in an attempt to reduce
tumor size in children with unresectable or incompletely resected HBL or HCC to allow for
subsequent surgery. Thirty -three children with HBL and 14 with HCC were entered in the
study. Twenty -six HBL patients completed the initial four courses of chemotherapy, 25
achieved either complete or partial response, and 22 of them had second-look surgery. Of the
22, 16 had complete resections and 15 of them are alive without evidence of disease. In nine
of the resected specimens, no viable tumor was identified. Of the 25 children who had a
response to chemotherapy, 19 (78%) are alive and disease free. The estimated 2-y ear
survival for the initial 33 patients with HBL is 67%. Children with HCC did not fare as well as
those with HBL; however, of the 14 patients with HCC, 12 died of progressive disease and 2
remained free of disease. Only 14% of the HCC patients had complete tumor removal at
second-look laparotomy (61).
The Pediatric Intergroup Hepatoma Study INT-0098 (CCG-8881/POG-8945)
demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and
cisplatin/doxorubicin in the treatment of HBL. Although equally effective in terms of overall
and event-free survival (EFS; p = 0.219) (Table 14.6 ), the combination of
cisplatin/vincristine/fluorouracil is significantly less toxic than that of cisplatin/doxorubicin.
Five-y ear EFS rates for patients with stage I, II, and resectable III, and IV HBL were 91%,
100%, and 83%, respectively. Patients with unresectable or metastatic disease had EFS of
50% and 10%, respectively (55,62,63). For patients with HCC, no differences were found
between the two programs for either EFS (p = 0.78) or OS (p = 0.80). All seven stage I
patients were event-free survivors (64,65), compared with 88%, 8%, and 0% for patients with
stage I, III, and IV HCC (65).
Table 14.6 Results of the Pediatric Intergroup Hepatoma Study for Hepatoblastoma
(CCG-8881 and POG-8945)
Page 339The German Cooperative Pediatric Liver Tumor Studies HB-89 and HB-94
treated 141 patients with HBL (Table 14.7 ). Forty -eight patients were primarily resected,
and 14/48 (30%) had micro- or macroscopic residual tumor in the liver. Most (81/141)
children were operated after an initial therapy with ifosfamide, cisplatin, and adriamy cin.
Only 15/78 (19%) cases were recognized as “incomplete resection” (p < 0.044). In cases of
insufficient tumor response, high-dose cisplatin and adriamy cin were added. With a median
follow-up of 6 y ears, disease-free survival (DFS) is 98% for stage I, 55% for stage II, 63%
for stage III, and 78% for stage IV. These results underline the necessity for preoperative
chemotherapy in all HBL (32,42,59).
Table 14.7 Summary of Recent Hepatoblastoma Multicenter Trials
(12,25,31,36,53,54,55,59,60,66,67,68)
HCC has epidemiologic and pathologic characteristics different from those of HBL. It
usually presented at an older age, involved the liver multifocally, and is more related to
vertical transmission of maternal hepatitis B virus. HCC is so infrequent in children that these
patients have often been treated according to HBL regimens. Surgical resection remains the
foundation of curative therapy. Unresected HCC are far less responsive to chemotherapy and
carry very poor prognosis. Unfortunately, complete surgical resection of HCC is possible in
fewer than 30% of children at diagnosis. HCC is only partially chemosensitive; thus,
chemotherapy and radiation have limited efficacy as adjuvant or neoadjuvant therapy,
although one or both are often used to temporarily control disease. In patients who are
chemosensitive, chemotherapy may allow a meaningful reduction in tumor size before
surgical control, and in some cases rendering unresectable tumors resectable. Commonly
used regimens in children are C5V or doxorubicin and cisplatin (PLADO). The 5-y ear
survival rates for patients undergoing multiagent therapy and surgical resection in Group I
disease is approximately 85–90%, 55–60% in group II, and less than 20% in groups III and
IV.
Page 341Thirty -nine children with HCC were registered on the SIOPEL-1 trial and
treated with preoperative chemotherapy (cisplatin and doxorubicin). EFS at 2 y ears was 23%,
and 17% at 5 y ears. Five-y ear OS, by PRETEXT group, was 44% for stages I and II, 22%
for III, and 8% for IV (22). In INT-0098 (CCG-8881/POG-8945) Pediatric Intergroup
Hepatoma Study, there were 46 patients with HCC, randomized postoperatively to cisplatin,
vincristine, and fluorouracil or cisplatin and doxorubicin. The 5-y ear EFS rates were 88%,
8%, and 0% for stages I, III, and IV, respectively. There was no difference with either
regimen (64). In meta-analy ses in adults, a clear benefit of adjuvant chemotherapy in HCC
cannot be shown (65).
Page 342Meta-analy sis of randomized controlled trials in adults with unresectable HCC
treated with transarterial chemoembolization (TACE) significantly reduced the overall 2-y ear
mortality rate (odds ratio, 0.54; 95% CI: 0.33, 0.89; p = 0.015) compared with best supportive
treatment (76). Experience with chemoembolization in children is limited but feasible and
effective in inducing surgical resectability of primary hepatic tumors in children (77,78).
Selected cases may benefit from chemoembolization as a “bridge” through the
pretransplantation waiting (79). Patients whose primary tumor remains unresectable after
chemotherapy should be considered for orthotopic liver transplantation. Liver transplantation
has been a successful therapy for children with unresectable HCC; survival is about 60%, with
most deaths resulting from tumor recurrence. If the primary tumor is not resectable after
chemotherapy and the patient is not a transplant candidate, alternative treatment approaches
used in adults include: Sorafenib, Cry osurgery, Radiation therapy.
Recently, sorafenib, an oral multikinase inhibitor, which suppresses tumor cell
proliferation and angiogenesis, was approved by the US FDA for the first-line treatment of
HCC after the completion of a phase III trial, Sorafenib versus Placebo in Advanced
Hepatocellular Carcinoma (SHARP) for adult patients (80,81). Nevertheless, there are no
data on the safety and dosing in children.
Bevacizumab, a monoclonal antibody that exclusively targets vascular endothelial
growth factor (VEGF), was evaluated in several phase II trials alone and in combination with
chemotherapy in HCC. A survival benefit supports phase III trial of bevacizumab in HCC
(82).
Radiation Therapy
Radiation therapy has been used preoperatively and postoperatively as an aid to the curative
treatment of HBL and HCC. Its preoperative use has been intended to reduce the tumor
burden and increase the probability of resection. Contemporary treatment for HBL favors
using chemotherapy alone preoperatively (83), and in children who have unresectable
tumors after initial chemotherapy, radiotherapy can also be considered (84,85). POG-8697,
included five patients in whom radiotherapy was added to chemotherapy when their disease
remained unresectable after initial chemotherapy. Three of them ultimately became
resectable (69,86).
Some evidence also exists that postoperative radiotherapy is valuable in children who
have residual disease after an attempt at resection. A combined CCSG–POG protocol studied
177 children with HBL or HCC. Patients with microscopic residual disease (stage II) received
postoperative chemotherapy and 45 Gy of radiation to the tumor bed. The 3-y ear
progression-free survival was 60% for stage II and 22% for stage III (11). The Institute
Gustave Roussy administered preoperative chemotherapy, performed surgical resection, and
then gave radiotherapy and additional chemotherapy if there was microscopic or
macroscopic persistent tumor at surgery. A dosage of 25–45 Gy was given, targeted to the
area of postoperative disease only. Seven of nine children were disease free at 22–98 months
of follow-up, two patients died, one from local failure and another from both local and distant
failure (84). The evidence in favor of the use of irradiation for residual disease is not
unequivocal, and we cannot y et determine that chemotherapy by itself would not have
ultimately controlled the persistent microscopic disease. No clear treatment policy can be
developed and adopted on the basis of the current limited evidence.
When radiotherapy is to be considered preoperatively to improve resectability or
postoperatively for residual disease, the defining of tumor volume is crucial. It is essential to
spare as much normal liver tissue as possible. Therefore, the radiation oncologist must
carefully examine the diagnostic imaging studies and any available operative and
histopathologic reports.
The tumor volume should be delineated and covered by portals with a 1- to 2-cm
margin. Extra margin (0.5–2.5 cm) is added in the cephalocaudal direction to cover
diaphragmatic respiratory excursion. This should be confirmed fluoroscopically. Techniques
to control breath including respiratory gating, deep inspiration breath hold, and abdominal
compression for external beam radiotherapy may enable a margin reduction on tumor
volume. This, in turn, may allow dosage escalation without increasing toxicity (87). In the
majority of cases, three dimensionally planned or intensity modulated fields from a linear
accelerator are used. On occasion, the best treatment plan is anterior and posterior fields. If a
fair portion of the liver can be spared, then a total dosage of 50–60 Gy would be appropriate.
As we described in the previous section concerning POG-8697, preoperative irradiation of an
unresectable HBL may convert it to resectability (53).
Comparing to the photons used in current radiotherapy, proton beam radiotherapy has
lower entrance dose, sharper penumbra, and no dose deposits deep to the target. Because of
the superior dose distribution, proton therapy can achieve higher prescription dose with
adequate sparing of normal tissue and lower integral dose in avoidance of second
malignancies. Evidences for proton beam in treating HBL are scarce and limited to case
report and dosimetric studies (88,89). However, proton therapy has more potentials than
photon in bridging unresectable tumors to resectable tumors. The study for the role of proton
beam therapy as a definitive treatment in unresectable tumors is needed. Meanwhile, the
published treatment results of proton beam for adult HCC increase promptly. In general,
outcomes from proton therapy are better than those from conformal radiotherapy (90). One
study from University of Tsukuba recruited 318 patients, including 24% Child-Pugh B and 2%
Child-Pugh C. The 1-y ear and 5-y ear survival were 90% and 45%, respectively (91).
When postoperative irradiation is given for residual disease after a resection, 45 Gy to a
limited area is appropriate for microscopic disease, and 50–60 Gy is appropriate for bulkier
residual disease. Full attention must be given to respecting hepatic tissue tolerance to radiation.
In adults with unresectable HCC, available retrospective reviews suggest a dosage of 30 Gy
as the upper limit for normal liver tissue (92). If radiotherapy is to be administered to the
whole liver for advanced tumor, then parallel-opposed anterior and posterior fields are almost
alway s used. The dosage generally is prescribed to the mid-portion of the liver, and the
accepted parameters of liver tolerance to irradiation should not be exceeded. Therefore, with
palliative intent for advanced HBL or HCC, 20–25 Gy in 2–2.5 weeks is reasonable. The
treatment of metastatic lesions from HBL or HCC can have a palliative effect, and the usual
palliative dosages of irradiation (based on the surrounding normal tissue tolerance) may be
applied.
Page 343Investigational techniques that may have some promise include intraoperative
irradiation, regional hy perthermia in conjunction with intra-arterial y ttrium-90 microspheres,
intra-arterial iodine-131 lipiodol, and iodine-131 antiferritin administered along with
chemotherapy (93,94,95). For patients with more advanced disease, transarterial
chemoembolization (TACE) into isolated branches of the hepatic artery, which may benefit
patients with nonmetastatic but unresectable or recurrent tumor, has been used with promising
results. This is the more commonly used approach in adults, in whom sy stemic
chemotherapy has had essentially no impact on disease-free survival. The optimal scheduling
of radiotherapy and TACE is unknown.
Radiation-induced liver disease (RILD), previously called radiation hepatitis, can be a
serious complication of radiation therapy for HBL or HCC. Reactivation of viral hepatitis and
precipitation of underly ing liver disease also can occur after radiotherapy for HCC (96).
RILD is characterized by central liver lobular congestion, sinusoidal congestion, atrophy of
the liver plates, and focal necrosis. RILD can occur weeks to months after radiotherapy. One
should be particularly concerned about the risk of RILD in patients already compromised by
prior hepatic surgery, chronic viral hepatitis, or liver cirrhosis. The laboratory signs of RILD
include elevation of alkaline phosphatase and transaminases (96).
The mean liver dose associated with a 5% risk of RILD for patients with HCC is 28 Gy in
2-Gy fractions (97). As the majority of patients in the analy sis by Lawrence of the
University of Michigan were having Child A liver function, their results cannot be used to
describe the risk of toxicity in patients with Child B or C liver function. Intensity Modulated
Radiation Therapy (IMRT), compared to three-dimensional conformal radiotherapy, can
reduce the incidental dosages to the spinal cord, kidney s, and stomach. The application of
IMRT, which uses multiple fields with the mean dosage to the liver being higher than with
three-dimensional planning (29.2 Gy vs. 25.0 Gy, p = 0.009), should be done cautiously,
especially in patients with compromised liver function.
Is whole-lung irradiation (WLI) appropriate in HBL metastatic to the lung? Data on the
subject are sparse. Metastatic disease to the lung should be treated with surgical resection of
the metastatic deposits plus chemotherapy. However, there is alway s a risk of subsequent
pulmonary relapse (43). This understanding may be used as an argument in favor of WLI to
treat presumed small deposits of well-oxy genated metastatic disease. Based on the
experiences from Wilms, Ewing tumor, or osteosarcoma, for example, a total dosage of 12–
13 Gy would be considered appropriate for childhood HBL and HCC.
Figure: Hepatoblastoma Staging and Risk
Stratification
Figure: Multicenter Studies in
Hepatoblastoma—Comparison of Results
Figure: Results of the Pediatric Intergroup
Hepatoma Study for Hepatoblastoma (CCG-
8881 and POG-8945)
Figure: Summary of Recent Hepatoblastoma
Multicenter Trials
(12,25,31,36,53,54,55,59,60,66,67,68)
12 Sasaki F, Matsunaga T, Iwafuchi M, et al. Outcome of hepatoblastoma treated with the
JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: a report from the
Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg. 2002;37(6):851–856.
25 Aronson DC, Schnater JM, Staalman CR, et al. Predictive value of the pretreatment
extent of disease system in hepatoblastoma: results from the International Society of
Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol. 2005;23(6):1245–
1252.
31 Fuchs J, Rydzynski J, von Schweinitz D, et al. Pretreatment prognostic factors and
treatment results in children with hepatoblastoma: a report from the German Cooperative
Pediatric Liver Tumor Study HB 94. Cancer. 2002;95(1):172–182.
36 Zsíros J, Maibach R, Shafford E, et al. Successful treatment of childhood high-risk
hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final result of
the SIOPEL-3HR study. J Clin Oncol. 2010;28:2584–2590.
53 Douglass EC, Reynolds M, Finegold M, et al. Cisplatin, vincristine, and fluorouracil therapy
for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1993;11(1):96–99.
54 Perilongo G, Shafford E, Maibach R, et al. Risk-adapted treatment for childhood
hepatoblastoma—final report of the second study of the International Society of Paediatric
Oncology—SIOPEL 2. Eur J Cancer. 2004;40(3):411–421.
55 Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of
cisplatin/vincristine/fluorouracil and cisplatin/continuous-infusion doxorubicin for treatment
of pediatric hepatoblastoma: a report from the Children’s Cancer Group and the Pediatric
Oncology Group. J Clin Oncol. 2000;18(14):2665–2675.
59 von Schweinitz D, Byrd DJ, Hecker H, et al. Efficiency and toxicity of ifosfamide, cisplatin
and doxorubicin in the treatment of childhood hepatoblastoma. Study Committee of the
Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric
Oncology and Haematology. Eur J Cancer. 1997;33(8):1243–1249.
60 Malogolowkin MH, Katzenstein H, Krailo MD, et al. Intensified platinum therapy is an
ineffective strategy for improving outcome in pediatric patients with advanced
hepatoblastoma. J Clin Oncol. 2006;24(18):2879–2884.
66 Haeberle B, von Schweinitz D. Treatment of hepatoblastoma in German cooperative
pediatric liver tumor studies. Front Biosci. 2012;4:493–498.
67 Perilongo G, Maibach R, Shafford E, et al Cisplatin versus cisplatin plus doxorubicin for
standard risk hepatoblastoma. N Engl J Med. 2009;361:1662–1670.
68 Hishiki T, Matsunaga T, Sasaki F, et al. Outcome of hepatoblastoma treated using the
Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the JPLT.
Pediatr Surg Int. 2011;27:1–8.
Figure:
PRETEXT (Pretreatment Extent of Disease) and POSTTEXT (Posttreatment Extent of Disease)
extent of liver involvement system.
Recent cooperative studies with multimodality treatments have improved OS and EFS for
pediatric patients with HBL and HCC in the past two decades. The 5-y ear survival rates for
stages I, II, III, and IV were 95%, 100%, 65–70%, and 36–45%, respectively (Table
14.7 ). The choices of chemotherapy regimens include C5V, and PLADO (55).
Doxorubicin is used widely throughout Europe (52). Toxicity in previous North American
trials has limited its use (55); however, there are ongoing discussions regarding the
reintroduction of doxorubicin in North American clinical trials (62).
Surgery remains the cornerstone of curative treatment for HBL and HCC; preoperative
chemotherapy with or without radiotherapy increases the possibility of complete resection.
Radiotherapy is recommended in patients who have residual tumor after surgery. As surgical
technique advances and better immunosuppressive agents with fewer long-term side effects
become more available, a steady improvement in the success of liver transplant patients will
likely be observed. In addition, living donor transplantation has also become a promising
option (98). Early referral to liver transplant centers is encouraged for nonresectable tumors
or those that show chemotherapy resistance. Ongoing questions are to search for new
chemotherapeutic agents with less toxicity and to properly time and prioritize liver
transplantation for unresectable cases (44).
As more is understood of the molecular and genomic pathway s in HBL and HCC, the
development of newer targeted therapies may raise new hopes for better control of these
dreadful diseases. Newer targeted agents that “selectively ” interfere with pathway targets
involved in tumor growth, progression and vascular development such as insulin-like growth
factor (IGF-1), phosphatidy linositol 3-kinase (PI3K), mammalian target of rapamy cin
(mTOR) sirolimus, sorafenib as antiangiogenics, and vascular endothelial growth factor
(VEGF) are currently under development. Gene-directed treatment approaches and
immunotherapy have high potential as future treatment options (99). Both therapy options
have display ed promising results in preclinical models so far but are clearly only in the
infancy of their scientific evaluation.
REFERENCES
1. Darbari A, Sabin KM, Shapiro CN, et al. Epidemiology of primary hepatic malignancies
in U.S. children. Hepatology. 2003;38(3):560–566.
2. Luks FI, Yazbeck S, Brandt ML, et al. Benign liver tumors in children: a 25-y ear
experience. J Pediatr Surg. 1991;26(11):1326–1330.
3. Maguiness S, Guenther L. Kasabach–Merritt sy ndrome. J Cutan Med Surg.
2002;6(4):335–339.
4. Daller JA, Bueno J, Gutierrez J, et al. Hepatic hemangioendothelioma: clinical
experience and management strategy. J Pediatr Surg. 1999;34(1):98–105; discussion
105–106.
5. Draper H, Diamond IR, Temple M, et al. Multimodal management of endangering
hepatic hemangioma: impact on transplant avoidance: a descriptive case series. J
Pediatr Surg. 2008;43(1):120–125; discussion 126.
6. Stringer MD, Alizai NK. Mesenchy mal hamartoma of the liver: a sy stematic review. J
Pediatr Surg. 2005;40(11):1681–1690.
7. Page 344 Mey ers RL. Tumors of the liver in children. Surg Oncol. 2007;16(3):195–203.
8. Bellani FF, Massimino M. Liver tumors in childhood: epidemiology and clinics. J Surg
Oncol Suppl. 1993;3:119–121.
9. Schnater JM, Kohler SE, Lamers WH, et al. Where do we stand with hepatoblastoma? A
review. Cancer. 2003;98(4):668–678.
10. Farhi DC, Shikes RH, Murari PJ, et al. Hepatocellular carcinoma in y oung people.
Cancer. 1983;52(8):1516–1525.
11. Ablin A, Krailo M, Hass J. Hepatoblastoma and hepatocellular carcinoma in children: a
report from the Children’s Cancer Study Group (CCG) and the Pediatric Oncology
Group (POG). Med Pediatr Oncol. 1988;16:417.
12. Sasaki F, Matsunaga T, Iwafuchi M, et al. Outcome of hepatoblastoma treated with the
JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: a report from the
Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg. 2002;37(6):851–856.
13. Chang MH, Chen DS, Hsu HC, et al. Maternal transmission of hepatitis B virus in
childhood hepatocellular carcinoma. Cancer. 1989;64(11):2377–2380.
14. Chang MH, Shau WY, Chen CJ, et al. Hepatitis B vaccination and hepatocellular
carcinoma rates in boy s and girls. JAMA. 2000;284(23):3040–3042.
15. Chang MH. Cancer prevention by vaccination against hepatitis B. Recent Results Cancer
Res. 2009;181:85–94.
16. Katzenstein HM, Krailo MD, Malogolowkin MH, et al. Fibrolamellar hepatocellular
carcinoma in children and adolescents. Cancer. 2003;97(8):2006–2012.
17. Nicol K, Savell V, Moore J, et al. Distinguishing undifferentiated embry onal sarcoma of
the liver from biliary tract rhabdomy osarcoma: a Children’s Oncology Group study.
Pediatr Dev Pathol. 2007;10(2):89–97.
18. Cohen MD, Bugaieski EM, Haliloglu M, et al. Visual presentation of the staging of
pediatric solid tumors. Radiographics. 1996;16(3):523–545.
19. McCarville MB, Roebuck DJ. Diagnosis and staging of hepatoblastoma: imaging aspects.
Pediatr Blood Cancer. 2012;59:793–799.
20. Chung EM, Lattin GE, Lewis RB, et al. Pediatric liver masses: radiologic-athologic
correlation. Part 2: malignant tumors. Radiographics. 2011;31:483–507.
21. Schnater JM, Aronson DC, Plaschkes J, et al. Surgical view of the treatment of patients
with hepatoblastoma: results from the first prospective trial of the International Society
of Pediatric Oncology Liver Tumor Study Group. Cancer. 2002;94(4):1111–1120.
22. Czauderna P, Mackinlay G, Perilongo G, et al. Hepatocellular carcinoma in children:
results of the first prospective study of the International Society of Pediatric Oncology
Group. J Clin Oncol. 2002;20(12):2798–2804.
23. Figarola MS, McQuiston SA, Wilson F, et al. Recurrent hepatoblastoma with localization
by PET-CT. Pediatr Radiol. 2005;35(12):1254–1258.
24. Philip I, Shun A, McCowage G, et al. Positron emission tomography in recurrent
hepatoblastoma. Pediatr Surg Int. 2005;21:341–345.
25. Aronson DC, Schnater JM, Staalman CR, et al. Predictive value of the pretreatment
extent of disease sy stem in hepatoblastoma: results from the International Society of
Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol.
2005;23(6):1245–1252.
26. Eichenmüller M, Trippel F, Kreuder M, et al. The genomic landscape of hepatoblastoma
and their progenies with HCC-like features. J Hepatol. 2014;61(6):1312–1320.
27. Trevino LR, Wheeler DA, Finegold MJ, et al. Exome sequencing of hepatoblastoma
reveals recurrent mutations in NFE2L2 [abstract 4592]. Cancer Res. 2013;73(8 suppl):A-
4592.
28. Hiy ama E, Kurihara S, Onitake Y. Integrated exome analy sis in childhood
hepatoblastoma: biological approach for next clinical trial designs [abstract 5188].
Cancer Res. 2014;74(19 suppl): A-5188.
29. Vilarinho S, Erson-Omay EZ, Harmanci AS, et al. Paediatric hepatocellular carcinoma
due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic
ABCB11 mutations. J Hepatol. 2014;61(5):1178–1183.
30. Honey man JN, Simon EP, Robine N, et al. Detection of a recurrent DNAJB1-PRKACA
chimeric transcript in fibrolamellar hepatocellular carcinoma. Science.
2014;343(6174):1010–1014.
31. Fuchs J, Ry dzy nski J, von Schweinitz D, et al. Pretreatment prognostic factors and
treatment results in children with hepatoblastoma: a report from the German
Cooperative Pediatric Liver Tumor Study HB 94. Cancer. 2002;95(1):172–182.
32. Fuchs J, Ry dzy nski J, Hecker H, et al. The influence of preoperative chemotherapy and
surgical technique in the treatment of hepatoblastoma—a report from the German
Cooperative Liver Tumour Studies HB 89 and HB 94. Eur J Pediatr Surg.
2002;12(4):255–261.
33. Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical treatment of
hepatoblastoma in the modern era—recommendations from the Childhood Liver
Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL).
Eur J Cancer. 2005;41(7):1031–1036.
34. Rey nolds M. Conversion of unresectable to resectable hepatoblastoma and long-term
follow-up study. World J Surg. 1995;19(6):814–816.
35. Munro FD, Simpson E, Azmy AF. Resectability of advanced liver tumours in children
after combination chemotherapy. Ann R Coll Surg Engl. 1994;76(4):253–256.
36. Zsíros J, Maibach R, Shafford E, et al. Successful treatment of childhood high-risk
hepatoblastoma with dose-intensive multiagent chemotherapy and surgery : final result
of the SIOPEL-3HR study. J Clin Oncol. 2010;28:2584–2590.
37. Guglielmi M, Perilongo G, Cecchetto G, et al. Rationale and results of the International
Society of Pediatric Oncology (SIOP) Italian pilot study on childhood hepatoma:
surgical resection d’emblee or after primary chemotherapy ? J Surg Oncol Suppl.
1993;3:122–126.
38. Czauderna P, Lopez-Terrada D, Hiy ama E, et al. Hepatoblastoma state of the art:
pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr.
2014;26(1):19–28.
39. López-Terrada D, Alaggio R, de Dávila MT, et al. Towards an international pediatric liver
tumor consensus classification proceedings of the Los Angeles COG liver tumors
sy mposium. Mod Pathol. 2014;27:472–491.
40. Mey ers RL, Rowland JR, Krailo M, et al. Predictive power of pretreatment prognostic
factors in children with hepatoblastoma: a report from the Children’s Oncology Group.
Pediatr Blood Cancer. 2009;53:1016–1022.
41. Mey ers RL, Czauderna P, Otte JB. Surgical treatment of hepatoblastoma. Pediatr Blood
Cancer. 2012;59:800–808.
42. von Schweinitz D, Burger D, Mildenberger H. Is laparatomy the first step in treatment of
childhood liver tumors? the experience from the German Cooperative Pediatric Liver
Tumor Study HB-89. Eur J Pediatr Surg. 1994;4(2):82–86.
43. Feusner JH, Krailo MD, Haas JE, et al. Treatment of pulmonary metastases of initial
stage I hepatoblastoma in childhood—report from the Children Cancer Group. Cancer.
1993;71(3):859–864.
44. Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results
from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and
review of the world experience. Pediatr Blood Cancer. 2004;42(1):74–83.
45. Mejia A, Langnas AN, Shaw BW, et al. Living and deceased donor liver transplantation
for unresectable hepatoblastoma at a single center. Clin Transplant. 2005;19(6):721–725.
46. Otte JB, de Ville de Goy et J, Reding R. Liver transplantation for hepatoblastoma:
indications and contraindications in the modern era. Pediatr Transplant. 2005;9(5):557–
565.
47. Kasahara M, Ueda M, Haga H, et al. Living-donor liver transplantation for
hepatoblastoma. Am J Transplant. 2005;5(9):2229–2235.
48. D’Antiga L, Vallortigara F, Cillo U, et al. Features predicting unresectability in
hepatoblastoma. Cancer. 2007;110(5):1050–1058.
49. Sakamoto S, Kasahara M, Mizuta K, et al. Nationwide survey of the outcomes of living
donor liver transplantation for hepatoblastoma in Japan. Liver Transpl. 2014;20:333–346.
50. Cruz RJ Jr, Ranganathan S, Mazariegos G, et al. Analy sis of national and single-center
incidence and survival after liver transplantation for hepatoblastoma: new trends and
future opportunities. Surgery. 2013;153:150–159.
51. Mey ers RL, Tiao G, de Ville de Goy et J, et al. Hepatoblastoma state of the art: pre-
treatment extent of disease, surgical resection guidelines and the role of liver
transplantation. Curr Opin Pediatr. 2014;26(1):29–36.
52. Page 345 Pritchard J, Brown J, Shafford E, et al. Cisplatin, doxorubicin, and delay ed
surgery for childhood hepatoblastoma: a successful approach—results of the first
prospective study of the International Society of Pediatric Oncology. J Clin Oncol.
2000;18(22):3819–3828.
53. Douglass EC, Rey nolds M, Finegold M, et al. Cisplatin, vincristine, and fluorouracil
therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol.
1993;11(1):96–99.
54. Perilongo G, Shafford E, Maibach R, et al. Risk-adapted treatment for childhood
hepatoblastoma—final report of the second study of the International Society of
Paediatric Oncology —SIOPEL 2. Eur J Cancer. 2004;40(3):411–421.
55. Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of
cisplatin/vincristine/fluorouracil and cisplatin/continuous-infusion doxorubicin for
treatment of pediatric hepatoblastoma: a report from the Children’s Cancer Group and
the Pediatric Oncology Group. J Clin Oncol. 2000;18(14):2665–2675.
56. Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable or metastatic
hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy : a
report from the Children’s Cancer Study Group. J Clin Oncol. 1991;9(12):2167–2176.
57. Hingorani P, Eshun F, White-Collins A, et al. Gemcitabine, docetaxel, and bevacizumab
in relapsed and refractory pediatric sarcomas. J Pediatr Hematol Oncol. 2012;34:524–
527.
58. Qay ed M, Powell C, Morgan ER, et al. Irinotecan as maintenance therapy in high-risk
hepatoblastoma. Pediatr Blood Cancer. 2010;54(5):761–763.
59. von Schweinitz D, By rd DJ, Hecker H, et al. Efficiency and toxicity of ifosfamide,
cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Study
Committee of the Cooperative Paediatric Liver Tumour Study HB89 of the German
Society for Paediatric Oncology and Haematology. Eur J Cancer. 1997;33(8):1243–
1249.
60. Malogolowkin MH, Katzenstein H, Krailo MD, et al. Intensified platinum therapy is an
ineffective strategy for improving outcome in pediatric patients with advanced
hepatoblastoma. J Clin Oncol. 2006;24(18):2879–2884.
61. Pazdur R, Bready B, Cangir A. Pediatric hepatic tumors: clinical trials conducted in the
United States. J Surg Oncol Suppl. 1993;3:127–130.
62. Malogolowkin MH, Katzenstein HM, Krailo M, et al. Redefining the role of doxorubicin
for the treatment of children with hepatoblastoma. J Clin Oncol. 2008;26(14):2379–2383.
63. Douglass E, Ortega J, Feusner J. Hepatocellular carcinoma (HC) in children and
adolescents: results from the Pediatric Intergroup Hepatoma Study (CCG 8881/POG
8945). Proc Am Soc Clin Oncol. 1994;13(A-1439):420.
64. Katzenstein HM, Krailo MD, Malogolowkin MH, et al. Hepatocellular carcinoma in
children and adolescents: results from the Pediatric Oncology Group and the Children’s
Cancer Group intergroup study. J Clin Oncol. 2002;20(12):2789–2797.
65. Schwartz JD, Schwartz M, Mandeli J, et al. Neoadjuvant and adjuvant therapy for
resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet
Oncol. 2002;3(10):593–603.
66. Haeberle B, von Schweinitz D. Treatment of hepatoblastoma in German cooperative
pediatric liver tumor studies. Front Biosci. 2012;4:493–498.
67. Perilongo G, Maibach R, Shafford E, et al Cisplatin versus cisplatin plus doxorubicin for
standard risk hepatoblastoma. N Engl J Med. 2009;361:1662–1670.
68. Hishiki T, Matsunaga T, Sasaki F, et al. Outcome of hepatoblastoma treated using the
Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the
JPLT. Pediatr Surg Int. 2011;27:1–8.
69. Bowman LC, Riely CA. Management of pediatric liver tumors. Surg Oncol Clin N Am.
1996;5(2):451–459.
70. Zsíros J, Brugieres L, Brock P, et al. Efficacy of irinotecan single drug treatment in
children with refractory or recurrent hepatoblastoma—a phase II trial of the childhood
liver tumour strategy group (SIOPEL). Eur J Cancer. 2012;48:3456–3464.
71. Katzenstein HM, London WB, Douglass EC, et al. Treatment of unresectable and
metastatic hepatoblastoma: a Pediatric Oncology Group phase II study. J Clin Oncol.
2002;20(16):3438–3444.
72. Karski EE, Dvorak CC, Leung W, et al. Treatment of hepatoblastoma with high-dose
chemotherapy and stem cell rescue: the pediatric blood and marrow transplant
consortium experience and review of the literature. J Pediatr Hematol Oncol.
2014;36:362–368.
73. Perilongo G, Malogolowkin, MH, Feusner J. Hepatoblastoma clinical research: lessons
learned and future challenges. Pediatr Blood Cancer. 2012;59(5):818–821.
74. Zsiros J, Brugieres L, Brock P, et al. Dose-dense cisplatin-based chemotherapy and
surgery for children with high risk hepatoblastoma (SIOPEL 4): a prospective, single-
arm, feasibility study. Lancet Oncol. 2013;14:834–842.
75. Troubaugh-Lotrario AD, Katzenstein HM. Chemotherapeutic approaches for newly
diagnosed hepatoblastoma: past, present, and future strategies. Pediatr Blood Cancer.
2012;59:809–812.
76. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for
unresectable hepatocellular carcinoma: meta-analy sis of randomized controlled trials.
Radiology. 2002;224(1):47–54.
77. Malogolowkin MH, Stanley P, Steele DA, et al. Feasibility and toxicity of
chemoembolization for children with liver tumors. J Clin Oncol. 2000;18(6):1279–1284.
78. Ohtsuka Y, Matsunaga T, Yoshida H, et al. Optimal strategy of preoperative transcatheter
arterial chemoembolization for hepatoblastoma. Surg Today. 2004;34(2):127–133.
79. Czauderna P, Zbrzezniak G, Narozanski W, et al. Preliminary experience with arterial
chemoembolization for hepatoblastoma and hepatocellular carcinoma in children.
Pediatr Blood Cancer. 2006;46(7):825–828.
80. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma.
N Engl J Med. 2008;359(4):378–390.
81. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the
Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised,
double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.
82. Zhu AX, Blaszkowsky LS, Ry an DP, et al. Phase II study of gemcitabine and oxaliplatin
in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J
Clin Oncol. 2006;24(12):1898–1903.
83. Evans AE, Land VJ, Newton WA, et al. Combination chemotherapy (vincristine,
adriamy cin, cy clophosphamide, and 5-fluorouracil) in the treatment of children with
malignant hepatoma. Cancer. 1982;50(5):821–826.
84. Habrand JL, Nehme D, Kalifa C, et al. Is there a place for radiation therapy in the
management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat
Oncol Biol Phys. 1992;23(3):525–531.
85. Berry C, Keeling J. Hepatoblastoma. In: Berry CL, ed. Pediatric Pathology. Berlin,
Germany : Springer-Verlag; 1981:660–662.
86. Douglass EC, Green AA, Wrenn E, et al. Effective cisplatin (DDP) based chemotherapy
in the treatment of hepatoblastoma. Med Pediatr Oncol. 1985;13(4):187–190.
87. Wagman R, Yorke E, Ford E, et al. Respiratory gating for liver tumors: use in dose
escalation. Int J Radiat Oncol Biol Phys. 2003;55(3):659–668.
88. Wang X, Krishnan S, Zhang X, et al. Proton radiotherapy for liver tumors: dosimetric
advantages over photon plans. Med Dosim. 2008;33:259–267.
89. Oshiro Y, Okumura T, Mizumoto M, et al. Proton beam therapy for unresectable
hepatoblastoma in children: survival in one case. Acta Oncol. 2013;52:600–603.
90. Klein J, Dawson LA. Hepatocellular carcinoma radiation therapy : review of evidence
and future opportunities. Int J Radiat Oncol Biol Phys. 2013;87:22–32.
91. Nakay ama H, Sugahara S, Tokita M, et al. Proton beam therapy for hepatocellular
carcinoma. Cancer. 2009;115:5499–5506.
92. Cheng SH, Lin YM, Chuang VP, et al. A pilot study of three-dimensional conformal
radiotherapy in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol.
1999;14(10):1025–1033.
93. Grady ED, McLaren J, Auda SP, et al. Combination of internal radiation therapy and
hy perthermia to treat liver cancer. South Med J. 1983;76(9):1101–1105.
94. Leichner PK, Yang NC, Frenkel TL, et al. Dosimetry and treatment planning for 90Y-
labeled antiferritin in hepatoma. Int J Radiat Oncol Biol Phys. 1988;14(5):1033–1042.
95. Page 346 Order SE, Stillwagon GB, Klein JL, et al. Iodine 131 antiferritin, a new
treatment modality in hepatoma: a Radiation Therapy Oncology Group study. J Clin
Oncol. 1985;3(12):1573–1582.
96. Cheng JC, Wu JK, Lee PC, et al. Biologic susceptibility of hepatocellular carcinoma
patients treated with radiotherapy to radiation-induced liver disease. Int J Radiat Oncol
Biol Phys. 2004;60(5):1502–1509.
97. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin
Radiat Oncol. 2005;15(4):279–283.
98. Jensen MK, Alonso MH, Nathan JD, et al. Liver transplantation in children: indications
and surgical aspects. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children.
New York, NY: Cambridge University Press; 2014:760–772.
http://dx.doi.org/10.1017/CBO9781139012102.044 .
99. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of
hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12(12):681–700.
CH A P TER 15
Germ and Stromal Cell Tumors of the
Gonads and Extragonadal Germ Cell Tumors
Christian Carrie and Edward C. Halperin
Page 347Gonadal or extragonadal germ cell tumors (GCTs) represent less than 2% of
pediatric malignant tumors. They have three important features:
The origin is related to abnormal migration of primordial germ cells, and tumor can
occur along this migration path;
Serum tumor markers allow diagnostic and treatment evaluation; and
The cure rate is high if the clinician respects treatment guidelines.
GCTs result from malignant transformation of a primordial germ cell (Fig. 15.1 ).
FIGURE 15.1 Classification of germ cell tumors.
In the human embry o, the primordial germ cells are found in the vicinity of the allantoic
stalk. From this position, the germ cells migrate into the adjoining mesenchy me at 4–5 weeks
of gestation. The cells then assume positions in the germinal ridges and migrate along these
structures.
GCTs may occur in the ovary, testes, sacrococcy geal region, vagina, retroperitoneum,
pelvis, omentum, and mediastinal areas. Extragonadal and testicular sites predominate in
children less than 3 y ears of age. Gonadal sites are most common during and after puberty
(1). The main histologic ty pes are germinoma, embry onal carcinoma, y olk sac tumor (also
known as endodermal sinus tumor or Teilum tumor), chorioepithelioma malignant mixed
GCTs, and malignant teratomas (sometimes called immature teratomas) (Table 15.1 )
(2,3,4,5). Mature and immature teratomas have a benign behavior but can relapse with a
malignant part (6). Endodermal sinus tumor ty pically shows microcy tic areas, Shiller–Duval
bodies, and periodic acid–Schiff–positive extracellular hy aline droplets. The tumor is often
positive, on immunohistochemistry, for alpha-fetoprotein (AFP) and cy tokeratin (7).
Structural abnormalities of chromosome 1 are frequent (1).
TABLE 15.1 Biologic Characteristics of Pediatric Germ Cell Tumors
Page 348There is a bimodal age distribution for GCTs, with a peak in children y ounger than 3
y ears and a second peak in children older than 12 y ears. The male:female ratio is 2:1 (11).
Girls predominate in the patient population during the first 3 y ears of life because of a female
predominance in sacrococcy geal tumors. There is an association with intersex disorders
(1,12,13). The association between undescended testes and the development of testicular
cancer has been established. Currarino sy ndrome and Down sy ndrome could be associated
with mature or immature teratomas (6).
The staging workup should include assay s for AFP and human chorionic gonadotropin
(hCG). AFP is elevated in almost all cases of endodermal sinus tumor and in many other
patients with GCTs (14,15). Successful treatment, whether by surgery, chemotherapy, or
radiotherapy, is regularly associated with AFP decline, consistent with its half-life of 5 day s in
children 2 months or y ounger, 33 day s in 2- to 4-month-olds, and 5 day s in children 8 months
or older (1,15,16). AFP falling too slowly, failing to normalize after treatment, or rising
generally signifies inadequate tumor response and precedes clinical or radiographic evidence
of treatment failure. hCG activity is present in some tumors, particularly choriocarcinoma.
The half-time of beta-hCG is 24–36 hours.
Diagnostic imaging of the pelvis and presacral space is best performed with computed
tomography (CT), magnetic resonance imaging (MRI), and ultrasound (5). The role of a PET
scan is not well established, probably not necessary for nonseminomatous tumor and more
useful to identify viable tumor in case of residual lesion after chemotherapy (17). CT is
useful to assess the presence of pathologic retroperitoneal ly mph nodes and extension of
tumor into bone. Imaging may show GCTs to be cy stic, solid, or a combination of both.
Sacrococcy geal and ovarian lesions that are predominantly cy stic are less likely to be
malignant, whereas solid lesions are more likely to be malignant. However, the correlation is
far from perfect. This is particularly important because it argues strongly against using the
term solid teratoma as the equivalent of malignant or immature teratoma (4,5,18,19).
Data from seven COG and CCLG group trials were compiled by the MaGIC (Malignant
Germ Cell Tumor International Collaborative) in order to define new risk classification: from
this series of 519 patients with extracranial germ cell tumors, it appears that age >11 y ears,
ovarian stage IV, and extragonadal stage III to IV have the worst outcome (20).
Page 349Ovary
Of primary ovarian tumors of childhood, about
71% are GCTs, 17% are epithelial, and 12% are
sex cord stromal tumors (1,18,21). The histologic
distribution is approximately : mature teratoma,
47%; immature teratoma, 12%; dy sgerminoma,
5%; y olk sac tumor (endodermal sinus), 10%;
mixed GCTs, 0–24%; and choriocarcinoma,
<1% (1,9,22,23) (Fig. 15.2 ). In the series of
Taskinen, two cases had a predisposition
condition, that is, Turner sy ndrome (23).
The risk of germ cell malignancy in girls
more than 3 y ears old is 20%. All pediatric
ovarian tumors must be considered as malignant.
In the series by Germa, (22) 46% of girls
presented with pain. In the POG/CCG intergroup FIGURE 15.2 Ovarian dysgerminoma.
study, 11% of girls presented with an acute
abdomen due to rupture or torsion (24). The long infundibular pedicle in the child explains this
risk (14,22). Other presenting signs and sy mptoms included an asy mptomatic palpable mass
(19%), abdominal distention (36%), and, less commonly, menstrual irregularities, malaise,
nausea, vomiting, or vaginal bleeding (11,22,25,26,27,28,29,30,31,32,33,34). The stromal
Sertoli–Ley dig cell tumors may present with defeminization or virilization. Ovarian
dy sgerminomas are rarely hormonally active or productive of tumor markers. If a patient
with an ovarian dy sgerminoma is found to have an elevated AFP or signs of hormonal
imbalance, there should be a meticulous search of the pathology specimen for elements of
other tumors. Preoperative assessment is crucial for the postoperative management. Sample
AFP HGG and beta-hCG must be obtained in all solid ovarian tumors.
Both primary and second-look surgery are used to treat ovarian GCT. The initial surgical
procedure should remove as much tumor as possible with a reasonable possibility of retention
of fertility. At the time of laparotomy, the entire peritoneal surface should be examined for
the presence of metastasis. Particular attention should be paid to the surfaces of the liver and
to the inferior surface of the diaphragm (14). The involved ovary should be removed.
Dy sgerminoma has a 5–10% incidence of bilaterality (21). For childhood ovarian GCT other
than dy sgerminoma, the probability of bilateral involvement ranges from 0% to 14% (27).
Therefore, the contralateral ovary should be biopsied and, if there is no evidence of
malignancy, preserved (33). Palpation and biopsy of all suspicious ly mph nodes in the pelvic
and para-aortic regions should be done. Peritoneal biopsies and washings (or collection of
ascites) for cy tology are important to complete the surgical staging (34). When frontline
definitive surgery is not possible or appropriate, chemotherapy can be given followed by
second-look surgery (35).
In the POG study, positive ascetic cy tology was found among 100 girls despite negative
random biopsy samples:
Due to this finding, the Children’s Oncology
Group published new guidelines including
peritoneal washing (Tables 15.3 and 15.4 ).
Ovarian GCTs are lethal malignancies that
can kill by early metastasis and rapid invasion of
abdominal and pelvic structures. The prognosis
of girls with these tumors was poor when they
were treated with surgery only or surgery in
combination with either radiotherapy or single-
agent chemotherapy, except in some cases of
dy sgerminoma (18). An increasing body of
evidence indicates that postoperative
chemotherapy has increased the probability of Table 15.3 Children’s Oncology Group
survival (1,4,9,15,18,22,25,26,30,31,32,33). Surgical Guidelines for Ovarian Germ
Active drugs include cisplatin (P), vinblastine Cell Tumor in Pediatric Patients
(V), bleomy cin (B), adriamy cin (Ad),
actinomy cin (A), cy clophosphamide (C), etoposide (E), methotrexate (M), and vincristine
(O) (11,37,38,39). Combinations used include VAC, POMB-ACE-PAV, PVB-ACAd, and PEB
(5,12,18). PEB or PVB is most commonly used (9,40,41). A six-drug regimen (VAC, JEB, or
PEB) or JEB therapy have both achieved 5-y ear survival rates as high as 90% for all stages
(42,43). The report of MaGIC, including UK and COG studies, found no differences between
the different treatment regimens for GCT, and all could be considered as equivalent (20).
The generally accepted standard of care for pediatric ovarian GCT is summarized as
follows:
Page 350Benign mature teratomas and immature teratomas: surgery and observation
Stage I malignant GCT: surgery and observation
Stages II–IV malignant GCT: surgery and PEB or PVB (1)
Testis
Testicular GCTs generally present as a palpable
painless mass or with signs and sy mptoms that
simulate infection, torsion, or posttraumatic
hematoma (54). The diagnostic workup includes
testicular ultrasonography, CT of the abdomen
and chest, AFP, and hCG. The most common
GCT of the testes in pubertal children is y olk sac
tumor (endodermal sinus) (Fig. 15.3 )
(15,18,54). Oosterhuis classified the testicular
GCT in three groups according to their
pathogenesis and the overrepresentation of the
short arm of chromosome 12: ty pe I encompass
teratoma, y olk sac tumor without 12p
rearrangement, ty pe II seminoma and
nonseminomatous with 12p rearrangement, and Figure 15.3 Testicular yolk sac tumor.
ty pe III spermatocitic seminoma with gain of
chromosome 9 (55). Less common histologies include embry onal carcinoma, mature,
immature, and malignant teratoma, and mixed tumor. Prepubertal children more often have
non–germ-cell tumors such as Sertoli or Ley dig cell tumors or sarcomas. Testicular GCTs
usually are staged by the COG sy stem (Table 15.4 ) or the UICC 2009 (Table 15.5 ).
Most cases are stage I at diagnosis. Teenagers may hesitate to discuss the presence of
testicular mass and tend to have more advanced disease at diagnosis (11,14,54).
Page 351Most testicular tumors are
suspected before surgery. A radical orchiectomy
should be performed with high ligation of the
spermatic cord. Transscrotal procedures should
be avoided because they can spread tumor and
increase ly mphatic metastases. If a scrotal
biopsy has been done, some authorities advise a
hemiscrotectomy (54). Others cite data from
adults to argue that there is no increase in the
relapse rate in stage I tumors if
hemiscrotectomy is not done (56). Regarding
pure seminoma, clinical stage 1, the European
consensus for adults allows three strategies:
surveillance with salvage irradiation or
chemotherapy at relapse, adjuvant
chemotherapy with carboplatin, or adjuvant
radiation treatment (17). These options seem to TABLE 15.5 Children’s Oncology
be adaptable for childhood seminoma, but Group Staging for Pediatric Testicular
adjuvant radiotherapy is less and less used. Germ Cell Tumor
The debate concerning the role of
retroperitoneal ly mph node dissection in early -stage testicular GCT appears to be resolving in
favor of a limited role for the procedure. The older literature indicates that 0–33% of children
with GCT have involved retroperitoneal ly mph nodes (11,14,57,58,59). Proponents of
retroperitoneal ly mph node dissection suggested that it was important in staging and in the
removal of small foci of malignant cells and that it possibly improved the chance of cure.
Objections to dissection, based on loss of ejaculatory function, were obviated by the use of
the modified retroperitoneal dissection (50). With the widespread availability of serum tumor
marker studies and CT screening, however, it is now clear that the staging node dissection is
unnecessary in stage I disease. In children with tumor confined to the testes, where AFP
levels normalize within 1 month after orchiectomy and where the chest radiograph and
retroperitoneal imaging studies are normal, retroperitoneal ly mph node dissection is
unnecessary. In one study, 28 patients with stage I testicular y olk sac tumors were treated with
radical orchiectomy alone; 24 (86%) were cured. The remaining four (14%) relapsed and
were rendered free of disease by chemotherapy (58). Both the UK Children’s Cancer Study
Group and the St. Jude Children’s Research Hospital (SJCRH) series have almost uniform
survival for stage I patients treated with radical orchiectomy alone (16,54). There is no
difference in disease-free survival between children with stage I disease who undergo
retroperitoneal ly mph node dissection and those who do not (14,27,58). Retroperitoneal
ly mph node dissection may still be appropriate for children with no markers or unknown
markers at diagnosis to confirm staging, more aggressive histologies (i.e., embry onal cell),
demonstrable moderate-sized nodal metastasis at the time of presentation (i.e., SJCRH stage
II), or an elevated AFP after surgery (27,50,60). PET could be useful in this case (61).
The management strategy for testicular GCT is as follows:
For stage I, chemotherapy is used for documented relapse. The survival for all stages is of the
order of 90–100%.
For more advanced disease, patients should be treated according to the International
Germ Cell Cancer Consensus Group (IGCCGG) recommendation (62).
For a small primary tumor or bilateral testicular tumors, one could consider organ-
preserving surgery ; but this option is still experimental and must be done within a clinical trial
(63).
Extragonadal
Extragonadal GCTs usually are found in the midline, consistent with embry onic patterns of
migration. The most common sites are the sacrococcy geal, presacral, and buttock region.
This is followed by the mediastinal, vaginal, uterine, and prostatic regions. Other reported
sites of origin include the neck and face, retroperitoneum, stomach, orbit, pancreas, heart, and
pericardium (1,9,64).
Preoperative imaging studies help to determine the lesion’s ty pe, and they also evaluate
whether the lesion is invading adjacent structures rather than displacing them, a suggestion of
malignancy. Only a few malignant sacrococcy geal GCTs are resectable per primum and
16% of the patients reported by Garg had intraspinal extension (71). In general, the surgeon
obtains an initial biopsy, and chemotherapy is administered. There is evidence documenting
complete responses of both metastatic and primary disease to chemotherapy with long-term
survival. Unresectable tumors have been rendered resectable, with long-term survivorship
reported. If there is a satisfactory reduction of tumor volume, the tumor may be deemed
resectable at a later date. The POG (72) and a German protocol (73) MAKKEI did not show
any difference in survival rate between patients treated by preoperative or postoperative
chemotherapy. The 4-y ear overall survival was 90%. In summary, stage I extragonadal
mature and immature sacrococcy geal teratomas and completely resected malignant GCTs
are resected and observed. Stages II–IV malignant GCTs are treated with PEB or PVB plus
surgery even in the case of intraspinal extension survival rate reaching 90% (71).
Mediastinal GCT
Pediatric mediastinal GCTs account for <5% of all GCTs (9). They are generally in the
anterior mediastinum and can cause superior vena cava sy ndrome or acute respiratory
deficiency (74). Calcification in the tumor is one of the X-ray characteristics (Fig. 15.5 ).
As the tumor is generally unresectable at diagnosis, most patients undergo cisplatin-
based chemotherapy first, followed by surgery. The Indiana University reported 127
consecutive patients (adults and children): among them, 27 had a localized primary
mediastinal nonseminomatous germ cell tumor and 20 had a metastatic disease. All were
treated by upfront platinum-based
chemotherapy and thoracic surgery in all cases
even if the serum tumor marker was still
elevated after chemotherapy : 45 have still
residual germ cell tumor, but among the 27 with
localized disease 14 are free of disease with a
mean follow-up of 156 weeks (75). In a Belgium
report, mediastinal GCTs have the worst
prognosis of all GCTs with a mortality rate of
28% (76). In the last international analy sis done
Figure 15.5 Thoracic germinoma.
by Bokemey er (77), the 2-y ear survival rates
were, respectively, 34% and 84% for
nonseminomatous and seminomatous tumors.
In general, the survival rate for extragonadal GCT is not as high as for ovarian and
testicular lesions. The survival rate in the United States for mediastinum lesions is 40–60%. In
the recent International Society of Pediatric Oncology (SIOP) and German protocols, the 10-
y ear event-free results are as follows: ovarian, 89%; sacrococcy geal, 81%; testicular, 97%;
and all others (except brain), 88% (9,56).
Survival for stages I–II GCTs at gonadal sites approaches 100%. Survival for stages III–IV
GCTs at gonadal sites is about 95%. Extragonadal GCT survival is about 90% for stages I–II
and about 75% for stages III–IV (1).
REFERENCES
1. Rescorla FJ, Breitfeld PP. Pediatric germ cell tumors. Curr Probl Cancer. 1999;23:257–
303.
2. Brodeur GM, Howarth CB, Pratt CB, et al. Malignant germ cell tumors in 57 children and
adolescents. Cancer. 1981;48:1890–1898.
3. Hawkins EP, Finegold MJ, Hawkins HK, et al. Nongerminomatous malignant germ cell
tumors in children—a review of 89 cases from the Pediatric Oncology Group, 1971–
1984. Cancer. 1986;58:2579–2584.
4. Slay ton RE, Park RC, Silverberg SG, et al. Vincristine, dactinomy cin, and
cy clophosphamide in the treatment of malignant germ cell tumors of the ovary —a
Gy necologic Oncology Group Study (a final report). Cancer. 1985;56:243–248.
5. Wells RG, Sty JR. Imaging of sacrococcy geal germ cell tumors. Radiographics.
1990;10:701–713.
6. Terenziani M, D’Angelo P, Inserra A et al. Mature and immature teratoma: a report from
the second Italian pediatric study. Pediatr Blood Cancer. 2015;62:1202–1208.
7. Manavis J, Alexiadis G, Lambropoulou M et al. Extragonadal retroperitoneal
endodermal sinus tumor in an eight-month-old female infant. Eur J Gynaecol Oncol.
2001;22:345–346.
8. Terenziani M, D’Angelo P, Bisogno G, et al. Teratoma with a malignant somatic
component in pediatric patients: the Associazione Italiana Ematologia Oncologia
Pediatrica (AIEOP) experience. Pediatr Blood Cancer. 2010;54:532–537.
9. Gobel U, Schneider DT, Calaminus G, et al. Germ-cell tumors in childhood and
adolescence—GPOH MAKEI and the MAHO study groups. Ann Oncol. 2000;11:263–
271.
10. Rushton HG, Belman AB, Sesterhenn I, et al. Testicular sparing surgery for prepubertal
teratoma of the testis: a clinical and pathological study. J Urol. 1990;144:726–730.
11. Yolk sac carcinoma. Tumor Board of the Children’s Hospital of Philadelphia. Med
Pediatr Oncol. 1987;15:96–101.
12. Jereb B, Wollner N, Exelby P. Radiation in multidisciplinary treatment of children with
malignant ovarian tumors. Cancer. 1979;43:1037–1042.
13. Lack EE, Travis WD, Welch KJ. Retroperitoneal germ cell tumors in childhood—a
clinical and pathologic study of 11 cases. Cancer. 1985;56:602–608.
14. Green DM. The diagnosis and treatment of y olk sac tumors in infants and children.
Cancer Treat Rev. 1983;10:265–288.
15. Mann JR, Pearson D, Barrett A, et al. Results of the United Kingdom Children’s Cancer
Study Group’s malignant germ cell tumor studies. Cancer. 1989;63:1657–1667.
16. Huddart SN, Mann JR, Gornall P, et al. The UK Children’s Cancer Study Group: testicular
malignant germ cell tumours 1979–1988. J Pediatr Surg. 1990;25:406–410.
17. Krege S, Bey er J, Souchon R, et al. European consensus conference on diagnosis and
treatment of germ cell cancer: a report of the second meeting of the European Germ
Cell Cancer Consensus group (EGCCCG): part I. Eur Urol. 2008;53:478–496.
18. Brammer HM III, Buck JL, Hay es WS, et al. From the archives of the AFIP—malignant
germ cell tumors of the ovary : radiologic- pathologic correlation. Radiographics.
1990;10:715–724.
19. Page 355 Cham WC, Wollner N, Exelby P, et al. Patterns of extension as a guide to
radiation therapy in the management of ovarian neoplasms in children. Cancer.
1976;37:1443–1448.
20. Frazier AL, Hale JP, Rodriguez-Galindo C, et al. Revised risk classification for pediatric
extracranial germ cell tumors based on 25 y ears of clinical trial data from the United
Kingdom and United States. J Clin Oncol. 2015;33:195–201.
21. Buskirk SJ, Schray MF, Podratz KC, et al. Ovarian dy sgerminoma: a retrospective
analy sis of results of treatment, sites of treatment failure, and radiosensitivity. Mayo Clin
Proc. 1987;62:1149–1157.
22. Germa JR, Izquierdo MA, Segui MA, et al. Malignant ovarian germ cell tumors: the
experience at the Hospital de la Santa Creu i Sant Pau. Gynecol Oncol. 1992;45:153–159.
23. Taskinen S, Fagerholm R, Lohi J, et al. Pediatric ovarian neoplastic tumors: incidence,
age at presentation, tumor markers and outcome. Acta Obstet Gynecol Scand.
2015;94:425–429.
24. Billmire D, Vinocur C, Rescorla F, et al. Outcome and staging evaluation in malignant
germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr
Surg. 2004;39:424–429.
25. Flamant F, Schwartz L, Delons E, et al. Nonseminomatous malignant germ cell tumors in
children—multidrug therapy in Stages III and IV. Cancer. 1984;54:1687–1691.
26. Gershenson DM, Kavanagh JJ, Copeland LJ, et al. Treatment of malignant
nondy sgerminomatous germ cell tumors of the ovary with vinblastine, bleomy cin, and
cisplatin. Cancer. 1986;57:1731–1737.
27. Grosfeld JL, Billmire DF. Teratomas in infancy and childhood. Curr Probl Cancer.
1985;9:1–53.
28. Kersh CR, Constable WC, Hahn SS, et al. Primary malignant extragonadal germ cell
tumors—an analy sis of the effect of the effect of radiotherapy. Cancer. 1990;65:2681–
2685.
29. Lucraft HH. A review of thirty -three cases of ovarian dy sgerminoma emphasising the
role of radiotherapy. Clin Radiol. 1979;30:585–589.
30. Nichols CR, Heerema NA, Palmer C, et al. Klinefelter’s sy ndrome associated with
mediastinal germ cell neoplasms. J Clin Oncol. 1987;5:1290–1294.
31. Noseworthy J, Lack EE, Kozakewich HP, et al. Sacrococcy geal germ cell tumors in
childhood: an updated experience with 118 patients. J Pediatr Surg. 1981;16:358–364.
32. Raney RB Jr, Sinclair L, Uri A, et al. Malignant ovarian tumors in children and
adolescents. Cancer. 1987;59:1214–1220.
33. Red E. Study : save contralateral ovary in girls with ovarian malignancy. Oncol Times.
1986;8:1–16.
34. Tewfik HH, Tewfik FA, Latourette HB. A clinical review of seventeen patients with
ovarian dy sgerminoma. Int J Radiat Oncol Biol Phys. 1982;8:1705–1709.
35. Palenzuela G, Martin E, Meunier A, et al. Comprehensive staging allows for excellent
outcome in patients with localized malignant germ cell tumor of the ovary. Ann Surg.
2008;248:836–841.
36. Billmire DF. Germ cell tumors. Surg Clin North Am. 2006;86:489–503, xi.
37. Donnellan WA, Swenson O. Benign and malignant sacrococcy geal teratomas. Surgery.
1968;64:834–846.
38. Etcubanas E, Thompson E, Rao B. Treatment of childhood germ cell tumors (GCT):
results of a prospective study. Proc ASCO. 1985;4:238.
39. Williams SD, Birch R, Einhorn LH, et al. Treatment of disseminated germ-cell tumors
with cisplatin, bleomy cin, and either vinblastine or etoposide. N Engl J Med.
1987;316:1435–1440.
40. Creasman WT, Fetter BF, Hammond CB, et al. Germ cell malignancies of the ovary.
Obstet Gynecol. 1979;53:226–230.
41. Gobel G, Calaminus G, Harms D. SIOP teratoma 95, a randomized cooperative protocol
for chemotherapy. Med Pediatr Oncol. 1995;25:319.
42. Baranzelli MC, Bouffet E, Quintana E, et al. Non-seminomatous ovarian germ cell
tumours in children. Eur J Cancer. 2000;36:376–383.
43. Mann JR, Raafat F, Robinson K, et al. The United Kingdom Children’s Cancer Study
Group’s second germ cell tumor study : carboplatin, etoposide, and bleomy cin are
effective treatment for children with malignant extracranial germ cell tumors, with
acceptable toxicity. J Clin Oncol. 2000;18:3809–3818.
44. Ablin AR, Krailo MD, Ramsay NK, et al. Results of treatment of malignant germ cell
tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol.
1991;9:1782–1792.
45. Oliver RT, Mason MD, Mead GM, et al. Radiotherapy versus single-dose carboplatin in
adjuvant treatment of stage I seminoma: a randomised trial. Lancet. 2005;366:293–300.
46. Krepart G, Smith JP, Rutledge F, et al. The treatment for dy sgerminoma of the ovary.
Cancer. 1978;41:986–990.
47. Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary : a
clinical and pathologic study of 58 cases. Cancer. 1976;37:2359–2372.
48. Wollner N, Exelby PR, Woodruff JM, et al. Malignant ovarian tumors in childhood:
prognosis in relation to initial therapy. Cancer. 1976;37:1953–1964.
49. Brody S. Clinical aspects of dy sgerminoma of the ovary. Acta Radiol. 1961;56:209–230.
50. Vassal G, Flamant F, Caillaud JM, et al. Juvenile granulosa cell tumor of the ovary in
children: a clinical study of 15 cases. J Clin Oncol. 1988;6:990–995.
51. Vogelzang NJ, Anderson RW, Kennedy BJ. Successful treatment of mediastinal germ
cell/endodermal sinus tumors. Chest. 1985;88:64–69.
52. Lappohn RE, Burger HG, Bouma J, et al. Inhibin as a marker for granulosa-cell tumors.
N Engl J Med. 1989;321:790–793.
53. Carmignani L, Colombo R, Gadda F et al. Conservative surgical therapy for ley dig cell
tumor. J Urol. 2007;178:507–511.
54. Fernandes ET, Etcubanas E, Rao BN, et al. Two decades of experience with testicular
tumors in children at St Jude Children’s Research Hospital. J Pediatr Surg. 1989;24:677–
681.
55. Oosterhuis JW, Stoop JA, Rijlaarsdam MA, et al. Pediatric germ cell tumors presenting
bey ond childhood? Andrology. 2015;3:70–77.
56. Kennedy CL, Hendry WF, Peckham MJ. The significance of scrotal interference in
stage I testicular cancer managed by orchiectomy and surveillance. Br J Urol.
1986;58:705–708.
57. Dehnard L. Gonadal and extragonadal germ cell neoplasms: teratomas in childhood. In:
Feingold M, ed. Pathology of Neoplasia in Children and Adolescents. Philadelphia, PA:
WB Saunders; 1986:282–312.
58. Flamant F, Diez P. Cure of testicular stage I y olk sac tumor (endodermal sinus tumor) in
children by conservative treatment. Proc ASCO. 1985;4:235.
59. Ise T, Ohtsuki H, Matsumoto K, et al. Management of malignant testicular tumors in
children. Cancer. 1976;37:1539–1545.
60. Duckett J. Testicular tumors in childhood. In: Hay s DM, ed. Pediatric Surgical Oncology.
Orlando, FL: Grune & Stratton; 1986:189–204.
61. De Santis M, Pont J. The role of positron emission tomography in germ cell cancer.
World J Urol. 2004;22:41–46.
62. International Germ Cell Consensus Classification: a prognostic factor-based staging
sy stem for metastatic germ cell cancers—International Germ Cell Cancer Collaborative
Group. J Clin Oncol. 1997;15:594–603.
63. Heidenreich A, Weissbach L, Holtl W, et al. Organ sparing surgery for malignant germ
cell tumor of the testis. J Urol. 2001;166:2161–2165.
64. Puri A, Chandrasekharam VV, Agarwala S, et al. Pediatric extragonadal germ cell
tumor of the scalp. J Pediatr Surg. 2001;36:1602–1603.
65. Bianchi DW, Crombleholme TM, D’Alton ME. Diagnosis and Management of the Fetal
Patient. New York, NY: McGraw-Hill Medical Publishing Division; 2010.
66. Altman RP, Randolph JG, Lilly JR. Sacrococcy geal teratoma: American Academy of
Pediatrics Surgical Section Survey -1973. J Pediatr Surg. 1974;9:389–398.
67. Coleman A, Shaaban A, Keswani S, et al. Sacrococcy geal teratoma growth rate predicts
adverse outcomes. J Pediatr Surg. 2014; 49:985–989.
68. Ein SH, Mancer K, Adey emi SD. Malignant sacrococcy geal teratoma—endodermal
sinus, y olk sac tumor—in infants and children: a 32-y ear review. J Pediatr Surg.
1985;20:473–477.
69. De Backer A, Madern GC, Hakvoort-Cammel FG, et al. Study of the factors associated
with recurrence in children with sacrococcy geal teratoma. J Pediatr Surg. 2006;41:173–
181.
70. Lukish JR, Powell DM. Laparoscopic ligation of the median sacral artery before
resection of a sacrococcy geal teratoma. J Pediatr Surg. 2004;39:1288–1290.
71. Page 356 Garg R, Agarwala S, Bakhshi S, et al. Sacrococcy geal malignant germ cell
tumor (SC-MGCT) with intraspinal extension. J Pediatr Surg. 2014;49:1113–1115.
72. Rescorla F, Billmire D, Stolar C, et al. The effect of cisplatin dose and surgical resection
in children with malignant germ cell tumors at the sacrococcy geal region: a pediatric
intergroup trial (POG 9049/CCG 8882). J Pediatr Surg. 2001;36:12–17.
73. Gobel U, Schneider DT, Calaminus G, et al. Multimodal treatment of malignant
sacrococcy geal germ cell tumors: a prospective analy sis of 66 patients of the German
cooperative protocols MAKEI 83/86 and 89. J Clin Oncol. 2001;19:1943–1950.
74. Billmire D, Vinocur C, Rescorla F, et al. Malignant mediastinal germ cell tumors: an
intergroup study. J Pediatr Surg. 2001;36:18–24.
75. Schneider BP, Kesler KA, Brooks JA, et al. Outcome of patients with residual germ cell
or non-germ cell malignancy after resection of primary mediastinal nonseminomatous
germ cell cancer. J Clin Oncol. 2004;22:1195–1200.
76. De Backer A, Madern GC, Pieters R, et al. Influence of tumor site and histology on long-
term survival in 193 children with extracranial germ cell tumors. Eur J Pediatr Surg.
2008;18:1–6.
77. Bokemey er C, Nichols CR, Droz JP, et al. Extragonadal germ cell tumors of the
mediastinum and retroperitoneum: results from an international analy sis. J Clin Oncol.
2002;20:1864–1873.
CH A P TER 16
Endocrine, Aerodigestive Tract, and Breast
Tumors
Line Claude, Xavier Druet, and Anne Laprie
Epidemiology
ACC is rare around the world (0.2% of child cancer), except in Southern Brazil (3.5
cases/million children y ounger than 15 y ears) (1,2,3,4,5). The frequency is dependent on the
age: 0.4 per million before 4 y ears and decreases to 0.1–0.2 per million after 10 y ears (4,6).
Sex ratio is 1:5.3 before 4 y ears and 1:0.8 after 4 y ears (5).
Genetics
ACC occurs more frequently among individuals with the Li-Fraumeni sy ndrome, which
results primarily from germline mutations in the TP53 gene (7,8) (Table 16.1 ). Screening
and surveillance of heterozy gous carriers of TP53 mutation could be effective in detecting
adrenocortical tumors (9).
Clinical Aspects
Virilization (pubic hair, clitoromegaly or phallomegaly, acne, deep voice, and hirsutism) is the
most common sign of ACC. In the large Brazilian experience, more than 90% of the patients
had pubic hair, and more than 80% of girls had clitoris hy pertrophy. Other frequent signs are
abdominal pain in 50% and Cushing sy ndrome in
30% (hy pertension, centripetal fat distribution,
moon face, buffalo hump of the neck,
accelerated growth velocity, weight gain).
Biology
Because the tumor cells may secrete a number
of adrenal hormones either alone or in
combination (androgens, glucocorticoids,
mineralocorticoids, and estrogens), it is possible
to establish an endocrine profile of most
pediatric ACC. Urinary 17-ketosteroids (17-KS)
and 17-OH steroids are elevated in more than
90% of the cases (5). Table 16.1 Constitutional Genetic
Abnormalities Associated with Adrenal
Molecular Biology Cortical Tumors (ACT)
In adult series, Ki-67 marker proliferation, p53 mutation, mdm-2 mutation, and p21 mutation
have been identified as associated with ACC, but no specific pattern is known. While tumor
cell proliferation (Ki-67) correlates with mitotic activity and morphologic index, tumor
morphology remains a better predictor of metastatic risk (10).
Prognostic Factors
The distinction between benign and malignant ACC is made on cy tologic abnormality, tumor
weight, and presence of metastases (11). Some lesions are frankly malignant on microscopic
examination. For those of borderline histologic appearance, one should consider resectability,
the extent of capsular invasion, adherence to surrounding structures, the presence of aberrant
vessels on angiography, tumor size, and the presence or absence of metastases to distinguish
benign from malignant lesions. Well-encapsulated and easily excised tumors may be cured
by surgery alone. In the remaining resected but more locally advanced cases, there is a
substantial risk of local relapse and distant metastases (10,12).While stages are well defined in
adults (McFarlane classification (3), classification is less clear in childhood. Michalkiewicz et
al. (4) proposed a classification based on more than 250 patients. Factors independently
associated with good prognosis in terms of survival include Stage I tumor (tumor completely
excised, tumor weight <200 g, and absence of metastasis), virilization alone, age <4 y ears
(4). The proliferation marker Ki67 has been recently confirmed as an important prognostic
factor after resection (13).
Imaging
Imaging studies are of great importance for
surgical planning and disease staging. Magnetic
resonance imaging (MRI) and
tomodensitometry (TDM) are necessary to
determine the size of tumor and to detect
invasion of local structures, metastasis, and
vessels involvement (vena cava, for example).
Due to frequent liver and lung metastasis, TDM
is recommended. Brain and bone metastases are
rare but possible; technetium bone scan and/or
brain MRI should be performed in case of
observed sy mptoms. Positron emission
tomography (PET) scan has not been
extensively studied, but in a very small series in
adults, it can y ield additional information in
defining tumor metabolic activity and necrosis,
and in the earlier detection of metastases in
comparison with computed tomography (CT)
(14) (Fig. 16.1A and B ).
Figure 16.1 A & B: Young girl, 17 years
Page 358Treatment old, diagnosed with a left ACC. FDG PET
clearly shows the main mass but also a
Surgery
large vena cava involvement. Lung
As in adults, for localized disease, open and metastases were seen on CT as well as on
potentially laparoscopic adrenalectomy for FDG PET.
selected patients is the main treatment
(5,15).Tumor friability often justifies en bloc resection to avoid tumor spillage and rupture of
the capsule and to compromise prognosis. Therefore, transabdominal approach is necessary.
Chemotherapy
Patients with residual disease after surgery or with metastatic disease usually receive
chemotherapy using different regimens, including mitotane, cisplatin, etoposide, and
doxorubicin. Results are generally poor (16). The use of mitotane (1-(2-chloropheny l)-1-(4-
chloropheny l)-2,2-dichloroethane) in combination with etoposide, doxorubicin, and cisplatin
in the treatment of metastatic disease has been assessed in an international randomized trial
(FIRM-ACT trial) involving adult patients and is now the established first-line cy totoxic
therapy. Mitotane is an isomer of the insecticide DDD, which has adrenoly tic activity. It has
been used as a neoadjuvant to treat advanced metastatic ACC in cases of inoperable tumors,
in adjuvant situation for patients at high risk to relapse, and to control sy mptoms associated
with production of adrenal hormones (5). Administration of this drug is associated with toxic
effects such as nausea, vomiting, renal and hepatic dy sfunction, and neurologic alterations.
As in the adult series, response rates to mitotane are heterogeneous (0–56%) and highly
dependent on achieving a serum therapeutic level to 20 µg/mL (13).
Radiotherapy
Radiotherapy (RT) has often been considered ineffective. However, old clinical reports have
described tumor response rates up to 42% (17), which indicate that ACC is not resistant to RT.
The only series reported with children is Magee’s study (11). Fifteen patients including five
children were treated for ACC. Nine of them had postoperative irradiation. Three were girls
who presented under the age of 2 y ears with hormonally active tumors and who survived for
more than 10 y ears after gross total tumor resection, followed by 30 Gy in 4 weeks. Two of
these three patients died of second malignancies arising in the irradiated field. The high
frequency of second primary malignancies is observed in other studies, and it points out the
need for close surveillance after RT (18).
Page 359Recommendations of an international consensus conference were published in
2005 for adults without any data for children. Radiation therapy is recommended in the
treatment of bone, brain, and other metastases. It is also recommended in the treatment of
sy mptomatic local recurrences. Concerning adjuvant situations, it should be discussed in case
of incomplete local resection. There is no recommendation concerning adjuvant RT in cases
of complete resection, and no major evidence to support it (19). However, some
retrospective studies supported the efficiency of adjuvant RT of the tumor bed (± bilateral
para-aortic ly mph node in seven patients due to ly mph node involvement) in terms of local
control with no impact on survival (20,21,22). If there is a high risk for local recurrence (e.g.,
incomplete/R1 resection), a total dose of >40 Gy with 1.8–2 Gy fraction should be delivered,
including a boost volume to reach 50–60 Gy. The high frequency of Li-Fraumeni disease in
children with ACC makes one reluctant to use RT due to the high risk of radio-induced cancer.
Follow-Up
Hormonal monitoring every 2 months in the first y ear followed by monitoring every 4
months in the second y ear should be done, and from then on, monitoring every 6 months was
done (19). Imaging studies are indicated only in the presence of hormonal abnormalities for
functional ACC.
Results
In children, considering all the stages, 5-y ear overall survival (OS) ranges from 30% to 55%.
Event-free survival (EFS) and OS are very close (4). Stages (quality of resection, tumor
weight, and metastasis), age, virilization, and Ki67 rates are factors significantly associated
with survival. In patients with stage III or IV, OS is from 0% to 20% at 5 y ears; 5-y ear OS for
stages I and II is 80–100% and 30–50%, respectively (4).The Surveillance, Epidemiology,
and End Results (SEER) database was queried for the y ears 1973 through 2008 for 85 patients
with ACC less than 20 y ears of age (23). Overall 5-y ear OS was 57%; 5-y ear OS for patients
<4 y ears was 91% and that for patients ages 5–19 y ears was 30%.
Figure: Constitutional Genetic
Abnormalities Associated with Adrenal
Cortical Tumors (ACT)
Figure:
A & B: Young girl, 17 years old, diagnosed with a left ACC. FDG PET clearly shows the main
mass but also a large vena cava involvement. Lung metastases were seen on CT as well as
on FDG PET.
PHEOCHROMOCYTOMA AND PARAGANGLIOMA
Definition
These tumors arise from the chromaffin cells in the sy mpathetic adrenal sy stem (24,25,26).
Pheochromocy tomas (PHs) develop from medullary gland, whereas paragangliomas
(PGLs) come from extramedullary chromaffin cells (27). Adrenal medullary PHs produce
epinephrine and norepinephrine, whereas PGLs produce only norepinephrine. Some PGLs
are nonsecretant. PGLs are described to have larger size, a higher rate of open surgery, more
R2 resection, and more malignant histology than PHs (28).
Histology
As with many other neuroendocrine tumors, distinction between benign and malignant tumors
is difficult. The histologic scaling sy stem “Pheochromocy toma of the Adrenal Gland Scaled
Score” uses a range of histologic criteria (vascular and capsular invasion, necrosis, and
increased mitotic figures) to determine aggressive behavior, but it cannot predict malignancy.
Histologic markers (Ki67, p53) may be indicative of a malignant disease, but none has been
shown to be a prognostic marker (29). Malignancy is often defined retrospectively by
presence of metastases (27).
Epidemiology
PHs and PGLs in the pediatric population are rare, accounting for <1% of childhood cancer,
with an incidence of 2 per million (30,31,32). Two-thirds of pediatric cases occur in boy s. The
incidence of malignant PHs ranges from 3% to 36% (33).
Genetics
Classically, it was thought that 10% of PH/PGL cases were hereditary, the remaining 90%
being sporadic or nonsporadic. Familial PH/PGL was associated with three endocrine tumor
sy ndromes: multiple endocrine neoplasias 2 (mutation of RET gene, PH, medullary thy roid
cancer, and hy perparathy roidism), Von Hippel–Lindau, and neurofibromatosis (NF1)
diseases. In 2000, the identification of germline mutation in succinate dehy drogenase
complex changed our understanding of this tumor. A mutation in one of six susceptibility
genes VHL, RET, SDHB, SDHC, SDHD, and NF1 was identified in 24–27% of cases
(34,35,36); in a pediatric series, this proportion was 40% (32). Genetic counseling is
recommended after diagnosis of PGL/PH.
Clinical Aspect
The classical triad presentation is headache, sweating, and palpitations. Hormone secretion
can be associated with a wide variety of sy mptoms (fever, nausea, weight loss, fatigue, and
headache), although hy pertension is the most consistent clinical sign (29). Childhood
hy pertension can be explained by PH/PGL in 1% of cases. Convulsions and hy pertrophic
cardiomy opathy can also occur (31). Prevalence of asy mptomatic PH is estimated to be
21% more in sporadic tumors. Children with PH have a higher incidence of bilaterality than
adults (31,37).
Biology
Urinary 24-hour and plasma levels of normetanephrine and norepinephrine had a high
diagnostic sensitivity (31), 100% in pediatric series. Urinary and plasma levels of epinephrine
or its metabolites (vany l mandelic acid) had lower sensitivity (33–57%) (38).
Imaging
TDM and MRI are sensitive to localize the tumor; iodine 131-MIBG scan confirms the
functional aspect. 18-F-DOPA TEP is promising for more accurate diagnosis of PGL/PH,
particularly in patients with negative MIBG (39,40).
Treatment
En bloc resection is the major treatment for this condition. Appropriate preoperative
management is necessary to avoid perioperative complication due to catecholamine
secretion. Alpha blockers (i.e., prazosin) and calcium blockers (i.e., nicardipine) are used to
reduce hemody namic instability. Introduction of medical preoperative treatment in 1950
reduced perioperative mortality from 45% to less than 2% (29). Laparoscopic resection is
preferred to open procedure because it decreases the blood loss during surgery and
postoperative length of stay (38). Open procedures are reserved for very large tumors or
suspicion of malignancy with regional disease (29,32). Cortical-sparing adrenalectomy
avoids long-term corticosteroid dependence in the majority of patients with hereditary PH
with minimal risk of acute adrenal insufficiency. It can be considered in case of bilateral
lesions or in case of Von Hippel–Lindau sy ndrome (41). The risk of local relapse is low.
Chemotherapy was described in malignant disease in one pediatric series using cisplatin and
adriamy cin. Cy clophosphamide, vincristine, and dacarbazine were used in an adult series
(31,42). No randomized studies are available. Chemotherapy can provide tumor regression
and sy mptom improvement in up to 50% of patients. External beam irradiation (EBRT) is
effective for metastases. A recent retrospective study on 24 patients reported conformal
EBRT to a mean dose of 31.8 Gy to 3.3 Gy /fraction, or fractionated stereotactic radiosurgery,
delivered in 24 adult patients. Sy mptomatic control was achieved in 81% of lesions (43). Yu et
al. (44) reported efficacy of RT in nerve decompression. I-labeled MIBG therapy is the
single most valuable treatment after surgery in metastatic disease (33). Sy mptomatic
response was observed in 77–85% of cases in an adult series. A meta-analy sis on 17 studies
(243 patients) was published in 2014. It suggests that stable disease and a partial hormonal
response can be achieved in over 50% and 40% of patients, respectively. Better results are
obtained for PGLs than for PHs (45). There is no consensus regarding the doses. The major
adverse effect is bone marrow aplasia. No benefit was observed on 5-y ear survival
(46,47,48).
Page 360Results
OS and 5-y ear disease-free survival (DFS) depend on malignancy and genetic abnormalities.
Coutant et al. (49) described 30 cases of pediatric malignant PHs with 3-y ear survival rates
significantly lower in SDHB mutation than in other cases (36). A 100% OS and 5-y ear DFS
were found in a series with low malignant rates (38). The probability of late recurrence
justifies an indefinite clinical and biochemical follow-up (36).
THYROID CARCINOMA
Histology/Epidemiology
Thy roid cancers are divided into:
Imaging
Ultrasonography (US) is the better and less invasive examination to explore thy roid nodules
or neck adenopathy. US criteria used to identify malignant nodule in children are
controversial. As previously reported, a recent study on 184 children and adolescents with
thy roid nodules confirmed that microcalcifications, hy poechogenic pattern, intranodular
vascularization at Doppler US examination, ly mph node alterations, and thy roid stimulating
hormone concentration were independent predictors of malignant outcome (56). In a recent
meta-analy sis on 750 thy roid nodules, the presence of internal calcifications and enlarged
cervical ly mph nodes were the US features with the highest likelihood ratio for thy roid cancer
(50). Fine-needle aspiration and cy tology of thy roid are justified in nodules >1 cm diameter
or in US suspicious nodules. Accuracy of fine-needle aspiration and cy tology of thy roid
nodule are less well-known in childhood than in adults, but “follicular lesion” at cy tology
indicates the need for surgery to establish a diagnosis (57).
Prognostic Factor
In papillary thy roid cancer, mutations of RET, BRAF, or RAS, activating the MAP kinase
pathway, are found. Contradictory data are reported, but it seems that RET rearrangements
are more frequent in children and the BRAF mutation is absent (58). No correlation with a
genetic pattern and an aggressive behavior of thy roid carcinoma is established y et (59).
Treatment
Surgery
Before surgery, a whole-neck US is required to optimize the preoperative surgical plan. FNA
of suspicious lateral neck ly mph nodes is recommended. In addition, imaging by MRI or CT
with contrast should be performed in patients with large or fixed thy roid masses, vocal cord
paraly sis, or bulky metastatic ly mphadenopathy to optimize surgical planning. Total
thy roidectomy with en bloc dissection of the central compartment is the preferred operation
in T1 stage or higher followed by postoperative serum thy roglobulin (Tg) levels monitoring
and I-131 therapy (59,60,61). Lobectomy alone was discussed in the past, but this less-
aggressive strategy leads to higher recurrences due to the high rate of multifocal disease. The
extent of ly mph node removal is also debated; central compartment dissection is
recommended, while routine removal of jugular–carotid chains remains controversial. A
cy tologic confirmation of metastatic disease to ly mph nodes in the lateral neck prior to
surgery is desirable. Routine prophy lactic lateral neck dissection (levels III, IV, anterior V,
and II) is not recommended, except in patients with cy tologic evidence of metastases to the
lateral neck (60). A complication of surgery is permanent hy poparathy roidism. In a high-
volume tertiary endocrine surgical practice, the risk of permanent hy poparathy roidism
<2.5% (61,62,63). Other complications can rarely occur including spinal accessory nerve
injury or Horner sy ndrome.
Follow-Up
Follow-up is recommended by TSH, T3L, T4L, and Tg measurement at 3 months, with US of
the neck. Tg measurement after R-TSH is performed at 6 and 12 months. In cases of
persistent or relapsed disease, repeated ly mph node or metastasis removal is possible.
American Thy roid Association Guidelines have been recently published specifically for
children and should be followed (60).
Results
Survival rates for children diagnosed with a thy roid cancer are good, 97% in the EUROpean
CAncer REgistry –based study on survival and CARE of cancer patients (EUROCARE study )
(68), and similar data are reported in the United States (69). In a study on 227 patients (<20
y ears) treated between 1979 and 2012, the 10-, 20-, and 30 y ear-OS rates were 99, 99, and
97%, respectively. The 10-, 20-, and 30-DFS rates were 84, 71, and 64.0%, respectively.
Gender and preoperative ly mph node metastasis were identified as significant factors related
to DFS in the multivariate analy sis (70) (Table 16.2 ).
Table 16.2 Differentiated Thyroid Cancer in Children from 11 Pediatric Series
Figure: Differentiated Thyroid Cancer in
Children from 11 Pediatric Series
RADIATION-ASSOCIATED THYROID CANCER IN CHILDREN
Cancer Survivors
In the Childhood Cancer Survivor Study, including more than 20,000 survivors of leukemia,
central nervous sy stem (CNS) cancer, Hodgkin disease, non-Hodgkin ly mphoma, kidney
cancers, neuroblastoma, soft tissue sarcoma, and bone tumors, any radiation exposure to the
thy roid gland was associated with a 2.6-fold increased risk of thy roid cancer (95% IC 1,1–
7,1) (78,79). Histologic subty pe was papillary in 78% of cases. Sixty -six percent of thy roid
cancers were diagnosed 10–19 y ears after the first cancer (median 15–19 y ears). Risk of
thy roid cancer increased with radiation until 30 Gy and decreased after, consistent with a
cell-killing effect of radiation at high dose. The dose–response relation differed by age at first
cancer diagnosis, and the peak of relative risk was higher if the first cancer was diagnosed
after 10 y ears. Hodgkin ly mphoma seems to be a risk factor for thy roid malignancy,
independent of radiation dose and age at the time of first cancer diagnosis. Thy roid cancers
were usually diagnosed at lower tumor size after Hodgkin disease, due to sy stematic
surveillance of Hodgkin survivors. A recent publication concerning 2548 patients followed
after Hodgkin disease is available (80). Totally 147 cases of secondary malignant neoplasia
occurrence were diagnosed in 138 patients, including 47 second thy roid cancers; 41 of the 47
patients had a papillary carcinoma. The median time between thy roid cancer and first
treatment was 13 y ears. All patients had received RT to the neck and/or mediastinum. No
difference was seen between men and women, among different age groups at the time of the
treatment, or relates to different RT doses. Long-term follow-up guideline for survivors of
childhood cancer recommends a y early clinical examination of the thy roid gland. US
screening should be considered (81).
Clinical Aspect
Medullary Thy roid Carcinoma (MTC) accounts for up to 8% of thy roid cancer in adults (85)
and 5% in children. It is a tumor derived from parafollicular or C-cells of the thy roid, which
can secrete calcitonin. As a consequence, clinical presentation is mainly thy roid nodes with
or without diarrhea, due to calcitonin secretion (85). The diagnosis of MTC in childhood is
based on serum calcitonin (Ct) levels and neck US. If a thy roid nodule is present, fine-needle
aspiration is recommended.
Genetics
One-fourth of the adult cases are associated with MEN 2A sy ndrome (MTC, PH, and
parathy roid gland hy perplasia), MEN 2B (MTC, PH, no hy perparathy roidism, and
marfanoid status), or familial non-MEN MTC (strong predisposition to develop MTC without
other clinical manifestation of MEN 2A), with different mutation of RET oncogene. Even if
these sy ndromes are rare, recognition is important to genetic counseling (86). Children with
clinically evident MTC are usually belonging to MEN2 families, particularly MEN2A and
MEN2B (87). A strong genoty pe–phenoty pe correlation was observed with aggressiveness,
time of onset MTC, and presence or absence of other endocrine tumors (86). Primary
surgery is curative in the majority of patients with early stages, but up to 80% of patients with
palpable disease have nodal involvement.
Treatment
Genoty pe–phenoty pe correlation and clinical presentation are the basis for a
recommendation for prophy lactic thy roidectomy in childhood (86). Three levels of risk were
defined in a codon-based genoty pe–phenoty pe correlation.
Transforming potential of level 3 (codon 918 and 883 in MEN 2B) and level 2 (e.g.,
codon 634 in MEN 2A) mutations are well established, and total thy roidectomy is
recommended, respectively, as early as possible, preferably before the first y ears of birth
and before the age of 5 y ears (86). For level 1 (FMTC, codon 804 or 891 MEN 2A), age at
prophy lactic surgery is discussed, when Ct level rises before 5 or 10 y ears of age (86). For
localized MTC in children, the standard treatment is total thy roidectomy and central neck
node dissection (88). The neck node dissection could be avoided in case of Ct <30 pg/mL.
Distant metastases are observed in up to 25% of cases. Reoperation is the best treatment, but
cy totoxic chemotherapy drugs such as cy clophosphamide and vincristine have been tested,
with a poor response rate (85). Interferon-γ or somatostatin analogs are used to improve
diarrheal sy mptoms. Thy roid kinase inhibitors, such as vandetanib, sorafenib, motesanib, or
sunitinib, have been studied in this indication based on the inhibition of RET protein. For
advanced metastatic cases, vandetanib has been demonstrated to be effective in adults and in
children. Local invasion can be eventually treated by external beam radiotherapy, with poor
results (85,89,90).
AERODIGESTIVE TRACT
Histology
JNA is a benign but locally aggressive vascular tumor, developed from the posterolateral wall
of the nasal cavity. JNA may extend to the nasal cavity, the maxilla, involve the skull base,
and extend intracranially. JNA tends to extend along natural foramina and fissures, spreading
toward the paranasal sinus (ethmoid, sphenoid, and maxillary ) and through the
ptery gopalatine fossa laterally. This growth in soft tissue spaces is limited only by bone,
which can be eroded by pressure. The vascular structures of the basisphenoid region can be
involved, especially in the area of the sphenopalatine foramen (95). Intracranial extension
had been reported in 10–20% of all cases before the era of modern neuroimaging. JNA is
composed of a proliferating and irregular vascular component within a fibrous stroma (96).
Some angiogenic markers, growth factors, and proliferation markers have been found to be
associated with the pathogenesis of JNA, and some were also described in vascular anomalies
(97,98). In recent immunohistochemical studies, vascular endothelial growth factor (VEGF),
its transcriptional regulator hy poxia-inducible factor-1 (HIF-1), and other proangiogenic
factors have been localized in JNA stromal cells, suggesting that deregulated vessel growth is
driven by stromal derived growth factor (99,100).
Page 364Clinical Aspect
Patients with JNA usually present with recurrent painless spontaneous epistaxis, nasal
obstruction, facial deformation, and nasal discharge. Less frequently, a reduced sense of
smell, snoring, headache and facial swelling, and cranial nerve palsies can lead to JNA
diagnosis (101,102).
Imaging
The tumor mass is usually seen on CT as a well-delineated and high-density lesion that
display s a homogeneous enhancement in the posterior nasal cavity and ptery gopalatine fossa.
Erosion of bone behind the sphenopalatine foramen with extension to the upper medial
ptery goid plate must be assessed. Good bone imaging on CT is essential to show invasion of
the cancellous bone of the sphenoid. MRI scans are particularly useful in analy zing the
intracranial and intraorbital extension. The characteristic features on MRI are due to the high
vascularity of the tumor causing signal voids and strong postcontrast enhancement. The
vascular supply may come from the internal maxillary, accessory meningeal, ascending
phary ngeal or ascending palatine arteries. MRI shows the preoperative soft tissue extent of
angiofibroma optimally, but an equally important application is to provide postoperative
surveillance to show any residual or recurrent tumor, record tumor growth or natural
involution, and monitor the effects of RT (103,104). Due to the possibility of asy mptomatic
relapses, a CT or/and MRI is recommended about 4 months after surgery, to rule out
posterolateral or extranasophary ngeal recurrences (105).
Prognostic Factors
The reported rate of recurrences following treatment varies between 0% and 57%
(96,106,107). The main predictor of recurrence seems to be the invasion: the deeper the
extension, the larger the potential tumor remnant is likely to be left following surgery. In a
retrospective study on 55 males treated for JNA, size of tumor and ty pe of invasion were
predictive for relapse: invasion to anterior infratemporal fossae (ITF) and/or to
ptery gomaxillary fossae, to the posterior ITF, or intracranial extension were associated with
recurrences in 2 of 15, in 8 of 18, and in 8 of 12 cases, respectively. Tumors less than, greater
than, or equal to 6 cm were associated with zero and with 18 recurrences, respectively (p =
0.006) (108). Similarly, a retrospective review of 44 cases treated between 1985 and 1996
invasion of the skull base affected two-thirds of the patients, and the rate of recurrence was
27.5%. Extensions to the infratemporal fossa, sphenoid sinus, base of ptery goids and clivus,
cavernous sinus, foramen lacerum, and anterior fossa were correlated with more frequent
recurrence (104).
Classification
A wide variety of scales and staging sy stems have been described, but Radkowski’s
classification is the most often used in recent publications (109). More recently, Yi et al. (110)
proposed another classification based on a modern therapeutic approach. The management
and prognosis for the three ty pes of JNA were compared and evaluated and this classification
seems to be reliable. Ty pe I includes JNAs fundamentally localized to the nasal cavity,
paranasal sinus, nasophary nx, or ptery gopalatine fossa. Ty pe II includes JNA extending into
the infratemporal fossa, cheek region, or orbital cavity, with anterior and/or minimal middle
cranial fossa extension but intact dura mater. Ty pe III represents massive tumor lobe in the
middle cranial fossa.
Treatment
Surgical Approach
Endoscopic resection is nowaday s the main definitive treatment for JNA. Endoscopic
resection achieves similar local control rates than those obtained with open surgery, but with
less blood loss, hospital stay, and local sequelae. Open surgical management of JNA is
performed in case of massive intracranial extension or optic nerve or internal carotid artery
entrapment by the tumor. Surgery is challenging. In a sy stematic review reported in 2013 on
72 patients from 15 studies, the mean follow-up period was 47 months and the recurrence
rate was 18%. Facial paresthesia was reported in 16%, followed by ophthalmoplegia (12%)
and intranasal crusting (12%) (111). As a consequence, intracranial infiltration sometimes
leads clinicians to propose RT as an alternate to the risks of surgery (112). More recently,
radiosurgery after surgery in critical sites has been reported in few patients with encouraging
results. From 1999 to 2007, 10 advanced JNAs were treated by primary surgical resection
followed by Gamma Knife Radiosurgery of residual tumor. After a 3-y ear minimum follow-
up, all the patients are asy mptomatic and have stable disease or partial response (113).
Radical Surgery
There are several surgical approaches: transpalatal, lateral rhinectomy, and craniofacial
resection, with infratemporal approach. Preoperative hormone therapy such as flutamide
(114) and embolization before surgery are still discussed. With adequate operative exposure
and resection, 70–100% of the patients are cured without adjuvant treatment.
Endoscopic Resection
The use of an endoscopic approach to treat small JNA is supported by good results from a
number of operative series published since the beginning of the 2000s. A quite large study
identified 65 patients treated for JNA, mean age 15 y ears. Six consecutive patients underwent
successful resection of JNA by way of an endoscopic approach since 2001. Compared with
the conventional surgery group, the endoscopic group had less intraoperative blood loss (225
vs. 1250 mL), a lower occurrence of complications (1 patient vs. ≥30 patients), shorter length
of hospital stay (2 vs. 5 day s), and lower rate of recurrence (0% vs. 24%) (115). Most of the
studies confirm that endoscopic approach gives excellent results in small dimension tumors
(Radkowski’s stages I–IIb tumors and selective IIc-IIIb lesions), whereas open surgery
remains a more standard procedure for patients with larger tumors. In terms of long-term
results of the endoscopic approach, a sy stematic review was published in 2014 on 92 studies
(over 800 patients) (116). Recurrence occurred in 10%, 9.3% had complications, and 7.7%
had residual tumor (117).
Page 365Chemotherapy
Chemotherapy with doxorubicin and dacarbazine or vincristine, actinomy cin, and
cy clophosphamide has been used for recurrent lesions that are not amenable to additional
surgery or irradiation with some success (118,119). Flutamide has also been tested in
neoadjuvant JNA treatment, with poor results; the mean tumor reduction was 11% in a small
series of seven patients (120,121). It seems to give better results in postpubertal patients (121).
Radiotherapy
RT has been employ ed for advanced disease or for relapse after surgery. Doses ranging from
30 to 50 Gy at 1.8–2 Gy per day give excellent results (Table 16.3 ) considering the more
recent studies available (118,122,123,127). More recently, 24 patients treated with definitive
RT were reported. A dose response for tumor control was described: 77% with 30–32 Gy
versus 91% with 35–36 Gy leading to recommend a total dose of at least 36 Gy. All
recurrences were at the primary site and presented within 5 y ears of completing
radiotherapy (92).
Table 16.3 Radiotherapy for Juvenile Nasopharyngeal Angiofibroma: Most Recent
Studies
Patients are usually treated in conformal RT, or with intensity modulation, using a head
holder. Inadequate treatment fields are the major cause of local failure (128). Proper
mapping of the tumor volume is crucial, using CT and MRI (fusion) to establish the treatment
volume, including cranial extension if necessary. McAffee et al. (92) used approximately 2-
cm margins around the tumor for the treatment planning with excellent local control.
Late effects, especially the risk of malignant cancer, neuroendocrine dy sfunction, and
cataract, must alway s be considered; but these effects remain quite rare and should be
weighed against the risk of surgery in case of advanced disease. In a retrospective study on
130 patients treated over a 41-y ear period (1960–2000), 27 patients received radiation (30–55
Gy ) as first treatment (123). Fifteen percent of the irradiated patients developed relapse 2–5
y ears later. Fifteen percent of the patients developed significant late complication, including
growth retardation, pan-hy popituitarism, temporal lobe necrosis, cataracts, and radiation
keratopathy. Two of the patients developed in-field cutaneous basal cell carcinomas but were
at risk for skin tumors. Cummings et al. (128) reported one patient who developed thy roid
carcinoma after 35 Gy. The main visual complication after RT is cataract formation, while
optic neuropathy and retinopathy are uncommon at conventionally fractionated doses
between 30 and 36 Gy. Cummings et al. (128) reported cataract development in 2 of 55
patients (3.6%). Lee et al. (123) observed cataracts in 3 patients on 27 (11%). Cummings
examined the risk factors associated with surgery and RT and found that the relative risks of
significant complications were similar with both treatment modalities (128). Intracavitary RT
has been used rarely (126) due to major bleeding and often inadequate coverage of the
treatment volume (128). Conformal RT or IMRT can be used. IMRT offers a better sparing of
critical organs in complex volumes but also leads to deliver low doses to larger volumes
(129,130).
Page 366Epidemiology
NPC represents 1% of all childhood cancers, and one-third of all malignancies involving the
nasophary nx in children (133). The classical age incidence is bimodal, with a first peak of
incidence at 10–20 y ears and a second at 40–60 y ears. The incidence of NPC varies
according to racial and geographic factors. Undifferentiated NPC is an endemic tumor that is
common in southern parts of China, Southeast Asia, Alaska, and in the Mediterranean Basin
(incidence 20/100,000) (134). In children, the median age of NPC development is 13 y ears,
with a male predominance (sex ratio 1.8:1) (135).
Genetics
Individuals who have human leukocy te antigen A2 Bsin2 haploty pe, Aw19, Bw46, and B17
ty pes were found to have an increased risk of NPC (136,137).
Clinical Aspects
The tumor initially develops in the walls of the nasophary nx without any sy mptoms,
explaining the usually late diagnosis. The most common presenting sy mptom is a painless
mass in the upper neck; 421 cases (135,138). Local tumor effects can include nasal
obstruction, blood-tinged drainage, bleeding, and conductive hearing loss or serous otitis.
When the tumor invades the base of the skull through direct extension, the cranial nerves are
frequently involved leading to sy mptoms (drooping of the upper ey elid, ey e pain, loss of
vision, double vision, difficulty swallowing, spasms of masticatory muscles, disturbances of
taste and voice).
About 20% of patients have distant metastasis at diagnosis including the bones (60–70%),
liver (about 30%), lungs (about 20%), bone marrow (about 20%), and mediastinum.
Biology
An Epstein–Barr virus (EBV) infection association with NPC has been well described in
childhood (139,140). EBV has been identified as a causative agent in several patients. High
antibody titers of immunoglobulin G (IgG) and immunoglobulin A (IgA) against early antigen
or viral capsid antigen are commonly seen in patients with NPC, particularly those with the
undifferentiated form of the disease. Circulating EBV DNA load may be a useful prognostic
marker in endemic regions.
Imaging
Contrast-enhanced cranial CT and MRI are useful to assess the extent of local tumor growth
and base of skull involvement. A heterogeneous mass (primary tumors and ly mph nodes)
with necrosis has been reported as characteristic in adults (141). Thirteen patients, 30 y ears
old or less, with undifferentiated NPC were reviewed in terms of CT and MRI findings. The
signal intensity of tumors was slightly higher than that of muscles in six cases and isointense to
that of muscles in two cases on T1-weighted images. In all cases, the signal was higher than
that of muscle and lower than that of cerebellar gray matter on T2-weighted images. Internal
signals were homogeneous in both pre– and post–gadolinium-enhanced MR images in all
cases (142).
A large prospective study on adults (8) assessed the usefulness of fluorodeoxy glucose
(FDG)-PET in initial M staging of NPC. Three hundred patients with NPC were compared in
terms of staging. Conventional workup (CWU) included chest radiography, abdominal US,
and skeletal scintigraphy and was compared with FDG-PET staging. About 20% patients were
found to have distant metastases. FDG-PET was more effective than CWU (p < 0.001) to find
them, especially for detecting bone (p < 0.001) and chest metastases (p < 0.001). It was
equally effective for detecting hepatic metastases than abdominal ultrasound (143). A recent
study was performed on 18 pediatric patients, which concluded that FDG may underestimate
tumor extent and regional ly mphadenopathy compared with MRI at the time of diagnosis but
that it helped detect metastasis and clarify ambiguous findings. In the follow-up, it showed
disease clearance 3–6 months earlier than MRI without false positive or false negative
findings (144) (Fig. 16.2A and B ).
Classification
Several classifications for NPC have been done, but the most popular in Western countries is
the AJCC staging sy stem (147). The fifth edition of this classification was designed to merge
the best predictive factors of the fourth edition. Another staging sy stem is most frequently
applied to Asian populations, described by Ho (148) (Table 16.4 ).
Treatment
Indications
Treatment depends on the stage. Stage I patients
usually receive RT alone, while stages II and III
patients are treated with chemotherapy and RT.
Stage IV patients usually receive CT. Except for
a diagnostic biopsy, surgery is not part of the
treatment of NPC.
Stage I
RT alone remains the standard treatment of stage
I patients, without node involvement, leading to a
98% 10-y ear overall survival rate (149).
Stages II–III
The place of chemotherapy remains
controversial in the initial management of
localized NPC. In adults, phase III trials and
meta-analy sis comparing induction
chemotherapy with RT alone (150,151,152) did
not show any improvement in OS, despite a Figure 16.2 A & B: Young boy, 15
significant reduction in local and distant failures years old, diagnosed with large bilateral
(150,151). In addition, excess treatment-related NPC. FDG confirms a bilateral cervical
deaths were observed in the induction nodes involvement without
chemotherapy trials (153). supraclavicular disease.
In contrast, recent trials and meta-analy ses
in adults have confirmed the role of concomitant
chemotherapy with RT in locoregionally
advanced NPC. The last meta-analy sis of
chemotherapy in nasophary nx carcinoma
(MAC-NPC) was performed by the
Collaborative Group. Eight randomized trials
compared chemotherapy plus RT versus RT
alone in locally advanced NPC. All trials used
conventional RT and cisplatin-based
chemotherapy. A total of 1753 patients were
included. A significant benefit was found for OS
(6% at 5 y ears) and EFS (10% at 5 y ears) with
the addition of chemotherapy. The benefit on
survival was observed when chemotherapy was
administered concomitantly with RT (153).
Concomitant (cisplatin-based) chemo-
radiotherapy now appears to be the standard
treatment for locally advanced (T2B and more)
and/or node positive (Np) patients in adults (154).
In children, some large studies tend to
demonstrate the same results (155). Fifty -two
pediatric patients with stages I–IVB NPC
received RT dose of 60–66 Gy in 2-Gy fractions
to the nasophary nx and cervical nodes. Among
them, 22 also received chemotherapy with
cisplatin and 5-FU. Three-y ear DFS with
concurrent chemotherapy was 82% compared
to 40% for patients treated with RT alone (p =
0.001) without impact on 3-y ear OS. Thirty - Table 16.4 Staging System for
three patients, median age 14 y ears, were also Carcinoma of the Nasopharynx
treated for stages I–IVB NPC. Thirteen patients
(39%) received RT alone and 20 patients (61%) had chemotherapy and RT. The addition of
chemotherapy had no significant effect on locoregional control but did reduce the
development of distant metastases (16% vs. 57%, p = 0.01). Combined modality therapy
improved 10-y ear DFS (84% vs. 35%, p < 0.01) and survival (78% vs. 33%, p < 0.05) over
radiation alone (156).
Page 368Of 165 patients reviewed between 1978 and 2003, median age 14 y ears, 12.7%
patients were treated with RT alone, while 87.3% received chemotherapy and RT. The
median follow-up time was 48 months. In multivariate analy sis, patients treated with RT alone
had poorer locoregional relapses-free survival (p = 0.0001) as well as DFS than patients
treated with chemotherapy and RT (p = 0.002) (157). Most chemotherapy is cisplatin-based
combination, used weekly or once every 3 weeks. The question to add induction
chemotherapy followed by concomitant chemoradiotherapy remains controversial. In adults,
several phase II studies (158,159,160) have shown good results on a poor prognostic
population (T2B, 3, 4, and/or N+) selected on good performance status, but further studies are
needed, especially in children.
The use of interferon beta has been evaluated in a phase II trial, as maintenance therapy
after combined therapy with neoadjuvant chemotherapy and radio-chemotherapy.
Treatment was well tolerated and resulted in a very good outcome that was superior to the
outcomes of published results from all other pediatric NPC study groups.
Stage IV
Treatment of metastatic disease is based on chemotherapy. Anthracy clines and bleomy cin
were the first agents used. Platinum-based regimens are now the standard chemotherapy for
metastatic NPC patients, and cisplatin–5-FU combination remains the most often used in first-
line treatment (159). In a retrospective review of 84 patients, mean age 13 y ears, with NPC
chemotherapeutic regimens involved cy clophosphamide from 1972 to 1982; vincristine,
cy clophosphamide, epirubicin, and actinomy cin-D protocol from 1982 to 1999; and cisplatin,
methotrexate, and 5-FU with leucovorine rescue after 1999. A total of 78.5% of the patients
were at advanced stage (stages III and IV). The survival rates (80%) were higher with the
cisplatin combination regimen (131,135,161,162).
Radiotherapy
Radiotherapy Dose
Before the beginning of RT, dental evaluation and prophy laxis are necessary. Baseline
neuroendocrine testing and audiograms are also useful for the assessment of late effects. The
optimum dose for local control NPC in children is not precisely known. Doses greater than 65
Gy have been shown to achieve better local control in some studies (131,132,161,162), but
others have not shown any correlation between the dose of radiation, rate of local relapse,
and survival time (163). Generally, doses ranging between 50 and 70 Gy are recommended
for patients older than 10 y ears, and a 5–10% reduction in this dose is recommended for
children y ounger than 10 y ears of age (161) Daily fractions of 1.8–2.0 Gy, 5 day s a week are
usually proposed in children. One of the ongoing questions in children is to reduce the RT dose
to ly mph nodes and/or to the nasophary nx area in case of good response to chemotherapy, to
limit the late effects of high-dose RT. For instance, in a French study, 34 children were treated
for AJJC-TNM stage IV NPC. After chemotherapy, cervical nodal irradiation was reduced
(<50 Gy ) in the 15 cases of a good response to chemotherapy (≥90% of initial tumor
volume). Median nasophary ngeal RT was 59.4 Gy, up to 66 Gy in some cases of partial
response to CT. The overall prognosis was not influenced by the dose of local RT delivered or
response to initial chemotherapy, but EFS was better in patients with a good response to
chemotherapy. The cervical local failure rate was low despite RT dose reduction in the case
of a good response to neoadjuvant chemotherapy (164).
Radiotherapy Volumes
CT and MRI are used in the delineation of clinical target volumes (CTVs) (165,166). The
CTV should include the nasophary nx, half (posterior) of nasal cavity, entire sphenoid sinus,
and posterior ethmoid sinuses. The posterior limit of the CTV is usually at the anterior part of
medullary canal. The inferior limit is represented by orophary ngeal wall to the midtonsillar
fossa, basioccipital bone, cavernous sinus, base of skull, ptery goid fossae, posterior one-third
of the maxillary sinus, retrophary ngeal nodes, bilateral cervical nodes, and supraclavicular
nodes (166). If the tumor has invaded the base of the skull, the superior border should be
raised to include all of the pituitary gland, the base of the brain in the suprasellar area, the
adjacent middle cranial fossa, and the posterior portion of the anterior cranial fossa. Sham et
al. (167) have shown that the protection of pituitary gland did not lead to increase local failure
if the skull base was not involved.
Radiotherapy Technique
In adults, intensity modulated radiotherapy (IMRT) substantially improves head and neck-
related sy mptoms and quality of life of patients with NPC without decreasing local control
(168,169,170). IMRT may provide improved local control in children with less late sequelae
(132). Thirty -six children, median age 14 y ears, with localized NPC, were included in Uzel’s
study. All of them were treated with a combination of chemotherapy and RT. Nineteen
underwent IMRT and 17 underwent conformal RT. They have shown that IMRT significantly
reduces and delay s the onset of acute toxicity (grade 3 toxicity of skin, mucous membrane,
and phary nx), resulting in improved tolerance and treatment compliance for children with
NPC. IMRT also permitted a superior target coverage and normal tissue sparing compared
with CRT (171), with decreased acute toxicity on skin, mucous membrane, and lary nx.
Nevertheless, acute toxicity may be severe even with IMRT and the use of a feeding tube
may sometimes become necessary.
The sparing of salivary glands and hearing structures made possible by IMRT decreases
late effects. In five pediatric patients with NPC treated by IMRT and concomitant platinum-
based chemotherapy, with a median follow-up of 6.3 y ears, all patients experienced three or
more long-term toxicities, including hy pothy roidism, xerostomia, hearing loss, and dental
disease (172). Interestingly the dose constraint to the cochlea was 25 Gy, but it has been
recently published that 10 Gy is the dose constraint with concomitant cisplatin (173). A larger
recent retrospective study on 95 pediatric and adolescent patients described late effects with a
rate of 48% xerostomia, 28% hearing impairment and 41% neck fibrosis (related to dose) but
all late effects were grade 1 or 2 (174). Endocrine late effects are frequent due to the
proximity of pituitary gland.
Hyperfractionation
Experiences with altered fraction schedules in NPC remain limited in adults, and are
infrequently described in children. In adults, hy perfractionation and accelerated fractionation
have not demonstrated an increase in survival efficacy (176), but local control is usually
better (177). The high rate of toxicity limits the use in children (178,179). For example, Teo et
al. (176) reported increased risk of temporal lobe injury in adults with NPC after altered
fractionated RT (176).
Page 369Results
Survival Outcomes are shown in Table 16.5 .
Table 16.5 Survival in Childhood Nasopharyngeal Carcinomas: Studies During the 1990s
and 2000s
Late Effects
Late effects of treatment in children include hy popituitarism, thy roid dy sfunction (73%), and
fertility defects. Other effects include xerostomia, chronic sinusitis, dental caries, hearing
loss, and neck fibrosis. Second malignancies, encephalopathy, osteoradionecrosis, cranial
nerve dy sfunction, hy poplasia, and fibrosis of facial bones occur less frequently
(132,147,162,184).
Histology
EB is an aggressive malignant tumor derived from the olfactory specialized neuroepithelium
of the upper nasal cavity (187). Histologic features include small, round neuroepithelial cells
arranged in rosette or pseudorosette patterns, separated by fibrous elements. In cy tology,
fibrillary cy toplasm and smooth nuclear contours are usual; mitotic figures are generally
absent (188). The diagnosis needs a combination of parameters, including microscopic aspect
and immunohistochemical stains. The tumor may be positive for chromogranin,
sy naptophy sin, S-100 protein, and neuron-specific enolase (189). A histologic grading sy stem
is based on degree of differentiation, cellular anaplasia, and mitotic rate. This is a four-level
sy stem that is frequently simplified into low-grade (Hy ams grades I and II) and high-grade
(Hy ams grade III and IV) neoplasms (190). In a large recent report from SEER including
281 adults, patients with high-grade tumors had substantially worse survival rates than patients
with low-grade tumors. Surgery was an independent positive predictor of disease-specific
survival in patients with low-grade lesions. Kadish staging and radiotherapy were independent
positive predictors of disease-specific survival in patients with high-grade tumors (191).
Pathogenesis is not well known; however, nitroso derivatives (192) and viral induction (193)
have been discussed in the pathogenesis. EB has also been described as a member of Ewing
sarcoma and peripheral primitive neuroectodermal tumor (PNET) family, while the
EWS/FLI1 translocation has been shown in EB cell lines (194).
Imagery
Contrast-enhanced CT (<5-mm thick slices) is necessary, particularly to assess paranasal
cavities involvement. EBs are solid and aggressive nasal cavity tumors; erosion of osseous
structures can be seen. MRI is often necessary because it is more sensitive to explore
intracranial involvement (198).
Classification
The most commonly used classification is
Kadish staging sy stem (Table 16.6 ) (199).
About one-third of the patients are in group B,
half of them are in group C (197). Neck node
involvement has been reported in 10–50% of the
patients (195,200,201). Metastatic disease at
presentation occurs in 10–50% of patients, Table 16.6 Kadish Staging System
depending on the study reviewed (202,203). In
case of metastatic disease, the lesion area in 20–30% patients involves the subepithelial
endocrine cells (SNCs) that grow through the cribriform plate and invade the anterior basal
cranial base. It can then metastasize to brain parenchy ma or leptomeninges (197). Other
metastases are less frequently found in lung, liver, or bone (204).
Treatment
Due to low incidence of EB, even in adults, it is difficult to evaluate the efficiency of
treatment strategies. Options include surgery alone, RT alone, surgery and RT, chemotherapy,
and sometimes high-dose chemotherapy with autologous bone marrow transplantation. In
general, multimodality treatment offers the best survival rate, particularly with more
advanced disease.
Surgery
Outcomes improved significantly with the advent of craniofacial resection in the 1970s,
providing a more complete surgical resection (205). Surgical extirpation can usually be
accomplished, but obtaining standard oncologic negative margins in this area of critical
functional anatomy is not without great morbidity to the patient. Craniofacial resection allows
en bloc resection of tumor including the cribriform plate, with direct visualization of
intracranial extension and protection of the brain and optic nerves. DFS increased from 40%
to 80% when comparing extracranial resection with craniofacial resection in one published
study (205). Complications include infections, cerebrospinal fluid leak, and optic injury (205).
In a pediatric series, up to one-third of the patients had postoperative morbidities, including
complications involving the local wounds, the central nervous sy stem and the ocular orbit.
Postoperative mortality has also been reported in up to 5% of patients (206). If cervical
disease is present at diagnosis, complete neck dissection can be discussed (207). Due to
surgical morbidity and frequent indication for adjuvant therapies, other strategies have been
studied: treatment with smaller surgical margins followed by postoperative radiation, the use
of neoadjuvant chemotherapy followed by surgery and postoperative radiation, and the use
of chemoradiation without surgery (208,209). In particular, recent publications report
neoadjuvant chemotherapy in children. Less major surgical complications are thus reported
while delay ed surgery could be less aggressive (197). A meta-analy sis of adult data has been
published, concerning 361 patients treated between 1992 and 2008. A greater published
survival rate for endoscopic surgery compared to open surgery (p = 0.0019), even when
stratify ing for publication y ear (p = 0.0018), was found. Review of Kadish tumor staging for
each modality showed that larger tumors were more often treated with an open approach, but
open and endoscopic survival measures were comparable (210). In a large recent report
from SEER including 281 adults, surgery was the only independent positive predictor of
disease-specific survival in patients with low-grade lesions (191,211).
Radiotherapy
Multiple retrospective studies have demonstrated an improved outcome with the addition of
radiation before or after surgery (212). Delivering RT in preoperative situation offers several
theoretical advantages including an intact blood supply, leading potentially to a better radiation
efficacy. Definition of the tumor volume is also clearer before surgery. In small studies, RT
has been shown to provide a valuable complement to radical craniofacial resection, leading to
reduction in tumor burden in two-thirds of the patients. Patients experiencing reduction in
tumor volume by neoadjuvant therapy demonstrate an improved prognosis (213).
Postoperative radiation is generally accepted as important for treatment of advanced EB
(214,215,216). Broich et al. (212) reviewed the literature and reported 62.5% survival with
surgery alone and 72% survival with combined surgery and radiation at 5 y ears. It was
confirmed more recently in a large study on 70 adult patients (211). Patients who were
treated with surgery alone had a median disease-specific survival of 88 months versus 218
months for those who were treated with surgery and postoperative radiation. In a large recent
report from SEER including 281 adults, postoperative radiation therapy was a significant
independent factor in predicting disease-specific survival in only patients with high-grade
tumors (191). Even in pediatric series, despite the risk of late complications, the vast majority
of patients receive high-dose radiotherapy in adjuvant situation, leading to better local control
and the disease-free survival. In a recent study, all the 11 pediatric patients received
combined treatment including RT. It was performed in adjuvant situation in 10 of them and
with chemotherapy in one. The 5-y ear actuarial disease-free survival and overall survival
rate was 91% (217). Exclusive RT is not recommended as far as patients are eligible for
surgery and chemotherapy because the pattern of relapse is not only local. Benfari et al.
(218) reviewed 55 patients submitted only to radiotherapy alone. They had been selected
from publications between 1979 and 2006 according to the Kadish classification. With a
median follow-up period of 103.6 months, 6/6 stage A patients, 7/12 stage B patients (median
follow-up 120 months), and 7/37 stage C patients (median follow-up period of 77.3 months)
were free of disease.
Page 371RT technique is ty pically based on CT planning and simulation, with fusion of
MRIs to the treatment planning CT to more accurately define soft tissue and/or brain
parenchy mal extension. Ty pically, fields may include the entire nasal fossa, maxillary
sinuses with extension into the ethmoid, sphenoid sinuses, and the anterior cranial fossa.
Elective treatment of ipsilateral neck is controversial and likely not indicated without risk
factors for evidence of extension to the neck nodes; especially when chemotherapy is
delivered. In a recent study on 14 patients, no cervical nodal failure occurred in patients
treated with combined sy stemic chemotherapy regardless of elective nodal irradiation. In the
opposite neck, three cervical failures occurred in the four patients treated with ipsilateral neck
RT or neck dissection. These patients had not received sy stemic chemotherapy (219). Total
RT dose ranges from 50 Gy for microscopic disease to 55–60 Gy for gross disease
administered at 1.8/2.0 Gy per fraction. IMRT is often a good option due to the proximity of
organs at risk (220). Zabel et al. (221) reported that the IMRT plans gave equal dose coverage
and allowed more effective sparing of normal tissues in 13 cases. Proton beam RT has
allowed for dose intensification to the target volume with relative paring of adjacent normal
tissues, especially for bulky or unresectable diseases (222,223). Radiosurgery is another
treatment modality used for definitive treatment and for treatment of local relapse. It allows
the benefit of single fraction treatment. Small local relapses after previous RT may be treated
with this technique (224). In children, RT can cause significant late effects. A risk of second-
cancer, craniofacial growth impairment, damage to the permanent teeth, endocrine
dy sfunctions, and loss of the sense of smell represent the main late effects (225).
Chemotherapy
The role of chemotherapy is not well defined in the pediatric population. Chemotherapy has
been studied in the neoadjuvant and adjuvant situations in a small numbers of patients.
Cisplatin-based regimens, associated with cy clophosphamide, vincristine, or etoposide, have
been used (226,227,228). Some studies recommend chemotherapy in stage C disease. For
example, routine use of cy clophosphamide and vincristine in combination with RT and
surgery has demonstrated improved survival in a study at the University of Virginia (227). A
retrospective study on 19 patients <20 y ears of use has shown a benefit of multimodal
treatment regimens combining surgery and chemo- and RT for pediatric patients with Kadish
stage C. Chemotherapy appears to improve resectability, EFS, and OS (225). El Kababri et al.
(217) reported a 5-y ear actuarial disease-free survival and overall survival rate of 91% in 11
pediatric patients treated with neoadjuvant chemotherapy. High-dose chemotherapy with
stem cell rescue has been reported as primary and salvage therapy, with good results in small
series, after RT (229). A maintenance treatment by interferon has also been proposed (230).
Results
A meta-analy sis of data from 37 small
retrospective studies (386 patients) was published
in 2001, comparing outcomes by treatment
modality. Mean OS at 5 y ears was 45%. Survival
by treatment modality was 65% for surgery plus
RT, 51% for RT plus chemotherapy, 48% for
surgery alone, 47% for of all three modalities,
and 37% for RT alone. Higher histopathologic
grade and the presence of cervical ly mph node
metastases were poor prognostic factors (203)
(Table 16.7 ). Although recurrence can occur
with high frequency even after prolonged time
interval, long-time survival can be improved
after aggressive salvage therapy. Long-term
follow-up is mandatory (235). Recurrences have Table 16.7 Local Recurrence Rates in
been reported 15 y ears after treatment (236). Retrospective Series of the Treatment of
Esthesioneuroblastoma: Combined Adult
and Pediatric Series
Figure: Radiotherapy for Juvenile
Nasopharyngeal Angiofibroma: Most Recent
Studies
Figure:
A & B: Young boy, 15 years old, diagnosed with large bilateral NPC. FDG confirms a bilateral
cervical nodes involvement without supraclavicular disease.
Figure: Staging System for Carcinoma of the
Nasopharynx
Figure: Survival in Childhood
Nasopharyngeal Carcinomas: Studies During
the 1990s and 2000s
Figure: Kadish Staging System
Figure: Local Recurrence Rates in
Retrospective Series of the Treatment of
Esthesioneuroblastoma: Combined Adult
and Pediatric Series
MALIGNANCIES OF THE ORAL CAVITY, OROPHARYNX,
HYPOPHARYNX, AND LARYNX
Epidemiology
The German Childhood Cancer Registry has reported one of the largest studies, including 370
malignancies of the head and neck in children under the age of 15 between 1994 and 2003
(199 boy s and 171 girls). The overall incidence of malignancies of specific sites of the head
and neck in Germany is 4.48 per 100,000 children. The most frequently observed entities,
representing primary tumors, are soft tissue sarcomas (0.39/100,000), ly mphomas
(0.09/100,000), and thy roid carcinomas (0.07/100,000). The most commonly affected organs
are the thy roid (1.21/100,000), orbital region (0.91/100,000), nasophary nx (0.66/100,000),
tonsils (0.43/100,000), and paranasal sinuses (0.14/100,000) (237,238). A large American
study (SEER) confirmed the proportion of head and neck cancers to all cancers in the
pediatric population has remained stable between 1973 and 2010 in USA. The five most
prevalent head and neck cancers within the pediatric population were salivary gland tumors,
nasophary ngeal neoplasms, tumors of the nose, nasal cavity, and middle ear; gum and other
mouth tumors; and glossal tumors (239).
SALIVARY GLAND TUMORS
Page 372Epidemiology
Salivary gland tumors (benign or malignant) represent only 1% of head and neck tumors
(240,241). Only 5% of salivary gland cancers arise during childhood (242,243). Carcinomas
of the salivary glands represent 0.08% of cancer in the pediatric population (244).
Pathology
Fine-needle aspiration biopsy is generally used for the diagnosis of salivary gland mass
(245,246). Among epithelial tumors of the salivary glands, mucoepidermoid carcinoma
(MEC) and adenoid cy stic carcinoma (ACC) are the most frequent histologic ty pes in adults
and children. Histopathologic grades are usually defined as low, intermediate, or high. MECs
are more often low or intermediate grade in childhood than in adults. MECT1/MAML2 fusion
transcripts are also more common in children (247).
Clinical Aspects
The most frequent clinical presentation is an isolated, hardened, noninflammatory, painless,
and slow-growing tumefaction (251). Facial palsy is rare (250).
Treatment
MEC has a good prognosis in y oung patients. Differences in OS, specific survival, and DFS do
not seem statistically significant between the primary MEC tumors and the second cancers.
Definitive surgery is the treatment of choice and gives very good local control rates
(247,252). A neck node dissection is recommended in patients with advanced-stage disease,
and in high-grade tumors neck ly mph node metastasis is detected in 50% of cases (253,254).
A retrospective analy sis of clinical and histopathologic findings was published recently in 14
patients with MEC diagnosed at Texas Children’s Cancer Center between 2000 and 2014 (247).
They confirmed complete excision is the treatment of choice and is associated with excellent
outcome while no relapse occurred with a median follow-up of 24 months. The role of RT
after surgery remains unclear. A French study reported 38 pediatric patients, median age 14
y ears, treated for MEC: 37 patients had surgery, 29% received adjuvant RT, and 11%
received chemotherapy. With a median follow-up of 62 months, OS was 95%. One local
relapse (nodes) was reported. Low-/intermediate-grade lesions with early stage could be
treated by surgery alone. Neck dissection is recommended for high-grade lesion. They also
recommend adjuvant RT for high-grade or extensive MEC, and/or positive surgical margins
(255).
Surgery is the treatment of choice in adenoid cy stic carcinoma (ACC) for pediatric
patients, as for adults. The prognosis seems to be slightly better in childhood than in adults, and
for patients treated by surgery versus not, according to a large study (>3000 patients) from
the US National Cancer Institute’s SEER program (256). The overall 5-y ear, 10-y ear, and 15-
y ear survival outcomes for ACC patients were 90.3%, 79.9%, and 69.2%, respectively, for
the whole population (adults and children).
INFANTILE SUBGLOTTIC HEMANGIOMAS
Congenital subglottic hemangioma (SH) causes life-threatening airway obstruction during the
first few months of life. After an asy mptomatic neonatal period, the infant presents a
characteristic biphasic stridor as the lesion progressively obstructs the subglottic space. In 80–
90% of cases, these sy mptoms appear in the first 6 months of life. The involution process
generally begins at 12 months of age and continues until the SH regresses completely. The
mortality rate of recognized and untreated cases justifies active treatment. The aim of
therapy is to restore normal respiration, attempting to preserve the child’s voice and alter the
quality of life as little as possible.
Treatment
Sy stemic propranolol has demonstrated similar effectiveness to surgery and is now
considered as the standard of treatment (257,258). Twenty -seven patients, median age 2.3
y ears, were reported recently : 11 of 27 (41%) were managed with propranolol alone; the
remaining 16 of 27 (59%) also had a steroid injection. Propranolol dose was maintained at 2
mg/kg/d in all patients for a minimum of 7 months (range, 7–34 months; median, 15 months).
Stridor was eliminated within 24 hours or less of propranolol initiation in 23 of 27 (85%)
Before propranolol became widely used, endoscopic excision with carbon dioxide laser, used
alone or combined with other therapeutic techniques, was performed. A retrospective
comparative study of a previous cohort of 51 patients with SH was performed in which
patients were treated either by tracheostomy alone, tracheostomy and CO2 laser, sy stemic
steroids and CO2 laser with no tracheostomy and intralesional steroid injection, CO2 laser
therapy, or both, followed by intubation. Resolution of the SH was achieved in about 90% of
cases. However, a transitory tracheostomy was required in more than half of the cases. The
time to resolution of SH does not appear to be reduced by laser therapy compared with
treatment by tracheostomy alone. Intralesional steroid injection or laser therapy together
with intubation was associated with avoidance of a tracheostomy in 66% of cases (259).
Page 373Although RT is known to work, it carries a risk of inducing second thy roid
cancer later in life. In a series of 11 patients with SH, conventional RT was utilized in the first
7 patients. A radioactive gold grain directly was placed into the lesion in the last four patients,
leading to minimal thy roid gland irradiation compared to treatment by conventional RT. It
was successful in the four patients (260). When RT is used, a dose range between 3.5 and 5
Gy at 0.5–1.5 Gy per fraction is delivered. When dealing with a life-threatening situation, one
should be prepared to use irradiation if other treatment modalities are either inapplicable or
unsuccessful.
ESOPHAGEAL CANCERS
Esophageal carcinoma may develop in children; it may arise spontaneously, y ears after
chemical burns in the setting of Barrett esophagus (261), and, in one reported case, in
association with Cornelia de Lange sy ndrome (262). Both squamous cell carcinoma and
adenocarcinomas have been reported. They are managed similarly to adults (263) and have
usually poor prognosis. The rare case of esophageal sarcoma (leiomy osarcoma,
carcinosarcoma, and malignant schwannoma) may be treated with preoperative or
postoperative irradiation (264). Palliative RT is occasionally necessary for leukemia or
secondary or primary ly mphomatous infiltration of the esophagus (249,250). Other rare
esophageal neoplasms include leiomy oma, desmoid, and teratoma (265,266).
GASTROINTESTINAL MALIGNANCIES
Primary gastrointestinal (GI) malignancies are rare in childhood and adolescence. Non-
Hodgkin ly mphoma is the most common malignancy of the stomach in childhood (see
Chapter 8 ). As a group, leiomy osarcoma and leiomy oblastoma are the second most
common gastric malignancies in children (267,268). The average size of a gastric
leiomy osarcoma in childhood is 6–7 cm in diameter. Infiltration of tumor to adjacent
structures, including the liver or nodal metastasis, may occur (268). Therapy of gastric
leiomy osarcoma begins with surgery. The operative bed and the upper abdomen are
common sites of tumor recurrence. Postoperative RT is justifiable when there is a
particularly high risk of local recurrence created by positive surgical margins or posterior
penetration. However, the efficacy of adjuvant RT in this setting is not proven.
Gastric adenocarcinoma is rare in children, representing 0.05% of all gastrointestinal
malignancies (267,269). It may occur de novo or in association with Peutz–Jeghers
sy ndromes (270). Among the few pediatric cases reported in the literature, median survival
after diagnosis is poor, approximately 5 months (271). Initial chemotherapy is mainly
platinum-based. Large surgical resection offers the best option (271). There is epidemiologic
evidence that long-standing Helicobacter pylori infection and chronic gastritis are involved in
the development of a variety of gastric malignancies including adenocarcinomas,
ly mphomas, and mucosa-associated ly mphoid tissue ly mphomas. Acquisition of infection in
childhood appears to be a risk factor for development of neoplasia as an adult. However, the
impact of the treatment of all H. pylori–infected children on the risk of gastric malignancy
decades later is debated (272,273).
Gastrointestinal stromal tumors (GIST) have recently been identified by the
immunohistochemistry from other mesenchy mal tumors such as leiomy omas,
leiomy osarcomas, and plexosarcomas (274). The UK National Registry of Childhood
Tumours showed an annual incidence of 0.02 per million children below the age of 14 y ears
(275) representing about 1% of all GIST cases. GIST can occur sporadically or concurrently
with genetic sy ndromes, including familial GIST with germline KIT mutation,
neurofibromatosis ty pe 1, Carney triad and Carney –Stratakis sy ndrome. Multiple tumors are
frequently observed and regional recurrence rates are high in pediatric gastric GIST (276).
The most common sites of metastasis are liver, peritoneum and ly mph nodes.
Rhabdomy osarcoma, Hodgkin disease, malignant teratoma, GI stromal tumor, and nerve
sheath tumors also may occur in the stomach (277).
PULMONARY NEOPLASM
Epidemiology
Pulmonary neoplasms are unusual in the children and represent a wide spectrum of
pathology (278). An American study on patients 25 y ears of age has reported the relative
incidence of primary and metastatic lung tumors in children and adolescents through a single-
institution case series. A total of 204 pediatric lung tumors were diagnosed and analy zed.
About 83% were secondary lung lesions, 10% were benign lesions, and 7% were primary
malignant lesions.
Pathology
Adult lung cancers (adenocarcinoma, epidermoid carcinoma) are exceptional in childhood.
The most common primary lung malignancies in children are pleuropulmonary blastoma
(PPB) and carcinoid tumor and less frequent are peribronchial my ofibroblastic tumor and
other my ofibroblastic lesions, sarcomas (279), mesothelioma, and inflammatory
pseudotumor (plasma cell granuloma) of the bronchus. Metastatic lung tumors are relatively
common in children and also comprise a spectrum of cancers different from the adult
population (278,280).
Clinical Presentation
Sy mptoms are nonspecific: cough, fever, pulmonary infection, respiratory distress, weight
loss, pain, and hemopty sis (281).
Genetics
A constitutional genetic predisposition is suggested by the early age of diagnosis, the
association of PPB, and renal tumors (cy stic nephroma for instance), malignant germ cell
tumor, medulloblastoma, thy roid neoplasia together in patients and/or family members
(284,285). Recent data report a germline mutation in DICER1 is the genetic cause in the
majority of PPB cases (286).
Diagnosis
The median ages at diagnosis are 8–10, 34–35, and 41–44 months for ty pes I, II, and III,
respectively (International Pleuropulmonary Blastoma Registry, (286). The tumor equally
affects both genders. PPB in children aged <5 y ears is usually present as respiratory tract
infection or pneumothorax. PPB appears commonly as a solitary parenchy mal mass on
chest radiograph and CT (287). Large masses in the right hemithorax with heterogeneous low
attenuation, pleural effusion, contralateral mediastinal shift, lack of chest wall invasion (288),
and pneumothorax can be seen (289). Rarely, metastasis to central nervous sy stem, bones,
and liver can be seen in ty pe II and III PPB (290). A study on 39 patients showed that the
cumulative probability of cerebral metastasis by 5 y ears from diagnosis reached 11% for
ty pe II patients and 54% for ty pe III patients (291).
Treatment
Most cases are managed initially with surgery while total resection is associated with better
outcomes (292). However, the tumors often are large and locally extensive, making complete
surgical excision uncommon. Thoracic irradiation has been reported in case reports for the
postoperative treatment of patients with large tumors or positive margins (30–55 Gy ) with no
clear evidence of benefit (293). One should also consider RT for the treatment of local tumor
recurrence, where the situation is grim but not hopeless (294). Several reports describe the
need for combination chemotherapy for PPB without any consensus on the optimal regimen
(295,296). The agents that have been used are vincristine, actinomy cin D,
cy clophosphamide, doxorubicin, ifosfamide, etoposide, cisplatin, carboplatin, epirubicin,
methotrexate, and 5-fluorouracil. Recurrences after ty pe I PPB are usually advanced ty pes
II or III neoplasms with a poor prognosis. Salvage after ty pes II and III recurrence is poor
(about 40% in the best series).
Results
Despite the introduction of multimodal therapy (surgery, chemotherapy, and occasionally
RT), the prognosis for PPB patients remains poor. A report on 350 central pathology -
confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma
Registry showed the 5-y ear overall survival rate for ty pe I, II, and III patients were 91%,
71%, and 53%, respectively. All deaths in the group I were due to progression to ty pe II or III
(286). Almost all recurrences of this disease tend to occur within 24 months of diagnosis, and
with a few exceptions, within 36 months of diagnosis (297). Therefore, careful and strict
follow-up for 3 y ears is needed in patients with PPB. In terms of prognostic factors, the PPB
ty pe is the strongest predictor of outcome, as well as metastatic diseases (290,291). The
DICER1 germline mutation status does not seem to impact the outcome (286).
CARCINOID AND MUCOEPIDERMOID BRONCHIAL TUMORS
Endobronchial tumors are rare in children and often misdiagnosed. Although the true
incidence of this entity is unknown, bronchial adenomas alone may account for 5% of all
primary pulmonary neoplasms in children (298). The malignant lesions include bronchial
adenomas, carcinoids, MECs, and ACCs.
The most common endobronchial tumor in children and adolescents is carcinoid (281).
Carcinoid tumors can be divided into ty pical and aty pical forms with the latter exhibiting
histologically malignant features and aggressive clinical behavior. This histologic and clinical
distinction is not as clear in the pediatric age groups as it is in adults because of the limited
pediatric experience with this pathology (299). Because of the abundant vascularization,
endoscopic removal of these lesions can be hazardous and is not recommended. A
retrospective analy sis of all patients treated for a carcinoid or mucoepidermoid tumor in
France between 1984 and 2001 was performed to determine the characteristic features and
outcome of carcinoid or mucoepidermoid tumors in children (300). There were 11 cases of
carcinoid tumor and 6 cases of mucoepidermoid tumor. Twelve and six patients were
presented with evidence of bronchial obstruction and hemopty sis, respectively. Fiber-optic
bronchoscopy confirmed the presence of a bronchial tumor in all cases, and endobronchial
biopsies were diagnostic in 11 of 12 cases. Complete surgical resection (lobectomy in 15
patients and pneumonectomy in 2 patients) was performed in all cases without preoperative
chemotherapy or RT. With a mean follow-up of 4 y ears, no death was observed. In two
patients, auscultation asy mmetry and an episode of hemopty sis revealed the recurrence of a
mucoepidermoid tumor; a child was successfully cured by removal of the tumor and
chemotherapy and RT. The authors recommend a biopsy for diagnosis and a complete
surgical removal as treatment of choice. Long-term results are excellent in all the recent but
small series in childhood, but a long clinical follow-up is recommended (301,302).
NEOPLASMS OF THE PANCREAS
Primary neoplasms of the pancreas are rare in childhood. A retrospective review of the
Memorial Sloan Kettering Cancer center was undertaken of all patients less than 21 y ears of
age with malignant pancreatic tumors since 1967. Seventeen patients were identified mainly
with pancreatoblastoma (n = 5) and solid pseudopapillary tumor (n = 7), and more rarely
with acinar cell carcinoma, nonfunctioning pancreatic endocrine neoplasm, malignant
VIPoma, and PNET (303). Another more recent study has reported that malignant
pancreatic neoplasms were identified in 58 patients. They have reported an age- and
population-adjusted incidence of 0.021 (females) and 0.015 (males) per 100,000. Asians had
the highest incidence. Tumors were classified as exocrine in about half of the patients,
endocrine in one-third, or sarcomas in the rest (8%). Exocrine tumors included mainly
pancreatoblastoma and solid-cy stic tumor (SCT), less frequently ductal adenocarcinoma, and
acinar cell carcinoma. Ductal adenocarcinoma, SCT, acinar cell carcinoma, sarcomas, and
endocrine tumors were more common in children older than 10 y ears, whereas
pancreatoblastoma was more common in y ounger children. Almost half of the patients
presented with distant metastasis (304). Fourteen patients were also recently reported with
pediatric pancreatic tumors. Tumor ty pes were solid pseudopapillary neoplasm (n = 6),
insulinoma (n = 3), pancreatoblastoma (n = 1), congenital pancreatic cy st (n = 1), Burkitt
ly mphoma of the pancreas (n = 1) and metastatic lesions of other primary tumors (n = 2)
(305). In another study, 31 patients were identified with median age of 14.7 y ears (4–18
y ears). The most common histology was solid pseudopapillary tumor (71%), followed by
neuroendocrine tumors (13%), pancreatoblastoma (13%). %). On the whole, the prognosis is
good for pancreatic tumors in childhood. In the last described study, the overall 1- and 5-y ear
survival was 96% and 78%, respectively. Patients with pseudopapillary tumors have better
overall survival compared to patients with neuroendocrine tumors or pancreatoblastomas
(303,305,306).
PANCREATOBLASTOMA
Page 375Histology
Two components are seen: an epithelial component and a mesenchy matic component. It is
characterized by well-formed acinar areas along with squamoid corpuscles and zy mogen-
like granules. Because these organoid structures are similar to the pancreatic anlage,
pancreatoblastoma is thought to originate from pancreatic multipotential primordial cells
(307). Positive staining by periodic acid–Schiff, gamma-try psin, and gamma-keratin are
common (308). Elevated levels of alpha-fetoprotein (AFP) are seen in about two-thirds of
cases (309). AFP is also used in follow-up for the early diagnosis of relapse.
Diagnosis
The clinical sy mptomatology is often discrete, such as abdominal pain and/or intestinal transit
disturbances, and the revealing sign is usually the discovery of a voluminous abdominal mass
(310). Hy pogly cemia and jaundice can also be seen (309,311). Pancreatoblastoma is most
often located in the head or body of the pancreas but can be seen in any part of the pancreas.
It forms a full mass, rather well encapsulated, round and soft in consistency, often large in
size and that can develop bey ond the limits of the pancreatic gland. The most common
sy mptoms at presentation are abdominal pain, anorexia, and vomiting (305). Imaging
findings indicate usually a well-defined heterogeneous large mass in the pancreas or
mesentery. Pancreatoblastomas are heterogeneous and often multilocular with hy perechoic
and enhancing septa (312).
Treatment
Localized, nonmetastatic tumor that can be completely resected is generally cured by
surgery alone (311,313,314). An international study reported on 20 patients by the European
cooperative study group for pediatric rare tumors confirms the rarity of the disease, the
critical role of surgical resection both as therapy and as a prognostic parameter (315).
However, about 35% of patients present with metastases (mainly in the ly mph nodes, liver,
lungs and spleen) (310), and 50% die of tumor (303). A variety of chemotherapy programs
have been used to shrink unresectable tumors, to treat metastatic disease, or as adjuvant
therapy. There have been some notable successes in rendering unresectable tumors
resectable (303,307). The European cooperative study group for pediatric rare tumors
confirmed a response rate of 73% using chemotherapy before surgery (315). The
combination of cisplatin + adriamy cin seems to be the most effective neoadjuvant
chemotherapy regimen (310).
Local irradiation is indicated in case of incomplete resection or tumor spillage during
surgery since chemotherapy has not y et provided proven results in this context (310).
RT can also be discussed in case of relapse in patients naïve from previous RT. A dosage
of 40–50 Gy seems appropriate (309,307,313).
A variety of chemotherapy programs have been used to shrink unresectable tumors, to
treat metastatic disease, or as adjuvant therapy. There have been some notable successes in
rendering unresectable tumors resectable. Cy clophosphamide, vincristine, 5-FU, adriamy cin,
mitomy cin-C, cisplatin, etoposide, ifosfamide, actinomy cin D, bleomy cin, vinblastine, and
epirubicin have been used.
COLORECTAL MALIGNANCIES
Colorectal carcinoma (CRC) accounts for 2% of malignancies in adolescents and has been
reported in children as y oung as 9 months of age. In Japan, for example, one to three
pediatric colon carcinomas are identified annually (316). Based on the published reports,
which are small clinical trials or case reports, most CRC in children is sporadic (316,317).
Predisposing conditions include hereditary nonpoly posis colorectal cancer and familial
adenomatous poly posis (318). They also may occur as second malignant neoplasms after
treatment of childhood leukemia, rhabdomy osarcoma, Wilms tumor, or Hodgkin disease
(319). A sy stematic review was done recently on colorectal carcinoma diagnosed in the first
10 y ears of life (320). The mean age was 8.6 y ears and tumors were located in the rectum
and sigmoid in about 45% of the cases. More than 85% were adenocarcinomas.
Carcinomas of the colon and rectum in childhood present with pain, vomiting, anemia, a
palpable mass, hematochezia, diarrhea, or constipation (316,317). Because of the lack of
specificity of the sy mptoms and the rarity of the disease, the possibility of a child having
colorectal carcinoma is rarely considered, and the interval between clinical complaints and
diagnosis often is long (317,321). The median of latency of sy mptoms was 4–48 months in a
recent publication (71). As a consequence, involvement of regional ly mph nodes, distant
metastases, and inoperability are common in children (317).
Page 376The survival was poor in a recent review from Da Costa Vieira et al., about
15% at 5 y ears due to advanced stages at diagnosis (71,320). This is attributed to a delay in
diagnosis resulting in more advanced disease.
As a result of its rarity in children and the lack of prospective pediatric studies,
recommendations for therapy are primarily extrapolated from adult clinical trials. Complete
surgical resection with aggressive ly mph node dissection is essential for cure, and
neoadjuvant chemotherapy may be used in an effort to render unresectable lesions
resectable. In a study on 76 patients under 25 y ears with a CRC, overall survival significantly
increased in patients undergoing curative surgery. Other significant parameters on survival
were stage of disease, response to palliative chemotherapy in metastatic patients, and
postoperative adjuvant chemotherapy (72). Active agents in adults with CRC include FU,
folinic acid (leucovorin), oxaliplatin, and irinotecan. Furthermore, newer targeted therapeutic
agents, such as bevacizumab and cetuximab, have added additional efficacy to the standard
chemotherapy backbone but no trials have been done in pediatric population till now.
BREAST CANCER
Malignant lesions of the breast in children are rare and represent 0.08/100,000 cases. The
most common form of breast cancer occurring in y oung girls (or boy s rarely ) is juvenile
secretory carcinoma. Approximately 100 cases have been reported (73). The malignant cells
are characterized by abundant secretion of mucin and mucopoly saccharide-containing
materials (322,323). A unique pathologic feature is the presence of a thick-walled capsule that
is thought to be caused by a desmoplastic reaction around the tumor. This may be responsible
for its cy stic appearance on ultrasound (76). Surgery is the treatment of choice but there is
little consensus, however, about the extent of surgery. A sufficient number of case reports of
local recurrence suggest that local excision alone may not constitute adequate therapy, and
mastectomy has been advocated as standard treatment (324,325). Richard et al. reported a
literature review of 33 pediatric cases with a long follow-up. About 33% of the patients
treated by less than simple mastectomy demonstrated local recurrent disease (325). Sentinel
ly mph node biopsy seems to offer an interesting approach to explore the axillary ly mphatic
basin with a lower complication rate than formal dissection and is recommended by some
authors (326). For others, mastectomy with sentinel ly mph node biopsy or axillary ly mph
node dissection is recommended in any male case due to more relapses (316). The prognosis
is excellent in this benign tumor, and no RT or chemotherapy is generally necessary. There is
minimal experience with lumpectomy and RT.
Primary breast carcinoma is exceedingly rare in the pediatric age group. Less than 1%
occurs before the age of 30 y ears and less than 0.1/100,000 occurs before the age of 20
y ears. Infiltrating ductal, lobular, medullary, and inflammatory carcinomas have been
reported in y oung girls. Young women tend to have a more aggressive disease, hormonal
receptor negative and grade 3 lesions. Patients undergoing mastectomy have the same rate
for local recurrence as older women compared to a breast conservative surgery (317). With
almost no data available in children, we would be cautious about vary ing from the principles
of clinical management set by adult oncology (327). Seventy -five cases of teenage primary
breast carcinoma have been reviewed by Gutierrez et al. between 1973 and 2004: 55% were
carcinomas and 45% were sarcomas. In the carcinoma group, regionally advanced disease
was present in 11 patients (26.8%), whereas only 3 patients (7.3%) presented with metastatic
disease. All patients with sarcomatous tumors presented with localized disease. Ductal
carcinoma end phy llode sarcomas were the most frequent histology. Adjuvant RT was
administered in only 9.8% of carcinomas and 8.8% of sarcomas. About 85.4% of carcinoma
patients and 97.1% of sarcoma patients underwent surgical resection for their primary
disease. Subgroup analy sis revealed 5- and 10-y ear survival rates of 89.6% for patients with
sarcomatous tumors and 63.1% and 54.3% for carcinomas (318).
There have been case reports of primary non-Hodgkin ly mphoma, rhabdomy osarcoma,
ACC, radiation-induced spindle cell sarcoma, and cy stosarcoma phy llodes of the breast in
children (319,322,323,328). Reported breast metastases in children include hepatocarcinoma,
non-Hodgkin ly mphoma, rhabdomy osarcoma, Hodgkin disease, neuroblastoma, and
adenocarcinoma (181).
REFERENCES
1. Bradley EL. Primary and adjunctive therapy in carcinoma of the adrenal cortex. Surg
Gynecol Obstet. 1975;141(4):507–516.
2. Dackiw AP, Lee JE, Gagel RF, et al. Adrenal cortical carcinoma. World J Surg.
2001;25(7):914–926.
3. Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and
results of a 253-patient series from the French Association of Endocrine Surgeons study
group. World J Surg. 2001;25(7):891–897.
4. Michalkiewicz E, Sandrini R, Figueiredo B, et al. Clinical and outcome characteristics of
children with adrenocortical tumors: a report from the International Pediatric
Adrenocortical Tumor Registry. J Clin Oncol. 2004;22(5):838–845.
5. Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin
Endocrinol Metab. 1997;82(7):2027–2031.
6. Kerkhofs TMA, Ettaieb MHT, Verhoeven RHA, et al. Adrenocortical carcinoma in
children: first population-based clinicopathological study with long-term follow-up.
Oncol Rep. 2014;32(6):2836–2844.
7. Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer.
2004;40(8):1117–1126.
8. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al. Prevalence and functional
consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children’s
oncology group study. J Clin Oncol. 2015;33(6):602–609.
9. Custódio G, Parise GA, Kiesel Filho N, et al. Impact of neonatal screening and
surveillance for the TP53 R337H mutation on early detection of childhood
adrenocortical tumors. J Clin Oncol. 2013;31(20):2619–2626.
10. Stojadinovic A, Brennan MF, Hoos A, et al. Adrenocortical adenoma and carcinoma:
histopathological and molecular comparative analy sis. Mod Pathol. 2003;16(8):742–751.
11. Page 377 Magee BJ, Gattamaneni HR, Pearson D. Adrenal cortical carcinoma: survival
after radiotherapy. Clin Radiol. 1987;38(6):587–588.
12. Vierhapper H. Adrenocortical tumors: clinical sy mptoms and biochemical diagnosis. Eur
J Radiol. 2002;41(2):88–94.
13. Beuschlein F, Weigel J, Saeger W, et al. Major prognostic role of Ki67 in localized
adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab.
2015;100(3):841–849.
14. Ahmed M, Al-Sugair A, Alarifi A, et al. Whole-body positron emission tomographic
scanning in patients with adrenal cortical carcinoma: comparison with conventional
imaging procedures. Clin Nucl Med. 2003;28(6):494–497.
15. Mihai R. Diagnosis, treatment and outcome of adrenocortical cancer. Br J Surg.
2015;102(4):291–306.
16. Zancanella P, Pianovski MAD, Oliveira BH, et al. Mitotane associated with cisplatin,
etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane
monitoring and tumor regression. J Pediatr Hematol Oncol. 2006;28(8):513–524.
17. Percarpio B, Knowlton AH. Radiation therapy of adrenal cortical carcinoma. Acta
Radiol Ther Phys Biol. 1976;15(4):288–292.
18. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with
mitotane and a review of the literature. Cancer. 1993;72(11):3145–3155.
19. Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal
cancer: recommendations of an international consensus conference. Endocr Relat
Cancer. 2005;12(3):667–680.
20. Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor
bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab.
2006;91(11):4501–4504.
21. Sabolch A, Else T, Griffith KA, et al. Adjuvant radiation therapy improves local control
after surgical resection in patients with localized adrenocortical carcinoma. Int J Radiat
Oncol Biol Phys. 2015;92(2):252–259.
22. Sabolch A, Feng M, Griffith K, et al. Adjuvant and definitive radiotherapy for
adrenocortical carcinoma. Int J Radiat Oncol Biol Phys. 2011;80(5):1477–1484.
23. McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediatric adrenocortical
carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J
Pediatr Surg. 2013;48(5):1025–1031.
24. Newman KD, Ponsky T. The diagnosis and management of endocrine tumors causing
hy pertension in children. Ann N Y Acad Sci. 2002;970:155–158.
25. Caty MG, Coran AG, Geagen M, et al. Current diagnosis and treatment of
pheochromocy toma in children. Experience with 22 consecutive tumors in 14 patients.
Arch Surg. 1990;125(8):978–981.
26. Miller KA, Albanese C, Harrison M, et al. Experience with laparoscopic adrenalectomy
in pediatric patients. J Pediatr Surg. 2002;37(7):979–982; discussion 979–982.
27. DeLellis RA, Lloy d RV, Heitz PU, et al. WHO Classification of Tumours, Pathology and
Genetics of Tumours of Endocrine Organs. Ly on, France: IARC Press; 2004.
28. Ezzat Abdel-Aziz T, Prete F, Conway G, et al. Phaeochromocy tomas and
paragangliomas: a difference in disease behaviour and clinical outcomes. J Surg Oncol.
2015;112(5):486–491.
29. Adler JT, Mey er-Rochow GY, Chen H, et al. Pheochromocy toma: current approaches
and future directions. Oncologist. 2008;13(7):779–793.
30. Basu S, Nair N. Stable disease and improved health-related quality of life (HRQoL)
following fractionated low dose 131I-metaiodobenzy lguanidine (MIBG) therapy in
metastatic paediatric paraganglioma: observation on false “reverse” discordance during
pre-therapy work up and its implication for patient selection for high dose targeted
therapy. Br J Radiol. 2006;79(944):e53–e58.
31. Ciftci AO, Tany el FC, Senocak ME, et al. Pheochromocy toma in children. J Pediatr
Surg. 2001;36(3):447–452.
32. De Krijger RR, Petri B-J, Van Nederveen FH, et al. Frequent genetic changes in
childhood pheochromocy tomas. Ann N Y Acad Sci. 2006;1073:166–176.
33. Pacak K, Eisenhofer G. An assessment of biochemical tests for the diagnosis of
pheochromocy toma. Nat Clin Pract Endocrinol Metab. 2007;3(11):744–745.
34. Gimenez-Roqueplo A-P, Lehnert H, Mannelli M, et al. Phaeochromocy toma, new genes
and screening strategies. Clin Endocrinol (Oxf). 2006;65(6):699–705.
35. Neumann HPH, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsy ndromic
pheochromocy toma. N Engl J Med. 2002;346(19):1459–1466.
36. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocy toma or functional
paraganglioma. J Clin Oncol. 2005;23(34):8812–8818.
37. Garnier S, Réguerre Y, Orbach D, et al. [Pediatric pheochromocy toma and
paraganglioma: an update]. Bull Cancer. 2014;101(10):966–975.
38. Ludwig AD, Feig DI, Brandt ML, et al. Recent advances in the diagnosis and treatment
of pheochromocy toma in children. Am J Surg. 2007;194(6):792–796; discussion 796–
797.
39. Hoegerle S, Nitzsche E, Altehoefer C, et al. Pheochromocy tomas: detection with 18F
DOPA whole body PET—initial results. Radiology. 2002;222(2):507–512.
40. Kaji P, Carrasquillo JA, Linehan WM, et al. The role of 6-[18F]fluorodopamine positron
emission tomography in the localization of adrenal pheochromocy toma associated with
von Hippel–Lindau sy ndrome. Eur J Endocrinol. 2007;156(4):483–487.
41. Volkin D, Yerram N, Ahmed F, et al. Partial adrenalectomy minimizes the need for long-
term hormone replacement in pediatric patients with pheochromocy toma and von
Hippel–Lindau sy ndrome. J Pediatr Surg. 2012;47(11):2077–2082.
42. Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocy toma: effective
treatment with a combination of cy clophosphamide, vincristine, and dacarbazine. Ann
Intern Med. 1988;109(4):267–273.
43. Vogel J, Atanacio AS, Prodanov T, et al. External beam radiation therapy in treatment of
malignant pheochromocy toma and paraganglioma. Front Oncol. 2014;4:166.
44. Yu L, Fleckman AM, Chadha M, et al. Radiation therapy of metastatic
pheochromocy toma: case report and review of the literature. Am J Clin Oncol.
1996;19(4):389–393.
45. van Hulsteijn LT, Niemeijer ND, Dekkers OM, et al. (131)I-MIBG therapy for malignant
paraganglioma and phaeochromocy toma: sy stematic review and meta-analy sis. Clin
Endocrinol (Oxf). 2014;80(4):487–501.
46. Loh KC, Fitzgerald PA, Matthay KK, et al. The treatment of malignant
pheochromocy toma with iodine-131 metaiodobenzy lguanidine (131I-MIBG): a
comprehensive review of 116 reported patients. J Endocrinol Invest. 1997;20(11):648–
658.
47. Bomanji JB, Wong W, Gaze MN, et al. Treatment of neuroendocrine tumours in adults
with 131I-MIBG therapy. Clin Oncol (R Coll Radiol). 2003;15(4):193–198.
48. Yoshinaga K, Oriuchi N, Wakabay ashi H, et al. Effects and safety of 131I-
metaiodobenzy lguanidine (MIBG) radiotherapy in malignant neuroendocrine tumors:
results from a multicenter observational registry. Endocr J. 2014;61(12):1171–1180.
49. Coutant R, Pein F, Adamsbaum C, et al. Prognosis of children with malignant
pheochromocy toma. Report of 2 cases and review of the literature. Horm Res.
1999;52(3):145–149.
50. Al Nofal A, Gionfriddo MR, Javed A, et al. Accuracy of thy roid nodule sonography for
the detection of thy roid cancer in children: sy stematic review and meta-analy sis. Clin
Endocrinol (Oxf). 2016;84(3):423–430.
51. Collini P, Mattavelli F, Pellegrinelli A, et al. Papillary carcinoma of the thy roid gland of
childhood and adolescence: Morphologic subty pes, biologic behavior and prognosis: a
clinicopathologic study of 42 sporadic cases treated at a single institution during a 30-
y ear period. Am J Surg Pathol. 2006;30(11):1420–1426.
52. Jarzab B, Handkiewicz Junak D, Włoch J, et al. Multivariate analy sis of prognostic factors
for differentiated thy roid carcinoma in children. Eur J Nucl Med. 2000;27(7):833–841.
53. Schlumberger M, Pacini F, Wiersinga WM, et al. Follow-up and management of
differentiated thy roid carcinoma: a European perspective in clinical practice. Eur J
Endocrinol. 2004;151(5):539–548.
54. Alzahrani AS, Alkhafaji D, Tuli M, et al. Comparison of differentiated thy roid cancer in
children and adolescents (≤20 y ears) with y oung adults. Clin Endocrinol (Oxf).
2016;84:571–577.
55. Silva-Vieira M, Santos R, Leite V, et al. Review of clinical and pathological features of 93
cases of well-differentiated thy roid carcinoma in pediatric age at the Lisbon Centre of
the Portuguese Institute of Oncology between 1964 and 2006. Int J Pediatr
Otorhinolaryngol. 2015;79(8):1324–1329.
56. Mussa A, De Andrea M, Motta M, et al. Predictors of malignancy in children with
thy roid nodules. J Pediatr. 2015;167(4):886.e1–892.e1.
57. Anne S, Teot LA, Mandell DL. Fine needle aspiration biopsy : role in diagnosis of
pediatric head and neck masses. Int J Pediatr Otorhinolaryngol. 2008;72(10):1547–1553.
58. Page 378 Klugbauer S, Lengfelder E, Demidchik EP, et al. High prevalence of RET
rearrangement in thy roid tumors of children from Belarus after the Chernoby l reactor
accident. Oncogene. 1995;11(12):2459-67.
59. Dinauer CA, Breuer C, Rivkees SA. Differentiated thy roid cancer in children: diagnosis
and management. Curr Opin Oncol. 2008;20(1):59–65.
60. Francis GL, Waguespack SG, Bauer AJ, et al. Management guidelines for children with
thy roid nodules and differentiated thy roid cancer. Thyroid. 2015;25(7):716–759.
61. Gingalewski CA, Newman KD. Seminars: controversies in the management of pediatric
thy roid malignancy. J Surg Oncol. 2006;94(8):748–752.
62. La Quaglia MP, Black T, Holcomb GW, et al. Differentiated thy roid cancer: clinical
characteristics, treatment, and outcome in patients under 21 y ears of age who present
with distant metastases—a report from the Surgical Discipline Committee of the
Children’s Cancer Group. J Pediatr Surg. 2000;35(6):955–959; discussion 960.
63. Kundel A, Thompson GB, Richards ML, et al. Pediatric endocrine surgery : a 20-y ear
experience at the May o Clinic. J Clin Endocrinol Metab. 2014;99(2):399–406.
64. Chow S-M, Law SCK, Mendenhall WM, et al. Differentiated thy roid carcinoma in
childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer.
2004;42(2):176–183.
65. Jarzab B, Handkiewicz-Junak D, Wloch J. Juvenile differentiated thy roid carcinoma and
the role of radioiodine in its treatment: a qualitative review. Endocr Relat Cancer.
2005;12(4):773–803.
66. Brown AP, Chen J, Hitchcock YJ, et al. The risk of second primary malignancies up to
three decades after the treatment of differentiated thy roid cancer. J Clin Endocrinol
Metab. 2008;93(2):504–515.
67. Kim T-H, Yang D-S, Jung K-Y, et al. Value of external irradiation for locally advanced
papillary thy roid cancer. Int J Radiat Oncol Biol Phys. 2003;55(4):1006–1012.
68. Gatta G, Capocaccia R, Stiller C, et al. Childhood cancer survival trends in Europe: a
EUROCARE Working Group study. J Clin Oncol. 2005;23(16):3742–3751.
69. Steliarova-Foucher E, Stiller CA, Pukkala E, et al. Thy roid cancer incidence and survival
among European children and adolescents (1978–1997): report from the Automated
childhood cancer information sy stem project. Eur J Cancer. 2006;42(13):2150–2169.
70. Sugino K, Nagahama M, Kitagawa W, et al. Papillary thy roid carcinoma in children and
adolescents: long-term follow-up and clinical characteristics. World J Surg.
2015;39(9):2259–2265.
71. Gong J, Zhang R, Chen H. [Childhood thy roid carcinoma: an analy sis of 14 cases].
Zhonghua Zhong Liu Za Zhi. 2000;22(4):324–326.
72. Harness JK, Thompson NW, McLeod MK, et al. Differentiated thy roid carcinoma in
children and adolescents. World J Surg. 1992;16(4):547–553; discussion 553–554.
73. Samuel AM, Sharma SM. Differentiated thy roid carcinomas in children and adolescents.
Cancer. 1991;67(8):2186–2190.
74. Zimmerman D, Hay ID, Gough IR, et al. Papillary thy roid carcinoma in children and
adults: long-term follow-up of 1039 patients conservatively treated at one institution
during three decades. Surgery. 1988;104(6):1157–1166.
75. Ceccarelli C, Pacini F, Lippi F, et al. Thy roid cancer in children and adolescents. Surgery.
1988;104(6):1143–1148.
76. Schlumberger M, De Vathaire F, Travagli JP, et al. Differentiated thy roid carcinoma in
childhood: long term follow-up of 72 patients. J Clin Endocrinol Metab. 1987;65(6):1088–
1094.
77. Giuffrida D, Scollo C, Pellegriti G, et al. Differentiated thy roid cancer in children and
adolescents. J Endocrinol Invest. 2002;25(1):18–24.
78. Robison LL. Treatment-associated subsequent neoplasms among long-term survivors of
childhood cancer: the experience of the Childhood Cancer Survivor Study. Pediatr
Radiol. 2009;39(suppl 1):S32–S37.
79. Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thy roid cancer after a first
tumour in childhood (the Childhood Cancer Survivor Study ): a nested case-control study.
Lancet (London, England). 2005;365(9476):2014–2023.
80. Dörffel W, Riepenhausenl M, Lüders H, et al. Secondary malignancies following
treatment for Hodgkin’s Ly mphoma in childhood and adolescence. Dtsch Arztebl Int.
2015;112(18):320–327.
81. Brignardello E, Corrias A, Isolato G, et al. Ultrasound screening for thy roid carcinoma in
childhood cancer survivors: a case series. J Clin Endocrinol Metab. 2008;93(12):4840–
4843.
82. Tuttle RM, Vaisman F, Tronko MD. Clinical presentation and clinical outcomes in
Chernoby l-related paediatric thy roid cancers: what do we know now? What can we
expect in the future? Clin Oncol (R Coll Radiol). 2011;23(4):268–275.
83. Pacini F, Vorontsova T, Demidchik EP, et al. Post-Chernoby l thy roid carcinoma in
Belarus children and adolescents: comparison with naturally occurring thy roid
carcinoma in Italy and France. J Clin Endocrinol Metab. 1997;82(11):3563–3569.
84. Akulevich NM, Saenko VA, Rogounovitch TI, et al. Poly morphisms of DNA damage
response genes in radiation-related and sporadic papillary thy roid carcinoma. Endocr
Relat Cancer. 2009;16(2):491–503.
85. Schlumberger M, Carlomagno F, Baudin E, et al. New therapeutic approaches to treat
medullary thy roid carcinoma. Nat Clin Pract Endocrinol Metab. 2008;4(1):22–32.
86. Raue F, Frank-Raue K. Genoty pe-phenoty pe relationship in multiple endocrine neoplasia
ty pe 2. Implications for clinical management. Hormones (Athens). 2015;8(1):23–28.
87. Viola D, Romei C, Elisei R. Medullary thy roid carcinoma in children. Endocr Dev.
2014;26:202–213.
88. Berdelou A, Hartl D, Al Ghuzlan A, et al. [Medullary thy roid carcinoma in children].
Bull Cancer. 2013;100(7–8):780–788.
89. Fialkowski EA, Moley JF. Current approaches to medullary thy roid carcinoma, sporadic
and familial. J Surg Oncol. 2006;94(8):737–747.
90. Fox E, Widemann BC, Chuk MK, et al. Vandetanib in children and adolescents with
multiple endocrine neoplasia ty pe 2B associated medullary thy roid carcinoma. Clin
Cancer Res. 2013;19(15):4239–4248.
91. Bales C, Kotapka M, Loevner LA, et al. Craniofacial resection of advanced juvenile
nasophary ngeal angiofibroma. Arch Otolaryngol Head Neck Surg. 2002;128(9):1071–
1078.
92. McAfee WJ, Morris CG, Amdur RJ, et al. Definitive radiotherapy for juvenile
nasophary ngeal angiofibroma. Am J Clin Oncol. 2006;29(2):168–170.
93. Roger G, Tran Ba Huy P, Froehlich P, et al. Exclusively endoscopic removal of juvenile
nasophary ngeal angiofibroma: trends and limits. Arch Otolaryngol Head Neck Surg.
2002;128(8):928–935.
94. Schiff M. Juvenile nasophary ngeal angiofibroma. a theory of pathogenesis.
Laryngoscope. 1959;69:981–1016.
95. Iannetti G, Belli E, De Ponte F, et al. The surgical approaches to nasophary ngeal
angiofibroma. J Craniomaxillofac Surg. 1994;22(5):311–316.
96. Tewfik TL, Tan AK, al Noury K, et al. Juvenile nasophary ngeal angiofibroma. J
Otolaryngol. 1999;28(3):145–151.
97. Barnés CM, Huang S, Kaipainen A, et al. Evidence by molecular profiling for a
placental origin of infantile hemangioma. Proc Natl Acad Sci U S A.
2005;102(52):19097–19102.
98. Vikkula M, Boon LM, Mulliken JB, et al. Molecular basis of vascular anomalies. Trends
Cardiovasc Med. 1998;8(7):281–292.
99. Say lam G, Yücel OT, Sungur A, et al. Proliferation, angiogenesis and hormonal markers
in juvenile nasophary ngeal angiofibroma. Int J Pediatr Otorhinolaryngol.
2006;70(2):227–234.
100. Dillard DG, Cohen C, Muller S, et al. Immunolocalization of activated transforming
growth factor beta1 in juvenile nasophary ngeal angiofibroma. Arch Otolaryngol Head
Neck Surg. 2000;126(6):723–725.
101. Robinson AC, Khoury GG, Ash DV, et al. Evaluation of response following irradiation of
juvenile angiofibromas. Br J Radiol. 1989;62(735):245–247.
102. Roche P-H, Paris J, Régis J, et al. Management of invasive juvenile nasophary ngeal
angiofibromas: the role of a multimodality approach. Neurosurgery. 2007;61(4):768–
777; discussion 777.
103. Lloy d G, Howard D, Lund VJ, et al. Imaging for juvenile angiofibroma. J Laryngol Otol.
2000;114(9):727–730.
104. Herman P, Lot G, Chapot R, et al. Long-term follow-up of juvenile nasophary ngeal
angiofibromas: analy sis of recurrences. Laryngoscope. 1999;109(1):140–147.
105. Chagnaud C, Petit P, Bartoli J, et al. Postoperative follow-up of juvenile nasophary ngeal
angiofibromas: assessment by CT scan and MR imaging. Eur Radiol. 1998;8(5):756–764.
106. Howard DJ, Lloy d G, Lund V. Recurrence and its avoidance in juvenile angiofibroma.
Laryngoscope. 2001;111(9):1509–1511.
107. McCombe A, Lund VJ, Howard DJ. Recurrence in juvenile angiofibroma. Rhinology.
1990;28(2):97–102.
108. Page 379 Carrillo JF, Maldonado F, Albores O, et al. Juvenile nasophary ngeal
angiofibroma: clinical factors associated with recurrence, and proposal of a staging
sy stem. J Surg Oncol. 2008;98(2):75–80.
109. Radkowski D, McGill T, Healy GB, et al. Angiofibroma. Changes in staging and
treatment. Arch Otolaryngol Head Neck Surg. 1996;122(2):122–129.
110. Yi Z, Fang Z, Lin G, et al. Nasophary ngeal angiofibroma: a concise classification sy stem
and appropriate treatment options. Am J Otolaryngol. 2013;34(2):133–141.
111. Leong SC. A sy stematic review of surgical outcomes for advanced juvenile
nasophary ngeal angiofibroma with intracranial involvement. Laryngoscope.
2013;123(5):1125–1131.
112. Ward PH, Thompson R, Calcaterra T, et al. Juvenile angiofibroma: a more rational
therapeutic approach based upon clinical and experimental evidence. Laryngoscope.
1974;84(12):2181–2194.
113. Álvarez FL, Suárez V, Suárez C, et al. Multimodality approach for advanced-stage
juvenile nasophary ngeal angiofibromas. Head Neck. 2013;35(2):209–213.
114. Gates GA, Rice DH, Koopmann CF, et al. Flutamide-induced regression of
angiofibroma. Laryngoscope. 1992;102(6):641–644.
115. Pry or SG, Moore EJ, Kasperbauer JL. Endoscopic versus traditional approaches for
excision of juvenile nasophary ngeal angiofibroma. Laryngoscope. 2005;115(7):1201–
1207.
116. Garofalo P, Pia F, Policarpo M, et al. Juvenile nasophary ngeal angiofibroma:
comparison between endoscopic and open operative approaches. J Craniofac Surg.
2015;26(3):918–821.
117. Khoueir N, Nicolas N, Rohay em Z, et al. Exclusive endoscopic resection of juvenile
nasophary ngeal angiofibroma: a sy stematic review of the literature. Otolaryngol Head
Neck Surg. 2014;150(3):350–358.
118. Ungkanont K, By ers RM, Weber RS, et al. Juvenile nasophary ngeal angiofibroma: an
update of therapeutic management. Head Neck. 1996;18(1):60–66.
119. Goepfert H, Cangir A, Lee YY. Chemotherapy for aggressive juvenile nasophary ngeal
angiofibroma. Arch Otolaryngol. 1985;111(5):285–289.
120. Labra A, Chavolla-Magaña R, Lopez-Ugalde A, et al. Flutamide as a preoperative
treatment in juvenile angiofibroma (JA) with intracranial invasion: report of 7 cases.
Otolaryngol Head Neck Surg. 2004;130(4):466–469.
121. Thakar A, Gupta G, Bhalla AS, et al. Adjuvant therapy with flutamide for presurgical
volume reduction in juvenile nasophary ngeal angiofibroma. Head Neck.
2011;33(12):1747–1753.
122. Reddy KA, Mendenhall WM, Amdur RJ, et al. Long-term results of radiation therapy
for juvenile nasophary ngeal angiofibroma. Am J Otolaryngol.2001;22(3):172–175.
123. Lee JT, Chen P, Safa A, et al. The role of radiation in the treatment of advanced juvenile
angiofibroma. Laryngoscope. 2002;112(7 Pt 1):1213–1220.
124. Mallick S, Benson R, Bhasker S, et al. Long-term treatment outcomes of juvenile
nasophary ngeal angiofibroma treated with radiotherapy. Acta Otorhinolaryngol Ital.
2015;35(2):75–79.
125. Amdur RJ, Yeung AR, Fitzgerald BM, et al. Radiotherapy for juvenile nasophary ngeal
angiofibroma. Pract Radiat Oncol. 2011;1(4):271-8.
126. Economou TS, Abemay or E, Ward PH. Juvenile nasophary ngeal angiofibroma: an
update of the UCLA experience, 1960–1985. Laryngoscope. 1988;98(2):170–175.
127. Gullane PJ, Davidson J, O’Dwy er T, et al. Juvenile angiofibroma: a review of the
literature and a case series report. Laryngoscope. 1992;102(8):928–933.
128. Cummings BJ. Relative risk factors in the treatment of juvenile nasophary ngeal
angiofibroma. Head Neck Surg. 1980;3(1):21–26.
129. Chakraborty S, Ghoshal S, Patil VM, et al. Conformal radiotherapy in the treatment of
advanced juvenile nasophary ngeal angiofibroma with intracranial extension: an
institutional experience. Int J Radiat Oncol Biol Phys. 2011;80(5):1398–1404.
130. Kuppersmith RB, Teh BS, Donovan DT, et al. The use of intensity modulated
radiotherapy for the treatment of extensive and recurrent juvenile angiofibroma. Int J
Pediatr Otorhinolaryngol. 2000;52(3):261–268.
131. Wolden SL, Steinherz PG, Kraus DH, et al. Improved long-term survival with combined
modality therapy for pediatric nasophary nx cancer. Int J Radiat Oncol Biol Phys.
2000;46(4):859–864.
132. Uzel O, Yörük SO, Sahinler I, et al. Nasophary ngeal carcinoma in childhood: long-term
results of 32 patients. Radiother Oncol. 2001;58(2):137–141.
133. Desandes E, Clavel J, Berger C, et al. Cancer incidence among children in France, 1990–
1999. Pediatr Blood Cancer. 2004;43(7):749–757.
134. Boussen H, Bouaouina N, Daldoul O, et al. [Update on medical therapies of
nasophary ngeal carcinomas]. Bull Cancer. 2010;97(4):417–426.
135. Ay an I, Altun M. Nasophary ngeal carcinoma in children: retrospective review of 50
patients. Int J Radiat Oncol Biol Phys. 1996;35(3):485–492.
136. Vokes EE, Liebowitz DN, Weichselbaum RR. Nasophary ngeal carcinoma. Lancet
(London, England). 1997;350(9084):1087–1091.
137. Cvitkovic E, Bachouchi M, Armand JP. Nasophary ngeal carcinoma: biology, natural
history, and therapeutic implications. Hematol Oncol Clin North Am. 1991;5(4):821–838.
138. Pua KC, Khoo ASB, Yap YY, et al. Nasophary ngeal Carcinoma Database. Med J
Malaysia. 2008;63(suppl C):59–62.
139. Bogger-Goren S, Gotlieb-Stematsky T, Rachima M, et al. Nasophary ngeal carcinoma in
Israel: epidemiology and Epstein–Barr virus-related serology. Eur J Cancer Clin Oncol.
1987;23(9):1277–1281.
140. Bar-Sela G, Kuten A, Minkov I, et al. Prevalence and relevance of EBV latency in
nasophary ngeal carcinoma in Israel. J Clin Pathol. 2004;57(3):290–293.
141. Vogl T, Dresel S, Bilaniuk LT, et al. Tumors of the nasophary nx and adjacent areas: MR
imaging with Gd-DTPA. AJNR Am J Neuroradiol.1990;11(1):187–194.
142. Yabuuchi H, Fukuy a T, Muray ama S, et al. CT and MR features of nasophary ngeal
carcinoma in children and y oung adults. Clin Radiol. 2002;57(3):205–210.
143. Liu F-Y, Lin C-Y, Chang JT, et al. 18F-FDG PET can replace conventional work-up in
primary M staging of nonkeratinizing nasophary ngeal carcinoma. J Nucl Med.
2007;48(10):1614–1619.
144. Cheuk DKL, Sabin ND, Hossain M, et al. PET/CT for staging and follow-up of pediatric
nasophary ngeal carcinoma. Eur J Nucl Med Mol Imaging. 2012;39(7):1097–1106.
145. Sanguineti G, Bossi P, Pou A, et al. Timing of chemoradiotherapy and patient selection
for locally advanced nasophary ngeal carcinoma. Clin Oncol (R Coll Radiol).
2003;15(8):451–460.
146. Laskar S, Sanghavi V, Muckaden MA, et al. Nasophary ngeal carcinoma in children: ten
y ears’ experience at the Tata Memorial Hospital, Mumbai. Int J Radiat Oncol Biol Phys.
2004;58(1):189–195.
147. Fleming ID, Cooper JS, Henson DE, eds. AJCC Cancer Staging Manual. 5th ed.
Philadelphia, PA: Lippincott-Raven; 1997.
148. Ho JH. Stage classification of nasophary ngeal carcinoma: a review. IARC Sci Publ.
1978;(20):99–113.
149. Chua DTT, Sham JST, Kwong DLW, et al. Treatment outcome after radiotherapy alone
for patients with Stage I-II nasophary ngeal carcinoma. Cancer. 2003;98(1):74–80.
150. Chua DT, Sham JS, Choy D, et al. Preliminary report of the Asian-Oceanian Clinical
Oncology Association randomized trial comparing cisplatin and epirubicin followed by
radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally
advanced nasophary ngeal carcinom. Cancer. 1998;83(11):2270–2283.
151. Ma J, Mai HQ, Hong MH, et al. Results of a prospective randomized trial comparing
neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with
locoregionally advanced nasophary ngeal carcinoma. J Clin Oncol. 2001;19(5):1350–
1307.
152. Harey ama M, Sakata K, Shirato H, et al. A prospective, randomized trial comparing
neoadjuvant chemotherapy with radiotherapy alone in patients with advanced
nasophary ngeal carcinoma. Cancer. 2002;94(8):2217–2223.
153. Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advanced nasophary ngeal
carcinoma: an individual patient data meta-analy sis of eight randomized trials and 1753
patients. Int J Radiat Oncol Biol Phys. 2006;64(1):47–56.
154. Guigay J, Temam S, Bourhis J, et al. Nasophary ngeal carcinoma and therapeutic
management: the place of chemotherapy. Ann Oncol. 2006;17(suppl 1):x304–x307.
155. Venkitaraman R, Ramanan SG, Sagar TG. Nasophary ngeal cancer of childhood and
adolescence: a single institution experience. Pediatr Hematol Oncol.2007;24(7):493–502.
156. Page 380 Berberoğlu S, Ilhan I, Cetindağ F, et al. Nasophary ngeal carcinoma in Turkish
children: review of 33 cases. Pediatr Hematol Oncol. 2001;18(5):309–315.
157. Ozy ar E, Selek U, Laskar S, et al. Treatment results of 165 pediatric patients with non-
metastatic nasophary ngeal carcinoma: a Rare Cancer Network study. Radiother Oncol.
2006;81(1):39–46.
158. Chan ATC, Ma BBY, Lo YMD, et al. Phase II study of neoadjuvant carboplatin and
paclitaxel followed by radiotherapy and concurrent cisplatin in patients with
locoregionally advanced nasophary ngeal carcinoma: therapeutic monitoring with
plasma Epstein–Barr virus DNA. J Clin Oncol. 2004;22(15):3053–3060.
159. Ma BBY, Chan ATC. Recent perspectives in the role of chemotherapy in the
management of advanced nasophary ngeal carcinoma. Cancer. 2005;103(1):22–31.
160. Rischin D, Corry J, Smith J, et al. Excellent disease control and survival in patients with
advanced nasophary ngeal cancer treated with chemoradiation. J Clin Oncol.
2002;20(7):1845–1852.
161. Ingersoll L, Woo SY, Donaldson S, et al. Nasophary ngeal carcinoma in the y oung: a
combined M.D. Anderson and Stanford experience. Int J Radiat Oncol Biol Phys.
1990;19(4):881–887.
162. Mertens R, Granzen B, Lassay L, et al. Nasophary ngeal carcinoma in childhood and
adolescence: concept and preliminary results of the cooperative GPOH study NPC-91.
Gesellschaft für Pädiatrische Onkologie und Hämatologie. Cancer. 1997;80(5):951–959.
163. Berry MP, Smith CR, Brown TC, et al. Nasophary ngeal carcinoma in the y oung. Int J
Radiat Oncol Biol Phys. 1980;6(4):415–421.
164. Orbach D, Brisse H, Helfre S, et al. Radiation and chemotherapy combination for
nasophary ngeal carcinoma in children: radiotherapy dose adaptation after
chemotherapy response to minimize late effects. Pediatr Blood Cancer. 2008;50(4):849–
853.
165. Liu T. Issues in the management of nasophary ngeal carcinoma. Crit Rev Oncol Hematol.
1999;31(1):55–69.
166. Itami J, Anzai Y, Nemoto K, et al. Prognostic factors for local control in nasophary ngeal
cancer (NPC): analy sis by multivariate proportional hazard models. Radiother Oncol.
1991;21(4):233–239.
167. Sham J, Choy D, Kwong PW, et al. Radiotherapy for nasophary ngeal carcinoma:
shielding the pituitary may improve therapeutic ratio. Int J Radiat Oncol Biol Phys.
1994;29(4):699–704.
168. O’Meara WP, Lee N. Advances in nasophary ngeal carcinoma. Curr Opin Oncol.
2005;17(3):225–230.
169. Fang F-M, Tsai W-L, Chen H-C, et al. Intensity -modulated or conformal radiotherapy
improves the quality of life of patients with nasophary ngeal carcinoma: comparisons of
four radiotherapy techniques. Cancer. 2007;109(2):313–321.
170. Lee N, Xia P, Quivey JM, et al. Intensity -modulated radiotherapy in the treatment of
nasophary ngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol
Phys. 2002;53(1):12–22.
171. Laskar S, Bahl G, Muckaden M, et al. Nasophary ngeal carcinoma in children:
comparison of conventional and intensity -modulated radiotherapy. Int J Radiat Oncol
Biol Phys. 2008;72(3):728–736.
172. Louis CU, Paulino AC, Gottschalk S, et al. A single institution experience with pediatric
nasophary ngeal carcinoma: high incidence of toxicity associated with platinum-based
chemotherapy plus IMRT. J Pediatr Hematol Oncol. 2007;29(7):500–505.
173. Hitchcock YJ, Tward JD, Szabo A, et al. Relative contributions of radiation and cisplatin-
based chemotherapy to sensorineural hearing loss in head-and-neck cancer patients. Int
J Radiat Oncol Biol Phys. 2009;73(3):779–788.
174. Guo Q, Cui X, Lin S, et al. Locoregionally advanced nasophary ngeal carcinoma in
childhood and adolescence: analy sis of 95 patients treated with combined chemotherapy
and intensity -modulated radiotherapy. Head Neck. 2015;1–8.
175. Ipekci SH, Cakir M, Kiy ici A, et al. Radiotherapy -induced hy popituitarism in
nasophary ngeal carcinoma: the tip of an iceberg. Exp Clin Endocrinol Diabetes.
2015;123(7):411–418.
176. Teo PM, Leung SF, Chan AT, et al. Final report of a randomized trial on altered-
fractionated radiotherapy in nasophary ngeal carcinoma prematurely terminated by
significant increase in neurologic complications. Int J Radiat Oncol Biol Phys.
2000;48(5):1311–1322.
177. He X, Liu T, He S, et al. Late course accelerated hy perfractionated radiotherapy of
nasophary ngeal carcinoma (LCAF). Radiother Oncol. 2007;85(1):29–35.
178. Isobe K, Uno T, Kawakami H, et al. Hy perfractionated radiation therapy for
locoregionally advanced nasophary ngeal cancer. Jpn J Clin Oncol. 2005;35(3):116–120.
179. Jen YM, Hsu WL, Chen CY, et al. Different risks of sy mptomatic brain necrosis in NPC
patients treated with different altered fractionated radiotherapy techniques. Int J Radiat
Oncol Biol Phys. 2001;51(2):344–348.
180. Arush MW, Stein ME, Rosenblatt E, et al. Advanced nasophary ngeal carcinoma in the
y oung: the Northern Israel Oncology Center experience, 1973–1991. Pediatr Hematol
Oncol. 1995;12(3):271–276.
181. Werner-Wasik M, Winkler P, Uri A, et al. Nasophary ngeal carcinoma in children. Med
Pediatr Oncol. 1996;26(5):352–358.
182. Strojan P, Benedik MD, Kragelj B, et al. Combined radiation and chemotherapy for
advanced undifferentiated nasophary ngeal carcinoma in children. Med Pediatr Oncol.
1997;28(5):366–369.
183. Sahraoui S, Acharki A, Benider A, et al. Nasophary ngeal carcinoma in children under 15
y ears of age: a retrospective review of 65 patients. Ann Oncol. 1999;10(12):1499–1502.
184. Zubizarreta PA, D’Antonio G, Raslawski E, et al. Nasophary ngeal carcinoma in
childhood and adolescence: a single-institution experience with combined therapy.
Cancer. 2000;89(3):690–695.
185. Wormald R, Lennon P, O’Dwy er TP. Ectopic olfactory neuroblastoma: report of four
cases and a review of the literature. Eur Arch Otorhinolaryngol. 2011;268(4):555–560.
186. Benoit MM, Bhattachary y a N, Faquin W, et al. Cancer of the nasal cavity in the pediatric
population. Pediatrics. 2008;121(1):e141–e145.
187. Silva EG, Butler JJ, Mackay B, et al. Neuroblastomas and neuroendocrine carcinomas of
the nasal cavity : a proposed new classification. Cancer. 1982;50(11):2388–2405.
188. Bellizzi AM, Bourne TD, Mills SE, et al. The cy tologic features of sinonasal
undifferentiated carcinoma and olfactory neuroblastoma. Am J Clin Pathol.
2008;129(3):367–376.
189. Hirose T, Scheithauer BW, Lopes MB, et al. Olfactory neuroblastoma: an
immunohistochemical, ultrastructural, and flow cy tometric study. Cancer. 1995;76(1):4–
19.
190. Hy ams VJ, Batsakis JG, Micheals L. Tumors of the upper respiratory tract and ear. Atlas
Tumor Pathol. 1998;99:240–248.
191. Tajudeen BA, Arshi A, Suh JD, et al. Importance of tumor grade in
esthesioneuroblastoma survival: a population-based analy sis. JAMA Otolaryngol Head
Neck Surg. 2014;140(12):1124–1129.
192. Herrold KM. Induction of olfactory neuroepithelial tumors in sy rian hamsters by
diethy lnitrosamine. Cancer. 1964;17:114–121.
193. Koike K, Jay G, Hartley JW, et al. Activation of retrovirus in transgenic mice:
association with development of olfactory neuroblastoma. J Virol. 1990;64(8):3988–
3991.
194. Sorensen PH, Wu JK, Berean KW, et al. Olfactory neuroblastoma is a peripheral
primitive neuroectodermal tumor related to Ewing sarcoma. Proc Natl Acad Sci U S A.
1996;93(3):1038–1043.
195. Resto VA, Eisele DW, Forastiere A, et al. Esthesioneuroblastoma: the Johns Hopkins
experience. Head Neck. 2000;22(6):550–558.
196. Ebersold MJ, Olsen KD, Foote RL. Esthesioneublastoma. In: Kay e AH, Laws ER, eds.
Brain Tumors: An Encyclopedic Approach. New York, NY: Churchill Livingstone;
1995:825–838.
197. Bisogno G, Soloni P, Conte M, et al. Esthesioneuroblastoma in pediatric and adolescent
age—a report from the TREP project in cooperation with the Italian Neuroblastoma and
Soft Tissue Sarcoma Committees. BMC Cancer. 2012;12:117.
198. Schuster JJ, Phillips CD, Levine PA. MR of esthesioneuroblastoma (olfactory
neuroblastoma) and appearance after craniofacial resection. AJNR Am J Neuroradiol.
1994;15(6):1169–1177.
199. Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma: a clinical analy sis of 17
cases. Cancer. 1976;37(3):1571–1576.
200. Koka VN, Julieron M, Bourhis J, et al. Aesthesioneuroblastoma. J Laryngol Otol.
1998;112(7):628–633.
201. Foote RL, Morita A, Ebersold MJ, et al. Esthesioneuroblastoma: the role of adjuvant
radiation therapy. Int J Radiat Oncol Biol Phys. 1993;27(4):835–842.
202. Bradley PJ, Jones NS, Robertson I. Diagnosis and management of
esthesioneuroblastoma. Curr Opin Otolaryngol Head Neck Surg. 2003;11(2):112–118.
203. Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analy sis and
review. Lancet Oncol. 2001;2(11):683–690.
204. Eich HT, Hero B, Staar S, et al. Multimodality therapy including radiotherapy and
chemotherapy improves event-free survival in stage C esthesioneuroblastoma.
Strahlenther Onkol. 2003;179(4):233–240.
205. Page 381 Oskouian RJ, Jane JA, Dumont AS. Esthesioneuroblastoma: clinical
presentation, radiological, and pathological features, treatment, review of the literature,
and the University of Virginia experience. Neurosurg Focus. 2002;12(5):e4.
206. Gil Z, Patel SG, Cantu G, et al. Outcome of craniofacial surgery in children and
adolescents with malignant tumors involving the skull base: an international collaborative
study. Head Neck. 2009;31(3):308–317.
207. Eden BV, Debo RF, Larner JM, et al. Esthesioneuroblastoma. Long-term outcome and
patterns of failure—the University of Virginia experience. Cancer. 1994;73(10):2556–
2562.
208. Sny derman CH, Kassam AB. Endoscopic techniques for pathology of the anterior
cranial fossa and ventral skull base. J Am Coll Surg. 2006;202(3):563.
209. Batra PS, Citardi MJ, Worley S, et al. Resection of anterior skull base tumors: comparison
of combined traditional and endoscopic techniques. Am J Rhinol. 2005;19(5):521–528.
210. Devaiah AK, Andreoli MT. Treatment of esthesioneuroblastoma: a 16-y ear meta-
analy sis of 361 patients. Laryngoscope. 2009;119(7):1412–1416.
211. Ow TJ, Hanna EY, Roberts DB, et al. Optimization of long-term outcomes for patients
with esthesioneuroblastoma. Head Neck. 2014;36(4):524–530.
212. Broich G, Pagliari A, Ottaviani F. Esthesioneuroblastoma: a general review of the cases
published since the discovery of the tumour in 1924. Anticancer Res. 1997;17(4A):2683–
2706.
213. Polin RS, Sheehan JP, Chenelle AG, et al. The role of preoperative adjuvant treatment in
the management of esthesioneuroblastoma: the University of Virginia experience.
Neurosurgery. 1998;42(5):1029–1037.
214. Duthoy W, Boterberg T, Claus F, et al. Postoperative intensity -modulated radiotherapy in
sinonasal carcinoma: clinical results in 39 patients. Cancer. 2005;104(1):71–82.
215. Ganly I, Patel SG, Singh B, et al. Craniofacial resection for malignant paranasal sinus
tumors: report of an International Collaborative Study. Head Neck. 2005;27(7):575–584.
216. Schulz-Ertner D, Nikoghosy an A, Didinger B, et al. Therapy strategies for locally
advanced adenoid cy stic carcinomas using modern radiation therapy techniques.
Cancer. 2005;104(2):338–344.
217. El Kababri M, Habrand JL, Valteau-Couanet D, et al. Esthesioneuroblastoma in children
and adolescent: experience on 11 cases with literature review. J Pediatr Hematol Oncol.
2014;36(2):91–95.
218. Benfari G, Fusconi M, Ciofalo A, et al. Radiotherapy alone for local tumour control in
esthesioneuroblastoma. Acta Otorhinolaryngol Ital. 2008;28(6):292–297.
219. Noh OK, Lee S, Yoon SM, et al. Radiotherapy for esthesioneuroblastoma: is elective
nodal irradiation warranted in the multimodality treatment approach? Int J Radiat Oncol
Biol Phys. 2011;79(2):443–449.
220. Stieber VW, Munley M. Central nervous sy stem tumors. In: Mundt AJ, Roeske JC, eds.
Intensity-Modulated Radiation Therapy (IMRT):A Clinical Perspective. 1st ed. Ontario,
Canada: BC Decker Inc; 2005:231–263.
221. Zabel A, Thilmann C, Zuna I, et al. Comparison of forward planned conformal radiation
therapy and inverse planned intensity modulated radiation therapy for
esthesioneuroblastoma. Br J Radiol. 2002;75(892):356–361.
222. Suit H, Urie M. Proton beams in radiation therapy. J Natl Cancer Inst. 1992;84(3):155–
164.
223. Bhattachary y a N, Thornton AF, Joseph MP, et al. Successful treatment of
esthesioneuroblastoma and neuroendocrine carcinoma with combined chemotherapy
and proton radiation. Results in 9 cases. Arch Otolaryngol Head Neck Surg.
1997;123(1):34–40.
224. Unger F, Haselsberger K, Walch C, et al. Combined endoscopic surgery and
radiosurgery as treatment modality for olfactory neuroblastoma
(esthesioneuroblastoma). Acta Neurochir (Wien). 2005;147(6):595–601; discussion 601–
602.
225. Eich HT, Müller R-P, Micke O, et al. Esthesioneuroblastoma in childhood and
adolescence. Better prognosis with multimodal treatment? Strahlenther Onkol.
2005;181(6):378–384.
226. Fitzek MM, Thornton AF, Varvares M, et al. Neuroendocrine tumors of the sinonasal
tract. Results of a prospective study incorporating chemotherapy, surgery, and combined
proton-photon radiotherapy. Cancer. 2002;94(10):2623–2634.
227. Sheehan JM, Sheehan JP, Jane JA, et al. Chemotherapy for esthesioneuroblastomas.
Neurosurg Clin N Am. 2000;11(4):693–701.
228. McElroy EA, Buckner JC, Lewis JE. Chemotherapy for advanced
esthesioneuroblastoma: the May o Clinic experience. Neurosurgery. 1998;42(5):1023–
1027; discussion 1027–1028.
229. Mishima Y, Nagasaki E, Terui Y, et al. Combination chemotherapy (cy clophosphamide,
doxorubicin, and vincristine with continuous-infusion cisplatin and etoposide) and
radiotherapy with stem cell support can be beneficial for adolescents and adults with
estheisoneuroblastoma. Cancer. 2004;101(6):1437–1444.
230. Buehrlen M, Zwaan CM, Granzen B, et al. Multimodal treatment, including interferon
beta, of nasophary ngeal carcinoma in children and y oung adults: preliminary results
from the prospective, multicenter study NPC-2003-GPOH/DCOG. Cancer.
2012;118(19):4892–4900.
231. Argiris A, Dutra J, Tseke P, et al. Esthesioneuroblastoma: the Northwestern University
experience. Laryngoscope. 2003;113(1):155–160.
232. Elkon D, Hightower SI, Lim ML, et al. Esthesioneuroblastoma. Cancer. 1979;44(3):1087–
1094.
233. Gruber G, Laedrach K, Baumert B, et al. Esthesioneuroblastoma: irradiation alone and
surgery alone are not enough. Int J Radiat Oncol Biol Phys. 2002;54(2):486–491.
234. O’Connor TA, McLean P, Juillard GJ, et al. Olfactory neuroblastoma. Cancer.
1989;63(12):2426–2428.
235. Koch M, Constantinidis J, Dimmler A, et al. [Long-term experiences in the therapy of
esthesioneuroblastoma]. Laryngorhinootologie. 2006;85(10):723–730.
236. Bachar G, Goldstein DP, Shah M, et al. Esthesioneuroblastoma: the Princess Margaret
Hospital experience. Head Neck. 2008;30(12):1607–1614.
237. Gosepath J, Spix C, Talebloo B, et al. Incidence of childhood cancer of the head and neck
in Germany. Ann Oncol. 2007;18(10):1716–1721.
238. Schwartz I, Hughes C, Brigger MT. Pediatric head and neck malignancies: incidence and
trends, 1973–2010. Otolaryngol Head Neck Surg. 2015;152(6):1127–1132.
239. Cesmebasi A, Gabriel A, Niku D, et al. Pediatric head and neck tumors: an intra-
demographic analy sis using the SEER* database. Med Sci Monit. 2014;20:2536–2542.
240. Bentz BG, Hughes CA, Lüdemann JP, et al. Masses of the salivary gland region in
children. Arch Otolaryngol Head Neck Surg. 2000;126(12):1435–1439.
241. Callender DL, Frankenthaler RA, Luna MA, et al. Salivary gland neoplasms in children.
Arch Otolaryngol Head Neck Surg. 1992;118(5):472–476.
242. Jaques DA, Krolls SO, Chambers RG. Parotid tumors in children. Am J Surg.
1976;132(4):469–471.
243. Krolls SO, Trodahl JN, Boy ers RC. Salivary gland lesions in children. A survey of 430
cases. Cancer. 1972;30(2):459–469.
244. Kaste SC, Hedlund G, Pratt CB. Malignant parotid tumors in patients previously treated
for childhood cancer: clinical and imaging findings in eight cases. Am J Roentgenol.
1994;162(3):655–659.
245. Amedee RG, Dhurandhar NR. Fine-needle aspiration biopsy. Laryngoscope.
2001;111(9):1551–1557.
246. Klijanienko J, Vielh P, Batsakis JD, et al. Salivary gland tumours. Monogr Clin Cytol.
2000;15:III–XII, 1–138.
247. Techavichit P, Hicks MJ, López-Terrada DH, et al. Mucoepidermoid carcinoma in
children: a single institutional experience. Pediatr Blood Cancer. 2016;63(1);27–31.
248. Rutigliano DN, Mey ers P, Ghossein RA, et al. Mucoepidermoid carcinoma as a
secondary malignancy in pediatric sarcoma. J Pediatr Surg. 2007;42(7):E9–E13.
249. Henze M, Hittel JP. [Mucoepidermoid carcinoma of the salivary glands after high
dosage radiotherapy ]. Laryngorhinootologie. 2001;80(5):253–256.
250. Védrine PO, Coffinet L, Temam S, et al. Mucoepidermoid carcinoma of salivary glands
in the pediatric age group: 18 clinical cases, including 11 second malignant neoplasms.
Head Neck. 2006;28(9):827–833.
251. Thorvaldsson SE, Beahrs OH, Woolner LB, et al. Mucoepidermoid tumors of the major
salivary glands. Am J Surg. 1970;120(4):432–438.
252. Hicks J, Flaitz C. Mucoepidermoid carcinoma of salivary glands in children and
adolescents: assessment of proliferation markers. Oral Oncol. 2000;36(5):454–460.
253. Page 382 Spiro RH. Changing trends in the management of salivary tumors. Semin Surg
Oncol. 1995;11(3):240–245.
254. Armstrong JG, Harrison LB, Thaler HT, et al. The indications for elective treatment of
the neck in cancer of the major salivary glands. Cancer. 1992;69(3):615–619.
255. Thariat J, Vedrine P-O, Temam S, et al. The role of radiation therapy in pediatric
mucoepidermoid carcinomas of the salivary glands. J Pediatr. 2013;162(4):839–843.
256. Ellington CL, Goodman M, Kono SA, et al. Adenoid cy stic carcinoma of the head and
neck: incidence and survival trends based on 1973–2007 surveillance, epidemiology, and
end results data. Cancer. 2012;118(18):4444–4451.
257. Elluru RG, Friess MR, Richter GT, et al. Multicenter evaluation of the effectiveness of
sy stemic propranolol in the treatment of airway hemangiomas. Otolaryngol Head Neck
Surg. 2015;153(3):452–460.
258. Raol N, Metry D, Edmonds J, et al. Propranolol for the treatment of subglottic
hemangiomas. Int J Pediatr Otorhinolaryngol. 2011;75(12):1510–1514.
259. Chatrath P, Black M, Jani P, et al. A review of the current management of infantile
subglottic haemangioma, including a comparison of CO(2) laser therapy versus
tracheostomy. Int J Pediatr Otorhinolaryngol. 2002;64(2):143–157.
260. Benjamin B. Treatment of infantile subglottic hemangioma with radioactive gold grain.
Ann Otol Rhinol Laryngol. 1978;87(1 Pt 1):18–21.
261. Munitiz V, Parrilla P, Ortiz A, et al. High risk of malignancy in familial Barrett’s
esophagus: presentation of one family. J Clin Gastroenterol. 2008;42(7):806–809.
262. DuVall GA, Walden DT. Adenocarcinoma of the esophagus complicating Cornelia de
Lange sy ndrome. J Clin Gastroenterol. 1996;22(2):131–133.
263. Shahi UP, Sudarsan, Dattagupta S, et al. Carcinoma oesophagus in a 14 y ear old child:
report of a case and review of literature. Trop Gastroenterol. 1989;10(4):225–228.
264. Perch SJ, Soffen EM, Whittington R, et al. Esophageal sarcomas. J Surg Oncol.
1991;48(3):194–198.
265. Bourque MD, Spigland N, Bensoussan AL, et al. Esophageal leiomy oma in children: two
case reports and review of the literature. J Pediatr Surg. 1989;24(10):1103–1107.
266. Vade A, Nolan J. Posterior mediastinal teratoma involving the esophagus. Gastrointest
Radiol. 1989;14(2):106–108.
267. Wright JR, Ky riakos M, DeSchry ver-Kecskemeti K. Malignant fibrous histiocy toma of
the stomach. A report and review of malignant fibrohistiocy tic tumors of the alimentary
tract. Arch Pathol Lab Med. 1988;112(3):251–258.
268. Jaeger HJ, Schmitz-Stolbrink A, Albrecht M, et al. Gastric leiomy osarcoma in a child.
Eur J Radiol. 1996;23(2):111–114.
269. Siegel S, Hay s D, Romansky S, et al. Carcinoma of the stomach in childhood. Cancer.
1976;38(4):1781–1784.
270. Chatura K, Nadar S, Pulimood S. Gastric carcinoma as a complication of dy skeratosis
congenita in an adolescent boy. Dig Dis Sci. 1996;41(12):2340–2342.
271. Subbiah V, Varadhachary G, Herzog CE, et al. Gastric adenocarcinoma in children and
adolescents. Pediatr Blood Cancer. 2011;57(3):524–527.
272. Kurugoglu S, Mihmanli I, Celkan T, et al. Radiological features in paediatric primary
gastric MALT ly mphoma and association with Helicobacter pylori. Pediatr Radiol.
2002;32(2):82–87.
273. Cam S. Risk of gastric cancer in children with Helicobacter pylori infection. Asian Pac J
Cancer Prev. 2014;15(22):9905–9908.
274. Durham MM, Gow KW, Shehata BM, et al. Gastrointestinal stromal tumors arising from
the stomach: a report of three children. J Pediatr Surg. 2004;39(10):1495–1409.
275. Benesch M, Wardelmann E, Ferrari A, et al. Gastrointestinal stromal tumors (GIST) in
children and adolescents: a comprehensive review of the current literature. Pediatr
Blood Cancer. 2009;53(7):1171–1179.
276. Park J, Rubinas TC, Fordham LA, et al. Multifocal gastrointestinal stromal tumor (GIST)
of the stomach in an 11-y ear-old girl. Pediatr Radiol. 2006;36(11):1212–1214.
277. Li P, Wei J, West A, et al. Epithelioid gastrointestinal stromal tumor of the stomach with
liver metastases in a 12-y ear-old girl: aspiration cy tology and molecular study. Pediatr
Dev Pathol. 2002;5(4):386–394.
278. Dishop M, Kuruvilla S. Primary and metastatic lung tumors in the pediatric population: a
review and 25-y ear experience at a large children’s hospital. Arch Pathol Lab Med.
2008;132(7):1079–1103.
279. Mahour GH, Isaacs H, Chang L. Primary malignant tumors of the stomach in children. J
Pediatr Surg. 1980;15(5):603–608.
280. Chang H, Rosenberg A, Friedmann AM. Primary pulmonary rhabdomy osarcoma in a
5-month-old boy : a case report. J Pediatr Hematol Oncol. 2008;30(6):461–463.
281. Hancock B, Lorenzo M Di. Childhood primary pulmonary neoplasms. J Pediatr Surg.
1993;28(9):1133–1136.
282. Dosios T, Stinios J, Nicolaides P. Pleuropulmonary blastoma in childhood. A malignant
degeneration of pulmonary cy sts. Pediatr Surg Int. 2004;20(11):863–865.
283. Priest J, Hill D. Ty pe I pleuropulmonary blastoma: a report from the International
Pleuropulmonary Blastoma Registry. J Clin Oncol. 2006;24(27):4492–4498.
284. Boman F, Hill D, Williams G. Familial association of pleuropulmonary blastoma with
cy stic nephroma and other renal tumors: a report from the International
Pleuropulmonary Blastoma Registry. J Pediatr. 2006;149(6):850–854.
285. Priest JR, Watterson J, Strong L, et al. Pleuropulmonary blastoma: a marker for familial
disease. J Pediatr. 1996;128(2):220–224.
286. Messinger YH, Stewart DR, Priest JR, et al. Pleuropulmonary blastoma: a report on 350
central pathology -confirmed pleuropulmonary blastoma cases by the International
Pleuropulmonary Blastoma Registry. Cancer. 2015;121(2):276–285.
287. Lee H, Goo J, Kim K, et al. Pulmonary blastoma: radiologic findings in five patients.
Clin Imaging. 2004;28(2):113–118.
288. Naffaa L, Donnelly L. Imaging findings in pleuropulmonary blastoma. Pediatr Radiol.
2005;35(4):387–391.
289. Mut Pons R, Muro Velilla MD, Sangüesa Nebot C, et al. Pleuropulmonary blastoma in
children: imaging findings and clinical patterns. Radiologia. 2008;50(6):489–494.
290. Priest JR, McDermott MB, Bhatia S, et al. Pleuropulmonary blastoma: a
clinicopathologic study of 50 cases. Cancer. 1997;80(1):147–161.
291. Priest J, Magnuson J. Cerebral metastasis and other central nervous sy stem
complications of pleuropulmonary blastoma. Pediatr Blood Cancer. 2007;49(3):266–273.
292. Granata C, Gambini C, Carlini C, et al. Pleuropulmonary blastoma. Eur J Pediatr Surg.
11(4),2001,271–273.
293. Pinarli F, Oğuz A, Karadeniz C. Ty pe II pleuropulmonary blastoma responsive to
multimodal therapy. Pediatr Hematol Oncol. 2005;22(1):71–76.
294. Senac MO Jr, Wood BP, Isaacs H, et al. Pulmonary blastoma: a rare childhood
malignancy. Radiology. 1991;179(3):743–746.
295. Ozkay nak MF, Ortega JA, Laug W, et al. Role of chemotherapy in pediatric pulmonary
blastoma. Med Pediatr Oncol. 1990;18(1):53–56.
296. Baraniy a J, Desai S, Kane S, et al. Pleuropulmonary blastoma. Med Pediatr Oncol.
1999;32(1):52–56.
297. Indolfi P, Bisogno G. Prognostic factors in pleuro‐pulmonary blastoma. Pediatr Blood
Cancer. 2007;48(3):318–323.
298. Andrassy R, Feldtman R, Stanford W. Bronchial carcinoid tumors in children and
adolescents. J Pediatr Surg. 1977;12(4):513–517.
299. Al-Qahtani A, Lorenzo M Di, Yazbeck S. Endobronchial tumors in children: institutional
experience and literature review. J Pediatr Surg. 2003;38(5):733–736.
300. Fauroux B, Ay nie V, Larroquet M, et al. Carcinoid and mucoepidermoid bronchial
tumours in children. Eur J Pediatr. 2005;164(12):748–752.
301. Madafferi S, Catania VD, Accinni A, et al. Endobronchial tumor in children: unusual
finding in recurrent pneumonia, report of three cases. World J Clin Pediatr.
2015;4(2):30–34.
302. Yu Y, Song Z, Chen Z, et al. Chinese pediatric and adolescent primary tracheobronchial
tumors: a hospital-based study. Pediatr Surg Int. 2011;27(7):721–726.
303. Shorter NA, Glick RD, Klimstra DS, et al. Malignant pancreatic tumors in childhood and
adolescence: the memorial sloan-kettering experience, 1967 to present. J Pediatr Surg.
2002;37(6):887–892.
304. Perez E, Gutierrez J, Koniaris L, et al. Malignant pancreatic tumors: incidence and
outcome in 58 pediatric patients. J Pediatr Surg. 2009;44(1):197–203.
305. Page 383 Nasher O, Hall NJ, Sebire NJ, et al. Pancreatic tumours in children: diagnosis,
treatment and outcome. Pediatr Surg Int. 2015;31(9):831–835.
306. Dall’igna P, Cecchetto G, Bisogno G, et al. Pancreatic tumors in children and
adolescents: the Italian TREP project experience. Pediatr Blood Cancer.
2010;54(5):675–680.
307. Murakami T, Ueki K, Kawakami H, et al. Pancreatoblastoma: case report and review of
treatment in the literature. Med Pediatr Oncol. 1996;27(3):193–197.
308. Klimstra D, Wenig B. Pancreatoblastoma a clinicopathologic study and review of the
literature. Am J Surg Pathol. 1995;19(12):1343–1460
309. Defachelles AS, Martin De Lassalle E, Boutard P, et al. Pancreatoblastoma in childhood:
clinical course and therapeutic management of seven patients. Med Pediatr Oncol.
2001;37(1):47–52.
310. Defachelles A-S, Rocourt N, Branchereau S, et al. [Pancreatoblastoma in children:
diagnosis and therapeutic management]. Bull Cancer. 2012;99(7-8):793–799.
311. Jaksic T, Yaman M, Thorner P, et al. A 20-y ear review of pediatric pancreatic tumors. J
Pediatr Surg. 1992;27(10):1315–1317.
312. Chung EM, Travis MD, Conran RM. Pancreatic tumors in children: radiologic-pathologic
correlation. Radiographics. 2006;26(4):1211–1238.
313. Willnow U, Willberg B, Schwamborn D, et al. Pancreatoblastoma in children—case
report and review of the literature. Eur J Pediatr Surg. 2008;6(6):369–372.
314. Xu C, Zhong L, Wang Y, et al. Clinical analy sis of childhood pancreatoblastoma arising
from the tail of the pancreas. J Pediatr Hematol Oncol. 2012;34(5):e177–e181.
315. Bien E, Godzinski J, Dall’igna P, et al. Pancreatoblastoma: a report from the European
cooperative study group for paediatric rare tumours (EXPeRT). Eur J Cancer.
2011;47(15):2347–2352.
316. de Bree E, Askoxy lakis J, Giannikaki E, et al. Secretory carcinoma of the male breast.
Ann Surg Oncol. 2002;9(7):663–667.
317. Shannon C, Smith IE. Breast cancer in adolescents and y oung women. Eur J Cancer.
2003;39(18):2632–2642.
318. Gutierrez JC, Housri N, Koniaris LG, et al. Malignant breast cancer in children: a review
of 75 patients. J Surg Res. 2008;147(2):182–188.
319. Chung EM, Cube R, Hall GJ, et al. From the archives of the AFIP: breast masses in
children and adolescents: radiologic-pathologic correlation. Radiographics.
2009;29(3):907–931.
320. Rogers DA, Lobe TE, Rao BN, et al. Breast malignancy in children. J Pediatr Surg.
1994;29(1):48–51.
321. Liu W, Tang Y, Gao L, et al. Nasophary ngeal carcinoma in children and adolescents - a
single institution experience of 158 patients. Radiat Oncol. 2014;9(1):274.
322. Eskelinen M, Vainio J, Tuominen L, et al. Carcinoma of the breast in children. Eur J
Pediatr Surg. 2008;45(1):52–55.
323. Templeman C, Hertweck SP. Breast disorders in the pediatric and adolescent patient.
Obstet Gynecol Clin North Am. 2000;27(1):19–34.
324. Krausz T, Jenkins D, Grontoft O, et al. Secretory carcinoma of the breast in adults:
emphasis on late recurrence and metastasis. Histopathology. 1989;14(1):25–36.
325. Richard G, Hawk JC, Baker AS, et al. Multicentric adult secretory breast carcinoma:
DNA flow cy tometric findings, prognostic features, and review of the world literature. J
Surg Oncol. 1990;44(4):238–244.
326. Bond SJ, Buchino JJ, Nagaraj HS, et al. Sentinel ly mph node biopsy in juvenile secretory
carcinoma. J Pediatr Surg. 2004;39(1):120–121.
327. Kasper ME, Parsons JT, Mancuso AA, et al. Radiation therapy for juvenile
angiofibroma: evaluation by CT and MRI, analy sis of tumor regression, and selection of
patients. Int J Radiat Oncol Biol Phys. 1993;25(4):689–694.
328. Murphy JJ, Morzaria S, Gow KW, et al. Breast cancer in a 6-y ear-old child. J Pediatr
Surg. 2000;35(5):765–767.
CH A P TER 17
Langerhans Cell Histiocytosis
Edward C. Halperin
At autopsy, a yellow spot about the size of a five-cent piece was noticed near
the right parietal eminence. When the skull-cap was removed, this spot was
seen on the inner side as well, and the entire thickness of the bone there was
soft and movable…. The lymphatic glands all through the body were greatly
enlarged…. The liver and spleen were enlarged and firm, and the former had
minute gray nodules in its substance…. Microscopial sections showed nodular
masses of small, round-celled infiltration in the liver, spleen, kidneys (6).
Hand suspected that he was dealing with a case of TB. In 1921, he noted the similarity of
his original case to ones subsequently reported by Schuller, Christian, and Kay. Eventually,
the term Hand–Schuller–Christian disease or triad was used to describe a disease occurring in
children more than 2 y ears old characterized by exophthalmos, lesions in the bones of the
skull, and diabetes insipidus (DI). The full triad was rarely seen, and the prognosis was good
(6,7).
Page 385In 1924 and 1933, Letterer and Siwe described what they perceived to be an
entity distinct from Hand–Schuller– Christian disease. Letterer–Siwe disease generally
occurred in children less than 2 y ears old. The diagnostic criteria included splenomegaly,
hepatomegaly, ly mphadenopathy, anemia, and a hemorrhagic diathesis. The prognosis was
poor (6,7).
In 1940, Otani and Ehrlich (8) described a granuloma of bone simulating a primary
neoplasm. Eventually, the solitary eosinophilic granuloma was described as occurring in
children more than 2 y ears old, characterized by a solitary, usually bony site of involvement,
and an excellent prognosis (7,9).
In 1953, Lichtenstein argued that eosinophilic granuloma of bone, Letterer–Siwe disease,
and Hand–Schuller–Christian disease were related manifestations of a single nosologic entity
(9). He used the name histiocytosis X to refer to a spectrum of diseases of the mononuclear
phagocy te (histiocy te). The X referred to the unknown etiology and pathogenesis of the
disease or diseases. The diseases formerly grouped under the heading “Histiocy tosis X” are
now called Langerhans cell histiocytosis (LCH).
Figure:
Paul Langerhans (1847–1888).
DEFINITION, PATHOGENESIS, AND PATHOLOGY
The annual incidence of LCH is difficult to know. LCH goes by various names and as one of
many histiocy tic disorders is often lumped with them in incidence data. Our best estimate is
approximately 0.1–2.0 cases per 100,000 children per y ear. There is a slight male
predominance. Most cases are diagnosed between the ages of birth and 15 y ears
(12,14,16,22,23,24,25,26).
The form of clinical presentation is related to the child’s age
(22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37) (Tables 17.2 and 17.3 ). In children
less than 2 y ears old, there may be a widespread seborrheic rash (Fig. 17.4 ). The rash is
often most pronounced on the scalp and in the groin. Petechial hemorrhages in the involved
skin are characteristic. Erosive intertrigo in the groin, axilla, and perianal region is a common
feature. Ulceration and secondary skin infection may occur. Involvement of the mastoid and
middle ear may present as a chronic draining otitis (41). The infant may be irritable, with a
diminished appetite and failure to thrive. Palpable ly mphadenopathy may be seen secondary
to LCH infiltration. Liver involvement is common in disseminated LCH. Hepatomegaly,
elevation of liver enzy mes, increased conjugated bilirubin, ascites, edema, and failure to
thrive may be attributable to liver disease or involvement of the gastrointestinal tract.
Diarrhea may be the result of abnormal bile acid metabolism or malabsorption (17).
Splenomegaly may be accompanied by anemia, leukopenia, or thrombocy topenia (42).
Figure 17.4 Truncal rash and hepatosplenomegaly in an infant
with Langerhans cell histiocytosis. (From Berry CL, ed. Paediatric
Pathology. Berlin, Germany : Springer-Verlag; 1991, with
permission.)
In children more than 2 y ears old, the most common presenting sy mptoms are related to
bone involvement (Table 17.3 ). There is localized pain, with or without an associated soft
tissue mass. Involvement of the orbital bones may cause exophthalmos. LCH may produce
premature eruption of the teeth or tooth loss because of gum and mandibular disease (42,43).
Back pain and loss of vertebral height may be seen. Spinal cord compression is rare.
DI is the most common complication of CNS involvement. The incidence varies, in
different reports, from 11% to 50%. Magnetic resonance imaging (MRI) may show lesions in
the posterior pituitary or the pituitary stalk (44,45). The mechanism of injury is thought to be
either infiltration of the meninges adjacent to the posterior hy pothalamic–pituitary axis or
direct involvement of the brain. DI often is associated with skull lesions, which may be seen
before the DI (27,39,41,45,46,47,48,49). Lung and oral mucous membrane involvement with
LCH often occurs in patients in whom DI develops (46). In a Dutch–German–Austrian study,
3 of the 93 patients (3%) with primary localized
disease and 16 of the 106 patients (15%) with
dissemination of LCH at diagnosis had DI (46).
In a series of patients from London’s Hospital for
Sick Children, DI was more common among
children with multisy stem disease (12 of 32)
than among those with disease apparently
confined to bone (3 of 20). Fourteen of the 15
children with DI had bone disease involving the
skull. The cumulative risk of developing DI
during the first 4 y ears after presentation with
LCH was 42% (47). In a series from San
Francisco, 25% of patients developed DI (29).
Page 387Pulmonary LCH has been
reported in infants and older adults. However, it
affects primarily adults in their twenties and
thirties. Chest CT demonstrates multiple nodules Table 17.3 Sites of Bone Involvement
with a predominance in the upper lobes. If in Langerhans Cell Histiocytosis: A
bronchioalveolar lavage y ields more than 5% Summary from the Published Literature
LCH cells, then the procedure is diagnostic. The
cells are CD1a positive. In adults, the natural history of pulmonary LCH is variable. It is often
associated with cigarette smoking, and patients who continue to smoke progress to end-stage
fibrotic disease or develop extrapulmonary complications. Smoking cessation is the most
effective therapy (50).
Page 388Skull lesions often are the first sign of LCH. Often very slow growing, they
may be single or multiple and can occur without other bony involvement. Although they have
a predilection for the temple area, they can be found any where on the skull. On plain
radiographs they will appear as punched-out lesions. With time they can develop a sclerotic
border (51). Calvarial lesions can have epidural extension. They may extend beneath the
dura into the brain parenchy ma.
A diagnostic radiograph skeletal survey should be performed to assess the extent of bony
involvement (Fig. 17.5 ). Bone scans are also often used (15,52). PET scanning may
identify active lesions and differentiate them
from healed lesions after treatment (15,53,54).
In skeletal radiographs, LCH produces a focal
area of rarefaction. The lucent area begins with
the medullary cavity and extends to involve the
inner table of the cortical bone. MRI may show
that the area of bone abnormality is larger than
suspected from other studies.
In disseminated LCH, cerebral involvement
may occur (55,56). There can be meningeal
involvement with formation of large plaques of
subdural tumor and/or intraparenchy mal lesions. Figure 17.5 Langerhans cell
The most common sites for intraparenchy mal histiocytosis (LCH) involving the left
disease are the hy pothalamus and cerebellum. second rib in a 5-year-old girl. The lesion
Less common locations are the frontal and was painful. The involved portion of the
temporal lobes (57,58). Occasionally, LCH can rib was subtotally resected and was
first present to medical attention as an isolated, diagnostic of LCH. This localized, unifocal
unifocal lesion of the CNS. The hy pothalamus is bone lesion was adequately treated with
the most common site for this rare situation. In surgery alone. There was no recurrence
such cases, the diagnosis is made after surgical of LCH.
exploration and biopsy (55,56,57,58,59).
LCH has a variable prognosis, and a sy stem of grouping patients by predicted outcome is
a valuable guide for the clinician (12,15,60,61,62). Patients with localized disease (skin, bone,
or ly mph node) have a good prognosis and often require minimal or no treatment. In contrast,
multiple organ involvement, which is particularly frequent in children <2 y ears of age, has
the risk of a poor prognosis (Table 17.4 ). Lahey and coworkers (33,34,73) found a striking
difference in survival between patients with and without organ dy sfunction. Of the 50 patients
without organ dy sfunction, 2 (4%) died. In 33 patients with dy sfunction of one or more of the
three organ sy stems, 22 (67%) died.
Table 17.4 Treatment of Localized Langerhans Cell Histiocytosis of Bone with
Intralesional Corticosteroid Injection
(From Berry CL, ed. Paediatric Pathology. Berlin, Germany : Springer-Verlag; 1991, with
permission.)
Figure:
Langerhans cell histiocytosis (LCH) involving the left second rib in a 5-year-old girl. The lesion
was painful. The involved portion of the rib was subtotally resected and was diagnostic of
LCH. This localized, unifocal bone lesion was adequately treated with surgery alone. There
was no recurrence of LCH.
Figure: Treatment of Localized Langerhans
Cell Histiocytosis of Bone with Intralesional
Corticosteroid Injection
SELECTION OF THERAPY
In many cases LCH can take an indolent course or spontaneously remit. In some cases, it
may be possible to use minimal or no therapy. One should carefully balance the risks of
treatment against the apparent course of the disease. The potentially toxic effects of therapy
should not be engendered unless absolutely necessary (12,15,61,62,74,75,76,77,78,79,80,81).
In Table 17.5 , the authors outline a management strategy for LCH. A detailed discussion
of the particulars of the therapy follows.
Table 17.5 A Treatment Algorithm for Langerhans Cell Histiocytosis
Page 389Surgery
Regression of an isolated LCH bone lesion with no further treatment after the initial fine
needle aspiration biopsy has been reported. It is possible that a small amount of mechanical
perturbation of a LCH lesion is sufficient to initiate is regression without further treatment.
Pediatric Oncology Group (POG) Study 8047 evaluated the response rate of LCH bone
lesions to incisional or excisional biopsy. The study was open to patients less than 21 y ears old
with no more than two bone lesions and no sy stemic involvement by LCH. Open biopsy was
recommended, with curettage when possible. Needle biopsy was performed for vertebral
lesions, and excision was performed for expendable bone. Surgery proved highly effective:
20 of the 23 lesions (87%) were controlled without local LCH relapse (75).
Solitary bone lesions may be treated surgically. There is an equal probability of local
control with biopsy, curettage, or excision (75,81). In the past wide excision was considered in
an expendable bone such as the clavicle, ribs, or tip of the scapula. Now, more often, more
conservative surgery is done. In nonexpendable bone locations, a small, mill-like biopsy
instrument allows a tissue diagnosis and access to the medullary cavity for a curettage.
Relative contraindications to curettage are situations in which the procedure would result in
loss of function, severe orthopedic deformity, or poor cosmetic result. Gingival curettage
may be useful for gum disease.
Radiation Therapy
Through the span of time encompassed by the six editions of this book, the use of radiation
therapy (RT) to manage localized bone or soft tissue LCH has become very rare. This trend is
attributable to a better understanding of the prognostic factors predicting the behavior of LCH,
an appreciation of the frequency of disease remission after minimally toxic therapy, and
concern about the long-term ill effects of radiation, albeit at low dosages (17). The complete
response rate of solitary LCH in bone to curettage or excision is 70–90% (40,75,76,77,80,81).
There is no evidence that immediate postoperative irradiation improves these results.
Asy mptomatic bone lesions with sclerotic margins often resolve spontaneously and RT
usually is not necessary (75). If the clinician obtains follow-up radiographs of the child with
bony LCH, evidence of healing is common. Mey er et al. (44) described radiographic lesion
improvement in 14 out of 15 patients with multifocal LCH (93%) and 7 out of 8 patients with
unifocal LCH (88%). A change from a nontrabecular to a trabecular pattern, evolution of
sclerosis in a nonsclerotic lesion, and loss of distinct margins indicate healing (77). Minimum
time from diagnosis to evidence of mild healing was 3 months, although complete resolution
often takes longer (75).
Page 390Postoperative irradiation may be considered for patients who have no clinical
or radiographic signs of local healing. In addition, RT may be considered for local relapse
after surgery when the relapsed bone is the sole site of recurrent disease, where curettage is
not appropriate because of the risk of fracture (i.e., a ly tic lesion of the femoral neck;
mandibular involvement producing a loose, painful tooth, and reluctance to eat) or poor
cosmesis (i.e., the orbital bones) (40,43,62,73,120), when the potential compromise of critical
structures from expansile bone lesions (spinal cord compression, pressure on the globe or
optic nerve) demands a reliable and rapid response, or for pain relief. The success rate of RT
for bony LCH is extremely high (Table 17.5 ).
Vertebral lesions should be considered a special situation. Partial or complete collapse
(vertebra plana) of a vertebral body may be asy mptomatic (Fig. 17.6 ). These
asy mptomatic lesions generally do not warrant therapy because partial bone healing usually
occurs irrespective of treatment. However, if a vertebral lesion is painful, it may be treated
with chemotherapy or irradiated (120).
Figure 17.6 (A) Magnetic resonance imaging scan and (B) bone scan showing complete
vertebral collapse (vertebra plana) secondary to Langerhans cell histiocytosis (LCH) in 1992.
No therapy was given beyond a needle biopsy to establish the diagnosis. Pain resolved over a
month. Typically, healing includes fusion to adjacent vertebrae. The child remains without
evidence of recurrent LCH.
In patients with multifocal LCH or with organ dy sfunction, local RT may have a place.
Lesions that are painful despite chemotherapy should be considered for local RT (121).
Disfiguring bone or soft tissue lesions or bones at substantial immediate risk for fracture may
also be appropriate for local RT.
Recalcitrant skin lesions may be treated with electron beam or orthovoltage photon
therapy, but this should almost never be necessary in view of the other available agents
(49,122,123).
The value of RT for LCH-associated DI is very controversial. Greenberger et al. (123)
reported 21 patients irradiated for DI and noted a complete reversal of sy mptoms in four
patients with discontinuation of pitressin for 2, 5, 5, and 25 y ears. A complete response to RT
was observed in three of four patients treated within 1 week of the onset of sy mptoms. Only 1
of the 15 patients responded when the duration of sy mptoms before RT exceeded 2 weeks.
However, Smith et al. (124) reported no response in seven patients irradiated for DI.
Broadbent and Chu (125) reported six patients with DI who failed to respond to irradiation.
Selch and Parker (30) irradiated two patients with DI 3 months after the onset of sy mptoms.
Neither of these patients responded. There were no responses among seven patients treated
with chemotherapy with or without irradiation by Willis et al. (28). El-Say ed and Brewin
(108) reported successful radiotherapy of two patients with DI. Grois et al. (126) found that
none of the five patients treated with 10 Gy of radiotherapy to the pituitary within 1 month of
the occurrence of DI was able to decrease the desmopressin dosage. Some have discounted
the value of RT for DI without contributing additional supporting data to the literature
(21,39,124,127).
Page 392The largest series of DI in LCH has been reported by Minehan et al. (48) and
Kilpatrick et al. (31) from the May o Clinic. In 45 evaluable patients, the principal findings
were as follows: 10 of the 28 (36%) irradiated patients had a complete or partial
improvement in their DI, as opposed to none of the 17 nonirradiated patients; 6 patients were
complete responders, 5 of whom were irradiated within 14 day s of the diagnosis of DI; 77%
of all patients with LCH and DI had a non-CNS head and neck site involved with LCH;
computed tomography (CT) or MRI improvement in a pituitary –hy pothalamic mass did not
correlate well with improvement in DI; and in 12 of the 28 patients (43%) irradiated for DI,
growth hormone (GH) deficiency or parahy popituitarism developed. Minehan et al. (48) did
a literature review, to which we can add published patients they did not include, to generate an
overall response rate of less than 25% of DI to radiation (30,31,39,44,45,46,47,48,49,125). We
believe that RT is worth considering in DI if sy mptoms are of recent onset (approximately 1
week). Others recommend RT even for long-standing DI in the hope of preventing local
disease progression and additional neuroendocrine dy sfunction.
Focal LCH involving the brain can be treated successfully with radiotherapy (58). On
rare occasions, LCH may diffusely involve the parenchy ma of the brain (57). The true
incidence of this event is not known. Brain involvement of this sort occurs in the most
aggressive form of the disease. On MRI, cerebral LCH may demonstrate parenchy mal
masses that intensively enhance after gadolinium is administered. Other patients may show
diffuse infiltration of brain structures without tumor formation. A retrospective review by
Hund et al. (59) identified 36 histologically evaluated cases of cerebral LCH with an
extrahy pothalamic localization. Sixteen of the patients had cerebral involvement during the
course of the previously diagnosed LCH, whereas 20 patients had cerebral LCH without a
history or sy mptoms of sy stemic disease before the neurologic presentation. Solitary brain
lesions were treated by surgery in 13 patients. Six remained free of disease for up to 2 y ears
of follow-up. In another six, follow-up was not reported. One patient died 4 weeks after
resection of a posterior fossa mass. In an additional six patients, surgery was followed by RT
(10–41 Gy ) because of recurrence of a lesion or incomplete resection. In five of the six
patients, the lesions disappeared and did not recur for up to 2 y ears of follow-up. In three
patients with multiple lesions, the disease was controlled by radiation or chemotherapy for up
to 3 y ears. In others, regression, relapse, or new lesions occurred despite various treatments.
Eight of the 36 patients died; 4 had multiple intracranial lesions, and the remaining 4 had
localized lesions.
Page 393Chemotherapy
In the first three editions of this book, we stated that in multifocal LCH the indications for
sy stemic therapy are controversial. Because there was no agreement on the important
prognostic factors in LCH, the selection of patients needing chemotherapy was difficult
(128,129,130,131). The lack of a uniformly applied staging sy stem made comparison of
specific chemotherapy programs difficult. Many clinicians were reluctant to use
chemotherapy in multisy stem disease because of the study of McLelland et al. (25). Forty -
four children with multisy stem disease, including 22 with organ dy sfunction, were treated
conservatively. Five had no treatment, 1 received topical nitrogen mustard only, 2 received
radiotherapy alone, and 36 were treated with prednisone. Of these 36 children, 21 were given
cy totoxic drugs later when disease progressed despite prednisone. The 2-y ear mortality rate
(36% with organ dy sfunction, 0% without organ dy sfunction) was no different from that of
historical studies using aggressive upfront sy stemic cy totoxic chemotherapy. The rate of
development of DI in the group of McLelland et al. was 36%, which is higher than that in
some but not all other series of the era (25,124,125).
From the 1970s to the 1990s, the reported complete and partial response rates of
advanced LCH to prednisone and a wide variety of single-agent cy totoxic chemotherapeutic
agents (chlorambucil, cy clophosphamide, etoposide, vinblastine, and vincristine) were
between 50% and 100% (25,27,128,129,130,131,132,133). (These data are reviewed in Table
17.5 in the third edition of this book.) Relapse after initial therapy was common. By the
early 1990s, if sy stemic therapy was elected for LCH, then the consensus view was to begin
with high-dose steroids, usually prednisone. If that failed, then most clinicians opted for either
etoposide or vinblastine as a single agent.
There are now several large cooperative group studies that offer guidance in selecting
appropriate patients for chemotherapy.
AIEOP-CNR-HX*83
This prospective multicenter trial included 12 different Italian institutions (61,134). The
objectives were to determine the outcome of patients stratified according to the presence or
absence of organ dy sfunction, to test the efficacy of different single-agent chemotherapy
approaches in patients with a good prognosis, and to determine the incidence of disease-
related disabilities before and after treatment. In children with a single lesion, treatment was
variable and consisted of either incisional biopsy, curettage, total excision, RT, or
chemotherapy. This good-prognosis group was treated with immunotherapy with crude calf
thy mic extract and then sequential single-agent chemotherapy. First-line treatment was
vinblastine. Poor responders then received doxorubicin, and patients in whom doxorubicin
failed were placed on etoposide. The poor-prognosis group, consisting of patients with organ
dy sfunction, was treated with vincristine, cy clophosphamide, and prednisone. Of the 90
eligible patients, 84 were evaluable. The 16 patients with mono-ostotic LCH or a
paravertebral intradural mass survived. All had initial complete responses, and 15 were
recurrence free 3–6 months after diagnosis. Fifty -four patients with sy stemic disease but
without organ dy sfunction received good-prognosis chemotherapy. Thirty -four achieved a
complete response with vinblastine. The multiagent program for the poor prognosis group was
given to 11 patients. Only 2 achieved complete response and were recurrence free at 36 and
66 months, respectively. The overall survival for the 84 evaluable children was 93% at 48
months. Survival at 48 months was 100% for the 60 children more than 2 y ears old and 79%
for the 24 children less than 2 y ears old. All 73 children without organ dy sfunction were long-
term survivors, and the 11 patients with organ dy sfunction had a 46% survival rate at 12
months. Of the total 90 eligible patients, 18 developed DI. One patient developed acute
nonly mphocy tic leukemia (ANLL) 2 y ears after diagnosis and treatment with vinblastine and
etoposide.
DAL-HX83
This trial accrued 106 patients from institutions in Austria, Germany, and the Netherlands
from 1983 to 1989 (29,46,61,74,135). Disseminated disease was defined as the presence of
multiple LCH lesions of any ty pe or combination, with the exception of multiple skin lesions.
Group A patients were those with multifocal bone disease: lesions in multiple bones or more
than two lesions in one bone. Group B patients either had soft tissue involvement with or
without bone lesions and without signs of organ dy sfunction or patients with a single-bone
lesion and a biopsy -proven contiguous soft tissue mass, regional ly mph node involvement, or
endocrinologic disabilities. Group C patients had dy sfunction of liver, lung, or the
hematopoietic sy stem.
All patients with disseminated disease received chemotherapy immediately after
diagnosis with prednisone, vinblastine, and etoposide. Thereafter, all patients received
continuous oral 6-mercaptopurine (6 MP) for 46 weeks. Patients in group A received
prednisone and vinblastine. Patients in group B received continuation treatment with
prednisone, vinblastine, and etoposide. Patients in group C received continuation therapy with
those three agents plus methotrexate.
Complete resolution was achieved in 86% of all patients at 4 months. In group A, 25 of
the 28 patients (89%) achieved initial complete resolution of LCH. Recurrence occurred in
only three children (12%). In group B, 52 of the 57 patients (91%) achieved resolution of
disease. Twelve patients (23%) had recurrent disease. In group C, 14 of the 21 patients (67%)
achieved resolution of disease. Of these 14 patients, 6 (42%) developed a recurrence.
Disease-free survival was 88% in group A, 73% in group B, and 64% in group C (p < 0.05).
DI developed in 15% of patients.
Page 394DAL-HX90
DAL-HX90, a follow-up to DAL-HX83, made moderate changes including less aggressive
induction therapy utilizing fewer initial doses of etoposide for group C patients. Methotrexate
was eliminated from group C continuation. These changes produced no significant difference
in outcome.
LCH 1
In the Histiocy te Society ’s first LCH randomized trial, 447 patients were registered (61,133).
All patients with disseminated multisy stem LCH received high-dose methy lprednisolone. One
hundred and forty -three patients were then randomized to receive either etoposide (69
patients) or vinblastine (74 patients). Vinblastine and etoposide were equivalent in response at
week 6 of therapy, response at the last evaluation, toxicity, probability of survival, frequency
of disease reactivation, and risk of DI. After 6 weeks of treatment, 53% of patients were drug
responders. Reactivation of disease after a complete response occurred in 58% of these
patients after a median of 9 months. Overall, 4-y ear survival was 78%; 91% in responders to
initial therapy versus 34% in initial nonresponders. In general the results of the LCH trial 1
(LCH1) were compared unfavorably with those of the DAL-HX83/90 studies. The response
rate was lower, and the activation rate was higher. Poly chemotherapy given for 1 y ear
appeared superior to 6 months of monotherapy.
LCH2
The results of the LCH1 and the DAL-HX studies formed the basis of the Histiocy te Society ’s
LCH2 study, which opened in 1996. This randomized trial to compare the effect of oral
prednisone combined with vinblastine with or without the addition of etoposide in high-risk
patients defined as those with multisy stem disease with at least one of the organ sy stems
involved. Low-risk patients were more than 2 y ears old without involvement of the
hematopoietic sy stem, liver, lungs, or spleen (135). High-risk patients were randomized
between initial treatment with vinblastine and prednisone versus vinblastine, prednisone, and
etoposide. All high-risk patients received 6 MP in continuation. Low-risk patients were all
treated with vinblastine and prednisone and did not receive 6 MP.
LCH2 was an international randomized trial which randomized 193 patients to treatment
arm A which consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18
weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses versus these drugs plus
etoposide which was added in arm B. Considering all 193 randomized risk patients, there were
similar outcomes: rapid (6 weeks) response (arm A vs. arm B: 63%/71%), 5-y ear survival
probability (74%/79%), disease reactivation frequency (46%/46%), and permanent
consequences (43%/37%). Patients <2 y ears of age without risk organ involvement had 100%
survival and >80% rapid response. Risk organ involved patients not responding within 6 weeks
had highest mortality. The more intensive arm B reduced mortality in risk organ involved
patients. Comparison of risk organ involved patients in LCH1 and LCH2 confirmed that
increasing treatment intensity increased rapid responses (from 43% in arm A LCH1 to 68% in
arm B LCH2; p = 0.027) and reduced mortality (44% in arm A LCH1 to 27% in arm B LCH2;
p = 0.042) (15,136).
JLSG-96
The Japanese Langerhans Cell Histiocy tosis Study Group conducted a protocol that enrolled
patients with newly diagnosed multifocal LCH. There were 32 patients with single-organ
disease and 59 patients with multiorgan disease. All received induction therapy with
cy tarabine, vincristine, and prednisolone for 6 weeks followed by 6 months of maintenance
with cy tarabine, vincristine, and methotrexate. Patients found to be poor responders during
induction therapy were then switched to doxorubicin, cy clophosphamide, vincristine, and
prednisolone.
In the single-organ disease group, the 5-y ear overall survival was 100%. Seventy -six
percent of patients with multiorgan disease had some response with initial induction and 63%
achieved good response by the end of maintenance. Of the responders, 46% had a sustained
remission (61).
LCH3
LCH1 and LCH2 showed that “risk” organ involvement (hematopoietic sy stem, spleen, liver,
and lungs) and poor response to initial chemotherapy are the crucial prognostic factors for
LCH. Age <2 y ears at diagnosis was not of independent prognostic importance. LCH3 was
the treatment protocol of the third international study for LCH. It included a randomized trial
for clinical multisy stem LCH and a pilot study for patients with single sy stem multifocal bone
disease and localized special site disease. Prednisone and vinblastine were established in
LCH3 as first-line treatment for multisy stem disease and a total treatment duration of 12
months is superior to 6 months. Since VP-16 has not proven beneficial and is leukemogenic, it
was not been included in LCH3 (15,136,137). For single sy stem multifacial bone disease, 12
months of prednisone/vinblastine is appropriate.
Salvage Therapy
The LCH1S study was established to study salvage therapy for patients who did not respond to
initial chemotherapy (60,61,131). No superior strategy has been demonstrated for patients
who failed to respond to steroids and vinblastine or etoposide.
Some of the agents that have been used are:
Dosage
There is no clear relationship between the dosage of irradiation and local control of LCH.
Childs and Kennedy (151) reported 12 patients treated with radiotherapy. Their series began
with an infant treated in 1927–1928 with a radium source. They thought that a dosage of
approximately 600 roentgens was necessary. Smith et al. (124) reported on 89 courses of
irradiation administered with 250-kV X-ray s or cobalt-60. Less than 1000 cGy was
administered in 92% of the cases, and the local success rate was 87%. Three of five sites
treated with less than 450 cGy had a local failure but were salvaged with additional
irradiation. Dosages greater than 1000 cGy did not appear to be more effective than dosages
of 450–1000 cGy.
Greenberger et al. (123) described 89 patients receiving RT to 380 fields for control of
bone lesions. Between 100 and 2000 cGy, local control was obtained in 75% of courses (Fig.
17.7 ). In a study of 56 irradiated sites, Selch and Parker (30) found no difference in
median dosage between controlled and relapsed bony sites (9 Gy vs. 10 Gy ) or soft tissue
sites (median dosage 15 Gy for either controlled or relapsed sites). Overall local control was
82% (Fig. 17.8 ). A review of radiotherapy for LCH from eight German centers described
80 patients treated to 74 bony sites and 28 nonbony sites with total doses of 3–50.4 Gy and a
median total dose of 15 Gy. Local control was no different with doses more or less than 10
Gy. There was a 77% complete remission rate, 12.5% partial remission, and 80% long term
local control rate (40). Reviews describe a very wide range of total dosages, with 5–10 Gy in
three to five fractions being the favored range (Fig. 17.9 ) (49). Cassady (152) advised
using a total dosage of 15–20 Gy in patients older than 18 y ears because of a perceived
higher risk of local failure and a lower risk of bone damage by radiation.
Figure 17.7 Local control of bone
lesions as a function of dosage delivered.
(From Greenberger JS, Cassady JR, Jaffe
N, et al. Radiation therapy in patients
with histiocytosis: management of
diabetes insipidus and bone lesions. Int J
Radiat Oncol Biol Phys. 1979;5:1749–1755,
with permission.)
Figure 17.8 A 4-month-old boy developed a seborrheic skin
rash with focal areas of ulceration. Skin biopsy showed
Langerhans cell histiocytosis (LCH). No other organ systems were
involved. At 6 months of age, proptosis was noted, and orbital
computed tomography scan demonstrated erosion of the lateral
wall of the right orbit by a destructive lesion. Surgery was felt to
be ill-advised because of concern over damage to the lateral
rectus muscle and an unacceptable cosmetic result. Vinblastine
and prednisone were administered. Proptosis improved but then
subsequently worsened. A total dosage of 6 Gy in four fractions
was administered with a right anterior oblique half-beam-
blocked 4-MV photon field with shielding of the lens and two-
thirds of the globe in 1984. Vinblastine was continued for 15
months after radiotherapy. The bone lesion healed within 2
months after irradiation. There is no evidence of LCH 32 years
after the initial diagnosis, the patient is a college graduate,
employed, married, and a father.
Figure 17.9 An 11-month-old boy presented to medical attention with protrusion of the
superior aspect of the left ear. Computed tomographic scan showed a left mastoid soft tissue
mass with erosion into the temporal bone. Open biopsy made the diagnosis of Langerhans
cell histiocytosis (LCH). In 1987, the child received local irradiation with 12-MeV electrons to
a total dosage of 6 Gy in three fractions. After irradiation, he was treated with vinblastine
and prednisone. He remains without evidence of persistent or recurrent LCH.
For DI, Smith et al. (124) reported no relief in seven patients treated with 500–1830 cGy.
Greenberger et al. (123) administered 345–1600 cGy to 21 patients and, as discussed
previously, observed a complete response in four patients and a partial response in another
four patients. Minehan et al. (48) reported three of the five patients (60%) with DI responding
when treated with more than 15 Gy, compared with 7 of 23 (30%) treated with less than 15
Gy. Saliba et al. (117) irradiated one of two DI patients with success.
Page 396Volume
Bone lesions should be treated with a field designed to cover the radiographic abnormality
with a small margin. In the treatment of skull lesions, we attempt to minimize the dosage to
the underly ing brain by treating with electrons or orthovoltage equipment. If electrons are
used, an adjustment for attenuation by compact bone infiltrated by LCH should be made.
This is best done by taking density measurements of the involved bone with a cranial CT scan.
To treat DI, one uses parallel opposed fields, arcs, a three-field technique, or
conformally planned fields to cover the hy pothalamic–pituitary axis.
Figure:
Local control of bone lesions as a function of dosage delivered.
(From Greenberger JS, Cassady JR, Jaffe N, et al. Radiation therapy in patients with
histiocytosis: management of diabetes insipidus and bone lesions. Int J Radiat Oncol Biol Phys.
1979;5:1749–1755, with permission.)
Figure:
A 4-month-old boy developed a seborrheic skin rash with focal areas of ulceration. Skin biopsy
showed Langerhans cell histiocytosis (LCH). No other organ systems were involved. At 6
months of age, proptosis was noted, and orbital computed tomography scan demonstrated
erosion of the lateral wall of the right orbit by a destructive lesion. Surgery was felt to be ill-
advised because of concern over damage to the lateral rectus muscle and an unacceptable
cosmetic result. Vinblastine and prednisone were administered. Proptosis improved but then
subsequently worsened. A total dosage of 6 Gy in four fractions was administered with a right
anterior oblique half-beam-blocked 4-MV photon field with shielding of the lens and two-thirds
of the globe in 1984. Vinblastine was continued for 15 months after radiotherapy. The bone
lesion healed within 2 months after irradiation. There is no evidence of LCH 32 years after
the initial diagnosis, the patient is a college graduate, employed, married, and a father.
Figure:
An 11-month-old boy presented to medical attention with protrusion of the superior aspect of
the left ear. Computed tomographic scan showed a left mastoid soft tissue mass with erosion
into the temporal bone. Open biopsy made the diagnosis of Langerhans cell histiocytosis
(LCH). In 1987, the child received local irradiation with 12-MeV electrons to a total dosage of
6 Gy in three fractions. After irradiation, he was treated with vinblastine and prednisone. He
remains without evidence of persistent or recurrent LCH.
LONG-TERM SEQUELAE OF LCH AND ITS TREATMENT
Because of the low dosage of irradiation used, acute side effects of radiotherapy for LCH are
rare. However, it is common to see late sequelae of LCH, most of which may be attributable
to the disease and some of which may be attributable to the treatment (153,154).
The French LCH Group reported 320 living patients followed for a median of 39.5
months. The most common sequelae were DI (18%), GH deficiency and short stature (5%),
hy pothy roidism (2.5%), deafness (2.5%), and vertebra plana and orthopedic sequelae (2.5%)
(22). The most common sequelae in the University of California, San Francisco, series were
DI (26%), growth failure (20%), sex hormone deficiency (16%), and hearing loss (16%)
(28). The 90 children followed by the Italian Cooperative Group had an overall incidence of
disease-related disabilities of approximately 48%. These included DI, orthopedic
abnormalities, growth defects, tooth loss, chronic hepatitis, exophthalmus, and hearing loss
(134). McLelland et al. (25,155) described orthopedic abnormalities, endocrine dy sfunction,
and liver fibrosis as well as DI. The incidence of DI in conservatively treated patients with
multisy stem disease, for whom treatment was reserved only for exacerbations, was 36%
compared with a 15% incidence in the DAL series and 20% in the Italian trial, both of which
used intensive chemotherapy. However, the McLelland series is from a single institution, and
referral bias may be accounted for the difference. In a study of 15 long-term survivors of
LCH, Ransom et al. (154) found that 7 had an IQ < 89. In a large study of the Histiocy te
Society, DI (24%), orthopedic abnormalities (20%), hearing loss (13%), and neurologic
consequences (11%) were most frequent (155).
Page 397Growth and endocrine disorders are common in multisy stem LCH. A study of
144 patients with multisy stem LCH evaluated at the Great Ormond Street Hospital for Sick
Children in London showed that 50 had endocrinopathy, 49 of whom had DI. GH
insufficiency was present in 21 patients. GH therapy was able to significantly improve
growth in these patients. It was not clear that RT to the head increased the incidence of GH
insufficiency. It is clear that children with LCH should be investigated for hormone
insufficiency, especially those who have DI or growth failure. It appears that GH
insufficiency is secondary to direct hy pothalamic–pituitary involvement by the disease.
Thickening of the pituitary stalk on MRI scan provides additional evidence of GH
insufficiency (156).
The frequency of secondary malignancy after therapy for LCH is uncertain (7,60). In a
report describing the association between LCH and other malignancies (91 patients), 39 had
LCH and ly mphoma (Hodgkin or non-Hodgkin), 22 had LCH and leukemia, and 30 had LCH
and a solid tumor, most commonly lung cancer. Although the leukemias and nonlung solid
tumors most commonly occurred y ears after LCH, most of the ly mphomas and lung cancers
preceded LCH or were diagnosed concurrently, in an unexplained association (157). Affected
patients had initially received irradiation and chemotherapy, irradiation only, or chlorambucil
only (62,158). One case of leukemia was seen among 90 patients followed in the Italian
Cooperative Group Study (134). One case of leukemia was seen in 51 patients followed for
more than 3 y ears at the University of California, San Francisco (28). There were no second
malignancies in 106 patients with LCH treated in the Dutch–German–Austrian DAL-HX83
trial (29,74,135).
Haupt et al. (159) evaluated children with LCH enrolled in three protocols of the Italian
Association of Pediatric Hematology /Oncology. These patients received a variety of
chemotherapy programs including vinblastine, adriamy cin, etoposide, vincristine,
cy clophosphamide, and prednisone. The median follow-up after entry into the study cohort
was 5 y ears and 5 months. There were three cases of ANLL, all in children who had
received etoposide. Two had received etoposide alone, and one had received etoposide in
combination with alky lating agent chemotherapy and other chemotherapy or RT.
RESULTS
In patients presenting with solitary LCH of bone, close to 100% survival has been reported
(23,24,38,39,84). In the presence of organ dy sfunction with multisy stem disease, survival
ranges from 33% to 54%. In its absence, survival ranges from 82% to 96% (20,23,33,35,62).
In the 348 patients reported from 32 French centers treated from 1983 to 1993, the 6-y ear
actuarial survival according to the DAL-HX staging sy stem was as follows: localized disease,
isolated unifocal or bifocal bone involvement, 100%; soft tissue involvement with or without
bone involvement, no organ dy sfunction, 90%; liver, lung, or bone marrow dy sfunction, 49%
(19). In the DAL-HX83 trial, the probability of survival, using the DALHX83 staging sy stem
for disseminated disease described earlier in this chapter, was 100% for group A, 96% for
group B, and 62% for group C. The 15-y ear survival rates in the series of Willis et al., by ty pe
of initial presentation, were skin disease only, 83%; monostotic disease, 100%; poly ostotic
disease, 100%; and multisy stem disease, 76% (28,46,135).
REFERENCES
1. Langerhans P. Uber die nerven der menschlichen haut. Arch Pathol Anat. 1868;44:325–
327.
2. Langerhans P. Berichtigungen (u.a. zu den nervenenden der haut, und nervenfasern im
rete). Arch Mikrosk Anat. 1882;20:641–643.
3. Egeler RM, Zantinga AR, Coppes MJ. Paul Langerhans Jr. (1847–1888): a short life, y et
two epony mic legacies. Med Pediatr Oncol. 1994;22:129–132.
4. Egeler RM. The Langerhans cell histiocy tosis X files revealed. Br J Hematol.
2002;116:3–9.
5. Jolles S. Paul Langerhans: a historical perspective. J Clin Pathol. 2002;55:243.
6. Hand A. Poly uria and tuberculosis. Arch Pediatr. 1893;10:673–675.
7. Lieberman PH, Jones CR, Dargeon HWK, et al. A reappraisal of eosinophilic granuloma
of bone, Hand–Schuller–Christian sy ndrome and Letterer–Siwe sy ndrome. Medicine.
1969;48:375–400.
8. Otani E, Ehrlich J. Solitary eosinophilic granuloma of bone simulating primary
neoplasm. Am J Pathol. 1940;16:479–490.
9. Lichtenstein L. Histiocy tosis X: integration of eosinophilic granuloma of bone, “Letterer–
Siwe disease,” and “Schuller–Christian disease” as related manifestations of a single
nosologic entity. Arch Pathol. 1953;56:84–102.
10. Banchereau J. The long arm of the immune sy stem. Sci Am. 2002;287:52–59.
11. Mahmoud HH, Wang WC, Murphy SB. Cy closporine therapy for advanced Langerhans
cell histiocy tosis. Blood. 1991;77:721–725.
12. Grana N. Langerhans cell histiocy stosis. Cancer Control. 2014;21:328–334.
13. Hurwitz CA, Faquin WC. A 15-y ear-old boy with a retro-orbital mass and impaired
vision. N Engl J Med. 2002;146:513–520.
14. Pinkkus GS, Lones MA, Matsumara F, et al. Langerhans cell histiocy tosis:
immunohistochemical expression of fascin, a dendritic cell marker. Am J Clin Pathol.
2002;118:335–343.
15. Histiocy te Society. Evaluation and treatment guidelines. 2009;The Histiocy te Society.
16. Castleman B, McNeely BU. Case records of the Massachusetts General Hospital, case
17-1970. N Engl J Med. 1970;282:917–925.
17. Velez-Yanguas MC, Warrier RP. Langerhans’ cell histiocy tosis. Orthop Clin North Am.
1996;27:615–623.
18. Willman CL, Busque L, Griffith BB, et al. Langerhans cell histiocy tosis (histiocy tosis X):
a clonal proliferative disease. N Engl J Med. 1994;331:154–160.
19. Cotter FE, Pritchard J. Clonality in Langerhans cell histiocy tosis. BMJ. 1995;310:74–75.
20. Yu RC, Chu C, Buluwela L, et al. Clonal proliferation of Langerhans cells in Langerhans
cell histiocy tosis. Lancet. 1994;343:767–768.
21. Egeler RM, Nesbit ME. Langerhans cell histiocy tosis and other disorders of monocy te–
histiocy te lineage. Crit Rev Oncol Hematol. 1995;18:9–35.
22. French Langerhans’ Cell Histiocy tosis Study Group. A multicentre retrospective survey
of Langerhans’ cell histiocy tosis. 348 cases observed between 1983 and 1993. Arch Dis
Child. 1996;75:17–24.
23. Page 398 Raney RB Jr, D’Angio GJ. Langerhans’ cell histiocy tosis (histiocy tosis X):
experience at the Children’s Hospital of Philadelphia, 1970–1984. Med Pediatr Oncol.
1989;17:20–28.
24. Starling KA, Donaldson MH, Haggard ME, et al. Therapy of histiocy tosis X with
vincristine, vinblastine, and cy clophosphamide. Am J Dis Child. 1972;123:105–110.
25. McLelland DJ, Broadbent V, Yeomans E, et al. Langerhans cell histiocy tosis: the case for
conservative treatment. Arch Dis Child. 1990;65:301–303.
26. Golpanian S, Tashiro J, Gerth DJ, et al. Pediatric histicy stosis in the United States:
incidence and outcomes. J Surg Res. 2014;190:221–229.
27. Chu T. Langerhans cell histiocy tosis. Aust J Dermatol. 2001;42:237–242.
28. Willis B, Ablin A, Weinberg V, et al. Disease course and late sequelae of Langerhans’
cell histiocy tosis: 25-y ear experience at the University of California, San Francisco. J
Clin Oncol. 1996;14:2073–2082.
29. Gadner H, Heitger A, Grois N, et al. Treatment strategy for disseminated Langerhans
cell histiocy tosis. Med Pediatr Oncol. 1994;23:72–80.
30. Selch MT, Parker RG. Radiation therapy in the management of Langerhans cell
histiocy tosis. Med Pediatr Oncol. 1990;18:97–102.
31. Kilpatrick SE, Wenger DE, Gilchrist GS, et al. Langerhans’ cell histiocy tosis (histiocy tosis
X) of bone. A clinopathologic analy sis of 263 pediatric and adult cases. Cancer.
1995;76:2471–2484.
32. Broadbent V, Heaf D, Pritchard J, et al. Occult multisy stem involvement in histiocy tosis
X (HX). Med Pediatr Oncol. 1986;14:113.
33. Lahey ME. Histiocy tosis X: comparison of three treatment regimens. J Pediatr.
1975;87:179–183.
34. Lahey ME. Prognostic factors in histiocy tosis X. Am J Pediatr Hematol Oncol.
1981;3:57–60.
35. Lipton J. The pathogenesis, diagnosis, and treatment of histiocy tosis sy ndromes. Pediatr
Dermatol. 1983;1:112–120.
36. Starling KA. Chemotherapy of histiocy tosis. Am J Pediatr Hematol Oncol. 1981;3:157–
160.
37. Dagenais M, Pharoah MJ, Sikorski PA. The radiographic characteristics of histiocy tosis
X. Oral Surg Oral Med Oral Pathol. 1992;74:230–236.
38. Slater JM, Swarm OJ. Eosinophilic grenuloma of bone. Med Pediatr Oncol. 1980;8:151–
164.
39. Sessa S, Sommelet D, Lascombes P, et al. Treatment of Langerhans-cell histiocy tosis in
children. Experience at the Children’s Hospital of Nancy. J Bone Joint Surg Am.
1994;76(10):1513–1525.
40. Kriz J, Eich HT, Bruns F, et al. Radiotherapy in Langerhans cell histiocy tosis – a rare
indication in a rare disease. Radiation Oncology. 2013;8:233–239.
41. Abel-Aziz M, Rashed M, Khalifa B, et al. Easinophialic granuloma of the temporal lobe
in children. J Craniofac Surg. 2014;25:1076–1078.
42. Filcoma D, Weedleman H, Arceci R, et al. Pediatric histiocy tomas: characterization,
prognosis and oral management. Am J Pediatr Hematol Oncol. 1993;15:226–230.
43. Dhull AK, Aggarwal S, Kaushal V, Singh S. Into the wild world of eosinophilic
granuloma. BMJ Case Report 2013 Nov 19: 2013. pii: bcr2013200522. doi: 10.1136/bcr-
2013-200522
44. Mey er JS, Harty MP, Mahboudi S, et al. Langerhans cell histiocy tosis: presentation and
evolution of radiologic findings with clinical correlation. Radiographics. 1995;15:1135–
1146.
45. Ghafoori S, Mohsenis S, Larijani B, et al. Pituitory stalk thickening in a case of
Langerhans cell histiocy stosis. Arch Iran Med. 2015;18:193–195.
46. Grois N, Flucher-Wolfram B, Heitger A, et al. Diabetes insipidus in Langerhans cell
histiocy tosis: results from the DAL-HX 83 study. Med Pediatr Oncol. 1995;24:248–256.
47. Angeli SI, Hoffman HT, Alcalde J, et al. Langerhans cell histiocy tosis of the head and
neck in children. Ann Otol Rhinol Laryngol. 1995;104:173–180.
48. Minehan KJ, Chen MG, Zimmerman D, et al. Radiation therapy for diabetes insipidus
caused by Langerhans cell histiocy tosis. Int J Radiat Oncol Biol Phys. 1992;23:519–524.
49. Dunger DB, Broadbent V, Yeoman E, et al. The frequency and natural history of
diabetes insipidus in children with Langerhans’ cell histiocy tosis. N Engl J Med.
1989;321:1157–1162.
50. Seo P. Cases from the Osler medical service of Johns Hopkins University. Am J Med.
2002;112:667–669.
51. Pittman T, Grant J, Darling C, et al. An eight-month-old boy with a skull mass. Pediatr
Neurosurg. 2002;37:100–104.
52. Gerrard MP, Hendry MM, Eden OB. Comparison of radiographic and scintigraphic
assessment of skeletal lesions in histiocy tosis X. Med Pediatr Oncol. 1986;14:113.
53. Phillips M, Allen C, Gerson P, et al. Comparison of FDG-PET scans to conventional
radiography and bone scans in management of Langerhans cell histiocy tosis. Pediatr
Blood Cancer. 2009;52(1):97–101.
54. Onal C, Oy mak E, Rey han M, et al. Multifocal soft tissue Langerhans’ cell histiocy tosis
treated with PET-CT based conformal radiotherapy. Jpn J Radiol. 2015. doi:
10.1007/s11604-015-0466-6.
55. Hay ward J, Packer R, Finlay J. Central nervous sy stem and Langerhans’ cell
histiocy tosis. Med Pediatr Oncol. 1990;18:325–328.
56. Chellapandian D, Shaikl F, Van den Bos C, et al. Management and outcome of patients
with Langerhans cell histiocy tosis and single-bone CNS-risk lesions: a multi-institutional
retrospective study. Pediat Blood Cancer. 2015;62:2162–2166. doi: 10.1002/pbc.25645.
57. Rube J, Para SDL, Pickren JW. Histiocy tosis X with involvement of brain. Cancer.
1967;20:486–492.
58. Cai S, Zhang S, Liu X, et al. Solitary Langerhans cell histiocy tosis of frontal lobe: a case
report and literature review. Clin J Cancer Res. 2014;26:211–214.
59. Hund E, Steiner HH, Jansen O, et al. Treatment of cerebral Langerhans cell
histiocy tosis. J Neurol Sci. 1999;171:145–152.
60. Broadbent V, Gadner H. Current therapy for Langerhans cell histiocy tosis. Hematol
Oncol Clin North Am. 1998;12:327–338.
61. Allen CE, McKain KL. Langerhans’ cell histiocy tosis: a review of past, current and
future therapies. Drugs Today. 2007;43:627–643.
62. Greenberger JS, Crocker AC, Vawter G, et al. Results of treatment of 127 patients with
sy stemic histiocy tosis (Letterer–Siwe sy ndrome, Schuller–Christian sy ndrome and
multifocal eosinophilic granuloma). Medicine. 1981;60:311–338.
63. Cohen M, Fornoza J, Cangir A, et al. Direct injection of methy lprednisolone sodium
succinate in the treatment of solitary eosinophilic granuloma of bone. Radiology.
1980;136:289–293.
64. Scaglietti O, Marchetti PG, Bartolozzi P. Final results obtained in the treatment of bone
cy sts with methy lprednisolone acetate (Depo Medrol) and a discussion of the results
achieved in other bone lesions. Clin Orthop. 1982;165;33–42.
65. Nauert C, Zornoza J, Ay ala A, et al. Eosinophilic granuloma of bone: diagnosis and
management. Skeletal Radiol. 1983;10:227–235.
66. Ruff S, Chapman GK, Tay lor TKF, et al. The evolution of eosinophilic granuloma of
bone: a case report. Skeletal Radiol. 1983;10:37–39.
67. Capana R, Springfield DS, Ruggieri P, et al. Direct cortisone injection in eosinophilic
granuloma of bone. Radiology. 1980;136:289–293.
68. Fradis M, Podoshin L, Ben-David J, et al. Eosinophilic granuloma of the temporal bone. J
Laryngol Otal. 1985;99:475–479.
69. Wirtschafter JD, Nesbit ME, Anderson P, et al. Intralesional methy lprednisolone for
Langerhans’ cell histiocy tosis of the orbit and cranium. J Pediatr Ophthalmol Stabismus.
1987;24:194–197.
70. Jones LR, Toth BB, Cangir A. Treatment for solitary eosinophilic granuloma of the
mandible by steroid injection: report of a case. J Oral Maxillofac Surg. 1989;47:306–309.
71. Kindy -Degnan NA, Laflamme P, Duprat G, et al. Interlesional steroid in the treatment
of an orbital eosinophilic granuloma [letter]. Arch Ophthalmol. 1992;12:811–814.
72. Egeler RM, Thompson RC Jr, Voute PA, et al. Inralesional infiltration of corticosteroids in
localized Langerhans’ cell histiocy tosis. J Pediatr Orthop. 1992;12:811–814.
73. Lahey ME, Hey n RM, Newton WA Jr, et al. Histiocy tosis X: clinical trial of
chlorambucil: a report from Children’s Cancer Study Group. Med Pediatr Oncol.
1979;7:197–203.
74. Gadner H, Heitger A, Ritter J, et al. Langerhanszell-histiozy tose im kindesalter-
ergebnisse der DAL-HX 83 studies. Klin Padiatr. 1987;199:173–182.
75. Berry DH, Gresik M, May bee D, et al. Histiocy tosis in bone only. Med Pediatr Oncol.
1990;18:292–294.
76. McGaran MH, Spady HA. Eosinophilic granuloma of bone. A study of 28 cases. J Bone
Joint Surg. 1960;42A:979–992.
77. Sartoris DJ, Parker BR. Histiocy tosis X: rate and pattern of resolution of osseous lesions.
Radiology. 1984;152:679–684.
78. Page 399 Alexander JE, Seibert JJ, Berry DH, et al. Prognostic factors for healing of
bone lesions in histiocy tosis X. Pediatr Radiol. 1988;18:326–332.
79. Komp DM. Langerhans cell histiocy tosis. N Engl J Med. 1987;316:747–748.
80. Komp DM. Long-term sequelae of histiocy tosis X. Am J Pediatr Hematol Oncol.
1981;5:165–168.
81. Smith JH, Fulton L, O’Brien JM. Spontaneous regression of orbital Langerhans cell
granulomatosis in a three-y ear-old girl. Am J Ophthalmol. 1999;128:119–121.
82. Minkov M. Multisy stem Langerhans cell histiocy tosis in children: current treatment and
future directions. Paediatr Drugs. 2011;13:75–86.
83. Bernard F, Thomas C, Betrand Y, et al. Mult-centre pilot study of 2-
chlorodeoxy adenosine and cy tosine arabinoside combined chemotherapy in refractory
Langerhans cell histicy tosis with hoenatological dy sfunction. Eur J Cancer.
2005;41:2682–2689.
84. Smith DG, Nesbit ME Jr, D’Angio GJ, et al. Histiocy tosis X: role of radiation therapy in
management with special reference to dose levels employ ed. Radiology. 1973;106:419–
422.
85. Pfeifer J. Zur Diagnostik und Therapie des eosinophilen Knochengranuloms.
Strahlenther. 1965;126:42–52.
86. Bopp HJ, Gunther D. Die Strahlenbehandlung des eosinophilen Granuloms. Strahlenther.
1965;126:42–52.
87. Oshsner SF. Eosinophilic granuloma of bone: experience with 20 cases. Am J Roentgenol.
1966;97:719–726.
88. Davidson RE, Shillito J. Eosinophilic granuloma of the cervical spine in children.
Pediatrics. 1970;45:746–752.
89. Fowles JV, Bobechnkio WP. Solitary eosinophilic granuloma in bone. J Bone St Surg (Br).
1970;52-B:238–243.
90. Lindenbaum B, Gettes NI. Solitary eosinophilic granuloma of the cervical region—a
case report. Clin Orthop. 1970;68:112–114.
91. Winkelmann RK, Burgert EO. Therapy of histiocy tosis X. Br J Derm. 1970;82:169–175.
92. Rodrigues RJ, Lewis HH. Eosinophilic granuloma of bone—review of literature and case
presentation. Clin Orthop Relat Res. 1971;77:183–192.
93. Von Koppenfels R, Wannenmacher M. Zur Klink und Therapie des eosinophilen
Granuloms im Bereich des Geichtsschadels. Dtsch Zaharzl Z. 1973;28:514–519.
94. Metha DN, Romani GV, Chatterjee AK, et al. Eosinophilic granuloma of the temporal
bone. J Laryn Otol. 1974;88:185–191.
95. Mukadum FK, Pinto JM. Eosinophilic granuloma. Indian J Cancer. 1977;14:92–96.
96. Sweet RM, Kornblut AD, Hy ams VJ. Eosinophilic granuloma in the temporal bone.
Laryngoscope. 1979;89:1545–1552.
97. Gmelin E, von Lieven H. Zur Strahlentherapie des eosinophilen Kochengranuloms.
Strahlentherapie. 1980;156:611–615.
98. Pereslegin IA, Ustinova VF, Podly aschuk EL. Radiotherapy for eosinophilic granuloma
of bone. Int J Radiat Oncol Biol Phys. 1981;7:317–321.
99. Wester SM, Beabout JW, Unmi KK, et al. Langerhans’ cell granulomatosis (histiocy tosis
X) of bone in adults. Am J Surg Pathol. 1982;6:413–416.
100. Shelby JH, Sweet RM. Eosinophilic granuloma of the temporal bone: medical and
surgical management in the pediatric patient. South Med J. 1983;76(1):65–70.
101. Rawlings CE III, Wilkins RH. Solitary eosinophilic granuloma of the skull. Neurosurgery.
1984;15:155–161.
102. Hauk HK, Ahlendorf W. Strahlentherapie eines eosinophilen Granulomas mit multiplen
Kochenherden. Radiobiol Radiother. 1986;27:436–440.
103. Anonsen CK, Donaldson SS. Langerhans’ cell histiocy tosis of the head and neck.
Laryngoscope. 1987;97:537–542.
104. Selch MT, Fu YS. Regressing aty pical histiocy tosis: a case report of control following low
dose radiotherapy therapy. Int J Radiat Oncol Biol Phys. 1987;13:1739–1745.
105. Mackenzie WG, Morton KS. Eosinophilic granuloma of bone. Can J Surg. 1988;31:264–
267.
106. Rivera-Luna M, Martinez-Guerra G, Altamirano-Alvarez E, et al. Lagerhans’ cell
histiocy tosis: clinical experience with 124 patients. Pediatr Dermatol. 1988;5:145–150.
107. Wiegel T, Sommer K, Knop J, et al. Radiotherapy of solitary and multiple eosinophilic
granulomas of bone (stage 1). Strahlenther Onkol. 1991;167(7):403–406.
108. El-Say ed S, Brewin TB. Histiocy tosis X: does radiotherapy still have a role? Clin Oncol
(R Coll Radiol). 1992;4(1):27–31.
109. Fiorillo A, Sadile F, DeChiara C, et al. Bone lesions in Langerhans’ cell histiocy tosis. Clin
Pediatr Oncol. 1993;32:118–120.
110. Irving RM, Broadbent V, Jones NS. Langerhans’ cell histiocy tosis in childhood:
management of head and neck manifestations. Laryngoscope. 1994;104:64–70.
111. Floman Y, Bar-On E, Mosheiff R, et al. Eosinophilic granuloma of the spine.
Laryngoscope. 1987;97(5):537–542.
112. Dornfeld S, Winkler C, Dorr W, et al. Kasuistik eines eosinophilen Granuloms im
Erwachsenenalter und Literaturubersicht. Strahlenther Onkol. 1999;174:534–535.
113. Braier J, Chantada G, Rosso D, et al. Langerhans’ cell histiocy tosis: retrospective
evaluation of 125 patients at a single institution. Pediatr Hematol Oncol. 1999;16:377–385.
114. Hey d R, Strbmann G, Donnerstag F, et al. Strahlentherapie bie der Langerhanszell-
Histiozy tose Zwei Einzelfalberichte—Literaturubersicht. Röntgenpraxis. 2000;35:103–
115.
115. Ghanem I, Tolo VT, D’Ambra P, et al. Langerhans cell histiocy tosis of bone in children
and adolescents. J Pediatr Orthop. 2003;23(1):124–130.
116. Sarkar S, Singh M, Nag D, et al. A case report of unifocal Langerhans’ cell histiocy tosis
or eosinophilic granuloma. J Indian Med Assoc. 2007;105:218–220.
117. Saliba I, Sidani K, El Fata F, et al. Langerhans’ cell histiocy tosis of the temporal bone in
children. Int J Pediatr Otorhinolaryngol. 2008;72:775–786.
118. Olschewski T, Seegenschmiedt MH. Radiotherapy of Langerhans’ Cell Histiocy tosis:
Results and implication of a national Patterns-of-care Study. Strahlenther Onkol.
2006;182:629–634.
119. Kindy -Degnan NA, Laflamme P, Duprat G, et al. Intralesional steroid in the treatment
of an orbital eosinophilic granuloma [letter]. Arch Ophthalmol. 1991;109:617–628.
120. Kieffer SA, Nesbit ME, D’Angio GJ. Vertebra plane due to histiocy tosis X: serial studies.
Acta Radiol. 1969;8:241–250.
121. Alston RD, Tatevossian RG, McNanny RJ, et al. Incidence and survival of childhood
Langerhans cell histiocy tosis in Northwest England from 1954 to 1998. Pediatr Blood
Cancer. 2007;48(5):555–560.
122. Matus-Ridley M, Raney RB Jr, Thawerani H, et al. Histiocy tosis X in children: patterns
of disease and results of treatment. Med Pediatr Oncol. 1983;11:99–105.
123. Greenberger JS, Cassady JR, Jaffe N, et al. Radiation therapy in patients with
histiocy tosis: management of diabetes insipidus and bone lesions. Int J Radiat Oncol Biol
Phys. 1979;5:1749–1755.
124. Braier J, Rosso D, Pollano D, et al. Sy mptomatic bone Langerhans cell histiocy tosis
treated at diagnosis or after reactivation with indomethacin alone. J Pediatr Hematol
Oncol. 2014, on-line
125. Broadbent V, Chu AC. Langerhans cell histiocy tosis. In: Plowman PN, Pinkerson CR,
eds. Paediatric Oncology: Clinical Practices and Controversies. 2nd ed. London,
England: Chapman & Hall; 1997:546–560.
126. Grois N, Potschger U, Prosch H, et al. DALHX-and LCH1 and 11 Study Committee.
Pediatr Blood Cancer. 2006;46(2):228–233.
127. Demiral AN. The role of radiotherapy in the management of diabetes insipidus caused
by Langerhans cell histiocy tosis. J BUON. 2002;7:217–219.
128. Nezelof C, Barbey S, Gane P, et al. Histiocy tosis X: a proliferation disorder of the
Langerhans’ cell sy stem. Med Pediatr Oncol. 1986;14:108–109.
129. Berry DH, Gresik MV, Humphrey GB, et al. Natural history of histiocy tosis X: a
Pediatric Oncology Group study. Med Pediatr Oncol. 1986;14:1–5.
130. Raney RB Jr. Chemotherapy for children with aggressive fibromatosis and Langerhans’
cell histiocy tosis. Clin Orthop. 1991;262:58–63.
131. Savinas A, Rageliene L. Role of chemotherapy in disseminated Langerhans cell
histiocy tosis. Med Pediatr Oncol. 1992;20:452.
132. West WO. Velban as treatment for disseminated eosinophilic granuloma of bone: follow-
up note after seventeen y ears. J Bone Joint Surg Am. 1984;66:1128.
133. Katz BZ. Treatment for multisy stem Langerhans’ cell histocy tosis. J Pediatr.
2002;140:280.
134. Ceci A, DeTerlizzi M, Colella R, et al. Langerhans cell histiocy tosis in childhood: results
from the Italian Cooperative AIEOP-CNR-H.X. 1983 study. Med Pediatr Oncol.
1993;21:259–264.
135. Page 400 Gadner H, Grois N, Arico M, et al. A randomized trial of treatment for
multisy stem Langerhans cell histiocy tosis. J Pediatr. 2001;138:728–734.
136. Gadner H, Grois N, Pötschger U, et al. Improved outcome in multisy stem Langerhans
cell histiocy tosis is associated with therapy intensification. Blood. 2008;111(5):2556–
2562.
137. Satter EK, High WA. Langerhans cell histiocy tosis: a review of the current
recommendations of the Histiocy te Society. Pediatr Dermatol. 2008;25(3):291–295.
138. Rodriguez-Galindo C, Kelly P, Jeng M, et al. Treatment of children with Langerhans cell
histiocy tosis with 2-chlorodeoxy adenosine. Am J Hematol. 2002;69:179–184.
139. Hampshire AP, Saven A. Update of cladribine in the treatment of adults with
Langerhans-cell histiocy tosis. J Clin Oncol. 2004;22(145):6602.
140. Sheehan MP, Atherton DJ, Broadbent V, et al. Topical nitrogen mustard: an effective
treatment for cutaneous Langerhans cell histiocy tosis. J Pediatr. 1991;119:317–321.
141. May ou SC, Chu AC, Munro DD, et al. Langerhans cell histiocy tosis: excellent response
to etoposide. Clin Exp Dermatol. 1991;16:292–294.
142. Concepcion W, Esquivel CO, Terry A, et al. Liver transplantation in Langerhans’ cell
histiocy tosis (histiocy tosis X). Semin Oncol. 1991;8:24–28.
143. Gurthery SL, Heubi JE. Liver involvement in childhood histiocy tic sy ndromes. Curr
Opin Gastroenterol. 2001;17(5):474–478.
144. Conter V, Reciputo A, Arrigo C, et al. Bone marrow transplantation for refractory
Langerhans’ cell histiocy tosis. Haematologica. 1996;81:468–471.
145. Greinix HT, Storb R, Sanders JE, et al. Marrow transplantation for treatment of
multisy stem progressive Langerhans’ cell histiocy tosis. Bone Marrow Transplant.
1992;10:39–44.
146. Morgan G. My eloablative therapy and bone marrow transplantation for Langerhans’ cell
histiocy tosis. Br J Cancer. 1994;23(suppl):552–553.
147. Suminoe A, Matsuzaki A, Hattari H, et al. Unrelated cord blood transplantation for an
infant with chemotherapy -resistant progressive Langerhans cell histiocy tosis. J Pediatr
Hematol Oncol. 2001;23:633–636.
148. Nagarajan R, Neglia J, Ramsay N, et al. Successful treatment of refractory Langerhans
cell histiocy tosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol.
2001;23:629–632.
149. Steiner M, Matthes-Martin S, Attarbaschi A, et al. Improved outcome of treatment-
resistant high-risk Langerhans cell histiocy tosis after allogeneic stem cell transplantation
with reduced-intensity conditioning. Bone Marrow Transplant. 2005;36:215–222.
150. Lai CC, Huang WC, Chang SN. Successful treatment of refractory Langerhans cell
histiocy tosis by allogeneic peripheral blood stem cell transplantation. Pediatr Transplant.
2008;12(1):99–104.
151. Childs DS Jr, Kennedy RLJ. Reticuloendotheliosis of children: treatment with roentgen
ray s. Radiology. 1951;57:653–661.
152. Cassady JR. Current role of radiation therapy in the management of histiocy tosis X.
Hematol Oncol Clin North Am 1987; 1: 123-129.
153. Komp DM. Therapeutic strategies for Langerhans cell histiocy tosis. J Pediatr.
1991;119:274–275.
154. Ransom JL, Morris P, John RG, et al. Neuropsy chological late sequelae of histiocy tosis X
[abstract]. Pediatr Res. 1978;12:47.
155. McClelland J, Pritchard J, Chu AC. Current controversies. Hematol Oncol Clin North Am.
1987;1:147–162.
156. Nandurf VR, Barelile P, Pritchard J, et al. Growth and endocrine disorders in
multisy stem Langerhans’ cell histiocy tosis. Clin Endocrinol. 2000;53:509–515.
157. Haupt R, Nanduri V, Calevo MG, et al. Permanent consequences in Langerhans cell
histiocy tosis patients: a pilot study from the Histiocy te Society —Late Effects Study
Group. Pediatr Blood Cancer. 2004;42:483–484.
158. Egeler RM, Neglia JP, Puccetti DM, et al. The association of Langerhans’ cell
histiocy tosis with malignant neoplasms. Cancer. 1993;71:865–874.
159. Haupt R, Fears TR, Rosso P, et al. Increased risk of secondary leukemia after single-
agent treatment with etoposide for Langerhans’ cell histiocy tosis. Pediatr Hematol Oncol.
1994;11:499–507.
160. Richter MP, D’ANgio GJ. The role of radiation therapy in the management of children
with histiocy tosis X. Am J Pediatr Hematol Oncol. 1981;8:24–28.
161. Iwatsuki K, Tsugiki M, Yoshizawa N, et al. The effect of phototherapies on cutaneous
lesions of histiocy tosis X in the elderly. Cancer. 1986;57:1931–1936.
CH A P TER 18
Vascular Neoplasms and Skin Cancer
Natia Esiashvili and Ronica H. Nanda
Page 404In contrast, vascular malformations are essentially stable, demonstrating little or no
growth over time. These structural malformations include capillary (port-wine stain), venous,
ly mphatic, and arteriovenous malformations. Vascular malformations are subdivided into two
major groups: low- or slow-flow and high- or fast-flow.
Low-flow malformations involve a combination of capillary, venous, and ly mphatic
elements. High-flow malformations alway s have an arterial component along with variable
combinations of slow-flow elements. A variety of regional sy ndromes associated with low- or
fast-flow vascular malformations have been described.
Sturge–Weber sy ndrome, the most common of these, is thought to result from
nonhereditary defective regression and maturation of the primitive venous plexus. It presents
at birth with a facial capillary malformation (formerly port-wine stain), and seizures occur in
80% of children by 1 y ear (31). Mental retardation and glaucoma occur in 50% and 30% of
children, respectively. Sturge–Weber sy ndrome is progressive with no cure (32,33).
Klippel–Trenaunay sy ndrome is the second most common regional sy ndrome with low-
flow vascular malformations. It is thought to be caused by an anomaly of the ischial venous
sy stem leading to persistent malformed venous channels. Klippel–Trenaunay sy ndrome
presents with a regional capillary malformation, congenital varicose veins, and overgrowth
(34,35).
Parkes–Weber sy ndrome, although rare, is the most common regional sy ndrome with
high-flow vascular malformations. It may be confused with Klippel–Trenaunay sy ndrome
because of overlapping clinical manifestations, such as limb overgrowth.
Hereditary hemorrhagic telangiectasia, or Osler–Weber–Rendu sy ndrome, is the most
common diffuse sy ndrome with high-flow malformations. It is an autosomal dominant
disorder caused by abnormal growth factor (TGF)-β which controls mesenchy mal and soft-
tissue cell differentiation, proliferation, and cell death (36,37). Treatment depends on
sy mptoms but often requires multispecialty long-term planning. Catheter embolization of
feeder vessels has been successful; however, it comes with the risk of complications (38).
On rare occasions, the radiation oncologist is consulted on cases of vascular
malformations. Response of even large, sy mptomatic lesions to radiotherapy to a total dose
of 30–40 Gy can be substantial (39,40,41). Effective use of gamma knife radiosurgery has
been described for orbital hemangiomas, while increasing the possibility of visual function
preservation in selected cases in which the lesion is adjacent to the optic apparatus (42).
However, consideration of radiotherapy should be highly selective due to risk of late effects,
particularly secondary malignancy.
Rades et al. (43) analy zed the outcome after radiation therapy in the treatment of
sy mptomatic vertebral vascular malformations from University Hospital Eppendorf
(38,43,44,45,46,47). A total of 117 patients were evaluated, ranging in age from 12 to 78
y ears (median age 47 y ears). To identify a dose–effect relationship, patients were divided
into two groups based on the total radiation dose of 20 Gy (n = 62, median total dose 30 Gy )
or 36 Gy (n = 55, median dose 40 Gy ). Complete pain relief was achieved in 82% of the
higher dose group and 39% of the lower dose group (p = 0.003). Complete or partial pain
relief was obtained in 100% and 87% of the higher dose and lower dose patients, respectively.
This analy sis suggests that a total of 40 Gy delivered in 2 Gy per fraction can provide
effective palliation of sy mptomatic vertebral hemangiomas, likely mostly constituted of
vascular malformation based on the contemporary ISSVA classification sy stem (43).
Ly mphatic malformations usually are first noted in the neonate and can produce
sy mptoms at any age. They can occur throughout the body but predominate in the neck.
They may infiltrate the tongue or the floor of the mouth, causing deformity, pain associated
with frequent infections, and obstruction of the aerodigestive passages. Spontaneous
regression of these lesions is rare (48).
Four distinct forms have been described. These include capillary ly mphatic
malformations, an uncommon lesion that may have the appearance of an ordinary wart or
group of small vesicles. These lesions consist of a network of ly mphatic spaces formed by
small- and medium-sized vessels. Cavernous ly mphatic malformations occur in the skin and
subcutaneous tissue, salivary glands, and lips. These are diffuse spongy masses, often with
indistinct margins. They consist of multiple dilated ly mph channels that are lined with either
single or multiple lay ers of endothelial cells. Cy stic hy gromas are the most common
ly mphatic malformations. They are composed of cy sts ranging from a few millimeters to
several centimeters in diameter. The cy sts compress surrounding tissues, and small vessels
course over their walls.
Although surgical excision is the preferred therapy for ly mphatic malformations, this
may be difficult in certain situations and entail repeated operations (49,50,51). Various
sclerotherapy agents have been shown to have minimal effects and have been problematic
because of poor cosmetic outcome (52). Bleomy cin fat emulsions and, more recently, OK-
432 (Picibanil), an immunostimulant composed of group A Streptococcus pyogenes, have
been advocated for the treatment of unresectable malformations (49, 53,54,55). A sy stematic
review of the published literature regarding the efficacy of nonsurgical therapies in the
treatment of head and neck ly mphatic malformations in children was published in 2008 (56).
Random-effects modeling revealed that 43% of patients undergoing sclerotherapy with OK-
432 achieved a complete/excellent response, 23.5% achieved a good response, 16.9%
achieved a fair/poor response, and 15.4% observed no response. In the bleomy cin group, the
results were: 35.2% excellent, 37.1% good, 18.4% fair/poor, and 11.6% no response. Of note,
seven major complications were noted out of 289 patients in the series, including two
mortalities. The efficacy of this agent in treating large lesions in children has been questioned
elsewhere (57).
Radiation therapy is rarely used, although dramatic responses of neck, chest (58), vulva
(59), and mesenteric ly mphangiomas to external beam radiotherapy have been reported in
the literature (58,60,61,62). Fractionated radiotherapy to a total dosage of 15–30 Gy was
commonly used to treat the head and neck malformations. However, late toxicities, including
inhibition of bone growth and soft tissue development and the increased risk of cancer, should
be carefully considered in the decision to treat.
BASAL AND SQUAMOUS CELL CARCINOMAS
Page 405Nonmelanoma skin cancers like basal and squamous cell skin cancers are extremely
rare in childhood (63,64,65,66). Ty pically, they occur in predisposition sy ndromes, like in
basal cell nevus sy ndrome (BCNS) or xeroderma pigmentosa (XP). BCNS may provide a
unique example of the genetic–environmental interaction in the production of malignancies.
BCNS (also known as nevoid basal cell carcinoma sy ndrome or Gorlin sy ndrome) is
characterized by a positive family history for the sy ndrome, the occurrence of multiple basal
cell epitheliomas, keratocy sts of the jaw, epidermal cy st and hamartoma formation, palmar
and plantar pits, skeletal abnormalities, and oculoneurologic abnormalities (67). Intellectual
deficit is present in up to 5% of cases (67). Nevoid basal cell carcinoma sy ndrome is caused
by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with
complete penetrance and variable expressivity (68). XP is an autosomally dominant inherited
disease. The clinical manifestations occur primarily on sun-exposed skin that develops
abnormal pigmentation and multiple malignant tumors. Areflexia, mental retardation, and
other neurologic abnormalities are associated with XP. The biochemical defect appears to be
a poor ability to repair ultraviolet-induced DNA damage. Basal cell and squamous cell
carcinomas of the skin may develop in patients with XP.
There are several environmental exposures known to increase risk of nonmelanoma skin
cancers. They can arise in a nevus sebaceous (69), after thorium X treatment of a
hemangioma (70). Cranial irradiation for acute ly mphoblastic leukemia has significant
association with development of skin cancers (71). The Childhood Cancer Survivor Study
(CCSS) found that among the 13,132 five-y ear survivors of childhood and adolescent, 213
have reported nonmelanoma skin cancers (72). Radiotherapy was associated with a 6.3-fold
increase in risk. Ninety percent of patients had previously received radiation therapy ; 90% of
tumors occurred within the radiotherapy field. Another study evaluated 6306 patients who
received high-dose chemotherapy at ages 0–65 y ears after conditioning regimens with (n =
3870) or without (n = 2436) total-body irradiation (73). Patients were followed from 100 day s
to 36.2 y ears after receiving high-dose chemotherapy. The risk associated with radiation
exposure was higher for the y oung ones, with relative risks exceeding 20 for those
transplanted at ages below 10 y ears, and decreased with increasing age at exposure until age
40 y ears.
About 5–10% of BCNS develop in a setting of medulloblastoma therapy (74). Multiple
basal cell epitheliomas have been reported within 6 months to 3 y ears of craniospinal
irradiation. These skin cancers develop at an age distinctly earlier and in a distribution unlike
that of family members with BCNS. The distribution of basal cell epitheliomas corresponds to
the radiotherapy ports. The development of multiple cutaneous skin cancers has not been
generally reported in the long-term survivors in medulloblastoma outside BCNS setting (75).
Radiotherapy is relatively contraindicated in y oung children with BCNS. Because ionizing
radiation damage to XP cells is repaired normally, there is no theoretical objection to
radiotherapy treatment of tumors if indicated. However, situations in which radiotherapy is
appropriate are quite rare (76,77).
At St. Jude Children’s Research Hospital (SJCRH), eight children with skin carcinomas
were seen from 1962 to 1986. In four patients, basal cell epitheliomas developed in
previously irradiated fields (acute ly mphoblastic leukemia, Hodgkin disease, neuroblastoma).
There was a fifth patient with BCNS. The three patients treated for squamous cell carcinoma
had a prior diagnosis of XP (78). From 1971 to 1991, seven cases of basal cell carcinoma and
three cases of squamous cell carcinoma were encountered at the National Institute of
Pediatrics in Mexico City (63). Five of the seven children with basal cell carcinoma had XP,
one had BCNS, and one developed in a previous radiotherapy field. One of the three patients
with squamous cell carcinoma also had XP.
Patients with basal cell carcinoma of the skin may be treated with chemotherapy,
immunotherapy, electrodesiccation, cry otherapy, Mohs’ chemosurgery, or primary surgery
with reconstruction of the defect (68). Some children have been treated with radiotherapy,
although this treatment is generally reserved for adults.
MALIGNANT MELANOMA
Melanoma incidence is about 5–6 per million in children under age 20 y ears with only 300–
420 new cases diagnosed per y ear. As a result, there is sparse data regarding melanoma in
this age group compared to adults. Although melanoma in children and adolescents represents
less than 1% of cases of all cancers, melanoma is the second-most common adult-ty pe
cancer in this age group (after thy roid cancer). Incidence increases with age and varies by
sex, anatomic location of the lesion, and geographic residence across multiple age groups
(79,80). There is controversy about epidemiologic trends for pediatric melanoma. As in
adults, incidence has been linked with geographic residence. Childhood melanoma in
Australia is higher than that reported in other series, accounting for 3.3% of all pediatric
neoplasms. Melanoma is the most common cancer diagnosed in females between the ages of
25 and 29 y ears (81). This high incidence is attributed to excessive exposure to sunlight
(64,82). In the United States, the reported incidence of cutaneous melanoma rose
approximately twofold between 1974 and 1994, with the increase observed across all age
groups (83,84,85). Further reports also suggest its increase in the late 90s (86,87). However,
between 2000 and 2010, the incidence in the pediatric population started to decrease (88).
Regardless, melanoma should remain a prominent health concern in children and needs
further study.
Case–control studies in adults have identified multiple host and environmental factors
associated with increased risk of malignant melanoma. Host factors include fair skin, white
race, blond or red hair, light ey e color, tendency to burn with UV radiation exposure,
increased number of benign nevi, dy splastic nevi, family history of melanoma, and
xeroderma pigmentosum.
Environmental factors include sunburns, often in childhood, and increased exposure to
UV radiation. Proposed risk factors for pediatric melanoma include congenital, dy splastic, or
increased number of nevi; inability to tan; blue ey es; facial freckling; family history of
melanoma; disorders of DNA excision repair like xeroderma pigmentosum; acquired or
congenital immunosuppression; and a previous history of malignancy (89,90). Increased
exposure to UV radiation, measured by number of blistering sunburns (especially during
childhood), and reported time spent outdoors, confer a two- to fivefold increased risk of
melanoma in case–control studies of adults (91,92,93). Ethnic/racial predisposition or a lighter
skin color has previously been reported as a risk factor for the development of melanoma,
possibly related to a protective effect of (melanin) pigmentation (84). The risk of malignant
melanoma is also higher in congenital immunodeficiency sy ndromes and iatrogenic
immunosuppression, suggesting that immunoincompetence adversely influences melanoma
development. Sun exposure is a critical epidemiologic factor in the development of malignant
melanoma (87,94,95,96,97). Although there is a debate about the timing of sun exposure,
particularly severe sunburns, and the eventual development of malignant melanoma, the data
strongly support the concept that the lifetime total exposure to sunlight is directly related to the
incidence of malignant melanoma. Thus, medical practitioners, including radiation
oncologists, should counsel parents to protect children from excessive sun exposure.
Page 406Clinical and histopathologic features of pediatric melanoma are poorly
characterized. Melanoma can mimic benign lesions, like the Spitz nevus, and particularly in
children can delay diagnosis. Melanomas in children, especially prepubertal children, have
been observed to be more often amelanotic, nodular, and thicker at diagnosis than melanomas
in adults (79,98,99,100). Melanomas in children can also resemble other nonmelanocy tic
lesions such as py ogenic granulomas and warts (101,102,103). Previous publications have
specifically noted that prepubertal melanoma does not alway s follow the conventional ABCD
criteria (Asy mmetry, Border irregularity, Color variegation, and Diameter [6 mm])
(98,99,104,105).
To genetically characterize childhood melanoma, 21 pediatric patients were studied by
germline analy sis of CDKN2A, CDK4, and MC1R genes. Cutaneous melanoma in childhood
and adolescence shows frequent loss of INK4A and gain of KIT (56). Microscopically,
ambiguous melanocy tic proliferations with indeterminate malignant potential create
additional diagnostic dilemmas. Together with a low index of suspicion, features distinct from
those usually seen in adult melanoma may contribute to diagnostic delay s.
Pediatric melanoma is often classified by the mode of occurrence as well as the
histologic subty pe (98).
1. Transplacental melanoma, transmitted from the mother with melanoma to the fetus in
utero. There are rare reports of transplacental transmission of metastatic melanoma
from mother to child (106). The infant usually has disseminated disease at birth, and the
prognosis is poor.
2. Transformation from giant congenital melanocytic nevus. Large congenital nevocy tic nevi
(LCNN) are defined as congenital nevi 20 cm in diameter or larger. They may occur
any where on the body and include the so-called “bathing trunks” nevi. There is a
controversy in the literature regarding the relative risk of malignant melanoma arising in
LCNN, with lifetime risks ranging from 2% to 31% (98,106,107,108).
3. In association with congenital predisposing conditions such as xeroderma pigmentosum,
dysplastic nevus syndrome, and albinism. Familial dy splastic nevus sy ndrome is an
autosomal dominant trait characterized by unusual nevi at risk for developing melanoma.
Patients with XP are at significant risk for developing melanoma, as described earlier.
4. Development from healthy skin.
5. Development from a preexisting nevus. The total number of melanocy tic nevi strongly
influences the risk of developing melanoma later in life (82,83,84,85,98,106). In turn, the
number of melanocy tic nevi in children is closely associated with the degree of sun
exposure and the nevus counts in the parents (94).
Malignant melanoma is categorized histologically into four ty pes: lentigo maligna melanoma,
superficial spreading melanoma, acral lentiginous melanoma, and nodular melanoma.
Childhood melanoma may be staged with the following sy stem: stage I, localized disease;
stage II, regional ly mph node involvement; and stage III, distant metastatic disease (109).
Three important factors should be considered in evaluating stage I patients: the presence of
local ulceration, Clark’s level of invasion, and Breslow’s depth of invasion (Table 18.3 ). All
three have been shown to be important prognostic indicators in childhood melanoma (110). In
children, metastatic disease is rare in lesions less than 1.5 mm thick (109). In the SJCRH series
of 33 children treated from 1967 to 1988, there were no tumor-related deaths in children with
thin melanomas (Clark’s level I–II, Breslow thickness less than 1.5 mm). Twenty -four patients,
16 y ears of age or y ounger, with malignant melanoma were reviewed at St. Thomas’
Hospital, London, from 1981 to 1993. All the three patients with tumors 1.2 mm or smaller
were alive without tumor. In contrast, of the 19 children with tumors 1.6 mm or larger, 15
were disease-free, 3 were alive but suffered locoregional relapse, and 1 died of disease
(106). As in adult patients, brain metastases often occur and confer a poor prognosis (111).
Table 18.3 Classification of the Primary Lesion in Malignant Melanoma
(Adopted from 148. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab
versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372: 2006-2017).
Figure:
Actual survival rates of the adult and juvenile stage I patients registered at the Duke
University Melanoma Clinic.
(Adapted from 106. Reintgen DS, Vollmer R, Seigler HF. Juvenile malignant melanoma. Surg
Gynecol Obstet. 1989;168(3):249–253, with permission).
REFERENCES
Page 413With advances in multimodality therapy and supportive care, the cure rate for
childhood cancer continues to improve and now approaches 80% (1). However, the therapies
associated with this improved survival, chemotherapy, radiotherapy (RT), and surgery, can
lead to adverse long-term health-related outcomes. These are commonly known as late
effects and can manifest months, y ears, or even decades after completion of cancer
treatment. Late effects include organ dy sfunction, subsequent malignant and benign
neoplasms, and adverse psy chosocial sequelae. They place survivors of childhood cancer at
risk for chronic health conditions as they enter their adolescent and adult y ears. Although
surgical procedures can independently cause late effects or compound those caused by
radiation and/or chemotherapy, this chapter will focus on the latter two treatment modalities.
Subsequent malignancies will be discussed in great detail in another chapter of this textbook.
In a report from the Childhood Cancer Survivor Study (CCSS), the 30-y ear cumulative
incidence for severe (grade 3) or disabling/life-threatening (grade 4) conditions, or death
(grade 5) due to a chronic condition was 42% (2). In another report from this same cohort
study, the 30-y ear cumulative mortality was 18% among survivors; RT increased the risk 2.2-
fold (3). From the CCSS, where survivors all now have over 20 y ears of follow-up since
childhood cancer diagnosis, Figure 19.1 shows the cumulative incidence of chronic health
conditions by organ sy stem, noting the incidence of debilitating problems. Figure 19.2
shows the cumulative incidence of grade 3–5 conditions by primary childhood cancer
diagnosis of survivors compared to their siblings, demonstrating the significant variability in
both incidence and latency period for manifestation of late effects by disease. Of particular
note is the lack of any meaningful plateau in the steady rise in incidence of late effects
throughout the lifespan. Figure 19.3 shows the cause-specific cumulative late mortality.
Risk of death remains highest for recurrence of original disease, but 14% of deaths from this
cohort are now from subsequent malignancies (4).
Figure 19.1 Cumulative incidence of chronic health conditions of adult survivors of
childhood cancer by primary childhood cancer diagnosis and severity of condition. (From
Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of
childhood cancer. N Engl J Med. 2006;355:1572–1582, with permission.)
Figure 19.2 Cumulative incidence of chronic health conditions for severe, disabling, life-
threatening or fatal health conditions, by primary childhood cancer diagnosis. Leukemia (A),
CNS tumors (B), Hodgkin lymphoma (C), non-Hodgkin lymphoma (D), kidney tumors (E),
neuroblastoma (F), soft-tissue sarcoma (G), and bone tumors (H). (From Armstrong GT,
Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling, life-threatening, and
fatal events in the Childhood Cancer Survivor Study. J Clin Oncol. 2014;32:1218–1227.)
(From Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors
of childhood cancer. N Engl J Med. 2006;355:1572–1582, with permission.)
Figure:
Cumulative incidence of chronic health conditions for severe, disabling, life-threatening or
fatal health conditions, by primary childhood cancer diagnosis. Leukemia (A), CNS tumors
(B), Hodgkin lymphoma (C), non-Hodgkin lymphoma (D), kidney tumors (E), neuroblastoma
(F), soft-tissue sarcoma (G), and bone tumors (H).
(From Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling,
life-threatening, and fatal events in the Childhood Cancer Survivor Study. J Clin Oncol.
2014;32:1218–1227.)
Figure:
Cumulative cause-specific mortality.
(From Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood
cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27:2328–
2338, with permission.)
EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY ON NORMAL
TISSUE
Page 414Late effects have been reported in patients who received dosages of chemotherapy
and RT below the generally accepted threshold levels for either of the two when used alone.
Therefore, one must be circumspect in accepting “tolerance dosages” for normal tissues and
organs in the combined treatment modality era. Untoward reactions can occur at unexpected
times and in unpredictable way s. In rapid renewal sy stems, the same stem cell population is
affected, and one can usually mitigate the increase in acute toxicity of concurrent treatment
by treating sequentially. In slow renewal tissues, the additive ill effects of drugs and radiation
often are related to entirely different target cell populations in the same organ sy stem. Late
effects may not be avoidable because chemotherapy, whenever applied, can result in
additional stem cell kill and lead to expression of subclinical radiation effects. Therefore, the
tolerance dosages of fractionated RT, listed in Table 19.1 , might be lower in the setting of
chemotherapy and in y ounger children, as well as if daily doses of greater than 2 Gy are
administered, which is increasingly common with advanced radiation techniques. Table
19.2 lists some of the common adverse effects of chemotherapy, which may act
sy nergistically with RT.
Table 19.1 Tolerance Dosages, TD5–TD50 (Fractionated Dosage, Whole or Partial Organ)
Table 19.2 Common Chemotherapy Late Effects
Figure: Tolerance Dosages, TD5–TD50
(Fractionated Dosage, Whole or Partial
Organ)
Figure: Common Chemotherapy Late Effects
INFLUENCE OF THE DEVELOPMENTAL STAGE OF THE TARGET
ORGAN ON ITS SENSITIVITY TO THERAPY
The potential for the development of debilitating effects in normal tissues is related to the
cellular activity and maturation in the tissue under consideration. In children, a mosaic of
different tissues is developing at different rates and in different temporal sequences. In many
(but not all) tissues, organ development goes hand-in-hand with cell growth, and cellular
proliferation starts during the prenatal period. During the developmental period of each tissue,
stem cells within the embry o will move bey ond the pluripotent stage and, under the influence
of intrinsic and extrinsic factors, will follow one of two paths: (a) toward self-renewal, that is,
generation of more stem cells (multipotency ), or (b) toward differentiation, thereby giving
rise to a more specialized cell ty pe or tissue (unipotency ). Achieving a delicate balance
between these two processes is critical for an organ to achieve homeostasis. Thus, both
pathway s are involved in growth as well as the repair and regeneration of tissues. It can be
simplistically assumed that the downstream consequences from an injury, such as radiation,
may be predicted from the response of the respective stem cell populations since stem cells
and their progeny proliferate to ensure both organ growth and regeneration of injured and
dy ing cells. However, as adulthood/full maturation is reached, each organ will be made up of
a mosaic of both dividing and nondividing cells, not just within the tissue as a whole, but also
within each of the representative cell populations. Nondividing cells exist in several
compartments: for example, some may be found resting in G0 phase, although not all of
these are fully quiescent since some populations appear to be capable of re-entering cell
cy cle if the tissue is challenged or stimulated (6). Clinically, it is clear that the greater
potential for growth in pediatric tissues will mirror many of the adverse effects of radiation
therapy since insult will absolutely compromise growth potential and manifest as impaired
development. In fact, the injury that can occur in a pediatric tissue may not become manifest
until that tissue rapidly develops. An example of this is the impairment of bone growth seen
during adolescence due to radiation many y ears prior.
Page 416Traditionally, radiation dosages in children are modified by age, but without
specific recognition of the periods of active proliferation, differentiation, and eventual
maturation of one organ or tissue as it differs from another. Since intrinsic radiation sensitivity
and vulnerability to radiation-induced normal tissue damage are related to cellular activity
and level of maturity, it is important to understand tissue development and consider differing
sensitivities to the same insult at any given time in a child’s development as this could
drastically change the potential for adverse late outcomes. When does a pediatric tissue or
organ become similar to an adult tissue or organ? This is a major question that must be
addressed in order to predict the sensitivity to late effects (6).
Page 418The growth of specific tissues from birth to adulthood was characterized by
Tanner over a half century ago by four classical patterns: (1) ly mphoid, with accelerated
growth followed by involution at the time of puberty ; (2) brain, with rapid postnatal growth
that slows and essentially completes by early adolescence; (3) gonadal, with little change
during early life but rapid development just before and coincident with puberty ; and (4) a
more general pattern, epitomized by the musculoskeletal sy stem, characterized by two major
periods of rapid growth during the postnatal period and puberty. Figure 19.4 shows the
growth relationships according to time and ty pe of organ in the neonatal period and childhood,
while Table 19.3 provides specific data for a broader number of organs and sy stems.
Figure 19.4 Growth curves of different tissues. (From Tanner JM. Growth at Adolescence.
Oxford, England: Blackwell Scientific; 1962, with permission.)
Table 19.3 Anatomy and Physiology: Relative Rate of Development
As noted above, identify ing the different rates and ages at which each tissue matures is
necessary for determining the relative radiosensitivity of any tissue at any particular time
(7). In addition, recognizing the mechanism of organ growth—that is, an increase in the size
of cells (hy pertrophy ) as opposed to the number of cells (proliferation)—allows better
identification of relative radiosensitivity because organs that only hy pertrophy are less
vulnerable to functional disturbance by irradiation.
Although the classical growth curves provide valuable information, these data are limited
in that they only describe growth in terms of phy sical size and more specifically weight.
However, it is important to note that changes in the mass of an organ do not necessarily
correlate with other phy sical parameters (such as volume) and moreover that organs grow
through a variable combination of parenchy mal cell hy perplasia and hy pertrophy, as well as
stromal development. In regard to the variable sensitivity to late radiation toxicity, growth and
phy siologic functional development as measured by these parameters may be more
important than simple increases in size.
For example, in regard to mass, the ovaries follow the gonadal growth pattern, with little
change during early life and rapid development just before and coincident with puberty.
However, the organ’s sensitivity to late effects from radiation therapy does not follow this
pattern, at least in regard to sterility, since the mass of the ovary as a whole rapidly increases
before and during puberty, presumably because of stromal proliferation. The pool of oocy tes
that are responsible for fertility is continuously decreasing until menopause without
replenishment after a maximum number at 5 months gestational age (8).
Page 419A classical study showed that the effective sterilizing dose to the ovary after
fractionated radiotherapy decreased at increasing age of irradiation: 20.3 Gy at birth, 18.4
Gy at 10 y ears, 16.5 Gy at 20 y ears, and 14.3 Gy at 30 y ears of age (9). This finding is also
supported by the Childhood Cancer Survivor Study, which showed that cy clophosphamide
exposure was a risk factor for sterility in older (13–20 y ears), but not y ounger (<13 y ears)
children (10). Finally, data exist showing that late ovarian dy sfunction may be reduced in
children receiving total body irradiation prior to menarche compared to postmenarchal
children (11). A more complete discussion of ovarian late effects will be provided later in this
chapter.
This example further highlights the complexity of human growth and development, even
at the level of individual tissues and organs, and the need to expand our knowledge of growth
patterns bey ond simple increases in mass. In addition to expanding our understanding to
include additional measures of phy sical growth, such as volume (Fig. 19.5 ), and various
phy siologic parameters, determining differential mechanisms of growth, such as
parenchy mal cell proliferation and hy pertrophy versus stromal development, will enhance
our ability to predict and minimize differential late effects from therapy.
Figure 19.5 Heart and lung volumes as function of age, as defined on CT scan from a single
institution. A: Heart volume (male); B: Lung volume (male); C: Heart volume (female); D:
Lung volume (male). (From Dhakal S, Paulino AC, Constine LS. Pediatric growth and
development: impact on vulnerability to normal tissue damage from cancer therapy. In:
Schwartz CL, Hobbie WL, Constine LS, et al., eds. Survivors of Child and Adolescent Cancer: A
Multi-Disciplinary Approach. New York, NY: Springer; 2015:33–41, with permission.)
Figure:
Growth curves of different tissues.
(From Tanner JM. Growth at Adolescence. Oxford, England: Blackwell Scientific; 1962, with
permission.)
Figure: Anatomy and Physiology: Relative
Rate of Development
Figure:
Heart and lung volumes as function of age, as defined on CT scan from a single institution. A:
Heart volume (male); B: Lung volume (male); C: Heart volume (female); D: Lung volume
(male).
(From Dhakal S, Paulino AC, Constine LS. Pediatric growth and development: impact on
vulnerability to normal tissue damage from cancer therapy. In: Schwartz CL, Hobbie WL,
Constine LS, et al., eds. Survivors of Child and Adolescent Cancer: A Multi-Disciplinary
Approach. New York, NY: Springer; 2015:33–41, with permission.)
LATE EFFECTS BY ORGAN SYSTEM
Clinical Manifestations
Necrosis
The incidence of radiation necrosis after therapeutic dosages is uncertain. Quoted incidence
data range from 0.1% to 5% after dosages of 50–60 Gy fractionated over 5–6 weeks (13,14).
The variability in the data is the result of the uncertainty concerning the denominator, the long
time-delay until the occurrence of necrosis, the lack of histologic confirmation in many
surviving patients, and the absence of postmortem data in patients who succumb. The clinical
signs and sy mptoms of radiation necrosis are headache and mass effect. Surgical debulking is
performed when possible and is often therapeutic (14). Corticosteroids may offer transient
relief. There is limited evidence that anticoagulation or bevicizumab may also offer some
benefit (15).
Myelopathy
The spectrum of radiation injuries to the spinal cord includes both transient and irreversible
sy ndromes. Rarely, a rapidly evolving permanent paraly sis can occur, presumptively from
acute infarction of the cord. A more common form of radiation injury is manifested by the
Lhermitte sy mptom, which consists of an electric shock–like sensation that radiates down the
spine and often into the limbs (39). The location of the sensation can change with time. The
sy mptoms may be precipitated by flexion of the neck, walking/sitting on a hard surface, or
other forms of phy sical exertion. The sy ndrome generally occurs a few months after spinal
irradiation. The mechanism is thought to be transient demy elinization, although detailed
human pathologic studies are lacking. There are no known CT or MRI correlations. It is also
reported in association with cisplatin administration, where the results may be long-lasting
(40).
Page 422Chronic progressive radiation my elitis (CPRM) is rare. The initial sy mptoms,
generally subtle, are usually paresthesias and sensory changes (including diminished
temperature sensation or proprioception), which start 9–15 months after therapy and progress
over the subsequent y ear (41). Much longer intervals to initial sy mptoms are seen
occasionally. The neurologic lesion must be within the irradiated volume. Recurrent or
metastatic tumor must be ruled out. Cerebrospinal fluid (CSF) protein may be elevated, and
my elography can demonstrate cord swelling or atrophy. MRI and CT provide additional
supportive information.
The incidence of CPRM and the radiation dosage causing this event are poorly defined
because of the diagnostic difficulties and the variety of radiation techniques (with uncertain
dosimetries). A review by Wara et al. (42) suggests that 42 Gy in 25 fractions carries a 1%
risk, 45 Gy a 5% risk, and 61 Gy a 50% risk. Data from Marcus and William (43) suggest that
the cervical cord may be more tolerant to radiation than previously presumed when 1.8- to
1.9-Gy fractional doses are used; in 324 patients treated to dosages of 55 Gy or less, no cases
of my elitis were seen. A higher risk of my elopathy is associated with higher individual
fraction sizes, shorter overall treatment time, higher total dosages, and long lengths of the cord
treated (especially more than 10 cm). Children may be more susceptible to CPRM,
developing it after lower radiation dosages and with shorter latency periods (41).
Cerebrovascular Disease
The risk of stroke is also increased among survivors of childhood cancer. Data from the CCSS
suggests a RR of 29.0 for the occurrence of a stroke in survivors of brain tumors relative to
their siblings and a RR of 6.4 in survivors of leukemia. Cranial RT was associated with stroke
risk in a dose-dependent fashion with doses above 30 Gy portending some risk and doses
above 50 Gy with the highest risk (44). Both cranial and cervical RTs were associated with
increased stroke risk among survivors of HL (45).
Additional Manifestations
Irradiation of the brain of a child can result in the somnolence sy ndrome. This develops 4–8
weeks after irradiation and is characterized by drowsiness, nausea, irritability, anorexia,
apathy, and dizziness. It most frequently occurs after treatment for ALL but can occur after
treatment for brain tumors. The somnolence sy ndrome resolves spontaneously ;
corticosteroids hasten recovery.
Arterial vasculopathy is an uncommon occurrence, almost alway s described after
irradiation to the parasellar region, primarily in children. Single- or multiple-vessel narrowing
or obliteration results in ty pical stroke deficits (46).
Table 19.4 reviews several CNS late effects with respect to causative treatments,
signs and sy mptoms, screening and diagnostic tests, and management and intervention (47).
Table 19.4 Evaluation of Patients at Risk for Late Effects: Central Nervous System
Psychosocial
Psychological Effects
Due to the lack of sy stematic screening for patients with and without evident psy chosocial
difficulties, the prevalence of psy chological distress among survivors is poorly characterized
and likely significantly underappreciated.
Many childhood cancer survivors report reduced quality of life or other adverse
psy chosocial outcomes. Survivors with neurocognitive deficits are particularly vulnerable to
adverse psy chosocial outcomes that affect achievement of expected social competence
during adulthood.
Childhood cancer survivors are also at risk of developing sy mptoms of psy chological
distress. In a 16-y ear longitudinal study of more than 4500 survivors, subgroups of survivors
were found to be at risk of developing persistent and increasing sy mptoms of anxiety and
depression, with those reporting pain and worsening health status at the greatest risk of
developing sy mptoms of anxiety, depression, and somatization (48). Long-term survivors of
childhood cancer are also significantly more likely to experience late suicidal ideation (OR
51.9) or recurrent suicidal ideation (OR 52.6) relative to healthy siblings (49). This
psy chological distress can lead to phy sical health problems; social withdrawal in adolescent
survivors of childhood cancer was associated with adult obesity and phy sical inactivity, risk
factors for a my riad of other conditions (50).
Sy mptoms of somatic distress and depression among 1834 survivors of HL in the CCSS
cohort were compared to healthy siblings. Eighty -seven had scores on the brief sy mptom
index that were sy mptomatic for depression, and 237 for somatic distress. Risk factors
included female sex, low socioeconomic status, lack of a complete high school education, lack
of employ ment, intensive chemotherapy, and elapsed time since therapy (51). In a
subsequent analy sis of the entire CCSS cohort, Mulrooney et al. (52) evaluated risk factors for
fatigue or sleep impairment. In univariate analy sis, compared with other diagnostic groups, a
diagnosis of HL or sarcoma was associated with higher risks of fatigue, depression, and sleep
impairment. In multivariate analy sis of the fatigue risk factors, hy pothy roidism and
depression were independent risk factors, and radiation therapy had a marginal association.
It is clear that a meaningful minority of childhood cancer survivors and their parents
demonstrate sy mptoms of uncertainty, distress, and posttraumatic stress, with some meeting
full criteria for posttraumatic stress disorder (PTSD). In a study from the CCSS, the
prevalence of PTSD and posttraumatic stress sy mptoms in y oung adult survivors of childhood
cancer was estimated to be 15–20%, depending on criteria used to define these conditions.
Because avoidance of places and people associated with cancer is part of PTSD, the
sy ndrome may interfere with appropriate access to health care. Risk factors include
perception of threat to life and severity of treatment, poor family functioning and decreased
social support (53,54,55,56,57,58).
Neuroendocrine
Hy pothalamic–pituitary (HP) irradiation may produce a large spectrum of neuroendocrine
abnormalities. In the SJLIFE cohort, 56.4% of survivors treated with cranial RT doses of
greater than 18 Gy developed a HP axis disorder (59).
Growth Hormone
Cranial irradiation most commonly effects growth hormone (GH) production and release.
GH is secreted episodically by the anterior pituitary gland. Growth hormone–releasing
hormone (GHRH), produced in the hy pothalamus, stimulates GH production. Somatostatin,
also produced in the hy pothalamus, excretes an inhibitory effect. In the liver and other
tissues, circulating GH stimulates the production of insulin-like growth factor 1 (IGF-1, also
called somatomedin-C), which promotes cell proliferation and protein sy nthesis. The
anatomic site of the radiation injury that produces GH deficiency is most frequently the
hy pothalamus.
Thyroid
Radiation-induced thy roid neoplasms are considered in Chapter 20 . The effects of
therapeutic irradiation on the endocrine function of the thy roid will be reviewed here. The
thy roid may be directly irradiated in the treatment of childhood head and neck cancers such
as rhabdomy osarcoma, nasophary ngeal ly mphoepithelioma, and squamous cell carcinoma,
a variety of other aerodigestive tract tumors, and HL. A photon spinal field used during
craniospinal irradiation for brain and spinal tumors and for leukemia will also deliver radiation
to the thy roid.
Pathophysiology
The thy roid gland consists of follicles filled with colloid and lined by follicular cells, which
trap iodide. The gly coprotein thy roglobulin is a major component of the colloid and
participates in the formation and storage of thy roid hormones. The primary, hormonally
active iodothy ronines, triiodothy ronine (T3) and thy roxine (T4), are largely bound to plasma
proteins when released by the gland. Thy roxine-binding globulin (TBG) is the major transport
protein, and only a small percentage of unbound T3 and T4 are available for activity. The
pituitary hormone thy roid-stimulating hormone (TSH) regulates sy nthesis and release of T3
and T4. TSH secretion is stimulated by the hy pothalamic hormone thy rotropin-releasing
hormone (TRH) and inhibited by the circulating free thy roid hormones.
The pathophy siology of radiation-induced thy roid dy sfunction is not precisely defined.
Direct radiation damage to the thy roid follicular cells, the thy roid vasculature, or the
supporting stroma may occur. Histopathologic changes in an irradiated thy roid gland include
progressive obliteration of the fine vasculature, degeneration of follicular cells and follicles,
atrophy of the stroma, and, less commonly, ly mphocy tic infiltration. Because radiation
damage depends on the degree of mitotic activity and the thy roid of a developing child grows
in parallel with body growth, this gland would be expected to show an age-related degree of
injury and repair.
Hypothyroidism
Of children treated with radiation therapy, most develop hy pothy roidism within the first 2–5
y ears posttreatment, though later dy sfunction is possible. Reports of thy roid dy sfunction
differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria
utilized to make the diagnosis. The most frequently reported abnormalities include elevated
TSH, depressed thy roxine (T4), or both (79,80,81,82). Compensated hy pothy roidism includes
an elevated TSH with a normal T4 and is asy mptomatic. Uncompensated hy pothy roidism
includes both an elevated TSH and a depressed T4.
The incidence of hy pothy roidism should
decrease with lower cumulative doses of
radiation therapy employ ed in newer protocols.
In a study of Hodgkin ly mphoma (HL) patients
treated between 1962 and 1979, hy pothy roidism
occurred in 4 of 24 patients who received mantle
doses less than 26 Gy but in 74 of 95 patients
who received greater than 26 Gy (75). Among a
cohort of CCSS patients treated for HL there was
a strong dose-response relationship between RT
dose and 20-y ear risk of hy pothy roidism (79).
The cumulative incidence of hy pothy roidism
among survivors 15 y ears following leukemia
diagnosis was found to be 1.6% in the CCSS
cohort. In multivariate analy sis, survivors who
Figure 19.10 Probability of developing
received ≥20 Gy cranial RT plus any spinal RT
an underactive thyroid after diagnosis of
had the highest risk of subsequent the Hodgkin disease. (From Diller L, Chow
hy pothy roidism (HR 8.3) compared with those EJ, Gurney JG, et al. Chronic disease in
treated with chemotherapy alone. In radiation
the Childhood Cancer Survivor Study
dosimetry analy sis, pituitary doses ≥20 Gy
Cohort: a review of published finding. J
combined with thy roid doses ≥10 Gy were Clin Oncol. 2009;27:2339–2355.)
associated with hy pothy roidism (83). Figure
19.10 shows the cumulative incidence of hy pothy roidism respectively after treatment for
HL.
Page 428Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at
increased risk of thy roid dy sfunction, with the risk being much lower (15–16%) after
fractionated TBI, as opposed to single-dose TBI (46–48%). While mildly elevated TSH is
common, it is usually accompanied by normal thy roxine concentration (84). Non–TBI-
containing regimens historically were not associated with an increased risk. However, in a
report from the Fred Hutchinson Cancer Research Center, the increased risk for thy roid
dy sfunction was not different between children receiving a TBI or busulfan-based regimen
compared with cy clophosphamide conditioning alone.
Central hy pothy roidism (low free T4 with low or inappropriately normal TSH) can also
occur. The threshold dose for development of central hy pothy roidism appears to be 42 Gy to
the hy pothalamus, with only 11% of those receiving less than 42 Gy developing the condition
and 44% receiving ≥42 Gy developing central hy pothy roidism (85).
Hyperthyroidism
Thy rotoxicosis may occur after mantle or cervical irradiation for HL. In Hancock et al.’s
report (86), approximately 2% of patients (n = 34) developed Graves’ disease. Almost all had
a diffuse goiter, high free T4, low TSH, and elevated thy roid uptake of radioiodine. One-half
of these patients developed infiltrative ophthalmopathy, as did an additional four patients who
did not have overt hy perthy roidism. The RR for Graves’ disease was 7.2–20.4. Six patients
developed silent thy roiditis characterized by transient mild sy mptoms of thy rotoxicosis,
elevated serum-free T4 and low TSH, no thy roid enlargement or tenderness, and low thy roid
uptake of radioiodine (87). All of these patients subsequently developed hy pothy roidism.
In the CCSS study of HL survivors by Sklar et al. (79), the relative risk for
hy perthy roidism compared with sibling control subjects was 8.0, with cases becoming
manifest 3–5 y ears after diagnosis. In the study of ALL survivors from the CCSS, the 15-y ear
cumulative incidence was 0.6%. Craniospinal RT was associated with an increased risk of
subsequent hy perthy roidism (HR 6.1) compared with chemotherapy alone. In radiation
dosimetry analy sis, pituitary doses ≥20 Gy combined with thy roid doses ≥15 Gy were
associated with hy perthy roidism (83).
Management
Patients with uncompensated hy pothy roidism (low serum concentration of thy roxine) clearly
need thy roid replacement therapy. Patients with elevated serum concentrations of TSH but
normal thy roxine are treated with thy roid replacement therapy in most institutions. The
rationale for this approach is that subclinical hy pothy roidism may evolve into overt
hy pothy roidism, and prolonged TSH stimulation of an irradiated thy roid gland may increase
the risk of carcinoma (75,86).
Table 19.6 reviews several thy roid late effects with respect to causative treatments,
signs and sy mptoms, screening and diagnostic tests, and management and intervention (88).
Table 19.6 Evaluation of Patients at Risk for Late Effects: Thyroid
Clinical Manifestations
Bone Growth Retardation
Clinically, radiation’s effects on growing bone may be most simply characterized as
shortening of long bones (i.e., femur, tibia, humerus) or hy poplasia of flat bones (i.e., ilium).
The crucial factors influencing the ultimate height of the patient may be inferred from the
data previously presented: the radiation total dose and dose per fraction; the energy, dose
distribution, and absorptive properties of the beams; the bones that are irradiated and the
epiphy seal plates that are encompassed; the age at the time of irradiation (imply ing that the
amount of growth already obtained is important in judging ultimate outcome); the influence
of other toxins on growth, such as exogenous steroids and cy totoxic chemotherapy ; and the
patient’s genetic constitution.
Page 430A large body of knowledge has been developed concerning loss of height after
childhood irradiation. Much of the data published in the 1970s and 1980s reflect treatment
with higher dosages of RT than those currently used. However, several recent reports indicate
that stature loss must still be considered in the late effects of RT. For children treated with
craniospinal RT, the cranial dosage can result in decreased growth by causing growth
hormone deficiency as previously discussed, and the spinal dosage can result in stature loss
through its effect on the vertebral bodies (62).
Patients who receive radiation therapy for the Wilms tumor are an ideal population for
study of the effect of RT and age at the time of treatment on stature. As a result of earlier
studies showing a higher risk of spinal curvature with asy mmetric radiation to the vertebral
bodies, standard flank radiation now includes the affected side and extends across the spinal
column but excludes the contralateral kidney. Hogeboom et al. (89) evaluated stature loss in
2778 children treated for Wilms tumors. For those under 12 months of age at diagnosis who
received more than 10 Gy, the estimated adult height deficit was 7.7 cm when contrasted with
the nonradiation group. For those who received 10 Gy the estimated trunk shortening was 2.8
cm or less. Among those whose height measurements in the teenage y ears were available,
patients who received more than 15 Gy of RT were 4–7 cm shorter on average than their
nonirradiated counterparts, with a dose–response relationship evident. Chemotherapy did not
confer additional risk.
Osteopenia
Bone mineral density in childhood cancer survivors may be reduced, especially in children
treated for ALL, or with HSCT, where it has been best studied. Risk factors include increased
age at the time of exposure, estrogen deficiency, female sex, corticosteroid use and ty pe, GH
deficiency, and cranial radiation. Prevalence, chronicity, and severity are not consistent
across studies, so the risk remains poorly defined (105,106,107,108). Further research into the
pathophy siology, the contribution of the various risk factors, the ty pe and frequency of
screening, the populations at highest risk, and interventions are clearly indicated.
Metabolic Syndrome
An increased risk of metabolic sy ndrome (central obesity with hy pertension, dy slipidemia,
and abnormal glucose metabolism) or its components has been observed among cancer
survivors (109,110,111,112,113). The evidence for this outcome ranges from clinically
manifested conditions that are self-reported by survivors to retrospectively assessed data in
medical records and hospital registries to sy stematic clinical evaluations of clinically well-
characterized cohorts. Studies have been limited by cohort selection and participation bias,
heterogeneity in treatment approach, time since treatment, and method of evaluation, as well
as the evolving definition of the metabolic sy ndrome itself. Despite these limitations,
compelling evidence indicates that the metabolic sy ndrome is highly associated with
cardiovascular events and mortality (110,112,114), and therefore survivors are good
candidates for targeted screening and lifesty le counseling regarding risk-reduction measures
(115,116).
Cardiac
The functional and structural complexity of the heart places it at risk for a spectrum of RT and
chemotherapy injuries that can occur. The radiation-associated sequelae include acute
pericarditis during radiation (rare and associated with juxtapericardial cancer); delay ed
pericarditis, which can present abruptly or as chronic pericardial effusion (rarely progressing
to tamponade); pancarditis, which includes pericardial and my ocardial fibrosis with or
without endocardial fibroelastosis; my opathy in the absence of significant pericardial disease;
coronary artery disease (uncommon, usually involving the left anterior descending artery );
functional valvular injury ; and conduction defects (117,118,119). The hallmark of these
injuries histologically is fibrosis in the interstitium with normal-appearing my ocy tes and
capillary and arterial narrowing.
Several parameters must be considered in the evaluation of these radiation-associated
injuries, including the relative weighting of the radiation portals and, therefore, the amount of
radiation delivered to different depths of the heart; the presence of juxtapericardial tumor; the
volume and specific areas of the heart irradiated; the total and fractional irradiation dosage;
the presence of other cardiovascular risk factors in each patient such as age, weight, blood
pressure, family history, lipoprotein levels, and smoking status; and the use of specific
chemotherapeutic agents.
The effects of thoracic RT are difficult to separate from those of anthracy clines because
few children are exposed to thoracic RT in the absence of anthracy clines. Both individually
cause a significant increase in risk of late cardiac toxicity ; combined, their effects are likely
additive (120), if not multiplicative (Fig. 19.12 ).
Figure 19.12 A & B: Marginal (Kaplan–Meier) and cause-specific (C & E) (competing risk)
cumulative incidence of cardiac events (CEs) in childhood cancer survivors stratified
according to different treatment groups. A: Marginal cumulative incidence for all CEs,
stratified according to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank p <
0.001. B: Marginal cumulative incidence for all CEs, stratified according to different CTX
therapies, log-rank p < 0.001. C: Cause-specific cumulative incidence for congestive heart
failure, stratified according to different treatment groups, log-rank p < 0.001. D: Cause-
specific cumulative incidence for cardiac ischemia, stratified according to cardiac
irradiation (RTX) or no RTX, log-rank p < 0.01. E: Cause-specific cumulative incidence for
valvular disease, stratified according to RTX or no RTX, log-rank p < 0.001. The shaded
colorized background areas refer to the 95% CIs. Ant, anthracycline. (From van der Pal H,
van Dalen EC, van Delden E, et al. High risk of symptomatic cardiac events in childhood
cancer survivors. J Clin Oncol. 2012;30:1429–1437, with permission).
It is important to note that the pathogenesis of injury differs. Anthracy clines cause direct
damage to my ocy tes, which are a terminally differentiated cells and thus relatively resistant
to the cy totoxic effects of radiation (121). The incidence of cardiac disease is strongly
associated with the average dose to the heart, with doses greater than 15 Gy associated with
significantly increased incidence of CHF, MI, valvular disease, and pericardial disease,
especially 15–20 y ears after irradiation, as noted in another analy sis of the CCSS (120).
Echocardiographic evidence of sy stolic dy sfunction can be found at cumulative doses of 1–
19.9 Gy and diastolic dy sfunction can be seen at doses of 20–20.9 Gy (122) (Fig. 19.13 ).
Figure 19.13 Cumulative incidence of cardiac disorders among childhood cancer
survivors by average cardiac radiation dose. (From Mulrooney DA, Yeazel MW, Kawashima T,
et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer:
retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606.)
Pericarditis
Delay ed acute pericarditis can be sy mptomatically occult or present suddenly with fever,
dy spnea, pleuritic chest pain, friction rub, ST- and T-wave changes, and decreased QRS
voltage. Up to 30% of patients treated for HL with a mean midplane heart dosage of 46 Gy
are affected (127). With equally weighted AP:PA fields and the use of subcarinal blocking,
the frequency decreases to 2.5% (128). The onset of delay ed acute pericarditis averages 6
months, and 92% of effusions (usually exudative) occur within 12 months. Although the
effusion usually self-resolves within 10 months, it may persist for y ears. Pericardiectomy is
a high-risk procedure in this setting because of the coexistence of other ty pes of radiation-
induced damage and is thus reserved only for severe cases. Hancock et al. (129) noted a 4%
(at 17 y ears) actuarial risk of pericardiectomy (occurring only in children treated with higher
radiation dosages), and most patients improved after surgery. In an analy sis of the CCSS, the
30-y ear incidence of pericardial disease is 3.0% among all survivors of childhood cancer;
children receiving cardiac doses of 15–35 Gy were 2.2 times more likely than their siblings to
develop pericardial disease. This jumped to a hazard ratio of 4.8 among those receiving >35
Gy (125).
Cardiomyopathy
Cardiomy opathy is highly potentiated by doxorubicin and other anthracy clines (idarubicin,
epirubicin, daunomy cin) but can occur in its absence (128,129). Although an in-depth
discussion of the late cardiotoxic effects of anthracy cline administration will not be presented,
its importance and frequency must be emphasized. This is especially important because
more contemporary HL treatment protocols are using lower dosages of RT but continue to
use doxorubicin in the 200–300-mg/m 2 range. Doxorubicin has been the most extensively
studied of the anthracy clines, and its cardiotoxicity is often progressive and disabling.
Increased risk of doxorubicin-related cardiomy opathy is associated with female sex,
cumulative dosages greater than 200–300 mg/m 2, y ounger age at the time of exposure, and
increased time from exposure (130,131,132,133,134,135).
Page 435Prevention or amelioration of anthracy cline-induced cardiomy opathy is of
utmost importance due to the use of anthracy clines in cancer therapy (136). Dexrazoxane
(DZR) is a bis-dioxopiperazine compound that readily enters cells and is subsequently
hy droly zed to form a chelating agent. DZR has been shown to prevent cardiac toxicity in
adults and children treated with anthracy clines (136,137,138,139,140). An unexpected finding
of increased risk of SMN following DZR use has been reported in a single study of its use in
HL, where it was administered within hours of not only doxorubicin, but etoposide, another
topoisomerase II inhibitor (141). This has not been found to date in other studies where DZR is
used as a cardioprotectant (142).
Cardiomy opathy is additionally a significant effect seen following chest-directed RT
though it is of a different flavor than anthracy cline-induced cardiomy opathy. The traditional
measure of sy stolic function, left ventricular ejection fraction (LVEF) is markedly reduced in
long-term survivors of childhood cancer at cumulative anthracy cline doses greater than 100
mg/m 2. A decrease in LVEF is not seen until cumulative chest-directed RT doses reach 20 Gy.
However, an alternative measure of sy stolic function, global longitudinal strain, is depressed
in children receiving even 1–19 Gy of chest-directed RT. Additionally, chest-directed RT
doses of greater than 20 Gy place survivors at risk for diastolic dy sfunction; no cumulative
dose of anthracy cline was found to cause this (122). Long-term survivors are at a 2.2-fold
increased risk of CHF if they received 15–35 Gy of cardiac radiation and a 4.5-fold increase
if >35 Gy relative to their siblings.
Children who need HSCT are at especially high risk of cardiac toxicity. They may have
received anthracy clines or RT with the heart in the field as part of their initial cancer therapy,
and they are subsequently exposed to conditioning regimens that may include high-dose
cy clophosphamide and TBI (143,144). Assessment of the cardiovascular complications of
BMT will assume greater importance with the increasing number of children undergoing this
therapy. In a report from the University of Minnesota on 63 transplanted children, 74% of
children old enough to undergo treadmill exercise testing had a borderline or abnormal
response to exercise, and 12.7% of patients had sy mptomatic cardiovascular abnormalities
(143). The preparative regimen included TBI in slightly more than half of the patients, but this
was independently associated with outcome.
A model was developed that can estimate the risk for the development of heart failure in
childhood survivors of malignancy based on data from the CCSS and verified against the
SJLIFE, NWTS, and Emma Children’s Hospital cohorts. The input variables are sex, age at
diagnosis, anthracy cline dose, and chest RT dose, further emphasizing the role of treatment
modalities in the risk of development of late cardiac toxicities (145).
Valvular Disease
Fibrous valvular endocardial thickening occurs in 80% of autopsied patients treated with high
radiation dosages. The mitral, aortic, and tricuspid valves are most often affected (146).
Although such valvular lesions are common, they rarely evolve into sy mptomatic valvular
disease. Long-term survivors receiving less than 15 Gy mean cardiac dose had no increased
risk for valvular disease; those receiving 15–35 Gy had a 3.3-fold increased risk and those
receiving >35 Gy had a 5.5-fold increased risk relative to siblings (125). In some patients, the
radiation-induced cellular injury to the valvular endocardium, combined with chronic
pressure-related trauma, may eventually lead to valvular deformity, resulting in stenosis or
insufficiency. In a report by Hancock et al. (129) on 635 children treated for HL, 2 patients
died of valvular disease, and 3 others have undergone aortic (2 patients) or mitral (1 patient)
valve replacement. A contribution of mediastinal irradiation to significant or accelerated
valvular disease could not be clearly determined. Unfortunately, in another report, valve
replacement in such patients was infrequently successful and operative mortality was high
(66%) (147).
Arrhythmia
High-degree atrioventricular (AV) conduction abnormalities are rarely seen and have been
attributed to fibrosis of the AV node conducting branches (148). In one series, all patients with
radiation-associated AV block had received more than 40 Gy to the chest, with a median time
to development of the block of 14 y ears (149). Again, as with cardiomy opathy, the effect of
doxorubicin should be considered.
Lungs
The target cells for pulmonary injury are ty pe I and II pneumocy tes, fibrocy tes, endothelial
cells, and macrophages (6,151). Several pulmonary radiation sy ndromes occur in the child.
Acute pneumonitis and chronic fibrosis result from injury to the ty pe II pneumocy tes and
endothelial cells. Chronic respiratory limitations result from impairment in the development
of new alveoli or from growth impairment of the established ones. Limitations of a different
character result from a reduction in growth of the muscle, cartilage, and bone that form the
thoracic cage.
Pathophysiology
The acute reactions of radiation pulmonary injury, known as the exudative phase, can be
detected within 24 hours of irradiation. It is signified by intra-alveolar edema and exudation
of proteinaceous material into the alveoli, impairing gas exchange. Infiltration by
inflammatory cells and desquamation of epithelial cells from the alveolar walls occur. A
proliferative phase occurs between 2 and 6 months with accumulation of ty pe II alveolar
cells and protein leakage into the alveolar spaces. Interstitial edema organizes into collagen
fibrils, leading to the thickening of the alveolar septa and a clinical pneumonitis. Injury to the
ty pe II pneumocy te, with resultant changes in the surfactant sy stem (and thus alveolar
surface tension and compliance) and in the endothelial cell and capillary permeability, causes
these changes (152). After 6 months the fibrotic phase occurs. Alveolar septa become fibrotic
and thickened by bundles of elastic fibers, forming the basis for chronic respiratory injury.
Eventually, the alveoli collapse and are obliterated by connective tissue. Capillaries are lost,
replaced, and then recanalized. The target cells that trigger this process are less clearly
established but include the septal fibrocy te and endothelial cell.
Clinical Manifestations
Acute pneumonitis usually occurs 3–6 months after the start of radiation. The sy mptoms
include fever, congestion, a hacking but eventually productive cough, dy spnea, chest
tightness, and pleuritic pain. Signs are initially absent, but consolidation and pleural fluid or a
friction rub may be detected. If a large enough volume (greater than 75%) of lung is treated
at dosages greater than 45 Gy, then cor pulmonale and death can occur. Surviving patients
experience a protracted phase that slowly resolves. Lung function abnormalities are
generally not detected for 4–8 weeks after completion of irradiation. Restrictive changes with
volume loss occur, accompanied by a fall in diffusion capacity with mild arterial hy poxemia.
Hy poperfusion of the irradiated area and decreased lung compliance can be demonstrated.
The earliest radiographic changes (1–3 months after therapy ) are a diffuse infiltrate
corresponding to the radiation field with volume loss.
Chronic fibrosis is seen months to y ears after therapy, but most changes are apparent by
1–2 y ears. Most patients are asy mptomatic, but chronic respiratory impairment with
dy spnea, orthopnea, cy anosis, or cor pulmonale may occur. Maximum breathing capacity
and tidal volume decrease. Chest radiographs show linear streaking that may extend outside
the irradiated field. Regional contraction, pleural thickening, and tenting of the diaphragm
occur.
Patients who are treated with HSCT are at greater risk of pulmonary toxicity, related to
preexisting pulmonary dy sfunction, the preparative regimen (which may include
cy clophosphamide, busulfan, carmustine, and TBI), and to the presence of GVHD
(162,163,164,165). Although most transplant survivors are not clinically compromised,
restrictive lung disease may occur. Obstructive disease is less common, as is the recently
described late-onset pulmonary sy ndrome, which includes the spectrum of restrictive and
obstructive disease. Bronchiolitis obliterans, cry ptogenic organizing pneumonia, diffuse
alveolar damage, and interstitial pneumonia may occur as a component of this sy ndrome,
generally 6–12 months after transplant. Cough, dy spnea, or wheezing may occur with either
normal chest radiograph or diffuse or patchy infiltrates; however, most patients are sy mptom
free (163,165).
Cerveri et al. (162) evaluated pulmonary function tests in survivors of pediatric HSCT; of
note, 44% of patients had abnormal pulmonary function testing at baseline. At 3–6 months
posttransplant, 85% had abnormalities. At 24 months, these persisted in 62% of patients. A
restrictive abnormality was most common at 3–6 months after transplant.
The risk of acute pneumonitis increases from 5% after autologous transplantation to 20%
after allogeneic. The use of fractionated and low-dose rate regimens may decrease the risk.
Fry er et al. (152) and Keane et al. (163) analy zed the relationship between single doses
of irradiation to the whole lung and the resulting fatal pneumonitis. After correction for an
increased lung transmission of 15–20%, a dose–response relationship was generated. Lethal
pneumonitis was seen in 5% of patients after 8.2 Gy, 50% after 9.3 Gy, and 90% after 11 Gy.
Thus, a difference of 2 Gy could change mortality from 0% to 50%, which emphasizes the
importance of correcting for lung density. Increasing the dose rate from 0.1 to 0.5 Gy per
minute increased the frequency of injury from 50% to 90%.
Page 439The tolerance of the whole lung to fractionated doses of radiation is well
described, particularly in Wilms tumor patients (164,165,166). In the absence of
chemotherapy and with daily doses of 1.3–1.5 Gy, the TD5 is 26.5 Gy and the TD50 is 30.5
Gy. Young children experience more chronic toxicity at lower doses than older children and
adults because of interference with lung and chest wall development, in addition to fibrosis
and volume loss (167). After 20 Gy, mean total lung volumes and DLCO are reduced to 60%
of predicted values (166). Even within the dose range currently used for whole lung
irradiation (11–14 Gy ), restrictive changes occur (165).
Table 19.9 reviews several pulmonary late effects with respect to causative
treatments, signs and sy mptoms, screening and diagnostic tests, and management and
intervention (47).
Table 19.9 Evaluation of Patients at Risk for Late Effects: Pulmonary
Ovary
Radiation and chemotherapy can cause transitory or permanent effects on reproductive
capacity, endocrine integrity, and sexual function. The complexity of defining these sequelae
stems from the dose-dependent effects caused by different chemotherapy agents, RT, and
their combination. Injury to the ovaries can cause both sterilization and suppressed hormone
production because of the relationship of the latter to the presence of ova and maturation of
the primary follicle. Therefore, affected patients can have impaired development of
secondary sexual characteristics, menstrual irregularities including amenorrhea, and
sy mptoms associated with menopause such as hot flashes, loss of libido, and osteoporosis.
Pathophysiology
The ovary produces oocy tes and secretes steroid hormones. Active mitosis of oogonia occurs
during fetal life. The cortices of the ovaries harbor the follicles within connective tissue. The
follicles arise from the germinal epithelium, which covers the free surface of the ovary.
Through involution, atresia, and, to a much lesser extent, ovulation, the follicles disappear
entirely at menopause. Hy pothalamic gonadotropin-releasing hormone (GnRH) surges in late
childhood to initiate puberty. GnRH stimulates release of the pituitary gonadotrophs, which
orchestrate follicular maturation (follicle-stimulating hormone, FSH) and ovarian luteinization
(LH). With sexual maturity comes the 28-day cy cle with an estrogen-dependent midcy cle
surge of FSH and LH. After ovulation, the corpus luteum forms and produces progesterone,
estradiol, and 17-hy droxy progesterone, and the resultant endometrial changes. Without
chorionic gonadotropin from a conceptus, the corpus luteum is exhausted and progesterone
and estrogen fall. As FSH increases, the endometrium sloughs (menstruation). Ovarian
hormones have critical phy siologic effects on other organs, including maturation and
maintenance of the breasts and vagina, bone mineralization, integrity of the cardiovascular
sy stem, and libido. With depletion of oocy tes by radiation, chemotherapy, or aging, the
ovaries undergo atresia, and menstruation and estrogen production cease.
Radiation causes a decrease in the number of small follicles, impaired follicular
maturation, cortical fibrosis and atrophy, generalized hy poplasia, and hy alinization of the
capsule. Alky lating chemotherapeutic agents affect the resting oocy te in a dose-dependent,
cell cy cle–independent manner. Thecal cells and ova are depleted, as are the primordial
follicles, resulting in arrest of follicular maturation and decreased estrogen secretion.
Primarily because girls treated before puberty have a greater complement of ova than do
older women, ovarian function is more resistant to the effects of chemotherapy RT in
y ounger girls.
Page 441
Breast
As would be expected, children and adults have different manifestations of late radiation
injury in the breast, with breast hy poplasia being the most common ty pe of late toxicity in
children. In 129 children less than 4 y ears of age receiving a mean dose of 2.3 Gy for
hemangioma, breast hy poplasia was observed in 53% (178). Others have also observed
breast hy poplasia after relatively low doses of radiation, such as for pulmonary metastases
from Wilms tumor where children receive bilateral lung irradiation to doses of 10–12 Gy
(179). The risk of development of secondary breast malignancies is strongly correlated with
age (children vs. adults). This is discussed in great detail in Chapter 20 .
Testes
Germ cell integrity, Ley dig and Sertoli cell functioning, and the neuromuscular control of
ejaculation are vulnerable to cancer therapy. Although fertility and hormone production are
closely related in the ovary because of their dependence on the ova and primary follicle,
these functions differ in the testes because of the differing sensitivity of the spermatogonia
and Ley dig cells to cy totoxic therapy. Therefore, the effects of surgery, radiation, and
chemotherapy must be considered in the context of various specific functions.
Pathophysiology
Spermatogenesis, or the formation of spermatozoa from immature germ cells, takes place in
the seminiferous epithelium in the tubules. The least differentiated germ cells, the
spermatogonia, divide to form spermatocy tes. Immediately after formation, these cells
undergo meiosis to form spermatids, which then metamorphose into motile spermatozoa. A
constant supply of germ cell precursors is essential to the continuous production of
spermatozoa, which are then transported through the lumen of the seminiferous tubules into
the epididy mis, where they are stored. Ley dig cells are the primary androgen-secreting cells
and account for at least 75% of the total testosterone produced by the normal man (180).
Normal secretion of LH by the pituitary gland is essential for Ley dig cell function; LH levels
rise if inadequate androgen is produced. The phy siologic role of FSH in spermatogenesis is to
trigger an event in the immature testis that is essential for the completion of spermiogenesis.
FSH levels rise if such spermatid differentiation is compromised. Once the process of
spermatogenesis is established, it proceeds continuously as long as the supply of testosterone
is available. Testosterone also stimulates the development of male secondary sex
characteristics and, through negative feedback, pituitary LH secretion. Measurement of
testosterone production by the testis, therefore, is of major significance in the evaluation of
testicular function.
Clinical Manifestations
There is no question that RT can cause infertility. The testes can be irradiated directly by
scattered irradiation, or by radiation transmitted through shielding blocks. Because the
spermatogonia are exquisitely sensitive to radiation, even small dosages can produce
measurable damage. Depression of sperm counts is discernible at dosages as low as 15 cGy.
This decrease in sperm counts may evolve 3–6 weeks after irradiation. Depending on the
dosage, recovery may take 1–3 y ears. The germinal epithelium is damaged by much lower
dosages (less than 1 Gy ) of RT than are Ley dig cells (20–30 Gy ) (181). Complete sterilization
may occur with fractionated irradiation to a dosage of 1–2 Gy. Spermatocy tes generally fail
to complete maturation division at dosages of 2–3 Gy and are visibly damaged after 4–6 Gy
with resulting azoospermia. Higher dosages are necessary to damage spermatids that will
damage the more sensitive spermatocy tes. At the highest dosages, permanent sterility is
common. At lower dosages, this reduced sperm count is seen 60–80 day s after exposure,
which is the time at which maturation would otherwise be complete (182).
Page 442A variety of studies have shown that multiple small fractions of radiation are
more toxic to spermatogenesis than a large, single fraction. This has been called the reverse
fractionation effect. It is the result of the extreme radiosensitivity of the testicular germinal
epithelium, the small number of stem cells, and rapid cell turnover (182). Table 19.12
summarizes the fractionated dose-related effect on spermatogenesis and Ley dig cell function
(168).
Table 19.12 Effect of Fractionated Testicular Irradiation on Spermatogenesis and
Leydig Cell Function
For abdominal RT, the effect of the testes results from scatter. Sklar et al. (183) evaluated
the effect of 12 Gy radiation to the abdomen on testicular function of long-term ALL
survivors and found 55% to have evidence of germ cell dy sfunction. Scatter from abdominal
radiation with dosages greater than 20 Gy for HL can cause transient elevation in FSH and
oligospermia, but there is no effect with lower dosages. When patients are treated for HL, the
scattered dosage to the testes from a mantle or para-aortic field is negligible. However, when
the pelvis is treated, the calculated dosage depends on the relative location of the testes to the
inguinal field, with dosages ranging from 3% to 10% without a specially designed testes shield
and less than 1% with such a shield. Therefore, the testis, with well-designed shielding,
receives less than 2 Gy, and this dosage can be reduced further with the use of multileaf
collimation. The available data on males treated for HL suggest that fertility is either
maintained or only transiently depressed.
The effects of RT are often combined with those of chemotherapy, particularly
alky lating agents. The germinal epithelium of prepubertal testes is susceptible to damage
produced by several chemotherapeutic agents including cy clophosphamide, nitrogen
mustard, and procarbazine. Testicular biopsies after chemotherapy have demonstrated
aplasia of the germinal epithelium. Spermatogenesis is highly sensitive to cy clophosphamide,
with a dose–response relationship and an effect exacerbated by coadministration of other
alky lating agents, such as procarbazine. This was illustrated in a study by Bokemey er et al.
(184) in which long-term gonadal toxicity was compared among survivors of HL and NHL.
Both groups had received comparable median cumulative dosages of cy clophosphamide, but
only the patients with HL received procarbazine. The incidence of gonadal toxicity was more
than three times higher in men in the HL group. The only men in the NHL group who had
FSH elevation had received far higher dosages of cy clophosphamide than the mean. There
has been a consensus that boy s who receive less than 4 g/m 2 of cy clophosphamide without
any other alky lating agents and without testicular or cranial radiation are likely to retain their
fertility. However, in a report from Hobbie et al. (185), even four cy cles of
cy clophosphamide, vincristine, procarbazine, prednisone (COPP)/ABV (doxorubicin,
bleomy cin, vinblastine), where procarbazine was given in addition to the cy clophosphamide,
without RT, can result in sterility in males.
Page 443More recently, ifosfamide has been used as part of multimodality therapy for a
variety of childhood cancers, often in combination with cy clophosphamide or
abdominopelvic RT. Little is known about its long-term gonadal toxicity. Several studies have
looked at small groups of male survivors and ifosfamide appears to be more sparing on
fertility and a cumulative dose of >60 g appears to be an important threshold (186,187).
In a study of 248 adult male long-term survivors of childhood cancer, gonadal function
was evaluated. Inhibin B was lower in survivors than controls and was the most sensitive
discriminator. Significantly decreased inhibin B levels and increased FSH levels were found in
men treated for HL and NHL, AML, neuroblastoma, and sarcoma as compared to other
malignancies. Cumulative dosages of procarbazine and cy clophosphamide were the only
independent chemotherapy -related predictors for the decrease of inhibin B levels and the
increase of FSH levels. Age at the time of treatment did not influence posttreatment inhibin B
or FSH levels (188). In a retrospective cohort study, proven fertility (ever fathered a
pregnancy ) was evaluated by self-report among 213 men treated for ALL before the age of
18 and compared with male siblings. Proven fertility of male survivors was not different
from that of controls (relative fertility (RF) = 0.95, 95% CI 0.63–1.43). However, married
men treated before the age of 10 with high-dose (24 Gy ) cranial RT, without spinal RT, had
only 9% of the fertility of controls. High-dose cranial RT at older ages was not associated with
a statistically significant fertility deficit (189).
The limited data available indicate that chemical changes in Ley dig cell function are
observable after direct testicular irradiation. Shalet et al. (190) studied 11 boy s irradiated with
24 Gy in 12–16 fractions for a testicular relapse of ALL. Abnormalities of gonadotropin
secretion consistent with testicular damage were seen in nine (82%) of the boy s. The
mechanism for the increase in FSH is not entirely clear, but it is inversely proportional to the
loss of germ cells in the seminiferous tubules. Brauner et al. (191) studied boy s treated with
24 Gy of testicular radiation with a mean follow-up of 3.8 y ears. Among 12 prepubertal
boy s, all had normal basal testosterone, 3 had elevated basal LH, and response to HCG was
diminished in 10. Among nine pubertal boy s, basal testosterone was diminished in six and
response to HCG was diminished in seven. A correlation exists between age and response to
HCG stimulation.
With the growing use of BMT to treat malignant and nonmalignant diseases, the effects
of the transplantation preoperative regimen on reproduction are of interest. High dosages of
alky lating agents often are used in the treatment program. After 200 mg/kg of
cy clophosphamide and marrow transplantation for aplastic anemia, 18 prepubertal boy s
were evaluated, on average, 9 y ears after transplant. All boy s over 13 y ears of age showed
normal progression through puberty and have demonstrated normal LH, FSH, and
testosterone levels. In eight patients who underwent semen analy sis, two are azoospermic and
six are normal. Another population of prepubertal boy s who received TBI or TBI plus
testicular irradiation was also studied. All boy s who received TBI plus additional testicular
irradiation of 18–24 Gy had delay ed development and elevated FSH and LH levels with
diminished testosterone levels. The majority of those who received TBI alone had normal LH
levels with elevated FSH (192). Table 19.13 reviews several testicular late effects with
respect to causative treatments, signs and sy mptoms, screening and diagnostic tests, and
management and intervention (47).
Table 19.13 Evaluation of Patients at Risk for Late Effects: Testicular
Urinary System
The radiosensitivity of the urinary sy stem varies widely, with the ureter being the most
resistant, the bladder having intermediate sensitivity, and the kidney the most sensitive.
Kidney
Pathophysiology
The progression of renal dy sfunction after irradiation is grouped into three periods. The acute
period (up to 6 months) is rarely sy mptomatic, though the glomerular filtration rate (GFR)
may be low. In the subacute period (6–12 months), the signs and sy mptoms include dy spnea
on exertion, headaches, ankle edema, lassitude, anemia, hy pertension, albuminuria,
papilledema, elevated blood urea, and urinary abnormalities (granular and hy alin casts, red
blood cells). Death might result from chronic uremia or left ventricular failure, pulmonary
edema, pleural effusion, and hepatic congestion. In the chronic period (generally after 18
months), either benign or malignant hy pertension is seen, depending on the severity of the
renal insult. Chronic radiation nephropathy in its mildest forms may not be diagnosed until
>10 y ears after therapy. Abnormalities may include only proteinuria and azotemia with
urinary casts and mild or no hy pertension.
The pathologic process is a progressive arteriolonephrosclerosis. The lesion involves the
microvasculature with injury to the intercellular connections between the renal capillary and
arterioles. There is degeneration and sclerosis of these arterioles with narrowing or occlusion
of the lumen and secondary degeneration of dependent structures (glomeruli, tubules).
Associated changes in connective tissue include a thickened basement membrane, increased
interstitial connective tissue, hy alinization, and fibrosis. Decreased perfusion of the kidney can
occur with capillary and venous thrombosis and, eventually, necrosis.
Late renal dy sfunction has been documented after TBI before BMT for childhood
malignancies. Tarbell et al. (219) reported a 35% incidence in children with ALL and a 71%
incidence in children with neuroblastoma who received fractionated TBI (12–14 Gy over 3–4
day s). Renal biopsies in two patients showed changes consistent with radiation nephropathy or
hemoly tic uremic sy ndrome. The onset of renal dy sfunction after TBI is 3–6 months, similar
to that of classically described radiation nephritis. Whereas Tarbell et al. (219) found that
renal injury occurs at a y oung age, Lonnerholm et al. (220) found an 18% incidence of renal
dy sfunction in autografted children without an apparent age effect. With more modern
techniques and longer interfraction intervals for TBI, less than 15% of children will develop
chronic renal insufficiency or hy pertension, and the risk is related to both the nephrotoxic
agents used and the TBI fractionation scheme and interfraction interval (221,222). Of interest
is that proximal tubular dy sfunction is more commonly abnormal than distal tubular function.
Chemotherapy can also adversely affect renal function. Cisplatin at dosages greater than
200 mg/m 2 can result in glomerular or tubular injury and renal insufficiency. Other
nephrotoxic agents such as aminogly cosides, amphotericin, and ifosfamide may further
increase risk. Effects can be seen acutely and may progress after completion of therapy
(223). A few small studies examining children treated with carboplatin have evaluated short-
and long-term nephrotoxicity related to carboplatin, finding none significant to date (224,225).
Page 447Ifosfamide can also cause glomerular and tubular (proximal greater than
distal) toxicity, with renal tubular acidosis, or the Fanconi sy ndrome. Dosages greater than 60
g/m 2, age less than 5 y ears at the time of treatment, and combination with cisplatin and
carboplatin increase risk. Abnormalities in glomerular filtration are less common and
generally not clinically significant. Further study of larger cohorts with longer follow-up is
needed (226,227,228). A study examining grades 3–4 ifosfamide-induced nephrotoxicity
among adult and pediatric patients found a prevalence of 17% in both, and neither age nor
cumulative ifosfamide dose was a risk factor (229). Table 19.14 reviews several renal late
effects with respect to causative treatments, signs and sy mptoms, screening and diagnostic
tests, and management and intervention (47).
Table 19.14 Evaluation of Patients at Risk for Late Effects: Genitourinary
Urinary Bladder
Pelvic or central nervous sy stem surgery, alky lator-containing chemotherapy including
cy clophosphamide or ifosfamide, pelvic radiation therapy, and certain spinal and
genitourinary surgical procedures have been associated with late effects involving the urinary
bladder.
Chemotherapy -associated hemorrhagic cy stitis presents as an acute toxicity and appears
to be a rare persistent effect among clinically well-characterized long-term survivor cohorts
(59). In a study of 6119 children treated between 1986 and 2010 (mean age, 12.2 y ears ± 6.3
SD), 1.6% (n = 97) developed hemorrhagic cy stitis, most of whom (75%) had severity scores
of II or III (scale, I–IV). Older age, previous bone marrow or peripheral stem cell
transplantation, and BK virus in the urine were risk factors for hemorrhagic cy stitis and were
associated with a higher severity score (230). Pelvic radiation therapy is also associated with
an increased risk of hemorrhagic cy stitis that may be either acute or chronic in presentation.
The risk of radiation-induced hemorrhagic cy stitis is greatest among survivors treated with
radiation doses of more than 30 Gy to the whole bladder or more than 60 Gy to a portion of
the bladder. Long-term bladder fibrosis and contracture may result as a sequelae of
hemorrhagic cy stitis or radiation therapy (231).
Naturally, surgical procedures involving the lower genitourinary tract have the potential
to impair normal function of the bladder and normal voiding mechanisms. Likewise, any
cancer therapy or tumor infiltration that disrupts innervation of the bladder can have
deleterious effects on bladder function that may manifest as impaired bladder storage,
inability to void and/or incontinence.
Digestive Tract
The esophagus, stomach, pancreas, and small and large intestines are irradiated in a variety
of pediatric malignancies. Although primary tumors of these organs are rare in childhood,
they may be incidentally irradiated in the treatment of HL and NHL, the Wilms tumor,
neuroblastoma, soft tissue sarcomas, and bone tumors.
The direct effect of digestive tract irradiation is loss of regenerating cells lining the gut.
Radiation damage of the fine vasculature of the digestive tract may progress to obliterative
vasculitis, with the ultimate development of ischemia (232). Acute radiation injury results
from the depletion of normally proliferating cell, mucosal sloughing, villus shortening, and
subsequent inflammatory infiltration and edema. The patient may suffer from ody nophagia,
dy sphagia, abdominal pain, or diarrhea, depending on the site affected. Late radiation injury
to the digestive tract is attributable to vascular injury. As the radiation vasculopathy
progresses to obliteration, necrosis, ulceration, stenosis, or perforation may result (232). Late
radiation enteropathy is characterized by malabsorption, pain, and recurrent episodes of
bowel obstruction, as well as perforation, infection, and death. The onset is generally 6–24
months after the conclusion of RT. Donaldson et al. (233) evaluated 44 children who received
abdominal irradiation for a variety of malignancies; 11% of the entire population and 36% of
the longterm survivors developed bowel obstruction. Contributing factors included prior
abdominal surgery, the use of concurrent actinomy cin D, and very y oung age. In general,
fractionated dosages of 20–30 Gy can be delivered to the small bowel without significant
long-term morbidity. Dosages greater than 40 Gy are needed to cause bowel obstruction or
chronic enterocolitis (234). Intestinal obstruction can be a particularly late effect, occurring at
a median of 12 y ears after diagnosis. The use of abdominal or pelvic RT increased this risk
(235). Sensitizing chemotherapeutic agents such as actinomy cin D and anthracy clines can
increase this risk. In a report of 42 survivors of the Wilms tumor treated from 1968 to 1994
with RT, actinomy cin D, and vincristine with or without doxorubicin, the actuarial incidence of
bowel obstruction at 5, 10, and 15 y ears was 9.5%, 13.0%, and 17.0%, respectively. Radiation
within 10 day s of surgery increased risk for obstruction (91).
The prevention and management of radiation digestive tract injury relies primarily on
the exclusion of normal tissues from the treatment beam whenever possible. For the
esophagus, stomach, and large bowel, this usually relies on beam direction planning and
patient positioning. For the mobile portions of the small bowel, the clinician also evaluates the
prone versus supine position; the use of compression, tilt tables, and false table tops; surgical
placement of omental slings and absorbable mesh; and other techniques. The patient with
acute radiation enteropathy may be helped by sy mptomatic interventions. Medical therapy
for late-onset radiation enteritis is unsatisfactory and has relied on intermittent steroids,
sulfasalazine, parenteral nutrition, and other supportive care. Surgical resection of damaged
or obstructed bowel may be used, but there is a high incidence of anastomotic dehiscence,
operative mortality, and reobstruction (232).
Pancreas
The pancreas has been thought to be relatively radioresistant because of a paucity of
information about late pancreatic-related effects. However, in the course of abdominal RT or
TBI, damage to the islet cells of the pancreas can occur manifesting with increased risk of
diabetes mellitus (DM) in long-term survivors of childhood cancer (236). This may be the
result of direct cy totoxicity to pancreatic cells from abdominal RT, but may also be related to
metabolic sy ndrome, discussed earlier in this chapter. In a study of 8599 survivors from the
CCSS, DM was reported in 2.5% of the survivors compared with 1.7% of the siblings. After
adjustment for body mass index, age, sex, race/ethnicity, household income, and insurance,
the survivors were 1.8 times more likely than the siblings to report DM. In adjusted models,
TBI was associated with a sevenfold increased risk, abdominal irradiation with a 2.7-fold
increased risk, alky lating agents with a 1.7-fold increased risk, and age 0–4 y ears at diagnosis
with a 2.4-fold increased risk (237).
Page 450Two studies have investigated dose/volume parameters associated with the
subsequent development of DM. In a retrospective cohort study, the risk of DM increased with
radiation therapy to the tail of the pancreas, where the islets of Langerhans are concentrated.
Risk increased up to 20–29 Gy and then plateaued. The estimated RR at 1 Gy was 1.61.
Radiation dose to other parts of the pancreas did not have a significant effect. Compared with
patients who did not receive radiation therapy, the RR of diabetes mellitus was 11.5 in patients
who received more than 10 Gy to the pancreas. Children y ounger than 2 y ears at the time of
radiation therapy were more sensitive than were older patients (RR at 1 Gy was 2.1 for the
y oung age group vs. 1.4 for older patients) (238). For the 511 patients who received more
than 10 Gy, the cumulative incidence of diabetes mellitus was 16% (238). Another study
evaluated the risk of diabetes mellitus in 2264 five-y ear survivors of Hodgkin ly mphoma
(42% y ounger than 25 y ears at diagnosis) After a median follow-up of 21.5 y ears, the
cumulative incidence of diabetes mellitus was 8.3% (95% CI, 6.9–9.8%) for the overall
cohort and 14.2% (95% CI, 10.7–18.3%) for those treated with more than 36 Gy para-aortic
radiation. Survivors treated with more than 36 Gy of radiation to the para-aortic ly mph nodes
and spleen had a 2.3-fold increased risk of diabetes mellitus compared with those who did not
receive radiation therapy. The risk of diabetes mellitus increased with higher doses to the
pancreatic tail (239).
Liver
The clinical signs and sy mptoms of radiation hepatitis include abdominal pain, increased
girth, ascites, weight gain, jaundice, and elevation of liver enzy mes. Severe
thrombocy topenia can be seen, most commonly in children who have also been treated with
actinomy cin D.
In the acute phase of radiation injury (less than 3 months after irradiation), the liver is
hy peremic and enlarged in the treated area (240). Dilatation and sinusoidal congestion
accompanied by atrophy around the central vein of the lobule may be seen. As the chronic
phase evolves (more than 3 months after treatment), characteristic central vein lesions
develop. The lumen narrows progressively with fibrotic changes involving the intima, leading
to increasing sinusoidal congestion and liver cell atrophy. Inflammatory exudate is uniformly
absent. After 6 months and up to 6 y ears after irradiation, the distance between the central
vein and portal space decreases, indicating the atrophy of hepatocy tes. Nodules of
regeneration are rare. Central veins become small and inconspicuous, and lobules are
distorted or collapsed. Concentric fibrosis in the portal spaces around the portal veins occurs.
This pathologic picture has been classified as veno-occlusive disease, a process that is
accelerated after BMT and can be seen with weeks of conditioning with TBI. With modern
chemotherapy and RT, it is the most critical hepatic toxicity. It is characterized by occlusion
and obliteration of the central veins of the hepatic lobules, with retrograde congestion and
secondary necrosis of hepatocy tes. Although there may be a dose effect of RT, this
complication is also reported after conditioning regimens with cy clophosphamide and
busulfan alone. Preexisting hepatic disease, including infection, and GVHD may increase the
risk (241). Escalation of cy clophosphamide dose is thought to be associated with increased risk
of veno-occlusive disease (242).
The cumulative dosage, volume of liver irradiated, and additional treatment with
chemotherapy are important risk factors for hepatic fibrosis. Radiation hepatopathy can
occur with dosages of 30–40 Gy to the entire liver, but significantly higher dosages to focal
volumes can be given with few clinical complications (243). Lower dosages can be
associated with hepatopathy if the child is also receiving sensitizing chemotherapy. This is
evident in a series of children treated for the Wilms tumor, neuroblastoma, or hepatoma with
RT to the liver and chemotherapy. Fractionated dosages to 12–25 Gy caused dy sfunction in
50% of patients, 25–35 Gy caused abnormalities in 63%, and more than 35 Gy was toxic in
86%. In the NWTSG, 16 out of 303 patients (5.3%) had liver toxicity with liver doses ranging
from less than 15 Gy to more than 30 Gy. Right-flank or whole-abdomen radiation increased
risk significantly more than isolated left-flank radiation. The injury was manifest as
thrombocy topenia, hepatomegaly, ascites, and, in four cases, hepatic failure. All patients
received chemotherapy, including vincristine, actinomy cin D, and, in some patients,
doxorubicin (244).
Table 19.15 reviews several gastrointestinal and hepatic effects with respect to
causative treatments, signs and sy mptoms, screening and diagnostic tests, and management
and intervention (47).
Table 19.15 Evaluation of Patients at Risk for Late Effects: Gastrointestinal
Eye
The ey e is composed of several tissues that vary greatly in their radiosensitivity. Acute
reactions include iridocy clitis, keratitis, conjunctivitis, and blepharitis. Delay ed reactions,
which generally occur after 6 months, include retinopathy, optic neuropathy, lacrimal gland
atrophy or duct stenosis, glaucoma resulting from iridocy clitis, cataract, corneal
vascularization and scarring, conjunctival telangiectasia, and ey elid atrophy with entropion or
ectropion.
Retina
Radiation retinopathy is characterized by a slowly progressive microangiopathy, which may
result in macular edema, capillary nonperfusion, retinal and disc neovascularization, vitreous
hemorrhage, and traction retinal detachment. The microangiopathic changes may appear 6
months to 3 y ears after therapy (245). Visual loss is painless unless neovascular glaucoma
develops. Using 1.8–2 Gy per fraction, the threshold for injury is 46 Gy, although the
frequency is rare below dosages of 60 Gy. As fraction size increases bey ond 2.5 Gy, the
frequency of injury increases (246). It is important to note that certain chemotherapeutic
agents can cause retinal toxicity, and the risk is higher in children with impaired renal function
who thereby accumulate renally cleared drugs (247).
Lens
Whereas retinitis and lacrimal duct abnormalities are caused only by high RT dosages, low-
dose irradiation damages the germinal zone of the epithelium on the equator of the lens (249).
The radiation-induced cataract is a central, posterior subcapsular opacity that appears as a dot
at the posterior pole of the lens. As the cataract enlarges, small vacuoles and granules appear
around it. With continued enlargement, the opacity develops a clear center, giving it a
doughnut-shaped appearance (245). This progresses to the anterior pole, and the cortex then
becomes opaque. Merriam and Focht (250) reported an evaluation of the dose–response
relationship in 1958. After single doses of 200 cGy, abnormalities were detected but were not
clinically significant until dosages exceeded 400 cGy. With fractionated irradiation, a 60%
frequency (progressive in one-half) was seen after 750–950 cGy, whereas 100% was seen
after 1150 cGy (251). Reevaluation of atomic bomb survivor data suggests a 20–40%
incidence of radiation cataract after a single ey e dosage of 5 Gy mixed photons and neutrons
(252). The interval to abnormality in various studies is 2–3 y ears, but ranges from 6 months to
35 y ears depending on dosage.
Patients treated with TBI are also at greater risk of cataracts. Belkacemi et al. (253)
reported on cataracts after TBI in survivors of leukemia who underwent HSCT.
Hy perfractionation and lower dose rate were associated with decreased incidence of
cataracts. These data are shown in Figure 19.18 . Corticosteroids, GVHD, older age, and
allogeneic transplantation are also risk factors (253,254,255,256). In a French study of 271
children treated with TBI, 41.7% of patients treated with TBI developed a cataract with a
median follow-up of 10.3 y ears. Of note, only 8.1% required surgical intervention. The
cumulative incidence at 20 y ears was 78%; no plateau was seen in cataract incidence,
suggesting that with prolonged follow-up nearly all patients treated with TBI will develop
cataracts (257).
Page 452
Optic Nerve
Injury to the distal nerve end produces ischemic optic neuropathy, whereas more proximal
injury produces retrobulbar optic neuropathy. These are potentially blinding complications.
The peak onset is 1–2 y ears, manifested by visual field deficits or central scotoma (260).
Lid
Rounding of the lid margins is not seen below 40 Gy, and ectropion is uncommon below 60
Gy. The ey elash usually is spared by anterior beams so that it may remain partially intact
(245).
Orbit
For survivors of retinoblastoma, a small orbital volume may result after either enucleation or
RT. Age less than 1 y ear may increase risk, but this is not consistent across studies (261).
Better management of prosthetic implants and newer methods of delivering RT are likely to
reduce risk (261). Newer strategies for treating retinoblastoma use chemotherapy to reduce
tumor size, combined with local ophthalmic therapies that include thermotherapy,
cry otherapy, and plaque radiation. These strategies may be associated with local
complications that can affect vision; particularly tumors located near the macula and fovea
increase the risk of complications leading to visual loss (262,263,264,265).
One group of patients at risk for all of the aforementioned complications are survivors of
orbital rhabdomy osarcoma, who are at risk of dry ey e, cataract, orbital hy poplasia, ptosis,
retinopathy, optic neuropathy, lid epithelioma, and impairment of vision after RT dosages of
30–65 Gy. The higher dosages (more than 50 Gy ) are associated with lid epitheliomas,
keratoconjunctivitis, lacrimal duct atrophy, and severe dry ey e. Retinitis and optic neuropathy
may also occur after dosages of 50–65 Gy, and even at lower total dosages if the individual
fraction size is greater than 2 Gy (260). Cataracts are reported after lower dosages of 10–18
Gy (249,266).
Table 19.16 reviews several late effects involving the ey e with respect to causative
treatments, signs and sy mptoms, screening and diagnostic tests, and management and
intervention (47).
Hearing
The auditory apparatus may be irradiated during the treatment of brain tumors, aerodigestive
tract malignancies, soft tissue sarcomas, and ly mphoma. Fractionated dosages of more than
50 Gy can produce permanent changes in the temporal bone and adjacent soft tissues,
including empty lacunae in the bone, resorption, absent marrow, and replacement by fibrous
tissue. Temporal bone osteoradionecrosis is extremely rare with modern pediatric RT
technique. Radiation changes in the external auditory canal may include thickening of the
epithelium overly ing the ty mpanic membrane, atrophic ceruminous glands, and absent hair
follicles. On occasion, the combination of abnormal epithelium of the external auditory canal
and bacterial overgrowth can produce a persistent otitis externa necessitating the use of wicks,
otic antibiotics, and otic steroid preparations (267).
Cranial irradiation alone rarely has a
significant effect on hearing. RT can result in
cochlear damage, with sensorineural hearing
loss (SNHL) occurring in about 25% of patients
treated with dosages approaching 60 Gy, but
SNHL is considered rare at lower RT dosages in
the absence of cisplatin. Recent data suggest that
cochlear dosages of 30–50 Gy can cause
intermediate-frequency SNHL and that CSF
shunting procedures increase the risk (268). At
dosages as low as 270 mg/m 2, cisplatin can
result in hearing loss when combined with
cranial RT dosages of 40–50 Gy (269). The
sequence of chemoradiotherapy appears to Figure 19.19 Mean hearing thresholds
influence risk. Risk and severity of ototoxicity for three groups of patients with brain
are greater when cisplatin is administered after tumors. Group I (GRI; red) received
cranial radiation (Fig. 19.19 ) (270). cranial irradiation only, group II (GRII;
Page 455Hearing loss in the speech range blue) received cisplatin, and group III
(0.5–3 kHz), which may compromise language (GRIII, green) received cranial irradiation,
reception and expression, is reported with then cisplatin. (From McHaney V, Kavnar
cumulative cisplatin dosages of at least 360 E, Meyer W, et al. Effects of radiation
mg/m 2, and a 25% incidence of hearing loss is therapy and chemotherapy on hearing.
In: Green DM, D’Angio GJ, eds. Late
reported with dosages greater than 720 mg/m 2 in
Effects of Treatment for Childhood Cancer.
the absence of any RT. Fifty percent of children
New York, NY: Wiley-Liss; 1992:7–10, with
treated with cisplatin dosages greater than 450
permission.)
mg/m 2 have SNHL in the high-frequency range
(6–8 kHz). Younger age at the time of administration increases risk (270,271). Carboplatin
may be less ototoxic, but further follow-up in patients treated with high cumulative dosages is
necessary before a clear dose threshold can be established (271,272,273). In a series of
patients with neuroblastoma, the combined effects of cisplatin and carboplatin were
investigated. Severe (grade 3/4) deficits affected 25% of patients receiving cumulative doses
of cisplatin of 400 mg/m 2, 54% patients receiving cumulative doses of cisplatin of 600
mg/m 2, and 50% of patients receiving that dose of cisplatin, followed by my eloablative doses
of carboplatin. Patients <5 y ears at diagnosis had greater ototoxicity than adolescents or
y oung adults (274).
Hearing loss in the child with cancer merits detailed attention because it may lead to
additional difficulties with communication, speech and language acquisition, and development
of learning skills.
Table 19.17 reviews several late effects involving the ear with respect to causative
treatments, signs and sy mptoms, screening and diagnostic tests, and management and
intervention (47).
Table 19.17 Evaluation of Patients at Risk for Late Effects: Ear
Bone Marrow
The hematopoietic progenitor cells and their offspring are cradled on a stroma of endothelial
cells, adventitial cells, fibroblasts, macrophages, and fat cells. Mechanisms of marrow-
induced failure include direct killing of hematopoietic progenitor cells, accessory cells (e.g.,
ly mphocy tes and monocy tes), damage to the stroma and microcirculation, and disturbance
of hematopoietic growth and regulatory factors (285).
The bone marrow is extremely sensitive to irradiation, to the degree that some injury is
produced by any fractional dosage. Irradiated bone marrow becomes hy pocellular. There is
destruction of fine vasculature followed by fatty marrow replacement of the normal
hematopoietic marrow (286). If the radiation dosage is sufficiently high, destruction of the
sinusoidal circulation precludes migration of hematopoietic cells from distant nonirradiated
sites. After 40 Gy fractionated irradiation, 85% of irradiated sites show a return of activity in
2 y ears; in 55% of those areas, recovery becomes complete. Conversely, single doses of 20
Gy to localized regions can produce permanent aplasia. Radiation-induced changes in bone
marrow may be detected by increased signal intensity on MRI because of the decreased T1
relaxation time of the increased fatty marrow content. Dosages greater than 50 Gy seem to
produce irreversible depletion of my eloid tissue (287).
Page 457The regenerative capacity of the bone marrow depends on the volume
irradiated 288). After irradiation to less than 25% of the bone marrow, the unexposed portion
is stimulated and successful in compensating for hematopoietic demands, and the treated
portion may never regenerate. When volumes in excess of 50% are irradiated, the unexposed
bone marrow is not adequate to meet the body ’s demands. Consequently, the paradoxical
phenomenon of in-field regeneration is seen 2–5 y ears later, and extension of bone marrow
activity into previously quiescent long bones is seen within 1–2 y ears.
Page 458Differences between children and adults in the response of the bone marrow to
irradiation relate primarily to the differing extent of active bone marrow at different ages
(289). In the immediate postnatal period, conversion from active red to fatty y ellow marrow
begins and is first evident in the extremities. This conversion progresses from peripheral
(appendicular) toward the central (axial) skeleton and from diaphy seal to metaphy seal in
individual long bones (Fig. 19.21 ).
Figure 19.21 The relative amount of red and yellow bone marrow in different anatomic
sites as a function of age. (From Kricun ME. Red–yellow marrow conversion: its effect on the
location of some solitary bone lesions. Skeletal Radiol. 1985;14:10–19, with permission.)
(From Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for
pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and
hearing deficits. J Clin Oncol. 2009;27:3691–3697.)
Figure:
Full-scale IQ change by baseline intelligence. Blue, baseline IQ < 100; Red, baseline IQ > 100.
(From Ris MD, Packer R, Goldwein J, et al. Intellectual outcome after reduced dose radiation
therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study.
J Clin Oncol. 2001;19:3470–3476, with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Central Nervous System
Figure:
Peak growth hormone (GH) according to hypothalamic mean dose and time after start of
radiation. According to equation 2, peak GH = exp{2.5947 + time × [0.00079 × mean dose]}.
(From Merchant TE, Rose SR, Bosley C, et al. Growth hormone secretion after conformal
radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol.
2011;29:4776–4780.)
Figure:
Height standard deviation scores (SDS) for ALL survivors, treated pre- or postpubertally with
chemotherapy alone, cranial or craniospinal RT.
(From Chow EJ, Friedman DL, Yasui Y, et al. Decreased adult height in survivors of childhood
acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J
Pediatr. 2007;150:370–375, with permission)
Figure: Evaluation of Patients at Risk for
Late Effects: Neuroendocrine
Figure:
Probability of developing an underactive thyroid after diagnosis of the Hodgkin disease.
(From Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor
Study Cohort: a review of published finding. J Clin Oncol. 2009;27:2339–2355.)
Figure: Evaluation of Patients at Risk for
Late Effects: Thyroid
Figure:
Cumulative incidence (CI) of bony morbidity for 176 children treated for ALL between 1987
and 1991. With 7.6 years of median follow-up, the overall 5-year CI (±SE) was 30% ± 4%. The
5-year CI of fracture was 28% ± 3%, and of osteonecrosis, 7% ± 2%.
(From Strauss AJ, Su JT, Dalton VM, et al. Bony morbidity in children treated for acute
lymphoblastic leukemia. J Clin Oncol. 2001;19:3066–3072, with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Musculoskeletal
Figure:
A & B: Marginal (Kaplan–Meier) and cause-specific (C & E) (competing risk) cumulative
incidence of cardiac events (CEs) in childhood cancer survivors stratified according to
different treatment groups. A: Marginal cumulative incidence for all CEs, stratified according
to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank p < 0.001. B: Marginal
cumulative incidence for all CEs, stratified according to different CTX therapies, log-rank p <
0.001. C: Cause-specific cumulative incidence for congestive heart failure, stratified
according to different treatment groups, log-rank p < 0.001. D: Cause-specific cumulative
incidence for cardiac ischemia, stratified according to cardiac irradiation (RTX) or no RTX,
log-rank p < 0.01. E: Cause-specific cumulative incidence for valvular disease, stratified
according to RTX or no RTX, log-rank p < 0.001. The shaded colorized background areas refer
to the 95% CIs. Ant, anthracycline.
(From van der Pal H, van Dalen EC, van Delden E, et al. High risk of symptomatic cardiac
events in childhood cancer survivors. J Clin Oncol. 2012;30:1429–1437, with permission).
Figure:
Cumulative incidence of cardiac disorders among childhood cancer survivors by average
cardiac radiation dose.
(From Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult
survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer
Survivor Study cohort. BMJ. 2009;339:b4606.)
Figure:
Location of the coronary vessels (dark lines) on a standard mantle field is illustrated. The
blocks are outlined in white.
(From King V, Constine LS, Clark D, et al. Symptomatic coronary artery disease after mantle
irradiation for Hodgkin’s disease. Int J Radiat Oncol Biol Phys.1996;36:881–889, with
permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Cardiac
Figure:
Cumulative incidence of chronic pulmonary conditions by type of therapy (CRX, chest
radiation; PTC, pulmonary toxic chemotherapy).
(From Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor
Study cohort: a review of published findings. J Clin Oncol. 2009;27:2339–2355, with
permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Pulmonary
Figure: Effect of Fractionated Irradiation on
Ovarian Function in Women of
Reproductive Age
Figure:
Cumulative incidence of nonsurgical premature menopause.
(From Green DM, Sklar CA, Boice JD Jr, et al. Ovarian failure and reproductive outcomes
after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin
Oncol. 2009;27:2374–2381, with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Ovarian
Figure: Effect of Fractionated Testicular
Irradiation on Spermatogenesis and Leydig
Cell Function
Figure: Evaluation of Patients at Risk for
Late Effects: Testicular
Figure:
Radiation dose–response curve for the occurrence of symptomatic radiation nephropathy
generated from data presented in several reports. An approximate threshold dosage of 15 Gy
(conventional fractionation) is seen, and a plateau is noted beyond dosages of 30 Gy.
(Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys.1995;31:1249–1256,
with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Genitourinary
Figure: Evaluation of Patients at Risk for
Late Effects: Gastrointestinal
Figure:
Product-limit estimates for cataract incidence according to fractionation and dose rate.
FTBI, fractionated total body irradiation; HDR, high dose rate (>0.04 Gy/minute); LDR, low
dose rate (≤0.04 Gy/minute); STBI, single-dose total-body irradiation.
(From Belkacemi Y, Labopin M, Vernant JP, et al. Cataracts after total body irradiation and
bone marrow transplantation in patients with acute leukemia in complete remission: a study
of the European Group for Blood and Marrow Transplantation. Int J Radiat Biol Oncol
Phys.1998;41(3):659–668, with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Eye
Figure:
Mean hearing thresholds for three groups of patients with brain tumors. Group I (GRI; red)
received cranial irradiation only, group II (GRII; blue) received cisplatin, and group III (GRIII,
green) received cranial irradiation, then cisplatin.
(From McHaney V, Kavnar E, Meyer W, et al. Effects of radiation therapy and chemotherapy
on hearing. In: Green DM, D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer.
New York, NY: Wiley-Liss; 1992:7–10, with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Ear
Figure:
Proportion of unirradiated and irradiated parotid gland with measurable salivary flow as a
function of radiation dosage.
(From Marks J, Davis C, Gottsman V, et al. The effects of radiation on parotid salivary
function. Int J Radiat Oncol Biol Phys.1981;7:1013–1019, with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Dental and Salivary
Figure:
The relative amount of red and yellow bone marrow in different anatomic sites as a function
of age.
(From Kricun ME. Red–yellow marrow conversion: its effect on the location of some solitary
bone lesions. Skeletal Radiol. 1985;14:10–19, with permission.)
Figure: Antineoplastic Drug Category and
Agent with Their Relative Degree and
Duration of Myelosuppression
CONCLUSIONS AND FUTURE DIRECTIONS
RT and chemotherapy can result in adverse long-term phy siologic sequelae for survivors of
childhood cancer. However, these treatment modalities have resulted in a markedly increased
survival rate for almost all pediatric malignancies. Therefore, it is essential to balance the
benefits against risks. Both length of survival and the impact of phy siologic late effects on the
quality of that survival must be considered in therapy selection.
The pathophy siologic mechanisms of damage from RT and chemotherapy to normal
tissues are well described. However, what is unclear is the interindividual variation in
responses to the same therapeutic exposures. Although many children and adolescents are
treated with the same RT dosages, fields, and volumes, there is a significant degree of
variability in the proportion of those who develop radiation-related toxicities. For some, the
cy totoxicity of chemotherapy may enhance the RT effects. For others, effects related to
surgical intervention may augment the burden of late effects. However, little is known about
host-related factors, such as genetic susceptibility. This may include inherited differences in
radiation sensitivity to normal tissue or genes of xenobiotic metabolism, nucleotide provision,
or DNA repair. In addition, environmental and lifesty le factors such as diet, sun, tobacco, and
alcohol exposure that are etiologically related to the major problems in an aging population
are likely to influence the development of late effects for a given therapeutic exposure. New
patterns of late morbidity and mortality may emerge as survivors continue to age, and it is
only through continued study that such patterns will be identified and interventions for
treatment and prevention designed.
Page 459Furthermore, it is clear that the potential for the development of late effects in
normal tissues is related to cellular activity and maturation. As discussed, at any point in
development, a child’s body is a mosaic of different tissues developing at different rates and
in different temporal sequences. Since intrinsic radiation sensitivity and vulnerability to
radiation-induced normal tissue damage are related to cellular activity and level of maturity,
it is important to understand tissue development and consider differing sensitivities to the same
insult at any given time in a child’s development as this could drastically change the potential
for adverse late outcomes. Lastly, recognizing the mechanism of organ growth—that is, an
increase in the size of cells (hy pertrophy ) as opposed to the number of cells (proliferation)—
allows better identification of relative radiosensitivity because organs that only hy pertrophy
are less vulnerable to functional disturbance by irradiation.
REFERENCES
1. Ries LAG, Smith MA, Gurney JG, et al. Cancer incidence and survival among children
and adolescents: United States SEER Program 1975–1995, National Cancer Institute,
SEER Program. NIH Pub. No. 99-4649, Bethesda, MD; 1999:1–15.
2. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors
of childhood cancer. N Engl J Med. 2006;355:1572–1582.
3. Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-y ear survivors of
childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol.
2009:27:2328–2338.
4. Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-y ear
survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst.
2008;100:1368–1379.
5. Cohen L, Creditor M. Iso-effect tables for tolerance of irradiated normal human tissues.
Int J Radiat Oncol Biol Phys. 1983;9:233–241.
6. Rubin P, Cassarett GW. Clinical Radiation Pathology, Vols I and II. Philadelphia, PA: WB
Saunders; 1968.
7. Krasin MJ, Constine LS, Friedman DL, et al. Radiation-related treatment effects across
the age spectrum: differences and similarities, or what the old and y oung can learn from
each other. Semin Radiat Oncol. 2010;20:21–29.
8. Wallace WH, Kelsey TW. Human ovarian reserve from conception to menopause. PLoS
One. 2010;5:e8772.
9. Wallace WH, Thomson AB, Saran F, et al. Predicting age of ovarian failure after
radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys. 2005;62:738–
744.
10. Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer
survivor study. J Clin Endocrinol Metab. 2006;91:1723–1728.
11. Ogilvy -Stuart AL, Clark DJ, Wallace WH, et al. Endocrine deficit after fractionated total
body irradiation. Arch Dis Child. 1992;67:1107–1110.
12. Dobbing J, Sands J. The quantitative growth and development of the human brain. Arch
Dis Child. 1963;48:757–767.
13. Marks JE, Wong J. The risk of cerebral radionecrosis in relation to dose, time, and
fractionation—a follow-up study. Prog Exp Tumor Res. 1985;29:210–218.
14. Danoff BF, Cowchock S, Marquette C, et al. Assessment of the long-term effects of
primary radiation therapy for brain tumors in children. Cancer. 1982;49:1580–1586.
15. Torcuator R, Zuniga R, Mohan YS, et al. Initial experience with bevacizumab treatment
for biopsy confirmed cerebral radiation necrosis. J Neurooncol. 2009;94:63–68.
16. Duffner PK, Cohen ME. Long-term consequences of CNS treatment for childhood
cancer. Part II: clinical consequences. Pediatr Neurol. 1991;7:237–242.
17. Griffin TW. White matter necrosis, microangiopathy and intellectual abilities in survivors
of childhood leukemia—association with central nervous sy stem irradiation and
methotrexate therapy. In: Gilbert HA, Kagan AR, eds. Radiation Damage to the Nervous
System. New York, NY: Raven Press; 1980:155–174.
18. Hertzberg H, Huk W, Ueberall M, et al. CNS late effects after ALL therapy in childhood.
Part I: neuroradiological findings in long-term survivors of childhood ALL. Med Pediatr
Oncol. 1997;28:387–400.
19. Duffner PK, Cohen ME. The long-term effects of central nervous sy stem therapy on
children with brain tumors. Neurol Clin. 1991;9:479–495.
20. Palmer SL, Goloubeva O, Reddick WE, et al. Patterns of intellectual development
among survivors of pediatric medulloblastoma: a longitudinal analy sis. J Clin Oncol.
2001;19:2302–2308.
21. Reddick W, White H, Glass J, et al. Developmental model relating white matter volume
to neurocognitive deficits in pediatric brain tumor survivors. Cancer. 2003;97:2523–2529.
22. Kiehna E, Mulhern R, Li C, et al. Changes in attentional performance of children and
y oung adults with localized primary brain tumors after conformal radiation therapy. J
Clin Oncol. 2006;24:5283–5290.
23. Ris MD, Packer R, Goldwein J, et al. Intellectual outcome after reduced-dose radiation
therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group
study. J Clin Oncol. 2001;19:3470–3476.
24. Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsy chologic functioning of survivors
of childhood medulloblastoma randomized to receive conventional or reduced-dose
craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol. 1998;16:1723–
1728.
25. Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with
medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant
chemotherapy : a Children’s Cancer Group study. J Clin Oncol. 1999;17:2127–2136.
26. Merchant TE, Schreiber JE, Wu S, et al. Critical combinations of radiation dose and
volume predict intelligence quotient and academic achievement scores after
craniospinal irradiation in children with medulloblastoma. Int J Radiat Oncol Biol Phys.
2014;90:554–561.
27. Meadows AT, Gordon J, Massari DJ. Declines in IQ scores and cognitive dy sfunctions in
children with acute ly mphocy tic leukemia treated with cranial irradiation. Lancet.
1981;2:1015–1018.
28. Silber JH, Radcliffe J, Peckham V, et al. Whole-brain irradiation and decline in
intelligence: the influence of dose and age on IQ score. J Clin Oncol. 1992;10:1390–
1396.
29. Kingma A, Van Dommelen RI, Mooy aart EL, et al. No major cognitive impairment in
y oung children with acute ly mphoblastic leukemia using chemotherapy only : a
prospective longitudinal study. J Pediatr Hematol Oncol. 2002;24:106–114.
30. Waber DP, Shapiro BL, Carpentieri SC, et al. Excellent therapeutic efficacy and minimal
late neurotoxicity in children treated with 18 gray of cranial radiation therapy for high-
risk acute ly mphoblastic leukemia: a 7-y ear follow-up study of the Dana–Farber Cancer
Institute Consortium protocol 87-01. Cancer. 2001;92:15–22.
31. Page 460 Riva D, Giorgi C, Nichelli F, et al. Intrathecal methotrexate affects cognitive
function in children with medulloblastoma. Neurology. 2002;59:48–53.
32. Brown RT, Madan-Swain A, Pais R, et al. Chemotherapy for acute ly mphocy tic
leukemia: cognitive and academic sequelae. J Pediatr. 1992;121:885–889.
33. Ochs J, Mulhern R, Fairclough D, et al. Comparison of neuropsy chologic functioning and
clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given
cranial radiation or parenteral methotrexate: a prospective study. J Clin Oncol.
1991;9:145–151.
34. Butler RW, Hill JM, Steinherz PG, et al. Neuropsy chologic effects of cranial irradiation,
intrathecal methotrexate, and sy stemic methotrexate in childhood cancer. J Clin Oncol.
1994;12:2621–2629.
35. Kaleita TA, Reaman GH, MacLean WE, et al. Neurodevelopmental outcome of infants
with acute ly mphoblastic leukemia: a Children’s Cancer Group report. Cancer.
1999;85:1859–1865.
36. Hill DE, Ciesielski KT, Sethre-Hofstad L, et al. Visual and verbal short-term memory
deficits in childhood leukemia survivors after intrathecal chemotherapy. J Pediatr
Psychol. 1997;22:861–870.
37. Jansen N, Kingma A, Schuitema A, et al. Neuropsy chological outcome in
chemotherapy -only -treated children with acute ly mphoblastic leukemia. J Clin Oncol.
2008;26:3025–3030.
38. Kadan-Lottick NS, Brouwers P, Breiger D, et al. A comparison of neurocognitive
functioning in children previously randomized to dexamethasone or prednisone in the
treatment of childhood acute ly mphoblastic leukemia. Blood. 2009;114:1746–1752.
39. Jones AM. Transient radiation my elopathy (with reference to Lhermitte’s sign of
electrical paresthesia). Br J Radiol. 1964;37:727–744.
40. Inbar M, Merimsky O, Wigler N, et al. Cisplatin-related Lhermitte’s sign. Anticancer
Drugs. 1992;3:375–377.
41. Schultheiss TE, Higgins EM, El-Mahdi HM. The latent period in radiation my elopathy.
Int J Radiat Oncol Biol Phys. 1984;10:1109–1115.
42. Wara W, Phillips T, Sheline G, et al. Radiation tolerance of the spinal cord. Cancer.
1975;35:1558–1562.
43. Marcus R, William R. The incidence of my elitis after irradiation of the cervical spinal
cord. Int J Radiat Oncol Biol Phys. 1990;19:3–8.
44. Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors
of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor
Study. J Clin Oncol. 2006;24:5277–5282.
45. De Bruin ML, Dorresteijn LD, van’t Veer MB, et al. Increased risk of stroke and transient
ischemic attack in 5-y ear survivors of Hodgkin ly mphoma. J Natl Cancer Inst.
2009;101:928–937.
46. Mitchell WG, Fishman LS, Miller JH, et al. Stroke as a late sequel of cranial irradiation
for childhood brain tumors. J Child Neurol. 1991;6:128–133.
47. Schwartz CL, Hobbie WL, Constine LS. Facilitated assessment of chronic treatment by
sy mptom and organ sy stems. In: Schwartz CL, Hobbie WL, Constine LS, et al., eds.
Survivors of Child and Adolescent Cancer: A Multi-Disciplinary Approach. Berlin,
Germany : Springer; 2015:17–34.
48. Brinkman TM, Zhu L, Zeltzer LK, et al. Longitudinal patterns of psy chological distress in
adult survivors of childhood cancer. Br J Cancer. 2013;109:1373–1381.
49. Brinkman TM, Zhang N, Recklitis CJ, et al. Suicide ideation and associated mortality in
adult survivors of childhood cancer. Cancer. 2014;120:271–277.
50. Krull KR, Huang S, Gurney JG, et al. Adolescent behavior and adult health status in
childhood cancer survivors. J Cancer Surviv. 2010;4:210–217.
51. Zebrack BJ, Zeltzer LK, Whitton J, et al. Psy chological outcomes in long-term survivors
of childhood leukemia, Hodgkin ly mphoma, and non-Hodgkin’s ly mphoma: a report
from the Childhood Cancer Survivor Study. Pediatrics. 2002;110:42–52.
52. Mulrooney DA, Mertens AC, Neglia JP, et al. Fatigue and sleep disturbance in survivors
of childhood cancer: a report from the Childhood Cancer Survivor Study. Proc Annu
Meet Am Soc Clin Oncol. 2003;22:761.
53. Pai AL, Kazak AE. Pediatric medical traumatic stress in pediatric oncology : family
sy stems interventions. Curr Opin Pediatr. 2006;18:558–562.
54. Santacroce SJ, Lee YL. Uncertainty, posttraumatic stress, and health behavior in y oung
adult childhood cancer survivors. Nurs Res. 2006;55:259–266.
55. Kazak AE, Rourke MT, Alderfer MA, et al. Evidence-based assessment, intervention and
psy chosocial care in pediatric oncology : a blueprint for comprehensive services across
treatment. J Pediatr Psychol. 2007;32:1099–1110.
56. Kazak AE, Alderfer M, Rourke MT, et al. Posttraumatic stress disorder (PTSD) and
posttraumatic stress sy mptoms (PTSS) in families of adolescent childhood cancer
survivors. J Pediatr Psychol. 2004;29:211–219.
57. Kazak AE, Boeving CA, Alderfer MA, et al. Posttraumatic stress sy mptoms during
treatment in parents of children with cancer. J Clin Oncol. 2005;23:7405–7410.
58. Patino-Fernandez AM, Pai AL, Alderfer M, et al. Acute stress in parents of children
newly diagnosed with cancer. Pediatr Blood Cancer. 2008;50:289–292.
59. Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of health outcomes
among adults treated for childhood cancer. JAMA. 2013;309:2371–2381.
60. Merchant TE, Rose SR, Bosley C, et al. Growth hormone secretion after conformal
radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol.
2011;29:4776–4780.
61. Sklar C, Mertens A, Walter A, et al. Final height after treatment for childhood acute
ly mphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2499
centigray s of cranial irradiation. J Pediatr. 1993;123:59–64.
62. Chow EJ, Friedman DL, Yasui Y, et al. Decreased adult height in survivors of childhood
acute ly mphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J
Pediatr. 2007;150:370–375.
63. Sanders JE. Endocrine problems in children after bone marrow transplant for
hematologic malignancies. Bone Marrow Transplant. 1991;8:2–4.
64. Wingard JR, Plotnick LP, Freemer CS, et al. Growth in children after bone marrow
transplantation: busulfan plus cy clophosphamide versus cy clophosphamide plus total
body irradiation. Blood. 1992;79:1068–1073.
65. Huma Z, Boulad F, Black P, et al. Growth in children after bone marrow transplantation
for acute leukemia. Blood. 1995;86:819–824.
66. Sklar CA, Mertens AC, Mitby P, et al. Risk of disease recurrence and second neoplasms
in survivors of childhood cancer treated with growth hormone: a report from the
Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2002;87:3136–3141.
67. Bogarin R, Steinbok P. Growth hormone treatment and risk of recurrence or progression
of brain tumors in children: a review. Childs Nerv Syst. 2009:25:273–279.
68. Leung W, Rose SR, Zhou Y, et al. Outcomes of growth hormone replacement therapy in
survivors of childhood acute ly mphoblastic leukemia. J Clin Oncol. 2002;20:2959–2964.
69. Shalet SM, Brennan BM. Puberty in children with cancer. Horm Res. 2002;57:39–42.
70. Shalet SM, Crowne EC, Didi MA, et al. Irradiation-induced growth failure. Baillieres Clin
Endocrinol Metab. 1992;6:513–526.
71. Rappaport R, Brauner R, Czernichow P, et al. Effect of hy pothalamic and pituitary
irradiation on pubertal development in children with cranial tumors. J Clin Endocrinol
Metab. 1982;54:1164–1168.
72. Constine LS, Woolf PD, Cann D, et al. Hy pothalamic–pituitary dy sfunction after
radiation for brain tumors. N Engl J Med. 1993;328:87–94.
73. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al. A population-based study of
thy roid function after radiotherapy and chemotherapy for a childhood brain tumor. J
Clin Endocrinol Metab. 2003;88:136–140.
74. Gurney JG, Kadan-Lottick NS, Packer RJ. Endocrine and cardiovascular late effects
among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study.
Cancer. 2003;97:663–673.
75. Constine LS, Donaldson SS, McDougall IR, et al. Thy roid dy sfunction after radiotherapy
in children with Hodgkin ly mphoma. Cancer. 1984;53:878–883.
76. Paulino AC. Hy pothy roidism in children with medulloblastoma: a comparison of 3600
and 2340 cGy craniospinal radiotherapy. Int J Radiat Oncol Biol Phys. 2002;53:543–547.
77. Constine LS, Rubin P, Woolf PD, et al. Hy perprolactinemia and hy pothy roidism
following cy totoxic therapy for central nervous sy stem malignancies. J Clin Oncol.
1987;5:1841–1851.
78. Page 461 Samaan NA, Vieto R, Schultz PN, et al. Hy pothalamic pituitary and thy roid
dy sfunction after radiotherapy to the head and neck. Int J Radiat Oncol Biol Phys.
1982;8:1857–1867.
79. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thy roid in survivors of Hodgkin
ly mphoma: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab.
2000;85:3227–3232.
80. Shalet SM. Endocrine sequelae of cancer therapy. Eur J Endocrinol. 1996;135:135–143.
81. Oberfield SE, Chin D, Uli N, et al. Endocrine late effects of childhood cancers. J Pediatr.
1997;131(1 pt 2):S37–S41.
82. Hancock S, McDougall I, Constine L. Thy roid abnormalities after therapeutic external
radiation. Int J Radiat Oncol Biol Phys. 1995;31:1165–1170.
83. Chow EJ, Friedman DL, Stovall M, et al. Risk of thy roid dy sfunction and subsequent
thy roid cancer among survivors of acute ly mphoblastic leukemia: a report from the
Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2009:53:432–437.
84. Borgstrom B, Bolme P. Thy roid function in children after allogeneic bone marrow
transplantation. Bone Marrow Transplant. 1994;13:59–64.
85. Laughton SJ, Merchant TE, Sklar CA, et al. Endocrine outcomes for children with
embry onal brain tumors after risk-adapted craniospinal and conformal primary -site
irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J
Clin Oncol. 2008;26(7):1112–1118.
86. Hancock SL, Cox RS, McDougall IR. Thy roid diseases after treatment of Hodgkin
ly mphoma. N Engl J Med. 1991;325:599–605.
87. Petersen M, Keeling CA, McDougall IR. Hy perthy roidism with low radioiodine uptake
after head and neck irradiation for Hodgkin ly mphoma. J Nucl Med. 1989;30:255–257.
88. Donaldson SS. Effects of irradiation on skeletal growth and development. In: Green DM,
D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer. New York, NY: Wiley -
Liss; 1992:63–70.
89. Hogeboom CJ, Grosser SC, Guthrie KA, et al. Stature loss following treatment for Wilms
tumor. Med Pediatr Oncol. 2001;36:295–304.
90. Riseborough EJ, Grabias SL, Burton RI, et al. Skeletal alterations following irradiation for
Wilms’ tumor. J Bone Joint Surg. 1976;58A:526–536.
91. Paulino AC, Wen BC, Brown CK, et al. Late effects in children treated with radiation
therapy for Wilms’ tumor. Int J Radiat Oncol Biol Phys. 2000;46:1239–1246.
92. Silverman CL, Thomas PR, McAlister WH, et al. Slipped femoral capital epiphy sis in
irradiated children: dose, volume, and age relationships. Int J Radiat Oncol Biol Phys.
1981;7:1357–1363.
93. Fletcher BD, Crom DB, Krance RA, et al. Radiation-induced bone abnormalities after
bone marrow transplantation for childhood leukemia. Radiology. 1994;191:231–235.
94. Kadan-Lottick NS, Dinu I, Wasilewski-Masker K, et al. Osteonecrosis in adult survivors of
childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol.
2008;26:3038–3045.
95. French D, Hamilton LH, Mattano LA Jr, et al. A PAI-1 (SERPINE1) poly morphism
predicts osteonecrosis in children with acute ly mphoblastic leukemia: a report from the
Children’s Oncology Group. Blood. 2008;111:4496–4499.
96. Sala A, Mattano LA Jr, Barr RD. Osteonecrosis in children and adolescents with cancer
—an adverse effect of sy stemic therapy. Eur J Cancer. 2007;43:683–689.
97. Mattano LA Jr, Sather HN, Trigg ME, et al. Osteonecrosis as a complication of treating
acute ly mphoblastic leukemia in children: a report from the Children’s Cancer Group. J
Clin Oncol. 2000;18:3262–3272.
98. Gay non PS, Lustig RH. The use of glucocorticoids in acute ly mphoblastic leukemia of
childhood. Molecular, cellular, and clinical considerations. J Pediatr Hematol Oncol.
1995;17:1–12.
99. Strauss AJ, Su JT, Dalton VM, et al. Bony morbidity in children treated for acute
ly mphoblastic leukemia. J Clin Oncol. 2001;19:3066–3072.
100. Morris LL, Cassady JR, Jaffe N. Sternal changes following mediastinal irradiation for
childhood Hodgkin ly mphoma. Radiology. 1975;115:701–705.
101. Murphy s FD, Blount WP. Cartilaginous exostoses following irradiation. J Bone Joint Surg.
1981;44:662–668.
102. Rutherford H, Dodd GD. Complications of radiation therapy : growing bone. Semin
Roentgenol. 1974;9:15–27.
103. Jaffe N, Toth BB, Hoar RE, et al. Dental and maxillo-facial abnormalities in long-term
survivors of childhood cancer: effects of treatment with chemotherapy and radiation to
the head and neck. Pediatrics. 1984;73:816–823.
104. Goldwein JW. Effects of radiation therapy on skeleton growth in childhood. Clin Orthop.
1991;262:101–107.
105. Kaste SC, Jones-Wallace D, Rose SR, et al. Bone mineral decrements in survivors of
childhood acute ly mphoblastic leukemia: frequency of occurrence and risk factors for
their development. Leukemia. 2001;15:728–734.
106. Kadan-Lottick N, Marshall JA, Baron AE, et al. Normal bone mineral density after
treatment for childhood acute ly mphoblastic leukemia diagnosed between 1991 and
1998. J Pediatr. 2001;138:898–904.
107. Bhatia S, Ramsay NK, Weisdorf D, et al. Bone mineral density in patients undergoing
bone marrow transplantation for my eloid malignancies. Bone Marrow Transplant.
1998;22(1):87–90.
108. Ny som K, Holm K, Michaelsen KF, et al. Bone mass after allogeneic BMT for childhood
leukaemia or ly mphoma. Bone Marrow Transplant. 2000;25:191–196.
109. Oeffinger KC, Mertens AC, Sklar CA, et al. Obesity in adult survivors of childhood acute
ly mphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin
Oncol. 2003;21:1359–1365.
110. Warner JT, Evans WD, Webb DK, et al. Body composition of long-term survivors of
acute ly mphoblastic leukaemia. Med Pediatr Oncol. 2002;38:165–172.
111. Reilly JJ, Kelly A, Ness P, et al. Premature adiposity rebound in children treated for
acute ly mphoblastic leukemia. J Clin Endocrinol Metab. 2001;86:2775–2778.
112. Chow EJ, Pihoker C, Hunt K, et al. Obesity and hy pertension among children after
treatment for acute ly mphoblastic leukemia. Cancer. 2007:110:2313–2320.
113. Gurney JG, Ness KK, Sibley SD, et al. Metabolic sy ndrome and growth hormone
deficiency in adult survivors of childhood acute ly mphoblastic leukemia. Cancer.
2006;107:1303–1312.
114. Oeffinger KC. Are survivors of acute ly mphoblastic leukemia (ALL) at increased risk of
cardiovascular disease? Pediatr Blood Cancer. 2008;50(2 suppl):462–468.
115. Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors and major cardiac
events among adult survivors of childhood cancer. J Clin Oncol. 2013;31:3673–3680.
116. Smith WA, Li C, Nottage KA, et al. Lifesty le and metabolic sy ndrome in adult survivors
of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Cancer.
2014;120:2742–2750.
117. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease
after treatment of Hodgkin ly mphoma. JAMA. 1993;270:1949–1955.
118. King V, Constine LS, Clark D, et al. Sy mptomatic coronary artery disease after mantle
irradiation for Hodgkin ly mphoma. Int J Radiat Oncol Biol Phys. 1996;36:881–889.
119. Adams MJ, Lipshultz S, Schwartz C, et al. Radiation associated cardiovascular disease:
manifestations and management. Semin Radiat Oncol. 2003;13:346–356.
120. Haddy N, Diallo S, El-Fay ech C, et al. Cardiac diseases following childhood cancer
treatment: cohort Study. Circulation. 2016;133:31–38.
121. Darby SC, Cutter DJ, Boerma M, et al. Radiation-related heart disease: current
knowledge and future prospects. Int J Radiat Oncol Biol Phys. 2010;76:656–665.
122. Armstrong GT, Joshi VM, Ness KK, et al. Comprehensive echocardiographic detection
of treatment-related cardiac dy sfunction in adult survivors of childhood cancer: results
from the St. Jude Lifetime Cohort Study. J Am Coll Cardiol. 2015;65:2511–2522.
123. Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among
survivors of childhood cancer. JAMA. 2010;304:172–179.
124. Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling,
life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol.
2014;32:1218–1227.
125. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult
survivors of childhood and adolescent cancer: retrospective analy sis of the Childhood
Cancer Survivor Study cohort. BMJ. 2009;339:b4606.
126. Schellong G, Riepenhausen M, Bruch C, et al. Late valvular and other cardiac diseases
after different doses of mediastinal radiotherapy for Hodgkin disease in children and
adolescents: report from the longitudinal GPOH follow-up project of the German-
Austrian DAL-HD studies. Pediatr Blood Cancer. 2010;55:1145–1152.
127. Page 462 Green DM, Gingell RL, Pearce J, et al. The effect of mediastinal irradiation on
cardiac function of patients treated during childhood and adolescence for Hodgkin
ly mphoma. J Clin Oncol. 1987;5:239–245.
128. Mauch PM, Weinstein H, Botnick L, et al. An evaluation of long-term survival and
treatment complications in children with Hodgkin ly mphoma. Cancer. 1983;51:925–932.
129. Hancock S, Donaldson S, Hoppe R. Cardiac disease following treatment of Hodgkin
ly mphoma in children and adolescents. J Clin Oncol. 1993;11:1208–1215.
130. Creutzig U, Diekamp S, Zimmerman M, et al. Longitudinal evaluation of early and late
anthracy cline cardiotoxicity in children with AML. Pediatr Blood Cancer. 2007;48:651–
662.
131. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of
Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol. 2004;22:3139–3148.
132. Adams MJ, Lipshultz SE. Pathophy siology of anthracy cline- and radiation-associated
cardiomy opathies: implications for screening and prevention. Pediatr Blood Cancer.
2005;44:600–606.
133. Lipshultz SE, Alvarez JA, Scully RE. Anthracy cline associated cardiotoxicity in survivors
of childhood cancer. Heart. 2008;94:525–533.
134. Hudson MM. Anthracy cline cardiotoxicity in long-term survivors of childhood cancer:
the light is not at the end of the tunnel. Pediatr Blood Cancer. 2007;48:649–650.
135. Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and higher drug dose as risk factors
for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med.
1995;332:1738–1743.
136. Wouters KA, Kremer LC, Miller TL, et al. Protecting against anthracy cline-induced
my ocardial damage: a review of the most promising strategies. Br J Haematol.
2005;131:561–578.
137. Herman EH, Zhang J, Rifai N, et al. The use of serum levels of cardiac troponin T to
compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-
induced cardiotoxicity. Cancer Chemother Pharmacol. 2001;48:297–304.
138. Barry E, Alvarez JA, Scully RE, et al. Anthracy cline-induced cardiotoxicity : course,
pathophy siology, prevention and management. Expert Opin Pharmacother. 2007;8:1039–
1058.
139. Swain SM, Whaley F, Gerber M. Cardioprotection with dexrazoxane for doxorubicin-
containing therapy in advanced breast cancer. J Clin Oncol. 1997;15:1318–1332.
140. Venturini M, Michelotti A, Del Mastro L, et al. Multicenter randomized controlled clinical
trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women
receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol.
1996;14:3112–3120.
141. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute
my eloid leukemia/my elody splastic sy ndrome and other secondary malignancies in
pediatric Hodgkin’s disease. J Clin Oncol. 2007;25:493–500.
142. Barry EV, Vrooman LM, Dahlberg SE, et al. Absence of secondary malignant
neoplasms in children with high-risk acute ly mphoblastic leukemia treated with
dexrazoxane. J Clin Oncol. 2008;26:1106–1111.
143. Eames G, Crosson J, Steinberger J, et al. Cardiovascular function in children following
bone marrow transplant: a cross-sectional study. Bone Marrow Transplant. 1997;19:61–
66.
144. Hogarty AN, Leahey A, Zhao H, et al. Longitudinal evaluation of cardiopulmonary
performance during exercise after bone marrow transplantation in children. J Pediatr.
2000;136:311–317.
145. Chow EJ, Chen Y, Kremer LC, et al. Individual prediction of heart failure among
childhood cancer survivors. J Clin Oncol. 2015;33:394–402.
146. Carlson RG, May field WR, Norman S, et al. Radiation-associated valvular disease.
Chest. 1991;99:538–545.
147. Jakacki R, Goldwein J, Larsen R, et al. Cardiac dy sfunction following spinal irradiation
during childhood. J Clin Oncol. 1993;11:1033–1038.
148. Cohen SI, Bharati S, Glass J, et al. Radiotherapy as a cause of complete atrioventricular
block as Hodgkin ly mphoma: an electrophy siological–pathological correlation. Arch
Intern Med. 1981;141:676–679.
149. Kadota R, Burgert E, Driscoll D, et al. Cardiopulmonary function in long-term survivors
of childhood Hodgkin’s ly mphoma: a pilot study. Mayo Clin Proc. 1988;63:362–367.
150. Hancock SL, Hoppe RT, Horning SJ, et al. Intercurrent death after Hodgkin’s disease
therapy in radiotherapy and adjuvant MOPP trials. Ann Intern Med. 1988;109:183–189.
151. Rubin P, Finkelstein JN, Siemann DW, et al. Predictive biochemical assay s for late
radiation effects. Int J Radiat Oncol Biol Phys. 1986;12:469–476.
152. Fry er CJH, Fitzpatrick PJ, Rider WD, et al. Radiation pneumonitis: experience following
a large single dose of radiation. Int J Radiat Oncol Biol Phys. 1978;4:931–936.
153. Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor
Study cohort: a review of published findings. J Clin Oncol. 2009;27:2339–2355.
154. Mertens AC, Yasui Y, Liu Y. Pulmonary complications in survivors of childhood and
adolescent cancer. Cancer. 2002;95:2431–2441.
155. McDonald S, Rubin P, Phillips T, et al. Injury to the lung from cancer therapy : clinical
sy ndromes, measurable endpoints, and potential scoring sy stems. Int J Radiat Oncol Biol
Phys. 1995;31:1187–1203.
156. Bradley JI, Zoberi I, Wasserman TH. Thoracic radiotherapy : complications and injury
to normal tissue. Prin Prac Radiat Oncol Updates. 2002;3:1–16.
157. Armenian SH, Landier W, Francisco L, et al. Long-term pulmonary function in survivors
of childhood cancer. J Clin Oncol. 2015;33:1592–600.
158. Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol.
1992;19:508–520.
159. Fry er C, Hutchinson RJ, Krailo M, et al. Efficacy and toxicity of 12 courses of ABVD
chemotherapy followed by low-dose regional radiation in advanced Hodgkin ly mphoma
in children: a report from the Children’s Cancer Study Group. J Clin Oncol. 1990;8:1971–
1980.
160. Marina NM, Greenwald CA, Fairclough DL, et al. Serial pulmonary function studies in
children treated for newly diagnosed Hodgkin ly mphoma with mantle radiotherapy plus
cy cles of cy clophosphamide, vincristine, and procarbazine alternating with cy cles of
doxorubicin, bleomy cin, vinblastine, and dacarbazine. Cancer. 1995;75:1706–1711.
161. Oguz A, Tay fun T, Citak EC, et al. Long-term pulmonary function in survivors of
childhood Hodgkin disease and non-Hodgkin ly mphoma. Pediatr Blood Cancer.
2007;49:699–703.
162. Cerveri I, Fulgoni P, Giorgiani G. Lung function abnormalities after bone marrow
transplantation in children: has the trend recently changed? Chest. 2001;120:1900–1906.
163. Keane T, van Dy ke J, Rider W. Idiopathic interstitial pneumonia following bone marrow
transplantation: the relationship with total body irradiation. Int J Radiat Oncol Biol Phys.
1981;7:1365–1370.
164. Bolling T. Pulmonary effects of antineoplastic therapy : whole lung irradiation in patients
with exclusively pulmonary metastases of Ewing tumors—toxicity analy sis and
treatment results of the EICESS-92 trial. Strahlenther Onkol. 2008;184:193–197.
165. Miller RW, Fusner JE, Fink RJ, et al. Pulmonary function abnormalities in long-term
survivors of childhood cancer. Med Pediatr Oncol. 1986;14:202–207.
166. Wohl ME, Griscom NT, Traggis DG, et al. Effects of therapeutic irradiation delivered in
early childhood upon subsequent lung function. Pediatrics. 1975;55:507–516.
167. Motosue MS, Zhu L, Srivastava K, et al. Pulmonary function after whole lung irradiation
in pediatric patients with solid malignancies. Cancer. 2012;118:1450–1456.
168. Ash P. The influence of radiation on fertility in man. Br J Radiol. 1980;53:271–278.
169. Lushbaugh CC, Casarett GW. The effects of gonadal irradiation in clinical radiation
therapy : a review. Cancer. 1976;37:1111–1120.
170. Wallace WHB, Shalet SM, Crowne EC, et al. Ovarian failure following abdominal
irradiation in childhood: natural history and prognosis. Clin Oncol. 1989;1:75–79.
171. Halperin EC. Concerning the spinal component of the craniospinal irradiation field for
central nervous sy stem malignancies. Int J Radiat Oncol Biol Phys. 1993;26:357–362.
172. Haie-Meder C, Mlika-Cabanne N, Michel G, et al. Radiotherapy after ovarian
transposition: ovarian function and fertility preservation. Int J Radiat Oncol Biol Phys.
1993;25:419–424.
173. Page 463 By rne J, Mulvihill JJ, My ers MH, et al. Effects of treatment on fertility in long-
term survivors of childhood or adolescent cancer. N Engl J Med. 1987;317:1315–1321.
174. Green DM, Kawashima T, Stovall M, et al. Fertility of female survivors of childhood
cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27:2677–
2685.
175. Green DM, Sklar CA, Boice JD Jr, et al. Ovarian failure and reproductive outcomes after
childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin
Oncol. 2009;27:2374–2381.
176. Sklar CA, Kim TH, Williamson JF, et al. Ovarian function after successful bone marrow
transplantation in post-menarchal females. Med Pediatr Oncol. 1983;11:361–364.
177. Sanders JE, Buckner CD, Leonard JM, et al. Late effects on gonadal function of
cy clophosphamide, total-body irradiation, and marrow transplantation. Transplantation.
1983;36:252–255.
178. Fürst CJ, Lundell M, Ahlbäck SO, et al. Breast hy poplasia following irradiation of the
female breast in infancy and early childhood. Acta Oncol. 1989;28:519–523.
179. Macklis RM, Oltikar A, Sallan SE. Wilms’ tumor patients with pulmonary metastases. Int
J Radiat Oncol Biol Phys. 1991;21:1187–1193.
180. Izard M. Ley dig cell function and radiation: a review of the literature. Radiother Oncol.
1995;34:1–8.
181. Thomson AB, Critchley HO, Kelnar CJ, et al. Late reproductive sequelae following
treatment of childhood cancer and options for fertility preservation. Best Pract Res Clin
Endocrinol Metab. 2002;16:311–334.
182. Heller GC. Effects on the germinal epithelium in radiobiological factors in manned
space flight. In: Langham WH, ed. NRC Publication 1487. Washington, DC: National
Academy of Sciences, National Research Council; 1967:124–133.
183. Sklar CA, Robison LL, Nesbit ME, et al. Effects of radiation on testicular function in long-
term survivors of childhood acute ly mphoblastic leukemia: a report from the Children’s
Cancer Study Group. J Clin Oncol. 1990;8:1981–1987.
184. Bokemey er C, Schmoll HJ, van Rhee J, et al. Long-term gonadal toxicity after therapy
for Hodgkin’s and non-Hodgkin’s ly mphoma. Ann Hematol. 1994;68:105–110.
185. Hobbie WL, Ginsberg JP, Ogle SK, et al. Fertility in males treated for Hodgkin’s disease
with COPP/ABV hy brid. Pediatr Blood Cancer. 2005;44:193–196.
186. Longhi A, Macchiagodena M, Vitali G, et al. Fertility in male patients treated with
neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol. 2003;25:292–
296.
187. Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatr
Blood Cancer. 2008;50:347–351.
188. van Casteren NJ, van der Linden GH, Hakvoort-Cammel FG, et al. Effect of childhood
cancer treatment on fertility markers in adult male long-term survivors. Pediatr Blood
Cancer. 2009;52:108–112.
189. By rne J, Fears TR, Mills JL, et al. Fertility of long-term male survivors of acute
ly mphoblastic leukemia diagnosed during childhood. Pediatr Blood Cancer. 2004;42:364–
372.
190. Shalet SM, Horner A, Akrned SR, et al. Ley dig cell damage after testicular irradiation
for acute ly mphoblastic leukemia. Med Pediatr Oncol. 1985;13:65–68.
191. Brauner R, Catlabiano P, Rappaport R, et al. Ley dig cell insufficiency after testicular
irradiation for acute ly mphoblastic leukemia. Horm Res. 1988;30:111–114.
192. Sanders JE. Effects of bone marrow transplantation on reproductive function. In: Green
DM, D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer. New York, NY:
Wiley -Liss; 1992:95–102.
193. Critchley HO, Bath LE, Wallace WH. Radiation damage to the uterus: review of the
effects of treatment of childhood cancer. Hum Fertil. 2002;5:61–66.
194. Green DM, Whitton JA, Stovall M. Pregnancy outcome of partners of male survivors of
childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol.
2003;21:716–721.
195. Green DM, Peabody EM, Nan B. Pregnancy outcome after treatment for Wilms tumor:
a report from the National Wilms Tumor Study Group. J Clin Oncol. 2002;20:2506–
2513.
196. Winther JF, Boice JD Jr, Svendsen AL, et al. Spontaneous abortion in a Danish
population-based cohort of childhood cancer survivors. J Clin Oncol. 2008;26:4340–4346.
197. Signorello LB, Cohen SS, Bosetti C, et al. Female survivors of childhood cancer: preterm
birth and low birth weight among their children. J Natl Cancer Inst. 2006;98:1453–1461.
198. By rne J, Rasmussen SA, Steinhorn SC. Genetic disease in offspring of long term
surivivors of childhood and adolescent cancer. Am J Hum Genet. 1998;62:45–52.
199. Teinturier C, Hartmann O, Valteau-Couanet D, et al. Ovarian function after autologous
bone marrow transplantation in childhood: high-dose busulfan is a major cause of
ovarian failure. Bone Marrow Transplant. 1998;22:989–994.
200. Sanders JE, Hawley J, Levy W. Pregnancies following high-dose cy clophosphamide
with or without high-dose busulfan or total-body irradiation and bone marrow
transplantation. Blood. 1996;87:3045–3052.
201. Bath LE, Hamish W, Wallace B, et al. Late effects of the treatment of childhood cancer
on the female reproductive sy stem and the potential for fertility preservation. Int J
Obstet Gynaecol. 2002;109(2):107–114.
202. Agarwal A. Semen banking in patients with cancer: 20-y ear experience. Int J Androl.
2000;23(suppl 2):16–19.
203. Hallak J, Hendin B, Thomas A, et al. Investigation of fertilizing capacity of
cry opreserved spermatogonia from patients with cancer. J Urol. 1998;159:1217–1220.
204. Muller J, Sonksen J, Sommer P, et al. Cry opreservation of semen from pubertal boy s
with cancer. Med Pediatr Oncol. 2000;34:191–194.
205. Damani MN, Master V, Meng MV. Postchemotherapy ejaculatory azoospermia:
fatherhood with sperm from testis tissue with intracy toplasmic sperm injection. J Clin
Oncol. 2002;20:930–936.
206. Pfeifer S, Coutifaris C. Reproductive technologies 1998: options available for the cancer
patient. Med Pediatr Oncol. 1999;33:34–40.
207. Donnez J, Godin P, Qu J, et al. Gonadal cry opreservation in the y oung patient with
gy naecological malignancy. Curr Opin Obstet Gynecol. 2000;12:1–9.
208. Newton H. The cry opreservation of ovarian tissue as a strategy for preserving the
fertility of cancer patients. Hum Reprod Update. 1998;4:237–247.
209. Hansen M, Kurinczuk JJ, Bower C, et al. The risk of major birth defects after
intracy toplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725–
730.
210. Bonduelle M, Liebaers I, Deketelaere V, et al. Neonatal data on a cohort of 2889 infants
born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999). Hum
Reprod. 2002;17:671–694.
211. Simpson JL, Lamb DJ. Genetic effects of intracy toplasmic sperm injection. Semin
Reprod Med. 2001;19:239–249.
212. Serafini P. Outcome and follow-up of children born after IVF-surrogacy. Hum Reprod
Update. 2001;7:23–27.
213. Ericson A, Kallen B. Congenital malformations in infants born after IVF: a population-
based study. Hum Reprod. 2001;16:504–509.
214. Sankila R, Olsen JH, Anderson H, et al. Risk of cancer among offspring of childhood-
cancer survivors. N Engl J Med. 1998;338:1339–1344.
215. Friedman DL, Kadan-Lottick N, Liu Y, et al. History of cancer among first-degree
relatives of childhood cancer survivors: a report from the Childhood Cancer Survivor
Study. Proc Annu Meet Am Soc Clin Oncol. 2001:433a.
216. Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys. 1995;31:1249–
1256.
217. Smith GR, Thomas PR, Ritchey M, et al. Long-term renal function in patients with
irradiated bilateral Wilms tumor. National Wilms’ Tumor Study Group. Am J Clin Oncol.
1998;21:58–63.
218. Breslow NE, Takashima JR, Ritchey ML, et al. Renal failure in the Deny s–Drash and
Wilms’ tumor–aniridia sy ndromes. Cancer Res. 2000;60:4030–4032.
219. Tarbell N, Guinan E, Neimey er C, et al. Late onset of renal dy sfunction in survivors of
bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1988;15:99–104.
220. Lonnerholm G, Carlson K, Bratteby LE, et al. Renal function after autologous bone
marrow transplantation. Bone Marrow Transplant. 1991;8:129–134.
221. Leiper AD. Non-endocrine late complications of bone marrow transplantation in
childhood: part II. Br J Haematol. 2002;118:23–43.
222. Page 464 Patzer L, Hempel L, Ringelmann F, et al. Renal function after conditioning
therapy for bone marrow transplantation in childhood. Med Pediatr Oncol. 1997;28:274–
283.
223. Bianchetti MG, Kanaka C, Ridolfi-Luthy A, et al. Persisting renotubular sequelae after
cisplatin in children and adolescents. Am J Nephrol. 1991;11:127–130.
224. Mey er WH, Pratt CB, Poquette CA. Carboplatin/ifosfamide window therapy for
osteosarcoma: results of the St Jude Children’s Research Hospital OS-91 trial. J Clin
Oncol. 2001;19:171–182.
225. Stern JW, Bunin N. Prospective study of carboplatin-based chemotherapy for pediatric
germ cell tumors. Med Pediatr Oncol. 2002;39:163–167.
226. Arndt C, Morgenstern B, Hawkins D, et al. Renal function following combination
chemotherapy with ifosfamide and cisplatin in patients with osteogenic sarcoma. Med
Pediatr Oncol. 1999;32:93–96.
227. Loebstein R, Koren G. Ifosfamide-induced nephrotoxicity in children: critical review of
predictive risk factors. Pediatrics. 1998;10:E8.
228. Skinner R, Pearson AD, English MW, et al. Risk factors for ifosfamide nephrotoxicity in
children. Lancet. 1996;348:578–580.
229. McCune JS, Friedman DL, Schuetze S, et al. Influence of age upon ifosfamide-induced
nephrotoxicity. Pediatr Blood Cancer. 2004;42:427–432.
230. Riachy E, Krauel L, Rich BS, et al. Risk factors and predictors of severity score and
complications of pediatric hemorrhagic cy stitis. J Urol. 2014;191:186–192.
231. Ritchey M, Ferrer F, Shearer P, et al. Late effects on the urinary bladder in patients
treated for cancer in childhood: a report from the Children’s Oncology Group. Pediatr
Blood Cancer. 2009;52:439–446.
232. Sher ME, Bauer J. Radiation induced enteropathy. Am J Gastroenterol. 1990;85:121–128.
233. Donaldson SS, Jundt S, Ricour C, et al. Radiation enteritis in children. Cancer.
1975;35:1167–1178.
234. Emami B, Ly man J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation.
Int J Radiat Oncol Biol Phys. 1991;21:109–122.
235. Madenci AL, Fisher S, Diller LR, et al. Intestinal obstruction in survivors of childhood
cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2015;33:2893–
2900.
236. Neville KA, Cohn RJ, Steinbeck KS, et al. Hy perinsulinemia, impaired glucose tolerance,
and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin
Endocrinol Metab. 2006;91:4401–4407.
237. Meacham LR, Sklar CA, Li S, et al. Diabetes mellitus in long-term survivors of childhood
cancer. Increased risk associated with radiation therapy : a report for the Childhood
Cancer Survivor Study. Arch Intern Med. 2009:169:1381–1388.
238. de Vathaire F, El-Fay ech C, Ben Ay ed FF, et al. Radiation dose to the pancreas and risk of
diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet
Oncol. 2012;13:1002–1010.
239. van Nimwegen FA, Schaapveld M, Janus CP, et al. Risk of diabetes mellitus in long-term
survivors of Hodgkin ly mphoma. J Clin Oncol. 2014;32:3257–3263.
240. Ingold JA, Reed GB, Kaplan HS, et al. Radiation hepatitis. Am J Roentgenol.
1963;93:200–208.
241. Hasegawa S, Horibe K, Kawabe T, et al. Veno-occlusive disease of the liver after
allogeneic bone marrow transplantation in children with hematologic malignancies:
incidence, onset time and risk factors. Bone Marrow Transplant. 1998;22:1191–1197.
242. Ortega J, Donaldson S, Percy S, et al. Venoocclusive disease of the liver after
chemotherapy with vincristine, actinomy cin D, and cy clophosphamide for the treatment
of rhabdomy osarcoma—a report of the Intergroup Rhabdomy osarcoma Study Group.
Cancer. 1997;79:2435–2439.
243. Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the liver. Semin Radiat
Oncol. 2001;11:240–246.
244. Thomas PRM, Tefft M, D’Angio GJ, et al. Acute toxicities associated with radiation in the
second National Wilms’ Tumor Study. J Clin Oncol. 1988;6:1694–1698.
245. Nanda SK, Schachat AP. Ocular complications following radiation therapy to the orbit.
In: Green DM, D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer. New
York, NY: Wiley -Liss; 1992:11–22.
246. Wara W, Irvine A, Neger R, et al. Radiation retinopathy. Int J Radiat Oncol Biol Phys.
1979;5:81–83.
247. Hilliard L, Berkow R, Watterson J, et al. Retinal toxicity associated with cisplatin and
etoposide in pediatric patients. Med Pediatr Oncol. 1997;28:310–313.
248. Parsons J, Fitzgerald C, Hood C, et al. The effects of irradiation of the ey e and optic
nerve. Int J Radiat Oncol Biol Phys. 1983;9:609–622.
249. Paulino AC, Simon JH, Zhen W, et al. Long-term effects in children treated with
radiotherapy for head and neck rhabdomy osarcoma. Int J Radiat Oncol Biol Phys.
2000;48:1489–1495.
250. Merriam G, Focht E. Radiation dose to the lens in treatment of tumors of the ey e and
adjacent structures: possibilities of cataract formation. Radiology. 1958;71:357–369.
251. Britten M, Halman K, Meredith W. Radiation cataract: new evidence on radiation dosage
to the lens. Br J Radiol. 1966;39:612–617.
252. Otake M, Schull WJ. A review of forty -five y ears study of Hiroshima and Nagasaki
atomic bomb survivors radiation cataract. J Radiat Res. 1991;32:283–293.
253. Belkacemi Y, Labopin M, Vernant JP, et al. Cataracts after total body irradiation and
bone marrow transplantation in patients with acute leukemia in complete remission: a
study of the European Group for Blood and Marrow Transplantation. Int J Radiat Biol
Oncol Phys. 1998;41:659–668.
254. van Kempen-Harteveld ML, Belkacemi Y, Kal HB, et al. Dose–effect relationship for
cataract induction after single-dose total body irradiation and bone marrow
transplantation for acute leukemia. Int J Radiat Oncol Biol Phys. 2002;52:1367–1374.
255. van Kempen-Harteveld ML, Struikmans H, Kal HB. Cataract after total body irradiation
and bone marrow transplantation: degree of visual impairment. Int J Radiat Oncol Biol
Phys. 2002;52:1375–1380.
256. Zierhut D, Lohr F, Schraube P. Cataract incidence after total-body irradiation. Int J
Radiat Oncol Biol Phys. 2000;46:131–135.
257. Horwitz M, Auquier P, Barlogis V, et al. Incidence and risk factors for cataract after
haematopoietic stem cell transplantation for childhood leukaemia: an LEA study. Br J
Haematol. 2015;168:518–525.
258. McCormick B, Ellsworth R, Abramson D, et al. Results of external beam radiation for
children with retinoblastoma: a comparison of two techniques. J Pediatr Ophthalmol
Strabismus. 1989;26:239–243.
259. Brooks HL Jr, Mey er D, Shields JA, et al. Removal of radiation-induced cataracts in
patients treated for retinoblastoma. Arch Ophthalmol. 1990;108:1701–1708.
260. Kline L, Kim J, Ceballos R. Radiation optic neuropathy. Ophthalmology. 1985;92:1118–
1126.
261. Kaste S, Chen G, Fontanesi J, et al. Orbital development in long-term survivors of
retinoblastoma. J Clin Oncol. 1997;15:1183–1189.
262. Shields CL, Honavar SG, Shields JA, et al. Factors predictive of recurrence of retinal
tumors, vitreous seeds, and subretinal seeds following chemoreduction for
retinoblastoma. Arch Ophthalmol. 2002;120:460–464.
263. Shields CL, Meadows AT, Leahey AM, et al. Continuing challenges in the management
of retinoblastoma with chemotherapy. Retina. 2004;24:849–862.
264. Shields CL, Mashay ekhi A, Cater J, et al. Chemoreduction for retinoblastoma: analy sis of
tumor control and risks for recurrence in 457 tumors. Trans Am Ophthalmol Soc.
2004;102:35–45.
265. Shields CL, Mashay ekhi A, Au AK, et al. The international classification of
retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280.
266. Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomy osarcoma: survival
and late effects of treatment—results of an international workshop. J Clin Oncol.
2001;19:197–204.
267. Adler M, Hawke M, Bergern G, et al. Radiation effects on the external auditory canal. J
Otolaryngol. 1985;14:226.
268. Huang E, The BS, Strother DR. Intensity -modulated radiation therapy for pediatric
medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol
Phys. 2002;52:599–605.
269. Merchant TE, Gould CJ, Xiong X, et al. Early neuro-otologic effects of three-
dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol Biol
Phys. 2004;58:1194–1207.
270. Page 465 McHaney VA, Thibadoux G, Hay es FA, et al. Hearing loss in children
receiving cisplatin chemotherapy. J Pediatr. 1983;10:314–317.
271. Landier W. Hearing loss related to ototoxicity in children with cancer. J Pediatr Oncol
Nurs. 1998;15:195–206.
272. Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al. Analy sis of ototoxicity in y oung
children receiving carboplatin in the context of conservative management of unilateral
or bilateral retinoblastoma. Pediatr Blood Cancer. 2009;52:637–643.
273. Dean JB, Hay ashi SS, Albert CM, et al. Hearing loss in pediatric oncology patients
receiving carboplatin-containing regimens. J Pediatr Hematol Oncol. 2008;30:130–134.
274. Kushner BH, Budnick A, Kramer K, et al. Ototoxicity from high-dose use of platinum
compounds in patients with neuroblastoma. Cancer. 2006;107:417–422.
275. Maguire A, Craft A, Evans R, et al. The long-term effects of treatment on the dental
condition of children surviving malignant disease. Cancer. 1987;60:2570–2575.
276. Holtta P, Alahuusua S, Saarinen-Pihkala UM, et al. Long-term adverse effects on
dentition in children with poor-risk neuroblastoma treated with high-dose chemotherapy
and autologous stem cell transplantation with or without total body irradiation. Bone
Marrow Transplant. 2002;29:121–127.
277. Dahllof G, Barr M, Balme P, et al. Disturbances in dental development after total body
irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol.
1988;65:41–44.
278. Kaste S, Hopkins K, Crom D, et al. Dental abnormalities in children treated for acute
ly mphoblastic leukemia. Leukemia. 1997;11:792–796.
279. Fromm M, Littman P, Raney B, et al. Late effects after treatment of twenty children
with soft tissue sarcomas of the head and neck. Cancer. 1986;57:2070–2076.
280. Bucker J, Fleming T, Fuller L, et al. Preliminary observations on the effect of mantle
field radiotherapy on salivary flow rates in patients with Hodgkin ly mphoma. J Dent
Res. 1988;6:518–521.
281. Marks J, Davis C, Gottsman V, et al. The effects of radiation on parotid salivary function.
Int J Radiat Oncol Biol Phys. 1981;7:1013–1019.
282. Jensen SB, Pedersen AM, Vissink A, et al. A sy stematic review of salivary gland
hy pofunction and xerostomia induced by cancer therapies: management strategies and
economic impact. Support Care Cancer. 2010;18:1061–1079.
283. Johnson J, Ferretti G, Nethery J, et al. Oral pilocarpine for post-irradiation xerostomia in
patients with head and neck cancer. N Engl J Med. 1993;329:390–395.
284. Yeazel MW, Gurney JG, Oeffinger KC, et al. An examination of the dental utilization
practices of adult survivors of childhood cancer: a report from the Childhood Cancer
Survivor Study. J Public Health Dent. 2004;64:50–54.
285. Hendry J. The cellular basis of long-term marrow injury after irradiation. Radiother
Oncol. 1985;3:331–338.
286. Storb R, Deeg HJ, Applebaum FR, et al. Total-body irradiation in bone marrow
transplantation. In: Browne D, ed. Treatment of Radiation Injuries. New York, NY:
Plenum Press; 1990:29–33.
287. Casamassima F, Ruggkiero C, Carmaella D, et al. Hematopoietic bone marrow recovery
after radiation therapy : MRI evaluation. Blood. 1989;73:1677–1681.
288. Sachs E, Goris M, Glatstein E, et al. Bone marrow regeneration following large field
irradiation. Influence of volume, age, dose and time. Cancer. 1978;42:1057–1065.
289. Cristy M. Active bone marrow distribution as a function of age in humans. Phys Med
Biol. 1981;26:389–400.
CH A P TER 20
Second Primary Cancers
Smita Bhatia and Louis S. Constine
Page 466Significant improvements in therapeutic options and supportive care strategies have
resulted in 5-y ear survival rates now approaching 70% for adult-onset cancers and 85%
childhood cancer (1). This improvement in survival has resulted in a growing population of
cancer survivors; currently in the United States, there are over 14.5 million cancer survivors.
However, this survival is associated with significant morbidity. In fact, 50% of y oung adult
survivors of childhood cancer will develop a life-threatening or fatal complication by age 50
y ears (2), and second primary cancers (SPCs) are the most devastating of these
complications.
SECOND PRIMARY CANCERS: THE SCOPE OF THE PROBLEM
Primary Diagnosis
Hereditary retinoblastoma, Hodgkin ly mphoma, and soft tissue sarcomas are
overrepresented among patients who develop SPCs relative to their prevalence in the general
population (7,16). This could result from an interaction between genetic predisposition and
genotoxic insult (chemotherapy /radiation), as is clear in patients with hereditary
retinoblastoma and familial soft tissue sarcoma (16,17). In individuals with Hodgkin
ly mphoma, it is not clear whether the primary diagnosis is an independent risk factor for the
development of SPC or whether the specific therapies used to treat the primary cancer are
the major contributors to the development of SPCs. Associations between first and second
primary cancers are summarized in Table 20.1 .
Table 20.1 Second Primary Cancers and their Relationship with Primary Cancers
Sex
Female sex is associated with a higher risk of SPCs, contributed to primarily by the excess
occurrence of secondary breast and thy roid cancers among female cancer survivors (7,21).
Moreover, some studies indicate a greater susceptibility of women to known carcinogens such
as cigarette smoke (22). Possible mechanisms that underlie this greater susceptibility include
higher activity of cy tochrome P450 (CYP) enzy mes, enhanced formation of DNA adducts,
and the effects of hormones such as estrogen on tumor promotion (22).
Radiation induces solid SMNs, within the radiation field and in a dose-dependent fashion.
A recent report assessed the relationship between the irradiated tissue volume (including
the tissue exposed to low doses adjacent to the target volume and thus the integral dose)
and the likelihood of developing a secondary malignancy. In a cohort of 4401 patients
who were 3-y ear survivors of all ty pes of childhood cancer, a dose–response
relationship was found between the overall risk of an SMN and the estimated integral
dose (Table 20.2 , Fig. 20.3 ) (38). As a corollary, data from Diallo et al. (39)
showed that a greater volume of tissues receives low or intermediate radiation doses in
regions bordering the irradiated volume with modern multiple beam radiation therapy
administrations, including intensity modulated radiation therapy (IMRT). However, in a
report that modeled risk for children treated with IMRT versus conventional therapy, an
increase was not seen (40). Additional data will be necessary to settle this issue.
SPCs may also be induced by agents other than radiation (chemotherapy, environmental
exposures, and genetic predisposition). The low-dose radiation dose–response curve
could be influenced by these confounding factors to produce a result that is the sum of
two independent rates or may be greater than simple addition would indicate. A variety
of chemotherapeutic agents, especially alky lators, are known to be carcinogenic, and
they may be additive or sy nergistic with radiation.
A large number of irradiated patients are necessary to calculate a radiation
carcinogenesis risk with reasonable accuracy.
Page 471Latent periods vary according to the induced tumor. At least two patterns of
latent periods for radiation-induced cancer have been described. The first, exemplified
by the risk of leukemia in atomic bomb survivors, consists of an early wavelike pulse of
increased risk followed by a gradual decline to baseline levels. The second, more ty pical
of solid tumors, is an increase in relative risk of SPCs over many y ears, which remains
constant over time thereafter. The latter pattern suggests that a multievent pattern of
carcinogenesis is involved: the initial event (radiation) is followed by promoting events
(i.e., smoking, alcohol, or environmental exposures) over many y ears (41). Long latent
periods complicate the study of radiation-induced cancer because the presence of other
carcinogens or disease processes may not be well documented.
The duration of follow-up for any study population influences the frequency of tumors
seen.
It is unclear whether the risk of tumor development after exposure is simply an absolute
increase that is proportional to the radiation dosage or a relative increase that builds on an
underly ing spontaneous risk (greater for some patients) of developing a malignancy.
Age is a critical factor in determining radiation risk. In children, the most common SPCs
occur in tissues undergoing rapid proliferation such as bone, thy roid, and breast. An
actively proliferating tissue may be more susceptible to malignant transformation in any
single cell because of the greater number of cell divisions. This might explain the higher
frequency of secondary bone tumors in children than in adults (42).
Chemotherapeutic Agents
Alky lating agents and topoisomerase II inhibitors are associated with t-MDS/AML (18,43,44).
Alky lating agents have also been linked with bone tumors (45,46) and bladder cancer (47). t-
MDS/AML has been reported in patients with HL, NHL, ALL, sarcomas, ovarian cancer,
testicular cancer, breast cancer, multiple my eloma (10), with the cumulative incidence
approaching 2% at 15 y ears after therapy (10). The incidence of t-MDS/AML ty pically
peaks at 4–6 y ears from diagnosis of the primary cancer and reaches a plateau after 15
y ears. The clinical observation that the risk of t-MDS/AML does not extend bey ond 15 y ears,
indicates that the at-risk population of cells is likely depleted (48). It may be that this period of
time allows early pluripotent hematopoietic progenitors to undergo clonal extinction and be
replaced from the compartment of resting stem cells by clonal succession. It is possible that
stem cells in the resting phase of the cell cy cle are relatively protected from the genotoxic
effects of chemotherapy and radiation and that the excess risk of t-MDS/AML would diminish
as undamaged cells were recruited into active hematopoiesis. t-MDS/AML is associated with
poor outcome, with an estimated 12-month survival of 10% (49). t-MDS/AML is a clonal
disorder characterized by distinct chromosomal changes (49,50,51). Two ty pes are
recognized by the WHO classification: alky lating agent–related ty pe and topoisomerase II
inhibitor-related ty pe (52).
Musculoskeletal Tumors
The estimated risk of subsequent bone tumors among survivors of childhood cancer is
reported to be 133 times that of the general population (95% CI, 98–176) (45). The risk of
sarcoma was more than ninefold higher among childhood cancer survivors than among the
general population (SIR = 9.0, 95% CI, 7.4–10.9) (66). The excess absolute risk was 3.3 per
10,000 person-y ears. Higher risk was associated with primary sarcoma diagnosis (RR = 10.1,
95% CI, 4.7–21.8), radiation therapy (RR = 3.1, 95% CI, 1.5–6.2), with a history of other
SPCs (RR = 2.2, 95% CI, 1.1–4.5), and with treatment with higher doses of anthracy clines
(RR = 2.3, 95% CI, 1.2–4.3) or alky lating agents (RR = 2.2, 95% CI, 1.1–4.6). Radiation-
associated bone tumors and sarcomas demonstrate a clear association with radiation therapy
(66,67). The secondary bone tumors develop in the radiation field, ty pically after a latency
period of 10 y ears. As compared with matched controls who had survived cancer in
childhood but not developed bone cancer later, the risk (95% CI, 1.0–7.7) of developing a
bone tumor was 2.7 times higher in patients who received radiation therapy, with a sharp
dose–response gradient, reaching 40 times higher after dosages to the bone of more than 60
Gy. After adjustment for radiation therapy, treatment with alky lating agents was also linked to
bone cancer (RR = 4.7, 95% CI, 1.0–22.3), with the risk increasing with cumulative drug
exposure. Both bone tumors and sarcomas may be aggressive and respond poorly to therapy
(45,46).
Breast Cancer
Breast cancer is the most common solid SPC after Hodgkin ly mphoma, largely due to chest
radiation for treatment of Hodgkin ly mphoma (Table 20.3 ). The risk of radiation-related
breast cancer among female Hodgkin ly mphoma survivors ranges from 25- to 55-fold that of
the general population (7,13,72). The latency after chest radiation ranges from 7 to 10 y ears,
and the risk of breast cancer increases in a linear fashion with radiation dose with an
estimated relative risk of 6.4 at a dose of 20 Gy and 11.8 at a dose of 40 Gy (73). Moreover,
40% of identified cases were found to have developed contralateral disease. Among women
treated for childhood cancer with chest radiation therapy, those treated with whole-lung
irradiation have a greater risk of breast cancer than previously recognized, demonstrating the
importance of radiation volume (74). There appears to be a protective effect of early
menopause either because of alky lating agents or radiation dose above 5 Gy to the ovaries,
suggesting that ovarian hormones play an important role in promoting tumorigenesis once an
initiating event has been produced by radiation (69,73,75). The 25-y ear cumulative incidence
of breast cancer is reported to be 11% after allogeneic HCT (76). Allogeneic HCT survivors
are at a 2.2-fold increased risk for developing breast cancer, when compared with age- and
sex-matched general population. The median latency from HCT to diagnosis of breast cancer
is 12.5 y ears. The incidence is higher among those exposed to TBI (17%) than among those
who did not receive TBI (3%). The risk is increased among those exposed to TBI at a y ounger
age. The substantially increased relative risks of breast cancer observed at 10–20 y ears
postdiagnosis are not sustained into ages at which the risk of breast cancer in the general
population becomes substantial; among women who survived to an age of at least 50 y ears,
there is currently no evidence of an increased risk of breast cancer, as compared with the
general population (77). Importantly, mortality associated with breast cancer after childhood
cancer is substantial; breast cancer–specific mortality at 5 and 10 y ears was 12% and 19%,
respectively (74). Travis et al. (78) developed estimates of cumulative absolute risk for use in
counseling patients. For example, the cumulative absolute risks for an HL survivor who was
treated at age 25 y ears with a chest radiation dose of 40 Gy or more without alky lating agents
were estimated to be 1.4% after 10 y ears, 11% after 20 y ears, and 29% after 30 y ears.
Page 473
Table 20.3 Risk of Breast Cancer in Hodgkin Lymphoma Survivors by Age and Latency
Thyroid Cancer
Thy roid cancer is observed after neck radiation for Hodgkin ly mphoma, acute ly mphoblastic
leukemia, brain tumors and after TBI for hematopoietic cell transplantation (7,10). The risk of
thy roid cancer has been reported to be 18-fold that of the general population (79). Radiation
therapy at a y oung age is the major risk factor for the development of thy roid cancer. A
linear dose–response relationship between thy roid cancer and radiation is observed up to 20
Gy, with a decline in the odds ratio at higher doses, demonstrating evidence for a cell kill
effect (15,80,81) (Fig. 20.2 ). Female sex, y ounger age at exposure and longer time since
exposure are significant modifiers of the radiation-related risk of thy roid cancer (81).
Thy roid cancer develops after a latency of 8.5 y ears and is associated with an excellent
outcome.
Brain Tumor
Meningiomas and gliomas develop after cranial radiation for management of central nervous
sy stem disease among patients treated for acute ly mphoblastic leukemia or non-Hodgkin
ly mphoma, or after cranial radiation for histologically distinct brain tumors. Gliomas occur a
median of 9 y ears from the original diagnosis; for meningiomas, the latency is 17 y ears. For
gliomas, the excess relative risk per gray is highest among children exposed at less than 5
y ears of age. Childhood cancer survivors were 8.7-fold more likely to develop gliomas, and
the excess absolute risk (EAR) was 1.9 per 1000 person-y ears (7,14,82,83,84). The risk for
second brain tumors demonstrates a linear relation with radiation dose; the dose–response
appears weaker for gliomas than for meningiomas (Fig. 20.2 ) (14,84). Possible effects of
chemotherapy on the risk of second brain tumors have also been described by some (85,86).
Increased exposure to intrathecal methotrexate significantly increases risk of meningioma
(84).
Other Carcinomas
Bassal et al. (87) analy zed the risk of secondary carcinomas in 13,136 childhood cancer
survivors (>5 y ears) in the CCSS. Seventy -one carcinomas were diagnosed at a median age
of 27 y ears and a median elapsed time of 15 y ears, and included genitourinary sy stem
(35%), head and neck (32%), gastrointestinal (23%), and other sites (10%). Fifty -nine percent
developed the SPC in an irradiated field.
Lung Cancer
Lung cancer is reported after chest radiation for Hodgkin ly mphoma. Smoking is linked with
lung cancer developing after radiation for HL; the increase in risk of lung cancer with
increasing radiation dose is greater among the patients who smoke after exposure to radiation
than among those who refrain from smoking (53).
Melanoma
Survivors of childhood cancer have a 2.5-fold increased risk of melanoma when compared
with the general population (91,92). Melanoma is reported in (HCT) recipients (93).
Radiotherapy may contribute to an increased risk of melanoma, but only at very high doses
of low linear energy transfer radiation (94). Previous studies have found that certain variants
of MC1R, CDKN2A, MTAP and PLAS2G6 genes are associated with an increased risk of
developing melanoma (95,96). Hereditary retinoblastoma survivors have are at a higher risk
of melanoma (97). The excess of melanoma following retinoblastoma is probably due to
common etiologic factors between these two tumor ty pes: the retinoblastoma protein (pRB) is
phosphory lated by CDK4 and CDK6, the two target kinases of CDKN2A.
Bladder
The risk of bladder cancer in childhood cancer survivors is increased 3- to 5-fold that of the
general population (87,98). Heritable retinoblastoma, exposure to cy clophosphamide and
pelvic radiation are associated with an increased risk (98,99).
Renal Cell Carcinoma
Childhood cancer survivors are at an eightfold increased risk of developing renal cell
carcinoma when compared with the general population (100). The highest risk is observed
among neuroblastoma survivors (101). Radiation to the renal bed at doses greater than 5 Gy
and platinum-based therapy increase the risk.
DNA Repair
DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and
oncogenes that can lead to cancer initiation and progression. Small differences in an
individual’s DNA repair capacity may be magnified in conjunction with exposure to
chemotherapy or radiotherapy. A number of DNA repair genes contain poly morphic
variants, resulting in large interindividual variations in DNA repair capacity. In fact, one-tenth
of the general population is known to have a reduced capacity to repair DNA damage (110).
Thus, individuals with altered DNA repair mechanisms are likely susceptible to the
development of genetic instability that drives the process of carcinogenesis as it relates to
SPCs.
Role of Genetic Susceptibility in Therapy-Related Leukemia
Table 20.4 summarizes the extant literature on the role of genetic susceptibility in t-
MDS/AML.
SL ID ESHOW
Table 20.4 Role of Genetic Susceptibility in the Development of Therapy-Related
Myelodysplasia/Acute Myeloid Leukemia
Breast cancer
Ionizing radiation is an established breast carcinogen. The ATM gene is a key regulator of
cellular responses to the DNA damage induced by ionizing radiation. Women who carry rare
deleterious ATM missense variants and who are exposed to radiation may have an elevated
risk of developing contralateral breast cancer (133). However, the rarity of these deleterious
missense variants (<1%) implies that ATM mutations could account for only a small portion
of radiation-related breast cancers.
Meningioma
While ionizing radiation is an established risk factor for meningioma, a very small fraction of
irradiated individuals develop this tumor, suggesting the role for genetic susceptibility. The
SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility
gene 1–interacting protein 1, has been shown to be associated with an increased risk of
developing meningioma (137). Given that approximately 28% of the European population are
carriers of at-risk genoty pes for rs4968451, the variant is likely to make a substantial
contribution to the development of meningioma. Another study used the family -based
association test program, and showed that haploty pe associations were attained at 18q21.1,
18q21.31 and 10q21.3, providing support for a variation in PIAS2, KATNAL2, TCEB3C,
TCEB3CL, and CTNNA3 genes as risk factors for radiation-associated meningioma (135).
These findings suggest that genetic susceptibility to radiation-associated meningioma is likely
mediated through the co-inheritance of multiple risk alleles.
Thyroid cancer
The ATM G5557A and XRCC1 Arg399Gln poly morphisms (DNA damage response genes), is
shown to be associated with a decreased risk of papillary thy roid cancer. TP53 Arg72Pro is
associated with increased risk of radiogenic papillary thy roid cancer. In the analy ses of
ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC
genoty pe is associated with radiation-induced papillary thy roid cancer. The results indicate
that poly morphisms of DNA damage response genes may be potential risk modifiers of
ionizing radiation-induced papillary thy roid cancer (136). Significant associations have also
been reported for rs1801516 in ATM and rs1867277 in the promoter region of FOXE1,
suggesting that thy roid morphogenesis pathway, in addition to DNA double-strand break repair
pathway are involved in the etiology of papillary thy roid cancer risk (138). Telomere
shortening is observed in response to ionizing radiation exposure. An inverse relation between
telomere content and radiation-related thy roid cancer has been observed (139), suggesting
that shorter telomeres (resulting in genomic instability ) may contribute to thy roid cancer in
childhood cancer survivors.
In summary, radiation exposure to an un-involved organ (e.g., breast, thy roid, brain,
etc.) results in DNA damage, which in turn, initiates cellular responses to the DNA damage.
Aberrant DNA damage response results in an increase in mutational burden. Inability to
repair the DNA damage results in the development of specific genetic lesions. Finally, clonal
expansion of cells carry ing specific genetic lesions results in the development of solid SMNs.
Figure: Second Primary Cancers and their
Relationship with Primary Cancers
Figure:
A: Dose-risk for RT-induced CNS tumors from Childhood Cancer Survivor Study. (From Neglia
JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous system in
survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl
Cancer Inst. 2006;98:1528–1537, with permission). B: Dose-risk for RT-induced breast cancer
from Childhood Cancer Survivor Study. (Inskip PD, Robison LL, Stovall M, et al. Radiation
dose and breast cancer risk in the childhood cancer survivor study. J Clin Oncol.
2009;27:3901–3907 with permission.) C: Dose-risk for RT-induced thyroid cancer from
Childhood Cancer Survivor Study.
(Bhatti P, Veiga LHS, Ronckers CM, et al. Risk of second primary thyroid cancer after
radiotherapy for a childhood cancer in a large cohort study: an update from the Childhood
Cancer Survivor Study. Radiat Res. 2010;174:741–752.)
Figure:
Integral dose and SMN risk in pediatric cancer survivors.
(From Nguyen F, Rubino C, Guerin S, et al. Risk of a second malignant neoplasm after cancer
in childhood treated with radiotherapy: correlation with the integral dose restricted to the
irradiated fields. Int J Radiat Oncol Biol Phys. 2008;70:908–915, with permission.)
Figure: Characteristics of Therapy-Related
Myelodysplasia or Acute Myeloid Leukemia
after Treatment with Alkylating Agents and
Topoisomerase II Inhibitors
Figure:
Standardized incidence ratio by type of second primary cancer.
(From Neglia JP, Friedman DL, Yutaka Y, et al. Second malignant neoplasms in five-year
survivors of childhood cancer: Childhood Cancer Survivor Study. J Natl Cancer Inst. 2001;93:
618–629, with permission.)
Figure: Risk of Breast Cancer in Hodgkin
Lymphoma Survivors by Age and Latency
Slideshow: Table 20.4: Role of Genetic
Susceptibility in the Development of
Therapy-Related Myelodysplasia/Acute
Myeloid Leukemia
Figure: Role of Genetic Susceptibility in the
Development of Therapy-Related Solid
Subsequent Malignant Neoplasms
PRIMARY CANCERS ASSOCIATED WITH SECOND PRIMARY CANCERS
This section focuses on certain primary cancers that are associated with a significantly
greater risk of SPCs (e.g., retinoblastoma and Hodgkin ly mphoma). It also focuses on
primary cancers, with large, well-characterized cohorts of patients followed for sufficiently
long periods of time to develop SPCs (e.g., ALL and the Wilms tumor).
Retinoblastoma
Children with hereditary retinoblastoma are at exceptionally high risk of developing multiple
primary cancers, especially osteosarcoma and soft tissue sarcomas (16,140). On the other
hand, patients with nonhereditary retinoblastoma appear not to be at greater risk for SPCs.
The cumulative incidence of an SPC at 50 y ears after diagnosis was reported to be 51%
(±6.2%) for hereditary retinoblastoma and 5% (±3%) for nonhereditary retinoblastoma. The
high risk of multiple primary cancers in patients with hereditary retinoblastoma is attributable
primarily to germline mutations in the retinoblastoma tumor suppressor gene, RB1. For
second primary soft tissue sarcomas, the relative risks showed stepwise increase for all
dosage categories of radiation therapy at 10–29.9 Gy and 30–59.9 Gy. Third and additional
nonocular tumors (soft tissue sarcomas, bone tumors, and skin cancers) have been reported
among patients with retinoblastoma who had developed a radiation-related SPC (141), with
the 5- and 10-y ear incidence rates reported to be 11% and 22%, respectively. The cumulative
probability of death from an SPC has been reported to be 26% at 40 y ears after bilateral
retinoblastoma diagnosis (97). An extended (40+ y ears) follow-up of patients with bilateral
retinoblastoma reveals that these patients are at a 35-fold higher risk of developing SPCs
(sarcomas, melanomas, brain tumors, uterine malignancies, and lung cancer) (142).
Radiotherapy for retinoblastoma further increased the risk of mortality from second cancers
in this report. The risk for six subty pes of soft tissue sarcoma (fibrosarcoma, liposarcoma,
histiocy toma, leiomy osarcoma, rhabdomy osarcoma, and others) was evaluated in a cohort
of 963 one-y ear survivors of hereditary retinoblastoma (143). The study demonstrated
elevated risk for all sarcomas combined (standardized incidence ratio [SIR] = 184, 95% CI,
143–233), and for individual subty pes. The cumulative risk for any soft tissue sarcoma was
13.1% at 50 y ears (95% CI, 9.7–17%). Leiomy osarcoma was the most frequent subty pe (SIR
= 390, 95% CI, 247–585), with 78% of the leiomy osarcomas diagnosed 30 or more y ears
after the retinoblastoma diagnosis. Among patients treated with radiotherapy for
retinoblastoma, there was a statistically significantly increased risk of soft tissue sarcomas in
the field of radiation, as well as outside the field, indicating the role for genetic predisposition
independent of radiation. These studies indicate that genetic predisposition has a substantial
impact on risk of SPCs in patients with retinoblastoma; the risk is further increased by
radiation therapy. Moreover, patients with retinoblastoma are at a higher risk for developing
third and fourth tumors, although the location and other risk factors are similar to those
described for SPCs.
Prevention Strategies
The absolute excess risk of SPC is small, with fewer than two excess SPCs occurring per 1000
patient-y ears of follow-up (7). The ongoing efforts to improve survival after childhood
cancer must not be overshadowed by the risk of SPC. However, of all possible late sequelae,
SPC can be the most devastating. It is therefore imperative that patients and healthcare
providers are aware of the risk of SPC and the populations at greater risk for developing SPCs
so that surveillance is focused and early prevention strategies can be implemented.
Page 482Examples of primary prevention strategies include use of gender-specific
therapy for patients with Hodgkin ly mphoma to reduce the risk of radiation-associated breast
cancer among female survivors and elimination of the use of etoposide for stem cell
mobilization (shown to be associated with t-MDS/AML).
Page 483The elevated risk of breast cancer noted among survivors of childhood and
adolescent cancers supports the importance of evidence-based screening guidelines for this
high-risk group (72). Because outcome after breast cancer is closely linked to stage at
diagnosis, close surveillance resulting in early diagnosis should confer survival advantage.
Mammography, the most widely accepted screening tool for breast cancer in the general
population, may not be the ideal screening tool by itself, for radiation-related breast cancers
occurring in relatively y oung women with dense breasts; hence, the American Cancer
Society recommends including adjunct screening with MRI (145). Thus, the following are
recommendations for females who received radiation with potential impact to the breast (i.e.,
radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields):
monthly breast self-examination beginning at puberty ; annual clinical breast examinations
beginning at puberty until age 25 y ears; and a clinical breast examination every 6 months,
with annual mammograms and MRIs beginning 8 y ears after radiation or at age 25
(whichever occurs later). Females who received TBI or cumulative chest radiation doses of
10–19 Gy should be counseled regarding the benefits and risks/harms of screening; if a
decision is made to screen, the same recommendations apply as for those women who
received radiation doses of 20 Gy or higher (146). Screening of those at risk for early -onset
colorectal cancer (i.e., radiation doses of 30 Gy or higher to the abdomen, pelvis, or spine)
should include colonoscopy every 5 y ears beginning at age 35 y ears or 10 y ears following
radiation (whichever occurs last). Joint recommendations for monitoring long-term survivors
of HCT by the EBMT/CIBMTR/ASBMT suggest that all recipients of HCT should be advised
of risks for subsequent malignancies and encouraged to perform screening self-examinations,
such as breast and skin examinations. All patients should be advised to avoid high-risk
behaviors, including avoidance of tobacco or excessive unprotected exposure of skin to
ultraviolet light (147).
Future Directions
While the body of literature documenting the increased risk of SPCs is substantial, there still
remain many unknowns about the very long-term effects. Ongoing surveillance will, with
time, provide answers to these questions: (i) the magnitude of risk among survivors of adult-
onset cancer; (ii) clearly defined associations with therapeutic exposures in these survivors of
the adult-onset cancers; (iii) the nature and risk of SPCs in childhood cancer survivors
followed for an extended period of time; (iv) impact of the prevention strategies on the
reduction in risk of SPCs.
SPCs provide us with a unique opportunity to understand the etiology and pathogenesis of
cancer. The exact timing and magnitude of the primary exposure (i.e., cancer therapy ) are
known, and following the patients closely may lead to a better understanding of the
progression of events and perhaps the identification of biomarkers that would identify patients
who ultimately develop SPCs. Several such studies that involve prospective, longitudinal
follow-up of patients are being undertaken to elucidate the sequence of events that ultimately
lead to the development of SPC.
Figure:
Overall survival of patients according to whether they developed no secondary malignancy,
a solid secondary malignancy, a hematopoietic secondary malignancy, or any secondary
malignancy.
(From Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated
for Hodgkin’s disease: associations with gender and radiation dose. Int J Radiat Oncol Biol
Phys. 2008;72:24–33, with permission).
Figure:
Cumulative proportion of second malignancies according to gender, with standard errors.
(From Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated
for Hodgkin’s disease: associations with gender and radiation dose. Int J Radiat Oncol Biol
Phys. 2008;72:24–33, with permission).
Figure:
Cumulative proportion of second malignancies according to gender, with standard errors,
after excluding breast cancer.
(From Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated
for Hodgkin’s disease: associations with gender and radiation dose. Int J Radiat Oncol Biol
Phys. 2008;72:24–33, with permission).
REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
2. Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling,
life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol.
2014;32:1218–1227.
3. Curtis RE, Freedman DM, Ron E, et al. New malignancies among cancer survivors:
SEER cancer registries, 1973–2000, NIH Publ. No. 05-5302. Bethesda, MD: National
Cancer Institute; 2006.
4. Dong C, Hemminki K. Second primary neoplasms in 633,964 cancer patients in Sweden,
1958–1996. Int J Cancer. 2001;93:155–161.
5. Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47,697 patients
treated for childhood cancer in the Nordic countries. J Natl Cancer Inst. 2009;101:806–
813.
6. Reulen RC, Frobisher C, Winter DL, et al. Long-term risks of subsequent primary
neoplasms among survivors of childhood cancer. JAMA. 2011;305:2311–2319.
7. Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-y ear survivors
of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst.
2010;102:1083–1095.
8. Cardous-Ubbink MC, Heinen RC, Bakker PJ, et al. Risk of second malignancies in long-
term survivors of childhood cancer. Eur J Cancer. 2007;43:351–362.
9. Armstrong GT, Liu W, Leisenring W, et al. Occurrence of multiple subsequent
neoplasms in long-term survivors of childhood cancer: a report from the childhood
cancer survivor study. J Clin Oncol. 2011;29:3056–3064.
10. Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nat Rev Cancer.
2002;2:124–132.
11. Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-y ear
survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst.
2008;100:1368–1379.
12. Bhatia S, Robison LL, Francisco L, et al. Late mortality in survivors of autologous
hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor
Study. Blood. 2005;105:4215–4222.
13. Bhatia S, Yasui Y, Robison LL, et al. High risk of subsequent neoplasms continues with
extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study
Group. J Clin Oncol. 2003;21:4386–4394.
14. Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous
sy stem in survivors of childhood cancer: a report from the Childhood Cancer Survivor
Study. J Natl Cancer Inst. 2006;98:1528–1537.
15. Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thy roid cancer after a first
tumour in childhood (the Childhood Cancer Survivor Study ): a nested case-control study.
Lancet. 2005;365:2014–2023.
16. Wong FL, Boice JDJ, Abramson DH, et al. Cancer incidence after retinoblastoma—
radiation dose and sarcoma risk. JAMA. 1997;278:1262–1267.
17. Strong LC, Stine M, Norsted TL. Cancer in survivors of childhood soft tissue sarcoma and
their relatives. J Natl Cancer Inst. 1987;79:1213–1220.
18. Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second neoplasms after
childhood Hodgkin’s disease. N Engl J Med. 1996;334:745–751.
19. Neglia JP, Meadows AT, Robison LL, et al. Second neoplasms after acute ly mphoblastic
leukemia in childhood. N Engl J Med. 1991;325:1330–1336.
20. Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow
transplantation. Blood. 1996;87:3633–3639.
21. Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated
for Hodgkin’s disease: associations with gender and radiation dose. Int J Radiat Oncol Biol
Phys. 2008;72:24–33.
22. Zang EA, Wy nder EL. Differences in lung cancer risk between men and women:
examination of the evidence. J Natl Cancer Inst. 1996;88:183–192.
23. Garwicz S, Anderson H, Olsen JH, et al. Second malignant neoplasms after cancer in
childhood and adolescence: a population-based case-control study in the 5 Nordic
countries. The Nordic Society for Pediatric Hematology and Oncology. The Association
of the Nordic Cancer Registries. Int J Cancer. 2000;88:672–678.
24. Page 484 Report on a workshop to examine methods to arrive at risk estimates for
radiation-induced cancer in the human based on laboratory data—jointly sponsored by
the Office of Health and Energy Research, Department of Energy, and Columbia
University. Radiat Res. 1993;135:434–437.
25. Wiley ALJ, Vogel HHJ, Clifton KH. The effect of variations in LET and cell cy cle on
radiation hepatocarcinogenesis. Radiat Res. 1973;54:284–293.
26. Kohn HI, Fry RJ. Radiation carcinogenesis. N Engl J Med. 1984;310:504–511.
27. Okey A, Harper P, Grant D, et al. Chemical and radiation carcinogenesis. In: Tannock I,
Hill R, eds. The Basic Science of Oncology. 3rd ed. ed. New York, NY: McGraw-Hill;
1998:166–196.
28. Haselow RE, Nesbit M, Dehner LP, et al. Second neoplasms following megavoltage
radiation in a pediatric population. Cancer. 1978;42:1185–1191.
29. Potish RA, Dehner LP, Haselow RE, et al. The incidence of second neoplasms following
megavoltage radiation for pediatric tumors. Cancer. 1985;56:1534–1537.
30. Richardson RB. Past and revised risk estimates for cancer induced by irradiation and
their influence on dose limits. Br J Radiol. 1990;63:235–245.
31. Wolden SL, Lamborn KR, Cleary SF, et al. Second cancers following pediatric Hodgkin’s
disease. J Clin Oncol. 1998;16:536–544.
32. Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent malignant neoplasms among
1641 Hodgkin’s disease patients diagnosed in childhood and adolescence: a population-
based cohort study in the five Nordic countries. J Clin Oncol. 1996;14:1442–1446.
33. Schellong G, Riepenhausen M, Creutzig U, et al. Low risk of secondary leukemias after
chemotherapy without mechlorethamine in childhood Hodgkin’s disease. German-
Austrian Pediatric Hodgkin’s Disease Group. J Clin Oncol. 1997;15:2247–2253.
34. Tucker MA, Meadows AT, Boice JDJ, et al. Leukemia after therapy with alky lating
agents for childhood cancer. J Natl Cancer Inst. 1987;78:459–464.
35. Pui CH, Ribeiro RC, Hancock ML, et al. Acute my eloid leukemia in children treated with
epipodophy llotoxins for acute ly mphoblastic leukemia. N Engl J Med. 1991;325:1682–
1687.
36. Winick NJ, McKenna RW, Shuster JJ, et al. Secondary acute my eloid leukemia in
children with acute ly mphoblastic leukemia treated with etoposide. J Clin Oncol.
1993;11:209–217.
37. Sugita K, Furukawa T, Tsuchida M, et al. High frequency of etoposide (VP-16)-related
secondary leukemia in children with non-Hodgkin’s ly mphoma. Am J Pediatr Hematol
Oncol. 1993;15:99–104.
38. Nguy en F, Rubino C, Guerin S, et al. Risk of a second malignant neoplasm after cancer in
childhood treated with radiotherapy : correlation with the integral dose restricted to the
irradiated fields. Int J Radiat Oncol Biol Phys. 2008;70:908–915.
39. Diallo I, Haddy N, Adjadj E, et al. Frequency distribution of second solid cancer
locations in relation to the irradiated volume among 115 patients treated for childhood
cancer. Int J Radiat Oncol Biol Phys. 2009;74:876–883.
40. Schneider U, Lomax A, Timmermann B. Second cancers in children treated with
modern radiotherapy techniques. Radiother Oncol. 2008;89:135–140.
41. Land CE. Temporal distributions of risk for radiation-induced cancers. J Chronic Dis.
1987;40:45S–57S.
42. Tucker MA, Coleman CN, Cox RS, et al. Risk of second cancers after treatment for
Hodgkin’s disease. N Engl J Med. 1988;318:76–81.
43. Smith MA, McCaffrey RP, Karp JE. The secondary leukemias: challenges and research
directions. J Natl Cancer Inst. 1996;88:407–418.
44. Hawkins MM, Wilson LM, Stovall MA, et al. Epipodophy llotoxins, alky lating agents, and
radiation and risk of secondary leukaemia after childhood cancer. Br Med J.
1992;304:951–958.
45. Tucker MA, D’Angio GL, Boice JDJ, et al. Bone sarcomas linked to radiotherapy and
chemotherapy in children. N Engl J Med. 1987;317:588–593.
46. Hawkins MM, Wilson LM, Burton HS, et al. Radiotherapy, alky lating agents, and risk of
bone cancer after childhood cancer. J Natl Cancer Inst. 1996;88:270–278.
47. Pedersen-Bjergaard J, Erbsoll J, Hansen VL, et al. Carcinoma of the urinary bladder
after treatment with cy clophosphamide for non-Hodgkin’s ly mphoma. N Engl J Med.
1988;318:1028–1032.
48. Blay ney DW, Longo DL, Young RC, et al. Decreasing risk of leukemia with prolonged
follow-up after chemotherapy and radiotherapy for Hodgkin’s disease. N Engl J Med.
1987;316:710–714.
49. Schoch C, Kern W, Schnittger S, et al. Kary oty pe is an independent prognostic
parameter in therapy -related acute my eloid leukemia (t-AML): an analy sis of 93
patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia.
2004;18:120–125.
50. Smith SM, Le Beau MM, Huo D, et al. Clinical-cy togenetic associations in 306 patients
with therapy -related my elody splasia and my eloid leukemia: the University of Chicago
series. Blood. 2003;102:43–52.
51. Pedersen-Bjergaard J, Christiansen DH, Desta F, et al. Alternative genetic pathway s and
cooperating genetic abnormalities in the pathogenesis of therapy -related my elody splasia
and acute my eloid leukemia. Leukemia. 2006;20:1943–1949.
52. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO)
classification of the my eloid neoplasms. Blood. 2002;100:2292–2302.
53. van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiotherapy and smoking in
lung cancer following Hodgkin’s disease. J Natl Cancer Inst. 1995;87:1530–1537.
54. Shiels MS, Gibson T, Sampson J, et al. Cigarette smoking prior to first cancer and risk of
second smoking-associated cancers among survivors of bladder, kidney, head and neck,
and Stage I lung cancers. J Clin Oncol. 2014;32:3989–3995.
55. Druesne-Pecollo N, Keita Y, Touvier M, et al. Alcohol drinking and second primary
cancer risk in patients with upper aerodigestive tract cancers: a sy stematic review and
meta-analy sis of observational studies. Cancer Epidemiol Biomarkers Prev. 2013;23:
324–331.
56. Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or my elody splastic
sy ndrome after treatment with epipodophy llotoxins. J Clin Oncol. 1999;17:569–577.
57. Karp JE, Sarkodee-Adoo CB. Therapy -related acute leukemia. Clin Lab Med.
2000;20:71–81.
58. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al. Genetic pathway s in
therapy -related my elody splasia and acute my eloid leukemia. Blood. 2002;99:1909–
1912.
59. Corbett AH, Osheroff N. When good enzy mes go bad: conversion of topoisomerase II to
a cellular toxin by antineoplastic drugs. Chem Res Toxicol. 1993;6:585–597.
60. Lovett BD, Strumberg D, Blair IA, et al. Etoposide metabolites enhance DNA
topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints.
Biochemistry. 2001;40:1159–1170.
61. Megonigal MD, Cheung NK, Rappaport EF, et al. Detection of leukemia-associated
MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II
inhibitors. Proc Natl Acad Sci U S A. 2000;97:2814–2819.
62. Felix CA, Lange BJ, Hosler MR, et al. Chromosome band 11q23 translocation breakpoints
are DNA topoisomerase II cleavage sites. Cancer Res. 1995;55:4287–4292.
63. Libura J, Slater DJ, Felix CA, et al. Therapy -related acute my eloid leukemia-like MLL
rearrangements are induced by etoposide in primary human CD34+ cells and remain
stable after clonal expansion. Blood. 2005;105:2124–2131.
64. Rowley JD, Olney HJ. International workshop on the relationship of prior therapy to
balanced chromosome aberrations in therapy -related my elody splastic sy ndromes and
acute leukemia: overview report. Genes Chromosomes Cancer. 2002;33:331–345.
65. Le Deley MC, Leblanc T, Shamsaldin A, et al. Risk of secondary leukemia after a solid
tumor in childhood according to the dose of epipodophy llotoxins and anthracy clines: a
case-control study by the Societe Francaise d’Oncologie Pediatrique. J Clin Oncol.
2003;21:1074–1081.
66. Henderson TO, Whitton J, Stovall M, et al. Secondary sarcomas in childhood cancer
survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst.
2007;99:300–308.
67. Henderson TO, Rajaraman P, Stovall M, et al. New primary sarcomas in survivors of
childhood cancer: a detailed analy sis of the effects of treatment—a report from the
Childhood Cancer Survivor Study. J Clin Oncol. 2008;26:10007.
68. Friedman DL, Rovo A, Leisenring W, et al. Increased risk of breast cancer among
survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and
the EBMT-Late Effect Working Party. Blood. 2008;111:939–944.
69. Page 485 Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy
and chemotherapy among y oung women with Hodgkin disease. JAMA. 2003;290:465–
475.
70. Hancock SL, Tucker MA, Hoppe RT. Breast cancer after treatment of Hodgkin’s disease.
J Natl Cancer Inst. 1993;85:25–31.
71. Metay er C, Ly nch C, Clarke EA, et al. Second cancers among long-term survivors of
Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol. 2000;18:2435–
2443.
72. Henderson TO, Amsterdam A, Bhatia S, et al. Sy stematic review: surveillance for breast
cancer in women treated with chest radiation for childhood, adolescent, or y oung adult
cancer. Ann Intern Med. 2010;152:444–455.
73. Inskip PD, Robison LL, Stovall M, et al. Radiation dose and breast cancer risk in the
childhood cancer survivor study. J Clin Oncol. 2009;27:3901–3907.
74. Moskowitz CS, Chou JF, Wolden SL, et al. Breast cancer after chest radiation therapy for
childhood cancer. J Clin Oncol. 2014 32:2217–2223.
75. van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation dose, chemotherapy,
and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst.
2003;95:971–980.
76. Tay lor AJ, Little MP, Winter DL, et al. Population-based risks of CNS tumors in survivors
of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol.
2010;28:5287–5293.
77. Reulen RC, Tay lor AJ, Winter DL, et al. Long-term population-based risks of breast
cancer after childhood cancer. Int J Cancer. 2008;123:2156–2163.
78. Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for y oung
women treated for Hodgkin ly mphoma. J Natl Cancer Inst. 2005;97:1428–1437.
79. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thy roid in survivors of
Hodgkin’s disease: data from the Childhood Cancer Survivor Study. J Clin Endocrine
Metab. 2000;85:3227–3232.
80. Ronckers CM, Sigurdson AJ, Stovall M, et al. Thy roid cancer in childhood cancer
survivors: a detailed evaluation of radiation dose response and its modifiers. Radiat Res.
2006;166:618–628.
81. Bhatti P, Veiga LH, Ronckers CM, et al. Risk of second primary thy roid cancer after
radiotherapy for a childhood cancer in a large cohort study : an update from the
childhood cancer survivor study. Radiat Res. 2010;174:741–752.
82. Bhatia S, Sather HN, Pabustan OB, et al. Low incidence of second neoplasms among
children diagnosed with acute ly mphoblastic leukemia after 1983. Blood. 2002;99:4257–
4264.
83. Bowers DC, Nathan PC, Constine L, et al. Subsequent neoplasms of the CNS among
survivors of childhood cancer: a sy stematic review. Lancet Oncol. 2013;14:e321–e328.
84. Pappo AS, Armstrong GT, Liu W, et al. Melanoma as a subsequent neoplasm in adult
survivors of childhood cancer: a report from the childhood cancer survivor study. Pediatr
Blood Cancer. 2013;60:461–466.
85. Little MP, de Vathaire F, Shamsaldin A, et al. Risks of brain tumour following treatment
for cancer in childhood: modification by genetic factors, radiotherapy and
chemotherapy. Int J Cancer. 1998;78:269–275.
86. Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours
after radiotherapy and antimetabolites. Lancet. 1999;354:34–39.
87. Bassal M, Mertens AC, Tay lor L, et al. Risk of selected subsequent carcinomas in
survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin
Oncol. 2006;24:476–483.
88. Leisenring W, Friedman DL, Flowers ME, et al. Nonmelanoma skin and mucosal
cancers after hematopoietic cell transplantation. J Clin Oncol. 2006;24:1119–1126.
89. Schwartz JL, Kopecky KJ, Mathes RW, et al. Basal cell skin cancer after total-body
irradiation and hematopoietic cell transplantation. Radiat Res. 2009;171:155–163.
90. Perkins JL, Liu Y, Mitby PA, et al. Nonmelanoma skin cancer in survivors of childhood
and adolescent cancer: a report from the childhood cancer survivor study. J Clin Oncol.
2005;23:3733–3741.
91. Braam KI, Overbeek A, Kaspers GJ, et al. Malignant melanoma as second malignant
neoplasm in long-term childhood cancer survivors: a sy stematic review. Pediatr Blood
Cancer. 2012;58:665–674.
92. Wilson CL, Ness KK, Neglia JP, et al. Renal carcinoma after childhood cancer: a report
from the childhood cancer survivor study. J Natl Cancer Inst. 2013;105:504–508.
93. Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow
transplantation for childhood acute leukemia. J Clin Oncol. 2000;18:348–357.
94. Guerin S, Dupuy A, Anderson H, et al. Radiation dose as a risk factor for malignant
melanoma following childhood cancer. Eur J Cancer. 2003;39:2379–2386.
95. Soufir N, Avril MF, Chompret A, et al. Prevalence of p16 and CDK4 germline mutations
in 48 melanoma-prone families in France—The French Familial Melanoma Study
Group. Hum Mol Genet. 1998;7:209–216.
96. Bishop DT, Demenais F, Iles MM, et al. Genome-wide association study identifies three
loci associated with melanoma risk. Nat Genet. 2009;41:920–925.
97. Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term
survivors of retinoblastoma. J Natl Cancer Inst. 1993;85:1121–1128.
98. Frobisher C, Gurung PM, Leiper A, et al. Risk of bladder tumours after childhood cancer:
the British Childhood Cancer Survivor Study. BJU Int. 2010;106:1060–1069.
99. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following
cy clophosphamide therapy for non-Hodgkin’s ly mphoma. J Natl Cancer Inst.
1995;87:524–530.
100. Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and side
effects. N Engl J Med. 2003;348:538–549.
101. Fleitz JM, Wootton-Gorges SL, Wy att-Ashmead J, et al. Renal cell carcinoma in long-
term survivors of advanced stage neuroblastoma in early childhood. Pediatr Radiol.
2003;33:540–545.
102. Boukheris H, Stovall M, Gilbert ES, et al. Risk of salivary gland cancer after childhood
cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys.
2013;85:776–783.
103. Shore-Freedman E, Abrahams C, Recant W, et al. Neurilemomas and salivary gland
tumors of the head and neck following childhood irradiation. Cancer. 1983;51:2159–2163.
104. Schneider AB, Lubin J, Ron E, et al. Salivary gland tumors after childhood radiation
treatment for benign conditions of the head and neck: dose-response relationships. Radiat
Res. 1998;30:149:625.
105. Travis LB, Demark Wahnefried W, Allan JM, et al. Aetiology, genetics and prevention of
secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol. 2013;10:289–310.
106. Allan JM. Genetic susceptibility to radiogenic cancer in humans. Health Phys.
2008;95:677–686.
107. Kalow W, Ozdemir V, Tang BK, et al. The science of pharmacological variability : an
essay. Clin Pharmacol Ther. 1999;66:445–447.
108. Larson RA, Wang Y, Banerjee M, et al. Prevalence of the inactivating 609C–>T
poly morphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with
primary and therapy -related my eloid leukemia. Blood. 1999;94:803–807.
109. Berwick M, Vineis P. Markers of DNA repair and susceptibility to cancer in humans: an
epidemiologic review. J Natl Cancer Inst. 2000;92:874–897.
110. Rai R, Peng G, Li K, et al. DNA damage response: the play ers, the network and the role
in tumor suppression. Cancer Genomics Proteomics. 2007;4:99–106.
111. Felix CA, Walker AH, Lange BJ, et al. Association of CYP3A4 genoty pe with treatment-
related leukemia. Proc Natl Acad Sci U S A. 1998;95:13176–13181.
112. Rund D, Krichevsky S, Bar-Cohen S, et al. Therapy -related leukemia: clinical
characteristics and analy sis of new molecular risk factors in 96 adult patients. Leukemia.
2005;19:1919–1928.
113. Blanco JG, Edick MJ, Hancock ML, et al. Genetic poly morphisms in CYP3A5, CYP3A4
and NQO1 in children who developed therapy -related my eloid malignancies.
Pharmacogenetics. 2002;12:605–611.
114. Bolufer P, Collado M, Barragan E, et al. Profile of poly morphisms of drug metabolizing
enzy mes and the risk of therapy -related leukaemia. Br J Haematol. 2007;136:590–596.
115. Ellis NA, Huo D, Yildiz O, et al. MDM2 SNP309 and TP53 Arg72Pro interact to alter
therapy -related acute my eloid leukemia susceptibility. Blood. 2008;112:741–749.
116. Naoe T, Takey ama K, Yokozawa T, et al. Analy sis of genetic poly morphism in NQO1,
GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy -related
leukemia/my elody splastci sy ndrome and de novo acute my eloid leukemia. Clin Cancer
Res. 2000;6:4091–4095.
117. Page 486 Allan JM, Wild CP, Rollingson S, et al. Poly morphism in glutathione S-
transferase P1 is associated with susceptibility to chemotherapy -induced leukemia.
PNAS. 2001;98:11592–11597.
118. Woo MH, Shuster JJ, Chen CL, et al. Gluthathione S-transferase genoty pes in children
who develop treatment-related acute my eloid malignancies. Leukemia. 2000;14.
119. Weisberg I, Tran P, Christensen B, et al. A second genetic poly morphism in
methy lenetetrahy drofolate reductase (MTHFR) associated with decreased enzy me
activity. Mol Genet Metab. 1998;64:169–172.
120. Worrillow LJ, Travis LB, Smith AG, et al. An intron splice acceptor poly morphism in
hMSH2 and risk of leukemia after treatment with chemotherapeutic alky lating agents.
Clin Cancer Res. 2003;9:3012–3020.
121. Worrillow LJ, Smith AG, Scott K, et al. Poly morphic MLH1 and risk of cancer after
methy lating chemotherapy for Hodgkin ly mphoma. J Med Genet. 2008;45:142–146.
122. Jawad M, Seedhouse CH, Russell N, et al. Poly morphisms in human homeobox HLX1
and DNA repair RAD51 genes increase the risk of therapy -related acute my eloid
leukemia. Blood. 2006;108:3916–3918.
123. Allan JM, Smith AG, Wheatley K, et al. Genetic variation in XPD predicts treatment
outcome and risk of acute my eloid leukemia following chemotherapy. Blood.
2004;104:3872–3877.
124. Seedhouse C, Bainton R, Lewis M, et al. The genoty pe distribution of the XRCC1 gene
indicates a role for base excision repair in the development of therapy -related acute
my eloblastic leukemia. Blood. 2002;100:3761–3766.
125. Seedhouse C, Faulkner R, Ashraf N, et al. Poly morphisms in genes involved in
homologous recombination repair interact to increase the risk of developing acute
my eloid leukemia. Clin Cancer Res. 2004;10:2675–2680.
126. Guillem VM, Collado M, Terol MJ, et al. Role ofMTHFR (677, 1298) haploty pe in the risk
of developing secondary leukemia after treatment of breast cancer and hematological
malignancies. Leukemia. 2007;21:1413–1422.
127. Ding Y, Sun C-L, Li L, et al. Genetic susceptibility to therapy -related leukemia after
Hodgkin ly mphoma or non-Hodgkin ly mphoma: role of drug metabolism, apoptosis, and
DNA repair. BCJ. 2012;2:e58.
128. Knight JA, Skol AD, Shinde A, et al. Genome-wide association study to identify novel
loci associated with therapy -related my eloid leukemia susceptibility. Blood.
2009;113:5575–5582.
129. Josting A, Wiedenmann S, Franklin J, et al. Secondary my eloid leukemia and
my elody splastic sy ndromes in patients treated fpr Hodgkin’s disease: a report from the
German Hodgkin’s ly mphoma Study Group. J Clin Oncol. 2003;21:3440–3446.
130. Yu CL, Tucker MA, Abramson DH, et al. Cause-specific mortality in long-term
survivors of retinoblastoma. J Natl Cancer Inst. 2009;101:581–591.
131. Best T, Li DL, Skol AD, et al. Variants at 6q21 implicate PRDM1 in the etiology of
therapy -induced second malignancies after Hodgkin’s ly mphoma. Nat Med.
2011;17:941–943.
132. Mertens AC, Mitby PA, Radloff G, et al. XRCC1 and glutathione-S-transferase gene
poly morphisms and susceptibility to radiotherapy -related malignancies in survivors of
Hodgkin disease. Cancer. 2004;101:1463–1472.
133. Bernstein JL, Haile RW, Stovall M, et al. Radiation exposure, the ATM gene, and
contralateral breast cancer in the women’s environmental cancer and radiation
epidemiology study. J Natl Cancer Inst. 2010;102:475–483.
134. Brooks JD, Teraoka SN, Reiner AS, et al. Variants in Activators and downstream targets
of ATM, radiation exposure, and contralateral breast cancer risk on the WECARE study.
Hum Mutat. 2012;33:158–164.
135. Hosking FJ, Feldman D, Bruchim R, et al. Search for inherited susceptibility to radiation-
associated meningioma by genomewide SNP linkage disequilibrium mapping. Br J
Cancer. 2011;104:1049–1054.
136. Akulevich NM, Saenko VA, Rogounovitch TI, et al. Poly morphisms of DNA damage
response genes in radiation-related and sporadic papillary thy roid carcinoma. Endocr
Relat Cancer. 2009;16:491–503.
137. Bethke L, Murray A, Webb E, et al. Comprehensive analy sis of DNA repair gene
variants and risk of meningioma. J Natl Cancer Inst. 2008;100:270–276.
138. Damiola F, By rnes G, Moissonnier M, et al. Contribution of ATM and FOXE1 (TTF2) to
risk of papillary thy roid carcinoma in Belarusian children exposed to radiation. Int J
Cancer. 2014;134:1659–1668.
139. Gramatges MM, Liu Q, Yasui Y, et al. Telomere content and risk of second malignant
neoplasm in survivors of childhood cancer: a report from the Childhood Cancer Survivor
Study. Clin Cancer Res. 2014;20:904–911.
140. Moll AC, Imhof SM, Schouten-Van Meeteren AY, et al. Second primary tumors in
hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on
radiation-related risk? Ophthalmology. 2001;108:1109–1114.
141. Abramson DH, Ellsworth RM, Kitchin FD, et al. Second nonocular tumors in
retinoblastoma survivors are they radiation-induced? Ophthalmology. 1984;91:1351–
1355.
142. Neglia JP, Friedman DL, Yutaka Y, et al. Second malignant neoplasms in five-y ear
survivors of childhood cancer: Childhood Cancer Survivor Study. J Natl Cancer Inst.
2001;93:618–629.
143. Kleinerman RA, Tucker MA, Abramson DH, et al. Risk of soft tissue sarcomas by
individual subty pe in survivors of hereditary retinoblastoma. J Natl Cancer Inst.
2007;99:24–31.
144. Green DM, Hy land A, Barcos MP, et al. Second malignant neoplasms after treatment
for Hodgkin’s disease in childhood or adolescence. J Clin Oncol. 2000;18:1492–1499.
145. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast
screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75–89.
146. Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood,
adolescent, and y oung adult cancers, version 4.0. Monrovia, CA: Children’s Oncology
Group; 2013. www.survivorshipguidelines.org .
147. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices
for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow
Transplant. 2012;18:348–371.
CH A P TER 21
Anesthesia for External Beam Radiotherapy
Scott R. Schulman, Marla B. Ferschl, Heather J. Frederick, and Edward C.
Halperin
Harrison and Bennet (1) made these observations more than 50 y ears ago. Their classic
article, “Radiotherapy Without Tears,” was the first published report describing anesthesia for
radiotherapy in children. The problem of inadequate sedation prompted the authors to
develop
Forty y ears of progress in anesthesiology have validated not only Harrison and Bennet’s
observation but also their solution to the problem of providing anesthesia for radiotherapy.
This chapter reviews issues in the sedation of children with an emphasis on monitoring the
anesthetized child in the radiotherapy suite, develops a model of the ideal anesthetic for
pediatric radiotherapy, explores anesthetic options for radiotherapy, and discusses the
implications of the child’s underly ing disease that influence the anesthetic choice.
BEHAVIORAL TECHNIQUES TO AVOID ANESTHESIA
When possible, children should be irradiated without anesthesia. In some cases, a behavioral
program to teach children how to cooperate with radiation treatment without sedation and
anesthesia may be successful. Behavioral therapy techniques, called desensitization or
exposure therapy, were originally developed for treating severe anxiety, fears, and phobias.
The procedure involves inducing a relaxed state using music, cartoons, stories, or videos.
Subsequently, one introduces the staff, equipment, and routines needed for radiation
treatment.
A behavioral technique called differential positive reinforcement is used to strengthen
cooperation and coping. Incentives such as praise, stickers, toy s, and prizes are provided when
the child attempts to cooperate. These are used to shape the child’s ability to inhibit movement
when instructed to do so. Shaping is a behavioral psy chology technique whereby the criteria
for reinforcement are gradually altered as the child improves performance. At the beginning,
an approximation of the desired behavior is acceptable. After a while, more challenging and
rigid criteria are set for reinforcement.
Videos of cartoons or movies may be used to provide relaxation, distractions, and
ongoing positive reinforcement in training y oung children to cooperate with radiation therapy.
A small monitor or projection screen can be suspended near the treatment machine and
connected to an electronic device so that movies or cartoons may be play ed during
radiotherapy while the child is in the treatment position. Slifer et al. (2,3,4) demonstrated the
efficacy of this technique in children between the ages of 2½ and 7 y ears. Nine of 11
children were able to successfully undergo all of their radiation planning and treatment
sessions without sedation. Alternative strategies include play ing music to the child, or reading
them a book over a loudspeaker for the duration of the treatment.
The implementation of a psy choeducational intervention consisting of careful
preparation of the patient for radiotherapy through the use of picture books, medical play, and
reward sy stems reduced the need for anesthesia in a longitudinal study (5). After
implementing the intervention, the percentage of children requiring anesthesia decreased
from 21% to 9%. The authors concluded that the cost of implementation (median 6 hours of
time by a qualified nurse, plus materials) was offset by the reduced requirement for
anesthesia.
Page 488Many pediatric radiotherapy centers have thoughtful programs designed to
provide the services described above. Music therapists, psy chologists, child life specialists,
social workers, and radiation therapists throughout the world have created a variety of
culturally appropriate tools that they are almost alway s willing to share with colleagues,
including radiation therapy “comic books,” “coloring books,” video education tools, “make
y our own movie about radiotherapy with y ou as the star,” cheerful murals painted on the
walls of the radiotherapy waiting room, and decorating stabilization devices with child-
friendly themes. At meetings of professional societies, these heart-warming ideas are freely
shared with colleagues.
FREQUENCY OF ANESTHESIA FOR PEDIATRIC RADIOTHERAPY
When behavioral techniques to achieve patient cooperation and stability fail, anesthesia or
sedation must be used. The frequency of anesthesia use as a function of patient age at the
initiation of external beam radiation therapy in the Duke University Medical Center pediatric
radiotherapy population is shown in Table 21.1 . For very y oung children (≤3 y ears),
anesthesia is almost alway s needed. After approximately 5 y ears of age, however,
anesthesia is rarely needed. This has been further validated by a recent publication from
Indiana University, which demonstrated that almost all children age 3 y ears and under
required anesthesia for radiation therapy, but for those over age 3 y ears, anesthetic need
decreases in an age-dependent fashion (6).
To accomplish the twin goals of irradiating the treatment volume while sparing healthy tissue,
control of patient movement must be precise and absolute. How are these goals achieved in
children? The approach varies depending on the institutional resources. Conscious or deep
sedation is used in some centers, whereas general anesthesia is used in others. Regardless of
the institutional practice, there is no substitute for vigilant monitoring and prompt intervention
by people skilled in detecting and managing complications associated with the administration
of sedative drugs to infants and children.
Anesthesiologists are increasingly asked to provide care outside the traditional operating
room setting, such as in the radiotherapy suite. This is appropriate because the specialty has
unique expertise in patient evaluation, selection, and monitoring and the ability to respond
immediately to any complication of therapy. Expertise in drug selection and a
comprehensive approach to the care of the child, which includes preanesthetic evaluation,
postanesthetic care, and the provision of up-to-date feeding guidelines, are hallmarks of the
anesthesiologist.
A prolonged fast before the induction of general anesthesia is no longer necessary. The
American Society of Anesthesiology recommendations on preanesthetic fasting apply to all
ages and are widely followed as standard of care (7). All patients can safely drink clear
liquids (e.g., apple juice, water, popsicles) until 2 hours before induction. Breast milk is
allowed up to 4 hours, and milk or formula until 6 hours before induction. A light breakfast, for
example toast and milk, may be allowed up to 6 hours prior to anesthesia for afternoon cases,
but ty pically solid foods are withheld after midnight, especially in older children.
The goals of anesthesia for pediatric radiotherapy are listed in Table 21.2 . There are
several options that, to vary ing degrees, accomplish the listed goals. There are no prospective,
randomized studies in the setting of pediatric radiotherapy that demonstrate the superiority of
one technique of general anesthesia over another.
Several routes of drug administration are available for sedation of children. Each drug
and drug combination has its own set of side effects and contraindications. Several general
guidelines may be considered. First, the route of administration of the drug should be the least
traumatic for the particular child. Oral or inhalational administration, avoiding intramuscular
or intravenous administration, should be considered when feasible. Second, it should be kept in
mind that some children will develop a tolerance to certain drugs used for sedation. Over
time, the amount of drug and time needed to achieve sedation may both increase.
Page 489Several general anesthetic options exist for radiotherapy. The anesthesiologist
individualizes therapy based on data obtained from the patient’s history, phy sical and
laboratory examination, and discussions with the child, parents, and radiation oncologist. The
phy sical limitations of the radiotherapy suite (such as the presence of an air exhaust sy stem
so that volatile anesthetic agents can be used) are also important in devising the anesthetic
plan.
General anesthesia is accomplished with
either inhaled agents (Table 21.3 ) or
intravenous agents (e.g., barbiturates, ketamine,
propofol). The use of inhalational agents requires
an anesthesia machine, gas source and, ideally, a
waste scavenging sy stem. The first report of
anesthesia for pediatric radiotherapy used
halothane. Halothane is a halogenated Table 21.3 Inhalation Anesthetic
hy drocarbon volatile anesthetic first introduced Agents Commonly Used in Pediatric
for clinical use in 1956. Halothane has a long Radiation Therapy
history of safe, effective use in pediatric
patients. It rapidly produces an anesthetic state when inhaled, with minimal airway
complications such as coughing and lary ngospasm. Due to its tendency to depress
cardiovascular function in a dose-dependent fashion and its arrhy thmogenic potential, it has
generally been replaced by sevoflurane for mask induction in children (8). Sevoflurane has
minimal pungency compared with halothane and may be more readily tolerated by children.
It has less cardiovascular side effects than halothane, and its lower solubility permits a more
precise control over the delivery of anesthesia as well as a more rapid induction of and
recovery from anesthesia. Sevoflurane also seems to have a lower respiratory irritant
capacity than halothane and produces less coughing and breath holding than some other
inhaled agents (9,10,11,12) (Fig. 21.1 ).
A risk of inhalation anesthesia is upper
airway obstruction, which is often exacerbated
in radiation therapy by the position of the patient.
Positioning often entails immobilization of the
child’s head in a stabilization device (Fig.
21.2 ), which can impede airway patency
(Fig. 21.3 ) when an insufflation technique is
used. This obstruction is relieved with an
orophary ngeal or nasophary ngeal airway or a
lary ngeal mask airway (LMA). Although
endotracheal intubation may be necessary in a
Figure 21.1 Anesthesia for radiation
small proportion of patients presenting for
therapy may be initiated with an
radiotherapy, it is preferable to avoid this
intravenous drug and maintained by
technique because repeated lary ngoscopy and
inhalation anesthesia; it may be initiated
intubation carry the risk of airway edema and
and maintained with an intravenous
trauma to the lary ngeal structures. Intensity -
agent, or, as shown in this procedure, it
modulated radiotherapy and tomotherapy
may be initiated and maintained by an
techniques often allow the radiation oncologist to
inhaled agent. The 2-year-old patient with
use a supine rather than a prone position for
stage IV neuroblastoma is seated on a
irradiation of the craniospinal axis, for example.
trusted caregiver’s lap while the
Management of the airway in a supine patient is
anesthesiologist administers the drug. A
far easier for the anesthesiologist. This is an
therapist is diverting the child by giving a
example of how the anesthesiologist and
“high five” because “you are being so
pediatric radiation oncologist can collaborate to
cooperative.” The child received twice-
ease each other’s contribution to the care of the
daily radiotherapy for 12 days.
child.
Page 490An adjunct for airway
management during pediatric radiotherapy is the LMA. The LMA (Fig. 21.4 ) is a silicone
tube, the distal end of which has an elliptical-shaped cuff that, when correctly inserted and
inflated, forms a low-pressure seal around the lary nx and allows spontaneous ventilation in a
variety of body positions without the need for endotracheal intubation. Therefore, the LMA
provides many of the advantages of endotracheal intubation: relief of upper airway
obstruction without the disadvantages of repeated lary ngoscopy and intubation. The LMA has
been used for radiotherapy in children as y oung as 3 weeks of age. Grebenik et al. (13)
reported the use of the LMA for pediatric radiotherapy in 25 children who received more
than 300 anesthetics. They observed no complications directly related to the use of the LMA.
Morris and Marjot (14) reported one case of
posterior phary ngeal wall edema that
corresponded to the area of contact between the
posterior surface of the LMA and the
orophary nx in a child repeatedly anesthetized
with an LMA for radiotherapy. Moy lan and Luce
(15) reported more than 2500 anesthetics given
to 145 children with an LMA over a 4-y ear
period for radiotherapy. They raised the concern
that a prone position for radiotherapy with the
neck partially flexed can produce kinking of the
LMA, with the possibility of airway obstruction.
A reinforced LMA may help alleviate this
problem (16). Generally speaking, LMA use is
most successful in the supine position, though
lateral and prone LMA placement is possible.
Page 491In summary, general inhalation anesthesia has the following features that make
it an attractive technique for pediatric radiotherapy : onset is rapid, depth is easily controllable,
administration is not generally unpleasant, recovery is rapid, the incidence of nausea and
vomiting is low, and airway patency is well preserved.
Figure: Inhalation Anesthetic Agents
Commonly Used in Pediatric Radiation
Therapy
Figure:
Anesthesia for radiation therapy may be initiated with an intravenous drug and maintained
by inhalation anesthesia; it may be initiated and maintained with an intravenous agent, or,
as shown in this procedure, it may be initiated and maintained by an inhaled agent. The 2-
year-old patient with stage IV neuroblastoma is seated on a trusted caregiver’s lap while the
anesthesiologist administers the drug. A therapist is diverting the child by giving a “high five”
because “you are being so cooperative.” The child received twice-daily radiotherapy for 12
days.
Figure:
A: Intensity-modulated radiotherapy delivered from multiple directions by a linear
accelerator is facilitated in this anesthetized child with a thermoplastic head immobilization
device combined with a polyurethane foam–customized head and neck support. The gas
mask is incorporated into the head immobilization device, and the treating therapist has
placed beam setup marks directly on the device. The capnometry monitor is entering the
airway tubing at the top. B: This 35-month-old girl with recurrent medulloblastoma received
craniospinal irradiation over a course of 37 days. This picture was taken on her final day of
therapy during the primary tumor site boost.
Figure:
To minimize the effects of external beam irradiation on the mandible and neck of this child
with embryonal rhabdomyosarcoma on the tongue, resected with positive margins, daily
fractionated radiotherapy was administered via an orthovoltage intraoral cone while the
child was anesthetized. A: The mouth is held open with a standard surgical mouth gag used
commonly in the operating room. The anesthesiologist stabilizes the gas tubes attached to
the airway. B: The tumor bed is painted with methylene blue to make it easy to identify. The
tongue is pulled forward with a plastic towel clip over gauze. A lead shield, inside a surgical
glove, is placed behind the tongue to shield the floor of the mouth. C: The intraoral cone is
docked. The tongue is held in place by the towel clip, which is pulled taut by a strap seen in
the far right of the picture. The child is alive and well, with satisfactory speech development,
4 years after radiotherapy.
Figure:
A mobile anesthesia machine such as the Narkomed Mobile (Drager) with a remote screen
for data and alarms is suitable for the radiotherapy suite.
INTRAVENOUS ANESTHETICS
Intravenous anesthesia is also a popular and effective technique for pediatric radiotherapy.
Intravenous anesthesia relies on either intermittent or continuous infusion of anesthetic agent
into a peripheral or central vein in order to maintain a therapeutic concentration (17).
Although it is not a new concept (sodium thiopental was administered by continuous drip as
early as 1944), the advent of newer, short-acting anesthetic drugs, better equipment for
infusing these drugs, and an improved understanding of pharmacokinetics in pediatric patients
have led to a resurgence of interest in this technique. Postulated advantages of intravenous
anesthesia include fewer peaks and troughs in serum concentration of drug, providing a
steady -state serum concentration. Proponents of intravenous anesthesia contend that this
steady -state concentration results in a more rapid induction of and emergence from
anesthesia when compared with inhaled anesthetics. The time to emergence for short-
duration cases (less than 45 minutes) is likely to be rapid with either technique. With longer
cases, the emergence with inhalational anesthesia may even be quicker, depending on the
depth of anesthesia. The use of intravenous anesthesia does not require an anesthesia
machine, but still requires an oxy gen source as well as a patient monitoring sy stem.
There is an extensive body of experience with ketamine in the radiotherapy suite
(18,19,20). Since its release in the early 1970s, this dissociative anesthetic has been widely
used for radiation therapy in children. Ketamine produces excellent analgesia and amnesia of
short duration. Ketamine is easy to administer (it can be given intramuscularly if there is no
intravenous access) (21), and is felt to preserve respiration and airway patency more
effectively than inhaled anesthetics. One series described a child with a phary ngeal tumor
who experienced airway obstruction with halothane anesthesia. When ketamine was
substituted for halothane, the patient had an uneventful anesthetic treatment, which resulted in
satisfactory conditions for radiotherapy (22).
Ketamine and midazolam can be used to produce repetitive intravenous anesthesia for a
child undergoing radiation therapy. Ketamine is a phency clidine derivative that produces
dissociative anesthesia, characterized by electroencephalographic evidence of dissociation
between the thalamus and the limbic sy stem. The drug has a rapid onset of action, a short
duration, and high lipid solubility. It does not produce significant depression of ventilation.
There is an increase in sy stemic and pulmonary arterial blood pressure, cardiac output,
cardiac work, and my ocardial oxy gen needs. The drug is metabolized extensively by hepatic
microsomal enzy mes. There have been case reports of tolerance developing with repeat
administration of ketamine (23).
Ketamine is not a panacea. There are several caveats to its use. Ketamine has ocular
effects that have implications for radiotherapy. The onset of ketamine anesthesia often is
accompanied by ny stagmus (more commonly horizontal than vertical). Ny stagmus with
ketamine usually is transient; however, if it persists, it may be impossible to use a hanging lens
block in an anterior field for the treatment of retinoblastoma. Ketamine can also produce
involuntary movement of other muscle groups (jerking), which is undesirable in pediatric
radiotherapy. Ketamine raises blood pressure and heart rate. Its use in the setting of elevated
intracranial pressure (ICP) is contraindicated because it causes ICP to increase. Although
ketamine generally preserves respiratory drive and airway patency, apnea can occur after
an intravenous bolus. In addition, it is a potent sialogogue, and copious secretions often
accompany its use. Secretions can cause airway obstruction. Ketamine also sensitizes the
airway to irritable stimuli, and reflex lary ngeal closure (lary ngospasm) often occurs. A
dry ing agent such as atropine or gly copy rrolate should be given in conjunction with ketamine.
Page 492Finally, emergence from ketamine anesthesia often is characterized by
hallucinations and nightmares. The incidence of emergence reactions ranges from 10% to
30% in adult patients. Emergence reactions are much less common in children. The reason
for this difference is not known. Whatever the mechanism, the occurrence of these
emergence reactions can be reduced if a benzodiazepine such as diazepam or midazolam is
used.
Benzodiazepines are rarely used as the sole agents for radiotherapy in children.
Diazepam (Valium) is painful to administer when given intravenously, and its duration of
action exceeds the duration of most radiotherapy sessions.
Midazolam (Versed) is a water-soluble benzodiazepine that is two to three times as potent
as diazepam. It is short acting and not painful when given intravenously, but when used by
itself it does not produce satisfactory sedation for radiotherapy. A plateau in sedative effect
often accompanies its use, so additional dosing does not produce the desired clinical effect. In
the event that a patient receives an overdose of benzodiazepine or demonstrates an
exaggerated clinical effect, the drug can be displaced from its receptor by flumazenil, a
benzodiazepine antagonist. Flumazenil should not be used in patients who chronically receive
benzodiazepines, as it can precipitate acute withdrawal.
Barbiturates are sedative–hy pnotic drugs that depress the activity of the central nervous
sy stem (CNS). These drugs produce sleep within seconds of intravenous administration.
Awakening is rapid and occurs by redistribution of the drug from the CNS. Barbiturates are
given as an intravenous bolus or as a bolus followed by a continuous infusion. The short-acting
barbiturates thiopental and methohexital have been used in pediatric radiotherapy (24,25).
Side effects include apnea, hiccoughs, lary ngospasm, and paradoxical CNS excitation. Some
radiotherapists use droperidol, a buty rophenone derivative with pharmacologic actions similar
to those of haloperidol and phenothiazines, generally followed by pentobarbital for
intravenous anesthesia.
Narcotic analgesics produce sedation as a side effect. Potent sy nthetic opioids such as
fentany l, sufentanil, alfentanil, and remifentanil may be used to supplement intravenous
anesthesia, but their use is limited by their ability to depress respiration, cause chest wall
rigidity, and produce tolerance. These side effects of narcotics make opiate anesthesia
undesirable for radiotherapy. Radiotherapy is not a painful procedure; narcotics should not be
necessary. Mixed opiate agonist–antagonists such as nalbuphine and butorphanol are touted as
producing sedation and analgesia with less respiratory depression (plateau effect), and may
be useful adjuncts in anesthesia for radiotherapy.
Propofol is an intravenous anesthetic that has hy pnotic–sedative properties. The active
ingredient, 2,6-diisopropy lphenol, is formulated in an emulsion of soy bean oil, gly cerol, and
egg lecithin. This formulation gives it a milky -white appearance. It is a highly lipid-soluble
compound and therefore has a rapid distribution into the CNS and a rapid elimination, which
has made it a popular anesthetic agent for day surgery and short procedures. It can be given
via a central venous line or a peripheral intravenous catheter. When it is given peripherally,
pain on injection is common. This pain can be reduced by administering the drug with
lidocaine. Propofol has been increasingly used by anesthesiologists in pediatric radiotherapy
and, at some centers, is the drug-of-choice. It is given as an intermittent bolus or as a bolus
followed by continuous infusion. Awakening is rapid, and the incidence of side effects is low.
When it is administered as a rapid intravenous bolus, apnea and hy potension are common.
However, when the dosage is fractionated and administered slowly, spontaneous respiration
and blood pressure are preserved. Propofol appears to possess antiemetic properties, which
adds to its appeal.
Rapid and safe induction of anesthesia with propofol in children usually entails a loading
dose of 2.5 mg/kg administered intravenously. The dosage is higher in nonpremedicated
children. Maintenance of anesthesia is achieved by continuous infusion of 2.5 mg/kg/hr if it is
supplemented by analgesics and nitrous oxide. Tachy phy laxis with propofol is rare (26,27).
Fast awakening after the propofol infusion is stopped results from its short elimination half-life
and the lack of substantial accumulation during administration over a long period. The
elimination half-life after a single injection is even shorter in children than in adults.
Respiratory depression during injection of propofol anesthesia can occur primarily through
an overly rapid injection. Controlled administration of the induction dose, using an automatic
pump, guarantees a slow and steady injection. Clinically significant respiratory depression
during the maintenance phase of sedation can be avoided by stabilizing the infusion rate using
an automatic pump (28).
Scheiber et al. (29), from the University Hospital of Essen in Germany, reported 155
propofol anesthetic sessions performed on consecutive pediatric radiation therapy patients
with a mean age of 30 months. The mean duration of anesthesia was 18 minutes. There were
no clinically important complications involving respiration, circulation, or neurologic
functions except for one transient episode of desaturation managed by suctioning and change
in head position. Children awakened spontaneously at an average of 4 minutes after the
propofol infusion was discontinued. No tachy phy laxis or unpleasant side effects were
observed.
A lipid-based anesthetic agent such as propofol can support rapid microbial growth at
room temperature. Bennett et al. (30) documented the association of propofol with
postoperative infections. Eleven of 74 children receiving radiotherapy at Duke University
Medical Center in the 1990s who had a central venous line developed proven sepsis (15%)
with fever and a positive blood culture drawn through the central line. Of these 11 children, 8
had received prior chemotherapy (73%). Six of the 11 had been anesthetized with propofol
(55%), 4 with a short-acting barbiturate induction plus inhalation anesthetic (36%), and 1 with
inhalation anesthesia alone (9%). The pathogens cultivated from these 11 children included
Staphylococcus, Bacillus, Streptococcus, Enterobacter, and Candida (31). These cases
occurred prior to the addition of antimicrobial preservatives to propofol, which were added
by the manufacturer in response to such reports. One formulation of the drug (Diprivan)
contains EDTA; newer generic versions contain sodium metabisulfite or benzy l alcohol. Since
the addition of preservatives, there have been no documented postoperative infections
attributed to propofol. When infections do occur, they appear to be associated with a lapse in
aseptic technique.
Page 493There are four potential sources of central venous access colonization
producing sepsis: the skin insertion site, the catheter hub, hematogenous seeding of the
catheter, and infusate contamination such as might be caused by propofol (32). In the setting
of anesthesia for pediatric external beam radiotherapy, one is concerned about the possible
contamination of the catheter through repeated use by the anesthesiologist, as well as other
catheter-related complications, such as breakage to thrombosis. A more recent study of 170
patients undergoing daily radiation therapy demonstrated a 19.7% complication rate.
Peripherally inserted central catheter (PICC) lines had the highest complication rate at 38%,
central lines had a complication rate of 20.5%, and indwelling port-a cath lines a 13.6%
complication rate. Port-a caths were accessed following induction on Monday mornings, and
left accessed until Friday in this study. The authors recommend indwelling ports as the line of
choice in patients undergoing daily radiotherapy (33). It is well known that there is a high
incidence of central venous line sepsis in a variety of high-risk settings including patients
receiving chemotherapy or total parenteral nutrition, burn unit patients, and those in the
intensive care unit (31,32). The risk of sepsis with repeated catheter use in such settings ranges
from 5% to 29%. Therefore, though catheter infections should be minimized by strict
adherence to aseptic technique, there is alway s the potential for sepsis in the child whose
central venous line is accessed repeatedly, regardless of the anesthetic technique. The
pediatric radiation oncologist must work closely with the anesthesia team to be sure that the
appropriate equipment is provided in the radiation treatment area to assure an aseptic process
for drug administration.
Dexmedetomidine has become a popular agent for intravenous sedation and anesthesia
in pediatric patients. It is a highly specific alpha-2 adrenergic receptor agonist that provides
sedation with less respiratory depression than narcotics. Although apnea is possible, it
generally preserves minute ventilation and is considered a safer agent for sedation in patients
with potential respiratory compromise. The most common hemody namic effect in children
is brady cardia, which may require pharmacologic therapy with an anticholinergic agent such
as atropine or gly copy rrolate (34). Though no studies have y et evaluated the safety of daily
exposure to dexmedetomidine in children or adults, a case report describes the successful use
of dexmedetomidine as the sole sedative for 9 of 12 treatments in a 21-month-old undergoing
radiotherapy for a posterior fossa tumor (35). One disadvantage of dexmedetomidine
compared to propofol is its slow rate of onset.
SEDATION OR ANESTHESIA?
The minimum monitoring standards for all patients undergoing anesthesia in any setting
are continuous display of the electrocardiogram (ECG), arterial blood pressure and heart rate
determined and evaluated at least every 5 minutes, pulse oximetry, capnometry, and
monitoring of the fraction inspired oxy gen in the breathing circuit.
Provisions made for monitoring in radiotherapy suites include closed-circuit television
screens on which are display ed the patient and the oxy genation, ventilation, circulation, and
temperature monitors and/or leaded glass windows through which the patient and monitors
can be viewed while the radiation treatment is delivered (Fig. 21.5 ).
Figure 21.5 The laryngeal mask airway is a silicon tube. The distal end of the tube has an
elliptical-shaped cuff that, when correctly inserted and inflated, forms a low-pressure seal
around the larynx and allows spontaneous ventilation without the need for endotracheal
intubation. (Photographed by permission of Gensia, Inc., San Diego, CA.)
Early reports of anesthesia for radiotherapy relied on visual inspection of patient color as
a monitor of adequacy of oxy genation. However, the unreliability of direct observation for
detecting cy anosis is known (43). Pulse oximetry is an accurate, noninvasive, continuous
measure of arterial oxy gen saturation. A pulse oximeter is an optical sensor that measures the
concentration of oxy hemoglobin by transmitting red and infrared light through tissue beds
such as a finger, earlobe, or nose. The use of a pulse oximeter is mandatory for any patient
receiving sedative or anesthetic drugs. The Oxisensor (Nellcor, Inc.), a disposable pediatric
digit oxy gen transducer, can be used for these children. It is an expensive device, but with
proper handling it can be reused from day to day (32). The pediatric pulse oximeter using
Masimo Signal Extraction Technology (Masimo Corporation, Irvine, CA) may be more
sensitive than conventional pulse oximeters in detecting hy poxic events (44) (Fig. 21.6 ).
It is important to emphasize that in patients
receiving supplemental oxy gen, decreasing
oxy gen saturation as measured by a pulse
oximeter is a late sign of hy poventilation. How is
ventilation best monitored? The first report of
anesthesia for radiotherapy used continual visual
observation of the thorax and abdomen
combined with a wisp of cotton placed over the
mouth. The cotton fibers moved in and out with
inspiration and expiration, respectively,
amplify ing air movement. Amplifiers are used Figure 21.6 The anesthetized child is
because the anesthesiologist cannot be monitored, in the accelerator vault, with
phy sically present while radiation therapy is the electrocardiogram, pulse oximetry,
being delivered. While the anesthesiologist will and capnometry. Notice that the gas
rely on the oximeter, ECG, capnometry (vide delivery mask is well integrated into the
infra), and a video monitor tracing of respiration, radiotherapy head stabilization device.
several amplifiers of ventilation were described
for use in radiotherapy prior to the era of remote electronic monitoring. These amplifiers
may still be used, in conjunction with modern monitoring, to good effect. Visual amplifier
methods include attaching a cotton-tipped applicator to the thorax and observing via a closed-
circuit television monitor the excursions of the cotton tip with inspiration and expiration and
placing a small light box on the patient’s abdomen or chest and observing on the television
monitor the movement of the light bulb with each respiratory cy cle. Aural amplifiers allow
the anesthesiologist to hear the patient’s breath sounds from outside the treatment area. An
esophageal or precordial stethoscope can be connected to an audio amplifier, and the output
can be heard on a speaker or earphone.
Page 495Observation of the movements of the reservoir breathing bag by the
anesthesiologist is an excellent monitor of gas exchange. This technique is applicable to
patients anesthetized with inhalational agents whose tracheas are intubated, those who have an
LMA in place, or those who have a simple face mask applied over the nose and mouth. If the
breathing bag cannot easily be seen on the closed-circuit monitor or through the leaded glass
window, its movements can be amplified by a stick made of tongue blades. One end of the
stick is attached to the neck of the breathing bag with a piece of tape, and a flag of white paper
is placed at the opposite end of the stick. This long lever arm greatly accentuates the
movements of the breathing bag and serves as an amplifier of ventilation.
The gold standard for assessing ventilation is capnometry. Capnometry is the quantitative
measurement of the partial pressure of CO2 produced by the patient during the ventilatory
cy cle. Capnography is the continuous graphic display of CO2 concentration as a function of
time. End-tidal CO2 analy sis is a mean of assessing alveolar ventilation, airway patency, and
the functioning of the breathing circuit and ventilator. End-tidal CO2 monitoring has been
shown to be an effective monitor in pediatric anesthesia, capable of the early detection of
many potentially life-threatening events such as apnea, bronchospasm, and disconnections in
the breathing circuit (45).
The adequacy of circulatory function during the administration of anesthesia is assessed
by continuous display of the ECG and by measurement of blood pressure. Noninvasive,
automated oscillometric blood pressure determination (DINAMAP, Criti Kom, Inc., Tampa,
FL) is readily available and uniquely suited for remote monitoring of blood pressure. The
ECG and DINAMAP display s are viewed indirectly on the closed-circuit monitor or directly
through a leaded glass window if the radiotherapy suite is so equipped.
No matter how rigorous the adherence to recommendations and guidelines intended to
promote high-quality care, it is impossible to guarantee specific patient outcomes. The
provision of anesthesia for radiotherapy carries with it the additional challenge of remote
monitoring of patients whose airway s may be compromised not only by their underly ing
disease but also by the constraints of positioning for the procedure (Figs. 21.7 and
21.8 ). A postanesthetic recovery area must be established for care following the
anesthetic. Nursing staff trained in recovery room nursing need be present to assist with
emergence from anesthesia. Administration of an antiemetic drug such as ondansetron is
considered in all patients as radiation therapy can promote nausea (46).
Figure 21.7 A: The face mask is secured with straps and
provides a stable, unobstructed airway. End-tidal CO2 is
monitored via sidestream capnography. The pediatric pulse
oximetry probe fits most children and is reusable. B: The entire
body is stabilized in a polyurethane custom foam mold.
Figure 21.8 Monitoring from immediately outside the
treatment room is accomplished with a video screen displaying
the child, an intercom system for audio, and a video monitor
displaying the electrocardiogram, respiratory wave, and fraction
of inspired oxygen. An additional camera allows viewing of the
patient simultaneously.
Figure:
The laryngeal mask airway is a silicon tube. The distal end of the tube has an elliptical-shaped
cuff that, when correctly inserted and inflated, forms a low-pressure seal around the larynx
and allows spontaneous ventilation without the need for endotracheal intubation.
Page 496Radiotherapy is used to treat several different pediatric malignancies. In the Duke
series, the diagnoses leading to treatment with external beam radiotherapy under anesthesia
were primary CNS tumor (28%), retinoblastoma (26%), neuroblastoma (18%), acute
leukemia (9%), rhabdomy osarcoma (7%), Wilms tumor (5%), Langerhans cell histiocy tosis
(4%), and other (3%) (Fig. 21.9 ). It is not surprising that the diagnoses leading to
radiotherapy under anesthesia differ somewhat from the most common diagnoses of cancer
in childhood. Leukemia is an uncommon indication for radiotherapy under anesthesia
because it is, in general, a malignancy of older children, and the role of radiation therapy in
leukemia is limited. Diseases associated with y ounger children for which radiotherapy is
more frequently used dominate the list (31). Many of these malignancies have implications
for the pediatric anesthesiologist. Children with supratentorial brain tumors can have elevated
ICP. Management of anesthesia for patients with elevated ICP includes the avoidance of
drugs that can raise ICP, such as ketamine. Anesthetic techniques that result in elevations in
arterial CO2 tension can produce intracranial hy pertension by increasing cerebral blood flow.
Some neuroblastomas secrete catecholamines and cause sy stemic hy pertension. Blood
pressure elevations are associated with abdominal palpation. This problem is rare in pediatric
radiotherapy because the tumor is not manipulated—the most common indications for
radiotherapy in neuroblastoma are treatment of the tumor bed as part of a high-dose
chemotherapy /marrow rescue procedure for advanced disease or for the palliative treatment
of metastases.
Wilms tumors often are massive and can impair ventilation by increasing intra-
abdominal pressure. An occasional child with a Wilms tumor will undergo endotracheal
intubation for respiratory failure before presenting to the radiation oncologist for
radiotherapy. These tumors can also extend into the inferior vena cava and renal vein,
producing renovascular distortion and sy stemic hy pertension.
Children with Hodgkin disease, non-Hodgkin ly mphomas, and T-cell acute ly mphoblastic
leukemia can present with anterior mediastinal masses. These masses can produce tracheal
compression and impair ventilation. They can also produce superior vena cava sy ndrome by
compressing the great veins. Some patients with anterior mediastinal masses are referred to
the pediatric radiation oncologist for external beam therapy before tissue biopsy. Radiation
therapy before tissue biopsy is recommended in some of these patients because the induction
of anesthesia for surgery in some patients with anterior mediastinal masses can be fatal.
Death on induction of general anesthesia in these patients is caused by either the inability to
ventilate because of airway compression or the inability of the heart to circulate blood
because of tumor encroachment on the right heart or pulmonary circulation (47). Prospective
identification of children with anterior mediastinal masses who are at risk for
cardiorespiratory collapse on induction of general anesthesia involves a thorough history and
phy sical examination aimed at eliciting signs and sy mptoms of airway and cardiovascular
impairment. Laboratory studies useful in assessing preanesthetic risk include a chest
radiograph, computed tomography scan, and upright and supine flow–volume loops. The
pediatric radiotherapist may treat patients with anterior mediastinal masses for whom the
risks of general anesthesia are felt to outweigh the benefits of obtaining tissue before the
institution of therapy. These patients should not receive anesthesia or sedation.
Page 497In addition to these considerations, the pediatric anesthesiologist must consider
the associated implications of treating malignancy in children. These implications include the
cardiac, hematologic, pulmonary, immunologic, and neurologic impairments caused by
chemotherapy (45).
Anemia is one of the most common problems in children with cancer. Anemia
decreases oxy gen delivery to the tissues. Oxy gen delivery is the product of the arterial
oxy gen content and the cardiac index. If oxy gen delivery to the tissues is inadequate, organ
sy stem failure occurs. The minimum acceptable hemoglobin value in anesthetized children is
unknown. Hemoglobin values as low as 7 g/dL may be adequate if the patient has normal
cardiovascular compensatory mechanisms. However, many patients cannot compensate for
low levels of hemoglobin because they have
chemotherapy -induced my ocardial dy sfunction.
Children receiving sy stemic chemotherapy
in concert with radiation therapy may be
immunocompromised. Consequently, they may
be more prone to upper respiratory tract
infections, a condition which may increase the
risk of anesthesia significantly, especially when
an airway device such as an LMA is used (48).
Patients should be assessed before each
anesthetic for presence of fever, cough, or
increased mucus production, all of which are
associated with increased complications.
Children with moderate to severe sy stemic
illness should likely delay treatment for a day or
two to lessen the risk of general anesthesia (49).
The anthracy cline antibiotic
chemotherapeutic agents doxorubicin and
daunorubicin are cardiotoxic. These drugs have
both an acute and a chronic effect. Acute
toxicity manifests as rhy thm and conduction
disturbances such as supraventricular
tachy cardia, ventricular ectopic beats, and heart
block. Chronic toxicity manifests as a
cardiomy opathy, which can progress to left
ventricular failure in 2–10% of patients. Factors
that increase the risk of anthracy cline
cardiotoxicity include dosages greater than 550
mg/m 2, age y ounger than 1 y ear, concurrent
use of other chemotherapeutic agents such as
cy clophosphamide and cisplatin, and a history of
mediastinal irradiation.
Figure 21.9 A–C: The nurse is at the
Pulmonary toxicity occurs in 5–10% of
bedside in the recovery area in the
patients treated with the antibiotic
radiotherapy department. Oxygen,
chemotherapeutic agent bleomy cin. Bleomy cin
suction, and pulse oximetry monitoring
produces interstitial pulmonary fibrosis, which
are immediately available.
results in restrictive lung disease. The damage is
thought to be caused by oxy gen free radical
formation. The role of exogenous oxy gen in promoting the pulmonary toxicity of bleomy cin
is controversial. However, it is prudent to avoid inspired oxy gen concentrations >28% when
anesthetizing patients who have been treated with bleomy cin, provided that they maintain
satisfactory levels of arterial oxy gen tension.
On rare occasions, the child undergoing anesthesia for radiotherapy has received a prior
course of irradiation to the head and neck or lungs. The anesthesiologist should be aware that
these children may be at higher risk for lary ngeal edema after instrumentation of the airway
and for difficulty in maintaining oxy genation (50,51,52,53).
Figure:
A–C: The nurse is at the bedside in the recovery area in the radiotherapy department.
Oxygen, suction, and pulse oximetry monitoring are immediately available.
REFERENCES
1. Page 498 Harrison GG, Bennet MB. Radiotherapy without tears. Br J Anaesth.
1963;35(11):720–723.
2. Slifer KJ. A video sy stem to help children cooperate with motion control for radiation
treatment without sedation. J Pediatr Oncol Nurs. 1996;13(2):91–97.
3. Slifer KJ, Bucholtz JD, Cataldo MD. Behavioral training of motion control in y oung
children undergoing radiation treatment without sedation. J Pediatr Oncol Nurs.
1994;11(2):55–63.
4. Slifer KJ, Cataldo MF, Cataldo MD, et al. Behavior analy sis of motion control for
pediatric neuroimaging. J Appl Behav Anal. 1993;26(4):469–470.
5. Haeberli S, Grotzer MA, Niggli FK, et al. A psy choeducational intervention reduces the
need for anesthesia during radiotherapy for y oung childhood cancer patients. Radiat
Oncol. 2008;3:17.
6. McMullen KP, Hanson T, Bratton J, Johnstone PAS. Parameters of anesthesia/sedation in
children receiving radiotherapy. Radiation Oncol. 2015;10:65.
7. Practice guidelines for preoperative fasting and the use of pharmacologic agents to
reduce the risk of pulmonary aspiration: application to healthy patients undergoing
elective procedures: a report by the American Society of Anesthesiologist Task Force on
preoperative fasting. Anesthesiology. 1999;90(3):896–905.
8. Sarner JB, Levine M, Davis PJ, et al. Clinical characteristics of sevoflurane in children—
a comparison with halothane. Anesthesiology. 1995;82(1):38–46.
9. Eger EI II. New inhaled anesthetics. Anesthesiology. 1994;80(4):906–922.
10. Eger EI II. New drugs in anesthesia. Int Anesthesiol Clin. 1995;33(1):61–80.
11. Lerman J. Sevoflurane in pediatric anesthesia. Anesth Analg. 1995;81(suppl 6):S4–S10.
12. Smith I, Nathanson MH, White PF. The role of sevoflurane in outpatient anesthesia.
Anesth Analg. 1995;81(suppl 6):S67–S72.
13. Grebenik CR, Ferguson C, White A. The lary ngeal mask airway in pediatric
radiotherapy. Anesthesiology. 1990;72(3):474–477.
14. Morris GN, Marjot R. Lary ngeal mask airway performance: effect of cuff deflation
during anaesthesia. Br J Anaesth. 1996;76(3):456–458.
15. Moy lan SL, Luce MA. The reinforced lary ngeal mask airway in paediatric
radiotherapy. Br J Anaesth. 1993;71(1):172.
16. Wilson IG. The lary ngeal mask airway in paediatric practice. Br J Anaesth.
1993;70(2):124–125.
17. Jacobs JR, Reves JG, Glass PS. Rationale and technique for continuous infusions in
anesthesia. Int Anesthesiol Clin. 1991;29(4):23–38.
18. Amberg HL, Gordon G. Low-dose intramuscular ketamine for pediatric radiotherapy : a
case report. Anesth Analg. 1976;55(1):92–94.
19. Bennett JA, Bullimore JA. The use of ketamine hy drochloride anaesthesia for
radiotherapy in y oung children. Br J Anaesth. 1973;45(2):197–201.
20. Edge WG, Morgan M. Ketamine and paediatric radiotherapy. Anaesth Intensive Care.
1977;5(2):153–156.
21. Soy annwo OA, Amanor-Boadu SD, Adenipekun A, et al. Ketamine anaesthesia for
y oung children undergoing radiotherapy. West Afr J Med. 2001;20(2):136–139.
22. Cronin MM, Bousfield JD, Hewett EB, et al. Ketamine anaesthesia for radiotherapy in
small children. Anaesthesia. 1972;27(2):135–142.
23. Worrell JB, Mccune WJ. A case report: the use of ketamine and midazolam intravenous
sedation for a child undergoing radiotherapy. AANA J. 1993;61(1):99–102.
24. Menache L, Eifel PJ, Kennamer DL, et al. Twice-daily anesthesia in infants receiving
hy perfractionated irradiation. Int J Radiat Oncol Biol Phys. 1990;18(3):625–629.
25. Metriy akool K. Methohexital as alternative to propofol for intravenous anesthesia in
children undergoing daily radiation treatment: a case report. Anesthesiology.
1998;88(3):821–822.
26. Buehrer S, Immoos S, Frei M, et al. Evaluation of propofol for repeated prolonged deep
sedation in children undergoing proton radiation therapy. Br J Anaesth. 2007;99(4):556–
560.
27. Keidan I, Perel A, Shabtai EL, et al. Children undergoing repeated exposures for
radiation therapy do not develop tolerance to propofol: clinical and bispectral index data.
Anesthesiology. 2004;100(2):251–254.
28. Seiler G, De Vol E, Khafaga Y, et al. Evaluation of the safety and efficacy of repeated
sedations for the radiotherapy of y oung children with cancer: a prospective study of
1033 consecutive sedations. Int J Radiat Oncol Biol Phys. 2001;49(3):771–783.
29. Scheiber G, Ribeiro FC, Karpienski H, et al. Deep sedation with propofol in preschool
children undergoing radiation therapy. Paediatr Anaesth. 1996;6(3):209–213.
30. Bennett SN, McNeil MM, Bland LA, et al. Postoperative infections traced to
contamination of an intravenous anesthetic, propofol. N Engl J Med. 1995;333(3):147–
154.
31. Fortney JT, Halperin EC, Hertz CM, et al. Anesthesia for pediatric external beam
radiation therapy. Int J Radiat Oncol Biol Phys. 1999;44(3):587–591.
32. Daghistani D, Horn M, Rodriguez Z, et al. Prevention of indwelling central venous
catheter sepsis. Med Pediatr Oncol. 1996;26(6):405–408.
33. Bratton J, Johnstone PAS, McMullen KP. Outpatient managemtns of vascular access
devices in children receiving radiotherapy : Complications and morbidity. Pediatr Blood
Cancer. 2014;61:499–501.
34. Tobias JD. Dexmedetomidine: applications in pediatric critical care and pediatric
anesthesiology. Pediatr Crit Care Med. 2007;8(2):115–131.
35. Shukry M, Ramadhy ani U. Dexmedetomidine as the primary sedative agent for brain
radiation therapy in a 21-month old child. Paediatr Anaesth. 2005;15(3):241–242.
36. Anghelescu DL, Burgoy ne LL, Liu W, et al. Safe anesthesia for radiotherapy in pediatric
oncology : St. Jude Children’s Research Hospital Experience, 2004–2006. Int J Radiat
Oncol Biol Phys. 2008;71(2):491–497.
37. Buchsbaum JC, McMullen KP, Douglas JG, et al. Repetitive pediatric anesthesia in a non-
hospital setting. Int J Radiat Oncol Biol Phys. 2013;85(5):1296–1300.
38. Owusu-Agy emang P, Grosshans D, Arunkumar R, et al. Non-invasive anesthesia for
children undergoing proton radiation therapy. Radiother Oncol. 2014;111:30–34.
39. American Academy of Pediatrics Committee on Drugs: Guidelines for monitoring and
management of pediatric patients during and after sedation for diagnostic and
therapeutic procedures. Pediatrics.1992;89(6 pt 1):1110–1115.
40. Bucholtz JD. Cost savings in pediatric monitoring during sedation for radiation therapy.
Oncol Nurs Forum. 1991;18(7):1246.
41. Bucholtz JD. Issues concerning the sedation of children for radiation therapy. Oncol Nurs
Forum. 1992;19(4):649–655.
42. ASA house of delegates, C.O.S.A.P.P. Standards for basic anesthetic monitoring
(American Society of Anesthesiologists (ASA), approved 1986 and last amended in
2004).
43. Comroe JHJ, Botelho S. The reliability of cy anosis in the recognition of arterial
hy poxemia. Am J Med Sci. 1947;214:1–6.
44. Malviy a S, Rey nolds PI, Voepel-Lewis T, et al. False alarms and sensitivity of
conventional pulse oximetry versus the masimo set technology in the pediatric
postanesthesia care unit. Anesth Analg. 2000;90(6):1336–1340.
45. Tobias JD. Special considerations for the pediatric oncology patient. In: Berry FA,
Steward DJ, eds. Pediatrics for the Anesthesiologist. New York, NY: Churchill
Livingstone; 1993:287–303.
46. Harris EA. Sedation and anesthesia options for pediatric patients in the radiation
oncology suite. Int J Pediatr. 2010;2010:870921.
47. Keon TP. Death on induction of anesthesia for cervical node biopsy. Anesthesiology.
1981;55(4):471–472.
48. von Ungern-Sternberg BS, Boda K, Schwab C, et al. Lary ngeal mask airway is
associated with an increased risk of adverse respiratory events in children with recent
upper repiratory tract infections. Anesthesiology. 2007;107(5):714–719.
49. McFay den JG, Pelly N, Orr RJ. Sedation and anesthesia for the pediatric patient
undergoing radiation therapy. Curr Opin Anaesthesiol. 2011;24:433–438.
50. Ginsberg RJ. Surgical considerations after preoperative treatment. Lung Cancer.
1994;10(suppl 1):S213–S217.
51. Glauber DT, Audenaert SM. Anesthesia for children undergoing craniospinal
radiotherapy. Anesthesiology. 1987;67(5):801–803.
52. Mark RJ, Bailet JW, Poen J, et al. Postirradiation sarcoma of the head and neck. Cancer.
1993;72(3):887–893.
53. Mendel P, Anaes FC, Bristow A. New methods of dealing with the complications of
panendoscopy. J Laryngol Otol. 1992;106(10):903–904.
CH A P TER 22
Psychosocial Aspects of Radiotherapy for
the Child and Family with Cancer
Shulamith Kreitler, Myriam Weyl Ben Arush, Elena Abigail Krivoy, Hana
Golan, Michal Yalon Oren, and Amos Toren
Page 499As cure can be achieved in a large majority of pediatric cancer patients, long-term
effects and quality of life of the survivors are nowaday s the principal challenges to pediatric
oncologists. In recent y ears, it has become increasingly clear that the psy chosocial effects of
a treatment are an integral part of the treatment and should be considered when evaluating its
overall effect and its impact on the patient’s quality of life.
The rate of pediatric cancer survival has reached about 80% and is increasing. Health
professionals, parents, and pediatric patients are increasingly aware of the effects of
treatment. Hence, there is a growing body of studies of the psy chosocial correlates and
effects of pediatric cancer treatments. Some of the effects are direct, while others are
indirect and result from a variety of effects of radiation therapy (RT) on phy sical functions.
COGNITIVE EFFECTS OF RADIOTHERAPY
A large number of studies deal with investigating and assessing the cognitive effects of
radiotherapy. The bulk of these studies focus on the cognitive effects of cranial radiotherapy
(CRT), since it is in this domain that cognitive effects are likely to be most easily detectable.
Up to 40% of childhood cancer survivors who were exposed to CRT may experience
neurocognitive impairment in one or more specific domains (1). Recent y ears have
witnessed a remarkable advancement in the number and quality of studies focusing on
cognitive effects following CRT (2). This surge of interest has led to an increase in
information about the kind of cognitive effects of RT as well as the relations between these
effects and various characteristics of RT. Nevertheless, the findings need to be considered
with caution for two main reasons. First, although in this chapter special care was taken to
include only studies that refer directly to the effects of RT per se, it is likely that many of the
children participating in these studies did not undergo exclusively RT but in addition surgery
and chemotherapy that could have also impacted cognition in unspecified way s. Second,
many of the children treated with RT got the treatment as a cure for brain tumors, which
could have affected cognition independently of the RT.
The effects of radiation on the brain are usually described in terms of three stages: the
acute phase, often associated with a sudden neurologic deterioration, the subacute phase (or
early delay ed, 2–6 weeks after radiotherapy ) when the “somnolence sy ndrome” may occur
attended by fatigue and a transient exaggeration of the neurologic signs, and, finally, the late
phase in which various gradual neurocognitive deficits show up (3,4). Most of the reported
findings refer to the third phase.
Effects of RT on Intelligence
A large number of studies report the effects of RT on intelligence (Table 22.1 ). The studies
vary greatly in the characteristics of the samples and the administered doses of RT. However,
the majority support the general conclusion that CRT brings about a decline of about 5–20
points in IQ, which according to many studies, but not all, tends to be more pronounced if the
RT dose has been higher and the child who got RT is y ounger. The decline in IQ persists over
time, even to over 10 y ears after RT. There is evidence that the decline in IQ may be due at
least partly to a decreased rate of acquiring new information (24).
Table 22.1 Studies about the Effects of RT on IQ Scores
In view of the difficulties and crises that children undergo in the course of the disease, the
treatments, and their sequelae, it can be expected that they may suffer from difficulties in
behavioral adjustment. A body of studies shows that children who had undergone RT tend to
have problems in two major domains: in social adjustment and in mood (Table 22.2 ). The
problems persist bey ond the termination of treatment. It has also been noted that the child’s
behavioral adjustment depends in addition on stress in the family and coping of the parents
(59).
Table 22.2 Behavioral and Social Effects of RT
Depression seems to be the most salient psy chiatric sy mptom that persists even 10 y ears
after termination of treatment in children treated with RT (60,61,62), particularly CRT (63).
It may be assumed that body image defects may play an important role in the child’s
adjustment. Few studies dealt mainly with this issue. In one study, 110 survivors of ALL
disease who were free of disease for at least 1 y ear were administered a psy chosocial
assessment battery by telephone. Those who received CRT had poorer self-image in regard
to their body than the others (64). Notably, tumors of CNS treated by CRT may cause
endocrine morbidities attended by negative effects on growth, which may cause in the
pediatric patients concerns with body image appearance and composition (65).
It seems that many of the pediatric cancer survivors are at risk for having problems in
social adjustment and interpersonal relations in general. Given the stability of poor peer
relationships and known linkages between peer problems and subsequent academic and
psy chiatric difficulties, it is evident that more attention should be devoted to the social
adjustment of the pediatric cancer patients so as to diagnose as early as possible likely
problems and launch intervention projects for their minimization.
Figure: Behavioral and Social Effects of RT
CHILDREN’S DISTRESS IN THE COURSE OF RT
There are several obvious reasons why it may be expected that children undergoing RT are
likely to be distressed and anxious. First, the treatment is given under special unfamiliar
conditions to the child, which differ from those of chemotherapy ; second, the child stay s
alone during the treatment; and third, the child is required not to move during the treatment.
Anesthesia that is often used for the alleviation of RT-related anxiety may have various
shortcomings, such as increased risks for medical complications, and difficulties in eating and
sleeping (66) (Fig. 22.1 ).
One study focused on the distress instead of children prior to their first RT experience
which was to be a simulation session in which no RT was administered but the procedural
demands and overall experience were identical to actual RT (67). The participants were 80
pediatric cancer children with various diagnoses, 2–7 y ears old, with no or mild degrees of
functional impairment, about to receive RT in an outpatient clinic. After explaining the study,
and before the simulation was introduced, information about distress in the children was
obtained directly from the children through a behavioral observational checklist and by
checking their heart rate, and indirectly from the parents by means of questionnaires that
they were asked to fill (State-Trait Anxiety Inventory and a questionnaire about RT). The
findings showed that 65% of children manifested at least some degree of anticipatory
behavioral distress, while 16% manifested high distress both in their behavior and heart rate.
The major factors that contributed to the child’s high level of distress were y ounger age of the
child and higher expectations of the parents that the child would experience distress, which in
turn was at least partly a function of the child’s y oung age. Notably, the parents’ anxiety levels
were unrelated to their expectations of the child’s distress reactions.
Page 504A further study (68) with a similar sample of 79 children applied anesthesia as
a measure of distress prior to the simulation session, in addition to the above-described
measures of Observation Scale of Behavioral Distress and heart rate. At simulation, 62% of
patients required pharmacologic intervention for completing the procedure. Further, y ounger
age and higher behavioral distress predicted the use of anesthesia for the simulation. Higher
baseline heart rate predicted lower behavioral distress. Notably, a prone position during
simulation was related to increases in behavioral distress and higher heart rate.
In sum, the reported studies provide clear evidence that pediatric cancer patients are
prone to experience distress prior to the simulation session, in the simulation session, and in the
course of administration of RT proper. These findings confirm a host of informal observations
of health professionals about the distress of children undergoing RT. Further supporting
evidence comes from studies showing that children treated with RT may suffer from
depression at the time of treatment and later (62,63).
Page 508The major reviewed domains include cognitive effects, behavioral and social
effects, and distress in the course of RT, complemented by a more recent concern with
quality of life. The major cognitive effects of CRT and RT are declines in general intelligence
and specific deficits in nonverbal and verbal cognitive functions, mainly memory and
attention, that increase with time since RT and are especially notable in children who have
received RT at a y ounger age. The dose and location of RT seem to play a role in determining
the degree of cognitive impairment. Positive results of some cognitive intervention programs
are a potentially important indication of arresting the cognitive decline following RT. Yet,
there are indications that overall academic performance may be a function of factors
additional to the cognitive deficits and sometimes overriding the deficits. The major social
and behavioral effects concern interpersonal relations and possible difficulties in social
adjustment. Children are conscious of short-term and long-term effects of RT, and emphasize
in particular the risks for fertility, body image changes, and mood swings including
depression. Various programs for alleviating the distress of children during the administration
of RT are underway. Yet, it appears that children still suffer unduly in the course of RT,
mainly because of the need to be alone and without moving in the treatment room.
Psy chosocial interventions designed to alleviate distress in the course of RT and also after
termination of treatment are highly recommended for improving the children’s quality of life
during the course of treatment and in later y ears.
REFERENCES
1. Krull KR, Gioia G, Ness KK, et al. Reliability and validity of the childhood cancer
survivor study neurocognitive questionnaire. Cancer. 2008;113:2188–2197.
2. Ris MD. Lessons in pediatric neuropsy cho-oncology : what we have learned since
Johnny Gunther. J Pediatr Psychol. 2007;32:1029–1037.
3. Moore BD. Neurocognitive outcomes in survivors of childhood cancer. J Pediatr
Psychol. 2005;30:51–63.
4. Mulhern RK, Reddick WE, Palmer SL, et al. Neurocognitive deficits in medulloblastoma
survivors and white matter loss. Ann Neurol. 1999;46:834–841.
5. Sugita Y, Kobay ashi S, Uegaki M, et al. [Assessment of functional status in children with
brain tumors]. No Shinkei Geka. 1987;15:643–649.
6. Mulhern RK, Hancock J, Fairclough D, et al. Neuropsy chological status of children
treated for brain tumors: a critical review and integrative analy sis. Med Pediatr Oncol.
1992;20:181–191.
7. Dowell RE Jr, Copeland DR, Francis DJ, et al. Absence of sy nergistic effects of CNS
treatments on neuropsy chologic test performance among children. J Clin Oncol.
1991;9:1029–1036.
8. Schatz J, Kramer JH, Ablin A, et al. Processing speed, working memory, and IQ: a
developmental model of cognitive deficits following cranial radiation therapy.
Neuropsychology. 2000;14:189–200.
9. Mulhern RK, Merchant TE, Gajjar A, et al. Late neurocognitive sequelae in survivors of
brain tumors in childhood. Lancet Oncol. 2004;5:399–408.
10. Harila MJ, Winqvist S, Lanning M, et al. Progressive neurocognitive impairment in
y oung adult survivors of childhood acute ly mphoblastic leukaemia. Pediatr Blood
Cancer. 2009;53:156–161.
11. Palmer SL, Gajjar A, Reddick WE, et al. Predicting intellectual outcome among
children treated with 35–40 Gy craniospinal irradiation for medulloblastoma.
Neuropsychology. 2003;17:548–555.
12. Ily eskoski I, Pihko H, Wiklund T, et al. Neurologic late effects in children with malignant
brain tumors treated with surgery, radiotherapy and “8 in 1” chemotherapy.
Neuropediatrics. 1996;27:124–129.
13. Mabbott DJ, Penkman L, Witol A, et al. Core neurocognitive functions in children treated
for posterior fossa tumors. Neuropsychology. 2008;22:159–168.
14. Reinhardt D, Thiele C, Creutzig U. [Neuropsy chological sequelae in children with AML
treated with or without prophy lactic CNS-irradiation]. Klin Paediatr. 2002;214:22–29.
15. Kolotas C, Daniel M, Demetriou L, et al. Long-term effects on the intelligence of
children treated for acute ly mphoblastic leukemia. Cancer Invest. 2001;19:581–587.
16. Fossen A, Abrahamsen TG, Storm-Mathisen I. Psy chological outcome in children
treated for brain tumor. Pediatr Hematol Oncol. 1998;15:479–488.
17. Bhatia S, Landler W. Evaluating survivors of pediatric cancer. Cancer J. 2005;1:340–354.
18. Spiegler BJ, Bouffet E, Greenberg ML, et al. Change in neurocognitive functioning after
treatment with cranial radiation in childhood. J Clin Oncol. 2004;22:706–713.
19. Monleon BMC, Andreu LJA, Estelles SII, et al. [Psy chological sequelae in long term
cancer survivors]. An Esp Pediatr. 2000;3:553–560.
20. Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsy chologic functioning of survivors
of childhood medulloblastoma randomized to receive conventional or reduced-dose
craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol. 1998;16:1723–
1728.
21. Halberg FE, Wara WM, Fippin LF, et al. Low-dose craniospinal radiation therapy for
medulloblastoma. Int J Radiat Oncol Biol Phys. 1991;20:651–654.
22. Kramer JH, Crittenden MR, Halberg FE, et al. A prospective study of cognitive
functioning following low-dose cranial radiation for bone marrow transplantation.
Pediatrics. 1992;90:447–449.
23. Ky ung JA, Yoo SJ, Ki WS, et al. Health-related quality of life and cognitive functioning
aton-and off-treatment periods in children aged between 6-13 y ears old with brain
tumors: a prospective longitudinal study. Yonsei Med J. 2013;54:306–314.
24. Palmer SL, Goloubeva O, Reddick WE, et al. Patterns of intellectual development in long
term survivors of pediatric medulloblastoma: a longitudinal analy sis. J Clin Oncol.
2001;19:2302–2308.
25. Askins MA, Moore BD III. Preventing neurocognitive late effects in childhood cancer
survivors. J Child Neurol. 2008;23:1160–1171.
26. Monje M. Cranial radiation therapy and damage to hippocampal neurogenesis. Dev
Disabil Res Rev. 2008;14:238–242.
27. Conklin HM, Li C, Xiong X, et al. Predicting change in academic abilities after
conformal radiation therapy for localized ependy moma. J Clin Oncol. 2008;26:3965–
3970.
28. Mulhern RK, Palmer SL, Merchant TE, et al. Neurocognitive consequences of risk-
adapted therapy for childhood medulloblastoma. J Clin Oncol. 2005;20:5511–5519.
29. Mabbott DJ, Spiegler BJ, Greenberg ML, et al. Serial evaluation of academic and
behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol.
2005;23:2256–2263.
30. Ribi K, Relly C, Landolt MA, et al. Outcome of medulloblastoma in children: long-term
complications and quality of life. Neuropediatrics. 2005;36:357–365.
31. Shah AJ, Epport K, Azen C, et al. Progressive declines in neurocognitive function among
survivors of hematopoietic stem cell transplantation for pediatric hematologic
malignancies. J Pediatr Hematol Oncol. 2008;30:411–418.
32. Butler RW, Hill JM, Steinherz PG, et al. Neuropsy chologic effects of cranial irradiation,
intrathecal methotrexate, and sy stemic methotrexate in childhood cancer. J Clin Oncol.
1994;12:2621–2629.
33. Page 509 Massimo LM, Wiley TJ, Bonassi S, et al. Longitudinal psy chosocial outcomes
in two cohorts of adult survivors from childhood acute leukaemia treated with or without
cranial radiation. Minerva Pediatr. 2006;58:1–7.
34. Copeland DR, DeMoor C, Moore BD. Neurocognitive development of children after a
cerebellar tumor in infancy : a longitudinal study. J Clin Oncol. 1999;17:3476–3486.
35. Mulhern RK, Palmer SL, Rddick WE, et al. Risks of y oung age for selected
neurocognitive deficits in medulloblastoma are associated with white matter loss. J Clin
Oncol. 2001;19:472–479.
36. Kiehna EN, Mulhern RK, Li C, et al. Changes in attentional performance of children and
y oung adults with localized primary brain tumors after conformal radiation therapy. J
Clin Oncol. 2006;24:5283–5290.
37. Papazoglou A, King TZ, Morris RD, et al. Attention mediates radiation’s impact on daily
living skills in children treated for brain tumors. Pediatr Blood Cancer. 2008;50:1253–
1257.
38. Netson KL, Conklin HM, Wu S, et al. A 6-y ears investigation of children’s adaptive
functioning following conformal radiation therapy for localized ependy moma. Int J
Radiat Oncol Biol Phys. 2012;84:217–223.
39. Landau E, Boop FA, Conklin HM, et al. Supratentorial ependy moma: disease control,
complications, and functional outcomes after irradiation. J Radiat Oncol Biol Phys.
2013;85:e193–e199.
40. Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine,
neurocognitive and visual profiles of proton radiation for pediatric low-grade gliomas. J
Radiat Oncol Biol Phys. 2014;89:1060–1068.
41. Merchant TE, Sharma S, Xiong X, et al. Effect of cerebellum radiation dosimetry on
cognitive outcomes in children with infratentorial ependy moma. Int J Radiat Oncol Biol
Phys. 2014;90:547–553.
42. Armstron CL, Gy ato K, Avadalla AW, et al. A crtical review of the clinical effects of the
therapeutic irradiation damage in the brain: the roots of controversy. Neuropsychol Rev.
2004;14:65–86.
43. Hoang D, Pagnier A, Kuichardet A, et al. Cognitive disorders in pediatric
medulloblastoma: what neuroimaging has to offer. J Neurosurg Pediatr. 2014;14:136–
144.
44. Palmer SL, Glass JO, Li Y, et al. White matter integrity is associated with cognitive
processing in patients treated for a posterior foss brain tumor. Neuro Oncol.
2012;14:1185–1193.
45. Kristin J, Redmond E, Mahone M, et al. Association between radiation dose to neuronal
projenitor cell niches and temporal lobes and performance on neuropsy chological
testing in children: a prospective study. Neuro Oncol. 2013;15:360–369.
46. Trautman PD, Erickson C, Shaffer D, et al. Prediction of intellectual deficits in children
with acute ly mphoblastic leukemia. J Dev Behav Pediatr. 1988;9:122–128.
47. Whitt JK, Wells RJ, Lauria MM, et al. Cranial radiation in childhood acute ly mphocy tic
leukemia. Neuropsy chologic sequelae. Am J Dis Child. 1984;138:730–736.
48. Nelson KL, Conklin HM, Wu S, et al. Longitudinal investigation of adaptive functioning
following conformal irradiation for pediatric phary ngioma and low-grade glioma. Int J
Radiat Oncol Biol Phys. 2013;85:1301–1306.
49. Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents
surviving cancer. J Pediatr Psychol. 2005;30:65–78.
50. Tallal P, Merzenich MM, Miller SL, et al. Language learning impairments: integrating
basic science, technology, and intervention. Exp Brain Res. 1998;123:210–219.
51. Kreitler S, Yalon M, Margalit K, et al. A meaning-basedintervention for pediatric brain
cancer patients. [Study in progress.]
52. Carpentieri SC, Mulhern RK, Douglas S, et al. Behavioral resiliency among children
surviving brain tumors: a longitudinal study. J Clin Child Psychol. 1993;22:236–246.
53. LeBaron S, Zeltzer PM, Zeltzer LK, et al. Assessment of quality of survival in children
with medulloblastoma and cerebellar astrocy toma. Cancer. 1988;62:179–185.
54. Mulhern RK, Carpentieri S, Shema S, et al. Factors associated with social and behavioral
problems among children recently diagnosed with brain tumor. J Pediatr Psychol.
1993;18:339–350.
55. Radcliffe J, Bennett D, Kazak AE, et al. Adjustment in childhood brain tumor survival:
child, mother, and teacher report. J Pediatr Psychol. 1996;21:529–539.
56. Seaver E, Gey er R, Sulzbacher S, et al. Psy chosocial adjustment in long-term survivors
of childhood medulloblastoma and ependy moma treated with craniospinal irradiation.
Pediatr Neurosurg. 1994;20:248–253.
57. Vannatta K, Gerhardt CA, Wells RJ, et al. Intensity of CNS treatment for pediatric
cancer: prediction of social outcomes in survivors. Pediatr Blood Cancer. 2007;49:716–
722.
58. Maurice-Stam H, Grootenhuis MA, Caron HN, et al. Course of life of survivors of
childhood cancer is related to quality of life in y oung adulthood. J Pychosoc Oncol.
2007;25:43–58.
59. Carlson-Green B, Morris RD, Krawiecki N. Family and illness predictors of outcome in
pediatric brain tumors. J Pediatr Psychol. 1995;20:769–784.
60. Beneddito Monleon MC, Lopez Andreu JA, Serra Estellesl L, et al. [Psy chological
sequelae in long term cancer survivors]. An Esp Pediatr. 2000;53:553–560.
61. Ross L, Johansen C, Dalton SO, et al. Psy chitric hospitalizations among survivors of
cancer in childhood or adolescence. N Engl J Med. 2003;349:650–657.
62. Portteus A, Ahmad N, Tobey D, et al. The prevalence and use of antidepressant
medication in pediatric cancer patients. J Child Adolesc Psychopharmacol. 2006;16:467–
473.
63. Laffond C, Dellatolas G, Alapetite C, et al. Quality -of-life, mood, and executive
functioning after childhood craniophary ngioma treated with surgery and proton beam
therapy. Brain Inj. 2012;26:270–281.
64. Hill JM, Kornblith AB, Jones D, et al. A comparative study of the long term psy chosocial
functioning of childhood acute ly mphoblastic leukemia survivors treated by intrathecal
methotrexate with or without cranial radiation. Cancer. 1998;82:208–218.
65. Mostoufi-Moab S, Grimberg A. Pediatric brain tumor treatment: Growth consequences
and their management. Pediatr Endocrinol Rev. 2010;8:6–17.
66. Lew CC. Special needs of children. In: Dow KH, Hilderly LJ, eds. Nursing Care in
Radiation Oncology. Philadelphia, PA: Saunders; 1992:177–202.
67. Ty c VL, Klosky JL, Kronenberg M, et al. Children’s distress in anticipation of radiation
therapy procedures. Child Health Care. 2002;31:11–27.
68. Klosky JL, Ty c VL, Tong X, et al. Predicting pediatric distress during radiation therapy
procedures: the role of medical, psy chosocial, and demographic factors. Pediatrics.
2007;119:1159–1166.
69. Noeker M. [Survivors of pediatric cancer: developmental paths and outcomes between
trauma and resilience]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz.
2012;55:481–492.
70. Chiang YC, Yeh CH, Lee SC, et al. [Fatigue in pediatric oncology patients]. Hu Li Za Zhi.
2005;51:27–33.
71. Jensen SB, Pedersen AM, Vissink A, et al. A sy stematic review of salivary gland
hy pofunction and xerostomia induced by cancer therapies: prevalence, severity and
impact on quality of life. Support Care Cancer. 2010;18:1039–1060.
72. Ginsberg JP. Educational paper: the effect of cancer therapy on fertility ; the assessment
of fertility and fertility preservation options for pediatric patients. Eur J Pediatr.
2011;170:703–708.
73. Kaley ias J, Manley P, Kothare SV, et al. Sleep disorders in children with cancer. Semin
Pediatr Neurol. 2012;19:25–34.
74. Tucker TL, Samant RS, Fitzgibbon EJ. Knowledge and utilization of pediatric
radiotherapy by paediatric oncologists. Curr Oncol. 2010;17:48–55.
75. Kreitler S, Kreitler MM. Quality of life in children. In: Kreitler S, Wey l Ben Arush M,
Martin A. eds. Pediatric Psycho-Oncology: Psychosocial Aspects and Clinical
Interventions. 2nd ed. Chichester, England: Wiley -Blackwell; 2012:18–31.
76. Bucholtz JD. Comforting children during radiotherapy. Oncol Nurs Forum. 1994;21:987–
994.
77. Slifer KJ, Bucholtz JD, Cataldo MD. Behavioral training of motion control in y oung
children undergoing radiation treatment without sedation. J Pediatr Oncol Nurs.
1994;11:55–63.
78. Garding J, Edwinson MM, Tomqvist E, et al. Caring for children undergoing radiotherapy
treatment: Swedish radiotherapy nurses’ perceptions. Eur J Oncol Nurs. 2015;19(6):660–
666.
79. Scott L, Langton F, O’Donoghue J. Minimising the use of sedation/anaesthesia in y oung
children receiving radiotherapy through an effective play preparation programme. Eur
J Oncol Nurs. 2002;6:15–22.
80. Filin A. Radiation therapy preparation by a multidisciplinary team for childhood cancer
patients aged 3 to 6 y ears. J Pediatr Oncol Nurs. 2009;26:81–85.
81. Klosky JL, Ty c VL, Srivastava DK, et al. Brief report: evaluation of an interactive
intervention designed to reduce pediatric distress during radiation therapy procedures. J
Pediatr Psychol. 2004;29:621–626.
82. Page 510 Haeberli S, Grotzer MA, Niggli FK, et al. A psy choeducational intervention
reduces the need for anesthesia during radiotherapy for y oung childhood cancer
patients. Radiat Oncol. 2008;3:17.
83. Shrimpton BJ, Willis DJ, Tongs CD, et al. Movie making as a cognitive distraction for
paeditric patients receiving radiotherapy treatment: qualitative interview study. BMJ
Open. 2013;3(1).
84. Barry P, O’Callagahan C, Wheeler G, et al. Music therapy CD creation for initial
pediatric radiation therapy : a mixed methods analy sis. J Music Ther. 2010;47:233–263.
85. LeBaron S, Zeltzer L. Research on hy pnotherapy for the relief of pain, anxiety, nausea
and vomiting in children with cancer. Texas Psychol. 1985;37:12–14.
86. LeBaron S, Zeltzer LK. The role of imagery in the treatment of dy ing children and
adolescents. J Dev Behav Pediatr. 1885;6:252–258.
87. Kreitler S, Oppenheim D, Segev-Shoham E. Fantasy, art therapies, humor and pets as
psy chosocial means of intervention. In: Kreitler S, Wey l Ben Arush M, eds. Psychosocial
Aspects of Pediatric Oncology. Chichester, England: Wiley ; 2004:351–388.
88. Trask CL, Welch JJ, Manley P, et al. Parental needs for information related to
neurocognitive late effects from pediatric cancer and its treatment. Pediatr Blood
Cancer. 2009;52:273–279.
Remarks
1 Dublin LI. Mortality Statistics of Insured Wage-Earners and Their Families. New York, NY:
Metropolitan Life Insurance Company ; 1919.
3 Ventura SJ, Peters KD, Martin JA, et al. Births and deaths: United States, 1996. Mon Vital
Stat Rep. 1997;46:29–34.
4 American Academy of Pediatrics. Guidelines for the pediatric cancer center and role of
such centers in diagnosis and treatment. Pediatrics. 1986;77:916–917.
5 American Cancer Society. Special section: cancer in children and adolescents. In: Cancer
Facts and Figures 2014. Atlanta, GA: American Cancer Society ; 2014.
6 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
8 Health Canada. Canadian Cancer Incidence Atlas, Vol. 1: Canadian Cancer Incidence.
Ottawa, ON: Minister of National Health and Welfare; 1995:138–139.
9 Anony mous. US incidence rates for selected childhood cancer. J Natl Cancer Inst.
2001;93:1201.
10 American Cancer Society. American Cancer Society Cancer Facts and Figures 2014.
Atlanta, GA: American Cancer Society ; 2014.
11 Plaschkes J. Epidemiology of neonatal tumours. In: Puri P, ed. Neonatal Tumours. London,
England: Springer-Verlag; 1996:1–10.
12 Halperin EC. Neonatal neoplasms. Int J Radiat Oncol Biol Phys. 2000;47:171–178.
13 Parkin DM, Stiller CA, Draper GJ, et al. eds. International Incidence of Childhood Cancer.
Ly on, France: World Health Organization, International Agency for Research on Cancer;
1988;101–107.
14 Gurney JG, Davis S, Severson RK, et al. Trends in cancer incidence among children in the
US. Cancer. 1996;78:532–541.
16 Shah SH, Pervez S, Hassan SH. Frequency of malignant solid tumors in children. J
Pakistan Med Assoc. 2000;50:86–88.
17 Martin AA, Alpert JA, Reno JS, et al. Incidence of childhood cancer in Cuba (1986–1990).
Cancer. 1997;72:551–555.
19 Ocheni S, Bioha FI, Ibegbulam OG, et al. Changing patterns of childhood malignancies in
Eastern Nigeria. West African Med J. 2008;27:3–6.
21 Merrill RM, Feuer EJ. Risk-adjusted cancer incidence rates (United States). Cancer Causes
Control. 1996;7:544–552.
22 Massey -Stokes M, Lanning B. Childhood cancer and environmental toxins: the debate
continues. Fam Community Health. 2002;24:27–38.
23 Halperin EC, Miranda ML, Watson D, et al. Medulloblastoma and birth date: evaluating
three U.S. data sets. Arch Environ Health. 2004;59:26–30.
24 Kraut A, Tate R, Tran N. Residential electric consumption and childhood cancer in Canada
(1971–1986). Arch Environ Health. 1994;3(49):156–159.
25 Brown PD, Hertz H, Olsen JH, et al. Incidence of childhood cancer in Denmark 1943–
1984. Int J Epidemiol. 1989;18:546–555.
26 Rey nolds P, von Behren J, Gunier RB, et al. Childhood cancer and agricultural pesticide
use: an ecologic study in California. Environ Health Perspect. 2002;110:319–324.
27 Bunin GR, Feurer EJ, Witman PA, et al. Increasing incidence of childhood cancer: report
of 20 y ears experience from the Greater Delaware Valley Pediatric Tumor Registry.
Paediatr Perinat Epidemiol. 1996;10:319–338.
28 Cushman JH Jr. U.S. reshaping cancer strategy as incidence in children rises. New York
Times. September 29, 1997:1.
29 Compact Edition of the Oxford English Dictionary. Oxford, England: Oxford University
Press; 1985.
30 Easson EC, Russel MH. The cure of Hodgkin’s disease. BMJ. 1963;1:1704–1707.
31 Greenwood M. The Errors of Sampling of the Survivorship Table. London, England: His
Majesty ’s Stationery Office; 1929. Reports on Public Health and Medical Subjects, No. 33.
Appendix I.
32 Barnes E. Between remission and cure: patients, practitioners and the transformation of
leukaemia in the late twentieth century. Chronic Iln. 2007;3:253–264.
33 Frei E, Gehan EA. Definition of cure for Hodgkin’s disease. Cancer Res. 1971;31:1828–
1833.
34 Podrasky PA. The family perspective of the cured patient. Cancer. 1986;58:522–523.
35 Pinkel D. Cure of the child with cancer: definition and perspective. In: Proceedings of the
National Conference on the Care of the Child with Cancer. New York, NY: American Cancer
Society ; 1979:191–200.
36 Feinstein AR, Sasin DM, Wells CK. The Will Rogers phenomenon: stage migration and
new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J
Med. 1985;312:1604–1608.
37 Duenwald M, Grady M. Young survivors of cancer battle effects of treatment. New York
Times. January 8, 2002:1.
38 Mulrooney DA, Neglia JP, Hudson MM. Caring for adult survivors of childhood cancer.
Curr Treat Options Oncol. 2008;9:51–66.
39 Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of
childhood cancer. N Eng J Med. 2006;355:1572–1582.
40 Boughton B. Childhood cancer treatment causes complications later in life. Lancet Oncol.
2002;3:390.
41 Armstrong GT, Yasui Y, Chen Y, et al. Reduction in late mortality among 5-y ear survivors
of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS). Abstract
LMA2. Presented at: ASCO Annual Meeting; May 30–June 2, 2015; Chicago, IL.
42 SanFilippo A. Late mortality rates have declined in pediatric cancer survivors. HemOnc
today. 2015;16:1, 10–11.
43 Gerber LH, Binder H. Rehabilitation of the child with cancer. In: Pizzo PA, Poplack DG,
eds. Principles and Practice of Pediatric Oncology. Philadelphia, PA: JB Lippincott;
1993:1079–1090.
44 Hammond D. Progress in the study, treatment and cure of the cancers of children. In:
Burchenal JH, Oehgen HF, eds. Cancer Achievement, Challenges, and Prospects for the 1980s.
New York, NY: Grune & Stratton; 1981:171–190.
45 Hay s DM, Landsverk J, Ruccione K, et al. Employ ment problems and workplace
experience of childhood cancer survivors. In: Green DM, D’Angio GJ, eds. Late Effects of
Treatment for Childhood Cancer. New York, NY: Wiley -Liss; 1992:171–178.
46 Mey er WH. Principles of total care: rehabilitation. In: Fernbach DJ, Vietti TJ, eds. Clinical
Pediatric Oncology. St Louis, MO: Mosby ; 1991:285–294.
47 Changes in pediatric cancer treatments y ield reduced late mortality. ASCO Daily News.
Wrap up edition; 2015:2.
48 Zebrack BJ, Zeltzer LK, Whitten J, et al. Psy chological outcomes in long-term survivors of
childhood leukemia, Hodgkin’s disease, and non-Hodgkin’s ly mphoma: a report from the
childhood cancer survivor study. Pediatrics. 2002;110:42–52.
49 Craft AW, Pearson ADJ. Three decades of chemotherapy for childhood cancer: from
cure “at any cost” to “cure at least cost.” Cancer Surv. 1989;8:605–629.
50 Dickens M. Miracles of Courage: How Families Meet the Challenge of a Child’s Critical
Illness. New York, NY: Dodd, Mead; 1985.
51 Crom DB, Lensing SY, Rai SN, et al. Marriage, employ ment, and health insurance in adult
survivors of childhood cancer. J Cancer Surv. 2007;1:237–245.
52 Schwartz CL, Hobbie WL, Constine LS, et al. Survivors of Childhood Cancer: Assessment
and Management. St Louis, MO: Mosby ; 1994.
53 Labotka RJ. Book review of principles and practice of pediatric oncology. JAMA.
2002;288:894–895.
54 Meek RS. Pediatric oncology : the team approach of the medical center of Delaware. Del
Med J. 1988;60:169–172, 177–178.
55 Cohen ME, Duffner PK, Kun LE, et al. The argument for a combined cancer consortium
research data base. Cancer. 1985;56:1897–1901.
56 Duffner PK, Cohen ME, Flannery JT. Referral patterns of childhood brain tumors in the
state of Connecticut. Cancer. 1982;50:1636–1640.
57 Lennox EL, Stiller CA, Morris-Jones P, et al. Nephroblastoma: treatment during 1970–1973
and the effect of inclusion in the first Medical Research Council trial. BMJ. 1979;2:567–569.
59 Stiller CA, Draper GJ. Treatment, centre size, trial entry and survival in acute
ly mphoblastic leukaemia. Arch Dis Child. 1989;64:798–807.
60 Griffel M. Wilms’ tumor in New York State: epidemiology and survivorship. Cancer.
1977;40:3140–3145.
61 Constine LS, Donaldson SS. Pediatric radiation oncology : subspecialty training? Int J
Radiat Oncol Biol Phys. 1992;24:881–884.
62 Halperin EC, Donaldson SS. Subspecialty training and certification in radiation oncology.
JACR. 2004;1:488–492.
63 Halperin EC, Travis J, Browning IR III, et al. Children are not supposed to die: combined
pediatric and radiation oncology grand rounds addresses severe illness and death. NC Med J.
1997;58:445–448
64 Sacks J. Not in God’s Name: Confronting Religious Violence. NY: Schocken Books, 2015.
66 Epicuraenism. In: Encyclopaedia Britannica Micropaedia. Vol. 4. 15th ed. Chicago, IL:
Ency clopaedia Britannica; 1994:522.
67 Mark JL, ed. The Problem of Evil: A Reader. Malden, MA: Blackwell; 2001:xix–xxi.
68 Tooley M. The problem of evil. In: Borchert DM, ed. The Stanford Encyclopedia of
Philosophy. New York, NY: Macmillan Preference; 2005.
69 Darwin F, ed. The Life and Letters of Charles Darwin. Vol. 2. New York, NY: D. Appleton;
1919:105–106.
71 Sokol M. Is there a “Halakhic” response to the problem of evil? Harvard Theol Rev.
1999;92:311–323.
1 Pui CH, Behm FG, Crist WM. Clinical and biologic relevance of immunologic marker
studies in childhood acute ly mphoblastic leukemia. Blood. 1993;82(2):343–362.
2 Moghrabi A, Levy DE, Asselin B, et al. Results of the Dana-Farber cancer institute ALL
consortium protocol 95-01 for children with acute ly mphoblastic leukemia. Blood.
2007;109(3):896–904.
3 Carroll WL, Bhojwani D, Min DJ, et al. Childhood acute ly mphoblastic leukemia in the age
of genomics. Pediatr Blood Cancer. 2006;46(5):570–578.
4 Pui CH, Evans WE. A 50-y ear journey to cure childhood acute ly mphoblastic leukemia.
Semin Hematol. 2013;50:185–196.
6 Jeha S, Pei D, Raimondi SC, et al. Increased risk for CNS relapse in pre-B cell leukemia
with the t(1;19)/TCF3-PBX1. Leukemia. 2009;23:1406–1409.
8 Pui CH, Mullighan CG, Evans WE, et al. Pediatric acute ly mphoblastic leukemia: where are
we going and how do we get there? Blood. 2012;120:1165–1174.
9 Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours after
radiotherapy and antimetabolites. Lancet. 1999;354(9172):34–39.
10 Pui CH, Boy ett JM, Hancock ML, et al. Outcome of treatment for childhood cancer in
black as compared with white children. The St Jude Children’s Research Hospital experience,
1962 through 1992. JAMA. 1995;273(8):633–637.
11 Price RA, Johnson WW. The central nervous sy stem in childhood leukemia. I. The
arachnoid. Cancer. 1973;31(3):520–533.
12 Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and treatment
assignment for children with acute ly mphoblastic leukemia. J Clin Oncol. 1996;14(1):18–24.
13 Pui CH, Campana D, Pei D, et al. Treatment of childhood acute ly mphoblastic leukemia
without prophy lactic cranial irradiation. N Engl J Med. 2009;360(26):2730–2741.
14 Moricke A, Reiter A, Zimmermann M, et al. Risk-adjusted therapy of acute ly mphoblastic
leukemia can decrease treatment burden and improve survival: treatment results of 2169
unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood.
2008;111(9):4477–4489.
15 Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual
disease measurements in the context of risk-based therapy in childhood acute ly mphoblastic
leukaemia: a prospective study. Lancet Oncol. 2015;16:465–474.
17 Pui CH, Relling MV, Downing JR. Acute ly mphoblastic leukemia. N Engl J Med.
2004;350(15):1535–1548.
18 Pui CH, Evans WE. Treatment of acute ly mphoblastic leukemia. N Engl J Med.
2006;354(2):166–178.
19 Pui CH, Sandlund JT, Pei D, et al. Results of therapy for acute ly mphoblastic leukemia in
black and white children. JAMA. 2003;290(15):2001–2007.
20 Mahmoud HH, Rivera GK, Hancock ML, et al. Low leukocy te counts with blast cells in
cerebrospinal fluid of children with newly diagnosed acute ly mphoblastic leukemia. N Engl J
Med. 1993;329(5):314–319.
21 Pui CH, Sallan S, Relling MV, et al. International Childhood Acute Ly mphoblastic
Leukemia Workshop: Sausalito, CA, 30 November-1 December 2000. Leukemia.
2001;15(5):707–715.
22 Gajjar A, Harrison PL, Sandlund JT, et al. Traumatic lumbar puncture at diagnosis
adversely affects outcome in childhood acute ly mphoblastic leukemia. Blood.
2000;96(10):3381–3384.
23 Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS
in paediatric leukaemia. Lancet Oncol. 2008;9(3):257–268.
24 Trigg ME, Sather HN, Reaman GH, et al. Ten-y ear survival of children with acute
ly mphoblastic leukemia: a report from the Children’s Oncology Group. Leuk Lymphoma.
2008;49(6):1142–1154.
25 Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in childhood acute
ly mphoblastic leukemia despite reduced use of anthracy clines and cranial radiotherapy :
results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood.
2000;95(11):3310–3322.
26 Pui CH, Sandlund JT, Pei D, et al. Improved outcome for children with acute
ly mphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children’s Research
Hospital. Blood. 2004;104(9):2690–2696.
29 Vora A, Goulden N, Wade R, et al. Treatment reduction for children and y oung adults with
low-risk acute ly mphoblastic leukaemia defined by minimal residual disease (UKALL 2003):
a randomised controlled trial. Lancet Oncol. 2013;14:199–209.
31 Pui CH, Pei D, Campana D, et al. A revised definition for cure of childhood acute
ly mphoblastic leukemia. Leukemia. 2014;28:2336–2343.
32 Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood
acute ly mphoblastic leukemia. N Engl J Med. 2003;349(7):640–649.
37 Simone JV, Aur RJ, Hustu HO, et al. Three to ten y ears after cessation of therapy in
children with leukemia. Cancer. 1978;42 (2 suppl):839–844.
38 George P, Hernandez K, Hustu O, et al. A study of “total therapy ” of acute ly mphocy tic
leukemia in children. J Pediatr. 1968;72(3):399–408.
39 Aur RJ, Simone JV, Hustu HO, et al. A comparative study of central nervous sy stem
irradiation and intensive chemotherapy early in remission of childhood acute ly mphocy tic
leukemia. Cancer. 1972;29(2):381–391.
40 George SL, Aur RJ, Mauer AM, et al. A reappraisal of the results of stopping therapy in
childhood leukemia. N Engl J Med. 1979;300(6):269–273.
41 Pui CH. Toward optimal central nervous sy stem-directed treatment in childhood acute
ly mphoblastic leukemia. J Clin Oncol. 2003;21(2):179–181.
43 Rivera GK, Raimondi SC, Hancock ML, et al. Improved outcome in childhood acute
ly mphoblastic leukaemia with reinforced early treatment and rotational combination
chemotherapy. Lancet. 1991;337(8733):61–66.
45 LeClerc JM, Billett AL, Gelber RD, et al. Treatment of childhood acute ly mphoblastic
leukemia: results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol.
2002;20(1):237–246.
46 Pullen J, Boy ett J, Shuster J, et al. Extended triple intrathecal chemotherapy trial for
prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute
ly mphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol. 1993;11(5):839–
849.
48 Waber DP, Turek J, Catania L, et al. Neuropsy chological outcomes from a randomized
trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS
treatment in acute ly mphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL
Consortium Protocol 95-01. J Clin Oncol. 2007;25(31):4914–4921.
51 Walter AW, Hancock ML, Pui CH, et al. Secondary brain tumors in children treated for
acute ly mphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol.
1998;16(12):3761–3767.
52 Conter V, Schrappe M, Arico M, et al. Role of cranial radiotherapy for childhood T-cell
acute ly mphoblastic leukemia with high WBC count and good response to prednisone.
Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster
groups. J Clin Oncol. 1997;15(8):2786–2791.
53 Mitchell CD, Richards SM, Kinsey SE, et al. Benefit of dexamethasone compared with
prednisolone for childhood acute ly mphoblastic leukaemia: results of the UK Medical
Research Council ALL97 randomized trial. Br J Haematol. 2005;129(6):734–745.
54 Clarke M, Gay non P, Hann I, et al. CNS-directed therapy for childhood acute
ly mphoblastic leukemia: Childhood ALL Collaborative Group Overview of 43 Randomized
Trials. J Clin Oncol. 2003;21(9):1798–1809.
55 Edelmann MN, Ogg RJ, Scoggins MA, et al. Dexamethasone exposure and memory
function in adult survivors of childhood acute ly mphoblastic leukemia: a report from the
SJLIFE cohort. Pediatr Blood Cancer. 2013;60:1778–1784.
56 Edelmann MN, Krull KR, Liu W, et al. Diffusion tensor imaging and neurocognition in
survivors of childhood acute ly mphoblastic leukaemia. Brain. 2014;137:2973–2983.
58 Armstrong GT, Reddick WE, Petersen RC, et al. Evaluation of memory impairment in
aging adult survivors of childhood acute ly mphoblastic leukemia treated with cranial
radiotherapy. J Natl Cancer Inst. 2013;105:899–907.
60 Kelly MJ, Trikalinos TA, Dahabreh IJ, et al. Cranial radiation for pediatric T-lineage acute
ly mphoblastic leukemia: a sy stematic review and meta-analy sis. Am J Hematol.
2014;89:992–997.
62 Halperin EC, Laurie F, Fitzgerald TJ. An evaluation of the relationship between the quality
of prophy lactic cranial radiotherapy in childhood acute leukemia and institutional experience:
a Quality Assurance Review Center-Pediatric Oncology Group study. Int J Radiat Oncol Biol
Phys. 2002;53(4):1001–1004.
63 Weiss E, Krebeck M, Kohler B, et al. Does the standardized helmet technique lead to
adequate coverage of the cribriform plate? An analy sis of current practice with respect to the
ICRU 50 report. Int J Radiat Oncol Biol Phys. 2001;49(5):1475–1480.
64 Cherlow JM, Sather H, Steinherz P, et al. Craniospinal irradiation for acute ly mphoblastic
leukemia with central nervous sy stem disease at diagnosis: a report from the Children’s
Cancer Group. Int J Radiat Oncol Biol Phys. 1996;36(1):19–27.
65 Pui CH, Mahmoud HH, Rivera GK, et al. Early intensification of intrathecal
chemotherapy virtually eliminates central nervous sy stem relapse in children with acute
ly mphoblastic leukemia. Blood. 1998;92(2):411–415.
67 Ritchey AK, Pollock BH, Lauer SJ, et al. Improved survival of children with isolated CNS
relapse of acute ly mphoblastic leukemia: a pediatric oncology group study. J Clin Oncol.
1999;17(12):3745–3752.
68 Ha CS, Chung WK, Koller CA, et al. Role of radiation therapy to the brain in leukemic
patients with cranial nerve palsies in the absence of radiological findings. Leuk Lymphoma.
1999;32(5–6):497–503.
69 Ribeiro RC, Rivera GK, Hudson M, et al. An intensive re-treatment protocol for children
with an isolated CNS relapse of acute ly mphoblastic leukemia. J Clin Oncol. 1995;13(2):333–
338.
70 Kun LE, Camitta BM, Mulhern RK, et al. Treatment of meningeal relapse in childhood
acute ly mphoblastic leukemia. I. Results of craniospinal irradiation. J Clin Oncol.
1984;2(5):359–364.
71 Winick NJ, Smith SD, Shuster J, et al. Treatment of CNS relapse in children with acute
ly mphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol. 1993;11(2):271–
278.
72 Kumar P, Kun LE, Hustu HO, et al. Survival outcome following isolated central nervous
sy stem relapse treated with additional chemotherapy and craniospinal irradiation in childhood
acute ly mphoblastic leukemia. Int J Radiat Oncol Biol Phys. 1995;31(3):477–483.
73 Gay non PS, Qu RP, Chappell RJ, et al. Survival after relapse in childhood acute
ly mphoblastic leukemia: impact of site and time to first relapse—the Children’s Cancer Group
Experience. Cancer. 1998;82(7):1387–1395.
75 Barredo JC, Devidas M, Lauer SJ, et al. Isolated CNS relapse of acute ly mphoblastic
leukemia treated with intensive sy stemic chemotherapy and delay ed CNS radiation: a
pediatric oncology group study. J Clin Oncol. 2006;24(19):3142–3149.
76 Bowman WP, Aur RJ, Hustu HO, et al. Isolated testicular relapse in acute ly mphocy tic
leukemia of childhood: categories and influence on survival. J Clin Oncol. 1984;2(8):924–929.
77 Rivera GK, Pinkel D, Simone JV, et al. Treatment of acute ly mphoblastic leukemia. 30
y ears’ experience at St. Jude Children’s Research Hospital. N Engl J Med. 1993;329(18):1289–
1295.
78 van den BH, Langeveld NE, Veenhof CH, et al. Treatment of isolated testicular recurrence
of acute ly mphoblastic leukemia without radiotherapy —report from the Dutch Late Effects
Study Group. Cancer. 1997;79(11):2257–2262.
79 Bunin N, Rivera G, Goode F, et al. Ocular relapse in the anterior chamber in childhood
acute ly mphoblastic leukemia. J Clin Oncol. 1987;5(2):299–303.
80 Patel SV, Herman DC, Anderson PM, et al. Iris and anterior chamber involvement in
acute ly mphoblastic leukemia. J Pediatr Hematol Oncol. 2003;25(8):653–656.
81 Meshinchi S, Arceci RJ. Prognostic factors and risk-based therapy in pediatric acute
my eloid leukemia. Oncologist. 2007;12(3):341–355.
82 Rubnitz JE. Childhood acute my eloid leukemia. Curr Treat Options Oncol. 2008;9(1):95–
105.
83 Razzouk BI, Estey E, Pounds S, et al. Impact of age on outcome of pediatric acute my eloid
leukemia: a report from 2 institutions. Cancer. 2006;106(11):2495–2502.
84 Aplenc R, Alonzo TA, Gerbing RB, et al. Ethnicity and survival in childhood acute my eloid
leukemia: a report from the Children’s Oncology Group. Blood. 2006;108(1):74–80.
85 Lange BJ, Gerbing RB, Feusner J, et al. Mortality in overweight and underweight children
with acute my eloid leukemia. JAMA. 2005;293(2):203–211.
86 Rubnitz JE, Gibson B, Smith FO. Acute my eloid leukemia. Pediatr Clin N Am. 2008;55:21–
51.
87 Abbott BL, Rubnitz JE, Tong X, et al. Clinical significance of central nervous sy stem
involvement at diagnosis of pediatric acute my eloid leukemia: a single institution’s experience.
Leukemia. 2003;17(11):2090–2096.
90 Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in
pediatric AML. Blood. 2006;108(12):3654–3661.
93 Lange BJ, Smith FO, Feusner J, et al. Outcomes in CCG-2961, a children’s oncology group
phase 3 trial for untreated pediatric acute my eloid leukemia: a report from the children’s
oncology group. Blood. 2008;111(3):1044–1053.
94 Smith FO, Alonzo TA, Gerbing RB, et al. Long-term results of children with acute my eloid
leukemia: a report of three consecutive Phase III trials by the Children’s Cancer Group: CCG
251, CCG 213 and CCG 2891. Leukemia. 2005;19(12):2054–2062.
95 Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation
versus intensive consolidation chemotherapy for acute my eloid leukemia in childhood.
Pediatric Oncology Group. N Engl J Med. 1996;334(22):1428–1434.
96 Gibson BE, Wheatley K, Hann IM, et al. Treatment strategy and long-term results in
paediatric patients treated in consecutive UK AML trials. Leukemia. 2005;19(12):2130–2138.
99 Ribera JM, Ortega JJ, Oriol A, et al. Comparison of intensive chemotherapy, allogeneic, or
autologous stem-cell transplantation as postremission treatment for children with very high
risk acute ly mphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol. 2007;25(1):16–24.
100 Kobay ashi R, Tawa A, Hanada R, et al. Extramedullary infiltration at diagnosis and
prognosis in children with acute my elogenous leukemia. Pediatr Blood Cancer.
2007;48(4):393–398.
101 Chang M, Raimondi SC, Ravindranath Y, et al. Prognostic factors in children and
adolescents with acute my eloid leukemia (excluding children with Down sy ndrome and acute
promy elocy tic leukemia): univariate and recursive partitioning analy sis of patients treated on
Pediatric Oncology Group (POG) Study 8821. Leukemia. 2000;14(7):1201–1207.
102 Vormoor J, Ritter J, Creutzig U, et al. Acute my elogenous leukemia in children under 2
y ears—experiences of the West German AML studies BFM-78, -83, and -87, AML-BFM
Study Group. Br J Cancer. 1992;66:S63–S67.
103 Johnston DL, Alonzo TA, Gerbing RB, et al. Risk factors and therapy for isolated central
nervous sy stem relapse of pediatric acute my eloid leukemia. J Clin Oncol.
2005;23(36):9172–9178.
104 Creutzig U, Zimmermann M, Ritter J, et al. Treatment strategies and long-term results in
paediatric patients treated in four consecutive AML-BFM trials. Leukemia. 2005;19(12):2030–
2042.
105 Pession A, Rondelli R, Basso G, et al. Treatment and long-term results in children with
acute my eloid leukaemia treated according to the AIEOP AML protocols. Leukemia.
2005;19(12):2043–2053.
106 Ribeiro RC, Razzouk BI, Pounds S, et al. Successive clinical trials for childhood acute
my eloid leukemia at St Jude Children’s Research Hospital, from 1980 to 2000. Leukemia.
2005;19(12):2125–2129.
108 Lake RA, Robinson BW. Immunotherapy and chemotherapy —a practical partnership.
Nat Rev Cancer. 2005;5(5):397–405.
109 Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host
disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300(19):1068–
1073.
110 Thomas ED. ALL and bey ond: implications for other hematologic malignancies.
Leukemia. 1997;11(suppl 4):S43–S45.
111 Schrauder A, von SA, Schrappe M, et al. Allogeneic hematopoietic SCT in children with
ALL: current concepts of ongoing prospective SCT trials. Bone Marrow Transplant.
2008;41(suppl 2): S71–S74.
112 Shenoy S, Smith FO. Hematopoietic stem cell transplantation for childhood malignancies
of my eloid origin. Bone Marrow Transplant. 2008;41(2):141–148.
113 Davies SM, Ramsay NK, Klein JP, et al. Comparison of preparative regimens in
transplants for children with acute ly mphoblastic leukemia. J Clin Oncol. 2000;18(2):340–347.
114 Hongeng S, Krance RA, Bowman LC, et al. Outcomes of transplantation with matched-
sibling and unrelated-donor bone marrow in children with leukaemia. Lancet.
1997;350(9080):767–771.
115 Bunin N, Aplenc R, Kamani N, et al. Randomized trial of busulfan vs total body
irradiation containing conditioning regimens for children with acute ly mphoblastic leukemia:
a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant.
2003;32(6):543–548.
117 Entz-Werle N, Suciu S, van der Werff ten Bosch, et al. Results of 58872 and 58921 trials in
acute my eloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow
transplantation in first complete remission: the EORTC Children Leukemia Group report.
Leukemia. 2005;19(12):2072–2081.
118 Oliansky DM, Camitta B, Gay non P, et al. Role of cy totoxic therapy with hematopoietic
stem cell transplantation in the treatment of pediatric acute ly mphoblastic leukemia: update of
the 2005 evidence-based review. Biol Blood Marrow Transplant. 2012;18:505–522.
119 Eapen M, Zhang MJ, Devidas M, et al. Outcomes after HLA-matched sibling
transplantation or chemotherapy in children with acute ly mphoblastic leukemia in a second
remission after an isolated central nervous sy stem relapse: a collaborative study of the
Children’s Oncology Group and the Center for International Blood and Marrow Transplant
Research. Leukemia. 2008;22(2):281–286.
120 Thomas ED, Clift RA, Hersman J, et al. Marrow transplantation for acute
nonly mphoblastic leukemic in first remission using fractionated or single-dose irradiation. Int
J Radiat Oncol Biol Phys. 1982;8(5):817–821.
121 Ravindranath Y, Chang M, Steuber CP, et al. Pediatric Oncology Group (POG) studies of
acute my eloid leukemia (AML): a review of four consecutive childhood AML trials
conducted between 1981 and 2000. Leukemia. 2005;19(12):2101–2116.
122 Willemze AJ, Geskus RB, Noordijk EM, et al. HLA-identical haematopoietic stem cell
transplantation for acute leukaemia in children: less relapse with higher biologically effective
dose of TBI. Bone Marrow Transplant. 2007;40(4):319–327.
125 Eapen M, Zhang MJ, Devidas M, et al. Outcomes after HLA-matched sibling
transplantation or chemotherapy in children with acute ly mphoblastic leukemia in a second
remission after an isolated central nervous sy stem relapse: a collaborative study of the
Children’s Oncology Group and the Center for International Blood and Marrow Transplant
Research. Leukemia. 2008;22:281–286.
127 Woolfrey AE, Anasetti C, Storer B, et al. Factors associated with outcome after unrelated
marrow transplantation for treatment of acute ly mphoblastic leukemia in children. Blood.
2002;99(6):2002–2008.
129 Corvo R, Paoli G, Barra S, et al. Total body irradiation correlates with chronic graft
versus host disease and affects prognosis of patients with acute ly mphoblastic leukemia
receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol Phys.
1999;43(3):497–503.
130 Zecca M, Pession A, Messina C, et al. Total body irradiation, thiotepa, and
cy clophosphamide as a conditioning regimen for children with acute ly mphoblastic leukemia
in first or second remission undergoing bone marrow transplantation with HLA-identical
siblings. J Clin Oncol. 1999;17(6):1838–1846.
133 Alexander BM, Wechsler D, Braun TM, et al. Utility of cranial boost in addition to total
body irradiation in the treatment of high risk acute ly mphoblastic leukemia. Int J Radiat Oncol
Biol Phys. 2005;63:1191–1196.
134 Aldoss I, Al Malki MM, Stiller T, et al. Implications and management of central nervous
sy stem involvement before allogeneic hematopoietic cell transplantation in acute
ly mphoblastic leukemia. Biol Blood Marrow Transplant. 2015;22:571–588.
135 Flowers ME, Doney KC, Storb R, et al. Marrow transplantation for Fanconi anemia with
or without leukemic transformation: an update of the Seattle experience. Bone Marrow
Transplant. 1992;9(3):167–173.
136 MacMillan ML, Auerbach AD, Davies SM, et al. Haema-topoietic cell transplantation in
patients with Fanconi anaemia using alternate donors: results of a total body irradiation dose
escalation trial. Br J Haematol. 2000;109(1):121–129.
137 Socie G, Devergie A, Girinski T, et al. Transplantation for Fanconi’s anaemia: long-term
follow-up of fifty patients transplanted from a sibling donor after low-dose
cy clophosphamide and thoraco-abdominal irradiation for conditioning. Br J Haematol.
1998;103(1):249–255.
139 Kroger N, Zabelina T, Renges H, et al. Long-term follow-up of allogeneic stem cell
transplantation in patients with severe aplastic anemia after conditioning with
cy clophosphamide plus antithy mocy te globulin. Ann Hematol. 2002;81(11):627–631.
140 Bunin N, Aplenc R, Iannone R, et al. Unrelated donor bone marrow transplantation for
children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T
cell depletion. Bone Marrow Transplant. 2005;35(4):369–373.
141 Broerse JJ, Dutreix A, Noordijk EM. Phy sical, biological and clinical aspects of total
body irradiation. Radiother Oncol. 1990;18(suppl 1):1–2.
142 Harden SV, Routsis DS, Geater AR, et al. Total body irradiation using a modified standing
technique: a single institution 7 y ear experience. Br J Radiol. 2001;74(887):1041–1047.
143 Cosset JM, Girinsky T, Malaise E, et al. Clinical basis for TBI fractionation. Radiother
Oncol. 1990;18(suppl 1):60–67.
144 Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in
patients with acute my eloid leukemia in first remission: a randomized trial of two irradiation
regimens. Blood. 1990;76(9):1867–1871.
145 Gopal R, Ha CS, Tucker SL, et al. Comparison of two total body irradiation fractionation
regimens with respect to acute and late pulmonary toxicity. Cancer. 2001;92(7):1949–1958.
146 Schultheiss TE, Wong J, Liu A, et al. Image-guided total marrow and total ly mphatic
irradiation using helical tomotherapy. Int J Radiat Oncol Biol Phys. 2007;67(4):1259–1267.
147 Sampath S, Schultheiss TE, Wong J. Dose response and factors related to interstitial
pneumonitis after bone marrow transplant. Int J Radiat Oncol Biol Phys. 2005;63(3):876–884.
148 Della VA, Ferreri AJ, Annaloro C, et al. Lethal pulmonary complications significantly
correlate with individually assessed mean lung dose in patients with hematologic
malignancies treated with total body irradiation. Int J Radiat Oncol Biol Phys.
2002;52(2):483–488.
149 Soule BP, Simone NL, Savani BN, et al. Pulmonary function following total body
irradiation (with or without lung shielding) and allogeneic peripheral blood stem cell
transplant. Bone Marrow Transplant. 2007;40(6):573–578.
150 Wong JY, Forman S, Somlo G, et al. Dose escalation of total marrow irradiation with
concurrent chemotherapy in patients with advanced acute leukemia undergoing allogeneic
hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2013;85: 148–156.
151 Kim JH, Stein A, Tsai N, et al. Extramedullary relapse following total marrow and
ly mphoid irradiation in patients undergoing allogeneic hematopoietic cell transplantation. Int J
Radiat Oncol Biol Phys. 2014;89:75–81.
152 Shank B, O’Reilly RJ, Cunningham I, et al. Total body irradiation for bone marrow
transplantation: the Memorial Sloan-Kettering Cancer Center experience. Radiother Oncol.
1990;18(suppl 1):68–81.
153 Thomas E, Storb R, Clift RA, et al. Bone-marrow transplantation (first of two parts). N
Engl J Med. 1975;292(16):832–843.
154 Gale RP, Butturini A, Bortin MM. What does total body irradiation do in bone marrow
transplants for leukemia? Int J Radiat Oncol Biol Phys. 1991;20(3):631–634.
155 Soejima T, Hirota S, Tsujino K, et al. Total body irradiation followed by bone marrow
transplantation: comparison of once-daily and twice-daily fractionation regimens. Radiat
Med. 2007;25(8):402–406.
156 Kim TH, Ry bka WB, Lehnert S, et al. Interstitial pneumonitis following total body
irradiation for bone marrow transplantation using two different dose rates. Int J Radiat Oncol
Biol Phys. 1985;11(7):1285–1291.
157 Peters LJ, Withers HR, Cundiff JH, et al. Radiobiological considerations in the use of
total-body irradiation for bone-marrow transplantation. Radiology. 1979;131(1):243–247.
158 Clift RA, Buckner CD, Appelbaum FR, et al. Long-term follow-Up of a randomized trial
of two irradiation regimens for patients receiving allogeneic marrow transplants during first
remission of acute my eloid leukemia. Blood. 1998;92(4):1455–1456.
159 Cheng JC, Schultheiss TE, Wong JY. Impact of drug therapy, radiation dose, and dose rate
on renal toxicity following bone marrow transplantation. Int J Radiat Oncol Biol Phys.
2008;71(5):1436–1443.
160 Corvo R, Lamparelli T, Bruno B, et al. Low-dose fractionated total body irradiation (TBI)
adversely affects prognosis of patients with leukemia receiving an HLA-matched allogeneic
bone marrow transplant from an unrelated donor (UD-BMT). Bone Marrow Transplant.
2002;30(11):717–723.
161 Bieri S, Helg C, Chapuis B, et al. Total body irradiation before allogeneic bone marrow
transplantation: is more dose better? Int J Radiat Oncol Biol Phys. 2001;49(4):1071–1077.
1 Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA
Cancer J Clin. 2014;64:83–103.
2 Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the
central nervous sy stem. Acta Neuropathol. 2007;114:97–109.
3 Louis DN, Ohgaki H, Wiestler OD. WHO Classification of Tumors of the Central Nervous
System. 4th ed. Ly on, France: IARC Press; 2007.
4 Sturm D, Orr BA, Toprak UH, et al. New brain tumor entities emerge from molecular
classification of CNS-PNETs. Cell. 2016;164:1060–1072.
7 Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous
sy stem in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
J Natl Cancer Inst. 2006;98:1528–1537.
8 Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes among adult survivors of
childhood central nervous sy stem malignancies in the Childhood Cancer Survivor Study. J
Natl Cancer Inst. 2009;101:946–958.
9 Perkins GH, Schomer DF, Fuller GN, et al. Gliomatosis cerebri: improved outcome with
radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56:1137–1146.
10 Bian SX, McAleer MF, Vats TS, et al. Pilocy tic astrocy toma with leptomeningeal
dissemination. Childs Nerv Syst. 2013;29:441–450.
11 Broniscer A, Baker SJ, West AN, et al. Clinical and molecular characteristics of malignant
transformation of low-grade glioma in children. J Clin Oncol. 2007;25:682–689.
13 Burger PC, Cohen KJ, Rosenblum MK, et al. Pathology of diencephalic astrocy tomas.
Pediatr Neurosurg. 2000;32:214–219.
14 Krouwer HG, Davis RL, Silver P, et al. Gemistocy tic astrocy tomas: a reappraisal. J
Neurosurg. 1991;74:399–406.
15 Babu R, Bagley JH, Park JG, et al. Low-grade astrocy tomas: the prognostic value of
fibrillary, gemistocy tic, and protoplasmic tumor histology. J Neurosurg. 2013;119:434–441.
16 Ida CM, Rodriguez FJ, Burger PC, et al. Pleomorphic xanthoastrocy toma: natural history
and long-term follow-up. Brain Pathol. 2015;25:575–586.
17 Shepherd CW, Scheithauer BW, Gomez MR, et al. Subependy mal giant cell astrocy toma: a
clinical, pathological, and flow cy tometric study. Neurosurgery. 1991;28:864–868.
18 Kieran MW. Targeting BRAF in pediatric brain tumors. Am Soc Clin Oncol Educ Book.
2014:e436–e440.
19 Pollack IF, Claassen D, al-Shboul Q, et al. Low-grade gliomas of the cerebral hemispheres
in children: an analy sis of 71 cases. J Neurosurg. 1995;82:536–547.
20 Wisoff JH, Sanford RA, Heier LA, et al. Primary neurosurgery for pediatric low-grade
gliomas: a prospective multi-institutional study from the Children’s Oncology Group.
Neurosurgery. 2011;68:1548–1554; discussion 54–55.
22 Hoffman HJ, Soloniuk DS, Humphrey s RP, et al. Management and outcome of low-grade
astrocy tomas of the midline in children: a retrospective review. Neurosurgery. 1993;33:964–
971.
23 Shaw EG, Wisoff JH. Prospective clinical trials of intracranial low-grade glioma in adults
and children. Neuro Oncol. 2003;5:153–160.
24 Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for
pediatric low-grade glioma. J Clin Oncol. 2009;27:3598–3604.
25 Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for
pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and
hearing deficits. J Clin Oncol. 2009;27:3691–3697.
26 Eaton BR, Yock T. The use of proton therapy in the treatment of benign or low-grade
pediatric brain tumors. Cancer J. 2014;20:403–408.
27 Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common
pediatric brain tumors: comparison of models of dose characteristics and their relationship to
cognitive function. Pediatr Blood Cancer. 2008;51:110–117.
28 Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine,
neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J
Radiat Oncol Biol Phys. 2014;89:1060–1068.
29 Bowers DC, Gargan L, Kapur P, et al. Study of the MIB-1 labeling index as a predictor of
tumor progression in pilocy tic astrocy tomas in children and adolescents. J Clin Oncol.
2003;21:2968–2973.
30 Mishra KK, Puri DR, Missett BT, et al. The role of up-front radiation therapy for
incompletely resected pediatric WHO grade II low-grade gliomas. Neuro Oncol. 2006;8:166–
174.
31 Bloom HJ, Glees J, Bell J, et al. The treatment and long-term prognosis of children with
intracranial tumors: a study of 610 cases, 1950-1981. Int J Radiat Oncol Biol Phys.
1990;18:723–745.
32 Reardon DA, Gajjar A, Sanford RA, et al. Bithalamic involvement predicts poor outcome
among children with thalamic glial tumors. Pediatr Neurosurg. 1998;29:29–35.
33 Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children
with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86:747–754.
34 Lafay -Cousin L, Sung L, Carret AS, et al. Carboplatin hy persensitivity reaction in pediatric
patients with low-grade glioma: a Canadian Pediatric Brain Tumor Consortium experience.
Cancer. 2008;112:892–899.
35 Chintagumpala M, Eckel SP, Krailo M, et al. A pilot study using carboplatin, vincristine, and
temozolomide in children with progressive/sy mptomatic low-grade glioma: a Children’s
Oncology Group study dagger. Neuro Oncol. 2015;17:1132–1138.
36 Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for
treatment of low-grade glioma in y oung children: a report from the Children’s Oncology
Group. J Clin Oncol. 2012;30:2641–2647.
37 Packer RJ, Jakacki R, Horn M, et al. Objective response of multiply recurrent low-grade
gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer. 2009;52:791–795.
38 Kandula S, Saindane AM, Prabhu RS, et al. Patterns of presentation and failure in patients
with gliomatosis cerebri treated with partial-brain radiation therapy. Cancer. 2014;120:2713–
2720.
39 Gajjar A, Bhargava R, Jenkins JJ, et al. Low-grade astrocy toma with neuraxis
dissemination at diagnosis. J Neurosurg. 1995;83:67–71.
42 Merchant TE, Kiehna EN, Li C, et al. Modeling radiation dosimetry to predict cognitive
outcomes in pediatric patients with CNS embry onal tumors including medulloblastoma. Int J
Radiat Oncol Biol Phys. 2006;65:210–221.
43 Merchant TE, Kiehna EN, Miles MA, et al. Acute effects of irradiation on cognition:
changes in attention on a computerized continuous performance test during radiotherapy in
pediatric patients with localized primary brain tumors. Int J Radiat Oncol Biol Phys.
2002;53:1271–1278.
44 Kida Y, Kobay ashi T, Mori Y. Gamma knife radiosurgery for low-grade astrocy tomas:
results of long-term follow up. J Neurosurg. 2000;93(suppl 3):42–46.
45 Tao ML, Barnes PD, Billett AL, et al. Childhood optic chiasm gliomas: radiographic
response following radiotherapy and long-term clinical outcome. Int J Radiat Oncol Biol
Phys. 1997;39:579–587.
46 Janss AJ, Grundy R, Cnaan A, et al. Optic pathway and hy pothalamic/chiasmatic gliomas
in children y ounger than age 5 y ears with a 6-y ear follow-up. Cancer. 1995;75:1051–1059.
47 Prada CE, Hufnagel RB, Hummel TR, et al. The use of magnetic resonance imaging
screening for optic pathway gliomas in children with neurofibromatosis ty pe 1. J Pediatr.
2015;167:851–856 e1.
48 Sy lvester CL, Drohan LA, Sergott RC. Optic-nerve gliomas, chiasmal gliomas and
neurofibromatosis ty pe 1. Curr Opin Ophthalmol. 2006;17:7–11.
49 Listernick R, Louis DN, Packer RJ, et al. Optic pathway gliomas in children with
neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force.
Ann Neurol. 1997;41:143–149.
50 Nicolin G, Parkin P, Mabbott D, et al. Natural history and outcome of optic pathway
gliomas in children. Pediatr Blood Cancer. 2009;53:1231–1237.
51 Grill J, Laithier V, Rodriguez D, et al. When do children with optic pathway tumours need
treatment? An oncological perspective in 106 patients treated in a single centre. Eur J Pediatr.
2000;159:692–696.
53 Gnekow AK, Kortmann RD, Pietsch T, et al. Low grade chiasmatic-hy pothalamic glioma-
carboplatin and vincristin chemotherapy effectively defers radiotherapy within a
comprehensive treatment strategy —report from the multicenter treatment study for children
and adolescents with a low grade glioma—HIT-LGG 1996—of the Society of Pediatric
Oncology and Hematology (GPOH). Klin Padiatr. 2004;216:331–342.
54 Alvord EC Jr, Lofton S. Gliomas of the optic nerve or chiasm—outcome by patients’ age,
tumor site, and treatment. J Neurosurg. 1988;68:85–98.
58 Ullrich NJ, Robertson R, Kinnamon DD, et al. Moy amoy a following cranial irradiation for
primary brain tumors in children. Neurology. 2007;68:932–938.
59 Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis 1 patients
treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 2006;24:2570–2575.
60 Laithier V, Grill J, Le Deley MC, et al. Progression-free survival in children with optic
pathway tumors: dependence on age and the quality of the response to chemotherapy —
results of the first French prospective study for the French Society of Pediatric Oncology. J
Clin Oncol. 2003;21:4572–4578.
61 Packer RJ. Chemotherapy : low-grade gliomas of the hy pothalamus and thalamus. Pediatr
Neurosurg. 2000;32:259–263.
62 Awdeh RM, Kiehna EN, Drewry RD, et al. Visual outcomes in pediatric optic pathway
glioma after conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2012;84:46–51.
63 Fuss M, Hug EB, Schaefer RA, et al. Proton radiation therapy (PRT) for pediatric optic
pathway gliomas: comparison with 3D planned conventional photons and a standard photon
technique. Int J Radiat Oncol Biol Phys. 1999;45:1117–1126.
64 Mork SJ, Lindegaard KF, Halvorsen TB, et al. Oligodendroglioma: incidence and biological
behavior in a defined population. J Neurosurg. 1985;63:881–889.
66 Cairncross JG, Wang M, Jenkins RB, et al. Benefit from procarbazine, lomustine, and
vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol.
2014;32:783–790.
67 van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and
vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term
follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344–350.
68 Kreiger PA, Okada Y, Simon S, et al. Losses of chromosomes 1p and 19q are rare in
pediatric oligodendrogliomas. Acta Neuropathol. 2005;109:387–392.
71 Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic
oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337–343.
72 Creach KM, Rubin JB, Leonard JR, et al. Oligodendrogliomas in children. J Neurooncol.
2012;106:377–382.
73 McGirt MJ, Chaichana KL, Attenello FJ, et al. Extent of surgical resection is independently
associated with survival in patients with hemispheric infiltrating low-grade gliomas.
Neurosurgery. 2008;63:700–707; author reply 7–8.
74 van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delay ed
radiotherapy for low-grade astrocy toma and oligodendroglioma in adults: the EORTC 22845
randomised trial. Lancet. 2005;366:985–990.
75 Shaw EG, Wang M, Coons SW, et al. Randomized trial of radiation therapy plus
procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade
glioma: initial results of RTOG 9802. J Clin Oncol. 2012;30:3065–3070.
77 Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential
radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or
temozolomide. J Clin Oncol. 2009;27:5874–5880.
78 Dudley RW, Torok MR, Gallegos DR, et al. Pediatric low-grade ganglioglioma:
epidemiology, treatments, and outcome analy sis on 348 children from the surveillance,
epidemiology, and end results database. Neurosurgery. 2015;76:313–319; discussion 9; quiz 9–
20.
83 Leenstra JL, Rodriguez FJ, Frechette CM, et al. Central neurocy toma: management
recommendations based on a 35-y ear experience. Int J Radiat Oncol Biol Phys.
2007;67:1145–1154.
85 Campos AR, Clusmann H, von Lehe M, et al. Simple and complex dy sembry oplastic
neuroepithelial tumors (DNT) variants: clinical profile, MRI, and histopathology.
Neuroradiology. 2009;51:433–443.
86 Fouladi M, Hunt DL, Pollack IF, et al. Outcome of children with centrally reviewed low-
grade gliomas treated with chemotherapy with or without radiotherapy on Children’s Cancer
Group high-grade glioma study CCG-945. Cancer. 2003;98:1243–1252.
87 Pietsch T, Tay lor MD, Rutka JT. Molecular pathogenesis of childhood brain tumors. J
Neurooncol. 2004;70:203–215.
88 Louis DN, Holland EC, Cairncross JG. Glioma classification: a molecular reappraisal. Am
J Pathol. 2001;159:779–786.
89 Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-
grade gliomas reveals key differences with the adult disease. J Clin Oncol. 2010;28:3061–
3068.
90 Pollack IF, Hamilton RL, James CD, et al. Rarity of PTEN deletions and EGFR
amplification in malignant gliomas of childhood: results from the Children’s Cancer Group
945 cohort. J Neurosurg. 2006;105:418–424.
91 Eisenstat DD, Pollack IF, Demers A, et al. Impact of tumor location and pathological
discordance on survival of children with midline high-grade gliomas treated on Children’s
Cancer Group high-grade glioma study CCG-945. J Neurooncol. 2015;121:573–581.
92 Halperin EC, Bentel G, Heinz ER, et al. Radiation therapy treatment planning in
supratentorial glioblastoma multiforme: an analy sis based on post mortem topographic
anatomy with CT correlations. Int J Radiat Oncol Biol Phys. 1989;17:1347–1350.
93 Chan JL, Lee SW, Fraass BA, et al. Survival and failure patterns of high-grade gliomas
after three-dimensional conformal radiotherapy. J Clin Oncol. 2002;20:1635–1642.
94 Wisoff JH, Boy ett JM, Berger MS, et al. Current neurosurgical management and the
impact of the extent of resection in the treatment of malignant gliomas of childhood: a report
of the Children’s Cancer Group trial no. CCG-945. J Neurosurg. 1998;89:52–59.
95 Pollack IF, Boy ett JM, Yates AJ, et al. The influence of central review on outcome
associations in childhood malignant gliomas: results from the CCG-945 experience. Neuro
Oncol. 2003;5:197–207.
97 Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and
chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226–231.
98 Venneti S, Santi M, Felicella MM, et al. A sensitive and specific histopathologic prognostic
marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol. 2014;128:743–
753.
99 Tsien C, Moughan J, Michalski JM, et al. Phase I three-dimensional conformal radiation
dose escalation study in newly diagnosed glioblastoma: Radiation Therapy Oncology Group
Trial 98-03. Int J Radiat Oncol Biol Phys. 2009;73:699–708.
100 Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a
randomised phase III study : 5-y ear analy sis of the EORTC-NCIC trial. Lancet Oncol.
2009;10:459–466.
102 Lashford LS, Thiesse P, Jouvet A, et al. Temozolomide in malignant gliomas of childhood:
a United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology
Intergroup Study. J Clin Oncol. 2002;20:4684–4691.
103 Sposto R, Ertel IJ, Jenkin RD, et al. The effectiveness of chemotherapy for treatment of
high grade astrocy toma in children: results of a randomized trial—a report from the Childrens
Cancer Study Group. J Neurooncol. 1989;7:165–177.
104 Finlay JL, Boy ett JM, Yates AJ, et al. Randomized phase III trial in childhood high-grade
astrocy toma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day
regimen—Childrens Cancer Group. J Clin Oncol. 1995;13: 112–123.
105 Cohen KJ, Pollack IF, Zhou T, et al. Temozolomide in the treatment of high-grade gliomas
in children: a report from the Children’s Oncology Group. Neuro Oncol. 2011;13:317–323.
106 Pollack IF, Hamilton RL, Sobol RW, et al. O6-methy lguanine-DNA methy ltransferase
expression strongly correlates with outcome in childhood malignant gliomas: results from the
CCG-945 Cohort. J Clin Oncol. 2006;24:3431–3437.
107 Donson AM, Addo-Yobo SO, Handler MH, et al. MGMT promoter methy lation
correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma.
Pediatr Blood Cancer. 2007;48:403–407.
108 Finlay JL, Goldman S, Wong MC, et al. Pilot study of high-dose thiotepa and etoposide
with autologous bone marrow rescue in children and y oung adults with recurrent CNS tumors
—The Children’s Cancer Group. J Clin Oncol. 1996;14:2495–2503.
109 MacDonald TJ, Arenson EB, Ater J, et al. Phase II study of high-dose chemotherapy
before radiation in children with newly diagnosed high-grade astrocy toma: final analy sis of
Children’s Cancer Group Study 9933. Cancer. 2005;104:2862–2871.
110 MacDonald TJ, Aguilera D, Kramm CM. Treatment of high-grade glioma in children and
adolescents. Neuro Oncol. 2011;13:1049–1058.
111 McDonald MW, Shu HK, Curran WJ Jr, et al. Pattern of failure after limited margin
radiotherapy and temozolomide for glioblastoma. Int J Radiat Oncol Biol Phys. 2011;79:130–
136.
112 Hermanto U, Frija EK, Lii MJ, et al. Intensity -modulated radiotherapy (IMRT) and
conventional three-dimensional conformal radiotherapy for high-grade gliomas: does IMRT
increase the integral dose to normal brain? Int J Radiat Oncol Biol Phys. 2007;67:1135–1144.
113 Sanders RP, Kocak M, Burger PC, et al. High-grade astrocy toma in very y oung children.
Pediatr Blood Cancer. 2007;49:888–893.
114 Rorke LB. The cerebellar medulloblastoma and its relationship to primitive
neuroectodermal tumors. J Neuropathol Exp Neurol. 1983;42:1–15.
116 Rubinstein LJ. Embry onal central neuroepithelial tumors and their differentiating potential
—a cy togenetic view of a complex neuro-oncological problem. J Neurosurg. 1985;62:795–
805.
117 Zaky W. Revisiting management of pediatric brain tumors with new molecular insights.
Cell. 2016;164:844–846.
118 Gajjar A, Bowers DC, Karajannis MA, et al. Pediatric brain tumors: innovative genomic
information is transforming the diagnostic and clinical landscape. J Clin Oncol. 2015;33:2986–
2998.
119 Reddy AT, Janss AJ, Phillips PC, et al. Outcome for children with supratentorial primitive
neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer.
2000;88:2189–2193.
120 Cohen BH, Zeltzer PM, Boy ett JM, et al. Prognostic factors and treatment results for
supratentorial primitive neuroectodermal tumors in children using radiation and
chemotherapy : a Childrens Cancer Group randomized trial. J Clin Oncol. 1995;13:1687–1696.
121 Hong TS, Mehta MP, Boy ett JM, et al. Patterns of failure in supratentorial primitive
neuroectodermal tumors treated in Children’s Cancer Group Study 921, a phase III combined
modality study. Int J Radiat Oncol Biol Phys. 2004;60:204–213.
122 Jakacki RI, Burger PC, Kocak M, et al. Outcome and prognostic factors for children with
supratentorial primitive neuroectodermal tumors treated with carboplatin during
radiotherapy : a report from the Children’s Oncology Group. Pediatr Blood Cancer.
2015;62:776–783.
123 Jakacki RI, Zeltzer PM, Boy ett JM, et al. Survival and prognostic factors following
radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in
infants and children: a report of the Childrens Cancer Group. J Clin Oncol. 1995;13:1377–
1383.
124 Kosnik EJ, Boesel CP, Bay J, et al. Primitive neuroectodermal tumors of the central
nervous sy stem in children. J Neurosurg. 1978;48:741–746.
125 Pizer BL, Weston CL, Robinson KJ, et al. Analy sis of patients with supratentorial primitive
neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study. Eur J Cancer.
2006;42:1120–1128.
128 Jimenez RB, Sethi R, Depauw N, et al. Proton radiation therapy for pediatric
medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very
y oung children treated with upfront chemotherapy. Int J Radiat Oncol Biol Phys.
2013;87:120–126.
129 Timmermann B, Kortmann RD, Kuhl J, et al. Role of radiotherapy in the treatment of
supratentorial primitive neuroectodermal tumors in childhood: results of the prospective
German brain tumor trials HIT 88/89 and 91. J Clin Oncol. 2002;20:842–849.
130 McBride SM, Daganzo SM, Banerjee A, et al. Radiation is an important component of
multimodality therapy for pediatric non-pineal supratentorial primitive neuroectodermal
tumors. Int J Radiat Oncol Biol Phys. 2008;72:1319–1323.
131 Gerber NU, von Hoff K, Resch A, et al. Treatment of children with central nervous
sy stem primitive neuroectodermal tumors/pinealoblastomas in the prospective multicentric
trial HIT 2000 using hy perfractionated radiation therapy followed by maintenance
chemotherapy. Int J Radiat Oncol Biol Phys. 2014;89:863–871.
132 Puget S, Garnett M, Wray A, et al. Pediatric craniophary ngiomas: classification and
treatment according to the degree of hy pothalamic involvement. J Neurosurg. 2007;106:3–12.
133 Brastianos PK, Shankar GM, Gill CM, et al. Dramatic response of BRAF V600E mutant
papillary craniophary ngioma to targeted therapy. J Natl Cancer Inst. 2016;108.
134 Merchant TE, Williams T, Smith JM, et al. Preirradiation endocrinopathies in pediatric
brain tumor patients determined by dy namic tests of endocrine function. Int J Radiat Oncol
Biol Phys. 2002;54:45–50.
139 Vinchon M, Weill J, Delestret I, et al. Craniophary ngioma and hy pothalamic obesity in
children. Childs Nerv Syst. 2009;25:347–352.
140 Clark AJ, Cage TA, Aranda D, et al. A sy stematic review of the results of surgery and
radiotherapy on tumor control for pediatric craniophary ngioma. Childs Nerv Syst.
2013;29:231–238.
141 Merchant TE, Kun LE, Hua CH, et al. Disease control after reduced volume conformal
and intensity modulated radiation therapy for childhood craniophary ngioma. Int J Radiat
Oncol Biol Phys. 2013;85:e187–e192.
142 Luu QT, Loredo LN, Archambeau JO, et al. Fractionated proton radiation treatment for
pediatric craniophary ngioma: preliminary report. Cancer J. 2006;12:155–159.
143 Pulsifer MB, Sethi RV, Kuhlthau KA, et al. Early cognitive outcomes following proton
radiation in pediatric patients with brain and central nervous sy stem tumors. Int J Radiat
Oncol Biol Phys. 2015;93:400–407.
144 Hasegawa T, Kobay ashi T, Kida Y. Tolerance of the optic apparatus in single-fraction
irradiation using stereotactic radiosurgery : evaluation in 100 patients with
craniophary ngioma. Neurosurgery. 2010;66:688–694; discussion 94–95.
145 Merchant TE, Kiehna EN, Kun LE, et al. Phase II trial of conformal radiation therapy
for pediatric patients with craniophary ngioma and correlation of surgical factors and
radiation dosimetry with change in cognitive function. J Neurosurg. 2006;104:94–102.
146 Desai SS, Paulino AC, Mai WY, et al. Radiation-induced moy amoy a sy ndrome. Int J
Radiat Oncol Biol Phys. 2006;65:1222–1227.
147 Hetelekidis S, Barnes PD, Tao ML, et al. 20-y ear experience in childhood
craniophary ngioma. Int J Radiat Oncol Biol Phys. 1993;27:189–195.
148 Kalapurakal JA, Goldman S, Hsieh YC, et al. Clinical outcome in children with recurrent
craniophary ngioma after primary surgery. Cancer J. 2000;6:388–393.
149 Kalapurakal JA, Goldman S, Hsieh YC, et al. Clinical outcome in children with
craniophary ngioma treated with primary surgery and radiotherapy deferred until relapse.
Med Pediatr Oncol. 2003;40:214–218.
150 Zheng J, Fang Y, Cai BW, et al. Intracy stic bleomy cin for cy stic craniophary ngiomas in
children. Cochrane Database Syst Rev. 2014;9:CD008890.
153 Combs SE, Thilmann C, Huber PE, et al. Achievement of long-term local control in
patients with craniophary ngiomas using high precision stereotactic radiotherapy. Cancer.
2007;109:2308–2314.
154 Boehling NS, Grosshans DR, Bluett JB, et al. Dosimetric comparison of three-dimensional
conformal proton radiotherapy, intensity -modulated proton therapy, and intensity -modulated
radiotherapy for treatment of pediatric craniophary ngiomas. Int J Radiat Oncol Biol Phys.
2012;82:643–652.
155 Regine WF, Kramer S. Pediatric craniophary ngiomas: long term results of combined
treatment with surgery and radiation. Int J Radiat Oncol Biol Phys. 1992;24:611–617.
157 Varlotto JM, Flickinger JC, Kondziolka D, et al. External beam irradiation of
craniophary ngiomas: long-term analy sis of tumor control and morbidity. Int J Radiat Oncol
Biol Phys. 2002;54:492–499.
158 Rajan B, Ashley S, Gorman C, et al. Craniophary ngioma—a long-term results following
limited surgery and radiotherapy. Radiother Oncol. 1993;26:1–10.
159 Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: a clinical
analy sis of 153 histologically verified cases. J Neurosurg. 1997;86:446–455.
160 Villano JL, Propp JM, Porter KR, et al. Malignant pineal germ-cell tumors: an analy sis of
cases from three tumor registries. Neuro Oncol. 2008;10:121–130.
161 Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and y oung
adults. N Engl J Med. 2000;343:998–1007.
162 MacDonald SM, Desai N, Heller G, et al. MRI changes in the “normal” pineal gland
following chemotherapy for suprasellar germ cell tumors. Pediatr Hematol Oncol.
2008;25:5–15.
163 Allen J, Chacko J, Donahue B, et al. Diagnostic sensitivity of serum and lumbar CSF
bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer. 2012;59:1180–1182.
164 Baranzelli MC, Patte C, Bouffet E, et al. Nonmetastatic intracranial germinoma: the
experience of the French Society of Pediatric Oncology. Cancer. 1997;80:1792–1797.
165 Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT 96: final report of outcome of
a prospective, multinational nonrandomized trial for children and adults with intracranial
germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal
primary site irradiation for patients with localized disease. Neuro Oncol. 2013;15:788–796.
166 Bamberg M, Kortmann RD, Calaminus G, et al. Radiation therapy for intracranial
germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J Clin
Oncol. 1999;17:2585–2592.
167 Cho J, Choi JU, Kim DS, et al. Low-dose craniospinal irradiation as a definitive treatment
for intracranial germinoma. Radiother Oncol. 2009;91:75–79.
168 Eom KY, Kim IH, Park CI, et al. Upfront chemotherapy and involved-field radiotherapy
results in more relapses than extended radiotherapy for intracranial germinomas:
modification in radiotherapy volume might be needed. Int J Radiat Oncol Biol Phys.
2008;71:667–671.
169 Haddock MG, Schild SE, Scheithauer BW, et al. Radiation therapy for histologically
confirmed primary central nervous sy stem germinoma. Int J Radiat Oncol Biol Phys.
1997;38:915–923.
170 Hardenbergh PH, Golden J, Billet A, et al. Intracranial germinoma: the case for lower
dose radiation therapy. Int J Radiat Oncol Biol Phys. 1997;39:419–426.
172 Allen JC, DaRosso RC, Donahue B, et al. A phase II trial of preirradiation carboplatin in
newly diagnosed germinoma of the central nervous sy stem. Cancer. 1994;74:940–944.
173 Wolden SL, Wara WM, Larson DA, et al. Radiation therapy for primary intracranial
germ-cell tumors. Int J Radiat Oncol Biol Phys. 1995;32:943–949.
174 Matsutani M; Japanese Pediatric Brain Tumor Study G. Combined chemotherapy and
radiation therapy for CNS germ cell tumors—the Japanese experience. J Neurooncol.
2001;54:311–316.
176 Calaminus G, Bamberg M, Baranzelli MC, et al. Intracranial germ cell tumors: a
comprehensive update of the European data. Neuropediatrics. 1994;25:26–32.
177 Robertson PL, DaRosso RC, Allen JC. Improved prognosis of intracranial non-
germinoma germ cell tumors with multimodality therapy. J Neurooncol. 1997;32:71–80.
178 Regis J, Bouillot P, Rouby -Volot F, et al. Pineal region tumors and the role of stereotactic
biopsy : review of the mortality, morbidity, and diagnostic rates in 370 cases. Neurosurgery.
1996;39:907–912; discussion 12–14.
179 Calaminus G, Bamberg M, Harms D, et al. AFP/beta-HCG secreting CNS germ cell
tumors: long-term outcome with respect to initial sy mptoms and primary tumor resection—
results of the cooperative trial MAKEI 89. Neuropediatrics. 2005;36:71–77.
180 Reddy AT, Wellons JC III, Allen JC, et al. Refining the staging evaluation of pineal region
germinoma using neuroendoscopy and the presence of preoperative diabetes insipidus. Neuro
Oncol. 2004;6:127–133.
181 Haas-Kogan DA, Missett BT, Wara WM, et al. Radiation therapy for intracranial germ
cell tumors. Int J Radiat Oncol Biol Phys. 2003;56:511–618.
182 Rogers SJ, Mosleh-Shirazi MA, Saran FH. Radiotherapy of localised intracranial
germinoma: time to sever historical ties? Lancet Oncol. 2005;6:509–519.
183 Shikama N, Ogawa K, Tanaka S, et al. Lack of benefit of spinal irradiation in the primary
treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180 patients.
Cancer. 2005;104:126–134.
184 Hasegawa T, Kondziolka D, Hadjipanay is CG, et al. The role of radiosurgery for the
treatment of pineal parenchy mal tumors. Neurosurgery. 2002;51:880–889.
185 Kellie SJ, Boy ce H, Dunkel IJ, et al. Primary chemotherapy for intracranial
nongerminomatous germ cell tumors: results of the second international CNS germ cell study
group protocol. J Clin Oncol. 2004;22:846–853.
186 Buckner JC, Peethambaram PP, Smithson WA, et al. Phase II trial of primary
chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin Oncol.
1999;17:933–940.
187 Allen JC, Kim JH, Packer RJ. Neoadjuvant chemotherapy for newly diagnosed germ-
cell tumors of the central nervous sy stem. J Neurosurg. 1987;67:65–70.
188 Sutton LN, Radcliffe J, Goldwein JW, et al. Quality of life of adult survivors of
germinomas treated with craniospinal irradiation. Neurosurgery. 1999;45:1292–1297;
discussion 7–8.
189 Merchant TE, Davis BJ, Sheldon JM, et al. Radiation therapy for relapsed CNS
germinoma after primary chemotherapy. J Clin Oncol. 1998;16:204–209.
190 Goldman S, Bouffet E, Fisher PG, et al. Phase II trial assessing the ability of neoadjuvant
chemotherapy with or without second-look surgery to eliminate measurable disease for
nongerminomatous germ cell tumors: a Children’s Oncology Group Study. J Clin Oncol.
2015;33:2464–2471.
191 Modak S, Gardner S, Dunkel IJ, et al. Thiotepa-based high-dose chemotherapy with
autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors. J
Clin Oncol. 2004;22:1934–1943.
192 Sung DI, Harisiadis L, Chang CH. Midline pineal tumors and suprasellar germinomas:
highly curable by irradiation. Radiology. 1978;128:745–751.
193 Alapetite C, Brisse H, Patte C, et al. Pattern of relapse and outcome of non-metastatic
germinoma patients treated with chemotherapy and limited field radiation: the SFOP
experience. Neuro Oncol. 2010;12:1318–1325.
194 Murray MJ, Bartels U, Nishikawa R, et al. Consensus on the management of intracranial
germ-cell tumours. Lancet Oncol. 2015;16:e470–e477.
195 Matsutani M, Ushio Y, Abe H, et al. Combined chemotherapy and radiation therapy for
central nervous sy stem germ cell tumors: preliminary results of a Phase II study of the
Japanese Pediatric Brain Tumor Study Group. Neurosurg Focus. 1998;5:e7.
196 Rich TA, Cassady JR, Strand RD, et al. Radiation therapy for pineal and suprasellar germ
cell tumors. Cancer. 1985;55:932–940.
1 Gurney JG, Davis S, Severson RK, et al. Trends in cancer incidence among children in the
U.S. Cancer. 1996;78:532–541.
2 Barnholtz-Sloan JS, Sloan AE, Schwartz AG. Relative survival rates and patterns of diagnosis
analy zed by time period for individuals with primary malignant brain tumor, 1973–1997. J
Neurosurg. 2003;99:458–466.
3 McNeil DE, Cote TR, Clegg L, et al. Incidence and trends in pediatric malignancies
medulloblastoma/primitive neuroectodermal tumor: a SEER update—Surveillance
Epidemiology and End Results. Med Pediatr Oncol. 2002;39:190–194.
7 Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours of the Central
Nervous System. 4th ed. Geneva, Switzerland: World Health Organization; 2007.
9 Wechsler-Rey a R, Scott MP. The developmental biology of brain tumors. Annu Rev
Neurosci. 2001;24:385–428.
14 de Bont JM, Packer RJ, Michiels EM, et al. Biological background of pediatric
medulloblastoma and ependy moma: a review from a translational research perspective.
Neuro Oncol. 2008;10:1040–1060.
15 Lamont JM, McManamy CS, Pearson AD, et al. Combined histopathological and
molecular cy togenetic stratification of medulloblastoma patients. Clin Cancer Res.
2004;10:5482–5493.
16 Brown HG, Kepner JL, Perlman EJ, et al. “Large cell/anaplastic” medulloblastomas: a
Pediatric Oncology Group study. J Neuropathol Exp Neurol. 2000;59:857–865.
17 Eberhart CG, Kepner JL, Goldthwaite PT, et al. Histopathologic grading of
medulloblastomas: a Pediatric Oncology Group study. Cancer. 2002;94:552–560.
19 Gajjar A, Bowers DC, Karajannis MA, et al. Pediatric brain tumors: innovative genomic
information is transforming the diagnostic and clinical landscape. J Clin Oncol.
2015;33(27):2986–2998.
23 Northcott PA, Shih DJ, Peacock J, et al. Subgroup-specific structural variation across 1,000
medulloblastoma genomes. Nature. 2012;488(7409):49–56.
24 Northcott PA, Shih DJ, Remke M, et al. Rapid, reliable, and reproducible molecular sub-
grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123(4):615–626.
25 Tay lor MD, Northcott PA, et al. Molecular subgroups of medulloblastoma: the current
consensus. Acta Neuropathol. 2012;123(4):465–472.
27 Amlashi SF, Riffaud L, Brassier G, et al. Nevoid basal cell carcinoma sy ndrome: relation
with desmoplastic medulloblastoma in infancy —a population-based study and review of the
literature. Cancer. 2003;98:618–624.
28 Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by
hedgehog pathway blockade. Science. 2002;297:1559–1561.
29 Ellison DW, Onilude OE, Lindsey JC, et al. Beta-catenin status predicts a favorable
outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group
Brain Tumour Committee. J Clin Oncol. 2005;23:7951–7957.
30 Clifford SC, Lusher ME, Lindsey JC, et al. Wnt/Wingless pathway activation and
chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas
associated with a favorable prognosis. Cell Cycle. 2006;5:2666–2670.
31 Gilbertson R. Paediatric embry onic brain tumours: biological and clinical relevance of
molecular genetic abnormalities. Eur J Cancer. 2002;38:675–685.
33 Fouladi M, Gajjar A, Boy ett JM, et al. Comparison of CSF cy tology and spinal magnetic
resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or
primitive neuroectodermal tumor. J Clin Oncol. 1999;17:3234–3237.
34 Helton KJ, Gajjar A, Hill DA, et al. Medulloblastoma metastatic to the suprasellar region
at diagnosis: a report of six cases with clinicopathologic correlation. Pediatr Neurosurg.
2002;37:111–117.
35 Chang CH, Housepian EM, Herbert C Jr. An operative staging sy stem and a megavoltage
radiotherapeutic technic for cerebellar medulloblastomas. Radiology. 1969;93:1351–1359.
36 Thomas PR, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: final analy sis of
trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol.
2000;18:3004–3011.
37 Zeltzer PM, Boy ett JM, Finlay JL, et al. Metastasis stage, adjuvant treatment, and residual
tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s
Cancer Group 921 randomized phase III study. J Clin Oncol. 1999;17:832–845.
38 Albright AL, Wisoff JH, Zeltzer PM, et al. Effects of medulloblastoma resections on
outcome in children: a report from the Children’s Cancer Group. Neurosurgery. 1996;38:265–
271.
39 Packer RJ, Sutton LN, Elterman R, et al. Outcome for children with medulloblastoma
treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg.
1994;81:690–698.
41 Packer RJ, Rood BR, MacDonald TJ. Medulloblastoma: present concepts of stratification
into risk groups. Pediatr Neurosurg. 2003;39:60–67.
42 Sanders RP, Onar A, Boy ett JM, et al. M1 Medulloblastoma: high risk at any age. J
Neurooncol. 2008;90:351–355.
43 Bourne JP, Gey er R, Berger M, et al. The prognostic significance of postoperative residual
contrast enhancement on CT scan in pediatric patients with medulloblastoma. J Neurooncol.
1992;14:263–270.
44 Gajjar A, Sanford RA, Bhargava R, et al. Medulloblastoma with brain stem involvement:
the impact of gross total resection on outcome. Pediatr Neurosurg. 1996;25:182–187.
45 Douglas JG, Barker JL, Ellenbogen RG, et al. Concurrent chemotherapy and reduced-dose
cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-
risk medulloblastoma: efficacy and patterns of failure. Int J Radiat Oncol Biol Phys.
2004;58:1161–1164.
46 Tay lor RE, Bailey CC, Robinson KJ, et al. Outcome for patients with metastatic (M2-3)
medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer.
2005;41:727–734.
47 von HK, Hinkes B, Gerber NU, et al. Long-term outcome and clinical prognostic factors in
children with medulloblastoma treated in the prospective randomised multicentre trial
HIT’91. Eur J Cancer. 2009;45:1209–1217.
48 Aguiar PH, Plese JP, Ciquini O, et al. Transient mutism following a posterior fossa
approach to cerebellar tumors in children: a critical review of the literature. Childs Nerv Syst.
1995;11:306–310.
49 Cochrane DD, Gustavsson B, Poskitt KP, et al. The surgical and natural morbidity of
aggressive resection for posterior fossa tumors in childhood. Pediatr Neurosurg. 1994;20:19–
29.
50 Eberhart CG, Cohen KJ, Tihan T, et al. Medulloblastomas with sy stemic metastases:
evaluation of tumor histopathology and clinical behavior in 23 patients. J Pediatr Hematol
Oncol. 2003;25:198–203.
51 Miller NG, Reddick WE, Kocak M, et al. Cerebellocerebral diaschisis is the likely
mechanism of postsurgical posterior fossa sy ndrome in pediatric patients with midline
cerebellar tumors. Am J Neuroradiol. 2010;31;288–294.
52 Korah MP, Esiashvili N, Mazewski CM, et al. Incidence, risks, and sequelae of posterior
fossa sy ndrome in pediatric medulloblastoma. Int J Radiat Oncol Biol Phys. 2010;77(1):106–
112.
54 Avula S, Mallucci C, Kumar R, et al. Posterior fossa sy ndrome following brain tumour
resection: review of pathophy siology and a new hy pothesis on its pathogenesis. Childs Nerv
Syst. 2015;31(10):1859–1867.
57 Cutler EC, Sosman MC, Vaughan WW. Place of radiation in treatment of cerebellar
medulloblastoma: report of 20 cases. Am J Roentgenol Radium Ther Nucl Med. 1936;35:429–
453.
58 Bloom HJG, Glees J, Bell J. The treatment and prognosis of medulloblastoma in children.
AJR Am J Roentgenol. 1969;105:43–62.
60 Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with medulloblastomas
with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy : a Children’s
Cancer Group Study. J Clin Oncol. 1999;17:2127–2136.
61 Merchant TE, Kun LE, Krasin MJ, et al. Multi-institution prospective trial of reduced-dose
craniospinal irradiation (23.4 Gy ) followed by conformal posterior fossa (36 Gy ) and
primary site irradiation (55.8 Gy ) and dose-intensive chemotherapy for average-risk
medulloblastoma. Int J Radiat Oncol Biol Phys. 2008;70:782–787.
62 Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy
followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J
Clin Oncol. 2006;24:4202–4208.
63 Tay lor RE, Bailey CC, Robinson KJ, et al. Impact of radiotherapy parameters on outcome
in the International Society of Paediatric Oncology /United Kingdom Children’s Cancer Study
Group PNET-3 study of preradiotherapy chemotherapy for M0–M1 medulloblastoma. Int J
Radiat Oncol Biol Phys. 2004;58:1184–1193.
64 Mulhern RK, Merchant TE, Gajjar A, et al. Late neurocognitive sequelae in survivors of
brain tumours in childhood. Lancet Oncol. 2004;5:399–408.
65 Merchant TE, Kiehna EN, Li C, et al. Modeling radiation dosimetry to predict cognitive
outcomes in pediatric patients with CNS embry onal tumors including medulloblastoma. Int J
Radiat Oncol Biol Phys. 2006;65:210–221.
68 Heideman RL, Kovnar EH, Kellie SJ, et al. Preirradiation chemotherapy with carboplatin
and etoposide in newly diagnosed embry onal pediatric CNS tumors. J Clin Oncol.
1995;13:2247–2254.
69 Kovnar EH, Kellie SJ, Horowitz ME, et al. Preirradiation cisplatin and etoposide in the
treatment of high-risk medulloblastoma and other malignant embry onal tumors of the central
nervous sy stem: a phase II study. J Clin Oncol. 1990;8:330–336.
71 Stewart CF, Iacono LC, Chintagumpala M, et al. Results of a phase II upfront window of
pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial
primitive neuroectodermal tumor. J Clin Oncol. 2004;22:3357–3365.
73 Jakacki RI, Feldman H, Jamison C, et al. A pilot study of preirradiation chemotherapy and
1800 cGy craniospinal irradiation in y oung children with medulloblastoma. Int J Radiat Oncol
Biol Phys. 2004;60:531–536.
75 Tarbell NJ, Friedman HS, Yock TI, et al. High-Risk Medulloblastoma: A Pediatric
Oncology Group (POG 9031) Randomized Trial of Chemotherapy before or after Radiation
Therapy, J Clin Oncol. 2013;31(23):2936–41.
76 Shih CS, Hale GA, Gronewold L, et al. High-dose chemotherapy with autologous stem cell
rescue for children with recurrent malignant brain tumors. Cancer. 2008;112:1345–1353.
77 Butturini AM, Jacob M, Aguajo J, et al. High-dose chemotherapy and autologous
hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and
supratentorial primitive neuroectodermal tumors: the impact of prior radiotherapy on
outcome. Cancer. 2009;115:2956–2963.
81 Saran F, Baumert BG, Creak AL, et al. Hy pofractionated stereotactic radiotherapy in the
management of recurrent or residual medulloblastoma/PNET. Pediatr Blood Cancer.
2008;50:554–560.
83 Landberg TG, Lindgren ML, Cavallin-Stahl EK, et al. Improvements in the radiotherapy
of medulloblastoma, 1946–1975. Cancer. 1980;45:670–678.
84 Wara WM, Le QT, Sneed PK, et al. Pattern of recurrence of medulloblastoma after low-
dose craniospinal radiotherapy. Int J Radiat Oncol Biol Phys. 1994;30:551–556.
85 Sun LM, Yeh SA, Wang CJ, et al. Postoperative radiation therapy for medulloblastoma—
high recurrence rate in the subfrontal region. J Neurooncol. 2002;58:77–85.
89 Kimura H, Ng JM, Curran T. Transient inhibition of the Hedgehog pathway in y oung mice
causes permanent defects in bone structure. Cancer Cell. 2008;13:249–260.
91 Merchant TE, Happersett L, Finlay JL, et al. Preliminary results of conformal radiation
therapy for medulloblastoma. Neurooncol. 1999;1:177–187.
92 Williams GB, Kun LE, Thompson JW, et al. Hearing loss as a late complication of
radiotherapy in children with brain tumors. Ann Otol Rhinol Laryngol. 2005;114:328–331.
93 Hua C, Bass JK, Khan R, et al. Hearing loss after radiotherapy for pediatric brain tumors:
effect of cochlear dose. Int J Radiat Oncol Biol Phys. 2008;72:892–899.
94 Merchant TE, Gould CJ, Xiong X, et al. Early neuro-otologic effects of three-dimensional
irradiation in children with primary brain tumors. Int J Radiat Oncol Biol Phys. 2004;58:1194–
1207.
95 Fukunaga-Johnson N, Lee JH, Sandler HM, et al. Patterns of failure following treatment
for medulloblastoma: is it necessary to treat the entire posterior fossa? Int J Radiat Oncol Biol
Phys. 1998;42:143–146.
97 Merchant TE, Wang MH, Haida T, et al. Medulloblastoma: long-term results for patients
treated with definitive radiation therapy during the computed tomography era. Int J Radiat
Oncol Biol Phys. 1996;36:29–35.
98 Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines is correlated with
radioresponsiveness of human tumors: analy sis of 101 published survival curves. Int J Radiat
Oncol Biol Phys. 1985;11:1699–1707.
99 Jenkin D, Goddard K, Armstrong D, et al. Posterior fossa medulloblastoma in childhood:
treatment results and a proposal for a new staging sy stem. Int J Radiat Oncol Biol Phys.
1990;19:265–274.
100 Goldwein JW, Radcliffe J, Johnson J, et al. Updated results of a pilot study of low dose
craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive
neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol Biol Phys. 1996;34:899–904.
101 Hudes RS, Gajjar A, Heideman RL, et al. High dose hy perfractionated craniospinal
irradiation (HF-CSI): feasibility, acute toxicity, outcome and late sequelae. Proceedings of the
40th Annual ASTRO Meeting, 1999;185.
102 Prados MD, Wara WM, Edwards MS, et al. Hy per-fractionated craniospinal radiation
therapy for primitive neuroectodermal tumors: early results of a pilot study. Int J Radiat
Oncol Biol Phys. 1994;28:431–438.
103 Tatcher M, Glicksman AS. Field matching considerations in craniospinal irradiation. Int J
Radiat Oncol Biol Phys. 1989;17:865–869.
104 Mah K, Danjoux CE, Manship S, et al. Computed tomographic simulation of craniospinal
fields in pediatric patients: improved treatment accuracy and patient comfort. Int J Radiat
Oncol Biol Phys. 1998;41:997–1003.
105 Parker WA, Freeman CR. A simple technique for craniospinal radiotherapy in the supine
position. Radiother Oncol. 2006;78:217–222.
106 South M, Chiu JK, Teh BS, et al. Supine craniospinal irradiation using intrafractional
junction shifts and field-in-field dose shaping: early experience at Methodist Hospital. Int J
Radiat Oncol Biol Phys. 2008;71:477–483.
108 Dunbar SF, Barnes PD, Tarbell NJ. Radiologic determination of the caudal border of the
spinal field in cranial spinal irradiation. Int J Radiat Oncol Biol Phys. 1993;26:669–673.
109 Halperin EC. Concerning the inferior portion of the spinal radiotherapy field for
malignancies that disseminate via the cerebrospinal fluid. Int J Radiat Oncol Biol Phys.
1993;26:357–362.
110 Parker W, Filion E, Roberge D, et al. Intensity -modulated radiotherapy for craniospinal
irradiation: target volume considerations, dose constraints, and competing risks. Int J Radiat
Oncol Biol Phys. 2007;69:251–257.
111 Wilson VC, McDonough J, Tochner Z. Proton beam irradiation in pediatric oncology : an
overview. J Pediatr Hematol Oncol. 2005;27:444–448.
112 Yock TI, Tarbell NJ. Technology insight: proton beam radiotherapy for treatment in
pediatric brain tumors. Nat Clin Pract Oncol. 2004;1:97–103.
113 Mu X, Bjork-Eriksson T, Nill S, et al. Does electron and proton therapy reduce the risk of
radiation induced cancer after spinal irradiation for childhood medulloblastoma?—a
comparative treatment planning study. Acta Oncol. 2005;44:554–562.
114 St Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional
X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat
Oncol Biol Phys. 2004;58:727–734.
115 Timmermann B, Lomax AJ, Nobile L, et al. Novel technique of craniospinal axis proton
therapy with the spot-scanning sy stem: avoidance of patching multiple fields and optimized
ventral dose distribution. Strahlenther Onkol. 2007;183:685–688.
116 Yom SS, Frija EK, Mahajan A, et al. Field-in-field technique with intrafractionally
modulated junction shifts for craniospinal irradiation. Int J Radiat Oncol Biol Phys.
2007;69:1193–1198.
117 Kiltie AE, Povall JM, Tay lor RE. The need for the moving junction in craniospinal
irradiation. Br J Radiol. 2000;73:650–654.
119 Cochran DM, Yock TI, Adams JA, et al. Radiation dose to the lens during craniospinal
irradiation—an improvement in proton radiotherapy technique. Int J Radiat Oncol Biol Phys.
2008;70:1336–1342.
120 Huang E, Teh BS, Strother DR, et al. Intensity -modulated radiation therapy for pediatric
medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys.
2002;52:599–605.
121 Lee CT, Bilton SD, Famiglietti RM, et al. Treatment planning with protons for pediatric
retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other
conformal techniques? Int J Radiat Oncol Biol Phys. 2005;63:362–372.
122 Paulino AC, Wen BC, May r NA, et al. Protracted radiotherapy treatment duration in
medulloblastoma. Am J Clin Oncol. 2003;26:55–59.
123 del Charco JO, Bolek TW, McCollough WM, et al. Medul-loblastoma: time-dose
relationship based on a 30-y ear review. Int J Radiat Oncol Biol Phys. 1998;42:147–154.
125 Marks LB, Halperin EC. The use of G-CSF during craniospinal irradiation. Int J Radiat
Oncol Biol Phys. 1993;26:905–906.
126 Childhood Brain Tumor Consortium. Supplement Report: Primary Brain Tumors in the
United States, 2004. Hinsdale, IL: Central Brain Tumor Registry of the United States, 2008.
127 Larouche V, Huang A, Bartels U, et al. Tumors of the central nervous sy stem in the first
y ear of life. Pediatr Blood Cancer. 2007;49:1074–1082.
128 Duffner PK, Horowitz ME, Krischer JP, et al. The treatment of malignant brain tumors in
infants and very y oung children: an update of the Pediatric Oncology Group experience.
Neuro Oncol. 1999;1:152–161.
129 Bloom HJ, Glees J, Bell J, et al. The treatment and long-term prognosis of children with
intracranial tumors: a study of 610 cases, 1950–1981. Int J Radiat Oncol Biol Phys.
1990;18:723–745.
130 Cohen BH, Packer RJ, Siegel KR, et al. Brain tumors in children under 2 y ears: treatment,
survival and long-term prognosis. Pediatr Neurosurg. 1993;19:171–179.
131 Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delay ed
radiation in children less than three y ears of age with malignant brain tumors. N Engl J Med.
1993;328:1725–1731.
132 Mey ers SP, Khademian ZP, Biegel JA, et al. Primary intracranial aty pical
teratoid/rhabdoid tumors of infancy and childhood: MRI features and patient outcomes. AJNR
Am J Neuroradiol. 2006;27:962–971.
133 Packer RJ, Biegel JA, Blaney S, et al. Aty pical teratoid/rhabdoid tumor of the central
nervous sy stem: report on workshop. J Pediatr Hematol Oncol. 2002;24:337–342.
134 Taratuto AL, Monges J, Ly ly k P, et al. Superficial cerebral astrocy toma attached to dura
—report of six cases in infants. Cancer. 1984;54:2505–2512.
135 Lonnrot K, Terho M, Kahara V, et al. Desmoplastic infantile ganglioglioma: novel aspects
in clinical presentation and genetics. Surg Neurol. 2007;68:304–308.
136 Jenkin D, Greenberg M, Hoffman H, et al. Brain tumors in children: long-term survival
after radiation treatment. Int J Radiat Oncol Biol Phys. 1995;31:445–451.
137 Tekautz TM, Fuller CE, Blaney S, et al. Aty pical teratoid/ rhabdoid tumors (AT/RT):
improved survival in children 3 y ears of age and older with radiation therapy and high-dose
alky lator-based chemotherapy. J Clin Oncol. 2005;23:1491–1499.
138 Wisoff JH, Boy ett JM, Berger MS, et al. Current neurosurgical management and the
impact of the extent of resection in the treatment of malignant gliomas of childhood: a report
of the Children’s Cancer Group trial no. CCG-945. J Neurosurg. 1998;89:52–59.
139 Albright AL, Wisoff JH, Zeltzer PM, et al. Current neurosurgical treatment of
medulloblastoma in children. Pediatr Neurosurg. 1989;177:633–641.
140 Walter AW, Mulhern RK, Gajjar A, et al. Survival and neurodevelopmental outcome of
y oung children with medulloblastoma at St. Jude Children’s Research Hospital. J Clin Oncol.
1999;17:3720–3728.
141 Duffner PK, Krischer JP, Burger PC, et al. Treatment of infants with malignant gliomas:
the Pediatric Oncology Group experience. J Neuro Oncol. 1996;28:245–256.
142 Dufour C, Grill J, Lellouch-Tubiana A, et al. High-grade glioma in children under 5 y ears
of age: a chemotherapy only approach with the BBSFOP protocol. Eur J Cancer.
2006;42:2939–2945.
143 Frappaz D. High-grade gliomas: babies are not small adults! Pediatr Blood Cancer.
2007;49:879–880.
144 Sanders RP, Kocak M, Burger PC, et al. High-grade astrocy toma in very y oung children.
Pediatr Blood Cancer. 2007;49:888–893.
145 Jakacki RI, Zeltzer PM, Boy ett JM, et al. Survival and prognostic factors following
radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in
infants and children: a report of the Childrens Cancer Group. J Clin Oncol. 1995;13:1377–
1383.
146 Gey er JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred
radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer
Group. J Clin Oncol. 2005;23:7621–7231.
149 Dhall G, Grodman H, Ji L, et al. Outcome of children less than three y ears old at
diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head
Start” I and II protocols. Pediatr Blood Cancer. 2008;50:1169–1175.
151 Grundy RG, Wilne SA, Weston CL, et al. Primary postoperative chemotherapy without
radiotherapy for intracranial ependy moma in children: the UKCCSG/SIOP prospective study.
Lancet Oncol. 2007;8:696–705.
152 Shim KW, Kim DS, Choi JU. The history of ependy moma management. Childs Nerv
Syst. 2009;25:1167–1183.
153 Massimino M, Giangaspero F, Garre ML, et al. Salvage treatment for childhood
ependy moma after surgery only : pitfalls of omitting “at once” adjuvant treatment. Int J
Radiat Oncol Biol Phys. 2006;65:1440–1445.
154 Qian X, Goumnerova LC, De GU, et al. Cerebrospinal fluid cy tology in patients with
ependy moma: a bi-institutional retrospective study. Cancer. 2008;114:307–314.
155 Gey er J, Zelter P, Boy ett J, et al. Survival of infants with primitive neuroectodermal
tumors or malignant ependy momas of the CNS treated with eight drugs in 1 day : a report
from the Children’s Cancer Group. J Clin Oncol. 1994;12:1607–1615.
156 Rutkowski S, Gerber NU, von HK, et al. Treatment of early childhood medulloblastoma
by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol. 2009;11:201–210.
157 Hong TS, Mehta MP, Boy ett JM, et al. Patterns of treatment failure in infants with
primitive neuroectodermal tumors who were treated on CCG-921: a phase III combined
modality study. Pediatr Blood Cancer. 2005;45:676–682.
158 Ridola V, Grill J, Doz F, et al. High-dose chemotherapy with autologous stem cell rescue
followed by posterior fossa irradiation for local medulloblastoma recurrence or progression
after conventional chemotherapy. Cancer. 2007;110:156–163.
159 Blaney SM, Kocak M, Gajjar A, et al. Pilot study of sy stemic and intrathecal
mafosfamide followed by conformal radiation for infants with intracranial central nervous
sy stem tumors: a pediatric brain tumor consortium study (PBTC-001). J Neurooncol.
2012;109(3):565–571.
160 Rorke LB, Packer RJ, Biegel JA. Central nervous sy stem aty pical teratoid/rhabdoid
tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996;85:56–65.
161 Squire SE, Chan MD, Marcus KJ. Aty pical teratoid/rhabdoid tumor: the controversy
behind radiation therapy. J Neurooncol. 2007;81:97–111.
162 Biegel JA, Fogelgren B, Zhou JY, et al. Mutations of the INI1 rhabdoid tumor suppressor
gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous
sy stem. Clin Cancer Res. 2000;6:2759–2763.
163 Biegel JA, Kalpana G, Knudsen ES, et al. The role of INI1 and the SWI/SNF complex in
the development of rhabdoid tumors: meeting summary from the workshop on childhood
aty pical teratoid/rhabdoid tumors. Cancer Res. 2002;62:323–328.
164 Burger PC, Yu IT, Tihan T, et al. Aty pical teratoid/rhabdoid tumor of the central nervous
sy stem: a highly malignant tumor of infancy and childhood frequently mistaken for
medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol. 1998;22:1083–1092.
165 Buscariollo DL, Park HS, Roberts KB, et al. Survival outcomes in aty pical teratoid
rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and
End Results analy sis. Cancer. 2012;118(17):4212–4219.
166 Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children
with newly diagnosed CNS aty pical teratoid rhabdoid tumor. J Clin Oncol. 2009;27:385–389.
167 Slavc I, Chocholous M, Leiss U, et al. Aty pical teratoid rhabdoid tumor: improved long-
term survival with an intensive multimodal therapy and delay ed radiotherapy —The Medical
University of Vienna Experience 1992–2012. Cancer Med. 2014;3(1):91–100.
168 Duffner PK, Kun LE, Burger PC, et al. Postoperative chemotherapy and delay ed
radiation in infants and very y oung children with choroid plexus carcinomas—the Pediatric
Oncology Group. Pediatr Neurosurg. 1995;22:189–196.
169 Krishnan S, Brown PD, Scheithauer BW, et al. Choroid plexus papillomas: a single
institutional experience. J Neurooncol. 2004;68:49–55.
171 Bahar M, Kordes U, Tekautz T, et al. Radiation therapy for choroid plexus carcinoma
patients with Li–Fraumeni sy ndrome: advantageous or detrimental? Anticancer Res.
2015;35(5):3013–3017.
172 Ater JL, van Ey s J, Woo SY, et al. MOPP chemotherapy without irradiation as primary
postsurgical therapy for brain tumors in infants and y oung children. J Neurooncol.
1997;32:243–252.
173 Strother D, Kepner J, Aronin P, et al. Dose-intensive (DI) chemotherapy (CT) prolongs
event-free survival (EFS) for very y oung children with ependy moma (EP)—results of
Pediatric Oncology Group (POG) study 9233. Proc Am Soc Clin Oncol. 2000;19:585a
(abstract 2302).
174 Cohen BH, Gey er JR, Miller DC, et al.. Pilot study of intensive chemotherapy with
peripheral hematopoietic cell support for children less than 3 y ears of age with malignant
brain tumors, the CCG-99703 Phase I/II Study —a report from the Children’s Oncology
Group. Pediatr Neurol. 2015;53(1):31–46.
175 Blaney SM, Boy ett J, Friedman H, et al. Phase I clinical trial of mafosfamide in infants
and children aged 3 y ears or y ounger with newly diagnosed embry onal tumors: a pediatric
brain tumor consortium study (PBTC-001). J Clin Oncol. 2005;23:525–531.
176 Blaney SM, Tagen M, Onar-Thomas A, et al. A phase-1 pharmacokinetic optimal dosing
study of intraventricular topotecan for children with neoplastic meningitis: a Pediatric Brain
Tumor Consortium study. Pediatr Blood Cancer. 2013;60(4):627–632.
177 Murphy ES, Merchant TE, Wu S, et al. Necrosis after craniospinal irradiation: results
from a prospective series of children with central nervous sy stem embry onal tumors. Int J
Radiat Oncol Biol Phys. 2012;83(5):e655–e660.
178 Indelicato DJ, Flampouri S, Rotondo RL, et al. Incidence and dosimetric parameters of
pediatric brainstem toxicity following proton therapy. Acta Oncol. 2014;53(10):1298–1304.
179 McGovern SL, Okcu MF, Munsell MF, et al. Outcomes and acute toxicities of proton
therapy for pediatric aty pical teratoid/rhabdoid tumor of the central nervous sy stem. Int J
Radiat Oncol Biol Phys. 2014;90(5):1143–1152.
180 Yock TI, Constine LS, Mahajan A. Protons, the brainstem, and toxicity : ingredients for an
emerging dialectic. Acta Oncol. 2014;53(1z0):1279–1282.
181 Gunther JR, Sato M, Chintagumpala M, et al. Imaging changes in pediatric intracranial
ependy moma patients treated with proton beam radiation therapy compared to intensity
modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(1):54–63.
182 Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common
pediatric brain tumors: comparison of models of dose characteristics and their relationship to
cognitive function. Pediatr Blood Cancer. 2008;51:110–117.
183 Dupuis-Girod S, Hartmann O, Benhamou E, et al. Will high dose chemotherapy followed
by autologous bone marrow transplantation supplant cranio-spinal irradiation in y oung
children treated for medulloblastoma? J Neurooncol. 1996;27:87–98.
184 Duffner PK, Cohen ME, Sanford RA, et al. Lack of efficacy of postoperative
chemotherapy and delay ed radiation in very y oung children with pineoblastoma—Pediatric
Oncology Group. Med Pediatr Oncol. 1995;25:38–44
185 Nazar GB, Hoffman HJ, Becker LE, et al. Infratentorial ependy momas in childhood:
prognostic factors and treatment. J Neurosurg. 1990;72:408–417.
187 Mack SC, Tay lor MD. The genetic and epigenetic basis of ependy moma. Childs Nerv
Syst. 2009;25:1195–1201.
188 Merchant TE, Fouladi M. Ependy moma: new therapeutic approaches including radiation
and chemotherapy. J Neurooncol. 2005;75:287–299.
189 Sanford RA, Merchant TE, Zwienenberg-Lee M, et al. Advances in surgical techniques
for resection of childhood cerebellopontine angle ependy momas are key to survival. Childs
Nerv Syst. 2009;25:1229–1240.
190 Yuh EL, Barkovich AJ, Gupta N. Imaging of ependy momas: MRI and CT. Childs Nerv
Syst. 2009;25:1203–1213.
192 Godfraind C. Classification and controversies in pathology of ependy momas. Childs Nerv
Syst. 2009;25:1185–1193.
193 Tay lor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of
ependy moma. Cancer Cell. 2005;8:323–335.
194 Ferri Niguez B, Martinez-Lage JF, Almagro MJ, et al. Embry onal tumor with abundant
neuropil and true rosettes (ETANTR): a new distinctive variety of pediatric PNET: a case-
based update. Childs Nerv Syst. 2010;26(8):1003–1008.
195 Rawlings CE III, Giangaspero F, Burger PC, et al. Ependy momas: a clinicopathologic
study. Surg Neurol. 1988;29:271–281.
196 Rorke LB. Relationship of morphology of ependy moma in children to prognosis. Prog
Exp Tumor Res. 1987;30:170–174.
198 Pollock BE. Gamma Knife surgery for focal brainstem gliomas. J Neurosurg.
2007;106:6–7.
199 Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric
ependy moma: a prospective study. Lancet Oncol. 2009;10:258–266.
201 Pollack IF, Gerszten PC, Martinez AJ, et al. Intracranial ependy momas of childhood:
long-term outcome and prognostic factors. Neurosurgery. 1995;37:655–666.
202 Rousseau P, Habrand JL, Sarrazin D, et al. Treatment of intracranial ependy momas of
children: review of a 15-y ear experience. Int J Radiat Oncol Biol Phys. 1994;28:381–386.
203 Merchant TE, Jenkins JJ, Burger PC, et al. Influence of tumor grade on time to
progression after irradiation for localized ependy moma in children. Int J Radiat Oncol Biol
Phys. 2002;53:52–57.
208 Hukin J, Epstein F, Lefton D, et al. Treatment of intracranial ependy moma by surgery
alone. Pediatr Neurosurg. 1998;29:40–45.
209 Duffner PK, Krischer JP, Sanford RA, et al. Prognostic factors in infants and very y oung
children with intracranial ependy momas. Pediatr Neurosurg. 1998;28:215–222.
210 Shu HK, Sall WF, Maity A, et al. Childhood intracranial ependy moma: twenty -y ear
experience from a single institution. Cancer. 2007;110:432–441.
211 Mansur DB, Perry A, Rajaram V, et al. Postoperative radiation therapy for grade II and
III intracranial ependy moma. Int J Radiat Oncol Biol Phys. 2005;61:387–391.
212 Conklin HM, Li C, Xiong X, et al. Predicting change in academic abilities after conformal
radiation therapy for localized ependy moma. J Clin Oncol. 2008;26:3965–3970.
213 Merchant TE, Kiehna EN, Li C, et al. Radiation dosimetry predicts IQ after conformal
radiation therapy in pediatric patients with localized ependy moma. Int J Radiat Oncol Biol
Phys. 2005;63:1546–1554.
214 Di Pinto M, Conklin HM, Li C, et al. Investigating verbal and visual auditory learning after
conformal radiation therapy for childhood ependy moma. Int J Radiat Oncol Biol Phys.
2010;77(4):1002–1008.
215 Merchant, TE, Bendel AE, Sabin N, et al. A Phase II trial of conformal radiation therapy
for pediatric patients with localized ependy moma, chemotherapy prior to second surgery for
incompletely resected ependy moma and observation for completely resected, differentiated,
supratentorial ependy moma. Int J Radiat Oncol Biol Phys. 2015;93(3S):S1.
216 Merchant TE, Boop FA, Kun LE, et al. A retrospective study of surgery and reirradiation
for recurrent ependy moma. Int J Radiat Oncol Biol Phys. 2008;71:87–97.
217 Bouffet E, Tabori U, Bartels U. Paediatric ependy momas: should we avoid radiotherapy ?
Lancet Oncol. 2007;8:665–666.
218 Eaton BR, Chowdhry V, Weaver K, et al. Use of proton therapy for re-irradiation in
pediatric intracranial ependy moma.” Radiother Oncol. 2015;116(2):301–308.
219 Stafford SL, Pollock BE, Foote RL, et al. Stereotactic radiosurgery for recurrent
ependy moma. Cancer. 2000;88:870–875.
220 Messahel B, Ashley S, Saran F, et al. Relapsed intracranial ependy moma in children in
the UK: patterns of relapse, survival and therapeutic outcome. Eur J Cancer.
2009;45(10):1815–1823.
221 Robertson PL, Zeltzer PM, Boy ett JM, et al. Survival and prognostic factors following
radiation therapy and chemo-therapy for ependy momas in children: a report of the
Children’s Cancer Group. J Neurosurg. 1998;88:695–703.
222 Needle MN, Molloy PT, Gey er JR, et al. Phase II study of daily oral etoposide in
children with recurrent brain tumors and other solid tumors. Med Pediatr Oncol. 1997;29:28–
32.
223 Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, et al. Adjuvant chemotherapy of
childhood posterior fossa ependy moma: cranio-spinal irradiation with or without adjuvant
CCNU, vincristine, and prednisone: a Children’s Cancer Group study. Med Pediatr Oncol.
1996;27:8–14.
224 Needle MN, Goldwein JW, Grass J, et al. Adjuvant chemotherapy for the treatment of
intracranial ependy moma of childhood. Cancer. 1997;80:341–347.
225 Gilbertson RJ, Bentley L, Hernan R, et al. ERBB receptor signaling promotes
ependy moma cell proliferation and represents a potential novel therapeutic target for this
disease. Clin Cancer Res. 2002;8:3054–3064.
228 Goldwein JW, Corn BW, Finlay JL, et al. Is craniospinal irradiation required to cure
children with malignant (anaplastic) intracranial ependy momas? Cancer. 1991;67:2766–2771.
230 Schroeder TM, Chintagumpala M, Okcu MF, et al. Intensity -modulated radiation therapy
in childhood ependy moma. Int J Radiat Oncol Biol Phys. 2008;71:987–993.
231 Merchant TE, Mulhern RK, Krasin MJ, et al. Preliminary results from a phase II trial of
conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric
patients with localized ependy moma. J Clin Oncol. 2004;22:3156–3162.
232 Merchant TE, Haida T, Wang MH, et al. Anaplastic ependy moma: treatment of pediatric
patients with or without craniospinal radiation therapy. J Neurosurg. 1997;86:943–949.
233 Edwards MS, Wara WM, Ciricillo SF, et al. Focal brain-stem astrocy tomas causing
sy mptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric
cases. J Neurosurg. 1994;80:20–25.
234 Vanuy tsel LJ, Bessell EM, Ashley SE, et al. Intracranial ependy moma: long-term results
of a policy of surgery and radiotherapy. Int J Radiat Oncol Biol Phys. 1992;23:313–319.
235 Conter C, Carrie C, Bernier V, et al. Intracranial ependy momas in children: society of
pediatric oncology experience with postoperative hy perfractionated local radiotherapy. Int J
Radiat Oncol Biol Phys. 2009;74:1536–1542.
236 MacDonald SM, Safai S, Trofimov A, et al. Proton radiotherapy for childhood
ependy moma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys.
2008;71:979–986.
237 Barkovich AJ, Krischer J, Kun LE, et al. Brain stem gliomas: a classification sy stem
based on magnetic resonance imaging. Pediatr Neurosurg. 1990;16:73–83.
238 Albright AL, Price RA, Guthkelch AN. Brain stem gliomas of children. A
clinicopathological study. Cancer. 1983;52:2313–2319.
239 Vandertop WP, Hoffman HJ, Drake JM, et al. Focal midbrain tumors in children.
Neurosurgery. 1992;31:186–194.
240 Ternier J, Wray A, Puget S, et al. Tectal plate lesions in children. J Neurosurg.
2006;104:369–376.
241 Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol
Phys. 1998;40:265–271.
242 Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brainstem
gliomas. J Clin Oncol. 2006;24:1266–1272.
243 Hoffman HJ, Becker L, Craven MA. A clinically and pathologically distinct group of
benign brain stem gliomas. Neurosurgery. 1980;7:243–248.
244 Stroink AR, Hoffman HJ, Hendrick EB, et al. Diagnosis and management of pediatric
brain-stem gliomas. J Neurosurg. 1986;65:745–750.
245 Freeman CR, Bourgouin PM, Sanford RA, et al. Long term survivors of childhood brain
stem gliomas treated with hy perfractionated radiotherapy —clinical characteristics and
treatment related toxicities—the Pediatric Oncology Group. Cancer. 1996;77:555–562.
247 Kwon JW, Kim IO, Cheon JE, et al. Paediatric brain-stem gliomas: MRI, FDG-PET and
histological grading correlation. Pediatr Radiol. 2006;36:959–964.
248 Yamaguchi S, Terasaka S, Kobay ashi H, et al. Indolent dorsal midbrain tumor: new
findings based on positron emission tomography. J Neurosurg Pediatr. 2009;3:270–275.
249 Pierre-Kahn A, Hirsch JF, Vinchon M, et al. Surgical management of brain-stem tumors
in children: results and statistical analy sis of 75 cases. J Neurosurg. 1993;79:845–852.
250 Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions
in children. J Neurosurg. 2007;107:1–4.
251 Pirotte BJ, Lubansu A, Massager N, et al. Results of positron emission tomography
guidance and reassessment of the utility of and indications for stereotactic biopsy in children
with infiltrative brainstem tumors. J Neurosurg. 2007;107:392–399.
252 Shrieve DC, Wara WM, Edwards MS, et al. Hy perfractionated radiation therapy for
gliomas of the brainstem in children and in adults. Int J Radiat Oncol Biol Phys. 1992;24:599–
610.
253 Mantravadi RV, Phatak R, Bellur S, et al. Brain stem gliomas: an autopsy study of 25
cases. Cancer. 1982;49:1294–1296.
254 Gilbertson RJ, Hill DA, Hernan R, et al. ERBB1 is amplified and overexpressed in high-
grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res. 2003;9:3620–3624.
255 Pollack IF, Stewart CF, Kocak M, et al. A phase II study of gefitinib and irradiation in
children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor
Consortium. Neuro Oncol. 2011;13(3):290–297.
256 Gururangan S, McLaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis
metastases in children with diffuse pontine glioma. J Neurooncol. 2006;77:207–212.
257 Pollack IF, Hoffman HJ, Humphrey s RP, et al. The long-term outcome after surgical
treatment of dorsally exophy tic brain-stem gliomas. J Neurosurg. 1993;78:859–863.
258 Khatib ZA, Heideman RL, Kovnar EH, et al. Predominance of pilocy tic histology in
dorsally exophy tic brain stem tumors. Pediatr Neurosurg. 1994;20:2–10.
259 Farmer JP, Montes JL, Freeman CR, et al. Brainstem gliomas—a 10-y ear institutional
review. Pediatr Neurosurg. 2001;34:206–214.
260 Boy dston WR, Sanford RA, Muhlbauer MS, et al. Gliomas of the tectum and
periaqueductal region of the mesencephalon. Pediatr Neurosurg. 1991;17:234–238.
261 Epstein F, McCleary EL. Intrinsic brain-stem tumors of childhood: surgical indications. J
Neurosurg. 1986;64:11–15.
262 Lesniak MS, Klem JM, Weingart J, et al. Surgical outcome following resection of
contrast-enhanced pediatric brainstem gliomas. Pediatr Neurosurg. 2003;39:314–322.
264 Freeman CR, Krischer JP, Sanford RA, et al. Final results of a study of escalating doses of
hy perfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group
study. Int J Radiat Oncol Biol Phys. 1993;27:197–206.
265 Prados MD, Wara WM, Edwards MS, et al. The treatment of brain stem and thalamic
gliomas with 78 Gy of hy perfractionated radiation therapy. Int J Radiat Oncol Biol Phys.
1995;32:85–91.
267 Yen CP, Sheehan J, Steiner M, et al. Gamma knife surgery for focal brainstem gliomas. J
Neurosurg. 2007;106:8–17.
268 Jenkin RD, Boesel C, Ertel I, et al. Brain-stem tumors in childhood: a prospective
randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A
report of the Children’s Cancer Study Group. J Neurosurg. 1987;66:227–233.
269 Allen J, Siffert J, Donahue B, et al. A phase I/II study of carboplatin combined with
hy perfractionated radiotherapy for brainstem gliomas. Cancer. 1999;86:1064–1069.
270 Walter AW, Gajjar A, Ochs JS, et al. Carboplatin and etoposide with hy perfractionated
radiotherapy in children with newly diagnosed diffuse pontine gliomas: a phase I/II study.
Med Pediatr Oncol. 1998;30:28–33.
271 Turner CD, Chi S, Marcus KJ, et al. Phase II study of thalidomide and radiation in
children with newly diagnosed brain stem gliomas and glioblastoma multiforme. J
Neurooncol. 2007;82:95–101.
272 Pollack IF, Jakacki RI, Blaney SM, et al. Phase I trial of imatinib in children with newly
diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium
report. Neuro Oncol. 2007;9:145–160.
273 Korones DN, Fisher PG, Kretschmar C, et al. Treatment of children with diffuse intrinsic
brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children’s Oncology
Group phase II study. Pediatr Blood Cancer. 2008;50:227–230.
275 Dunkel IJ, Garvin JH Jr, Goldman S, et al. High dose chemotherapy with autologous bone
marrow rescue for children with diffuse pontine brain stem tumors—Children’s Cancer
Group. J Neurooncol. 1998;37:67–73.
276 Jennings MT, Sposto R, Boy ett JM, et al. Preradiation chemotherapy in primary high-risk
brainstem tumors: phase II study CCG-9941 of the Children’s Cancer Group. J Clin Oncol.
2002;20:3431–3437.
277 Frappaz D, Schell M, Thiesse P, et al. Preradiation chemotherapy may improve survival
in pediatric diffuse intrinsic brainstem gliomas: final results of BSG 98 prospective trial. Neuro
Oncol. 2008;10:599–607.
278 Kretschmar CS, Tarbell NJ, Barnes PD, et al. Pre-irradiation chemotherapy and
hy perfractionated radiation therapy 66 Gy for children with brain stem tumors—a phase II
study of the Pediatric Oncology Group, Protocol 8833. Cancer. 1993;72:1404–1413.
279 Castel D, Philippe C, Calmon R, et al. . Histone H3F3A and HIST1H3B K27M mutations
define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and
phenoty pes. Acta Neuropathol. 2015;130(6):815–827.
280 Hennika T, Becher OJ. Diffuse intrinsic pontine glioma: time for cautious optimism. J
Child Neurol. 2015; Epub ahead of print.
281 Allen JC, Siffert J. Contemporary chemotherapy issues for children with brainstem
gliomas. Pediatr Neurosurg. 1996;24:98–102.
282 Halperin EC. Pediatric brain stem tumors: patterns of treatment failure and their
implications for radiotherapy. Int J Radiat Oncol Biol Phys. 1985;11:1293–1298.
283 Yoshimura J, Onda K, Tanaka R, et al. Clinicopathological study of diffuse ty pe brainstem
gliomas: analy sis of 40 autopsy cases. Neurol Med Chir (Tokyo). 2003;43:375–382.
284 Donahue B, Allen J, Siffert J, et al. Patterns of recurrence in brain stem gliomas:
evidence for craniospinal dissemination. Int J Radiat Oncol Biol Phys. 1998;40:677–680.
285 Gajjar A, Bhargava R, Jenkins JJ, et al. Low-grade astrocy toma with neuraxis
dissemination at diagnosis. J Neurosurg. 1995;83:67–71.
286 Frazier JL, Lee J, Thomale UW, et al. Treatment of diffuse intrinsic brainstem gliomas:
failed approaches and future strategies. J Neurosurg Pediatr. 2009;3:259–269.
287 Freeman CR, Kepner J, Kun LE, et al. A detrimental effect of a combined
chemotherapy –radiotherapy approach in children with diffuse intrinsic brain stem gliomas?
Int J Radiat Oncol Biol Phys. 2000;47:561–564.
288 Mandell L, Kadota R, Douglass EC, et al. It is time to rethink the role of hy perfractionated
radiotherapy in the management of children with newly diagnosed brainstem? Results of a
Pediatric Oncology Group Phase III trial comparing conventional versus hy perfractionated
radiotherapy. Int J Radiat Oncol Biol Phys. 1997;39:143.
289 Lewis J, Lucraft H, Gholkar A. UKCCSG study of accelerated radiotherapy for pediatric
brain stem gliomas—United Kingdom Childhood Cancer Study Group. Int J Radiat Oncol Biol
Phys. 1997;38:925–929.
290 Janssens GO, Gidding CE, Van Lindert EJ, et al. The role of hy pofractionation
radiotherapy for diffuse intrinsic brainstem glioma in children: a pilot study. Int J Radiat
Oncol Biol Phys. 2009;73:722–726.
291 Haas-Kogan DA, Banerjee A, Kocak M, et al. Phase I trial of tipifarnib in children with
newly diagnosed intrinsic diffuse brainstem glioma. Neuro Oncol. 2008;10:341–347.
292 Fouladi M, Nicholson HS, Zhou T, et al. A phase II study of the farnesy l transferase
inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma,
medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children’s
Oncology Group study. Cancer. 2007;110:2535–2541.
293 Packer RJ, Zimmerman RA, Kaplan A, et al. Early cy stic/ necrotic changes after
hy perfractionated radiation therapy in children with brain stem gliomas—data from the
Children’s Cancer Group. Cancer. 1993;71:2666–2674.
294 Panigrahy A, Nelson MD Jr, Finlay JL, et al. Metabolism of diffuse intrinsic brainstem
gliomas in children. Neuro Oncol. 2008;10:32–44.
295 Broniscer A, Laningham FH, Sanders RP, et al. Young age may predict a better outcome
for children with diffuse pontine glioma. Cancer. 2008;113:566–572.
296 Ilgren EB, Stiller CA. Cerebellar astrocy tomas—clinical characteristics and prognostic
indices. J Neurooncol. 1987;4:293–308.
297 Schneider JH Jr, Raffel C, McComb JG. Benign cerebellar astrocy tomas of childhood.
Neurosurgery. 1992;30:58–62.
298 Bigner DD, McLendon RE, Bruner JM. Russell & Rubinstein’s Pathology of Tumors of the
Nervous System. Vol. 1, 6th ed. London, England: Arnold; 1998.
299 Hay ostek CJ, Shaw EG, Scheithauer B, et al. Astrocy tomas of the cerebellum—a
comparative clinicopathologic study of pilocy tic and diffuse astrocy tomas. Cancer.
1993;72:856–869.
300 Pencalet P, Maixner W, Sainte-Rose C, et al. Benign cerebellar astrocy tomas in children.
J Neurosurg. 1999;90:265–273.
301 Desai KI, Nadkarni TD, Muzumdar DP, et al. Prognostic factors for cerebellar
astrocy tomas in children: a study of 102 cases. Pediatr Neurosurg. 2001;35:311–317.
302 Ilgren EB, Stiller CA. Cerebellar astrocy tomas: therapeutic management. Acta Neurochir
(Wien). 1986;81:11–26.
304 Sgouros S, Fineron PW, Hockley AD. Cerebellar astrocy toma of childhood: long-term
follow-up. Childs Nerv Syst. 1995;11:89–96.
305 Tomita T, McLone DG. Medulloblastoma in childhood: results of radical resection and
low-dose neuraxis radiation therapy. J Neurosurg. 1986;64:238–242.
306 Campbell JW, Pollack IF. Cerebellar astrocy tomas in children. J Neurooncol.
1996;28:223–231.
307 Pollack IF, Hurtt M, Pang D, et al. Dissemination of low grade intracranial astrocy tomas
in children. Cancer. 1994;73:2869–2878.
308 Prados M, Mamelak AN. Metastasizing low grade gliomas in children—redefining an old
disease. Cancer. 1994;73:2671–2673.
309 Garcia DM, Marks JE, Latifi HR, et al. Childhood cerebellar astrocy tomas: is there a role
for postoperative irradiation? Int J Radiat Oncol Biol Phys. 1990;18:815–818.
310 Sutton LN, Cnaan A, Klatt L, et al. Postoperative surveillance imaging in children with
cerebellar astrocy tomas. J Neurosurg. 1996;84:721–725.
311 Kulkarni AV, Becker LE, Jay V, et al. Primary cerebellar glioblastomas multiforme in
children. Report of four cases. J Neurosurg. 1999;90:546–550.
312 Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children
with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86:747–754.
313 Larson DA, Wara WM, Edwards MS. Management of childhood cerebellar astrocy toma.
Int J Radiat Oncol Biol Phys. 1990;18:971–973.
314 Lee MJ, Ra YS, Park JB, et al. Effectiveness of novel combination chemotherapy,
consisting of 5-fluorouracil, vincristine, cy clophosphamide and etoposide, in the treatment of
low-grade gliomas in children. J Neurooncol. 2006;80:277–284.
315 Packer RJ, Jakacki R, Horn M, et al. Objective response of multiply recurrent low-grade
gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer. 2009;52:791–795.
316 Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for
treatment of low-grade glioma in y oung children: a report from the Children’s Oncology
Group. J Clin Oncol. 2012;30(21):2641–2647.
317 Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for
pediatric low-grade glioma. J Clin Oncol. 2009;27:3598–3604.
318 Merchant TE, Zhu Y, Thompson SJ, et al. Preliminary results from a Phase II trail of
conformal radiation therapy for pediatric patients with localised low-grade astrocy toma and
ependy moma. Int J Radiat Oncol Biol Phys. 2002;52:325–332.
319 Beebe DW, Ris MD, Armstrong FD, et al. Cognitive and adaptive outcome in low-grade
pediatric cerebellar astrocy tomas: evidence of diminished cognitive and adaptive functioning
in National Collaborative Research Studies (CCG 9891/POG 9130). J Clin Oncol.
2005;23:5198–5204.
321 DeSousa AL, Kalsbeck JE, Mealey J Jr, et al. Intraspinal tumors in children—a review of
81 cases. J Neurosurg. 1979;51:437–445.
322 Zileli M, Coskun E, Ozdamar N, et al. Surgery of intrame-dullary spinal cord tumors. Eur
Spine J. 1996;5:243–250.
323 Goh KY, Velasquez L, Epstein FJ. Pediatric intramedullary spinal cord tumors: is surgery
alone enough? Pediatr Neurosurg. 1997;27:34–39.
324 Reimer R, Onofrio BM. Astrocy tomas of the spinal cord in children and adolescents. J
Neurosurg. 1985;63:669–675.
325 Nadkarni TD, Rekate HL. Pediatric intramedullary spinal cord tumors—critical review of
the literature. Childs Nerv Syst. 1999;15:17–28.
326 Albright AL. Pediatric intramedullary spinal cord tumors. Childs Nerv Syst. 1999;15:436–
438.
327 Curran WJ Jr, D’Angio GJ. Nonsurgical management of spinal tumors. In: Ashley DG,
Curran WJ Jr, D’Angio GJ, et al. Spinal Tumors in Children and Adolescents, the International
Review of Child Neurology. New York, NY: Raven Press; 1990:71–84.
328 Innocenzi G, Raco A, Cantore G, et al. Intramedullary astrocy tomas and ependy momas
in the pediatric age group: a retrospective study. Childs Nerv Syst. 1996;12:776–780.
329 Rossitch E Jr, Zeidman SM, Burger PC, et al. Clinical and pathological analy sis of spinal
cord astrocy tomas in children. Neurosurgery. 1990;27:193–196.
330 Epstein F. Spinal cord astrocy tomas of childhood. Prog Exp Tumor Res. 1987;30:135–153.
332 Pascual-Castroviejo I. Spinal Cord Tumors in Children and Adolescents. New York, NY:
Raven Press; 1990.
333 Houten JK, Weiner HL. Pediatric intramedullary spinal cord tumors: special
considerations. J Neurooncol. 2000;47:225–230.
334 Merchant TE, Kiehna EN, Thompson SJ, et al. Pediatric low-grade and ependy mal spinal
cord tumors. Pediatr Neurosurg. 2000;32:30–36.
335 Sonneland PR, Scheithauer BW, Onofrio BM. My xopapillary ependy moma—a
clinicopathologic and immunocy tochemical study of 77 cases. Cancer. 1985;56:883–893.
336 Bagley CA, Wilson S, Kothbauer KF, et al. Long term outcomes following surgical
resection of my xopapillary ependy momas. Neurosurg Rev. 2009;32:321–334.
337 Whitaker SJ, Bessell EM, Ashley SE, et al. Postoperative radiotherapy in the
management of spinal cord ependy moma. J Neurosurg. 1991;74:720–728.
338 Crawford JR, Zaninovic A, Santi M, et al. Primary spinal cord tumors of childhood:
effects of clinical presentation, radiographic features, and pathology on survival. J
Neurooncol. 2009;95:259–269.
339 Bouffet E, Pierre-Kahn A, Marchal JC, et al. Prognostic factors in pediatric spinal cord
astrocy toma. Cancer. 1998;83:2391–2399.
341 Epstein F, Epstein N. Surgical treatment of spinal cord astrocy tomas of childhood—a
series of 19 patients. J Neurosurg. 1982;57:685–689.
342 Minehan KJ, Brown PD, Scheithauer BW, et al. Prognosis and treatment of spinal cord
astrocy toma. Int J Radiat Oncol Biol Phys. 2009;73:727–733.
343 McCormick PC, Torres R, Post KD, et al. Intramedullary ependy moma of the spinal
cord. J Neurosurg. 1990;72:523–532.
344 Townsend N, Handler M, Fleitz J, et al. Intramedullary spinal cord astrocy tomas in
children. Pediatr Blood Cancer. 2004;43:629–632.
345 Mora J, Cruz O, Gala S, et al. Successful treatment of childhood intramedullary spinal
cord astrocy tomas with irinotecan and cisplatin. Neuro Oncol. 2007;9:39–46.
346 Allen JC, Aviner S, Yates AJ, et al. Treatment of high-grade spinal cord astrocy toma of
childhood with “8-in-1” chemotherapy and radiotherapy : a pilot study of CCG-945. Children’s
Cancer Group. J Neurosurg. 1998;88:215–220.
347 Linstadt DE, Wara WM, Leibel SA, et al. Postoperative radiotherapy of primary spinal
cord tumors. Int J Radiat Oncol Biol Phys. 1989;16:1397–1403.
348 O’Sullivan C, Jenkin RD, Doherty MA, et al. Spinal cord tumors in children: long-term
results of combined surgical and radiation treatment. J Neurosurg. 1994;81:507–512.
349 Chun HC, Schmidt-Ullrich RK, Wolfson A, et al. External beam radiotherapy for
primary spinal cord tumors. J Neurooncol. 1990;9:211–217.
350 Chan HS, Becker LE, Hoffman HJ, et al. My xopapillary ependy moma of the filum
terminale and cauda equina in childhood: report of seven cases and review of the literature.
Neurosurgery. 1984;14:204–210.
351 Chinn DM, Donaldson SS, Dahl GV, et al. Management of children with metastatic spinal
my xopapillary ependy moma using craniospinal irradiation. Med Pediatr Oncol.
2000;35:443–445.
2 Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci
U S A. 1971;68(4):820–823.
3 Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene
that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323(6089):643–646.
4 Corson TW, Gallie BL. One hit, two hits, three hits, more? Genomic changes in the
development of retinoblastoma. Genes Chromosomes Cancer. 2007;46(7):617–634.
6 Rushlow DE, Mol BM, Kennett JY, et al. Characterisation of retinoblastomas without RB1
mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013;14(4):327–334.
7 Bunin GR, Felice MA, Davidson W, et al. Medical radiation exposure and risk of
retinoblastoma resulting from new germline RB1 mutation. Int J Cancer. 2011;128(10):2393–
2404.
8 Amendola BE, Lamm FR, Markoe AM, et al. Radiotherapy of retinoblastoma—a review of
63 children treated with different irradiation techniques. Cancer. 1990;66(1):21–26.
9 Butros LJ, Abramson DH, Dunkel IJ. Delay ed diagnosis of retinoblastoma: analy sis of
degree, cause, and potential consequences. Pediatrics. 2002;109(3):E45.
11 Karcioglu ZA. Fine needle aspiration biopsy (FNAB) for retinoblastoma. Retina.
2002;22(6):707–710.
12 Brenner DJ, Hall EJ. Computed tomography —an increasing source of radiation exposure.
N Engl J Med. 2007;357(22):2277–2284.
13 Reese AB, Ellsworth RM. The evaluation and current concept of retinoblastoma therapy.
Trans Am Acad Ophthalmol Otolaryngol. 1963;67:164–172.
14 Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification.
Ophthalmol Clin North Am. 2005;18(1):41–53, viii.
15 Francis JH, Abramson DH, Brodie SE, et al. Indocy anine green enhanced transpupillary
thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br
J Ophthalmol. 2013;97(2):164–168.
16 Abramson DH, Ellsworth RM, Rozakis GW. Cry otherapy for retinoblastoma. Arch
Ophthalmol. 1982;100(8):1253–1256.
17 Moore RF. Choroidal sarcoma treated by the intraocular insertion of radon seeds. Br J
Ophthalmol. 1930;14(4):145–152.
18 Stallard HB. Retinoblastoma treated by radon seeds and radio-active disks. Ann R Coll Surg
Engl. 1955;16(6):349–366.
19 Abramson DH, Marks RF, Ellsworth RM, et al. The management of unilateral
retinoblastoma without primary enucleation. Arch Ophthalmol. 1982;100(8):1249–1252.
20 American Brachy therapy Society —Ophthalmic Oncology Task Force. The American
Brachy therapy Society consensus guidelines for plaque brachy therapy of uveal melanoma
and retinoblastoma. Brachytherapy. 2014;13(1):1–14.
21 Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma: long-term
tumor control and treatment complications in 208 tumors. Ophthalmology.
2001;108(11):2116–2121.
23 Francis JH, Barker CA, Wolden SL, et al. Salvage/adjuvant brachy therapy after
ophthalmic artery chemosurgery for intraocular retinoblastoma. Int J Radiat Oncol Biol
Phys. 2013;87(3):517–523.
25 Hilgartner HL. Report of case of double glioma treated with x-ray. 1903. Tex Med.
2005;101(7):10.
26 Marcus DM, Craft JL, Albert DM. Histopathologic verification of Verhoeff ’s 1918
irradiation cure of retinoblastoma. Ophthalmology. 1990;97(2):221–224.
27 Cassady JR, Sagerman RH, Tretter P, et al. Radiation therapy in retinoblastoma. An
analy sis of 230 cases. Radiology. 1969;93(2):405–409.
28 Egbert PR, Donaldson SS, Moazed K, et al. Visual results and ocular complications
following radiotherapy for retinoblastoma. Arch Ophthalmol. 1978;96(10):1826–1830.
30 Foote RL, Garretson BR, Schomberg PJ, et al. External beam irradiation for
retinoblastoma: patterns of failure and dose-response analy sis. Int J Radiat Oncol Biol Phys.
1989;16(3):823–830.
31 Buckley EG, Heath H. Visual acuity after successful treatment of large macular
retinoblastoma. J Pediatr Ophthalmol Strabismus. 1992;29(2):103–106.
32 Fontanesi J, Pratt CB, Hustu HO, et al. Use of irradiation for therapy of retinoblastoma in
children more than 1 y ear old: the St. Jude Children’s Research Hospital experience and
review of literature. Med Pediatr Oncol. 1995;24(5):321–326.
33 Fontanesi J, Pratt CB, Kun LE, et al. Treatment outcome and dose-response relationship in
infants y ounger than 1 y ear treated for retinoblastoma with primary irradiation. Med Pediatr
Oncol. 1996;26(5):297–304.
34 Toma NM, Hungerford JL, Plowman PN, et al. External beam radiotherapy for
retinoblastoma: II. Lens sparing technique. Br J Ophthalmol. 1995;79(2):112–117.
35 Blach LE, McCormick B, Abramson DH. External beam radiation therapy and
retinoblastoma: long-term results in the comparison of two techniques. Int J Radiat Oncol Biol
Phys. 1996;35(1):45–51.
36 Pradhan DG, Sandridge AL, Mullaney P, et al. Radiation therapy for retinoblastoma: a
retrospective review of 120 patients. Int J Radiat Oncol Biol Phys. 1997;39(1):3–13.
37 Scott IU, Murray TG, Feuer WJ, et al. External beam radiotherapy in retinoblastoma:
tumor control and comparison of 2 techniques. Arch Ophthalmol. 1999;117(6):766–770.
38 Merchant TE, Gould CJ, Hilton NE, et al. Ocular preservation after 36 Gy external beam
radiation therapy for retinoblastoma. J Pediatr Hematol Oncol. 2002;24(4):246–249.
39 Shields CL, Honavar SJ, Meadows AT, et al. Chemoreduction plus focal therapy for
retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or
enucleation. Am J Ophthalmol. 2002;133(5):657–664.
41 Berry JL, Jubran R, Kim JW, et al. Long-term outcomes of Group D ey es in bilateral
retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr
Blood Cancer. 2013;60(4):688–693.
42 Mansur DB, Klein EE, Maserang BP. Measured peripheral dose in pediatric radiation
therapy : a comparison of intensity -modulated and conformal techniques. Radiother Oncol.
2007;82(2):179–184.
43 Purdy JA. Dose to normal tissues outside the radiation therapy patient’s treated volume: a
review of different radiation therapy techniques. Health Phys. 2008;95(5):666–676.
44 Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in
long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol.
2005;23(10):2272–2279.
45 Mouw KW, Sethi RV, Yeap BY, et al. Proton radiation therapy for the treatment of
retinoblastoma. Int J Radiat Oncol Biol Phys. 2014;90(4):863–869.
46 Murphree AL, Villablanca JG, Deegan WF III, et al. Chemotherapy plus local treatment in
the management of intraocular retinoblastoma. Arch Ophthalmol. 1996;114(11):1348–1356.
48 Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic
therapy for intraocular retinoblastoma. J Clin Oncol. 2000;18(1):12–17.
49 Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction for unilateral
retinoblastoma. Arch Ophthalmol. 2002;120(12):1653–1658.
50 Gobin YP, Dunkel IJ, Marr BP, et al. Combined, sequential intravenous and intra-arterial
chemotherapy (bridge chemotherapy ) for y oung infants with retinoblastoma. PLoS One.
2012;7(9):e44322.
53 Abramson DH, Dunkel IGJ, Brodie SE, et al. Superselective ophthalmic artery
chemotherapy as primary treatment for retinoblastoma (chemosurgery ). Ophthalmology.
2010;117(8):1623–1629.
54 Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy for the management of
retinoblastoma: four-y ear experience. Arch Ophthalmol. 2011;129(6):732–737.
55 Dunkel IJ, Shi W, Salvaggio K, et al. Risk factors for severe neutropenia following intra-
arterial chemotherapy for intra-ocular retinoblastoma. PLoS One. 2014;9(10): e108692.
56 Abramson DH. Retinoblastoma: saving life with vision. Annu Rev Med. 2014;65:171–184.
57 Abramson DH, Dunkel IJ, Brodie SE, et al. Bilateral superselective ophthalmic artery
chemotherapy for bilateral retinoblastoma: tandem therapy. Arch Ophthalmol.
2010;128(3):370–372.
58 Francis JH, Abramson DH, Gobin YP, et al. Electroretinogram monitoring of dose-
dependent toxicity after ophthalmic artery chemosurgery in retinoblastoma ey es: six y ear
review. PLoS One. 2014;9(1):e84247.
59 Marr BP, Dunkel IJ, Linker A, et al. Periocular carboplatin for retinoblastoma: long-term
report (12 y ears) on efficacy and toxicity. Br J Ophthalmol. 2012;96(6):881–883.
61 Mulvihill A, Budning A, Jay V, et al. Ocular motility changes after subtenon carboplatin
chemotherapy for retinoblastoma. Arch Ophthalmol. 2003;121(8):1120–1124.
62 Schmack I, Hubbard GB, Kang SJ, et al. Ischemic necrosis and atrophy of the optic nerve
after periocular carboplatin injection for intraocular retinoblastoma. Am J Ophthalmol.
2006;142(2):310–315.
63 Yousef YA, Halliday W, Chan HS, et al. No ocular motility complications after subtenon
topotecan with fibrin sealant for retinoblastoma. Can J Ophthalmol. 2013;48(6):524–528.
64 Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous disease
in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol.
2012;96(8):1078–1083.
65 Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melphalan for persistent or
recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol.
2014;132(3):319–325.
66 Francis JH, Schaiquevich P, Buitrago E, et al. Local and sy stemic toxicity of intravitreal
melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study.
Ophthalmology. 2014;121(9):1810–1817.
68 Chintagumpala MM, Langholz B, Eagle R, et al. A large prospective trial of children with
unilateral retinoblastoma with and without histopathologic high-risk features and the role of
adjuvant chemotherapy : a Children’s Oncology Group (COG) study. J Clin Oncol.
2012;30:suppl;abstr 9515.
70 Chantada GL, Dunkel IJ, de Dávila MT, et al. Retinoblastoma patients with high risk ocular
pathological features: who needs adjuvant therapy ? Br J Ophthalmol. 2004;88(8):1069–1073.
75 Kim JW, Kathpalia V, Dunkel IJ, et al. Orbital recurrence of retinoblastoma following
enucleation. Br J Ophthalmol. 2009;93(4):463–467.
77 Namouni F, Doz F, Tanguy ML, et al. High-dose chemotherapy with carboplatin, etoposide
and cy clophosphamide followed by a haematopoietic stem cell rescue in patients with high-
risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer. 1997;33(14):2368–2375.
82 Palma J, Sasso DF, Dufort G, et al. Successful treatment of metastatic retinoblastoma with
high-dose chemotherapy and autologous stem cell rescue in South America. Bone Marrow
Transplant. 2012;47(4):522–527.
83 Dunkel IJ, Khakoo Y, Kernan NA, et al. Intensive multimodality therapy for patients with
stage 4a metastatic retinoblastoma. Pediatr Blood Cancer. 2010;55(1):55–59.
84 Blach LE, McCormick B, Abramson DH, et al. Trilateral retinoblastoma—incidence and
outcome: a decade of experience. Int J Radiat Oncol Biol Phys. 1994;29(4):729–733.
86 Dunkel IJ, Jubran RF, Gururangan S, et al. Trilateral retinoblastoma: potentially curable
with intensive chemotherapy. Pediatr Blood Cancer. 2010;54(3):384–387.
87 de Jong MC, Kors WA, de Graaf P, et al. Trilateral retinoblastoma: a sy stematic review
and meta-analy sis. Lancet Oncol. 2014;15(10):1157–1167.
88 Dunkel IJ, Chan HS, Jubran R, et al. High-dose chemotherapy with autologous
hematopoietic stem cell rescue for stage 4B retinoblastoma. Pediatr Blood Cancer.
2010;55(1):149–152.
89 Abramson DH. Retinoblastoma in the 20th century : past success and future challenges the
Weisenfeld lecture. Invest Ophthalmol Vis Sci. 2005;46(8):2683–2691.
91 Abramson DH, Du TT, Beaverson KL. (Neonatal) retinoblastoma in the first month of life.
Arch Ophthalmol. 2002;120(6):738–742.
92 Abramson DH, Ronner HJ, Ellsworth RM. Second tumors in nonirradiated bilateral
retinoblastoma. Am J Ophthalmol. 1979;87(5):624–627.
93 Abramson DH, Ellsworth RM, Kitchin FD, et al. Second nonocular tumors in
retinoblastoma survivors. Are they radiation-induced? Ophthalmology. 1984;91(11):1351–
1355.
94 Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term
survivors of retinoblastoma. J Natl Cancer Inst. 1993;85(14):1121–1128.
95 Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after retinoblastoma.
Radiation dose and sarcoma risk. JAMA. 1997;278(15):1262–1267.
96 Wong JR, Morton LM, Tucker MA, et al. Risk of subsequent malignant neoplasms in long-
term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol.
2014;32(29):3284–3290.
97 Li FP, Abramson DH, Tarone RE, et al. Hereditary retinoblastoma, lipoma, and second
primary cancers. J Natl Cancer Inst. 1997;89(1):83–84.
99 Kleinerman RA, Tucker MA, Abramson DH, et al. Risk of soft tissue sarcomas by
individual subty pe in survivors of hereditary retinoblastoma. J Natl Cancer Inst.
2007;99(1):24–31.
100 Kleinerman RA, Yu CL, Little MP, et al. Variation of second cancer risk by family
history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30(9):950–957.
101 Little MP, Schaeffer ML, Reulen RC, et al. Breast cancer risk after radiotherapy for
heritable and non-heritable retinoblastoma: a US-UK study. Br J Cancer. 2014;110(10):2623–
2632.
102 Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute my elogenous
leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology.
2007;114(7):1378–1383.
103 Marees T, van Leeuwen FE, Schaapveld M, et al. Risk of third malignancies and death
after a second malignancy in retinoblastoma survivors. Eur J Cancer. 2010;46(11):2052–
2058.
104 Abramson DH, Melson MR, Dunkel IJ, et al. Third (fourth and fifth) nonocular tumors in
survivors of retinoblastoma. Ophthalmology. 2001;108(10):1868–1876.
105 Friedman DN, Lis E, Sklar CA, et al. Whole-body magnetic resonance imaging (WB-
MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a
pilot study. Pediatr Blood Cancer. 2014;61(8):1440–1444.
106 Brooks HL Jr, Mey er D, Shields JA, et al. Removal of radiation-induced cataracts in
patients treated for retinoblastoma. Arch Ophthalmol. 1990;108(12):1701–1708.
107 Imhof SM, Mourits MP, Hofman P, et al. Quantification of orbital and mid-facial growth
retardation after megavoltage external beam irradiation in children with retinoblastoma.
Ophthalmology. 1996;103(2):263–268
108 Francis JH, Kim HY, Abramson DH. Ey e and orbit. In: Rubin P, Constine LS, Marks LB,
ed. Adverse Late Effects of Cancer Treatment. New York, NY: Springer-Verlag Berlin
Heidelberg; 2014:83–108.
109 Abramson DH, Notterman RB, Ellsworth RM, et al. Retinoblastoma treated in infants in
the first six months of life. Arch Ophthalmol. 1983;101(9):1362–1366.
110 Imhof SM, Hofman P, Tan KE. Quantification of lacrimal function after D-shaped field
irradiation for retinoblastoma. Br J Ophthalmol. 1993;77(8):482–484.Imhof SM, Hofman P,
Tan KE. Quantification of lacrimal function after D-shaped field irradiation for
retinoblastoma. Br J Ophthalmol. 1993;77(8):482–484.
2 Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA
Cancer J Clin. 2014;64:83–103.
3 Woods WG, Gao RN, Shuster JJ, et al. Screening of infants and mortality due to
neuroblastoma. N Eng J Med. 2002;346:1041–1046.
4 Schilling FH, Spix C, Berthold F, et al. Neuroblastoma screening at one y ear of age. N Engl J
Med. 2002;346:1047–1053.
6 Bosse KR, Maris JM. Advances in the translational genomics of neuroblastoma: from
improving risk stratification and revealing novel biology to identify ing actionable genomic
alterations. Cancer. 2016;122(1):20–33.
9 Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group
(INRG) classification sy stem: an INRG Task Force report. J Clin Oncol. 2009;27:289–297.
10 Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-my c
oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985;313:1111–1116.
13 Thompson D, Vo KT, London WB, et al. Identification of patient subgroups with markedly
disparate rates of MYCN amplification in neuroblastoma: a report from the International
Neuroblastoma Risk Group (INRG) Project. Cancer. 2016;122(6):935–945.
15 Attiy eh EF, London WB, Mosse YP, et al. Chromosome 1p and 11q deletions and outcome
in neuroblastoma. N Engl J Med. 2005;353:2243–2253.
17 Pugh TJ, Morozova O, Attiy eh EF, et al. The genetic landscape of high-risk neuroblastoma.
Nat Genet. 2013;45:279–284.
20 Peuchmaur M, d’Amore ES, Joshi VV, et al. Revision of the international neuroblastoma
pathology classification: confirmation of favorable and unfavorable prognostic subsets in
ganglioneuroblastoma, nodular. Cancer. 2003;98:2274–2281.
21 Vo KT, Matthay KK, Neuhaus J, et al. Clinical, biologic, and prognostic differences on the
basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma
risk group project. J Clin Oncol. 2014;32:3169–3176.
23 DuBois SG, Kalika Y, Lukens JN, et al. Metastatic sites in stage IV and IVS neuroblastoma
correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol. 1999;21:181–189.
24 Brisse HJ, McCarville MB, Granata C, et al. Guidelines for imaging and staging of
neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group
Project. Radiology. 2011;261:243–257.
25 Matthay KK, Shulkin B, Ladenstein R, et al. Criteria for evaluation of disease extent by
(123)I-metaiodobenzy lguanidine scans in neuroblastoma: a report for the International
Neuroblastoma Risk Group (INRG) Task Force. Br J Cancer. 2010;102:1319–1326.
26 Yanik GA, Parisi MT, Shulkin BL, et al. Semiquantitative mIBG scoring as a prognostic
indicator in patients with stage 4 neuroblastoma: a report from the Children’s oncology group.
J Nucl Med. 2013;54:541–548.
27 Sharp SE, Shulkin BL, Gelfand MJ, et al. 123I-MIBG Scintigraphy and 18F-FDG PET in
Neuroblastoma. J Nucl Med. 2009;50:1237–1243.
30 Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for
neuroblastoma diagnosis, staging, and response to treatment [see comments]. J Clin Oncol.
1993;11:1466–1477.
31 Strother DR, London WB, Schmidt ML, et al. Outcome after surgery alone or with
restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s
Oncology Group study P9641. J Clin Oncol. 2012;30:1842–1848.
32 Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group
(INRG) staging sy stem: an INRG Task Force report. J Clin Oncol. 2009;27:298–303.
33 Cecchetto G, Mosseri V, De Bernardi B, et al. Surgical risk factors in primary surgery for
localized neuroblastoma: the LNESG1 study of the European International Society of
Pediatric Oncology Neuroblastoma Group. J Clin Oncol. 2005;23:8483–8489.
34 Park JR, Bagatell R, London WB, et al. Children’s Oncology Group’s 2013 blueprint for
research: neuroblastoma. Pediatr Blood Cancer. 2013;60:985–993.
35 Baker DL, Schmidt ML, Cohn SL, et al. Outcome after reduced chemotherapy for
intermediate-risk neuroblastoma. N Engl J Med. 2010;363:1313–1323.
36 Mosse YP, Dey ell RJ, Berthold F, et al. Neuroblastoma in older children, adolescents and
y oung adults: a report from the International Neuroblastoma Risk Group project. Pediatr
Blood Cancer. 2014;61:627–635.
37 De Bernardi B, Gerrard M, Boni L, et al. Excellent outcome with reduced treatment for
infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol.
2009;27:1034–1040.
38 Kreissman SG, Seeger RC, Matthay KK, et al. Purged versus non-purged peripheral blood
stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3
trial. Lancet Oncol. 2013;14:999–1008.
39 Nickerson HJ, Matthay KK, Seeger RC, et al. Favorable biology and outcome of stage IV-
S neuroblastoma with supportive care or minimal therapy : a Children’s Cancer Group study. J
Clin Oncol. 2000;18:477–486.
40 Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with
intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-
retinoic acid. Children’s Cancer Group. N Engl J Med. 1999;341:1165–1173.
41 Zage PE, Kletzel M, Murray K, et al. Outcomes of the POG 9340/9341/9342 trials for
children with high-risk neuroblastoma: a report from the Children’s Oncology Group. Pediatr
Blood Cancer. 2008;51:747–753.
42 Park JR, Scott JR, Stewart CF, et al. Pilot induction regimen incorporating
pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk
neuroblastoma: a Children’s Oncology Group study. J Clin Oncol. 2011;29:4351–4357.
43 Pearson AD, Pinkerton CR, Lewis IJ, et al. High-dose rapid and standard induction
chemotherapy for patients aged over 1 y ear with stage 4 neuroblastoma: a randomised trial.
Lancet Oncol. 2008;9:247–256.
44 Ladenstein R, Philip T, Lasset C, et al. Multivariate analy sis of risk factors in stage 4
neuroblastoma patients over the age of one y ear treated with megatherapy and stem-cell
transplantation: a report from the European Bone Marrow Transplantation Solid Tumor
Registry. J Clin Oncol. 1998;16:953–965.
45 Matthay KK, Atkinson JB, Stram DO, et al. Patterns of relapse after autologous purged
bone marrow transplantation for neuroblastoma: a Childrens Cancer Group pilot study. J Clin
Oncol. 1993;11:2226–2233.
46 Philip T, Bernard JL, Zucker JM, et al. High-dose chemoradiotherapy with bone marrow
transplantation as consolidation treatment in neuroblastoma: an unselected group of stage IV
patients over 1 y ear of age. J Clin Oncol. 1987;5:266–271.
52 Philip T, Zucker JM, Bernard JL, et al. Improved survival at 2 and 5 y ears in the LMCE1
unselected group of 72 children with stage IV neuroblastoma older than 1 y ear of age at
diagnosis: is cure possible in a small subgroup? J Clin Oncol. 1991;9:1037–1044.
53 Shuster JJ, Cantor AB, McWilliams N, et al. The prognostic significance of autologous
bone marrow transplant in advanced neuroblastoma [see comments]. J Clin Oncol.
1991;9:1045–1049.
54 Pritchard J, Cotterill SJ, Germond SM, et al. High dose melphalan in the treatment of
advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European
Neuroblastoma Study Group. Pediatr Blood Cancer. 2005;44:348–357.
56 Matthay KK, Rey nolds CP, Seeger RC, et al. Long-term results for children with high-risk
neuroblastoma treated on a randomized trial of my eloablative therapy followed by 13-cis-
retinoic acid: a children’s oncology group study. J Clin Oncol. 2009;27:1007–1013.
57 Park JR, Slattery J, Gooley T, et al. Phase I topotecan preparative regimen for high-risk
neuroblastoma, high-grade glioma, and refractory /recurrent pediatric solid tumors. Med
Pediatr Oncol. 2000;35:719–723.
58 Ladenstein R, Potschger U, Hartman O, et al. 28 y ears of high-dose therapy and SCT for
neuroblastoma in Europe: lessons from more than 4000 procedures. Bone Marrow Transplant.
2008;41(suppl 2):S118–S127.
61 Yanik GA, Villablanca JG, Maris JM, et al. 131I-metaiodobenzy lguanidine with intensive
chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma—a new
approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant.
2015;21:673–681.
62 Matthay KK, Seeger RC, Rey nolds CP, et al. Allogeneic versus autologous purged bone
marrow transplantation for neuroblastoma: a report from the Childrens Cancer Group. J Clin
Oncol. 1994;12:2382–2389.
63 Finklestein JZ, Krailo MD, Lenarsky C, et al. 13-cis-retinoic acid (NSC 122758) in the
treatment of children with metastatic neuroblastoma unresponsive to conventional
chemotherapy : report from the Childrens Cancer Study Group. Med Pediatr Oncol.
1992;20:307–311.
64 Kohler JA, Imeson J, Ellershaw C, Lie SO. A randomized trial of 13-Cis retinoic acid in
children with advanced neuroblastoma after high-dose therapy. Br J Cancer. 2000;83:1124–
1127.
65 Maurer BJ, Kang MH, Villablanca JG, et al. Phase I trial of fenretinide delivered orally in
a novel organized lipid complex in patients with relapsed/refractory neuroblastoma—a report
from the new approaches to neuroblastoma therapy (NANT) consortium. Pediatr Blood
Cancer. 2013;60:1801–1808.
66 Yu AL, Gilman AL, Ozkay nak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2,
and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–1334.
67 Shusterman S, London WB, Gillies SD, et al. Antitumor activity of hu14.18-IL2 in patients
with relapsed/refractory neuroblastoma: a Children’s Oncology Group (COG) phase II study.
J Clin Oncol. 2010;28:4969–4975.
68 Kushner BH, Cheung IY, Modak S, et al. Phase I trial of a bivalent gangliosides vaccine in
combination with beta-glucan for high-risk neuroblastoma in second or later remission. Clin
Cancer Res. 2014;20:1375–1382.
69 Louis CU, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric
antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011;118:6050–6056.
70 Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients
with refractory solid tumours or anaplastic large-cell ly mphoma: a Children’s Oncology
Group phase 1 consortium study. Lancet Oncol. 2013;14:472–480.
71 Gustafson WC, Matthay KK. Progress towards personalized therapeutics: biologic- and
risk-directed therapy for neuroblastoma. Expert Rev Neurother. 2011;11:1411–1423.
73 Matthay KK, Perez C, Seeger RC, et al. Successful treatment of stage III neuroblastoma
based on prospective biologic staging: a Children’s Cancer Group study. J Clin Oncol.
1998;16:1256–1264.
77 Adkins ES, Sawin R, Gerbing RB, et al. Efficacy of complete resection for high-risk
neuroblastoma: a Children’s Cancer Group study. J Pediatr Surg. 2004;39:931–936.
78 Mullassery D, Farrelly P, Losty PD. Does aggressive surgical resection improve survival
in advanced stage 3 and 4 neuroblastoma? A sy stematic review and meta-analy sis. Pediatr
Hematol Oncol. 2014;31:703–716.
79 Englum BR, Rialon KL, Speicher PJ, et al. Value of surgical resection in children with
high-risk neuroblastoma. Pediatr Blood Cancer. 2015;62:1529–1535.
80 Simon T, Haberle B, Hero B, et al. Role of surgery in the treatment of patients with stage 4
neuroblastoma age 18 months or older at diagnosis. J Clin Oncol. 2013;31:752–758.
81 Haas-Kogan DA, Swift PS, Selch M, et al. Impact of radiotherapy for high-risk
neuroblastoma: a Children’s Cancer Group study. Int J Radiat Oncol Biol Phys. 2003;56:28–39.
88 Perez CA, Matthay KK, Atkinson JB, et al. Biologic variables in the outcome of stages I
and II neuroblastoma treated with surgery as primary therapy : a children’s cancer group
study. J Clin Oncol. 2000;18:18–26.
89 Matthay KK, Sather HN, Seeger RC, et al. Excellent outcome of stage II neuroblastoma is
independent of residual disease and radiation therapy. J Clin Oncol. 1989;7:236–244.
90 Hsu LL, Evans AE, D’Angio GJ. Hepatomegaly in neuroblastoma stage 4s: criteria for
treatment of the vulnerable neonate. Med Pediatr Oncol. 1996;27:521–528.
91 Paulino AC, May r NA, Simon JH, et al. Locoregional control in infants with
neuroblastoma: role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys.
2002;52:1025–1031.
92 Taggart DR, London WB, Schmidt ML, et al. Prognostic value of the stage 4S metastatic
pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth
and 18 months of age. J Clin Oncol. 2011;29:4358–4364.
93 Castleberry RP, Kun LE, Shuster JJ, et al. Radiotherapy improves the outlook for patients
older than 1 y ear with Pediatric Oncology Group stage C neuroblastoma. J Clin Oncol.
1991;9:789–795.
94 Wolden SL, Gollamudi SV, Kushner BH, et al. Local control with multimodality therapy
for stage 4 neuroblastoma. Int J Radiat Oncol Biol Phys. 2000;46:969–974.
97 Robbins JR, Krasin MJ, Pai Panandiker AS, et al. Radiation therapy as part of local control
of metastatic neuroblastoma: the St Jude Children’s Research Hospital experience. J Pediatr
Surg. 2010;45:678–686.
98 Polishchuk AL, Li R, Hill-Kay ser C, et al. Likelihood of bone recurrence in prior sites of
metastasis in patients with high-risk neuroblastoma. Int J Radiat Oncol Biol Phys.
2014;89:839–845.
99 Mazloom A, Louis CU, Nuchtern J, et al. Radiation therapy to the primary and
postinduction chemotherapy MIBG-avid sites in high-risk neuroblastoma. Int J Radiat Oncol
Biol Phys. 2014;90:858–862.
100 Matthay KK, Brisse H, Couanet D, et al. Central nervous sy stem metastases in
neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer. 2003;98:155–
165.
102 Rowland NC, Andrews J, Patel D, et al. Intracranial metastatic neuroblastoma treated
with gamma knife stereotactic radiosurgery : report of two novel cases. Case Rep Neurol Med.
2012;2012:690548.
103 Halperin EC, Cox EB. Radiation therapy in the management of neuroblastoma: the Duke
University Medical Center experience 1967–1984. Int J Radiat Oncol Biol Phys.
1986;12:1829–1837.
104 Kang TI, Brophy P, Hickeson M, et al. Targeted radiotherapy with submy eloablative
doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma. J
Pediatr Hematol Oncol. 2003;25:769–773.
105 Matthay KK, Yanik G, Messina J, et al. Phase II study on the effect of disease sites, age,
and prior therapy on response to iodine-131-metaiodobenzy lguanidine therapy in refractory
neuroblastoma. J Clin Oncol. 2007;25:1054–1060.
106 Franks LM, Bollen A, Seeger RC, et al. Neuroblastoma in adults and adolescents: an
indolent course with poor survival. Cancer. 1997;79:2028–2035.
109 Wheldon TE, Wilson L, Livingstone A, et al. Radiation studies on multicellular tumour
spheroids derived from human neuroblastoma: absence of sparing effect of dose
fractionation. Eur J Cancer Clin Oncol. 1986;22:563–566.
110 Deacon JM, Wilson P, Steel GG. Radiosensitivity of neuroblastoma. Prog Clin Biol Res.
1985;175:525–531.
111 Jacobson GM, Sause WT, O’Brien RT. Dose response analy sis of pediatric neuroblastoma
to megavoltage radiation. Am J Clin Oncol. 1984;7:693–697.
112 Gatcombe HG, Marcus RB Jr, Katzenstein HM, et al. Excellent local control from
radiation therapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2009;74:1549–
1554.
113 Simon T, Hero B, Bongartz R, et al. Intensified external-beam radiation therapy improves
the outcome of stage 4 neuroblastoma in children > 1 y ear with residual local disease.
Strahlenther Onkol. 2006;182:389–394.
114 Halperin EC. Long-term results of therapy for stage C neuroblastoma. J Surg Oncol.
1996;63:172–178.
115 Paulino AC, Ferenci MS, Chiang KY, et al. Comparison of conventional to intensity
modulated radiation therapy for abdominal neuroblastoma. Pediatr Blood Cancer.
2006;46:739–744.
116 Pai Panandiker AS, Beltran C, Billups CA, et al. Intensity modulated radiation therapy
provides excellent local control in high-risk abdominal neuroblastoma. Pediatr Blood Cancer.
2013;60:761–765.
117 Merchant TE. Clinical controversies: proton therapy for pediatric tumors. Semin Radiat
Oncol. 2013;23:97–108.
118 Oshiro Y, Mizumoto M, Okumura T, et al. Clinical results of proton beam therapy for
advanced neuroblastoma. Radiat Oncol. 2013;8:142.
119 Fuji H, Schneider U, Ishida Y, et al. Assessment of organ dose reduction and secondary
cancer risk associated with the use of proton beam therapy and intensity modulated radiation
therapy in treatment of neuroblastomas. Radiat oncol. 2013;8:255.
120 Gunther JR, Sato M, Chintagumpala M, et al. Imaging changes in pediatric intracranial
ependy moma patients treated with proton beam radiation therapy compared to intensity
modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93:54–63.
121 Indelicato DJ, Flampouri S, Rotondo RL, et al. Incidence and dosimetric parameters of
pediatric brainstem toxicity following proton therapy. Acta Oncol. 2014;53:1298–1304.
123 Flandin I, Hartmann O, Michon J, et al. Impact of TBI on late effects in children treated
by megatherapy for Stage IV neuroblastoma—a study of the French Society of Pediatric
oncology. Int J Radiat Oncol Biol Phys. 2006;64:1424–1431.
124 Donaldson SS. Lessons from our children. Int J Radiat Oncol Biol Phys. 1993;26:739–749.
125 Merchant TE, Zelefsky MJ, Sheldon JM, et al. High-dose rate intraoperative radiation
therapy for pediatric solid tumors. Med Pediatr Oncol. 1998;30:34–39.
126 Haas-Kogan DA, Fisch BM, Wara WM, et al. Intraoperative radiation therapy for high-
risk pediatric neuroblastoma. Int J Radiat Oncol Biol Phys. 2000;47:985–992.
128 Leavey PJ, Odom LF, Poole M, et al. Intra-operative radiation therapy in pediatric
neuroblastoma. Med Pediatr Oncol. 1997;28:424–428.
129 Gillis AM, Sutton E, Dewitt KD, et al. Long-term outcome and toxicities of intraoperative
radiotherapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2007;69:858–864.
130 Kunieda E, Hirobe S, Kaneko T, et al. Patterns of local recurrence after intraoperative
radiotherapy for advanced neuroblastoma. Jpn J Clin Oncol. 2008;38:562–566.
131 Kunieda E, Nishimura G, Kaneko T, et al. Spinal deformity after intra-operative
radiotherapy for paediatric patients. Br J Radiol. 2010;83:59–66.
132 Rubino C, Adjadj E, Guerin S, et al. Long-term risk of second malignant neoplasms after
neuroblastoma in childhood: role of treatment. Int J Cancer. 2003;107:791–796.
133 Laverdiere C, Cheung NK, Kushner BH, et al. Long-term complications in survivors of
advanced stage neuroblastoma. Pediatr Blood Cancer. 2005;45:324–332.
134 Ducassou A, Gambart M, Munzer C, et al. Long-term side effects of radiotherapy for
pediatric localized neuroblastoma: results from clinical trials NB90 and NB94. Strahlenther
Onkol. 2015;191:604–612.
135 Sutton EJ, Tong RT, Gillis AM, et al. Decreased aortic growth and middle aortic sy ndrome
in patients with neuroblastoma after radiation therapy. Pediatr Radiol. 2009;39:1194–1202.
136 Holtta P, Alaluusua S, Saarinen-Pihkala UM, et al. Long-term adverse effects on dentition
in children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous
stem cell transplantation with or without total body irradiation. Bone Marrow Transplant.
2002;29:121–127.
137 Gurney JG, Tersak JM, Ness KK, et al. Hearing loss, quality of life, and academic
problems in long-term neuroblastoma survivors: a report from the Children’s Oncology
Group. Pediatrics. 2007;120:e1229–e1236.
138 Martin A, Schneiderman J, Helenowski IB, et al. Secondary malignant neoplasms after
high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma.
Pediatric Blood Cancer. 2014;61:1350–1356.
139 Wolden SL, Lamborn KR, Cleary SF, et al. Second cancers following pediatric Hodgkin’s
disease. J Clin Oncol. 1998;16:536–544.
140 Applebaum MA, Henderson TO, Lee SM, et al. Second malignancies in patients with
neuroblastoma: the effects of risk-based therapy. Pediatr Blood Cancer. 2015;62:128–133.
141 Kraal KC, Ty tgat GA, van Eck-Smit BL, et al. Upfront treatment of high-risk
neuroblastoma with a combination of (131) I-MIBG and Topotecan. Pediatr Blood Cancer.
2015;62:1886–1891.
142 Kaneko M, Tsuchida Y, Uchino J, et al. Treatment results of advanced neuroblastoma
with the first Japanese study group protocol—study group of japan for treatment of advanced
neuroblastoma [see comments]. J Pediatr Hematol Oncol. 1999;21:190–197.
143 DuBois SG, Allen S, Bent M, et al. Phase I/II study of (131)I-MIBG with vincristine and 5
day s of irinotecan for advanced neuroblastoma. Br J Cancer. 2015;112:644–649.
144 Mueller S, Yang X, Sottero TL, et al. Cooperation of the HDAC inhibitor vorinostat and
radiation in metastatic neuroblastoma: efficacy and underly ing mechanisms. Cancer Lett.
2011;306:223–229.
145 DuBois SG, Groshen S, Park JR, et al. Phase I study of vorinostat as a radiation sensitizer
with 131I-Metaiodobenzy lguanidine ( 131I-MIBG) for patients with relapsed or refractory
neuroblastoma. Clin Cancer Res. 2015;21:2715–2721.
146 Mazzocco K, Defferrari R, Sementa AR, et al. Genetic abnormalities in adolescents and
y oung adults with neuroblastoma: a report from the Italian Neuroblastoma group. Pediatr
Blood Cancer. 2015;62:1725–1732.
147 Castleberry RP, Cantor AB, Green AA, et al. Phase II investigational window using
carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated
neuroblastoma: a Pediatric Oncology Group study [see comments]. J Clin Oncol.
1994;12:1616–1620.
148 Coze C, Hartmann O, Michon J, et al. NB87 induction protocol for stage 4 neuroblastoma
in children over 1 y ear of age: a report from the French Society of Pediatric Oncology. J Clin
Oncol. 1997;15:3433–3440.
149 Kushner BH, LaQuaglia MP, Bonilla MA, et al. Highly effective induction therapy for
stage 4 neuroblastoma in children over 1 y ear of age. J Clin Oncol. 1994;12:2607–2613.
152 Shamberger RC, Smith EI, Joshi VV, et al. The risk of nephrectomy during local control
in abdominal neuroblastoma. J Pediatr Surg. 1998;33:161–164.
154 Rosen EM, Cassady JR, Frantz CN, et al. Neuroblastoma: the Joint Center for Radiation
Therapy /Dana-Farber Cancer Institute/Children’s Hospital experience. J Clin Oncol.
1984;2:719–732.
155 Sibley GS, Mundt AJ, Goldman S, et al. Patterns of failure following total body irradiation
and bone marrow transplantation with or without a radiotherapy boost for advanced
neuroblastoma. Int J Radiat Oncol Biol Phys. 1995;32:1127–1135.
156 Kushner BH, Cheung NK, Barker CA, et al. Hy perfractionated low-dose (21 Gy )
radiotherapy for cranial skeletal metastases in patients with high-risk neuroblastoma. Int J
Radiat Oncol Biol Phys. 2009;75:1181–1186.
157 Haase GM, Meagher DP Jr, McNeely LK, et al. Electron beam intraoperative radiation
therapy for pediatric neoplasms. Cancer. 1994;74:740–747.
158 Aitken DR, Hopkins GA, Archambeau JO, et al. Intraoperative radiotherapy in the
treatment of neuroblastoma: report of a pilot study. Ann Surg Oncol. 1995;2:343–350.
1 Hodgkin T. On some morbid appearances of the absorbent gland and spleen. Med Chir
Trans. 1832;17:68–114.
6 Goodman L, Wintrobe M, Dameshe W, et al. Nitrogen mustard therapy : use of methy l-bis-
(chloroethy l)amine hy drochloride for Hodgkin’s disease, ly mphosarcoma, leukemia and
certain allied and miscellaneous disorders. JAMA. 1946;132:126–131.
11 Donaldson SS, Glatstein E, Rosenberg SA, et al. Pediatric Hodgkin’s disease. II. Results of
therapy. Cancer. 1976;37(5):2436–2447.
12 Donaldson SS, Link MP. Combined modality treatment with low-dose radiation and MOPP
chemotherapy for children with Hodgkin’s disease. J Clin Oncol. 1987;5(5):742–749.
13 Donaldson SS, Link MP. Hodgkin’s disease. Treatment of the y oung child. Pediatr Clin
North Am. 1991;38(2):457–473.
15 Schellong G. The balance between cure and late effects in childhood Hodgkin’s
ly mphoma: the experience of the German–Austrian Study Group since 1978. Ann Oncol.
1996;7(suppl 4):67–72.
16 Schellong G. Treatment of children and adolescents with Hodgkin’s disease: the experience
of the German–Austrian Paediatric Study Group. Baillieres Clin Haematol. 1996;9(3):619–
634.
18 Dionet C, Oberlin O, Habrand JL, et al. Initial chemotherapy and low-dose radiation in
limited fields in childhood Hodgkin’s disease: results of a joint cooperative study by the French
Society of Pediatric Oncology (SFOP) and Hôpital Saint-Louis, Paris. Int J Radiat Oncol Biol
Phys. 1988;15(2):341–346.
19 Jenkin D, Doy le J, Berry M, et al. Hodgkin’s disease in children: treatment with MOPP and
low-dose, extended field irradiation without laparotomy. Late results and toxicity. Med Pediatr
Oncol. 1990;18(4):265–272.
20 Cleary SF, Link MP, Donaldson SS. Hodgkin’s disease in the very y oung. Int J Radiat Oncol
Biol Phys. 1994;28(1):77–83.
23 Jox A, Zander T, Diehl V, et al. Clonal relapse in Hodgkin’s disease. N Engl J Med.
1997;337(7):499.
26 Gupta RK, Patel K, Bodmer WF, et al. Mutation of p53 in primary biopsy material and cell
lines from Hodgkin disease. Proc Natl Acad Sci U S A. 1993;90(7):2817–2821.
27 Ambinder RF, Browning PJ, Lorenzana I, et al. Epstein–Barr virus and childhood Hodgkin’s
disease in Honduras and the United States. Blood. 1993;81(2):462–467.
28 Weiss LM, Movahed LA, Warnke RA, et al. Detection of Epstein–Barr viral genomes in
Reed–Sternberg cells of Hodgkin’s disease. N Engl J Med. 1989;320(8):502–506.
29 Gupta RK, Whelan JS, Lister TA, et al. Direct sequence analy sis of the t(14;18)
chromosomal translocation in Hodgkin’s disease. Blood. 1992;79(8):2084–2088.
31 Stein H, Hummel M, Durkop H, et al. Biology of Hodgkin’s disease. In: Canellos GLT,
Lister TA, Sklar JL, et al., eds. The Lymphomas. Philadelphia, PA: W.B. Saunders; 1998:287–
304.
32 Gruss HJ, Pinto A, Duy ster J, et al. Hodgkin’s disease: a tumor with disturbed
immunological pathway s. Immunol Today. 1997;18(4):156–163.
33 Schwartz RS. Hodgkin’s disease: time for a change. N Engl J Med. 1997;337(7):495–496.
36 Jaffe ES. The 2008 WHO classification of ly mphomas: implications for clinical practice
and translational research. Hematology Am Soc Hematol Educ Program. 2009;523–31.
37 Barros MH, Zalcberg IR, Hassan R. Prognostic impact of CD15 expression and
proliferative index in the outcome of children with classical Hodgkin ly mphoma. Pediatr
Blood Cancer. 2008;50(2):428–429.
38 Dinand V, Malik A, Unni R, et al. Proliferative index and CD15 expression in pediatric
classical Hodgkin ly mphoma. Pediatr Blood Cancer. 2008;50(2):280–283.
39 Tan KL, Scott DW, Hong F, et al. Tumor-associated macrophages predict inferior
outcomes in classic Hodgkin ly mphoma: a correlative study from the E2496 Intergroup trial.
Blood. 2012;120(16):3280–7.
40 Klein JL, Nguy en TT, Bien-Willner GA, et al. CD163 immunohistochemistry is superior to
CD68 in predicting outcome in classical Hodgkin ly mphoma. Am J Clin Pathol.
2014;141(3):381–7.
42 Tarbell NJ, Gelber RD, Weinstein HJ, et al. Sex differences in risk of second malignant
tumours after Hodgkin’s disease in childhood. Lancet. 1993;341(8858):1428–1432.
43 Spitz MR, Sider JG, Johnson CC, et al. Ethnic patterns of Hodgkin’s disease incidence
among children and adolescents in the United States, 1973–82. J Natl Cancer Inst.
1986;76(2):235–239.
45 Trippett T, Mottl A, Oberlin O, et al. Hodgkin ly mphoma in adolescents. In: Bley er A, Barr
R, Albritton K, et al., eds. Cancer in Adolescents and Young Adults. Düsseldorf, Germany :
Springer-Verlag GmbH & Co; 2007:111–125.
46 Vianna NJ, Polan AK. Epidemiologic evidence for transmission of Hodgkin’s disease. N
Engl J Med. 1973;289(10):499–502.
47 Razzouk BI, Gan YJ, Mendonca C, et al. Epstein–Barr virus in pediatric Hodgkin disease:
age and histioty pe are more predictive than geographic region. Med Pediatr Oncol.
1997;28(4):248–254.
51 Jarrett RF, Stark GL, White J, et al. Impact of tumor Epstein–Barr virus status on presenting
features and outcome in age-defined subgroups of patients with classic Hodgkin ly mphoma: a
population-based study. Blood. 2005;106(7):2444–2451.
52 Herling M, Rassidakis GZ, Medeiros LJ, et al. Expression of Epstein–Barr virus latent
membrane protein-1 in Hodgkin and Reed–Sternberg cells of classical Hodgkin’s ly mphoma:
associations with presenting features, serum interleukin 10 levels, and clinical outcome. Clin
Cancer Res. 2003;9(6):2114–2120.
54 Robertson SJ, Lowman JT, Grufferman S, et al. Familial Hodgkin’s disease. A clinical and
laboratory investigation. Cancer. 1987;59(7):1314–1319.
55 Mack TM, Cozen W, Shibata DK, et al. Concordance for Hodgkin’s disease in identical
twins suggesting genetic susceptibility to the y oung-adult form of the disease. N Engl J Med.
1995;332(7):413–418.
56 Linabery AM, Erhardt EB, Richardson MR, et al. Family history of cancer and risk of
pediatric and adolescent Hodgkin ly mphoma: a Children’s Oncology Group study. Int J
Cancer. 2015;137(9):2163–74.
57 Watanabe N, De Rosa SC, Cmelak A, et al. Long-term depletion of naive T cells in patients
treated for Hodgkin’s disease. Blood. 1997;90(9):3662–3672.
60 Mauch PM, Kalish LA, Kadin M, et al. Patterns of presentation of Hodgkin disease.
Implications for etiology and pathogenesis. Cancer. 1993;71(6):2062–2071.
61 Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the
evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol.
1989;7(11):1630–1636.
63 Ferry JA, Harris NL. The pathology of Hodgkin’s disease: what’s new? Semin Radiat Oncol.
1996;6(3):121–130.
65 Punnett A, Tsang R, Hodgson DC. Hodgkin ly mphoma across the age spectrum:
epidemiology, therapy, and late effects. Semin Radiat Oncol. 2010;20(1):30–44.
66 Pui CH, Ip SH, Thompson E, et al. High serum interleukin-2 receptor levels correlate with
a poor prognosis in children with Hodgkin’s disease. Leukemia. 1989;3(7):481–484.
67 Gause A, Pohl C, Tschiersch A, et al. Clinical significance of soluble CD30 antigen in the
sera of patients with untreated Hodgkin’s disease. Blood. 1991;77(9):1983–1988.
69 Mahoney DH Jr, Schreuders LC, Gresik MV, et al. Role of staging bone marrow
examination in children with Hodgkin disease. Med Pediatr Oncol. 1998;30(3):175–177.
73 Bar-Shalom R, Yefremov N, Haim N, et al. Camera-based FDG PET and 67Ga SPECT in
evaluation of ly mphoma: comparative study. Radiology. 2003;227(2):353–360.
74 Wirth A, Sey mour JF, Hicks RJ, et al. Fluorine-18 fluorodeoxy glucose positron emission
tomography, gallium-67 scintigraphy, and conventional staging for Hodgkin’s disease and non-
Hodgkin’s ly mphoma. Am J Med. 2002;112(4):262–268.
75 Mody RJ, Bui C, Hutchinson RJ, et al. Comparison of (18)F flurodeoxy glucose PET with
Ga-67 scintigraphy and conventional imaging modalities in pediatric ly mphoma. Leuk
Lymphoma. 2007;48(4):6999–7007.
77 Smith R, Chen Q, Hudson M. Prognostic factors in pediatric Hodgkin’s disease. Int J Radiat
Oncol Biol Phys. 2001;51(3):199.
78 Maity A, Goldwein JW, Lange B, et al. Mediastinal masses in children with Hodgkin’s
disease. An analy sis of the Children’s Hospital of Philadelphia and the Hospital of the
University of Pennsy lvania experience. Cancer. 1992;69(11):2755–2760.
79 Ruhl U, Albrecht MR, Lueders H, et al. The German multinational GPOH-HD 95 trial:
treatment results and analy sis of failures in pediatric Hodgkin’s disease using combination
chemotherapy with and without radiation. Int J Radiat Oncol Biol Phys. 2004;60:S131.
81 Metzger ML, Castellino SM, Hudson MM, et al. Effect of race on the outcome of pediatric
patients with Hodgkin’s ly mphoma. J Clin Oncol. 2008;26(8):1282–1288.
82 Crnkovich MJ, Leopold K, Hoppe RT, et al. Stage I to IIB Hodgkin’s disease: the combined
experience at Stanford University and the Joint Center for Radiation Therapy. J Clin Oncol.
1987;5(7):1041–1049.
83 Pui CH, Ip SH, Thompson E, et al. Increased serum CD8 antigen level in childhood
Hodgkin’s disease relates to advanced stage and poor treatment outcome. Blood.
1989;73(1):209–213.
85 Warzocha K, Bienvenu J, Ribeiro P, et al. Plasma levels of tumour necrosis factor and its
soluble receptors correlate with clinical features and outcome of Hodgkin’s disease patients.
Br J Cancer. 1998;77(12):2357–2362.
86 Nadali G, Tavecchia L, Zanolin E, et al. Serum level of the soluble form of the CD30
molecule identifies patients with Hodgkin’s disease at high risk of unfavorable outcome. Blood.
1998;91(8):3011–3016.
87 Chronowski GM, Wilder RB, Tucker SL, et al. An elevated serum beta-2-microglobulin
level is an adverse prognostic factor for overall survival in patients with early -stage Hodgkin
disease. Cancer. 2002;95(12):2534–2538.
88 Bohlen H, Kessler M, Sextro M, et al. Poor clinical outcome of patients with Hodgkin’s
disease and elevated interleukin-10 serum levels. Clinical significance of interleukin-10 serum
levels for Hodgkin’s disease. Ann Hematol. 2000;79(3):110–113.
89 Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the
oncogenome of primary Hodgkin and Reed–Sternberg cells. Blood. 2015;125(7):1061–72.
90 Dukers DF, Meijer CJ, ten Berge RL, et al. High numbers of active caspase 3–positive
Reed–Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease
predict favorable clinical outcome. Blood. 2002;100(1):36–42.
93 Giles FJ, Vose JM, Do KA, et al. Clinical relevance of circulating angiogenic factors in
patients with non-Hodgkin’s ly mphoma or Hodgkin’s ly mphoma. Leuk Res. 2004;28(6):595–
604.
94 Ben Arush MW, Ben Barak A, Maurice S, et al. Serum VEGF as a significant marker of
treatment response in Hodgkin ly mphoma. Pediatr Hematol Oncol. 2007;24(2):111–115.
96 Casasnovas R, Mounier N, Brice P, et al. Plasma cy tokine and soluble receptor signature
predicts outcome of patients with classical Hodgkin’s ly mphoma: a study from Groupe
d’Etude des Ly mphomes de L’Adulte. J Clin Oncol. 2007;25(13):1732–1740.
97 von Wasielewski S, Franklin J, Fischer R, et al. Nodular sclerosing Hodgkin disease: new
grading predicts prognosis in intermediate and advanced stages. Blood. 2003;101(10):4063–
4069.
98 Shankar AG, Ashley S, Radford M, et al. Does histology influence outcome in childhood
Hodgkin’s disease? Results from the United Kingdom Children’s Cancer Study Group. J Clin
Oncol. 1997;15(7):2622–2630.
100 Kobe C, Dietlein M, Franklin J, et al. Positron emission tomography has a high negative
predictive value for progression or early relapse for patients with residual disease after first-
line chemotherapy in advanced-stage Hodgkin ly mphoma. Blood. 2008;112(10):3989–3994.
104 Schwartz CL, Friedman DL, McCarten K, et al. Predictors of early response and event-
free survival in Hodgkin ly mphoma (HL): PET versus CT imaging [abstract]. J Clin Oncol
2011;29:8006.
105 Bazzeh F, Rihani R, Howard S, et al. Comparing adult and pediatric Hodgkin ly mphoma in
the surveillance, epidemiology, and end results program, 1988–2005: an analy sis of 21,734
cases. Leuk Lymphoma. 2010;51:2198–2207.
106 Donaldson SS, Whitaker SJ, Plowman PN, et al. Stage I–II pediatric Hodgkin’s disease:
long-term follow-up demonstrates equivalent survival rates following different management
schemes. J Clin Oncol. 1990;8(7):1128–1137.
107 Schellong G, Bramswig JH, Hornig-Franz I. Treatment of children with Hodgkin’s disease:
results of the German Pediatric Oncology Group. Ann Oncol. 1992;3(suppl 4):73–76.
108 DeVita V, Mauch P, Harris NL. Hodgkin’s disease. In: DeVita VT Jr, Hellman S,
Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA:
Lippincott–Raven Publishers; 1997:2242–2283.
109 Longo DL, Young RC, Wesley M, et al. Twenty y ears of MOPP therapy for Hodgkin’s
disease. J Clin Oncol. 1986;4(9):1295–1306.
110 Horning SJ, Hoppe RT, Kaplan HS, et al. Female reproductive potential after treatment for
Hodgkin’s disease. N Engl J Med. 1981;304(23):1377–1382.
111 Fry er CJ, Hutchinson RJ, Krailo M, et al. Efficacy and toxicity of 12 courses of ABVD
chemotherapy followed by low-dose regional radiation in advanced Hodgkin’s disease in
children: a report from the Children’s Cancer Study Group. J Clin Oncol. 1990;8(12):1971–
1980.
112 Hutchinson R, Krailo M, Fry er C. Prognostic factor analy sis in advanced Hodgkin’s
disease (stages III and IV). Results of the CCG 521 trial. Med Pediatr Oncol. 1993;61.
115 LaMonte CS, Yeh SD, Straus DJ. Long-term follow-up of cardiac function in patients with
Hodgkin’s disease treated with mediastinal irradiation and combination chemotherapy
including doxorubicin. Cancer Treat Rep. 1986;70(4):439–444.
116 Nachman JB, Sposto R, Herzog P, et al. Randomized comparison of low-dose involved-
field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a
complete response to chemotherapy. J Clin Oncol. 2002;20(18):3765–3771.
117 Weiner MA, Leventhal B, Brecher ML, et al. Randomized study of intensive MOPP-
ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB,
IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: a Pediatric Oncology Group study.
J Clin Oncol. 1997;15(8):2769–2779.
118 Donaldson SS, Lamborn KR. Radiation in pediatric Hodgkin’s disease. J Clin Oncol.
1998;16(1):391–393.
119 Wolden SL, Chen L, Kelly KM, et al. Long-term results of CCG 5942: a randomized
comparison of chemotherapy with and without radiotherapy for children with Hodgkin’s
ly mphoma--a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(26):3174–
3180.
120 Hudson MM, Poquette CA, Lee J, et al. Increased mortality after successful treatment
for Hodgkin’s disease. J Clin Oncol. 1998;16(11):3592–3600.
121 Wolden SL, Lamborn KR, Cleary SF, et al. Second cancers following pediatric Hodgkin’s
disease. J Clin Oncol. 1998;16(2):536–544.
122 Ruhl U, Albrecht M, Dieckmann K, et al. Response-adapted radiotherapy in the treatment
of pediatric Hodgkin’s disease: an interim report at 5 y ears of the German GPOH-HD 95 trial.
Int J Radiat Oncol Biol Phys. 2001;51(5):1209–1218.
123 Dörffel W, Rühl U, Lüders H, et al. Treatment of children and adolescents with Hodgkin
ly mphoma without radiotherapy for patients in complete remission after chemotherapy : final
results of the multinational trial GPOH-HD95. J Clin Oncol. 2013;31(12):1562–1568.
125 Kung FH, Schwartz CL, Ferree CR, et al. POG 8625: a randomized trial comparing
chemotherapy with chemoradiotherapy for children and adolescents with Stages I, IIA,
IIIA1 Hodgkin Disease: a report from the Children’s Oncology Group. J Pediatr Hematol
Oncol. 2006;28(6):362–368.
126 Donaldson SS, Hudson MM, Lamborn KR, et al. VAMP and low-dose, involved-field
radiation for children and adolescents with favorable, early -stage Hodgkin’s disease: results of
a prospective clinical trial. J Clin Oncol. 2002;20(14):3081–3087.
127 Oberlin O, Leverger G, Pacquement H, et al. Low-dose radiation therapy and reduced
chemotherapy in childhood Hodgkin’s disease: the experience of the French Society of
Pediatric Oncology. J Clin Oncol. 1992;10(10):1602–1608.
129 Vecchi V, Pileri S, Burnelli R, et al. Treatment of pediatric Hodgkin disease tailored to
stage, mediastinal mass, and age. An Italian (AIEOP) multicenter study on 215 patients.
Cancer. 1993;72(6):2049–2057.
130 Friedmann AM, Hudson MM, Weinstein HJ, et al. Treatment of unfavorable childhood
Hodgkin’s disease with VEPA and low-dose, involved-field radiation. J Clin Oncol.
2002;20(14):3088–3094.
131 Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant
ly mphoma. J Clin Oncol. 2007;25(5):579–586.
132 Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for
response assessment of ly mphoma: consensus of the Imaging Subcommittee of International
Harmonization Project in Ly mphoma. J Clin Oncol. 2007;25(5):571–578.
134 Dieckmann K, Potter R, Hofmann J, et al. Does bulky disease at diagnosis influence
outcome in childhood Hodgkin’s disease and require higher radiation doses? Results from the
German–Austrian Pediatric Multicenter Trial DAL-HD-90. Int J Radiat Oncol Biol Phys.
2003;56(3):644–652.
135 Donaldson SS, Link MP, Weinstein HJ, et al. Final results of a prospective clinical trial with
VAMP and low-dose involved-field radiation for children with low-risk Hodgkin’s disease. J
Clin Oncol. 2007;25:332–337.
136 Metzger ML, Weinstein HJ, Hudson MM, et al. Association between radiotherapy vs no
radiotherapy based on early response to VAMP chemotherapy and survival among children
with favorable-risk Hodgkin ly mphoma. JAMA. 2012;307(24):2609–2616.
137 Tebbi CK, Mendenhall N, London WB, et al. Treatment of stage IA, IIA, IIIA1 pediatric
Hodgkin disease with doxorubicin, bleomy cin, vincristine, and etoposide (DBVE) and
radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer. 2006;46(2):198–
202.
138 Tebbi CK, Mendenhall NP, London WB, et al. Response- dependent and reduced
treatment in lower risk Hodgkin ly mphoma in children and adolescents, results of P9426: a
report from the Children’s Oncology Group. Pediatr Blood Cancer. 2012;59(7):1259–65.
141 Hudson MM, Krasin M, Link MP, et al. Risk-adapted, combined-modality therapy with
VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin’s
disease. J Clin Oncol. 2004;22(22):4541–4550.
143 Dharmarajan KV, Friedman DL, Schwartz CL, et al. Patterns of relapse from a phase 3
Study of response-based therapy for intermediate-risk Hodgkin ly mphoma (AHOD0031): a
report from the Children’s Oncology Group. Int J Radiat Oncol Biol Phys. 2015;92(1):60–66.
144 Kelly KM, Sposto R, Hutchinson R, et al. BEACOPP chemotherapy is a highly effective
regimen in children and adolescents with high-risk Hodgkin ly mphoma: a report from the
Children’s Oncology Group. Blood. 2011;117:2596–2603.
145 Yahalom J. Management of relapsed and refractory Hodgkin’s disease. Semin Radiat
Oncol. 1996;6(3):210–224.
146 Yahalom J. Do not miss a second (and possibly last) chance to cure Hodgkin’s disease. Int
J Radiat Oncol Biol Phys. 1997;39(3):595–597.
147 Harker-Murray PD, Drachtman RA, Hodgson DC, et al. Stratification of treatment
intensity in relapsed pediatric Hodgkin ly mphoma. Pediatr Blood Cancer. 2014;61:579–586.
148 Constine LS, Rapoport AP. Hodgkin’s disease, bone marrow transplantation, and involved
field radiation therapy : coming full circle from 1902 to 1996. Int J Radiat Oncol Biol Phys.
1996;36(1):253–255.
149 Benekli M, Smiley SL, Younis T, et al. Intensive conditioning regimen of etoposide (VP-
16), cy clophosphamide, and carmustine (VCB) followed by autologous hematopoietic stem
cell transplantation for relapsed and refractory Hodgkin’s ly mphoma. Bone Marrow
Transplant. 2008;41(7):613–619.
150 Engelhardt BG, Holland DW, Brandt SJ, et al. High-dose chemotherapy followed by
autologous stem cell transplantation for relapsed or refractory Hodgkin ly mphoma:
prognostic features and outcomes. Leuk Lymphoma. 2007;48(9):1728–1735.
151 Williams CD, Goldstone AH, Pearce R, et al. Autologous bone marrow transplantation
for pediatric Hodgkin’s disease: a case-matched comparison with adult patients by the
European Bone Marrow Transplant Group Ly mphoma Registry. J Clin Oncol.
1993;11(11):2243–2249.
152 Claviez A, Canals C, Dierick X, et al. Allogeneic hematopoietic stem cell transplantation
in children and adolescents with recurrent and refractory Hodgkin’s ly mphoma: an analy sis
of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(10):2060–
2067.
153 Stoneham S, Ashley S, Pinkerton R, et al. Hodgkin’s ly mphoma in children aged 5 y ears
or less—the United Kingdom experience. Eur J Cancer. 2007;43(9):1415–1421.
154 Bradley M, Cairo M. Stem cell transplantation for pediatric ly mphoma; past, present, and
future. Bone Marrow Transplant. 2008;41:149–158.
155 Baker KS, Gordon BG, Gross TG, et al. Autologous hematopoietic stem-cell
transplantation for relapsed or refractory Hodgkin’s disease in children and adolescents. J Clin
Oncol. 1999;17(3):825–831.
156 Wimmer RS, Chauvenet AR, London WB, et al. APE chemotherapy for children with
relapsed Hodgkin disease: a Pediatric Oncology Group trial. Pediatr Blood Cancer.
2006;46(3):320–324.
157 Uematsu M, Tarbell NJ, Silver B, et al. Wide-field radiation therapy with or without
chemotherapy for patients with Hodgkin disease in relapse after initial combination
chemotherapy. Cancer. 1993;72(1):207–212.
158 Wirth A, Corry J, Laidlaw C, et al. Salvage radiotherapy for Hodgkin’s disease following
chemotherapy failure. Int J Radiat Oncol Biol Phys. 1997;39(3):599–607.
159 Dhakal S, Biswas T, Liesveld J, et al. Patterns and timing of initial relapse in patients
subsequently undergoing transplantation for Hodgkin’s ly mphoma. Int J Radiat Oncol Biol
Phys. 2009;75(1):188–192.
160 Shahidi M, Kamangari N, Ashley S, et al. Site of relapse after chemotherapy alone for
stage I and II Hodgkin’s disease. Radiother Oncol. 2006;78(1):1–5.
161 Hancock SL, Hoppe RT. Long-term complications of treatment and causes of mortality
after Hodgkin’s disease. Semin Radiat Oncol. 1996;6(3):225–242.
162 Poen JC, Hoppe RT, Horning SJ. High-dose therapy and autologous bone marrow
transplantation for relapsed/refractory Hodgkin’s disease: the impact of involved field
radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys. 1996;36(1):3–
12.
163 Trippett TM, Schwartz CL, Guillerman RP, et al. Ifosfamide and vinorelbine is an
effective reinduction regimen in children with refractory /relapsed Hodgkin ly mphoma,
AHOD00P1: a children’s oncology group report. Pediatr Blood Cancer. 2015;62(1):60–4.
164 Cole PD, Schwartz CL, Drachtman RA, et al. Phase II study of weekly gemcitabine and
vinorelbine for children with recurrent or refractory Hodgkin’s disease: a children’s oncology
group report. J Clin Oncol. 2009;27:1456–1461.
165 Robinson SP, Goldstone AH, Mackinnon S, et al. Chemoresistant or aggressive ly mphoma
predicts for a poor outcome following reduced-intensity allogeneic progenitor cell
transplantation: an analy sis from the Ly mphoma Working Party of the European Group for
Blood and Bone Marrow Transplantation. Blood. 2002;100(13):4310–4316.
166 Kelly KM, Hodgson DC, Appel B, et al. Children’s Oncology Group’s 2013 Blueprint for
Research: Hodgkin Ly mphoma. Pediatr Blood Cancer. 2013;60:972–978.
167 Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab
vedotin for patients with relapsed or refractory Hodgkin’s ly mphoma. J Clin Oncol.
2012;30(18):2183–2189.
168 Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed
CD30-positive ly mphomas. N Engl J Med. 2010;363(19):1812–1821.
169 Dieckmann K, Potter R, Wagner W, et al. Up-front centralized data review and
individualized treatment proposals in a multicenter pediatric Hodgkin’s disease trial with 71
participating hospitals: the experience of the German–Austrian pediatric multicenter trial
DAL-HD-90. Radiother Oncol. 2002;62(2):191–200.
170 Dharmarajan KV, Friedman DL, FitzGerald TJ, et al. Radiotherapy quality assurance
report from children’s oncology group AHOD0031. Int J Radiat Oncol Biol Phys.
2015;91(5):1065–1071.
171 Kaplan HS, Rosenberg SA. The treatment of Hodgkin’s disease. Med Clin North Am.
1966;50(6):1591–1610.
172 Gottdiener JS, Katin MJ, Borer JS, et al. Late cardiac effects of therapeutic mediastinal
irradiation. Assessment by echocardiography and radionuclide angiography. N Engl J Med.
1983;308(10):569–572.
174 Girinsky T, van der Maazen R, Specht L, et al. Involved-node radiotherapy (INRT) in
patients with early Hodgkin ly mphoma: concepts and guidelines. Radiother Oncol.
2006;79(3):270–277.
175 Eich HT, Muller RP, Engenhart-Cabillic R, et al. Involved-node radiotherapy in early -
stage Hodgkin’s ly mphoma. Definition and guidelines of the German Hodgkin Study Group
(GHSG). Strahlenther Onkol. 2008;184(8):406–410.
177 Girinsky T, Specht L, Ghalibafian M, et al. The conundrum of Hodgkin ly mphoma nodes:
to be or not to be included in the involved node radiation fields. The EORTC-GELA
ly mphoma group guidelines. Radiother Oncol. 2008;88(2):202–210.
178 Girinsky T, Ghalibafian M, Bonniaud G, et al. Is FDG-PET scan in patients with early
stage Hodgkin ly mphoma of any value in the implementation of the involved-node
radiotherapy concept and dose painting? Radiother Oncol. 2007;85(2):178–186.
179 Campbell BA, Voss N, Pickles T, et al. Involved-nodal radiation therapy as a component
of combination therapy for limited-stage Hodgkin’s ly mphoma: a question of field size. J Clin
Oncol. 2008;26(32):5170–5174.
180 Lee YK, Cook G, Flower MA, et al. Addition of 18F-FDG-PET scans to radiotherapy
planning of thoracic ly mphoma. Radiother Oncol. 2004;73(3):277–283.
181 Hutchings M, Loft A, Hansen M, et al. Clinical impact of FDG-PET/CT in the planning of
radiotherapy for early -stage Hodgkin ly mphoma. Eur J Haematol. 2007;78(3):206–212.
182 Robertson VL, Anderson CS, Keller FG, et al. Role of FDG-PET in the definition of
involved-field radiation therapy and management for pediatric Hodgkin’s ly mphoma. Int J
Radiat Oncol Biol Phys. 2011;80(2):324–332.
184 Plowman PN, Cooke K, Walsh N. Indications for tomotherapy /intensity modulated
radiation therapy in pediatric radiotherapy extracranial disease. Br J Radiol. 2008;81:872–
880.
185 Hall EJ. Intensity -modulated radiation therapy, protons, and the risk of second cancers.
Int J Radiat Oncol Biol Phys. 2006;65(1):1–7.
186 Goodman KA, Toner S, Hunt M, et al. Intensity -modulated radiotherapy for ly mphoma
involving the mediastinum. Int J Radiat Oncol Biol Phys. 2005;62(1):198–206.
187 Yorke ED, Jackson A, Rosenzweig KE, et al. Dose-volume factors contributing to the
incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-
dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2002;54(2):329–339.
189 Filippi AR, Ciammella P, Piva C, et al. Involved-site image-guided intensity modulated
versus 3D conformal radiation therapy in early stage supradiaphragmatic Hodgkin
ly mphoma. Int J Radiat Oncol Biol Phys. 2014;89(2):370–375.
190 Andolino DL, Hoene T, Xiao L, et al. Dosimetric comparison of involved-field three-
dimensional conformal photon radiotherapy and breast-sparing proton therapy for the
treatment of Hodgkin’s ly mphoma in female pediatric patients. Int J Radiat Oncol Biol Phys.
2011;81(4):e667–e671.
191 Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node proton therapy in combined
modality therapy for Hodgkin ly mphoma: results of a phase 2 study. Int J Radiat Oncol Biol
Phys. 2014;89(5):1053–1059.
192 Coia LR, Hanks GE. Complications from large field intermediate dose
infradiaphragmatic radiation: an analy sis of the patterns of care outcome studies for
Hodgkin’s disease and seminoma. Int J Radiat Oncol Biol Phys. 1988;15(1):29–35.
193 Kinzie JJ, Hanks GE, MacLean CJ, et al. Patterns of care study : Hodgkin’s disease relapse
rates and adequacy of portals. Cancer. 1983;52(12):2223–2226.
194 Green DM, Gingell RL. Regarding cardiac function and morbidity in long-term survivors
of Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 1998;41(4):971.
196 Mertens AC, Yasui Y, Liu Y, et al. Pulmonary complications in survivors of childhood and
adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer.
2002;95(11):2431–2441.
197 Adams MJ, Hardenbergh PH, Constine LS, et al. Radiation-associated cardiovascular
disease. Crit Rev Oncol Hematol. 2003;45(1):55–75.
198 Green DM, Hy land A, Chung CS, et al. Cancer and cardiac mortality among 15-y ear
survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol.
1999;17(10):3207–3215.
199 Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s
disease in children and adolescents. J Clin Oncol. 1993;11(7):1208–1215.
200 Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thy roid in survivors of Hodgkin’s
disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab.
2000;85(9):3227–3232.
201 Constine LS, Donaldson SS, McDougall IR, et al. Thy roid dy sfunction after radiotherapy
in children with Hodgkin’s disease. Cancer. 1984;53(4):878–883.
202 Le Floch O, Donaldson SS, Kaplan HS. Pregnancy following oophoropexy and total nodal
irradiation in women with Hodgkin’s disease. Cancer. 1976;38(6):2263–2268.
203 Anselmo AP, Cartoni C, Bellantuono P, et al. Risk of infertility in patients with Hodgkin’s
disease treated with ABVD vs MOPP vs ABVD/MOPP. Haematologica. 1990;75(2):155–158.
204 Bramswig JH, Heimes U, Heiermann E, et al. The effects of different cumulative doses
of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin’s disease
during childhood or adolescence. Cancer. 1990;65(6):1298–1302.
205 By rne J, Fears TR, Gail MH, et al. Early menopause in long-term survivors of cancer
during adolescence. Am J Obstet Gynecol. 1992;166(3):788–793.
206 da Cunha MF, Meistrich ML, Fuller LM, et al. Recovery of spermatogenesis after
treatment for Hodgkin’s disease: limiting dose of MOPP chemotherapy. J Clin Oncol.
1984;2(6):571–577.
207 Green DM, Hall B. Pregnancy outcome following treatment during childhood or
adolescence for Hodgkin’s disease. Pediatr Hematol Oncol. 1988;5(4):269–277.
208 Pedrick TJ, Hoppe RT. Recovery of spermatogenesis following pelvic irradiation for
Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 1986;12(1):117–121.
209 Ortin TT, Shostak CA, Donaldson SS. Gonadal status and reproductive function following
treatment for Hodgkin’s disease in childhood: the Stanford experience. Int J Radiat Oncol Biol
Phys. 1990;19(4):873–880.
210 Hudson MM, Greenwald C, Thompson E, et al. Efficacy and toxicity of multiagent
chemotherapy and low-dose involved-field radiotherapy in children and adolescents with
Hodgkin’s disease. J Clin Oncol. 1993;11(1):100–108.
211 Jules-Ely see K, Stover DE, Yahalom J, et al. Pulmonary complications in ly mphoma
patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev
Respir Dis. 1992;146(2):485–491.
212 Marina NM, Greenwald CA, Fairclough DL, et al. Serial pulmonary function studies in
children treated for newly diagnosed Hodgkin’s disease with mantle radiotherapy plus cy cles
of cy clophosphamide, vincristine, and procarbazine alternating with cy cles of doxorubicin,
bleomy cin, vinblastine, and dacarbazine. Cancer. 1995;75(7):1706–1711.
213 Mefferd JM, Donaldson SS, Link MP. Pediatric Hodgkin’s disease: pulmonary, cardiac,
and thy roid function following combined modality therapy. Int J Radiat Oncol Biol Phys.
1989;16(3):679–685.
214 Koh ES, Sun A, Tran TH, et al. Clinical dose-volume histogram analy sis in predicting
radiation pneumonitis in Hodgkin’s ly mphoma. Int J Radiat Oncol Biol Phys. 2006;66:223–228.
215 Scholz KH, Herrmann C, Tebbe U, et al. My ocardial infarction in y oung patients with
Hodgkin’s disease: potential pathogenic role of radiotherapy, chemotherapy, and splenectomy.
Clin Invest. 1993;71(1):57–64.
216 Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for
acute ly mphoblastic leukemia in childhood. N Engl J Med. 1991;324(12):808–815.
218 Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of
Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol. 2004;22(15):3139–3148.
219 Kinsella TJ, Trivette G, Rowland J, et al. Long-term follow-up of testicular function
following radiation therapy for early -stage Hodgkin’s disease. J Clin Oncol. 1989;7(6):718–
724.
220 Hobbie WL, Ginsberg JP, Ogle SK, et al. Fertility in males treated for Hodgkins disease
with COPP/ABV hy brid. Pediatr Blood Cancer. 2005;44(2):193–196.
221 Viviani S, Santoro A, Ragni G, et al. Gonadal toxicity after combination chemotherapy
for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol.
1985;21(5):601–605.
222 Haukvik UK, Dieset I, Bioro T, et al. Treatment-related premature ovarian failure as a
long-term complication after Hodgkin’s ly mphoma. Ann Oncol. 2006;17(9):1428–1433.
224 Hodgson DC, Pintilie M, Gitterman L, et al. Fertility among female Hodgkin ly mphoma
survivors attempting pregnancy following ABVD chemotherapy. Hematol Oncol.
2007;25:11–15.
225 Wolden SL, Hancock SL, Carlson RW, et al. Management of breast cancer after Hodgkin’s
disease. J Clin Oncol. 2000;18(4):765–772.
226 van Leeuwen FE, Klokman WJ, Veer MB, et al. Long-term risk of second malignancy in
survivors of Hodgkin’s disease treated during adolescence or y oung adulthood. J Clin Oncol.
2000;18(3):487–497.
227 Schellong G, Riepenhausen M, Creutzig U, et al. Low risk of secondary leukemias after
chemotherapy without mechlorethamine in childhood Hodgkin’s disease. German–Austrian
Pediatric Hodgkin’s Disease Group. J Clin Oncol. 1997;15(6):2247–2253.
228 Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent malignant neoplasms among
1,641 Hodgkin’s diseasepatients diagnosed in childhood and adolescence: a population-based
cohort study in the five Nordic countries. J Clin Oncol. 1996;14(5):1442–1446.
229 Metay er C, Ly nch CF, Clarke EA, et al. Second cancers among long-term survivors of
Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol. 2000;18(12):2435–
2443.
230 Green DM, Hy land A, Barcos MP, et al. Second malignant neoplasms after treatment for
Hodgkin’s disease in childhood or adolescence. J Clin Oncol. 2000;18(7):1492–1499.
231 Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second neoplasms after
childhood Hodgkin’s disease. N Engl J Med. 1996;334(12):745–751.
232 Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malignancy after Hodgkin’s
disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol.
2000;18(3):498–509.
233 Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and
chemotherapy among y oung women with Hodgkin disease. JAMA. 2003;290(4):465–475.
234 Gilbert ES, Stovall M, Gospodarowicz M, et al. Lung cancer after treatment for Hodgkin’s
disease: focus on radiation effects. Radiat Res. 2003;159(2):161–173.
235 Basu SK, Schwartz C, Fisher SG, et al. Unilateral and bilateral breast cancer in women
surviving pediatric Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 2008;72(1):34–40.
236 Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated
for Hodgkin’s disease: associations with gender and radiation dose. Int J Radiat Oncol Biol
Phys. 2008;72:24–33.
237 Robison LL, Green DM, Hudson M, et al. Long-term outcomes of adult survivors of
childhood cancer. Cancer. 2005;104:2557–2564.
238 Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for y oung
women treated for Hodgkin ly mphoma. J Natl Cancer Inst. 2005;97:1428–1437.
239 Mertens AC, Mithy PA, Radloff G, et al. XRCC1 and glutathione-S-transferase gene
poly morphisms and susceptibility to radiotherapy -related malignancies in survivors of
Hodgkin disease. Cancer. 2004;101(6):1463–1472.
240 Bierman PJ, Vose JM, Leichner PK, et al. Yttrium 90–labeled antiferritin followed by
high-dose chemotherapy and autologous bone marrow transplantation for poor-prognosis
Hodgkin’s disease. J Clin Oncol. 1993;11(4):698–703.
241 Rooney CM, Smith CA, Ng CY, et al. Use of gene-modified virus-specific T
ly mphocy tes to control Epstein–Barr virus–related ly mphoproliferation. Lancet.
1995;345(8941):9–13.
1 Hodgkin T. On some morbid appearances of the absorbent gland and spleen. Med Chir
Trans. 1832;17:68–114.
2 Virchow R. Weisses Blut. In: Froriep’s neue Notizen, ed. Neue Notizen aus dem Gebete der
Natur und Heilkunde. Vol. 36. Berlin; 1845:151–156.
3 Sandlund JT, Downing JR, Crist WM. Non-Hodgkin’s ly mphoma in childhood. N Engl J Med.
1996;334:1238–1248.
7 Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin’s
ly mphomas: dissimilarities from ly mphomas in adults. Semin Oncol. 1980;7:332–339.
8 Young JL Jr, Ries LG, Silverberg E, et al. Cancer incidence, survival, and mortality for
children y ounger than age 15 y ears. Cancer. 1986;58:598–602.
9 Tay lor AM, Metcalfe JA, Thick J, et al. Leukemia and ly mphoma in ataxia telangiectasia.
Blood. 1996;87:423–438.
11 Weinstein H, Vance Z, Jaffe N, et al. Improved prognosis for patients with mediastinal
ly mphoblastic ly mphoma. Blood. 1979;53:687–694.
12 Shamberger RC, Holzman RS, Griscom NT, et al. Prospective evaluation by computed
tomography and pulmonary function tests of children with mediastinal masses. Surgery.
1995;118:468–471.
13 Loeffler JS, Leopold KA, Recht A, et al. Emergency prebiopsy radiation for mediastinal
masses: impact on subsequent pathologic diagnosis and outcome. J Clin Oncol. 1986;4:716–
721.
14 Magrath IT, Shiramizu B. Biology and treatment of small non-cleaved cell ly mphoma.
Oncology (Wiliston Park). 1989;3:41–53.
15 Cheson, BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging
and response assessment of Hodgkins and non-Hodgkin Ly mphoma: the Lugano classification.
J Clin Oncol. 2014;32(27):3059–3068
16 Bhojwani D, McCarville MB, Choi JK, et al. The role of FDG-PET/ CT in the evaluation of
residual disease in paediatric non-Hodgkin ly mphoma. Br J Haematol. 2015;168(6):845–853
18 Jaffe ES, Harris NL, Stein H, et al. Classification of ly mphoid neoplasms: the microscope
as a tool for disease discovery. Blood. 2008;112:4384–4399.
21 Head DR, Behm FG. Acute ly mphoblastic leukemia and the ly mphoblastic ly mphomas of
childhood. Semin Diagn Pathol. 1995;12(4):325–334.
22 Raetz EA, Perkins SL, Bhojwani D, et al. Gene expression profiling reveals intrinsic
differences between T-cell acute ly mphoblastic leukemia and T-cell ly mphoblastic
ly mphoma. Pediatr Blood Cancer. 2006;47:130–140.
23 Heerema NA, Bernheim A, Lim MS, et al. State of the art and future needs in
cy togenetic/molecular genetics/array s in childhood ly mphoma: summary report of workshop
at the First International Sy mposium on Childhood and Adolescent Non-Hodgkin ly mphoma,
April 9, 2003, NYC, NY. Pediatr Blood Cancer. 2005;45:616–622.
24 Dave BJ, Weisenburger DD, Higgins CM, et al. Cy togenetics and fluorescence in situ
hy bridization studies of diffuse large B-cell ly mphoma in children and y oung adults. Cancer
Genet Cytogenet. 2004;153:115–121.
26 Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPAD
chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin’s
ly mphoma: results of the FAB/LMB 96 international study. Br J Haematol. 2008;141:840–847.
27 Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-
risk central nervous sy stem B non-Hodgkin ly mphoma and B acute ly mphoblastic leukemia in
children and adolescents. Blood. 2007;109:2736–2743.
28 Gerrard M, Waxman IM, Sposto R, et al. Outcome and pathologic classification of children
and adolescents with mediastinal large B-cell ly mphoma treated with FAB/LMB96 mature B-
NHL therapy. Blood. 2013;121(2):278–285.
29 Murphy SB, Bley er WA. Cranial irradiation is not necessary for central-nervous-sy stem
prophy laxis in pediatric non Hodgkin’s ly mphoma. Int J Radiat Oncol Biol Phys. 1987;13:467–
468.
33 Laver JH, Mahmoud H, Pick TE, et al. Results of a randomized phase III trial in children
and adolescents with advanced stage diffuse large cell non-Hodgkin’s ly mphoma: a Pediatric
Oncology Group study. Leuk Lymphoma. 2001;42:399–405.
38 Mandell LR, Wollner N, Fuks Z. Is cranial radiation necessary for CNS prophy laxis in
pediatric NHL? Int J Radiat Oncol Biol Phys. 1987;13:359–363.
45 Alexander S, Kdraveka JM, Weitzman S, et al. Advanced stage anaplastic large cell
ly mphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of
APO versus a modified regimen with vinblastine: a report from the chidlren’s oncology
group. Pediatr Blood Cancer. 2014;61(12):2236–2242.
46 Bluhm E, Ronckers C, Hay ashi RJ, et al. Cause-specific mortality and second cancer
incidence after non-Hodgkin ly mphoma: a report from the Childhood Cancer Survivor Study.
Blood. 2008;111(81):4014–4021.
47 Giri S, Bhatt VR, Pathak R, et al. Role of radiation therpay in primary mediastinal large B-
cell ly mphoma in rituximab era: a US population-based analy sis. Am J. Hematol.
2015;90(11):1052–1054.
48 Armitage JO. Bone marrow transplantation in the treatment of patients with ly mphoma.
Blood. 1989;73:1749–1758.
49 Kobrinsky NL, Sposto R, Shah NR, et al. Outcomes of treatment of children and
adolescents with recurrent non-Hodgkin’s ly mphoma and Hodgkin’s disease with
dexamethasone, etoposide, cisplatin, cy tarabine, and L-asparaginase, maintenance
chemotherapy, and transplantation: Children’s Cancer Group Study CCG-5912. J Clin Oncol.
2001;19:2390–2396.
50 Harris RE, Termuhlen AM, Smith LM, et al. Autologous peripheral blood stem cell
transplantation in children with refractory or relapsed ly mphoma: results of Children’s
Oncology Group study A5962. Biol Blood Marrow Transplant. 2011;17(2):249–258.
4 Ambros IM, Ambros PF, Strehl S, et al. MIC2 is a specific marker for Ewing’s sarcoma and
peripheral primitive neuroectodermal tumors—evidence for a common histogenesis of
Ewing’s sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression
and specific chromosome aberration. Cancer. 1991;67:1886–1893.
5 Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors—a subgroup of small-
round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994;331:294–299.
6 Moll R, Lee I, Gould VE, et al. Immunocy tochemical analy sis of Ewing’s tumors—patterns
of expression of intermediate filaments and desmosomal proteins indicate cell ty pe
heterogeneity and pluripotential differentiation. Am J Pathol. 1987;127:288–304.
8 Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain
caused by chromosome translocation in human tumours. Nature. 1992;359:162–165.
9 Zwerner JP, May WA. PDGF-C is an EWS/FLI induced transforming growth factor in
Ewing family tumors. Oncogene. 2001;20:626–633.
10 Truong AH, Ben-David Y. The role of Fli-1 in normal cell function and malignant
transformation. Oncogene. 2000;19:6482–6489.
11 May WA, Gishizky ML, Lessnick SL, et al. Ewing sarcoma 11;22 translocation produces a
chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for
transformation. Proc Natl Acad Sci U S A. 1993;90:5752–5756.
12 Bailly RA, Bosselut R, Zucman J, et al. DNA-binding and transcriptional activation
properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing
sarcoma. Mol Cell Biol. 1994;14:3230–3241.
14 van Doorninck JA, Ji L, Schaub B, et al. Current treatment protocols have eliminated the
prognostic advantage of ty pe 1 fusions in Ewing sarcoma: a report from the Children’s
Oncology Group. J Clin Oncol. 2010;28:1989–1994.
15 Le Deley MC, Delattre O, Schaefer KL, et al. Impact of EWS-ETS fusion ty pe on disease
progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective
results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol. 2010;28:1982–1988.
16 Fletcher JA. Ewing’s sarcoma oncogene structure: a novel prognostic marker? J Clin
Oncol. 1998;16:1241–1243.
17 Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al. Multimodal therapy for the management of
primary, nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up of the First
Intergroup study. J Clin Oncol. 1990;8:1664–1674.
18 Braun BS, Frieden R, Lessnick SL, et al. Identification of target genes for the Ewing’s
sarcoma EWS/FLI fusion protein by representational difference analy sis. Mol Cell Biol.
1995;15:4623–4630.
20 Jenkin RD. Ewing’s sarcoma: radiation treatment at the primary site—regarding Dunst et
al., IJROBP 32:919-930; 1995. Int J Radiat Oncol Biol Phys. 1995;32:1253–1254.
21 Marcus RB Jr, Graham-Pole JR, Springfield DS, et al. High-risk Ewing’s sarcoma: end-
intensification using autologous bone marrow transplantation. Int J Radiat Oncol Biol Phys.
1988;15:53–59.
22 Brown AP, Fixsen JA, Plowman PN. Local control of Ewing’s sarcoma: an analy sis of 67
patients. Br J Radiol. 1987;60:261–268.
23 Kinsella TJ, Loeffler JS, Fraass BA, et al. Extremity preservation by combined modality
therapy in sarcomas of the hand and foot: an analy sis of local control, disease free survival
and functional result. Int J Radiat Oncol Biol Phys. 1983;9:1115–1119.
24 Mendenhall CM, Marcus RB Jr, Enneking WF, et al. The prognostic significance of soft
tissue extension in Ewing’s sarcoma. Cancer. 1983;51:913–917.
25 Anne P, Efird J, Spiro I. Ewing’s sarcoma: comparison of local treatment with radiation or
radiation plus surgery. Int J Radiat Oncol Biol Phys. 1993;27:295–296.
26 Thomas PR, Foulkes MA, Gilula LA, et al. Primary Ewing’s sarcoma of the ribs—a report
from the intergroup Ewing’s sarcoma study. Cancer. 1983;51:1021–1027.
27 Askin FB, Rosai J, Sibley RK, et al. Malignant small cell tumor of the thoracopulmonary
region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis. Cancer.
1979;43:2438–2451.
29 Shamberger RC, Laquaglia MP, Krailo MD, et al. Ewing sarcoma of the rib: results of an
intergroup study with analy sis of outcome by timing of resection. J Thorac Cardiovasc Surg.
2000;119:1154–1161.
30 Vietti TJ, Gehan EA, Nesbit ME Jr, et al. Multimodal therapy in metastatic Ewing’s
sarcoma: an Intergroup Study. Natl Cancer Inst Monogr. 1981;(56):279–284.
31 Marcus RB Jr. Current controversies in pediatric radiation oncology. Orthop Clin North Am.
1996;27:551–557.
32 Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone:
analy sis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study
Group. J Clin Oncol. 2000;18:3108–3114.
35 Wang CC, Schulz MD. Ewing’s sarcoma: a study of fifty cases treated at the Massachusetts
General Hospital, 1930-1952 inclusive. N Engl J Med. 1953;248:571–576.
36 Phillips TL, Sheline GE. Radiation therapy of malignant bone tumors. Radiology.
1969;92:1537–1545.
37 Dunst J, Jurgens H, Sauer R, et al. Radiation therapy in Ewing’s sarcoma: an update of the
CESS 86 trial. Int J Radiat Oncol Biol Phys. 1995;32:919–930.
38 Evans RG, Nesbit ME, Gehan EA, et al. Multimodal therapy for the management of
localized Ewing’s sarcoma of pelvic and sacral bones: a report from the second intergroup
study. J Clin Oncol. 1991;9:1173–1180.
39 Horowitz ME, Kinsella TJ, Wexler LH, et al. Total-body irradiation and autologous bone
marrow transplant in the treatment of high-risk Ewing’s sarcoma and rhabdomy osarcoma. J
Clin Oncol. 1993;11:1911–1918.
41 Thomas PR, Perez CA, Neff JR, et al. The management of Ewing’s sarcoma: role of
radiotherapy in local tumor control. Cancer Treat Rep. 1984;68:703–710.
42 Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-y ear
survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst.
2001;93:618–629.
43 Kinsella TJ, Lichter AS, Miser J, et al. Local treatment of Ewing’s sarcoma: radiation
therapy versus surgery. Cancer Treat Rep. 1984;68:695–701.
44 Jenkin RD, Rider WD, Sonley MJ. Ewing’s sarcoma: adjuvant total body irradiation,
cy clophosphamide and vincristine. Int J Radiat Oncol Biol Phys. 1976;1:407–413.
45 Bacci G, Picci P, Gitelis S, et al. The treatment of localized Ewing’s sarcoma: the
experience at the Istituto Ortopedico Rizzoli in 163 cases treated with and without adjuvant
chemotherapy. Cancer. 1982;49:1561–1570.
46 Kuttesch JF Jr, Wexler LH, Marcus RB, et al. Second malignancies after Ewing’s sarcoma:
radiation dose-dependency of secondary sarcomas. J Clin Oncol. 1996;14:2818–2825.
47 DuBois SG, Krailo MD, Gebhardt MC, et al. Comparative evaluation of local control
strategies in localized Ewing sarcoma of bone: a report from the Children’s Oncology Group.
Cancer. 2015;121:467–475.
49 Perez CA, Tefft M, Nesbit ME Jr, et al. Radiation therapy in the multimodal management
of Ewing’s sarcoma of bone: report of the Intergroup Ewing’s Sarcoma Study. Natl Cancer Inst
Monogr. 1981:(56):263–271.
50 Rosen G, Caparros B, Nirenberg A, et al. Ewing’s sarcoma: ten-y ear experience with
adjuvant chemotherapy. Cancer. 1981;47:2204–2213.
51 Wilkins RM, Pritchard DJ, Burgert EO Jr, et al. Ewing’s sarcoma of bone. Experience with
140 patients. Cancer. 1986;58:2551–2555.
53 Neff JR. Nonmetastatic Ewing’s sarcoma of bone: the role of surgical therapy. Clin Orthop
Relat Res. 1986:(204):111–118.
54 Sailer SL, Harmon DC, Mankin HJ, et al. Ewing’s sarcoma: surgical resection as a
prognostic factor. Int J Radiat Oncol Biol Phys. 1988;15(1):43–52.
55 Hay es FA, Thompson EI, Mey er WH, et al. Therapy for localized Ewing’s sarcoma of
bone. J Clin Oncol. 1989;7:208–213.
56 Sauer R, Jurgens H, Burgers JM, et al. Prognostic factors in the treatment of Ewing’s
sarcoma—The Ewing’s Sarcoma Study Group of the German Society of Paediatric
Oncology CESS 81. Radiother Oncol. 1987;10:101–110.
57 Hay es FA, Thompson EI, Parvey L, et al. Metastatic Ewing’s sarcoma: remission induction
and survival. J Clin Oncol. 1987;5:1199–1204.
58 Newton WA Jr. Meadows AT, Shimada H, et al. Bone sarcomas as second malignant
neoplasms following childhood cancer. Cancer. 1991;67:193–201.
60 Dunst J, Sauer R, Burgers JM, et al. Radiation therapy as local treatment in Ewing’s
sarcoma—results of the Cooperative Ewing’s Sarcoma Studies CESS 81 and CESS 86. Cancer.
1991;67:2818–2825.
61 Horowitz ME, Neff JR, Kun LE. Ewing’s sarcoma—radiotherapy versus surgery for local
control. Pediatr Clin North Am. 1991;38:365–380.
62 Scully SP, Temple HT, O’Keefe RJ, et al. Role of surgical resection in pelvic Ewing’s
sarcoma. J Clin Oncol. 1995;13:2336–2341.
63 Hay es FA, Thompson EI, Hustu HO, et al. The response of Ewing’s sarcoma to sequential
cy clophosphamide and adriamy cin induction therapy. J Clin Oncol. 1983;1:45–51.
64 Fellinger EJ, Garin-Chesa P, Triche TJ, et al. Immunohistochemical analy sis of Ewing’s
sarcoma cell surface antigen p30/32MIC2. Am J Pathol. 1991;139:317–325.
65 Tefft M, Razek A, Perez C, et al. Local control and survival related to radiation dose and
volume and to chemotherapy in non-metastatic Ewing’s sarcoma of pelvic bones. Int J Radiat
Oncol Biol Phys. 1978;4:367–372.
66 Burgert EO Jr, Nesbit ME, Garnsey LA, et al. Multimodal therapy for the management of
nonpelvic, localized Ewing’s sarcoma of bone: intergroup study IESS-II. J Clin Oncol.
1990;8:1514–1524.
67 Dunst J, Paulussen M, Jurgens H. Lung irradiation for Ewing’s sarcoma with pulmonary
metastases at diagnosis: results of the CESS-studies. Strahlenther Onkol. 1993;169:621–623.
69 Wunder JS, Paulian G, Huvos AG, et al. The histological response to chemotherapy as a
predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint
Surg Am. 1998;80:1020–1033.
70 Ahrens S, Hoffmann C, Jabar S, et al. Evaluation of prognostic factors in a tumor volume-
adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience—
Cooperative Ewing Sarcoma Study. Med Pediatr Oncol. 1999;32:186–195.
71 Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard
chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J
Med. 2003;348:694–701.
72 Yock TI, Krailo M, Fry er CJ, et al. Local control in pelvic Ewing sarcoma: analy sis from
INT-0091—a report from the Children’s Oncology Group. J Clin Oncol. 2006;24:3838–3843.
74 Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-
compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the
Children’s Oncology Group. J Clin Oncol. 2012;30:4148–4154.
75 Marcove RC, Rosen G. Radical en bloc excision of Ewing’s sarcoma. Clin Orthop Relat
Res. 1980;(153):86–91.
76 Pomeroy TC, Johnson R. Integrated therapy of Ewing’s sarcoma. Front Radiat Ther Oncol.
1975;10:152–166.
79 Arai Y, Kun LE, Brooks MT, et al. Ewing’s sarcoma: local tumor control and patterns of
failure following limited-volume radiation therapy. Int J Radiat Oncol Biol Phys.
1991;21:1501–1508.
82 Bolek TW, Marcus RB Jr, Mendenhall NP, et al. Local control and functional results after
twice-daily radiotherapy for Ewing’s sarcoma of the extremities. Int J Radiat Oncol Biol
Phys. 1996;35:687–692.
83 Marcus RB Jr, Cantor A, Heare TC, et al. Local control and function after twice-a-day
radiotherapy for Ewing’s sarcoma of bone. Int J Radiat Oncol Biol Phys. 1991;21:1509–1515.
84 Kushner BH, Mey ers PA, Gerald WL, et al. Very -high-dose short-term chemotherapy for
poor-risk peripheral primitive neuroectodermal tumors, including Ewing’s sarcoma, in
children and y oung adults. J Clin Oncol. 1995;13:2796–2804.
85 Jentzsch K, Binder H, Cramer H, et al. Leg function after radiotherapy for Ewing’s
sarcoma. Cancer. 1981;47:1267–1278.
86 Shamberger RC, Grier HE, Weinstein HJ, et al. Chest wall tumors in infancy and
childhood. Cancer. 1989;63:774–785.
87 Potter R, Knocke TH, Kovacs G, et al. Brachy therapy in the combined modality treatment
of pediatric malignancies. Principles and preliminary experience with treatment of soft tissue
sarcoma (recurrence) and Ewing’s sarcoma. Klin Padiatr. 1995;207:164–173.
88 Delaney TF, Kooy HM, eds. Proton and Charged Particle Radiotherapy. Philadelphia, PA:
Lippincott, Williams and Wilkins; 2008.
89 Lee CT, Bilton SD, Famiglietti RM, et al. Treatment planning with protons for pediatric
retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other
conformal techniques? Int J Radiat Oncol Biol Phys. 2005;63:362–372.
91 Ozkay nak MF, Matthay K, Cairo M, et al. Double-alky lator non-total-body irradiation
regimen with autologous hematopoietic stem-cell transplantation in pediatric solid tumors. J
Clin Oncol. 1998;16:937–944.
92 Casey DL, Wexler LH, Mey ers PA, et al. Radiation for bone metastases in Ewing sarcoma
and rhabdomy osarcoma. Pediatr Blood Cancer. 2015;62:445–449.
93 Berry MP, Jenkin RDT, Harwood AR, et al. Ewing’s sarcoma: a trial of adjuvant
chemotherapy and sequential half-body irradiation. Int J Radiat Oncol Biol Phys. 1986;12:19-
-24.
96 Mey ers PA, Krailo MD, Ladany i M, et al. High-dose melphalan, etoposide, total-body
irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk
Ewing’s sarcoma does not improve prognosis. J Clin Oncol. 2001;19:2812–2820.
97 Tucker MA, D’Angio GJ, Boice JD Jr, et al. Bone sarcomas linked to radiotherapy and
chemotherapy in children. N Engl J Med. 1987;317:588–593.
98 Kushner BH, Mey ers PA. How effective is dose-intensive/my eloablative therapy against
Ewing’s sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The
Memorial Sloan-Kettering experience and a literature review. J Clin Oncol. 2001;19:870–880.
99 Ahrens S, Dunst J, Rube C, et al. Second malignancies after treatment for Ewing’s
sarcoma. Int J Radiat Oncol Biol Phys. 1998;42:379–384.
3 Kumar R, David R, Madewell JE, et al. Radiographic spectrum of osteogenic sarcoma. AJR
Am J Roentgenol. 1987;148(4):767–772.
7 Miller JH, Ettinger LJ. Osteosarcoma. In: Miller JH, ed. Imaging in Pediatric Oncology.
Baltimore, MD: Williams & Wilkins; 1985:378–388.
8 Spjut HJ, Ay ala AG. Skeletal tumors in children and adolescents. Hum Pathol.
1983;14(7):628–642.
12 Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973
to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer.
2009;115(7):1531–1543.
14 Diller L, Kassel J, Nelson CE, et al. p53 functions as a cell cy cle control protein in
osteosarcomas. Mol Cell Biol. 1990;10(11):5772–5781.
15 Wei H, Zhao MQ, Dong W, et al. Expression of c-kit protein and mutational status of the c-
kit gene in osteosarcoma and their clinicopathological significance. J Int Med Res.
2008;36(5):1008–1014.
16 Kirpensteijn J, Kik M, Teske E, et al. TP53 gene mutations in canine osteosarcoma. Vet
Surg. 2008;37(5):454–460.
17 Fisher JL, Mackie PS, Howard ML, et al. The expression of the urokinase plasminogen
activator sy stem in metastatic murine osteosarcoma: an in vivo mouse model. Clin Cancer
Res. 2001;7(6):1654–1660.
18 Yao Y, Dong Y, Lin F, et al. The expression of CRM1 is associated with prognosis in human
osteosarcoma. Oncology Rep. 2009;21(1):229–235.
19 Xu-Dong S, Zan S, Shui-er Z, et al. Expression of Ezrin correlates with lung metastasis in
Chinese patients with osteosarcoma. Clin Invest Med. 2009;32(2):E180–E188.
20 Huang Y, Lin Z, Zhuang J, et al. Prognostic significance of alpha V integrin and VEGF in
osteosarcoma after chemotherapy. Onkologie. 2008;31(10):535–540.
21 Nathan SS, Pereira BP, Zhou YF, et al. Elevated expression of Runx2 as a key parameter in
the etiology of osteosarcoma. Mol Biol Rep. 2009;36(1):153–158.
24 Rodriguez NI, Hoots WK, Koshkina NV, et al. COX-2 expression correlates with survival in
patients with osteosarcoma lung metastases. J Pediatr Hematol Oncol. 2008;30(7):507–512.
27 Glasser DB, Lane JM, Huvos AG, et al. Survival, prognosis, and therapeutic response in
osteogenic sarcoma. The Memorial Hospital experience. Cancer. 1992;69(3):698–708.
28 Beattie EJ, Harvey JC, Marcove R, et al. Results of multiple pulmonary resections for
metastatic osteogenic sarcoma after two decades. J Surg Oncol. 1991;46(3):154–155.
30 Jaffe N, Link MP, Cohen D, et al. High-dose methotrexate in osteogenic sarcoma. Natl
Cancer Inst Monogr. 1981(56):201–206.
32 Aisen AM, Martel W, Braunstein EM, et al. MRI and CT evaluation of primary bone and
soft-tissue tumors. AJR Am J Roentgenol. 1986;146(4):749–756.
38 Tay lor WF, Ivins JC, Pritchard DJ, et al. Trends and variability in survival among patients
with osteosarcoma: a 7-y ear update. Mayo Clin Proc. 1985;60(2):91–104.
39 Hauben EI, Weeden S, Pringle J, et al. Does the histological subty pe of high-grade central
osteosarcoma influence the response to treatment with chemotherapy and does it affect
overall survival? A study on 570 patients of two consecutive trials of the European
Osteosarcoma Intergroup. Eur J Cancer. 2002;38(9):1218–1225.
40 Smeland S, Muller C, Alvegard TA, et al. Scandinavian Sarcoma Group Osteosarcoma
Study SSG VIII: prognostic factors for outcome and the role of replacement salvage
chemotherapy for poor histological responders. Eur J Cancer. 2003;39(4):488–494.
41 Sweetnam R. Tumours of bone and their management. Ann R Coll Surg Engl.
1974;54(2):63–71.
42 Sinovic JF, Bridge JA, Neff JR. Ring chromosome in parosteal osteosarcoma. Clinical and
diagnostic significance. Cancer Genet Cytogenet. 1992;62(1):50–52.
43 Okada K, Frassica FJ, Sim FH, et al. Parosteal osteosarcoma. A clinicopathological study. J
Bone Joint Surg Am. 1994;76(3):366–378.
48 Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma: the rationale for
preoperative chemotherapy and delay ed surgery. Cancer. 1979;43(6):2163–2177.
50 Sweetnam R. The surgical management of primary osteosarcoma. Clin Orthop Relat Res.
1975(111):57–64.
51 White VA, Fanning CV, Ay ala AG, et al. Osteosarcoma and the role of fine-needle
aspiration. A study of 51 cases. Cancer. 1988;62(6):1238–1246.
52 Wong AC, Akahoshi Y, Takeuchi S. Limb-salvage procedures for osteosarcoma. An
alternative to amputation. Int Orthop. 1986;10(4):245–251.
54 Mei J, Zhu XZ, Wang ZY, et al. Functional outcomes and quality of life in patients with
osteosarcoma treated with amputation versus limb-salvage surgery : a sy stematic review and
meta-analy sis. Arch Orthop Trauma Surg. 2014;134(11):1507–1516.
55 Sutow WW, Herson J, Perez C. Survival after metastasis in osteosarcoma. Natl Cancer Inst
Monogr. 1981(56):227–231.
56 Salunke AA, Chen Y, Tan JH, et al. Does a pathological fracture affect the prognosis in
patients with osteosarcoma of the extremities?: a sy stematic review and meta-analy sis. Bone
Joint J. 2014;96-B(10):1396–1403.
57 Bacci G, Ruggieri P, Bertoni F, et al. Local and sy stemic control for osteosarcoma of the
extremity treated with neoadjuvant chemotherapy and limb salvage surgery : the Rizzoli
experience. Oncol Rep. 2000;7(5):1129–1133.
60 By un BH, Kim SH, Lim SM, et al. Prediction of response to neoadjuvant chemotherapy in
osteosarcoma using dual-phase (18)F-FDG PET/CT. Eur Radiol. 2015;25(7):2015–2024.
61 Hirano T, Iwasaki K, Kumashiro T, et al. Low dose irradiation for limb salvage in
malignant bone tumours. Int Orthop. 1991;15(4):381–385.
62 Simon MA, Aschliman MA, Thomas N, et al. Limb-salvage treatment versus amputation
for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am. 1986;68(9):1331–1337.
63 Marina NM, Pratt CB, Rao BN, et al. Improved prognosis of children with osteosarcoma
metastatic to the lung(s) at the time of diagnosis. Cancer. 1992;70(11):2722–2727.
64 Kager L, Zoubek A, Potschger U, et al. Primary metastatic osteosarcoma: presentation
and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group
protocols. J Clin Oncol. 2003;21(10):2011–2018.
66 Mey er WH, Schell MJ, Kumar AP, et al. Thoracotomy for pulmonary metastatic
osteosarcoma. An analy sis of prognostic indicators of survival. Cancer. 1987;59(2):374–379.
67 Enneking WF, Spanier SS, Goodman MA. A sy stem for the surgical staging of
musculoskeletal sarcoma. Clin Orthop Relat Res. 1980(153):106–120.
69 Costelloe CM, Macapinlac HA, Madewell JE, et al. 18F-FDG PET/CT as an indicator of
progression-free and overall survival in osteosarcoma. J Nucl Med. 2009;50(3):340–347.
70 Kay ton ML, Huvos AG, Casher J, et al. Computed tomographic scan of the chest
underestimates the number of metastatic lesions in osteosarcoma. J Pediatr Surg.
2006;41(1):200–206; discussion 200–206.
71 Allen CV, Stevens KR. Preoperative irradiation for osteogenic sarcoma. Cancer.
1973;31(6):1364–1366.
75 Jenkin RD, Allt WE, Fitzpatrick PJ. Osteosarcoma. An assessment of management with
particular reference to primary irradiation and selective delay ed amputation. Cancer.
1972;30(2):393–400.
76 Jenkin RD. Radiation treatment of Ewing’s sarcoma and osteogenic sarcoma. Can J Surg.
1977;20(6):530–536.
77 Phillips TL, Sheline GE. Radiatio herapy of malignant bone tumors. Radiology.
1969;92(7):1537–1545.
79 van den Brenk HA, Kerr RC, Madigan JP, et al. Results from tourniquet anoxia and
hy perbaric oxy gen techniques combined with megavoltage treatment of sarcomas of bone
and soft tissues. Am J Roentgenol Radium Ther Nucl Med. 1966;96(3):760–776.
80 Lee ES, Mackenzie DH. Osteosarcoma. A study of the value of preoperative megavoltage
radiotherapy. Br J Surg. 1964;51:252–274.
85 Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-
free survival in patients with osteosarcoma of the extremity. N Engl J Med.
1986;314(25):1600–1606.
86 Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant
chemotherapy regimens in operable osteosarcoma of limbs in children and y oung adults: the
first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992;10(10):1579–1591.
87 Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of
chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup.
Lancet. 1997;350(9082):911–917.
88 Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of
the extremity with preoperative and postoperative chemotherapy : a report from the
Children’s Cancer Group. J Clin Oncol. 1997;15(1):76–84.
89 Purfurst C, Beron G, Torggler S, et al. [Results of the COSS-77 and COSS-80 studies on
adjuvant chemotherapy in osteosarcoma of the extremities]. Klin Padiatr. 1985;197(3):233–
238.
93 Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German–
Austrian–Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug
chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol. 1998;9(8):893–899.
94 Mey ers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramy l
tripeptide to chemotherapy improves overall survival--a report from the Children’s Oncology
Group. J Clin Oncol. 2008;26(4):633–638.
96 Machak GN, Tkachev SI, Solovy ev YN, et al. Neoadjuvant chemotherapy and local
radiotherapy for high-grade osteosarcoma of the extremities. Mayo Clin Proc.
2003;78(2):147–155.
97 Dincbas FO, Koca S, Mandel NM, et al. The role of preoperative radiotherapy in
nonmetastatic high-grade osteosarcoma of the extremities for limb-sparing surgery. Int J
Radiat Oncol Biol Phys. 2005;62(3):820–828.
99 Panizzoni GA, Gasparini G, Clauser L, et al. Osteosarcoma of the facial bones. Ann Oncol.
1992;3 (suppl 2):S47–S50.
100 Chambers RG, Mahoney WD. Osteogenic sarcoma of the mandible: current
management. Am Surg. 1970;36(8):463–471.
101 Suit HD. Radiation therapy for osteosarcoma, chordoma and chondrosarcoma. In:
Kumar S, ed. Advances in Medical Oncology, Research, and Education. Vol. 10. Clinical
Cancer Principle Sites 1. New York, NY: Pergamon; 1979:181–185.
103 Burgers JM, van Glabbeke M, Busson A, et al. Osteosarcoma of the limbs. Report of the
EORTC-SIOP 03 trial 20781 investigating the value of adjuvant treatment with chemotherapy
and/or prophy lactic lung irradiation. Cancer. 1988;61(5):1024–1031.
104 Lougheed MN, Palmer JD, Henderson I. Radiation and regional chemotherapy in
osteogenic sarcoma. Excerpta Med Int Cong Ser. 1965;105:1124–1128.
105 Newton KA. Prophy lactic irradiation of the lung in bone sarcoma. In: Price CHG, Ross
FGM, eds. Bone: Certain Aspects of Neoplasia: Proceedings of the twentyfourth Symposium of
the Colston Research Society held in the University of Bristol, April 5th to 8th, 1972. London,
England: Butterworths; 1973:307–311.
106 Rab GT, Ivins JC, Childs DS Jr, et al. Elective whole lung irradiation in the treatment of
osteogenic sarcoma. Cancer. 1976;38(2):939–942.
107 Zaharia M, Caceres E, Valdivia S, et al. Postoperative whole lung irradiation with or
without adriamy cin in osteogenic sarcoma. Int J Radiat Oncol Biol Phys. 1986;12(6):907–910.
108 Whelan JS, Burcombe RJ, Janinis J, et al. A sy stematic review of the role of pulmonary
irradiation in the management of primary bone tumours. Ann Oncol. 2002;13(1):23–30.
110 Breur K. Growth rate and radiosensitivity of human tumours. I. Growth rate of human
tumours. Eur J Cancer. 1966;2(2):157–171.
111 Breur K. Prophy lactische longbestraling bij bottumoren. Jaarboek van Kankeronderzoek
en Kanker Bestreiding in Nederland. Vol 22. Netherlands1973:27-43.
112 Baeza MR, Barkley HT Jr, Fernandez CH. Total-lung irradiation in the treatment of
pulmonary metastases. Radiology. 1975;116(1):151–154.
113 Kalapurakal JA, Zhang Y, Kepka A, et al. Cardiac-sparing whole lung IMRT in children
with lung metastasis. Int J Radiat Oncol Biol Phys. 2013;85(3):761–767.
115 Caceres E, Zaharia M, Moran M, et al. Adjuvant whole-lung radiation with or without
adriamy cin treatment in osteogenic sarcoma. Cancer Treat Rep. 1978;62(2):297–299.
116 Age and dose of chemotherapy as major prognostic factors in a trial of adjuvant therapy
of osteosarcoma combining two alternating drug combinations and early prophy lactic lung
irradiation. French Bone Tumor Study Group. Cancer. 1988;61(7):1304–1311.
117 Gilchrist GS, Pritchard DJ, Dahlin DC, et al. Management of osteogenic sarcoma: a
perspective based on the May o Clinic experience. Natl Cancer Inst Monogr. 1981(56):193–
199.
118 Ellis ER, Marcus RB Jr, Cicale MJ, et al. Pulmonary function tests after whole-lung
irradiation and doxorubicin in patients with osteogenic sarcoma. J Clin Oncol.
1992;10(3):459–463.
119 Claude L, Rousmans S, Carrie C, et al. [Standards and Options for the use of radiation
therapy in the management of patients with osteosarcoma. Update 2004]. Cancer Radiother.
2005;9(2):104–121.
120 Ivins JC, Tay lor WF, Wold LE. Elective whole-lung irradiation in osteosarcoma treatment:
appearance of bilateral breast cancer in two long-term survivors. Skeletal Radiol.
1987;16(2):133–135.
121 Thompson DK, Li FP, Cassady JR. Breast cancer in a man 30 y ears after radiation for
metastatic osteogenic sarcoma. Cancer. 1979;44(6):2362–2365.
122 Russo CL, McInty re J, Goorin AM, et al. Secondary breast cancer in patients presenting
with osteosarcoma: possible involvement of germline p53 mutations. Med Pediatr Oncol.
1994;23(4):354–358.
123 Heij HA, Vos A, de Kraker J, et al. Prognostic factors in surgery for pulmonary
metastases in children. Surgery. 1994;115(6):687–693.
124 Weichselbaum RR, Cassady JR, Jaffe N, et al. Preliminary results of aggressive
multimodality therapy for metastatic osteosarcoma. Cancer. 1977;40(1):78–83.
126 Yu W, Tang L, Lin F, et al. Stereotactic radiosurgery, a potential alternative treatment for
pulmonary metastases from osteosarcoma. Int J Oncol. 2014;44(4):1091–1098.
127 Giritsky AS, Etcubanas E, Mark JB. Pulmonary resection in children with metastatic
osteogenic sarcoma: improved survival with surgery, chemotherapy, and irradiation. J Thorac
Cardiovasc Surg. 1978;75(3):354–362.
128 Hong A, Stevens G, Stalley P, et al. Extracorporeal irradiation for malignant bone tumors.
Int J Radiat Oncol Biol Phys. 2001;50(2):441–447.
129 Yamamoto T, Akisue T, Marui T, et al. Osteosarcoma of the distal radius treated by
intraoperative extracorporeal irradiation. J Hand Surg Am. 2002;27(1):160–164.
130 Hong AM, Millington S, Ahern V, et al. Limb preservation surgery with extracorporeal
irradiation in the management of malignant bone tumor: the oncological outcomes of 101
patients. Ann Oncol. 2013;24(10):2676–2680.
131 Puri A, Gulia A, Jambhekar N, et al. The outcome of the treatment of diaphy seal
primary bone sarcoma by resection, irradiation and re-implantation of the host bone:
extracorporeal irradiation as an option for reconstruction in diaphy seal bone sarcomas. J
Bone Joint Surg Br. 2012;94(7):982–988.
133 Benjamin RS, Baker LH, O’Bry an RM, et al. Chemotherapy for metastic osteosarcoma--
studies by the M.D. Anderson Hospital and the Southwest Oncology Group. Cancer Treat Rep.
1978;62(2):237–238.
134 Hudson M, Jaffe MR, Jaffe N, et al. Pediatric osteosarcoma: therapeutic strategies,
results, and prognostic factors derived from a 10-y ear experience. J Clin Oncol.
1990;8(12):1988–1997.
135 Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic
sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the
primary tumor to preoperative chemotherapy. Cancer. 1982;49(6):1221–1230.
136 Benjamin RS, Chawla SP, Carrasco CH, et al. Preoperative chemotherapy for
osteosarcoma with intravenous adriamy cin and intra-arterial cis-platinum. Ann Oncol.
1992;3(suppl 2): S3–S6.
137 Pratt CB, Champion JE, Fleming ID, et al. Adjuvant chemotherapy for osteosarcoma of
the extremity. Long-term results of two consecutive prospective protocol studies. Cancer.
1990;65(3):439–445.
138 Caceres E, Zaharia M, Valdivia S, et al. Local control of osteogenic sarcoma by radiation
and chemotherapy. Int J Radiat Oncol Biol Phys. 1984;10(1):35–39.
139 Goorin AM, Perez-Atay de A, Gebhardt M, et al. Weekly high-dose methotrexate and
doxorubicin for osteosarcoma: the Dana-Farber Cancer Institute/the Children’s Hospital--
study III. J Clin Oncol. 1987;5(8):1178–1184.
142 Thorpe WP, Reilly JJ, Rosenberg SA. Prognostic significance of alkaline phosphatase
measurements in patients with osteogenic sarcoma receiving chemotherapy. Cancer.
1979;43(6):2178–2181.
143 Bentzen SM, Poulsen HS, Kaae S, et al. Prognostic factors in osteosarcomas. A regression
analy sis. Cancer. 1988;62(1):194–202.
144 Edmonson JH, Green SJ, Ivins JC, et al. A controlled pilot study of high-dose
methotrexate as postsurgical adjuvant treatment for primary osteosarcoma. J Clin Oncol.
1984;2(3):152–156.
145 Holland JF. Adjuvant chemotherapy of osteosarcoma: no runs, no hits, two men left on
base. J Clin Oncol. 1987;5(1):4–6.
146 Link MP, Goorin AM, Horowitz M, et al. Adjuvant chemotherapy of high-grade
osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study.
Clinical Orthop Relat Res. 1991(270):8–14.
147 Link MP. The multi-institutional osteosarcoma study : an update. In: Humphrey GB,
Koops HS, Molenaar WM, eds. Osteosarcoma in Adolescents and Young Adults: New
Developments and Controversies. Boston, MA: Kluwer; 1993:261–267.
148 Link MP. Commentary of the use of presurgical chemotherapy. In: Humphrey GB,
Koops HS, Molenaar WM, eds. Osteosarcoma in Adolescents and Young Adults: New
Developments and Controversies. Boston, MA: Kluwer; 1993:383–385.
149 Arndt CA, Koshkina NV, Inwards CY, et al. Inhaled granulocy te-macrophage colony
stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free
survival and immunomodulation. a report from the Children’s Oncology Group. Clin Cancer
Res. 2010;16(15):4024–4030.
150 Ebb D, Mey ers P, Grier H, et al. Phase II trial of trastuzumab in combination with
cy totoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal
growth factor receptor 2 overexpression: a report from the children’s oncology group. J Clin
Oncol. 2012;30(20):2545–2551.
153 Suit HD. Role of therapeutic radiology in cancer of bone. Cancer. 1975;35(3 suppl):930–
935.
154 Urtasun RC, Connachie PR. Disapperance of osteogenic sarcoma after irradiation:
immunologic observations. J Can Assoc Radiol. 1976;27(2):80–83.
155 Marcove RC, Martini N, Rosen G. The treatment of pulmonary metastasis in osteogenic
sarcoma. Clin Orthop Relat Res. 1975(111):65–70.
156 Goffinet DR, Kaplan HS, Donaldson SS, et al. Combined radiosensitizer infusion and
irradiation of osteogenic sarcomas. Radiology. 1975;117(1):211–214.
157 Chauvel P. Osteosarcomas and adult soft tissue sarcomas: is there a place for high LET
radiation therapy ? Ann Oncol. 1992;3 (suppl 2):S107–S110.
158 Laramore GE, Griffith JT, Boespflug M, et al. Fast neutron radiotherapy for sarcomas of
soft tissue, bone, and cartilage. Am J Clin Oncol. 1989;12(4):320–326.
159 Wambersie A. Fast neutron therapy at the end of 1988--a survey of the clinical data.
Strahlenther Onkol. 1990;166(1):52–60.
160 Salinas R, Hussey DH, Fletcher GH, et al. Experience with neutron therapy for locally
advanced sarcomas. Int J Radiat Oncol Biol Phys. 1980;6(3):267–272.
161 Battermann JJ, Breur K. Fast neutron therapy for locally advanced sarcomas. Int J
Radiat Oncol Biol Phys. 1981;7(8):1051–1053.
162 Yamamuro T, Kotoura Y. Intraoperative radiation therapy for osteosarcoma. In:
Humphrey GB, Koops HS, Molenaar WM, eds. Osteosarcoma in Adolescents and Young
Adults: New Developments and Controversies. Boston, MA: Kluwer; 1993:177–183.
163 Cohen L, Hendrickson F, Mansell J, et al. Response of sarcomas of bone and of soft tissue
to neutron beam therapy. Int J Radiat Oncol Biol Phys. 1984;10(6):821–824.
164 Duncan W, Arnott SJ, Jack WJ. The Edinburgh experience of treating sarcomas of soft
tissues and bone with neutron irradiation. Clin Radiol. 1986;37(4):317–320.
165 Carrie C, Breteau N, Negrier S, et al. The role of fast neutron therapy in unresectable
pelvic osteosarcoma: preliminary report. Med Pediatr Oncol. 1994;22(5):355–357.
166 Li HG, Ma ZT, He Q. [Fast neutron treatment of osteosarcoma]. Zhonghua Zhong Liu Za
Zhi. 1994;16(3):199–202.
167 Castro JR, Linstadt DE, Bahary JP, et al. Experience in charged particle irradiation of
tumors of the skull base: 1977–1992. Int J Radiat Oncol Biol Phys. 1994;29(4):647–655.
168 Hug EB, Fitzek MM, Liebsch NJ, et al. Locally challenging osteo- and chondrogenic
tumors of the axial skeleton: results of combined proton and photon radiation therapy using
three-dimensional treatment planning. Int J Radiat Oncol Biol Phys. 1995;31(3):467–476.
169 Kamada T, Tsujii H, Tsuji H, et al. Efficacy and safety of carbon ion radiotherapy in
bone and soft tissue sarcomas. J Clin Oncol. 2002;20(22):4466–4471.
172 Tsuboy ama T, Toguchida J, Kotoura Y, et al. Intra-operative radiation therapy for
osteosarcoma in the extremities. Int Orthop. 2000;24(4):202-207.
173 Anderson PM, Wiseman GA, Dispenzieri A, et al. High-dose samarium-153 ethy lene
diamine tetramethy lene phosphonate: low toxicity of skeletal irradiation in patients with
osteosarcoma and bone metastases. J Clin Oncol. 2002;20(1):189–196.
176 Franzius C, Schuck A, Bielack SS. High-dose samarium-153 ethy lene diamine
tetramethy lene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma
and bone metastases. J Clin Oncol. 2002;20(7):1953–1954.
177 Bruland OS, Skretting A, Solheim OP, et al. Targeted radiotherapy of osteosarcoma using
153 Sm-EDTMP. A new promising approach. Acta oncol. 1996;35(3):381–384.
178 Anderson PM, Wiseman GA, Erlandson L, et al. Gemcitabine radiosensitization after
high-dose samarium for osteoblastic osteosarcoma. Clin Cancer Res. 2005;11(19 Pt 1):6895–
6900.
179 Humm JL, Sartor O, Parker C, et al. Radium-223 in the treatment of osteoblastic
metastases: a critical clinical review. Int J Radiat Oncol Biol Phys. 2015;91(5):898–906.
183 Beck JC, Wara WM, Bovill EG Jr, et al. The role of radiation therapy in the treatment of
osteosarcoma. Radiology. 1976;120(1):163–165.
184 Tiet TD, Hopy an S, Nadesan P, et al. Constitutive hedgehog signaling in chondrosarcoma
up-regulates tumor cell proliferation. Am J Pathol. 2006;168(1):321–330.
185 Hug EB, Sweeney RA, Nurre PM, et al. Proton radiotherapy in management of pediatric
base of skull tumors. Int J Radiat Oncol Biol Phys. 2002;52(4):1017–1024.
186 Rutz HP, Weber DC, Goitein G, et al. Postoperative spot-scanning proton radiation
therapy for chordoma and chondrosarcoma in children and adolescents: initial experience at
paul scherrer institute. Int J Radiat Oncol Biol Phys. 2008;71(1):220–225.
187 Combs SE, Nikoghosy an A, Jaekel O, et al. Carbon ion radiotherapy for pediatric patients
and y oung adults treated for tumors of the skull base. Cancer. 2009;115(6):1348–1355.
188 Rombi B, Ares C, Hug EB, et al. Spot-scanning proton radiation therapy for pediatric
chordoma and chondrosarcoma: clinical outcome of 26 patients treated at paul scherrer
institute. Int J Radiat Oncol Biol Phys. 2013;86(3):578–584.
190 Hindi N, Casali PG, Morosi C, et al. Imatinib in advanced chordoma: a retrospective case
series analy sis. Eur J Cancer. 2015;51(17):2609–2614.
191 Di Maio S, Yip S, Al Zhrani GA, et al. Novel targeted therapies in chordoma: an update.
Ther Clin Risk Manag. 2015;11:873–883.
192 Heery CR, Singh BH, Rauckhorst M, et al. Phase I trial of a y east-based therapeutic
cancer vaccine (GI-6301) targeting the transcription factor Brachy ury. Cancer Immunol Res.
2015;3(11):1248–1256.
193 Dantonello TM, Int-Veen C, Leuschner I, et al. Mesenchy mal chondrosarcoma of soft
tissues and bone in children, adolescents, and y oung adults: experiences of the CWS and
COSS study groups. Cancer. 2008;112(11):2424–2431.
1 Newton WA Jr, Soule EH, Hamoudi AB, et al. Histopathology of childhood sarcomas,
Intergroup Rhabdomy osarcoma Studies I and II: clinicopathologic correlation. J Clin Oncol.
1988;6(1):67–75.
2 Parham DM, Webber B, Holt H, et al. Immunohistochemical study of childhood
rhabdomy osarcomas and related neoplasms–results of an Intergroup Rhabdomy osarcoma
study project. Cancer. 1991;67(12):3072–3080.
4 Stout AP. Rhabdomy osarcoma of the skeletal muscles. Ann Surg. 1946;123(3):447–472.
6 Paulino AC. Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat
Oncol Biol Phys. 2004;60(1):265–274.
7 Cassady JR, Sagerman RH, Tretter P, Ellsworth RM. Radiation therapy for
rhabdomy osarcoma. Radiology. 1968;91(1):116–120.
8 Hey n RM, Holland R, Newton WA Jr, et al. The role of combined chemotherapy in the
treatment of rhabdomy osarcoma in children. Cancer. 1974;34(6):2128–2142.
9 Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup Rhabdomy osarcoma Study -I
—a final report. Cancer. 1988;61(2):209–220.
10 Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup Rhabdomy osarcoma Study -
II. Cancer. 1993;71(5):1904–1922.
11 Crist W, Gehan EA, Ragab AH, et al. The Third Intergroup Rhabdomy osarcoma Study. J
Clin Oncol. 1995;13(3):610–630.
12 Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomy osarcoma study -IV: results
for patients with nonmetastatic disease. J Clin Oncol. 2001;19(12):3091–3102.
13 Raney RB, Anderson JR, Barr FG, et al. Rhabdomy osarcoma and undifferentiated
sarcoma in the first two decades of life: a selective review of intergroup rhabdomy osarcoma
study group experience and rationale for Intergroup Rhabdomy osarcoma Study V. J Pediatr
Hemato Oncol. 2001;23(4):215–220.
14 Walterhouse DO, Pappo AS, Meza JL, et al: Shorter-duration therapy using vincristine,
dactinomy cin, and lower-dose cy clophosphamide with or without radiotherapy for patients
with newly diagnosed low-risk rhabdomy osarcoma: a report from the Soft Tissue Sarcoma
Committee of the Children’s Oncology Group. J Clin Oncol. 2014;32(31):3547-52.
16 Kingston JE, McElwain TJ, Malpas JS. Childhood rhabdomy osarcoma: experience of the
Children’s Solid Tumour Group. Br J Cancer. 1983;48(2):195–207.
20 Pedrick TJ, Donaldson SS, Cox RS. Rhabdomy osarcoma: the Stanford experience using a
TNM staging sy stem. J Clin Oncol. 1986;4(3):370–378.
22 Breneman JC, Ly den E, Pappo AS, et al. Prognostic factors and clinical outcomes in
children and adolescents with metastatic rhabdomy osarcoma—a report from the Intergroup
Rhabdomy osarcoma Study IV. J Clin Oncol. 2003;21(1):78–84.
23 Qualman SJ, Coffin CM, Newton WA, et al: Intergroup Rhabdomy osarcoma Study :
Update for Pathologists. Pediatric and Developmental Pathology. 1998;1(6):550-61.
24 Gurney JG, Severson RK, Davis S, et al. Incidence of cancer in children in the United
States. Sex-, race-, and 1-y ear age-specific rates by histologic ty pe. Cancer.
1995;75(8):2186–2195.
25 Stat bite: age-specific cancer incidence among children under 15. J Natl Cancer Inst.
1999;91(24):2076.
26 Ruy mann FB, Maddux HR, Ragab A, et al. Congenital anomalies associated with
rhabdomy osarcoma: an autopsy study of 115 cases—a report from the Intergroup
Rhabdomy osarcoma Study Committee (representing the Children’s Cancer Study Group, the
Pediatric Oncology Group, the United Kingdom Children’s Cancer Study Group, and the
Pediatric Intergroup Statistical Center). Med Pediatr Oncol. 1988;16(1):33–39.
27 Birch JM, Hartley AL, Blair V, et al. Cancer in the families of children with soft tissue
sarcoma. Cancer. 1990;66(10):2239–2248.
28 McKeen EA, Bodurtha J, Meadows AT, et al. Rhabdomy osarcoma complicating multiple
neurofibromatosis. J Pediatr. 1978;93(6):992–993.
31 Lupo PJ, Dany sh HE, Plon SE, et al: Family history of cancer and childhood
rhabdomy osarcoma: a report from the Children’s Oncology Group and the Utah Population
Database. Cancer medicine. 2015;4(5):781-90.
32 Constine LS, Marcus RB Jr, Halperin EC. The future of therapy for childhood
rhabdomy osarcoma: clues from molecular biology. Int J Radiat Oncol Biol Phys.
1995;32(4):1245–1249; discussion 1263.
33 Pappo AS, Shapiro DN, Crist WM, et al. Biology and therapy of pediatric
rhabdomy osarcoma. J Clin Oncol. 1995;13(8):2123–2139.
34 Williamson D, Missiaglia E, de Rey nies A, et al: Fusion gene-negative alveolar
rhabdomy osarcoma is clinically and molecularly indistinguishable from embry onal
rhabdomy osarcoma. J Clin Oncol. 2010;28(13):2151-8.
35 Parham DM, Qualman SJ, Teot L, et al. Correlation between histology and PAX/FKHR
fusion status in alveolar rhabdomy osarcoma: a report from the Children’s Oncology Group.
Am J Surg Pathol. 2007;31(6):895–901.
36 Edwards RH, Chatten J, Xiong QB, et al. Detection of gene fusions in rhabdomy osarcoma
by reverse transcriptase-poly merase chain reaction assay of archival samples. Diagn Mol
Pathol. 1997;6(2):91–97.
37 Kelly KM, Womer RB, Barr FG. Minimal disease detection in patients with alveolar
rhabdomy osarcoma using a reverse transcriptase-poly merase chain reaction method.
Cancer. 1996;78(6):1320–1327.
40 Shapiro DN, Parham DM, Douglass EC, et al. Relationship of tumor-cell ploidy to
histologic subty pe and treatment outcome in children and adolescents with unresectable
rhabdomy osarcoma. J Clin Oncol. 1991;9(1):159–166.
41 Pappo AS, Crist WM, Kuttesch J, et al. Tumor-cell DNA content predicts outcome in
children and adolescents with clinical group III embry onal rhabdomy osarcoma—the
Intergroup Rhabdomy osarcoma Study Committee of the Children’s Cancer Group and the
Pediatric Oncology Group. J Clin Oncol. 1993;11(10):1901–1905.
42 De Zen L, Sommaggio A, d’Amore ES, et al. Clinical relevance of DNA ploidy and
proliferative activity in childhood rhabdomy osarcoma: a retrospective analy sis of patients
enrolled onto the Italian Cooperative Rhabdomy osarcoma Study RMS88. J Clin Oncol.
1997;15(3):1198–1205.
43 Dias P, Parham DM, Shapiro DN, et al. My ogenic regulatory protein (My oD1) expression
in childhood solid tumors: diagnostic utility in rhabdomy osarcoma. Am J Pathol.
1990;137(6):1283–1291.
46 Felix CA, Kappel CC, Mitsudomi T, et al. Frequency and diversity of p53 mutations in
childhood rhabdomy osarcoma. Cancer Res. 1992;52(8):2243–2247.
47 Hettmer S, Archer NM, Somers GR, et al: Anaplastic rhabdomy osarcoma in TP53
germline mutation carriers. Cancer. 2014;120(7):1068-75.
49 Wharam MD, Beltangady MS, Hey n RM, et al. Pediatric orofacial and
lary ngophary ngeal rhabdomy osarcoma—an Intergroup Rhabdomy osarcoma Study report.
Arch Otolaryngol Head Neck Surg. 1987;113(11):1225–1227.
50 Lawrence W Jr, Hay s DM, Hey n R, et al. Ly mphatic metastases with childhood
rhabdomy osarcoma—a report from the Intergroup Rhabdomy osarcoma Study. Cancer.
1987;60(4):910–915.
53 Volker T, Denecke T, Steffen I, et al. Positron emission tomography for staging of pediatric
sarcoma patients: results of a prospective multicenter trial. J Clin Oncol. 2007;25(34):5435–
5441.
54 Weiss AR, Ly den ER, Anderson JR, et al: Histologic and clinical characteristics can guide
staging evaluations for children and adolescents with rhabdomy osarcoma: a report from the
Children’s Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol. 2013;31(26):3226-
32.
55 Parham DM, Kelly DR, Donnelly WH, et al. Immunohistochemical and ultrastructural
spectrum of hepatic sarcomas of childhood: evidence for a common histogenesis. Mod
Pathol. 1991;4(5):648–653.
57 Asmar L, Gehan EA, Newton WA, et al. Agreement among and within groups of
pathologists in the classification of rhabdomy osarcoma and related childhood sarcomas.
Report of an international study of four pathology classifications. Cancer. 1994;74(9):2579–
2588.
58 Newton WA Jr, Gehan EA, Webber BL, et al. Classification of rhabdomy osarcomas and
related sarcomas—pathologic aspects and proposal for a new classification—an Intergroup
Rhabdomy osarcoma Study. Cancer. 1995;76(6):1073–1085.
59 Parham DM, Ellison DA. Rhabdomy osarcomas in adults and children: an update. Arch
Pathol Lab Med. 2006;130(10):1454–1465.
61 Donaldson SS, Belli JA. A rational clinical staging sy stem for childhood
rhabdomy osarcoma. J Clin Oncol. 1984;2(2):135–139.
62 Lawrence W Jr, Anderson JR, Gehan EA, et al. Pretreatment TNM staging of childhood
rhabdomy osarcoma: a report of the Intergroup Rhabdomy osarcoma Study Group. Children’s
Cancer Study Group. Pediatric Oncology Group. Cancer. 1997;80(6):1165–1170.
63 Kodet R, Newton WA Jr, Hamoudi AB, et al. Orbital rhabdomy osarcomas and related
tumors in childhood: relationship of morphology to prognosis—an Intergroup
Rhabdomy osarcoma study. Med Pediatr Oncol. 1997;29(1):51–60.
64 Rodeberg DA, Wharam MD, Ly den ER, et al: Delay ed primary excision with subsequent
modification of radiotherapy dose for intermediate-risk rhabdomy osarcoma: a report from
the Children’s Oncology Group Soft Tissue Sarcoma Committee. International journal of
cancer. 2015;137:204-11.
65 Lawrence W Jr, Hay s DM, Moon TE. Ly mphatic metastasis with childhood
rhabdomy osarcoma. Cancer. 1977;39(2):556–559.
66 La Quaglia MP, Heller G, Ghavimi F, et al. The effect of age at diagnosis on outcome in
rhabdomy osarcoma. Cancer. 1994;73(1):109–117.
67 Ragab AH, Hey n R, Tefft M, et al. Infants y ounger than 1 y ear of age with
rhabdomy osarcoma. Cancer. 1986;58(12):2606–2610.
68 Salloum E, Flamant F, Rey A, et al. Rhabdomy osarcoma in infants under one y ear of age:
experience of the Institut Gustave-Roussy. Med Pediatr Oncol. 1989;17(5):424–428.
69 Raney RB Jr, Tefft M, Newton WA, et al. Improved prognosis with intensive treatment of
children with cranial soft tissue sarcomas arising in nonorbital parameningeal sites—a report
from the Intergroup Rhabdomy osarcoma Study. Cancer. 1987;59(1):147–155.
70 Mandell LR, Massey V, Ghavimi F. The influence of extensive bone erosion on local
control in non-orbital rhabdomy osarcoma of the head and neck. Int J Radiat Oncol Biol Phys.
1989;17(3):649–653.
71 Koscielniak E, Harms D, Henze G, et al: Results of treatment for soft tissue sarcoma in
childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma
Study CWS-86. Journal of clinical oncology: official journal of the American Society of
Clinical Oncology. 1999;17(12):3706-19.
72 Burke M, Anderson JR, Kao SC, et al. Assessment of response to induction therapy and its
influence on 5-y ear failure-free survival in group III rhabdomy osarcoma: the Intergroup
Rhabdomy osarcoma Study -IV experience—a report from the Soft Tissue Sarcoma
Committee of the Children’s Oncology Group. J Clin Oncol. 2007;25(31):4909–4913.
75 Casey DL, Wexler LH, Fox JJ, et al: Predicting outcome in patients with
rhabdomy osarcoma: role of [(18)f]fluorodeoxy glucose positron emission tomography.
International journal of radiation oncology, biology, physics. 2014;90:1136-42.
76 Dharmarajan KV, Wexler LH, Gavane S, et al: Positron emission tomography (PET)
evaluation after initial chemotherapy and radiation therapy predicts local control in
rhabdomy osarcoma. International journal of radiation oncology, biology, physics.
2012;84:996-1002.
78 Ladra MM, Szy monifka JD, Mahajan A, et al: Preliminary results of a phase II trial of
proton radiotherapy for pediatric rhabdomy osarcoma. J Clin Oncol. 2014;32(33):3762-70.
79 Maurer HM. Rhabdomy osarcoma in childhood and adolescence. Curr Probl Cancer.
1978;2(9):1–36.
80 Hay s DM, Raney RB, Wharam MD, et al. Children with vesical rhabdomy osarcoma
(RMS) treated by partial cy stectomy with neoadjuvant or adjuvant chemotherapy, with or
without radiotherapy —A report from the Intergroup Rhabdomy osarcoma Study (IRS)
Committee. J Pediatr Hematol Oncol. 1995;17(1):46–52.
82 Neville HL, Andrassy RJ, Lobe TE, et al. Preoperative staging, prognostic factors, and
outcome for extremity rhabdomy osarcoma: a preliminary report from the Intergroup
Rhabdomy osarcoma Study IV (1991–1997). J Pediatr Surg. 2000;35(2):317–321.
83 Kay ton ML, Delgado R, Busam K, et al. Experience with 31 sentinel ly mph node biopsies
for sarcomas and carcinomas in pediatric patients. Cancer. 2008;112(9):2052–2059.
84 Donaldson SS, Castro JR, Wilbur JR, et al. Rhabdomy osarcoma of head and neck in
children—combination treatment by surgery, irradiation, and chemotherapy. Cancer.
1973;31(1):26–35.
85 Sandler E, Ly den E, Ruy mann F, et al. Efficacy of ifosfamide and doxorubicin given as a
phase II “window” in children with newly diagnosed metastatic rhabdomy osarcoma: a report
from the Intergroup Rhabdomy osarcoma Study Group. Med Pediatr Oncol. 2001;37(5):442–
448.
86 Breitfeld PP, Ly den E, Raney RB, et al. Ifosfamide and etoposide are superior to
vincristine and melphalan for pediatric metastatic rhabdomy osarcoma when administered
with irradiation and combination chemotherapy : a report from the Intergroup
Rhabdomy osarcoma Study Group. J Pediatr Hematol Oncol. 2001;23(4):225–233.
87 Arndt CA, Hawkins DS, Stoner JA, et al. Randomized phase III trial comparing vincristine,
actinomy cin, cy clophosphamide (VAC) with VAC/V topotecan/cy clophosphamide (TC) for
intermediate risk rhabdomy osarcoma (IRRMS). D9803, COG study. [Abstract] J Clin Oncol.
2007;25(suppl 18):A-9509, 528s.
88 Pappo AS, Ly den E, Breitfeld P, et al. Two consecutive phase II window trials of irinotecan
alone or in combination with vincristine for the treatment of metastatic rhabdomy osarcoma:
the Children’s Oncology Group. J Clin Oncol. 2007;25(4):362–369.
89 Furman WL, Stewart CF, Poquette CA, et al. Direct translation of a protracted irinotecan
schedule from a xenograft model to a phase I trial in children. J Clin Oncol. 1999;17(6):1815–
1824.
90 Rodriguez-Galindo C, Crews KR, Stewart CF, et al. Phase I study of the combination of
topotecan and irinotecan in children with refractory solid tumors. Cancer Chemother
Pharmacol. 2006;57(1):15–24.
91 Cosetti M, Wexler LH, Calleja E, et al. Irinotecan for pediatric solid tumors: the Memorial
Sloan-Kettering experience. J Pediatr Hematol Oncol. 2002;24(2):101–105.
92 Hawkins DS, Gupta AA, Rudzinski ER: What is new in the biology and treatment of
pediatric rhabdomy osarcoma? Current Opinion in Pediatrics. 2014;26(1):50-6.
93 Weigel BJ, Ly den E, Anderson JR, et al: Intensive Multiagent Therapy, Including Dose-
Compressed Cy cles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cy clophosphamide,
Irinotecan, and Radiation, in Patients With High-Risk Rhabdomy osarcoma: A Report From the
Children’s Oncology Group. Journal of clinical oncology: official journal of the American
Society of Clinical Oncology. 2016;34:117-22.
94 Arndt CA, Hawkins DS, Mey er WH, et al. Comparison of results of a pilot study of
alternating vincristine/doxorubicin/cy clophosphamide and etoposide/ifosfamide with IRS-IV
in intermediate risk rhabdomy osarcoma: a report from the Children’s Oncology Group.
Pediatr Blood Cancer. 2008;50(1):33–36.
95 Wharam MD, Hanfelt JJ, Tefft MC, et al. Radiation therapy for rhabdomy osarcoma: local
failure risk for Clinical Group III patients on Intergroup Rhabdomy osarcoma Study II. Int J
Radiat Oncol Biol Phys. 1997;38(4):797–804.
96 Stobbe GD, Dargeon HW. Embry onal rhabdomy osarcoma of the head and neck in
children and adolescents. Cancer. 1950;3(5):826–836.
97 Regine WF, Fontanesi J, Kumar P, et al. Local tumor control in rhabdomy osarcoma
following low-dose irradiation: comparison of group II and select group III patients. Int J
Radiat Oncol Biol Phys. 1995;31(3):485–491.
98 Tefft M, Lindberg RD, Gehan EA. Radiation therapy combined with sy stemic
chemotherapy of rhabdomy osarcoma in children: local control in patients enrolled in the
Intergroup Rhabdomy osarcoma Study. Natl Cancer Inst Monogr. 1981(56):75–81.
100 Maurer HM. The Intergroup Rhabdomy osarcoma Study II: objectives and study design.
J Pediatr Surg. 1980;15(3):371–372.
101 Wharam MD, Meza J, Anderson J, et al. Failure pattern and factors predictive of local
failure in rhabdomy osarcoma: a report of group III patients on the third Intergroup
Rhabdomy osarcoma Study. J Clin Oncol. 2004;22(10):1902–1908.
102 Wolden SL, Anderson JR, Crist WM, et al. Indications for radiotherapy and
chemotherapy after complete resection in rhabdomy osarcoma: a report from the Intergroup
Rhabdomy osarcoma Studies I to III. J Clin Oncol. 1999;17(11):3468–3475.
103 Donaldson SS, Meza J, Breneman JC, et al. Results from the IRS-IV randomized trial of
hy perfractionated radiotherapy in children with rhabdomy osarcoma—a report from the
IRSG. Int J Radiat Oncol Biol Phys. 2001;51(3):718–728.
104 Stevens MC, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomy osarcoma in
childhood and adolescence: third study of the International Society of Paediatric Oncology —
SIOP Malignant Mesenchy mal Tumor 89. J Clin Oncol. 2005;23(12):2618–2628.
105 Hay s DM, Raney RB Jr, Lawrence W Jr, et al. Primary chemotherapy in the treatment
of children with bladder—prostate tumors in the Intergroup Rhabdomy osarcoma Study (IRS-
II). J Pediatr Surg. 1982;17(6):812–820.
106 Scholtmeijer RJ, Tromp CG, Hazebroek FW. Embry onal rhabdomy osarcoma of the
urogenital tract in childhood. Eur Urol. 1983;9(2):69–74.
107 LaQuaglia M. Genitourinary rhabdomy osarcoma in children. Urol Clin North Am.
1991;18(3):575–580.
108 Tefft M, Jaffe N. Proceedings: sarcoma of the bladder and prostate in children. Rationale
for the role of radiation therapy based on a review of the literature and a report of fourteen
additional patients. Cancer. 1973;32(5):1161–1177.
109 Klem ML, Grewal RK, Wexler LH, et al. PET for staging in rhabdomy osarcoma: an
evaluation of PET as an adjunct to current staging tools. J Pediatr Hematol Oncol.
2007;29(1):9–14.
110 Ferrer FA, Isakoff M, Koy le MA. Bladder/prostate rhabdomy osarcoma: past, present and
future. J Urol. 2006;176(4 Pt 1):1283–1291.
111 Hay s DM, Raney RB Jr, Lawrence W Jr, et al. Bladder and prostatic tumors in the
intergroup Rhabdomy osarcoma study (IRS-I): results of therapy. Cancer. 1982;50(8):1472–
1482.
112 Hay s DM, Lawrence W Jr, Crist WM, et al. Partial cy stectomy in the management of
rhabdomy osarcoma of the bladder: a report from the Intergroup Rhabdomy osarcoma Study.
J Pediatr Surg. 1990;25(7):719–723.
113 Voute PA, Vos A, de Kraker J, Behrendt H. Rhabdomy osarcomas: chemotherapy and
limited supplementary treatment program to avoid mutilation. Natl Cancer Inst Monogr.
1981(56):121–125.
114 Tefft M, Hay s D, Raney RB Jr, et al. Radiation to regional nodes for rhabdomy osarcoma
of the genitourinary tract in children: is it necessary ? A report from the Intergroup
Rhabdomy osarcoma Study No. 1 (IRS-1). Cancer. 1980;45(12):3065–3068.
115 Raney RB Jr, Gehan EA, Hay s DM, et al. Primary chemotherapy with or without
radiation therapy and/or surgery for children with localized sarcoma of the bladder, prostate,
vagina, uterus, and cervix—a comparison of the results in Intergroup Rhabdomy osarcoma
Studies I and II. Cancer. 1990;66(10):2072–2081.
116 Hey n R, Newton WA, Raney RB, et al. Preservation of the bladder in patients with
rhabdomy osarcoma. J Clin Oncol. 1997;15(1):69–75.
118 Leuschner I, Harms D, Mattke A, et al. Rhabdomy osarcoma of the urinary bladder and
vagina: a clinicopathologic study with emphasis on recurrent disease: a report from the Kiel
Pediatric Tumor Registry and the German CWS Study. Am J Surg Pathol. 2001;25(7):856–
864.
119 Arndt C, Rodeberg D, Breitfeld PP, et al. Does bladder preservation (as a surgical
principle) lead to retaining bladder function in bladder/prostate rhabdomy osarcoma? Results
from intergroup rhabdomy osarcoma study iv. J Urol. 2004;171(6 Pt 1):2396–2403.
120 Ladra MM, Edgington SK, Mahajan A, et al: A dosimetric comparison of proton and
intensity modulated radiation therapy in pediatric rhabdomy osarcoma patients enrolled on a
prospective phase II proton study. Radiother Oncol. 2014;113:77-83.
121 Raney RB Jr, Hay s DM, Lawrence W Jr, et al. Paratesticular rhabdomy osarcoma in
childhood. Cancer. 1978;42(2):729–736.
122 Raney RB Jr, Tefft M, Lawrence W Jr, et al. Paratesticular sarcoma in childhood and
adolescence—a report from the Intergroup Rhabdomy osarcoma Studies I and II, 1973–1983.
Cancer. 1987;60(9):2337–2343.
123 Wiener ES, Anderson JR, Ojimba JI, et al. Controversies in the management of
paratesticular rhabdomy osarcoma: is staging retroperitoneal ly mph node dissection
necessary for adolescents with resected paratesticular rhabdomy osarcoma? Semin Pediatr
Surg. 2001;10(3):146–152.
124 Ferrari A, Bisogno G, Casanova M, et al. Paratesticular rhabdomy osarcoma: report from
the Italian and German Cooperative Group. J Clin Oncol. 2002;20(2):449–455.
125 Wiener ES, Lawrence W, Hay s D, et al. Retroperitoneal node biopsy in paratesticular
rhabdomy osarcoma. J Pediatr Surg. 1994;29(2):171–177; discussion 178.
126 Hey n R, Raney RB Jr, Hay s DM, et al. Late effects of therapy in patients with
paratesticular rhabdomy osarcoma. Intergroup Rhabdomy osarcoma Study Committee. J Clin
Oncol. 1992;10(4):614–623.
127 Skolarus TA, Bhay ani SB, Chiang HC, et al. Laparoscopic retroperitoneal ly mph node
dissection for low-stage testicular cancer. J Endourol. 2008;22(7):1485–1489.
128 Andrassy RJ, Hay s DM, Raney RB, et al. Conservative surgical management of vaginal
and vulvar pediatric rhabdomy osarcoma: a report from the Intergroup Rhabdomy osarcoma
Study III. J Pediatr Surg. 1995;30(7):1034–1036; discussion 1036–1037.
129 Hay s DM, Shimada H, Raney RB Jr, et al. Clinical staging and treatment results in
rhabdomy osarcoma of the female genital tract among children and adolescents. Cancer.
1988;61(9):1893–1903.
131 Andrassy RJ, Wiener ES, Raney RB, et al. Progress in the surgical management of
vaginal rhabdomy osarcoma: a 25-y ear review from the Intergroup Rhabdomy osarcoma
Study Group. J Pediatr Surg. 1999;34(5):731–734; discussion 734–735.
132 Arndt CA, Donaldson SS, Anderson JR, et al. What constitutes optimal therapy for
patients with rhabdomy osarcoma of the female genital tract? Cancer. 2001;91(12):2454–
2468.
133 Walterhouse DO, Meza JL, Breneman JC, et al: Local control and outcome in children
with localized vaginal rhabdomy osarcoma: a report from the Soft Tissue Sarcoma committee
of the Children’s Oncology Group. Pediatric blood & cancer. 2011;57:76-83.
134 Magne N, Oberlin O, Martelli H, et al. Vulval and vaginal rhabdomy osarcoma in
children: update and reappraisal of Institut Gustave Roussy brachy therapy experience. Int J
Radiat Oncol Biol Phys. 2008;72(3):878–883.
135 Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles
in mid-life: implications for forecasting menopause. Hum Reprod. 1992;7(10):1342–1346.
136 Hay s DM, Shimada H, Raney RB Jr, et al. Sarcomas of the vagina and uterus: the
Intergroup Rhabdomy osarcoma Study. J Pediatr Surg. 1985;20(6):718–724.
137 Brand E, Berek JS, Nieberg RK, et al. Rhabdomy osarcoma of the uterine cervix.
Sarcoma botry oides. Cancer. 1987;60(7):1552–1560.
138 Martelli H, Oberlin O, Rey A, et al. Conservative treatment for girls with nonmetastatic
rhabdomy osarcoma of the genital tract: a report from the Study Committee of the
International Society of Pediatric Oncology. J Clin Oncol. 1999;17(7):2117–2122.
139 Lawrence W Jr, Hay s DM, Hey n R, et al. Surgical lessons from the Intergroup
Rhabdomy osarcoma Study (IRS) pertaining to extremity tumors. World J Surg.
1988;12(5):676–684.
140 Neville HL, Raney RB, Andrassy RJ, Cooley DA. Multidisciplinary management of
pediatric soft-tissue sarcoma. Oncology (Williston Park). 2000;14(10):1471–1481; discussion
1482–1476, 1489–1490.
141 Oberlin O, Rey A, Brown KL, et al: Prognostic Factors for Outcome in Localized
Extremity Rhabdomy osarcoma. Pooled Analy sis from Four International Cooperative
Groups. Pediatric blood & cancer. 2015;62:2125-31.
142 Ben Arush MW, Bar Shalom R, Postovsky S, et al. Assessing the use of FDG-PET in the
detection of regional and metastatic nodes in alveolar rhabdomy osarcoma of extremities. J
Pediatr Hematol Oncol. 2006;28(7):440–445.
143 Neville HL, Andrassy RJ, Lally KP, et al. Ly mphatic mapping with sentinel node biopsy
in pediatric patients. J Pediatr Surg. 2000;35(6):961–964.
145 Raney RB, Meza J, Anderson JR, et al. Treatment of children and adolescents with
localized parameningeal sarcoma: experience of the Intergroup Rhabdomy osarcoma Study
Group protocols IRS-II through -IV, 1978–1997. Med Pediatr Oncol. 2002;38(1):22–32.
147 Raney RB. Soft-tissue sarcoma in childhood and adolescence. Curr Oncol Rep.
2002;4(4):291–298.
148 Blatt J, Sny derman C, Wollman MR, et al. Delay ed resection in the management of non-
orbital rhabdomy osarcoma of the head and neck in childhood. Med Pediatr Oncol.
1997;28(4):294–298.
149 Spalding AC, Hawkins DS, Donaldson SS, et al: The effect of radiation timing on patients
with high-risk features of parameningeal rhabdomy osarcoma: an analy sis of IRS-IV and
D9803. International journal of radiation oncology, biology, physics. 2013;87(3):512-6.
150 Chen C, Shu HK, Goldwein JW, et al. Volumetric considerations in radiotherapy for
pediatric parameningeal rhabdomy osarcomas. Int J Radiat Oncol Biol Phys.
2003;55(5):1294–1299.
151 Kozak KR, Adams J, Krejcarek SJ, et al. A dosimetric comparison of proton and
intensity -modulated photon radiotherapy for pediatric parameningeal rhabdomy osarcomas.
Int J Radiat Oncol Biol Phys. 2009;74(1):179–186.
152 Sagerman RH, Cassady JR, Tretter P. Radiation therapy for rhabdomy osarcoma of the
orbit. Trans Am Acad Ophthalmol Otolaryngol. 1968;72(6):849–854.
154 Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomy osarcoma: survival
and late effects of treatment--results of an international workshop. J Clin Oncol.
2001;19(1):197–204.
156 Hey n R, Ragab A, Raney RB Jr, et al. Late effects of therapy in orbital
rhabdomy osarcoma in children—a report from the Intergroup Rhabdomy osarcoma Study.
Cancer. 1986;57(9):1738–1743.
159 Pappo AS, Meza JL, Donaldson SS, et al. Treatment of localized nonorbital,
nonparameningeal head and neck rhabdomy osarcoma: lessons learned from intergroup
rhabdomy osarcoma studies III and IV. J Clin Oncol. 2003;21(4):638–645.
160 Wolden SL, Wexler LH, Kraus DH, et al. Intensity -modulated radiotherapy for head-
and-neck rhabdomy osarcoma. Int J Radiat Oncol Biol Phys. 2005;61(5):1432–1438.
161 Curtis AE, Okcu MF, Chintagumpala M, et al. Local control after intensity -modulated
radiotherapy for head-and-neck rhabdomy osarcoma. Int J Radiat Oncol Biol Phys.
2009;73(1):173–177.
162 Raney RB Jr, Ragab AH, Ruy mann FB, et al. Soft-tissue sarcoma of the trunk in
childhood. Results of the intergroup rhabdomy osarcoma study. Cancer. 1982;49(12):2612–
2616.
163 Hay es-Jordan A, Stoner JA, Anderson JR, et al. The impact of surgical excision in chest
wall rhabdomy osarcoma: a report from the Children’s Oncology Group. J Pediatr Surg.
2008;43(5):831–836.
164 Ortega JA, Wharam M, Gehan EA, et al. Clinical features and results of therapy for
children with paraspinal soft tissue sarcoma: a report of the Intergroup Rhabdomy osarcoma
Study. J Clin Oncol. 1991;9(5):796–801.
165 Raney RB, Anderson JR, Andrassy RJ, et al. Soft-tissue sarcomas of the diaphragm: a
report from the Intergroup Rhabdomy osarcoma Study Group from 1972 to 1997. J Pediatr
Hematol Oncol. 2000;22(6):510–514.
166 Crist WM, Raney RB, Tefft M, et al. Soft tissue sarcomas arising in the retroperitoneal
space in children—a report from the Intergroup Rhabdomy osarcoma Study (IRS)
Committee. Cancer. 1985;56(8):2125–2132.
167 Raney RB, Stoner JA, Walterhouse DO, et al. Results of treatment of fifty -six patients
with localized retroperitoneal and pelvic rhabdomy osarcoma: a report from The Intergroup
Rhabdomy osarcoma Study -IV, 1991–1997. Pediatr Blood Cancer. 2004;42(7):618–625.
168 Blakely ML, Lobe TE, Anderson JR, et al. Does debulking improve survival rate in
advanced-stage retroperitoneal embry onal rhabdomy osarcoma? J Pediatr Surg.
1999;34(5):736–741; discussion 741–742.
169 Ransom JL, Pratt CB, Hustu HO, et al. Retroperitoneal rhabdomy osarcoma in children—
results of multimodality therapy. Cancer. 1980;45(5):845–850.
170 Raney RB Jr, Crist W, Hay s D, et al. Soft tissue sarcoma of the perineal region in
childhood—a report from the Intergroup Rhabdomy osarcoma Studies I and II, 1972 through
1984. Cancer. 1990;65(12):2787–2792.
173 Spunt SL, Lobe TE, Pappo AS, et al. Aggressive surgery is unwarranted for biliary tract
rhabdomy osarcoma. J Pediatr Surg. 2000;35(2):309–316.
175 Hay es-Jordan A, Doherty DK, West SD, et al. Outcome after surgical resection of
recurrent rhabdomy osarcoma. J Pediatr Surg. 2006;41(4):633–638; discussion 633–638.
176 Pappo AS, Anderson JR, Crist WM, et al. Survival after relapse in children and
adolescents with rhabdomy osarcoma: a report from the Intergroup Rhabdomy osarcoma
Study Group. J Clin Oncol. 1999;17(11):3487–3493.
177 Miser JS, Kinsella TJ, Triche TJ, et al. Ifosfamide with mesna uroprotection and
etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of
children and y oung adults. J Clin Oncol. 1987;5(8):1191–1198.
178 Say lors RL III, Stine KC, Sullivan J, et al. Cy clophosphamide plus topotecan in children
with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin
Oncol. 2001;19(15):3463–3469.
179 Mascarenhas L, Ly den ER, Breitfeld PP, et al: Randomized phase II window trial of two
schedules of irinotecan with vincristine in patients with first relapse or progression of
rhabdomy osarcoma: a report from the Children’s Oncology Group. Journal of clinical
oncology: official journal of the American Society of Clinical Oncology. 2010;28:4658-63.
180 Weigel BJ, Breitfeld PP, Hawkins D, et al. Role of high-dose chemotherapy with
hematopoietic stem cell rescue in the treatment of metastatic or recurrent
rhabdomy osarcoma. J Pediatr Hematol Oncol. 2001;23(5):272–276.
3 The Oxford English Dictionary. Oxford University Press; 2009;on-line edition, based on
second edition 1989. http://dictionary.oed.com/.
4 Conrad EU III, Bradford L, Chansky HA. Pediatric soft-tissue sarcomas. Orthop Clin North
Am. 1996;27:655–664.
6 Pappo AS, Parham DM, Rao BN, et al. Soft tissue sarcomas in children. Semin Surg Oncol.
1999;16:121–143.
7 Spunt SL, Pappo AS. Childhood nonrhabdomy osarcoma soft tissue sarcomas are not adult-
ty pe tumors. J Clin Oncol. 2006;24:1958–1959.
8 Ries LAG, Smith MA, Gurney JG, et al., eds. Cancer Incidence and Survival among
Children and Adolescents: United States SEER Program 1975–1995. Bethesda, MD: National
Cancer Institute, SEER Program; 1999.
9 Weihkopf T, Blettner M, Dantonello T, et al. Incidence and time trends of soft tissue
sarcomas in German children 1985-2004—a report from the population-based German
Childhood Cancer Registry. Eur J Cancer. 2008;44:432–440.
10 Ferrari A, Sultan I, Huang TT, et al. Soft tissue sarcoma across the age spectrum: a
population-based study from the surveillance epidemiology and end results database. Pediatr
Blood Cancer. 2011;57:943–949.
11 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
12 Pappo AS, Devidas M, Jenkins J, et al. Phase II trial of neoadjuvant vincristine, ifosfamide,
and doxorubicin with granulocy te colony -stimulating factor support in children and
adolescents with advanced-stage nonrhabdomy osarcomatous soft tissue sarcomas: a
Pediatric Oncology Group study. J Clin Oncol. 2005;23:4031–4038.
13 Pratt CB, Maurer HM, Gieser P, et al. Treatment of unresectable or metastatic pediatric
soft tissue sarcomas with surgery, irradiation, and chemotherapy : a Pediatric Oncology
Group study. Med Pediatr Oncol. 1998;30:201–209.
14 Pratt CB, Pappo AS, Gieser P, et al. Role of adjuvant chemotherapy in the treatment of
surgically resected pediatric nonrhabdomy osarcomatous soft tissue sarcomas: a Pediatric
Oncology Group study. J Clin Oncol. 1999;17:1219.
15 Spunt SL, Million L, Anderson JR, et al. Risk-based treatment for nonrhabdomy osarcoma
soft tissue sarcomas (NRSTS) in patients under 30 y ears of age: Children’s Oncology Group
study ARST0332. ASCO Meeting Abstracts. 2014;32:10008.
16 Aman P, Ron D, Mandahl N, et al. Rearrangement of the transcription factor gene CHOP
in my xoid liposarcomas with t(12;16)(q13;p11). Genes Chromosomes Cancer. 1992;5:278–
285.
17 Bennicelli JL, Barr FG. Chromosomal translocations and sarcomas. Curr Opin Oncol.
2002;14:412–419.
19 Fletcher JA, Kozakewich HP, Hoffer FA, et al. Diagnostic relevance of clonal cy togenetic
aberrations in malignant soft-tissue tumors. N Engl J Med. 1991;324:436–442.
20 Goldblum JR, Fletcher JA. Desmoid-ty pe fibromatosis. In: Fletcher CD, Unni KK, Mertens
F, eds. World Health Organizaiton Classification of Tumours: Pathology and Genetics of
Tumours of Soft Tissue and Bone. Ly on, France: International Agency for Research on Cancer
Press; 2002:83–84.
21 Jeon IS, Davis JN, Braun BS, et al. A variant Ewing’s sarcoma translocation (7;22) fuses the
EWS gene to the ETS gene ETV1. Oncogene. 1995;10:1229–1234.
26 Pedeutour F, Forus A, Coindre JM, et al. Structure of the supernumerary ring and giant rod
chromosomes in adipose tissue tumors. Genes Chromosomes Cancer. 1999;24:30–41.
28 Quade BJ, Wang TY, Sornberger K, et al. Molecular pathogenesis of uterine smooth
muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004;40:97–108.
29 Ren B, Yu YP, Jing L, et al. Gene expression analy sis of human soft tissue
leiomy osarcomas. Hum Pathol. 2003;34:549–558.
30 Spunt SL, Skapek SX, Coffin CM. Pediatric nonrhabdomy osarcoma soft tissue sarcomas.
Oncologist. 2008;13:668–678.
33 Turc-Carel C, Dal Cin P, Rao U, et al. Cy togenetic studies of adipose tissue tumors. I: a
benign lipoma with reciprocal translocation t(3;12)(q28;q14). Cancer Genet Cytogenet.
1986;23:283–289.
34 Turc-Carel C, Limon J, Dal Cin P, et al. Cy togenetic studies of adipose tissue tumors. II:
recurrent reciprocal translocation t(12;16)(q13;p11) in my xoid liposarcomas. Cancer Genet
Cytogenet. 1986;23:291–299.
35 van de Rijn M, Fletcher JA. Genetics of soft tissue tumors. Annu Rev Pathol. 2006;1:435–
466.
36 Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesy late
in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–480.
37 Wilson RA, Anderson JR, Gastier-Foster JM, et al. Preliminary analy sis of the mutational
landscape of non-rhabdomy osarcoma soft tissue sarcoma: a Children’s Oncology Group
study. ASCO Meeting Abstracts. 2014;32:10510.
38 Spunt SL, Poquette CA, Hurt YS, et al. Prognostic factors for children and adolescents with
surgically resected nonrhabdomy osarcoma soft tissue sarcoma: an analy sis of 121 patients
treated at St Jude Children’s Research Hospital. J Clin Oncol. 1999;17:3697–3705.
39 Hay es-Jordan AA, Spunt SL, Poquette CA, et al. Nonrhabdomy osarcoma soft tissue
sarcomas in children: is age at diagnosis an important variable? J Pediatr Surg. 2000;35:948–
953; discussion 953–944.
40 Brizel DM, Weinstein H, Hunt M, et al. Failure patterns and survival in pediatric soft tissue
sarcoma.[erratum appears in Int J Radiat Oncol Biol Phy s 1988 Nov;15(5):1258]. Int J Radiat
Oncol Biol Phys. 1988;15:37–41.
42 Hay ani A, Mahoney DH Jr, Hawkins HK, et al. Soft-tissue sarcomas other than
rhabdomy osarcoma in children. Med Pediatr Oncol. 1992;20:114–118.
43 Ly os AT, Goepfert H, Luna MA, et al. Soft tissue sarcoma of the head and neck in children
and adolescents. Cancer. 1996;77:193–200.
44 Waxweiler TV, Rusthoven CG, Proper MS, et al. Non-rhabdomy osarcoma soft tissue
sarcomas in children: a surveillance, epidemiology, and end results analy sis validating COG
risk stratifications. Int J Radiat Oncol Biol Phys. 2015;92:339–348.
47 Ben Arush MW, Nahum MP, Meller I, et al. The role of chemotherapy in childhood soft
tissue sarcomas other than rhabdomy osarcomas: experience of the Northern Israel Oncology
Center. Pediatr Hematol Oncol. 1999;16:397–406.
48 McGrory JE, Pritchard DJ, Arndt CA, et al. Nonrhabdomy osarcoma soft tissue sarcomas
in children—the May o Clinic experience. Clin Orthop Relat Res. 2000:247–258.
49 Carli M, Guglielmi M, Sotti G. Soft tissue sarcoma. In: Pinkerton CR, Plowman PN, eds.
Paediatric Oncology: Clinical Practice and Controversies. London, England: Chapman & Hall
Medical; 1997:380–416.
50 Paulino AC, Ritchie J, Wen BC. The value of postoperative radiotherapy in childhood
nonrhabdomy osarcoma soft tissue sarcoma. Pediatr Blood Cancer. 2004;43:587–593.
51 Horowitz M, Pratt C, Webber B. Childhood malignant soft tissue sarcomas other than
rhabdomy osarcoma: results of therapy. Proc ASCO. 1984;3:84.
52 Harris M, Hartley AL. Value of peer review of pathology to soft tissue sarcomas. In:
Verweij J, Pinedo HM, Suit HD, eds. Soft Tissue Sarcomas: Present Achievements and Future
Prospects. Boston, MA: Kluwer; 1997:1–8.
53 Scott SM, Reiman HM, Pritchard DJ, et al. Soft tissue fibrosarcoma—a clinicopathologic
study of 132 cases. Cancer. 1989;64:925–931.
55 Fletcher CD, Unni KK, Mertens F. Pathology and Genetics of Tumors of Soft Tissue and
Bone. Ly on, France: IARC Press (International Agency for Research on Cancer); 2002.
56 Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath
tumors—a clinicopathologic study of 120 cases. Cancer. 1986;57:2006–2021.
57 Coffin CM, Dehner LP. Peripheral neurogenic tumors of the soft tissues in children and
adolescents: a clinicopathologic study of 139 cases. Pediatr Pathol. 1989;9:387–407.
58 Rey nolds RM, Browning GG, Nawroz I, et al. Von Recklinghausen’s neurofibromatosis:
neurofibromatosis ty pe 1. Lancet. 2003;361:1552–1554.
59 Raney RB. Proceedings of the tumor board of The Children’s Hospital of Philadelphia:
sy novial sarcoma. Med Pediatr Oncol. 1981;9:41–45.
60 Okcu MF, Despa S, Choroszy M, et al. Sy novial sarcoma in children and adolescents: thirty
three y ears of experience with multimodal therapy. Med Pediatr Oncol. 2001;37:90–96.
61 Mazeron JJ, Suit HD. Ly mph nodes as sites of metastases from sarcomas of soft tissue.
Cancer. 1987;60:1800–1808.
63 Ladany i M, Antonescu CR, Leung DH, et al. Impact of SYT-SSX fusion ty pe on the
clinical behavior of sy novial sarcoma: a multi-institutional retrospective study of 243 patients.
Cancer Res. 2002;62:135–140.
64 Womer RB, Pressey JG. Rhabdomy osarcoma and soft tissue sarcoma in childhood. Curr
Opin Oncol. 2000;12:337–344.
65 Guillou L, Benhattar J, Bonichon F, et al. Histologic grade, but not SYT-SSX fusion ty pe, is
an important prognostic factor in patients with sy novial sarcoma: a multicenter, retrospective
analy sis. J Clin Oncol. 2004;22:4040–4050.
68 Neifeld JP, Berg JW, Godwin D, et al. A retrospective epidemiologic study of pediatric
fibrosarcomas. J Pediatr Surg. 1978;13:735–739.
69 Horowitz ME, Pratt CB, Webber BL, et al. Therapy for childhood soft-tissue sarcomas
other than rhabdomy osarcoma: a review of 62 cases treated at a single institution. J Clin
Oncol. 1986;4:559–564.
70 Canpolat C, Evans HL, Corpron C, et al. Fibromy xoid sarcoma in a four-y ear-old child:
case report and review of the literature. Med Pediatr Oncol. 1996;27:561–564.
71 Mutter RW, Singer S, Zhang Z, et al. The enigma of my xofibrosarcoma of the extremity.
Cancer. 2012;118:518–527.
72 Staples JJ, Robinson RA, Wen BC, et al. Hemangiopericy toma—the role of radiotherapy.
Int J Radiat Oncol Biol Phys. 1990;19:445–451.
75 Evans HL. Malignant mesenchy moma. In: Fletcher CD, Unni KK, Mertens F, eds.
Pathology and Genetics of Tumors of Soft Tissue and Bone. Ly on, France: IARC Press
(International Agency for Research on Cancer); 2002:215.
76 Boue DR, Parham DM, Webber B, et al. Clinicopathologic study of ectomesenchy momas
from Intergroup Rhabdomy osarcoma Study Groups III and IV. Pediatr Dev Pathol.
2000;3:290–300.
77 Enzinger FM, Weiss SW. Soft Tissue Sarcomas. St Louis, MO: CV Mosby ; 1983.
78 Gross E, Rao BN, Pappo A, et al. Epithelioid sarcoma in children. J Pediatr Surg.
1996;31:1663–1665.
79 Kim TH, Bell BA, Mauer HM. Sarcomas of soft tissues and their benign counterparts. In:
Fernbach DJ, Vietti TJ, eds. Clinical Pediatric Oncology. St Louis, MO: Mosby –Year Book;
1991:517–544.
80 Pappo AS. Rhabdomy osarcoma and other soft tissue sarcomas in children. Curr Opin
Oncol. 1996;8:311–316.
81 Casanova M, Ferrari A, Bisogno G, et al. Alveolar soft part sarcoma in children and
adolescents: a report from the Soft-Tissue Sarcoma Italian Cooperative Group. Ann Oncol.
2000;11:1445–1449.
82 Dehner LP. Primitive neuroectodermal tumor and Ewing’s sarcoma. Am J Surg Pathol.
1993;17:1–13.
83 Askin FB, Rosai J, Sibley RK, et al. Malignant small cell tumor of the thoracopulmonary
region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis. Cancer.
1979;43:2438–2451.
84 Roberts KB. Ewing’s sarcoma. N C Med J. 1991;52:319.
85 Gerald WL, Ladany i M, de Alava E, et al. Clinical, pathologic, and molecular spectrum of
tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its
variants. J Clin Oncol. 1998;16:3028–3036.
86 Goodman KA, Wolden SL, La Quaglia MP, et al. Whole abdominopelvic radiotherapy for
desmoplastic small round-cell tumor. Int J Radiat Oncol Biol Phys. 2002;54:170–176.
87 Lae ME, Roche PC, Jin L, et al. Desmoplastic small round cell tumor: a clinicopathologic,
immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol. 2002;26:823–
835.
89 Kushner BH, Laquaglia MP, Gerald WL, et al. Solitary relapse of desmoplastic small
round cell tumor detected by positron emission tomography /computed tomography. J Clin
Oncol. 2008;26:4995–4996.
90 Ferrari A, Casanova M, Bisogno G, et al. Clear cell sarcoma of tendons and aponeuroses in
pediatric patients: a report from the Italian and German Soft Tissue Sarcoma Cooperative
Group. Cancer. 2002;94:3269–3276.
91 Parasuraman S, Rao BN, Bodner S, et al. Clear cell sarcoma of soft tissues in children and
y oung adults: the St. Jude Children’s Research Hospital experience. Pediatr Hematol Oncol.
1999;16:539–544.
92 Ferrari A, Miceli R, Casanova M, et al. The sy mptom interval in children and adolescents
with soft tissue sarcomas. Cancer. 2010;116:177–183.
93 Raney RB Jr. Proceedings of the Tumor Board of the Children’s Hospital of Philadelphia:
alveolar soft-part sarcoma. Med Pediatr Oncol. 1979;6:367–370.
94 Raney RB Jr. Chemotherapy for children with aggressive fibromatosis and Langerhans’
cell histiocy tosis. Clin Orthop Relat Res. 1991:58–63.
95 Salloum E, Flamant F, Caillaud JM, et al. Diagnostic and therapeutic problems of soft tissue
tumors other than rhabdomy osarcoma in infants under 1 y ear of age: a clinicopathological
study of 34 cases treated at the Institut Gustave-Roussy. Med Pediatr Oncol. 1990;18:37–43.
96 Suit HD, Mankin HJ, Wood WC, et al. Preoperative, intraoperative, and postoperative
radiation in the treatment of primary soft tissue sarcoma. Cancer. 1985;55:2659–2667.
97 Jones DN, McCowage GB, Sostman HD, et al. Monitoring of neoadjuvant therapy
response of soft-tissue and musculoskeletal sarcoma using fluorine-18-FDG PET. J Nucl Med.
1996;37:1438–1444.
98 McCarville MB, Christie R, Daw NC, et al. PET/CT in the evaluation of childhood
sarcomas.[see comment]. AJR Am J Roentgenol. 2005;184:1293–1304.
99 Pappo AS, Rao BN, Jenkins JJ, et al. Metastatic nonrhabdomy osarcomatous soft-tissue
sarcomas in children and adolescents: the St. Jude Children’s Research Hospital experience.
Med Pediatr Oncol. 1999;33:76–82.
100 Spunt SL, Hill DA, Motosue AM, et al. Clinical features and outcome of initially
unresected nonmetastatic pediatric nonrhabdomy osarcoma soft tissue sarcoma. J Clin Oncol.
2002;20:3225–3235.
101 Ferrari A, Miceli R, Meazza C, et al. Soft tissue sarcomas of childhood and adolescence:
the prognostic role of tumor size in relation to patient body size. J Clin Oncol. 2009;27:371–
376.
102 LeVay J, O’Sullivan B, Cotton C. Outcome and prognostic factors in soft tissue sarcoma.
Int J Radiat Oncol Biol Phys. 1992;24:182–183.
103 Miser JS, Triche TJ, Pritchard DJ. Ewing’s sarcoma and the nonrhabdomy osarcoma soft
tissue sarcomas of childhood. In: Pizzo PA, Poplack DG, eds. Principles and Practice of
Pediatric Oncology. Philadelphia, PA: JB Lippincott; 1989:659–688.
104 Wenger J, Davidson R. Fibrosarcoma of the leg. Med Pediatr Oncol. 1984;12:209–211.
105 Broders A. Squamous cell epithelioma of the lip: a study of 537 cases. JAMA.
1920;74:656–664.
106 Broders A, Hargrave R, Mey erding HW. Pathological features of soft tissue
fibrosarcoma with special reference to the grading of its malignancy. Surg Gynecol Obstet.
1939;69:267–280.
107 Russell WO, Cohen J, Enzinger F, et al. A clinical and pathological staging sy stem for soft
tissue sarcomas. Cancer. 1977;40:1562–1570.
108 Parham DM, Webber BL, Jenkins JJ III, et al. Nonrhabdomy osarcomatous soft tissue
sarcomas of childhood: formulation of a simplified sy stem for grading. Mod Pathol.
1995;8:705–710.
109 Rao BN. Nonrhabdomy osarcoma in children: prognostic factors influencing survival.
Semin Surg Oncol. 1993;9:524–531.
110 Dey rup AT, Weiss SW. Grading of soft tissue sarcomas: the challenge of providing precise
information in an imprecise world. Histopathology. 2006;48:42–50.
111 Costa J, Wesley RA, Glatstein E, et al. The grading of soft tissue sarcomas—results of a
clinicohistopathologic correlation in a series of 163 cases. Cancer. 1984;53:530–541.
112 Trojani M, Contesso G, Coindre JM, et al. Soft-tissue sarcomas of adults; study of
pathological prognostic variables and definition of a histopathological grading sy stem. Int J
Cancer. 1984;33:37–42.
113 Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer
Institute and French Federation of Cancer Centers Sarcoma Group grading sy stems in a
population of 410 adult patients with soft tissue sarcoma. J Clin Oncol. 1997;15:350–362.
114 Khoury JD, Coffin CM, Spunt SL, et al. Grading of nonrhabdomy osarcoma soft tissue
sarcoma in children and adolescents: a comparison of parameters used for the Federation
Nationale des Centers de Lutte Contre le Cancer and Pediatric Oncology Group Sy stems.
Cancer. 2010;116:2266–2274.
115 Enneking WF, Spanier SS, Goodman MA. A sy stem for the surgical staging of
musculoskeletal sarcoma. Clin Orthop Relat Res. 1980:106–120.
116 Raney RB Jr, Littman P, Jarrett P, et al. Results of multimodal therapy for children with
neurogenic sarcoma. Med Pediatr Oncol. 1979;7:229–236.
117 Harmer C. Management of soft tissue sarcomas. In: Selby P, Bailey C, eds. Cancer and
the Adolescent. London, England: BMJ Publishing Group; 1996:69–89.
118 Mazanet R, Antman KH. Adjuvant therapy for sarcomas. Semin Oncol. 1991;18:603–612.
119 Suit HD. The George Edelsty n memorial lecture: radiation in the management of
malignant soft tissue tumours. Clin Oncol (R Coll Radiol). 1989;1:5–10.
120 Tepper JE, Suit HD. The role of radiation therapy in the treatment of sarcoma of soft
tissue. Cancer Invest. 1985;3:587–592.
121 Blakely ML, Spurbeck WW, Pappo AS, et al. The impact of margin of resection on
outcome in pediatric nonrhabdomy osarcoma soft tissue sarcoma. J Pediatr Surg.
1999;34:672–675.
122 Chui CH, Spunt SL, Liu T, et al. Is reexcision in pediatric nonrhabdomy osarcoma soft
tissue sarcoma necessary after an initial unplanned resection? J Pediatr Surg. 2002;37:1424–
1429.
124 Delaney TF, Stinson SF, Greenberg J. Effects on limb function of combined modality
limb-sparing therapy for extremity soft tissue sarcoma. Proc ASCO. 1991;10:350.
125 Eilber FR, Guiliano AE, Huth J, et al. High-grade soft-tissue sarcomas of the extremity :
UCLA experience with limb salvage. Prog Clin Biol Res. 1985;201:59–74.
126 Sadoski C, Suit HD, Rosenberg A, et al. Preoperative radiation, surgical margins, and
local control of extremity sarcomas of soft tissues. J Surg Oncol. 1993;52:223–230.
127 Eilber FR, Eckardt J. Surgical management of soft tissue sarcomas. Semin Oncol.
1997;24:526–533.
128 Lin PP, Schupak KD, Boland PJ, et al. Pathologic femoral fracture after periosteal
excision and radiation for the treatment of soft tissue sarcoma. Cancer. 1998;82:2356–2365.
129 Euler CI, Parent A, Griffin A, et al. Bone fractures following external beam radiotherapy
and limb-preservation surgery for extremity soft tissue sarcoma: relationship to irradiated
bone length, volume and dose. Int J Radiat Oncol Biol Phys. 2007;69:S745–S746.
130 Holt GE, Griffin AM, Pintilie M, et al. Fractures following radiotherapy and limb-salvage
surgery for lower extremity soft-tissue sarcomas—a comparison of high-dose and low-dose
radiotherapy. J Bone Joint Surg Am. 2005;87:315–319.
131 Kay ton ML, Delgado R, Busam K, et al. Experience with 31 sentinel ly mph node biopsies
for sarcomas and carcinomas in pediatric patients. Cancer. 2008;112:2052–2059.
132 Temeck BK, Wexler LH, Steinberg SM, et al. Metastasectomy for sarcomatous pediatric
histologies: results and prognostic factors. Ann Thorac Surg. 1995;59:1385–1389; discussion
1390.
133 Temeck BK, Wexler LH, Steinberg SM, et al. Reoperative pulmonary metastasectomy
for sarcomatous pediatric histologies. Ann Thorac Surg. 1998;66:908–912; discussion 913.
134 Jablons D, Steinberg SM, Roth J, et al. Metastasectomy for soft tissue sarcoma—further
evidence for efficacy and prognostic indicators. J Thorac Cardiovasc Surg. 1989;97:695–705.
135 Casson AG, Putnam JB, Natarajan G, et al. Efficacy of pulmonary metastasectomy for
recurrent soft tissue sarcoma. J Surg Oncol. 1991;47:1–4.
136 Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional phase I/II trial of
stereotactic body radiation therapy for lung metastases. J Clin Oncol. 2009;27:1579–1584.
137 Mehta N, Selch M, Wang PC, et al. Safety and efficacy of stereotactic body radiation
therapy in the treatment of pulmonary metastases from high grade sarcoma. Sarcoma.
2013;2013:360214.
138 Navarria P, Ascolese AM, Cozzi L, et al. Stereotactic body radiation therapy for lung
metastases from soft tissue sarcoma. Eur J Cancer. 2015;51:668–674.
139 Kalnicki S. Radiation therapy in the treatment of bone and soft tissue sarcomas. Orthop
Clin North Am. 1989;20:505–512.
140 Schray MF, Gunderson LL, Sim FH, et al. Soft tissue sarcoma—integration of
brachy therapy, resection, and external irradiation. Cancer. 1990;66:451–456.
141 Stockdale AD, Cassoni AM, Coe MA, et al. Radiotherapy and conservative surgery in the
management of musculo-aponeurotic fibromatosis. Int J Radiat Oncol Biol Phys.
1988;15:851–857.
142 Pediatric Oncology Group Protocol 8653/8654. A Study of Childhood Soft Tissue Sarcoma
Other than Rhabdomyosarcoma and Its Variations. Chicago, IL: Pediatric Oncology Group;
1986.
143 Marcus RB Jr. Current controversies in pediatric radiation oncology. Orthop Clin North
Am. 1996;27:551–557.
144 Spiro IJ, Gebhardt MC, Jennings LC, et al. Prognostic factors for local control of
sarcomas of the soft tissues managed by radiation and surgery. Semin Oncol. 1997;24:540–
546.
145 Rosenberg SA, Glatstein E, Chang AE. The role of adjuvant chemotherapy in the
treatment of soft tissue sarcomas: review of the National Cancer Institute studies. In: van
Oosteram AT, van Unnik JAM, eds. Management of Soft Tissue and Bone Sarcomas. New
York, NY: Raven Press; 1986:201–214.
146 Chang AE, Sugarbaker PH, Rosenberg SA. Quality of life after different treatment
modalities for soft tissue sarcoma: review of National Cancer Institute studies. In: van
Oosteram AT, van Unnik JAM, eds. Management of Soft Tissue and Bone Sarcomas. New
York, NY: Raven Press; 1986:225–232.
147 Stinson SF, DeLaney TF, Greenberg J, et al. Acute and long-term effects on limb function
of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat
Oncol Biol Phys. 1991;21:1493–1499.
148 Bertucio CS, Wara WM, Matthay KK, et al. Functional and clinical outcomes of limb-
sparing therapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys. 2001;49:763–
769.
149 Raney RB Jr, Allen A, O’Neill J, et al. Malignant fibrous histiocy toma of soft tissue in
childhood. Cancer. 1986;57:2198–2201.
150 Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of
adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin
Oncol. 1998;16:197–203.
151 Al Yami A, Griffin AM, Ferguson PC, et al. Positive surgical margins in soft tissue
sarcoma treated with preoperative radiation: is a postoperative boost necessary ? Int J Radiat
Oncol Biol Phys. 2010;77:1191–1197.
152 Pan E, Goldberg SI, Chen YL, et al. Role of post-operative radiation boost for soft tissue
sarcomas with positive margins following pre-operative radiation and surgery. J Surg Oncol.
2014;110:817–822.
153 Pisters PW, Harrison LB, Leung DH, et al. Long-term results of a prospective
randomized trial of adjuvant brachy therapy in soft tissue sarcoma. J Clin Oncol.
1996;14:859–868.
155 Davis AM, O’Sullivan B, Bell RS, et al. Function and health status outcomes in a
randomized trial comparing preoperative and postoperative radiotherapy in extremity soft
tissue sarcoma. J Clin Oncol. 2002;20:4472–4477.
156 O’Sullivan B, Davis A, Turcotte R, et al. Five-y ear results of a randomized phase III trial
of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma. J Clin
Oncol. 2004;22:9007.
157 Davis AM, O’Sullivan B, Turcotte R, et al. Late radiation morbidity following
randomization to preoperative versus postoperative radiotherapy in extremity soft tissue
sarcoma. Radiother Oncol. 2005;75:48–53.
158 Smith KB, Indelicato DJ, Knapik JA, et al. Adjuvant radiotherapy for pediatric and y oung
adult nonrhabdomy osarcoma soft-tissue sarcoma. Int J Radiat Oncol Biol Phys. 2011;81:150–
157.
159 Ferrari A, Brecht IB, Koscielniak E, et al. The role of adjuvant chemotherapy in children
and adolescents with surgically resected, high-risk adult-ty pe soft tissue sarcomas. Pediatr
Blood Cancer. 2005;45:128–134.
161 Mey er WH, Pratt CB, Thompson EI. Ifosfamide/etoposide (Ifos/VP-16) in patients with
previously untreated Ewing’s sarcoma or primitive neuro-ectodermal tumors. Proc ASCO.
1991;10:307.
162 Koscielniak E, Jurgens H, Winkler K, et al. Treatment of soft tissue sarcoma in childhood
and adolescence—a report of the German Cooperative Soft Tissue Sarcoma study. Cancer.
1992;70:2557–2567.
165 Orbach D, Rey A, Oberlin O, et al. Soft tissue sarcoma or malignant mesenchy mal
tumors in the first y ear of life: experience of the International Society of Pediatric Oncology
(SIOP) Malignant Mesenchy mal Tumor Committee. J Clin Oncol. 2005;23:4363–4371.
167 Bramwell V, Rouesse J, Steward W, et al. Adjuvant CYVADIC chemotherapy for adult
soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the
European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma
Group. J Clin Oncol. 1994;12:1137–1149.
168 Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue
sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J
Clin Oncol. 2001;19:1238–1247.
169 Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-
analy sis of individual data—Sarcoma Meta-analy sis Collaboration. Lancet. 1997;350:1647–
1654.
170 Tierney JF, Mosseri V, Stewart LA, et al. Adjuvant chemotherapy for soft-tissue
sarcoma: review and meta-analy sis of the published results of randomised clinical trials. Br J
Cancer. 1995;72:469–475.
171 Verweij J, Pinedo HM. Adjuvant chemotherapy of soft tissue sarcomas. In: Verweij J,
Pinedo HM, Suit HD, eds. Soft Tissue Sarcomas: Present Achievements and Future Prospects.
Boston, MA: Kluwer; 1997:173–188.
173 Le Cesne A, Van Glabbeke M, Woll PJ, et al. The end of adjuvant chemotherapy (adCT)
era with doxorubicin-based regimen in resected high-grade soft tissue sarcoma (STS): Pooled
analy sis of the two STBSG-EORTC phase III clinical trials. J Clin Oncol. 2008;26:559s.
174 Wiklund T, Saeter G, Strander H, et al. The outcome of advanced soft tissue sarcoma
patients with complete tumour regression after either chemotherapy alone or chemotherapy
plus surgery —the Scandinavian Sarcoma Group experience. Eur J Cancer. 1997;33:357–361.
175 Baldini EH, Goldberg J, Jenner C, et al. Long-term outcomes after function-sparing
surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin
Oncol. 1999;17:3252–3259.
176 Cahlon O, Brennan MF, Jia X, et al. A postoperative nomogram for local recurrence risk
in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation. Ann
Surg. 2012;255:343–347.
177 Pisters PWT, Pollock RE, Lewis VO, et al. Long-term results of prospective trial of
surgery alone with selective use of radiation for patients with T1 extremity and trunk soft
tissue sarcomas. Ann Surg. 2007;246:675–681.
179 Mundt AJ, Awan A, Sibley GS, et al. Conservative surgery and adjuvant radiation
therapy in the management of adult soft tissue sarcoma of the extremities: clinical and
radiobiological results. Int J Radiat Oncol Biol Phys. 1995;32:977–985.
180 Brecht IB, Ferrari A, Int-Veen C, et al. Grossly -resected sy novial sarcoma treated by the
German and Italian Pediatric Soft Tissue Sarcoma Cooperative Groups: discussion on the role
of adjuvant therapies. Pediatr Blood Cancer. 2006;46:11–17.
181 Carli M, Ferrari A, Mattke A, et al. Pediatric malignant peripheral nerve sheath tumor:
The Italian and German Soft Tissue Sarcoma Cooperative Group. J Clin Oncol.
2005;23:8422–8430.
182 Bisogno G, Ferrari A, Bergeron C, et al. The IVADo regimen: a pilot study with
ifosfamide, vincristine, actinomy cin D, and doxorubicin in children with metastatic soft tissue
sarcoma: a pilot study of behalf of the European Pediatric Soft Tissue Sarcoma Study Group.
Cancer. 2005;103:1719–1724.
183 Venkatramani R, Anderson JR, Million L, et al. Risk-based treatment for sy novial
sarcoma in patients under 30 y ears of age: Children’s Oncology Group study ARST0332.
ASCO Meeting Abstracts. 2015;33:10012.
184 Cheng EY, Dusenbery KE, Winters MR, et al. Soft tissue sarcomas: preoperative versus
postoperative radiotherapy. J Surg Oncol. 1996;61:90–99.
185 Tanabe K, Sherman N, Pollock R. Local control of extremity sarcomas treated with
preoperative radiotherapy and limb sparing surgery. Proc ASCO. 1991;10:351.
186 Keus RB, Rutgers EJ, Ho GH, et al. Limb-sparing therapy of extremity soft tissue
sarcomas: treatment outcome and long-term functional results. Eur J Cancer.
1994;30A:1459–1463.
187 Suit HD, Spiro I. Role of radiation in the management of adult patients with sarcoma of
soft tissue. Semin Surg Oncol. 1994;10:347–356.
188 Sawy er TE, Peterson IA, Pritchard DJ. Prognostic factors in extremity soft tissue
sarcomas treated with limb salvage therapy. Joint Meeting of European Musculo-Skeletal
Oncology Society and American Musculo-Skeletal Tumor Society ; Florence, Italy ; 1995.
189 Million L, Donaldson SS. Resectable pediatric nonrhabdomy osarcoma soft tissue
sarcoma: which patients benefit from adjuvant radiation therapy and how much? ISRN
Oncol. 2012;2012:341408.
190 Krasin MJ, Davidoff AM, Xiong X, et al. Preliminary results from a prospective study
using limited margin radiotherapy in pediatric and y oung adult patients with high-grade
nonrhabdomy osarcoma soft-tissue sarcoma. Int J Radiat Oncol Biol Phys. 2010;76:874–878.
191 White LM, Wunder JS, Bell RS, et al. Histologic assessment of peritumoral edema in soft
tissue sarcoma. Int J Radiat Oncol Biol Phys. 2005;61:1439–1445.
192 Lin C, Donaldson SS, Meza JL, et al. Effect of radiotherapy techniques (IMRT vs. 3D-
CRT) on outcome in patients with intermediate-risk rhabdomy osarcoma enrolled in COG
D9803—a report from the Children’s Oncology Group. Int J Radiat Oncol Biol Phys.
2012;82:1764–1770.
193 Sterzing F, Stoiber EM, Nill S, et al. Intensity modulated radiotherapy (IMRT) in the
treatment of children and adolescents—a single institution’s experience and a review of the
literature. Radiat Oncol. 2009;4:37.
195 Childs SK, Kozak KR, Friedmann AM, et al. Proton radiotherapy for parameningeal
rhabdomy osarcoma: clinical outcomes and late effects. Int J Radiat Oncol Biol Phys.
2012;82:635–642.
196 Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing’s
sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys. 2012;82:1142–1148.
200 Womer RB. Problems and controversies in the management of childhood sarcomas. Br
Med Bull. 1996;52:826–843.
201 Brizel DM, Scully SP, Harrelson JM, et al. Radiation therapy and hy perthermia improve
the oxy genation of human soft tissue sarcomas. Cancer Res. 1996;56:5347–5350.
202 Marcus KC, Grier HE, Shamberger RC, et al. Childhood soft tissue sarcoma: a 20-y ear
experience.[see comment]. J Pediatr. 1997;131:603–607.
203 Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomy osarcoma study -IV: results
for patients with nonmetastatic disease. J Clin Oncol. 2001;19:3091–3102.
204 Zagars GK, Ballo MT. Significance of dose in postoperative radiotherapy for soft tissue
sarcoma. Int J Radiat Oncol Biol Phys. 2003;56:473–481.
206 Merchant TE, Parsh N, del Valle PL, et al. Brachy therapy for pediatric soft-tissue
sarcoma. Int J Radiat Oncol Biol Phys. 2000;46:427–432.
207 Gerbaulet A, Panis X, Flamant F, et al. Iridium afterloading curietherapy in the treatment
of pediatric malignancies—the Institut Gustave Roussy experience. Cancer. 1985;56:1274–
1279.
208 Shiu MH, Hilaris BS, Harrison LB, et al. Brachy therapy and function-saving resection of
soft tissue sarcoma arising in the limb. Int J Radiat Oncol Biol Phys. 1991;21:1485–1492.
209 Alekhtey ar KM, Leung DH, Brennan MF, et al. The effect of combined external beam
radiotherapy and brachy therapy on local control and wound complications in patients with
high-grade soft tissue sarcomas of the extremity with positive microscopic margin. Int J
Radiat Oncol Biol Phys. 1996;36:321–324.
210 Burmeister BH, Dickinson I, Bry ant G, et al. Intra-operative implant brachy therapy in
the management of soft-tissue sarcomas. Aust N Z J Surg. 1997;67:5–8.
211 Nag S, Fernandes PS, Martinez-Monge R, et al. Use of brachy therapy to preserve
function in children with soft-tissue sarcomas. Oncology (Williston Park). 1999;13:361–369;
discussion 369–370, 373–364.
212 Nag S, Gupta N. A simple method of obtaining equivalent doses for use in HDR
brachy therapy. Int J Radiat Oncol Biol Phys. 2000;46:507–513.
213 Nag S, Shasha D, Janjan N, et al. The American Brachy therapy Society
recommendations for brachy therapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys.
2001;49:1033–1043.
214 Nag S, Tippin D, Ruy mann FB. Intraoperative high-dose-rate brachy therapy for the
treatment of pediatric tumors: the Ohio State University experience. Int J Radiat Oncol Biol
Phys. 2001;51:729–735.
215 Harrison LB, Franzese F, Gay nor JJ, et al. Long-term results of a prospective randomized
trial of adjuvant brachy therapy in the management of completely resected soft tissue
sarcomas of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys. 1993;27:259–
265.
216 Devlin PM, Harrison LB. Brachy therapy for soft tissue sarcomas. In: Verweig J, Pinedo
HM, Suit HD, eds. Soft Tissue Sarcomas: Present Achievements and Future Prospects. Boston,
MA: Kluwer; 1997:107–128.
217 Pisters PW, Harrison LB, Woodruff JM, et al. A prospective randomized trial of adjuvant
brachy therapy in the management of low-grade soft tissue sarcomas of the extremity and
superficial trunk. J Clin Oncol. 1994;12:1150–1155.
218 Habrand JL, Gerbaulet A, Pejovic MH, et al. Twenty y ears experience of interstitial
iridium brachy therapy in the management of soft tissue sarcomas. Int J Radiat Oncol Biol
Phys. 1991;20:405–411.
219 Willett CG, Suit HD, Tepper JE, et al. Intraoperative electron beam radiation therapy for
retroperitoneal soft tissue sarcoma. Cancer. 1991;68:278–283.
220 Battermann JJ, Breur K, Hart GA, et al. Observations on pulmonary metastases in
patients after single doses and multiple fractions of fast neutrons and cobalt-60 gamma ray s.
Eur J Cancer. 1981;17:539–548.
221 Glaholm J, Harmer C. Soft-tissue sarcoma: neutrons versus photons for post-operative
irradiation. Br J Radiol. 1988;61:829–834.
222 Laramore GE, Griffith JT, Boespflug M, et al. Fast neutron radiotherapy for sarcomas of
soft tissue, bone, and cartilage. Am J Clin Oncol. 1989;12:320–326.
224 Cecchetto G, Carli M, Sotti G, et al. Importance of local treatment in pediatric soft tissue
sarcomas with microscopic residual after primary surgery : results of the Italian Cooperative
Study RMS-88. Med Pediatr Oncol. 2000;34:97–101.
225 Smith KB, Indelicato DJ, Knapik JA, et al. Definitive radiotherapy for unresectable
pediatric and y oung adult nonrhabdomy osarcoma soft tissue sarcoma. Pediatr Blood Cancer.
2011;57:247–251.
226 Kiel KD, Suit HD. Radiation therapy in the treatment of aggressive fibromatoses
(desmoid tumors). Cancer. 1984;54:2051–2055.
227 Acker JC, Bossen EH, Halperin EC. The management of desmoid tumors. Int J Radiat
Oncol Biol Phys. 1993;26:851–858.
228 Enzinger FM, Shiraki M. Musculo-aponeurotic fibromatosis of the shoulder girdle (extra-
abdominal desmoid)—analy sis of thirty cases followed up for ten or more y ears. Cancer.
1967;20:1131–1140.
229 Suit H, Spiro I. Radiation in the multidisciplinary management of desmoid tumors. Front
Radiat Ther Oncol. 2001;35:107–119.
230 Coffin CM, Dehner LP. Soft tissue neoplasms in children: a clinicopathologic overview.
In: Finegold M, ed. Pathology of Neoplasia in Children and Adolescents. Philadelphia, PA: WB
Saunders; 1986:223–255.
231 Greenberg HM, Goebel R, Weichselbaum RR, et al. Radiation therapy in the treatment of
aggressive fibromatoses. Int J Radiat Oncol Biol Phys. 1981;7:305–310.
232 Nuy ttens JJ, Rust PF, Thomas CR Jr, et al. Surgery versus radiation therapy for patients
with aggressive fibromatosis or desmoid tumors: a comparative review of 22 articles. Cancer.
2000;88:1517–1523.
233 Kasper B, Strobel P, Hohenberger P. Desmoid tumors: clinical features and treatment
options for advanced disease. Oncologist. 2011;16:682–693.
234 Faulkner LB, Hajdu SI, Kher U, et al. Pediatric desmoid tumor: retrospective analy sis of
63 cases. J Clin Oncol. 1995;13:2813–2818.
235 Merchant TE, Nguy en D, Walter AW, et al. Long-term results with radiation therapy for
pediatric desmoid tumors. Int J Radiat Oncol Biol Phys. 2000;47:1267–1271.
236 Soto-Miranda MA, Sandoval JA, Rao B, et al. Surgical treatment of pediatric desmoid
tumors—a 12-y ear, single-center experience. Ann Surg Oncol. 2013;20:3384–3390.
237 Suit HD, Spiro I. Radiation in the multidisciplinary management of desmoid tumors. In:
Mey er JL, ed. The Radiation Therapy of Benign Disease Current Indicators and Techniques.
Basel, Switzerland: Karger; 2001;35:107–119.
238 Reitamo JJ. The desmoid tumor. IV: choice of treatment, results, and complications. Arch
Surg. 1983;118:1318–1322.
239 Suit HD, Spiro IJ, Speer M. Benign and low grade tumors of the soft tissues: role for
radiation therapy. In: Verweig J, Pinedo HM, Suit HD, eds. Soft Tissue Sarcomas: Present
Achievements and Future Prospects. Boston, MA: Kluwer; 1997:95–106.
240 Leibel SA, Wara WM, Hill DR, et al. Desmoid tumors: local control and patterns of
relapse following radiation therapy. Int J Radiat Oncol Biol Phys. 1983;9:1167–1171.
241 Keus R, Bartelink H. The role of radiotherapy in the treatment of desmoid tumours.
Radiother Oncol. 1986;7:1–5.
242 Bataini JP, Belloir C, Mazabraud A, et al. Desmoid tumors in adults: the role of
radiotherapy in their management. Am J Surg. 1988;155:754–760.
243 Zelefsky MJ, Harrison LB, Shiu MH, et al. Combined surgical resection and iridium 192
implantation for locally advanced and recurrent desmoid tumors. Cancer. 1991;67:380–384.
244 Plukker JT, van Oort I, Vermey A, et al. Aggressive fibromatosis (non-familial desmoid
tumour): therapeutic problems and the role of adjuvant radiotherapy. Br J Surg. 1995;82:510–
514.
245 Pritchard DJ, Nascimento AG, Petersen IA. Local control of extra-abdominal desmoid
tumors. J Bone Joint Surg Am. 1996;78:848–854.
246 Goy BW, Lee SP, Eilber F, et al. The role of adjuvant radiotherapy in the treatment of
resectable desmoid tumors. Int J Radiat Oncol Biol Phys. 1997;39:659–665.
247 Jelinek JA, Stelzer KJ, Conrad E, et al. The efficacy of radiotherapy as postoperative
treatment for desmoid tumors. Int J Radiat Oncol Biol Phys. 2001;50:121–125.
248 Zlotecki RA, Scarborough MT, Morris CG, et al. External beam radiotherapy for primary
and adjuvant management of aggressive fibromatosis. Int J Radiat Oncol Biol Phys.
2002;54:177–181.
249 McCollough WM, Parsons JT, van der Griend R, et al. Radiation therapy for aggressive
fibromatosis—the experience at the University of Florida. J Bone Joint Surg Am.
1991;73:717–725.
250 Kamath SS, Parsons JT, Marcus RB, et al. Radiotherapy for local control of aggressive
fibromatosis. Int J Radiat Oncol Biol Phys. 1996;36:325–328.
251 Schulz-Ertner D, Zierhut D, Mende U, et al. The role of radiation therapy in the
management of desmoid tumors. Strahlenther Onkol. 2002;178:78–83.
252 Park HC, Py o HR, Shin K-H, et al. Radiation treatment for aggressive fibromatosis:
findings from observed patterns of local failure. Oncology. 2003;64:346–352.
253 O’Dea FJ, Wunder J, Bell RS, et al. Preoperative radiotherapy is effective in the
treatment of fibromatosis. Clin Orthop Relat Res. 2003;(415):19–24.
254 Gronchi A, Casali PG, Mariani L, et al. Quality of surgery and outcome in extra-
abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution.
J Clin Oncol. 2003;21:1390–1397.
255 Micke O, Seegenschmiedt MH, German Cooperative Group on Radiotherapy for Benign
D. Radiation therapy for aggressive fibromatosis (desmoid tumors): results of a national
Patterns of Care Study. Int J Radiat Oncol Biol Phys. 2005;61:882–891.
256 Sherman NE, Romsdahl M, Evans H, et al. Desmoid tumors: a 20-y ear radiotherapy
experience. Int J Radiat Oncol Biol Phys. 1990;19:37–40.
257 Ballo MT, Zagars GK, Pollack A. Radiation therapy in the management of desmoid
tumors. Int J Radiat Oncol Biol Phys. 1998;42:1007–1014.
258 Guadagnolo BA, Zagars GK, Ballo MT. Long-term outcomes for desmoid tumors treated
with radiation therapy. Int JRadiat Oncol Biol Phys. 2008;71:441–447.
259 Rudiger HA, Ngan SYK, Ng M, et al. Radiation therapy in the treatment of desmoid
tumours reduces surgical indications. Eur J Surg Oncol. 2009;36:84–88.
261 Skapek SX, Ferguson WS, Granowetter L, et al. Vinblastine and methotrexate for desmoid
fibromatosis in children: results of a Pediatric Oncology Group Phase II Trial. J Clin Oncol.
2007;25:501–506.
262 Heinrich MC, McArthur GA, Demetri GD, et al. Clinical and molecular studies of the
effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol.
2006;24:1195–1203.
263 Mace J, Sy bil Biermann J, Sondak V, et al. Response of extraabdominal desmoid tumors
to therapy with imatinib mesy late. Cancer. 2002;95:2373–2379.
264 Lim CL, Walker MJ, Mehta RR, et al. Estrogen and antiestrogen binding sites in desmoid
tumors. Eur J Cancer Clin Oncol. 1986;22:583–587.
265 Maddalozzo J, Tenta LT, Hutchinson LR, et al. Juvenile fibromatosis: hormonal receptors.
Int J Pediatr Otorhinolaryngol. 1993;25:191–199.
266 De Pas T, Bodei L, Pelosi G, et al. Peptide receptor radiotherapy : a new option for the
management of aggressive fibromatosis on behalf of the Italian Sarcoma Group. Br J
Cancer. 2003;88:645–647.
268 Hansmann A, Adolph C, Vogel T, et al. High-dose tamoxifen and sulindac as first-line
treatment for desmoid tumors. Cancer. 2004;100:612–620.
270 Lackner H, Urban C, Kerbl R, et al. Noncy totoxic drug therapy in children with
unresectable desmoid tumors. Cancer. 1997;80:334–340.
271 Skapek SX, Anderson JR, Hill DA, et al. Safety and efficacy of high-dose tamoxifen and
sulindac for desmoid tumor in children: results of a Children’s Oncology Group (COG) Phase
II Study. Pediatr Blood Cancer. 2013;60:1108–1112.
2 Gairdner E. Case of fungus haematodes in the kidney s. Edin Med Surg J. 1828;29:312–315.
3 Osler W. Two cases of striated my osarcoma of the kidney. J Anat Physiol. 1879;14:229.
5 Zantinga AR, Coppes MJ. Historical aspects of the identification of the entity Wilms tumor,
and its management. Hematol Oncol Clin North Am. 1995;9:1145–1155.
6 Paterson R. The genital organs. In: Paterson R, ed. The Treatment of Malignant Disease by
Radium and X-Rays. London, England: Edward Arnold; 1948:404–405.
7 Dean AL, Guttman RJ. Radiation therapy in malignant diseases of the genito-urinary tract.
In: Pohle EA, ed. Clinical Radiation Therapy. Philadelphia, PA: Lea & Febiger; 1950:491–514.
8 Jacox HW, Cahill GF. Treatment of diseases of the kidney and adrenal gland. In: Portmann
UV, ed. Clinical Therapeutic Radiology. New York, NY: Thomas Nelson & Sons; 1950:254–
275.
9 Gurney JG, Davis S, Severson RK, et al. Trends in cancer incidence among children in the
U.S. Cancer. 1996;78:532–541.
10 Blute ML, Kelalis PP, Offord KP, et al. Bilateral Wilms’ tumor. J Urol. 1987;138(2):968–
973.
11 Breslow N, Olshan A, Beckwith JB, et al. Epidemiology of Wilms’ tumor. Med Pediatr
Oncol. 1993;21:172–181.
12 D’Angio GJ. National Wilms’ Tumor Study. Seattle, WA: NWTS Data and Statistical Center;
1991 [Informational Bulletin #19].
13 Breslow NE, Churchill G, Nesmith B, et al. Clinicopathologic features and prognosis for
Wilms’ tumor patients with metastases at diagnosis. Cancer. 1986;58:2501–2511.
14 Hadley GP, Jacobs C. The clinical presentation of Wilms’ tumour in black children. S Afr
Med J. 1990;77:565–567.
15 Knudson AG, Strong LC. Mutation and cancer: a model for Wilms’ tumor of the kidney. J
Natl Cancer Inst. 1972;48:313–324.
16 Grundy P, Coppes M. An overview of the clinical and molecular genetics of Wilms’ tumor.
Med Pediatr Oncol. 1996;27:394–397.
17 Blakely ML, Ritchey ML. Controversies in the management of Wilms’ tumor. Semin
Pediatr Surg. 2001;10:127–131.
18 Douglass EC, Look AT, Webber B, et al. Hy perdiploidy and chromosomal rearrangements
define the anaplastic variant of Wilms’ tumor. J Clin Oncol. 1986;4:975–981.
19 Riccardi VM, Hittner HM, Francke U, et al. The aniridia-Wilms’ tumor association: the
critical role of chromosome band 11p13. J Cancer Genet Cytogenet. 1980;2:131–137.
20 Palmer N, Evans AE. The association of aniridia and Wilms’ tumor: methods of
surveillance and diagnosis. Med Pediatr Oncol. 1983;11:73–75.
21 Pendergrass TW. Congenital anomalies in children with Wilms’ tumor: a new survey.
Cancer. 1976;37:403–409.
22 Breslow NE. Epidemiological features of Wilms’ tumor: results of the National Wilms’
Tumor Study. J Natl Cancer Inst. 1982;68:429–436.
23 Gessler M, Poutska A, Cavenee W, et al. Homozy gous deletion in Wilms’ tumors of zinc-
finger gene identified by chromosome jumping. Nature. 1990;343:774–778.
24 Bonetta L, Kuetin SE, Huang A, et al. Wilms’ tumor locus on 11p13 defined by multiple
CpG island-associated transcripts. Science. 1990;250:994–997.
26 Ping AJ, Reeve AE, Law DJ, et al. Genetic linkage of Beckwith–Wiedemann sy ndrome to
11p15. Am J Hum Genet. 1989;44:720–723.
27 Dome JS, Coppes MJ. Recent advances in Wilms tumor genetics. Curr Opin Pediatr.
2002;14:5–11.
28 Coppes MJ, Pritchard-Jones K. Principles of Wilms’ tumor biology. Urol Clin North Am.
2000;27:423–433.
29 Grundy PE, Breslow NE, Li S, et al. Loss of heterozy gosity for chromosomes 1p and 16q
is an adverse prognostic factor in favorable histology Wilms tumor: a report from the
National Wilms Tumor Study Group. J Clin Oncol. 2005;29:7312–7321.
30 Rivera MN, Kim WJ, Wells J, et al. An X chromosome gene, WTX, is commonly
inactivated in Wilms tumor. Science. 2007;315:642–645.
31 Maiti S, Alam R, Amos CI, et al. Frequent association of beta-catenin and WT1 mutations
in Wilms tumors. Cancer Res. 2000;60:6288–6292.
32 Scott RH, Douglas J, Baskcomb L, et al. Constitutional 11p15 abnormalities, including
heritable imprinting center mutations, cause nonsy ndromic Wilms tumor. Nat Genet.
2008;40:1329–1334.
33 Huang CC, Gadd S, Breslow N, et al. Predicting relapse in favorable histology Wilms
tumor using gene expression analy sis: a report from the Renal Tumor Committee of the
Children’s Oncology Group. Clin Cancer Res. 2009;15:1770–1778.
34 Sredni ST, Gadd S, Huang CC, et al. Subsets of very low risk Wilms tumor show distinctive
gene expression, histologic and clinical features. Clin Cancer Res. 2009;15:6800–6809.
35 Perlman EJ, Grundy PE, Anderson JR, et al. WT1 mutation and 11P15 loss of
heterozy gosity predict relapse in very low-risk Wilms tumors treated with surgery alone: a
Children’s Oncology Group Study. J Clin Oncol. 2011;29:698–703.
36 Gratias EJ, Jennings LJ, Anderson JR, et al. Gain of 1q is associated with inferior event-
free and overall survival in patients with favorable histology Wilms tumor. Cancer.
2013;119:3887–3894.
38 Beckwith JB. Wilms’ tumor and other renal tumors in childhood. In: Finegold M, ed.
Pathology of Neoplasia in Children and Adolescents. Philadelphia, PA: WB Saunders;
1986:313–332.
39 Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms’ tumor: results from the
First National Wilms’ Tumor Study. Cancer. 1978;41:1937–1948.
40 Schmidt D, Beckwith JB. Histopathology of childhood renal tumor. Hematol Oncol Clin
North Am. 1995;9:1179–1200.
41 D’Angio GJ, Evans AE, Breslow N, et al. The treatment of Wilms’ tumor: results of the
National Wilms’ Tumor Study. Cancer. 1976;38:633–646.
42 D’Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms’ tumor: results of the
Third National Wilms’ Tumor Study. Cancer. 1989;64:349–360.
43 Neville HL, Ritchey ML. Wilms’ tumor: overview of National Wilms’ Tumor Study Group
results. Urol Clin North Am. 2000;27:435–442.
44 Bonadio JF, Storer B, Norkool P, et al. Anaplastic Wilms’ tumor: clinical and pathologic
studies. J Clin Oncol. 1985;3:513–520.
45 Faria P, Beckwith JB, Mishra K, et al. Focal versus diffuse anaplasia in Wilms tumor—new
definitions with prognostic significance: a report from the National Wilms’ Tumor Study
Group. Am J Surg Pathol. 1996;20:909–920.
46 Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms tumor:
results from the fifth National Wilms Tumor Study. J Clin Oncol. 2006;24:2352–2358.
47 Green DM, Thomas PRM, Shochat S. The treatment of Wilms’ tumor: results of the
National Wilms’ Tumor Studies. Hematol Oncol Clin North Am. 1995;9:1267–1274.
48 Haas JE, Bonadio JF, Beckwith JB. Clear cell sarcoma of the kidney with emphasis of
ultrastructural studies. Cancer. 1984;54:2978–2987.
49 Seibel NL, Li S, Breslow NE, et al. Effect of duration of treatment on treatment outcome
for patients with clear cell sarcoma of the kidney : a report from the national Wilms tumor
Study Group. J Clin Oncol. 2004;22:468–473.
50 Gutjahr P. Progress and controversies in modern treatment of Wilms’ tumor. World J Urol.
1995;13:209–212.
51 Leape L, Breslow N, Bishop H. Surgical resection of Wilms’ tumor: results of the National
Wilms’ Tumor Study. Ann Surg. 1978;181:351–356.
52 Green DM, Jaffe N. Wilms’ tumor: model of a curable pediatric malignant solid tumor.
Cancer Treat Rev. 1978;5:143–172.
55 Feusner JH, Beckwith JB, D’Angio GJ. Clear cell sarcoma of the kidney : accuracy of
imaging methods for detecting bone metastases—report from the National Wilms’ Tumor
Study. Med Pediatr Oncol. 1990;18:225–227.
56 Cassady JR, Tefft M, Filler RM, et al. Considerations in the radiation therapy of Wilms’
tumor. Cancer. 1973;32:598–608.
57 Cassady JR, Jaffe N, Paed D, et al. The increasing importance of radiation therapy in the
improved prognosis of children with Wilms’ tumor. Cancer. 1977;39:825–829.
59 Green DM, Breslow NE, Beckwith JB, et al. Treatment with nephrectomy only for small,
stage I/favorable histology Wilms’ tumor: a report from the National Wilms’ Tumor Study
Group. J Clin Oncol. 2001;19:3719–3724.
60 Tefft M, D’Angio GJ, Grant W. Post-operative radiation therapy for residual Wilms’ tumor:
review of group III patients in the National Wilms’ Tumor Study. Cancer. 1976;37:2768–2772.
61 D’Angio GJ. Editorial: SIOP and the management of Wilms’ tumor. J Clin Oncol.
1983;1:595–596.
62 Beckwith JB. National Wilms’ Tumor Study : an update for pathologists. Pediatr Dev Pathol.
1998;1:79–84.
63 Weeks DA, Beckwith JB, Luckey DW. Relapse-associated variables in stage I favorable
histology Wilms tumor: a report from the National Wilms’ Tumor Study. Cancer.
1987;60:1204–1212.
64 Kalapurakal JA, Li SM, Breslow NE, et al. Intraoperative spillage of favorable histology
Wilms tumor cells: influence of irradiation and chemotherapy on abdominal recurrence—a
report from the National Wilms Tumor Study Group. Int J Rad Oncol Biol Phys.
2010;76:201–206.
65 Lemerle J, Voute PA, Tournade MF, et al. Preoperative versus postoperative radiotherapy,
single versus multiple courses of actinomy cin D, in the treatment of Wilms’ tumor. Cancer.
1976;38: 647–654.
68 Jereb B, Burgers JMV, Tournade MF, et al. Radiotherapy in the SIOP (International Society
of Pediatric Oncology ) nephroblastoma studies: a review. Med Pediatr Oncol. 1994;22:221–
227.
69 Tournade MF, Com-Nougue C, Coute PA, et al. Results of the Sixth International Society of
Pediatric Oncology Wilms’ Tumor Trial and Study : a risk-adapted therapeutic approach in
Wilms’ tumor. J Clin Oncol. 1993;11:1014–1023.
73 D’Angio GJ, Tefft M, Breslow N, et al. Radiation therapy of Wilms’ tumor: results
according to dose, field, post-operative timing and histology. Int J Radiat Oncol Biol Phys.
1978;4:769–780.
74 Breslow NE, Palmer NF, Hill LR, et al. Wilms’ tumor: prognostic factors for patients
without metastases at diagnosis: results of the National Wilms’ Tumor Study. Cancer.
1978;41:1577–1589.
75 -D’Angio GJ, Evans A, Breslow N, et al. The treatment of Wilms’ tumor: results of the
Second National Wilms’ Tumor Study. Cancer. 1981;47:2302–2311.
76 Vujanic GM, Harms D, Bohoslavsky R, et al. Nonviable tumor tissue should not upstage
Wilms’ tumor from stage I to stage II: a report from the SIOP 93-01 nephroblastoma trial and
study. Pediatr Dev Pathol. 2009;12:111–115.
77 Tefft M, D’Angio GJ, Beckwith B, et al. Patterns of intra-abdominal relapse in patients with
Wilms’ tumor who received radiation: analy sis by histopathology, a report of National Wilms’
Tumor Studies 1 and 2. Int J Radiat Oncol Biol Phys. 1980;6:663–667.
78 Thomas PR, Tefft M, Compaan PJ, et al. Results of two radiation therapy randomizations
in the Third National Wilms’ Tumor Study. Cancer. 1991;68:1703–1707.
79 Green DM, Breslow NE, Beckwith JB, et al. Comparison between single-dose and divided-
dose administration of dactinomy cin and doxorubicin for patients with Wilms’ tumor: a report
from the National Wilms’ Tumor Study Group. J Clin Oncol. 1998;16:237–245.
80 Mitchell C, Jones PM, Kelsey A, et al. The treatment of Wilms’ tumor: results of the
United Kingdom Children’s Cancer Study Group (UKCCSG) second Wilms’ tumor study. Br J
Cancer. 2000;83:602–608.
81 Breslow NE, Ou SS, Beckwith JB, et al. Doxorubicin for favorable histology, stage II–III
Wilms tumor. Results from the National Wilms Tumor Studies. Cancer. 2004;101:1072–1080.
82 Kalapurakal JA, Green DM, Haase G, et al. Outcomes of children with favorable histology
Wilms’ tumor and peritoneal implants treated on National Wilms’ Tumor Studies-4 and -5. Int
J Radiat Oncol Biol Phys. 2010;77:554–558.
83 Daw NC, Anderson JR, Hoffer FA, et al. A phase 2 study of vincristine and irinotecan in
metastatic diffuse anaplastic Wilms tumor: results from the Children’s Oncology Group
AREN0321 study. J Clin Oncol. 2014; ASCO Annual Meeting Abstracts;32(15 suppl).
84 Fernandez CV, Perlman D, Mullen EA, et al. Clinical outcome and biological peredictors
of relapse following nephrectomy only for very low risk Wilms tumor (VLRWT): a report
from the Children’s Oncology Group AREN0532 study. J Clin Oncol. 2015; ASCO Annual
Meeting Abstracts;33(15 suppl).
85 Fernandez CV, Mullen EA, Ehrlich PA, et al. Outcome and prognostic factors in stage III
favorable histology Wilms tumor: a report from the Children’s Oncology Group AREN0532
study. J Clin Oncol. 2015; ASCO Annual Meeting Abstracts;33(15 suppl).
86 Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for favorable-histology
Wilms tumor with combined loss of heterozy gosity of chromosomes 1p and 16q: a report
from the Children’s Oncology Group AREN0533 study. J Clin Oncol. 2015; ASCO Annual
Meeting Abstracts;33(15 suppl).
87 Dix DB, Gratias EJ, Seibel N, et al. Omission of lung radiation in patients with stage IV
favorable histology Wilms tumor showing complete long nodule response after
chemotherapy : a report from the Children’s Oncology Group AREN0533 study. J Clin Oncol.
2015; ASCO Annual Meeting Abstracts;33(15 suppl).
88 Dix DB, Fernandez CV, Chi YY, et al. Treatment of stage IV favorable-histology Wilms
tumor with incomplete lung metastasis response after chemotherapy : a report from the
Children’s Oncology Group AREN0533 study. J Clin Oncol. 2014; ASCO Annual Meeting
Abstracts;32(15 suppl).
90 Burgers JMV, Tournade MF, Bey P, et al. Abdominal recurrence in Wilms’ tumours: a
report from the SIOP Wilms’ tumour trial and studies. Radiother Oncol. 1986;5:175–182.
91 Ora I, van Tinteren H, Bergeron C, et al. Progression of localized Wilms’ tumor during
preoperative chemotherapy is an independent prognostic factor: a report from the SIOP 93-
01 nephroblastoma trial and study. Eur J Cancer. 2007;43:131–136.
93 Van den Heuvel-Eibrink MM, van Tinteren H, Bergeron C, et al. Outcome of localized
blastemal-ty pe Wilms tumor patients treated according to intensified treatment in SIOP WT
2001 protocol, a report of the SIOP renal tumor study group. Eur J Cancer. 2015;51:498–506.
95 Ladd WE. Embry oma of the kidney (Wilms’ tumor). Ann Surg. 1938;108:885–902.
96 Breslow N, Churchill G, Beckwith JB, et al. Prognosis for Wilms’ tumor patients with
nonmetastatic disease at diagnosis: results of the Second National Wilms’ Tumor Study. J Clin
Oncol. 1985;3:521–531.
97 Shamberger RC, Guthrie KA, Ritchey ML, et al. Surgery -related factors and local
recurrence of Wilms tumor in National Wilms’ Tumor Study 4. Ann Surg. 1999;229:292–297.
100 Ritchey ML, Shamberger RC, Haase G, et al. Surgical complications after primary
nephrectomy for Wilms’ tumor: report from the National Wilms’ Tumor Study Group. J Am
Coll Surg. 2001;192:63–68.
101 Ritchey ML, Kelalis PP, Breslow N, et al. Surgical complications after nephrectomy for
Wilms tumor. Surg Gynecol Obstet. 1992;175:507–514.
102 Ritchey ML, Othersen HB Jr, de Lorimier AA, et al. Renal vein involvement with
nephroblastoma: a report of the National Wilms’ Tumor Study 3. Eur Urol. 1990;17:139–144.
103 Green DM, Breslow NE, Beckwith JB, et al. Treatment with nephrectomy only for small,
stage I/favorable histology Wilms tumor: a report from the National Wilms Tumor Study. J
Clin Oncol. 2001;19:3719–3724.
104 Shamberger RC, Anderson JR, Breslow NE, et al. Long-term outcomes of infants with
very low risk Wilms tumor treated with surgery alone on National Wilms Tumor Study 5.
Ann Surg. 2010;251:555–558.
105 Ehrlich PF, Ritchey ML, Hamilton TE, et al. Quality assessment for Wilms tumor: a
report from the National Wilms Tumor Study -5. J Pediatr Surg. 2005;40:208–213.
106 Gross RE, Neuhauser EBD. Treatment of mixed tumors of the kidney in childhood.
Pediatrics. 1950;6:843–852.
107 Farber S. Chemotherapy in the treatment of leukemia and Wilms’ tumor. JAMA.
1966;138:826–836.
108 Kalapurakal JA, Li AM, Breslow NE, et al. Influence of radiation therapy delay on
abdominal tumor recurrence in patients with favorable histology Wilms’ tumor treated on
NWTS-3 and NWTS-4: a report from the National Wilms’ Tumor Study Group. Int J Radiat
Oncol Biol Phys. 2003;57:495–499.
109 Jeal P, Jenkins RDT. Abdominal irradiation in the treatment of Wilms’ tumor. Int J Radiat
Oncol Biol Phys. 1980;6:655–661.
110 Kalapurakal JA, Zhang Y, Kepka AG, et al. Advantages of cardiac-sparing whole lung
IMRT in children with lung metastasis. Int J Radiat Oncol Biol Phys. 2013;85:761–767.
113 Montgomery BT, Kelalis PP, Blute MD, et al. Extended follow-up of bilateral Wilms’
tumor: results of the National Wilms’ Tumor Study. J Urol. 1991;146:514–518.
114 Ritchey ML, Coppes MJ. The management of sy nchronous bilateral Wilms tumor.
Hematol Oncol Clin North Am. 1995;9:1303–1315.
115 Horwitz J, Ritchey ML, Moksness J, et al. Renal salvage procedures in patients with
sy nchronous bilateral Wilms tumors: a report of the NWTSG. J Pediatr Surg. 1999;31:1020–
1025.
116 Coppes MJ, deKraker J, vanKijken PJ, et al. Bilateral Wilms’ tumor: long-term survival
and some epidemiological features. J Clin Oncol. 1989;7:310–315.
117 Shamberger RC, Haase GC, Argani P, et al. Bilateral Wilms tumors with progressive or
nonresponsive disease. J Pediatr Surg. 2006;41:652–657.
118 Hamilton TE, Green DM, Perlman EJ, et al. Bilateral Wilms tumor with anaplasia:
lessons from the National Wilms Tumor Study. J Pediatr Surg. 2006;41:1641–1644.
119 Ritchey ML, Green DM, Thomas P, et al. Renal failure in Wilms tumor. Med Pediatr
Oncol. 1996;26:75–80.
120 Breslow NE, Takashima JR, Ritchey ML, et al. Renal failure in the Deny s–Drash &
Wilms tumor aniridia sy ndromes. Cancer Res. 2000;60:4030.
121 Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and
clinical considerations. Am J Med Genet. 1998;79:268–273.
122 Coppes MJ, Arnold M, Beckwith JB, et al. Factors affecting the risk of contralateral Wilms
tumor development. Cancer. 1999;85:1616–1625.
123 Pritchard J, Imeson J, Barnes J, et al. Results of the United Kingdom Children’s Cancer
Study Group First Wilms’ Tumor Study. J Clin Oncol. 1995;13:124–133.
124 Jereb B, Issac R, Tournade MF, et al. Survival of patients with metastases from Wilms’
tumor (SIOP 1, SIOP 2, SIOP 5). Eur Paediatr Haematol Oncol. 1985;2:71–76.
125 Nicolin G, Tay lor R, Bangham C, et al. Outcome after pulmonary radiotherapy in Wilms
tumor patients with pulmonary metastases at diagnosis: a UK Children’s Cancer Study Group,
Wilms tumor Working Group Study. Int J Radiat Oncol Biol Phys. 2008;70:175–180.
126 Dirks A, Li S, Breslow N, et al. Outcome of patients with lung metastases on NWTS 4 and
5. Med Pediatr Oncol. 2003;41:251–252.
127 Meisel JA, Guthrie KA, Breslow NE, et al. Significance and management of computed
tomography detected pulmonary nodules: a report from the National Wilms Tumor Study
Group. Int J Radiat Oncol Biol Phys. 1999;44:579–585.
128 Grundy PE, Green DM, Dirks AC, et al. Clinical significance of pulmonary nodules
detected by CT and not CXR in patients treated for favorable histology Wilms tumor on
NWTS -4 and -5—a report from the Children’s Oncology Group. Pediatr Blood Cancer.
2012;59:631–635.
129 Owens CM, Vey s PA, Pritchard J, et al. Role of chest computed tomography at diagnosis
in the management of Wilms tumor: a study by the United Kingdom Children’s Cancer Study
Group. J Clin Oncol. 2002;20:2768–2773.
130 Ehrlich PF, Hamilton TE, Grundy P, et al. The value of surgery in directing therapy for
patients with Wilms tumor with pulmonary disease—a report from the National Wilms
Tumor Study 5. J Pediatr Surg. 2006;41:162–167.
131 Ehrlich PF, Ferrerar F, Ritchey M, et al. Hepatic metastasis at diagnosis in favorable
histology Wilms tumor is not an independent adverse prognostic factor—a report from the
National Wilms Tumor Study Group. Ann Surg. 2009;250(4):642–648.
132 Miser JS, Tournade MF. The management of relapsed Wilms tumor. Hematol Oncol Clin
North Am. 1995;9:1287–1302.
133 Grundy P, Breslow NE, Green DM, et al. Prognostic factors for children with recurrent
Wilms’ tumor: results from the second and third Wilms’ tumor study. J Clin Oncol.
1989;7:638–647.
134 Groot-Loonen JJ, Pinkerton CR, Morris-Jones PH, et al. How curable is relapsed Wilms’
tumor? Arch Dis Child. 1990;65:968–970.
136 Radulescu VC, Gerrard M, Moertel C, et al. Treatment of recurrent clear cell sarcoma of
the kidney with brain metastasis. Pediatr Blood Cancer. 2008;50:246–249.
137 Green DM, Cotton CA, Malogolowkin M, et al. Treatment of Wilms tumor relapsing after
initial treatment with vincristine and actinomy cin D: a report from the National Wilms Tumor
Study Group. Pediatr Blood Cancer. 2007;48:493–499.
138 Malogolowkin M, Cotton CA, Green DM, et al. Treatment of Wilms tumor relapsing after
initial treatment with vincristine, actinomy cin D and doxorubicin—a report from the National
Wilms Tumor Study Group. Pediatr Blood Cancer. 2008;50:236–241.
139 Van den Heuvel-Eibrink MM, Grundy P, Graf N, et al. Characteristics and survival of 750
children diagnosed with a renal tumor in the first seven months of life: a collaborative study
by the SIOP/GPOH/SFOP, NWTSG and UKCCSG Wilms Tumor Study Groups. Pediatr
Blood Cancer. 2008;50:1130–1134.
140 Green DM, Narkool P, Breslow NE, et al. Severe hepatic toxicity after treatment with
vincristine and dactinomy cin using single-dose or divided-dose schedules: a report from the
National Wilms’ Tumor Study. J Clin Oncol. 1990;8:1525–1530.
141 Egeler RM, Wolff JE, Anderson RA, et al. Long-term complications and post-treatment
follow-up of patients with Wilms’ tumor. Semin Urol Oncol. 1999;17:55–61.
142 Warwick AB, Kalapurakal JA, Ou SS, et al. Portal hy pertension in children with Wilms
tumor: a report from the National Wilms Tumor Study Group. Int J Radiat Oncol Biol Phys.
2010;77:210–216.
143 Rate WR, Butler MS, Roibertson WW Jr, et al. Late orthopedic effects in children with
Wilms’ tumor treated with abdominal irradiation. Med Pediatr Oncol. 1991;19:265–268.
144 Westerinki HP, Alberts AS. Letter to the editor. Med Pediatr Oncol. 1992;21:382.
145 Makipernaa A, Heikkila JT, Merikanto J, et al. Spinal deformity induced by radiotherapy
for solid tumours of childhood: a long-term follow up study. Eur J Pediatr. 1993;152:197–200.
146 De Graaf SSN, van Gent H, Reitsma-Bierens WCC, et al. Renal function after unilateral
nephrectomy for Wilms’ tumour: the influence of radiation therapy. Eur J Cancer.
1996;32A:465–469.
147 Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for
Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol.
2001;19:1926–1934.
148 Green DM, Lange JM, Qu A, et al. Pulmonary disease after treatment for Wilms tumor:
a report from the National Wilms Tumor Long-term Follow Up Study. Pediatr Blood Cancer.
2013;60:1721–1726.
149 Green DM, Peabody EM, Nan B, et al. Pregnancy outcome after treatment for Wilms
tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol. 2002;20:2506–
2513.
150 Paulino AC, Wen B, Brown CK, et al. Late effects in children treated with radiation
therapy for Wilms’ tumor. Int J Radiat Oncol Biol Phys. 2000;46:1239–1246.
151 Breslow NE, Norkool PA, Olshan A, et al. Second malignant neoplasms in survivors of
Wilms’ tumor: a report from the National Wilms’ Tumor Study. J Natl Cancer Inst.
1988;80:592–595.
152 Kovalic JJ, Thomas PRM, Beckwith JB, et al. Hepatocellular carcinoma as second
malignant neoplasms in successfully treated Wilms’ tumor patients: a National Wilms’ Tumor
Study report. Cancer. 1991;67:342–344.
153 Breslow NE, Takashima JR, Whitton JA, et al. Second malignant neoplasms following
treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin
Oncol. 1995;13:1851–1859.
154 Shearer P, Kapoor G, Beckwith JB, et al. Secondary acute my elogenous leukemia in
patients previously treated for childhood renal tumors: a report from the National Wilms’
Tumor Study Group. J Pediatr Hematol Oncol. 2001;23:109–111.
155 Cotton CA, Peterson S, Norkool PA, et al. Early and late mortality after diagnosis of
Wilms tumor. J Clin Oncol. 2009;27:1304–1309.
156 Tay lor AJ, Winter DL, Pritchard-Jones K, et al. Second primary neoplasms in survivors
of Wilms tumor—a population-based cohort study from the British Cancer Survivor Study. Int
J Cancer. 2008;122:2085–2093.
157 Lange JM, Takashima JR, Peterson SM, et al. Breast cancer in female survivors of Wilms
tumor: a report from the National Wilms Tumor Late Effects Study. Cancer. 2014;120:3722–
3730.
158 Wallace WHB, Shalet SM, Morris-Jones PH, et al. Effect of abdominal irradiation on
growth in boy s treated for a Wilms’ tumor. Med Pediatr Oncol. 1990;18:441–446.
159 Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for
pediatric cancer survivors: the Children’s Oncology Group long-term follow up guidelines
from the Children’s Oncology Group Late Effects Committee and nursing discipline. J Clin
Oncol. 2004;22:4979–4990.
1 Darbari A, Sabin KM, Shapiro CN, et al. Epidemiology of primary hepatic malignancies in
U.S. children. Hepatology. 2003;38(3):560–566.
2 Luks FI, Yazbeck S, Brandt ML, et al. Benign liver tumors in children: a 25-y ear experience.
J Pediatr Surg. 1991;26(11):1326–1330.
6 Stringer MD, Alizai NK. Mesenchy mal hamartoma of the liver: a sy stematic review. J
Pediatr Surg. 2005;40(11):1681–1690.
7 Mey ers RL. Tumors of the liver in children. Surg Oncol. 2007;16(3):195–203.
8 Bellani FF, Massimino M. Liver tumors in childhood: epidemiology and clinics. J Surg Oncol
Suppl. 1993;3:119–121.
9 Schnater JM, Kohler SE, Lamers WH, et al. Where do we stand with hepatoblastoma? A
review. Cancer. 2003;98(4):668–678.
10 Farhi DC, Shikes RH, Murari PJ, et al. Hepatocellular carcinoma in y oung people. Cancer.
1983;52(8):1516–1525.
14 Chang MH, Shau WY, Chen CJ, et al. Hepatitis B vaccination and hepatocellular
carcinoma rates in boy s and girls. JAMA. 2000;284(23):3040–3042.
15 Chang MH. Cancer prevention by vaccination against hepatitis B. Recent Results Cancer
Res. 2009;181:85–94.
18 Cohen MD, Bugaieski EM, Haliloglu M, et al. Visual presentation of the staging of pediatric
solid tumors. Radiographics. 1996;16(3):523–545.
19 McCarville MB, Roebuck DJ. Diagnosis and staging of hepatoblastoma: imaging aspects.
Pediatr Blood Cancer. 2012;59:793–799.
20 Chung EM, Lattin GE, Lewis RB, et al. Pediatric liver masses: radiologic-athologic
correlation. Part 2: malignant tumors. Radiographics. 2011;31:483–507.
21 Schnater JM, Aronson DC, Plaschkes J, et al. Surgical view of the treatment of patients
with hepatoblastoma: results from the first prospective trial of the International Society of
Pediatric Oncology Liver Tumor Study Group. Cancer. 2002;94(4):1111–1120.
23 Figarola MS, McQuiston SA, Wilson F, et al. Recurrent hepatoblastoma with localization by
PET-CT. Pediatr Radiol. 2005;35(12):1254–1258.
27 Trevino LR, Wheeler DA, Finegold MJ, et al. Exome sequencing of hepatoblastoma
reveals recurrent mutations in NFE2L2 [abstract 4592]. Cancer Res. 2013;73(8 suppl):A-
4592.
30 Honey man JN, Simon EP, Robine N, et al. Detection of a recurrent DNAJB1-PRKACA
chimeric transcript in fibrolamellar hepatocellular carcinoma. Science.
2014;343(6174):1010–1014.
31 Fuchs J, Ry dzy nski J, von Schweinitz D, et al. Pretreatment prognostic factors and
treatment results in children with hepatoblastoma: a report from the German Cooperative
Pediatric Liver Tumor Study HB 94. Cancer. 2002;95(1):172–182.
32 Fuchs J, Ry dzy nski J, Hecker H, et al. The influence of preoperative chemotherapy and
surgical technique in the treatment of hepatoblastoma—a report from the German
Cooperative Liver Tumour Studies HB 89 and HB 94. Eur J Pediatr Surg. 2002;12(4):255–
261.
33 Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical treatment of
hepatoblastoma in the modern era—recommendations from the Childhood Liver Tumour
Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer.
2005;41(7):1031–1036.
34 Rey nolds M. Conversion of unresectable to resectable hepatoblastoma and long-term
follow-up study. World J Surg. 1995;19(6):814–816.
35 Munro FD, Simpson E, Azmy AF. Resectability of advanced liver tumours in children after
combination chemotherapy. Ann R Coll Surg Engl. 1994;76(4):253–256.
40 Mey ers RL, Rowland JR, Krailo M, et al. Predictive power of pretreatment prognostic
factors in children with hepatoblastoma: a report from the Children’s Oncology Group.
Pediatr Blood Cancer. 2009;53:1016–1022.
41 Mey ers RL, Czauderna P, Otte JB. Surgical treatment of hepatoblastoma. Pediatr Blood
Cancer. 2012;59:800–808.
43 Feusner JH, Krailo MD, Haas JE, et al. Treatment of pulmonary metastases of initial stage
I hepatoblastoma in childhood—report from the Children Cancer Group. Cancer.
1993;71(3):859–864.
44 Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results
from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of
the world experience. Pediatr Blood Cancer. 2004;42(1):74–83.
45 Mejia A, Langnas AN, Shaw BW, et al. Living and deceased donor liver transplantation for
unresectable hepatoblastoma at a single center. Clin Transplant. 2005;19(6):721–725.
50 Cruz RJ Jr, Ranganathan S, Mazariegos G, et al. Analy sis of national and single-center
incidence and survival after liver transplantation for hepatoblastoma: new trends and future
opportunities. Surgery. 2013;153:150–159.
51 Mey ers RL, Tiao G, de Ville de Goy et J, et al. Hepatoblastoma state of the art: pre-
treatment extent of disease, surgical resection guidelines and the role of liver transplantation.
Curr Opin Pediatr. 2014;26(1):29–36.
52 Pritchard J, Brown J, Shafford E, et al. Cisplatin, doxorubicin, and delay ed surgery for
childhood hepatoblastoma: a successful approach—results of the first prospective study of the
International Society of Pediatric Oncology. J Clin Oncol. 2000;18(22):3819–3828.
53 Douglass EC, Rey nolds M, Finegold M, et al. Cisplatin, vincristine, and fluorouracil therapy
for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1993;11(1):96–99.
56 Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable or metastatic
hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy : a report
from the Children’s Cancer Study Group. J Clin Oncol. 1991;9(12):2167–2176.
61 Pazdur R, Bready B, Cangir A. Pediatric hepatic tumors: clinical trials conducted in the
United States. J Surg Oncol Suppl. 1993;3:127–130.
62 Malogolowkin MH, Katzenstein HM, Krailo M, et al. Redefining the role of doxorubicin for
the treatment of children with hepatoblastoma. J Clin Oncol. 2008;26(14):2379–2383.
69 Bowman LC, Riely CA. Management of pediatric liver tumors. Surg Oncol Clin N Am.
1996;5(2):451–459.
71 Katzenstein HM, London WB, Douglass EC, et al. Treatment of unresectable and
metastatic hepatoblastoma: a Pediatric Oncology Group phase II study. J Clin Oncol.
2002;20(16):3438–3444.
72 Karski EE, Dvorak CC, Leung W, et al. Treatment of hepatoblastoma with high-dose
chemotherapy and stem cell rescue: the pediatric blood and marrow transplant consortium
experience and review of the literature. J Pediatr Hematol Oncol. 2014;36:362–368.
81 Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the
Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised,
double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.
82 Zhu AX, Blaszkowsky LS, Ry an DP, et al. Phase II study of gemcitabine and oxaliplatin in
combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin
Oncol. 2006;24(12):1898–1903.
83 Evans AE, Land VJ, Newton WA, et al. Combination chemotherapy (vincristine,
adriamy cin, cy clophosphamide, and 5-fluorouracil) in the treatment of children with
malignant hepatoma. Cancer. 1982;50(5):821–826.
84 Habrand JL, Nehme D, Kalifa C, et al. Is there a place for radiation therapy in the
management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat
Oncol Biol Phys. 1992;23(3):525–531.
85 Berry C, Keeling J. Hepatoblastoma. In: Berry CL, ed. Pediatric Pathology. Berlin,
Germany : Springer-Verlag; 1981:660–662.
86 Douglass EC, Green AA, Wrenn E, et al. Effective cisplatin (DDP) based chemotherapy
in the treatment of hepatoblastoma. Med Pediatr Oncol. 1985;13(4):187–190.
87 Wagman R, Yorke E, Ford E, et al. Respiratory gating for liver tumors: use in dose
escalation. Int J Radiat Oncol Biol Phys. 2003;55(3):659–668.
88 Wang X, Krishnan S, Zhang X, et al. Proton radiotherapy for liver tumors: dosimetric
advantages over photon plans. Med Dosim. 2008;33:259–267.
90 Klein J, Dawson LA. Hepatocellular carcinoma radiation therapy : review of evidence and
future opportunities. Int J Radiat Oncol Biol Phys. 2013;87:22–32.
91 Nakay ama H, Sugahara S, Tokita M, et al. Proton beam therapy for hepatocellular
carcinoma. Cancer. 2009;115:5499–5506.
92 Cheng SH, Lin YM, Chuang VP, et al. A pilot study of three-dimensional conformal
radiotherapy in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol.
1999;14(10):1025–1033.
93 Grady ED, McLaren J, Auda SP, et al. Combination of internal radiation therapy and
hy perthermia to treat liver cancer. South Med J. 1983;76(9):1101–1105.
94 Leichner PK, Yang NC, Frenkel TL, et al. Dosimetry and treatment planning for 90Y-
labeled antiferritin in hepatoma. Int J Radiat Oncol Biol Phys. 1988;14(5):1033–1042.
95 Order SE, Stillwagon GB, Klein JL, et al. Iodine 131 antiferritin, a new treatment modality
in hepatoma: a Radiation Therapy Oncology Group study. J Clin Oncol. 1985;3(12):1573–
1582.
96 Cheng JC, Wu JK, Lee PC, et al. Biologic susceptibility of hepatocellular carcinoma
patients treated with radiotherapy to radiation-induced liver disease. Int J Radiat Oncol Biol
Phys. 2004;60(5):1502–1509.
97 Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin
Radiat Oncol. 2005;15(4):279–283.
98 Jensen MK, Alonso MH, Nathan JD, et al. Liver transplantation in children: indications and
surgical aspects. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. New
York, NY: Cambridge University Press; 2014:760–772.
http://dx.doi.org/10.1017/CBO9781139012102.044.
1 Rescorla FJ, Breitfeld PP. Pediatric germ cell tumors. Curr Probl Cancer. 1999;23:257–303.
2 Brodeur GM, Howarth CB, Pratt CB, et al. Malignant germ cell tumors in 57 children and
adolescents. Cancer. 1981;48:1890–1898.
3 Hawkins EP, Finegold MJ, Hawkins HK, et al. Nongerminomatous malignant germ cell
tumors in children—a review of 89 cases from the Pediatric Oncology Group, 1971–1984.
Cancer. 1986;58:2579–2584.
4 Slay ton RE, Park RC, Silverberg SG, et al. Vincristine, dactinomy cin, and
cy clophosphamide in the treatment of malignant germ cell tumors of the ovary —a
Gy necologic Oncology Group Study (a final report). Cancer. 1985;56:243–248.
5 Wells RG, Sty JR. Imaging of sacrococcy geal germ cell tumors. Radiographics.
1990;10:701–713.
6 Terenziani M, D’Angelo P, Inserra A et al. Mature and immature teratoma: a report from
the second Italian pediatric study. Pediatr Blood Cancer. 2015;62:1202–1208.
10 Rushton HG, Belman AB, Sesterhenn I, et al. Testicular sparing surgery for prepubertal
teratoma of the testis: a clinical and pathological study. J Urol. 1990;144:726–730.
11 Yolk sac carcinoma. Tumor Board of the Children’s Hospital of Philadelphia. Med Pediatr
Oncol. 1987;15:96–101.
13 Lack EE, Travis WD, Welch KJ. Retroperitoneal germ cell tumors in childhood—a clinical
and pathologic study of 11 cases. Cancer. 1985;56:602–608.
14 Green DM. The diagnosis and treatment of y olk sac tumors in infants and children. Cancer
Treat Rev. 1983;10:265–288.
15 Mann JR, Pearson D, Barrett A, et al. Results of the United Kingdom Children’s Cancer
Study Group’s malignant germ cell tumor studies. Cancer. 1989;63:1657–1667.
16 Huddart SN, Mann JR, Gornall P, et al. The UK Children’s Cancer Study Group: testicular
malignant germ cell tumours 1979–1988. J Pediatr Surg. 1990;25:406–410.
18 Brammer HM III, Buck JL, Hay es WS, et al. From the archives of the AFIP—malignant
germ cell tumors of the ovary : radiologic-pathologic correlation. Radiographics.
1990;10:715–724.
19 Cham WC, Wollner N, Exelby P, et al. Patterns of extension as a guide to radiation therapy
in the management of ovarian neoplasms in children. Cancer. 1976;37:1443–1448.
20 Frazier AL, Hale JP, Rodriguez-Galindo C, et al. Revised risk classification for pediatric
extracranial germ cell tumors based on 25 y ears of clinical trial data from the United
Kingdom and United States. J Clin Oncol. 2015;33:195–201.
21 Buskirk SJ, Schray MF, Podratz KC, et al. Ovarian dy sgerminoma: a retrospective analy sis
of results of treatment, sites of treatment failure, and radiosensitivity. Mayo Clin Proc.
1987;62:1149–1157.
22 Germa JR, Izquierdo MA, Segui MA, et al. Malignant ovarian germ cell tumors: the
experience at the Hospital de la Santa Creu i Sant Pau. Gynecol Oncol. 1992;45:153–159.
23 Taskinen S, Fagerholm R, Lohi J, et al. Pediatric ovarian neoplastic tumors: incidence, age
at presentation, tumor markers and outcome. Acta Obstet Gynecol Scand. 2015;94:425–429.
27 Grosfeld JL, Billmire DF. Teratomas in infancy and childhood. Curr Probl Cancer.
1985;9:1–53.
28 Kersh CR, Constable WC, Hahn SS, et al. Primary malignant extragonadal germ cell
tumors—an analy sis of the effect of the effect of radiotherapy. Cancer. 1990;65:2681–2685.
29 Lucraft HH. A review of thirty -three cases of ovarian dy sgerminoma emphasising the
role of radiotherapy. Clin Radiol. 1979;30:585–589.
30 Nichols CR, Heerema NA, Palmer C, et al. Klinefelter’s sy ndrome associated with
mediastinal germ cell neoplasms. J Clin Oncol. 1987;5:1290–1294.
31 Noseworthy J, Lack EE, Kozakewich HP, et al. Sacrococcy geal germ cell tumors in
childhood: an updated experience with 118 patients. J Pediatr Surg. 1981;16:358–364.
32 Raney RB Jr, Sinclair L, Uri A, et al. Malignant ovarian tumors in children and
adolescents. Cancer. 1987;59:1214–1220.
33 Red E. Study : save contralateral ovary in girls with ovarian malignancy. Oncol Times.
1986;8:1–16.
34 Tewfik HH, Tewfik FA, Latourette HB. A clinical review of seventeen patients with ovarian
dy sgerminoma. Int J Radiat Oncol Biol Phys. 1982;8:1705–1709.
35 Palenzuela G, Martin E, Meunier A, et al. Comprehensive staging allows for excellent
outcome in patients with localized malignant germ cell tumor of the ovary. Ann Surg.
2008;248:836–841.
36 Billmire DF. Germ cell tumors. Surg Clin North Am. 2006;86:489–503, xi.
37 Donnellan WA, Swenson O. Benign and malignant sacrococcy geal teratomas. Surgery.
1968;64:834–846.
39 Williams SD, Birch R, Einhorn LH, et al. Treatment of disseminated germ-cell tumors
with cisplatin, bleomy cin, and either vinblastine or etoposide. N Engl J Med. 1987;316:1435–
1440.
40 Creasman WT, Fetter BF, Hammond CB, et al. Germ cell malignancies of the ovary.
Obstet Gynecol. 1979;53:226–230.
43 Mann JR, Raafat F, Robinson K, et al. The United Kingdom Children’s Cancer Study
Group’s second germ cell tumor study : carboplatin, etoposide, and bleomy cin are effective
treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity.
J Clin Oncol. 2000;18:3809–3818.
44 Ablin AR, Krailo MD, Ramsay NK, et al. Results of treatment of malignant germ cell
tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol.
1991;9:1782–1792.
45 Oliver RT, Mason MD, Mead GM, et al. Radiotherapy versus single-dose carboplatin in
adjuvant treatment of stage I seminoma: a randomised trial. Lancet. 2005;366:293–300.
46 Krepart G, Smith JP, Rutledge F, et al. The treatment for dy sgerminoma of the ovary.
Cancer. 1978;41:986–990.
47 Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary : a clinical
and pathologic study of 58 cases. Cancer. 1976;37:2359–2372.
48 Wollner N, Exelby PR, Woodruff JM, et al. Malignant ovarian tumors in childhood:
prognosis in relation to initial therapy. Cancer. 1976;37:1953–1964.
50 Vassal G, Flamant F, Caillaud JM, et al. Juvenile granulosa cell tumor of the ovary in
children: a clinical study of 15 cases. J Clin Oncol. 1988;6:990–995.
51 Vogelzang NJ, Anderson RW, Kennedy BJ. Successful treatment of mediastinal germ
cell/endodermal sinus tumors. Chest. 1985;88:64–69.
52 Lappohn RE, Burger HG, Bouma J, et al. Inhibin as a marker for granulosa-cell tumors. N
Engl J Med. 1989;321:790–793.
53 Carmignani L, Colombo R, Gadda F et al. Conservative surgical therapy for ley dig cell
tumor. J Urol. 2007;178:507–511.
54 Fernandes ET, Etcubanas E, Rao BN, et al. Two decades of experience with testicular
tumors in children at St Jude Children’s Research Hospital. J Pediatr Surg. 1989;24:677–681.
55 Oosterhuis JW, Stoop JA, Rijlaarsdam MA, et al. Pediatric germ cell tumors presenting
bey ond childhood? Andrology. 2015;3:70–77.
56 Kennedy CL, Hendry WF, Peckham MJ. The significance of scrotal interference in stage I
testicular cancer managed by orchiectomy and surveillance. Br J Urol. 1986;58:705–708.
57 Dehnard L. Gonadal and extragonadal germ cell neoplasms: teratomas in childhood. In:
Feingold M, ed. Pathology of Neoplasia in Children and Adolescents. Philadelphia, PA: WB
Saunders; 1986:282–312.
58 Flamant F, Diez P. Cure of testicular stage I y olk sac tumor (endodermal sinus tumor) in
children by conservative treatment. Proc ASCO. 1985;4:235.
61 De Santis M, Pont J. The role of positron emission tomography in germ cell cancer. World
J Urol. 2004;22:41–46.
63 Heidenreich A, Weissbach L, Holtl W, et al. Organ sparing surgery for malignant germ
cell tumor of the testis. J Urol. 2001;166:2161–2165.
64 Puri A, Chandrasekharam VV, Agarwala S, et al. Pediatric extragonadal germ cell tumor
of the scalp. J Pediatr Surg. 2001;36:1602–1603.
65 Bianchi DW, Crombleholme TM, D’Alton ME. Diagnosis and Management of the Fetal
Patient. New York, NY: McGraw-Hill Medical Publishing Division; 2010.
66 Altman RP, Randolph JG, Lilly JR. Sacrococcy geal teratoma: American Academy of
Pediatrics Surgical Section Survey -1973. J Pediatr Surg. 1974;9:389–398.
67 Coleman A, Shaaban A, Keswani S, et al. Sacrococcy geal teratoma growth rate predicts
adverse outcomes. J Pediatr Surg. 2014; 49:985–989.
68 Ein SH, Mancer K, Adey emi SD. Malignant sacrococcy geal teratoma—endodermal
sinus, y olk sac tumor—in infants and children: a 32-y ear review. J Pediatr Surg. 1985;20:473–
477.
69 De Backer A, Madern GC, Hakvoort-Cammel FG, et al. Study of the factors associated
with recurrence in children with sacrococcy geal teratoma. J Pediatr Surg. 2006;41:173–181.
70 Lukish JR, Powell DM. Laparoscopic ligation of the median sacral artery before resection
of a sacrococcy geal teratoma. J Pediatr Surg. 2004;39:1288–1290.
71 Garg R, Agarwala S, Bakhshi S, et al. Sacrococcy geal malignant germ cell tumor (SC-
MGCT) with intraspinal extension. J Pediatr Surg. 2014;49:1113–1115.
72 Rescorla F, Billmire D, Stolar C, et al. The effect of cisplatin dose and surgical resection in
children with malignant germ cell tumors at the sacrococcy geal region: a pediatric intergroup
trial (POG 9049/CCG 8882). J Pediatr Surg. 2001;36:12–17.
75 Schneider BP, Kesler KA, Brooks JA, et al. Outcome of patients with residual germ cell or
non-germ cell malignancy after resection of primary mediastinal nonseminomatous germ
cell cancer. J Clin Oncol. 2004;22:1195–1200.
76 De Backer A, Madern GC, Pieters R, et al. Influence of tumor site and histology on long-
term survival in 193 children with extracranial germ cell tumors. Eur J Pediatr Surg.
2008;18:1–6.
77 Bokemey er C, Nichols CR, Droz JP, et al. Extragonadal germ cell tumors of the
mediastinum and retroperitoneum: results from an international analy sis. J Clin Oncol.
2002;20:1864–1873.
1 Bradley EL. Primary and adjunctive therapy in carcinoma of the adrenal cortex. Surg
Gynecol Obstet. 1975;141(4):507–516.
2 Dackiw AP, Lee JE, Gagel RF, et al. Adrenal cortical carcinoma. World J Surg.
2001;25(7):914–926.
9 Custódio G, Parise GA, Kiesel Filho N, et al. Impact of neonatal screening and surveillance
for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin
Oncol. 2013;31(20):2619–2626.
11 Magee BJ, Gattamaneni HR, Pearson D. Adrenal cortical carcinoma: survival after
radiotherapy. Clin Radiol. 1987;38(6):587–588.
16 Zancanella P, Pianovski MAD, Oliveira BH, et al. Mitotane associated with cisplatin,
etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane
monitoring and tumor regression. J Pediatr Hematol Oncol. 2006;28(8):513–524.
17 Percarpio B, Knowlton AH. Radiation therapy of adrenal cortical carcinoma. Acta Radiol
Ther Phys Biol. 1976;15(4):288–292.
18 Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with
mitotane and a review of the literature. Cancer. 1993;72(11):3145–3155.
19 Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal
cancer: recommendations of an international consensus conference. Endocr Relat Cancer.
2005;12(3):667–680.
20 Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor bed
on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab.
2006;91(11):4501–4504.
21 Sabolch A, Else T, Griffith KA, et al. Adjuvant radiation therapy improves local control
after surgical resection in patients with localized adrenocortical carcinoma. Int J Radiat Oncol
Biol Phys. 2015;92(2):252–259.
23 McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediatric adrenocortical
carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr
Surg. 2013;48(5):1025–1031.
24 Newman KD, Ponsky T. The diagnosis and management of endocrine tumors causing
hy pertension in children. Ann N Y Acad Sci. 2002;970:155–158.
25 Caty MG, Coran AG, Geagen M, et al. Current diagnosis and treatment of
pheochromocy toma in children. Experience with 22 consecutive tumors in 14 patients. Arch
Surg. 1990;125(8):978–981.
27 DeLellis RA, Lloy d RV, Heitz PU, et al. WHO Classification of Tumours, Pathology and
Genetics of Tumours of Endocrine Organs. Ly on, France: IARC Press; 2004.
28 Ezzat Abdel-Aziz T, Prete F, Conway G, et al. Phaeochromocy tomas and paragangliomas:
a difference in disease behaviour and clinical outcomes. J Surg Oncol. 2015;112(5):486–491.
29 Adler JT, Mey er-Rochow GY, Chen H, et al. Pheochromocy toma: current approaches and
future directions. Oncologist. 2008;13(7):779–793.
30 Basu S, Nair N. Stable disease and improved health-related quality of life (HRQoL)
following fractionated low dose 131I-metaiodobenzy lguanidine (MIBG) therapy in metastatic
paediatric paraganglioma: observation on false “reverse” discordance during pre-therapy
work up and its implication for patient selection for high dose targeted therapy. Br J Radiol.
2006;79(944):e53–e58.
31 Ciftci AO, Tany el FC, Senocak ME, et al. Pheochromocy toma in children. J Pediatr Surg.
2001;36(3):447–452.
32 De Krijger RR, Petri B-J, Van Nederveen FH, et al. Frequent genetic changes in childhood
pheochromocy tomas. Ann N Y Acad Sci. 2006;1073:166–176.
35 Neumann HPH, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsy ndromic
pheochromocy toma. N Engl J Med. 2002;346(19):1459–1466.
38 Ludwig AD, Feig DI, Brandt ML, et al. Recent advances in the diagnosis and treatment of
pheochromocy toma in children. Am J Surg. 2007;194(6):792–796; discussion 796–797.
41 Volkin D, Yerram N, Ahmed F, et al. Partial adrenalectomy minimizes the need for long-
term hormone replacement in pediatric patients with pheochromocy toma and von Hippel–
Lindau sy ndrome. J Pediatr Surg. 2012;47(11):2077–2082.
42 Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocy toma: effective
treatment with a combination of cy clophosphamide, vincristine, and dacarbazine. Ann Intern
Med. 1988;109(4):267–273.
43 Vogel J, Atanacio AS, Prodanov T, et al. External beam radiation therapy in treatment of
malignant pheochromocy toma and paraganglioma. Front Oncol. 2014;4:166.
45 van Hulsteijn LT, Niemeijer ND, Dekkers OM, et al. (131)I-MIBG therapy for malignant
paraganglioma and phaeochromocy toma: sy stematic review and meta-analy sis. Clin
Endocrinol (Oxf). 2014;80(4):487–501.
46 Loh KC, Fitzgerald PA, Matthay KK, et al. The treatment of malignant
pheochromocy toma with iodine-131 metaiodobenzy lguanidine (131I-MIBG): a
comprehensive review of 116 reported patients. J Endocrinol Invest. 1997;20(11):648–658.
47 Bomanji JB, Wong W, Gaze MN, et al. Treatment of neuroendocrine tumours in adults
with 131I-MIBG therapy. Clin Oncol (R Coll Radiol). 2003;15(4):193–198.
51 Collini P, Mattavelli F, Pellegrinelli A, et al. Papillary carcinoma of the thy roid gland of
childhood and adolescence: Morphologic subty pes, biologic behavior and prognosis: a
clinicopathologic study of 42 sporadic cases treated at a single institution during a 30-y ear
period. Am J Surg Pathol. 2006;30(11):1420–1426.
52 Jarzab B, Handkiewicz Junak D, Włoch J, et al. Multivariate analy sis of prognostic factors
for differentiated thy roid carcinoma in children. Eur J Nucl Med. 2000;27(7):833–841.
54 Alzahrani AS, Alkhafaji D, Tuli M, et al. Comparison of differentiated thy roid cancer in
children and adolescents (≤20 y ears) with y oung adults. Clin Endocrinol (Oxf). 2016;84:571–
577.
56 Mussa A, De Andrea M, Motta M, et al. Predictors of malignancy in children with thy roid
nodules. J Pediatr. 2015;167(4):886.e1–892.e1.
57 Anne S, Teot LA, Mandell DL. Fine needle aspiration biopsy : role in diagnosis of pediatric
head and neck masses. Int J Pediatr Otorhinolaryngol. 2008;72(10):1547–1553.
59 Dinauer CA, Breuer C, Rivkees SA. Differentiated thy roid cancer in children: diagnosis
and management. Curr Opin Oncol. 2008;20(1):59–65.
60 Francis GL, Waguespack SG, Bauer AJ, et al. Management guidelines for children with
thy roid nodules and differentiated thy roid cancer. Thyroid. 2015;25(7):716–759.
62 La Quaglia MP, Black T, Holcomb GW, et al. Differentiated thy roid cancer: clinical
characteristics, treatment, and outcome in patients under 21 y ears of age who present with
distant metastases—a report from the Surgical Discipline Committee of the Children’s Cancer
Group. J Pediatr Surg. 2000;35(6):955–959; discussion 960.
63 Kundel A, Thompson GB, Richards ML, et al. Pediatric endocrine surgery : a 20-y ear
experience at the May o Clinic. J Clin Endocrinol Metab. 2014;99(2):399–406.
64 Chow S-M, Law SCK, Mendenhall WM, et al. Differentiated thy roid carcinoma in
childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer.
2004;42(2):176–183.
66 Brown AP, Chen J, Hitchcock YJ, et al. The risk of second primary malignancies up to
three decades after the treatment of differentiated thy roid cancer. J Clin Endocrinol Metab.
2008;93(2):504–515.
67 Kim T-H, Yang D-S, Jung K-Y, et al. Value of external irradiation for locally advanced
papillary thy roid cancer. Int J Radiat Oncol Biol Phys. 2003;55(4):1006–1012.
69 Steliarova-Foucher E, Stiller CA, Pukkala E, et al. Thy roid cancer incidence and survival
among European children and adolescents (1978–1997): report from the Automated
childhood cancer information sy stem project. Eur J Cancer. 2006;42(13):2150–2169.
70 Sugino K, Nagahama M, Kitagawa W, et al. Papillary thy roid carcinoma in children and
adolescents: long-term follow-up and clinical characteristics. World J Surg. 2015;39(9):2259–
2265.
71 Gong J, Zhang R, Chen H. [Childhood thy roid carcinoma: an analy sis of 14 cases].
Zhonghua Zhong Liu Za Zhi. 2000;22(4):324–326.
72 Harness JK, Thompson NW, McLeod MK, et al. Differentiated thy roid carcinoma in
children and adolescents. World J Surg. 1992;16(4):547–553; discussion 553–554.
73 Samuel AM, Sharma SM. Differentiated thy roid carcinomas in children and adolescents.
Cancer. 1991;67(8):2186–2190.
74 Zimmerman D, Hay ID, Gough IR, et al. Papillary thy roid carcinoma in children and
adults: long-term follow-up of 1039 patients conservatively treated at one institution during
three decades. Surgery. 1988;104(6):1157–1166.
75 Ceccarelli C, Pacini F, Lippi F, et al. Thy roid cancer in children and adolescents. Surgery.
1988;104(6):1143–1148.
77 Giuffrida D, Scollo C, Pellegriti G, et al. Differentiated thy roid cancer in children and
adolescents. J Endocrinol Invest. 2002;25(1):18–24.
79 Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thy roid cancer after a first
tumour in childhood (the Childhood Cancer Survivor Study ): a nested case-control study.
Lancet (London, England). 2005;365(9476):2014–2023.
81 Brignardello E, Corrias A, Isolato G, et al. Ultrasound screening for thy roid carcinoma in
childhood cancer survivors: a case series. J Clin Endocrinol Metab. 2008;93(12):4840–4843.
82 Tuttle RM, Vaisman F, Tronko MD. Clinical presentation and clinical outcomes in
Chernoby l-related paediatric thy roid cancers: what do we know now? What can we expect in
the future? Clin Oncol (R Coll Radiol). 2011;23(4):268–275.
83 Pacini F, Vorontsova T, Demidchik EP, et al. Post-Chernoby l thy roid carcinoma in Belarus
children and adolescents: comparison with naturally occurring thy roid carcinoma in Italy and
France. J Clin Endocrinol Metab. 1997;82(11):3563–3569.
84 Akulevich NM, Saenko VA, Rogounovitch TI, et al. Poly morphisms of DNA damage
response genes in radiation-related and sporadic papillary thy roid carcinoma. Endocr Relat
Cancer. 2009;16(2):491–503.
87 Viola D, Romei C, Elisei R. Medullary thy roid carcinoma in children. Endocr Dev.
2014;26:202–213.
88 Berdelou A, Hartl D, Al Ghuzlan A, et al. [Medullary thy roid carcinoma in children]. Bull
Cancer. 2013;100(7–8):780–788.
89 Fialkowski EA, Moley JF. Current approaches to medullary thy roid carcinoma, sporadic
and familial. J Surg Oncol. 2006;94(8):737–747.
90 Fox E, Widemann BC, Chuk MK, et al. Vandetanib in children and adolescents with
multiple endocrine neoplasia ty pe 2B associated medullary thy roid carcinoma. Clin Cancer
Res. 2013;19(15):4239–4248.
92 McAfee WJ, Morris CG, Amdur RJ, et al. Definitive radiotherapy for juvenile
nasophary ngeal angiofibroma. Am J Clin Oncol. 2006;29(2):168–170.
93 Roger G, Tran Ba Huy P, Froehlich P, et al. Exclusively endoscopic removal of juvenile
nasophary ngeal angiofibroma: trends and limits. Arch Otolaryngol Head Neck Surg.
2002;128(8):928–935.
96 Tewfik TL, Tan AK, al Noury K, et al. Juvenile nasophary ngeal angiofibroma. J
Otolaryngol. 1999;28(3):145–151.
97 Barnés CM, Huang S, Kaipainen A, et al. Evidence by molecular profiling for a placental
origin of infantile hemangioma. Proc Natl Acad Sci U S A. 2005;102(52):19097–19102.
98 Vikkula M, Boon LM, Mulliken JB, et al. Molecular basis of vascular anomalies. Trends
Cardiovasc Med. 1998;8(7):281–292.
99 Say lam G, Yücel OT, Sungur A, et al. Proliferation, angiogenesis and hormonal markers in
juvenile nasophary ngeal angiofibroma. Int J Pediatr Otorhinolaryngol. 2006;70(2):227–234.
101 Robinson AC, Khoury GG, Ash DV, et al. Evaluation of response following irradiation of
juvenile angiofibromas. Br J Radiol. 1989;62(735):245–247.
102 Roche P-H, Paris J, Régis J, et al. Management of invasive juvenile nasophary ngeal
angiofibromas: the role of a multimodality approach. Neurosurgery. 2007;61(4):768–777;
discussion 777.
103 Lloy d G, Howard D, Lund VJ, et al. Imaging for juvenile angiofibroma. J Laryngol Otol.
2000;114(9):727–730.
104 Herman P, Lot G, Chapot R, et al. Long-term follow-up of juvenile nasophary ngeal
angiofibromas: analy sis of recurrences. Laryngoscope. 1999;109(1):140–147.
105 Chagnaud C, Petit P, Bartoli J, et al. Postoperative follow-up of juvenile nasophary ngeal
angiofibromas: assessment by CT scan and MR imaging. Eur Radiol. 1998;8(5):756–764.
106 Howard DJ, Lloy d G, Lund V. Recurrence and its avoidance in juvenile angiofibroma.
Laryngoscope. 2001;111(9):1509–1511.
107 McCombe A, Lund VJ, Howard DJ. Recurrence in juvenile angiofibroma. Rhinology.
1990;28(2):97–102.
108 Carrillo JF, Maldonado F, Albores O, et al. Juvenile nasophary ngeal angiofibroma: clinical
factors associated with recurrence, and proposal of a staging sy stem. J Surg Oncol.
2008;98(2):75–80.
109 Radkowski D, McGill T, Healy GB, et al. Angiofibroma. Changes in staging and
treatment. Arch Otolaryngol Head Neck Surg. 1996;122(2):122–129.
110 Yi Z, Fang Z, Lin G, et al. Nasophary ngeal angiofibroma: a concise classification sy stem
and appropriate treatment options. Am J Otolaryngol. 2013;34(2):133–141.
111 Leong SC. A sy stematic review of surgical outcomes for advanced juvenile
nasophary ngeal angiofibroma with intracranial involvement. Laryngoscope.
2013;123(5):1125–1131.
112 Ward PH, Thompson R, Calcaterra T, et al. Juvenile angiofibroma: a more rational
therapeutic approach based upon clinical and experimental evidence. Laryngoscope.
1974;84(12):2181–2194.
113 Álvarez FL, Suárez V, Suárez C, et al. Multimodality approach for advanced-stage
juvenile nasophary ngeal angiofibromas. Head Neck. 2013;35(2):209–213.
114 Gates GA, Rice DH, Koopmann CF, et al. Flutamide-induced regression of angiofibroma.
Laryngoscope. 1992;102(6):641–644.
115 Pry or SG, Moore EJ, Kasperbauer JL. Endoscopic versus traditional approaches for
excision of juvenile nasophary ngeal angiofibroma. Laryngoscope. 2005;115(7):1201–1207.
116 Garofalo P, Pia F, Policarpo M, et al. Juvenile nasophary ngeal angiofibroma: comparison
between endoscopic and open operative approaches. J Craniofac Surg. 2015;26(3):918–821.
117 Khoueir N, Nicolas N, Rohay em Z, et al. Exclusive endoscopic resection of juvenile
nasophary ngeal angiofibroma: a sy stematic review of the literature. Otolaryngol Head Neck
Surg. 2014;150(3):350–358.
118 Ungkanont K, By ers RM, Weber RS, et al. Juvenile nasophary ngeal angiofibroma: an
update of therapeutic management. Head Neck. 1996;18(1):60–66.
119 Goepfert H, Cangir A, Lee YY. Chemotherapy for aggressive juvenile nasophary ngeal
angiofibroma. Arch Otolaryngol. 1985;111(5):285–289.
121 Thakar A, Gupta G, Bhalla AS, et al. Adjuvant therapy with flutamide for presurgical
volume reduction in juvenile nasophary ngeal angiofibroma. Head Neck. 2011;33(12):1747–
1753.
122 Reddy KA, Mendenhall WM, Amdur RJ, et al. Long-term results of radiation therapy for
juvenile nasophary ngeal angiofibroma. Am J Otolaryngol.2001;22(3):172–175.
123 Lee JT, Chen P, Safa A, et al. The role of radiation in the treatment of advanced juvenile
angiofibroma. Laryngoscope. 2002;112(7 Pt 1):1213–1220.
125 Amdur RJ, Yeung AR, Fitzgerald BM, et al. Radiotherapy for juvenile nasophary ngeal
angiofibroma. Pract Radiat Oncol. 2011;1(4):271-8.
126 Economou TS, Abemay or E, Ward PH. Juvenile nasophary ngeal angiofibroma: an
update of the UCLA experience, 1960–1985. Laryngoscope. 1988;98(2):170–175.
127 Gullane PJ, Davidson J, O’Dwy er T, et al. Juvenile angiofibroma: a review of the
literature and a case series report. Laryngoscope. 1992;102(8):928–933.
128 Cummings BJ. Relative risk factors in the treatment of juvenile nasophary ngeal
angiofibroma. Head Neck Surg. 1980;3(1):21–26.
129 Chakraborty S, Ghoshal S, Patil VM, et al. Conformal radiotherapy in the treatment of
advanced juvenile nasophary ngeal angiofibroma with intracranial extension: an institutional
experience. Int J Radiat Oncol Biol Phys. 2011;80(5):1398–1404.
130 Kuppersmith RB, Teh BS, Donovan DT, et al. The use of intensity modulated
radiotherapy for the treatment of extensive and recurrent juvenile angiofibroma. Int J
Pediatr Otorhinolaryngol. 2000;52(3):261–268.
131 Wolden SL, Steinherz PG, Kraus DH, et al. Improved long-term survival with combined
modality therapy for pediatric nasophary nx cancer. Int J Radiat Oncol Biol Phys.
2000;46(4):859–864.
132 Uzel O, Yörük SO, Sahinler I, et al. Nasophary ngeal carcinoma in childhood: long-term
results of 32 patients. Radiother Oncol. 2001;58(2):137–141.
133 Desandes E, Clavel J, Berger C, et al. Cancer incidence among children in France, 1990–
1999. Pediatr Blood Cancer. 2004;43(7):749–757.
136 Vokes EE, Liebowitz DN, Weichselbaum RR. Nasophary ngeal carcinoma. Lancet
(London, England). 1997;350(9084):1087–1091.
137 Cvitkovic E, Bachouchi M, Armand JP. Nasophary ngeal carcinoma: biology, natural
history, and therapeutic implications. Hematol Oncol Clin North Am. 1991;5(4):821–838.
138 Pua KC, Khoo ASB, Yap YY, et al. Nasophary ngeal Carcinoma Database. Med J
Malaysia. 2008;63(suppl C):59–62.
140 Bar-Sela G, Kuten A, Minkov I, et al. Prevalence and relevance of EBV latency in
nasophary ngeal carcinoma in Israel. J Clin Pathol. 2004;57(3):290–293.
141 Vogl T, Dresel S, Bilaniuk LT, et al. Tumors of the nasophary nx and adjacent areas: MR
imaging with Gd-DTPA. AJNR Am J Neuroradiol.1990;11(1):187–194.
142 Yabuuchi H, Fukuy a T, Muray ama S, et al. CT and MR features of nasophary ngeal
carcinoma in children and y oung adults. Clin Radiol. 2002;57(3):205–210.
143 Liu F-Y, Lin C-Y, Chang JT, et al. 18F-FDG PET can replace conventional work-up in
primary M staging of nonkeratinizing nasophary ngeal carcinoma. J Nucl Med.
2007;48(10):1614–1619.
144 Cheuk DKL, Sabin ND, Hossain M, et al. PET/CT for staging and follow-up of pediatric
nasophary ngeal carcinoma. Eur J Nucl Med Mol Imaging. 2012;39(7):1097–1106.
145 Sanguineti G, Bossi P, Pou A, et al. Timing of chemoradiotherapy and patient selection
for locally advanced nasophary ngeal carcinoma. Clin Oncol (R Coll Radiol). 2003;15(8):451–
460.
146 Laskar S, Sanghavi V, Muckaden MA, et al. Nasophary ngeal carcinoma in children: ten
y ears’ experience at the Tata Memorial Hospital, Mumbai. Int J Radiat Oncol Biol Phys.
2004;58(1):189–195.
147 Fleming ID, Cooper JS, Henson DE, eds. AJCC Cancer Staging Manual. 5th ed.
Philadelphia, PA: Lippincott-Raven; 1997.
148 Ho JH. Stage classification of nasophary ngeal carcinoma: a review. IARC Sci Publ. 1978;
(20):99–113.
149 Chua DTT, Sham JST, Kwong DLW, et al. Treatment outcome after radiotherapy alone
for patients with Stage I-II nasophary ngeal carcinoma. Cancer. 2003;98(1):74–80.
150 Chua DT, Sham JS, Choy D, et al. Preliminary report of the Asian-Oceanian Clinical
Oncology Association randomized trial comparing cisplatin and epirubicin followed by
radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally
advanced nasophary ngeal carcinom. Cancer. 1998;83(11):2270–2283.
151 Ma J, Mai HQ, Hong MH, et al. Results of a prospective randomized trial comparing
neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with
locoregionally advanced nasophary ngeal carcinoma. J Clin Oncol. 2001;19(5):1350–1307.
152 Harey ama M, Sakata K, Shirato H, et al. A prospective, randomized trial comparing
neoadjuvant chemotherapy with radiotherapy alone in patients with advanced
nasophary ngeal carcinoma. Cancer. 2002;94(8):2217–2223.
153 Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advanced nasophary ngeal
carcinoma: an individual patient data meta-analy sis of eight randomized trials and 1753
patients. Int J Radiat Oncol Biol Phys. 2006;64(1):47–56.
154 Guigay J, Temam S, Bourhis J, et al. Nasophary ngeal carcinoma and therapeutic
management: the place of chemotherapy. Ann Oncol. 2006;17(suppl 1):x304–x307.
155 Venkitaraman R, Ramanan SG, Sagar TG. Nasophary ngeal cancer of childhood and
adolescence: a single institution experience. Pediatr Hematol Oncol.2007;24(7):493–502.
157 Ozy ar E, Selek U, Laskar S, et al. Treatment results of 165 pediatric patients with non-
metastatic nasophary ngeal carcinoma: a Rare Cancer Network study. Radiother Oncol.
2006;81(1):39–46.
158 Chan ATC, Ma BBY, Lo YMD, et al. Phase II study of neoadjuvant carboplatin and
paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally
advanced nasophary ngeal carcinoma: therapeutic monitoring with plasma Epstein–Barr virus
DNA. J Clin Oncol. 2004;22(15):3053–3060.
159 Ma BBY, Chan ATC. Recent perspectives in the role of chemotherapy in the
management of advanced nasophary ngeal carcinoma. Cancer. 2005;103(1):22–31.
160 Rischin D, Corry J, Smith J, et al. Excellent disease control and survival in patients with
advanced nasophary ngeal cancer treated with chemoradiation. J Clin Oncol.
2002;20(7):1845–1852.
161 Ingersoll L, Woo SY, Donaldson S, et al. Nasophary ngeal carcinoma in the y oung: a
combined M.D. Anderson and Stanford experience. Int J Radiat Oncol Biol Phys.
1990;19(4):881–887.
162 Mertens R, Granzen B, Lassay L, et al. Nasophary ngeal carcinoma in childhood and
adolescence: concept and preliminary results of the cooperative GPOH study NPC-91.
Gesellschaft für Pädiatrische Onkologie und Hämatologie. Cancer. 1997;80(5):951–959.
163 Berry MP, Smith CR, Brown TC, et al. Nasophary ngeal carcinoma in the y oung. Int J
Radiat Oncol Biol Phys. 1980;6(4):415–421.
164 Orbach D, Brisse H, Helfre S, et al. Radiation and chemotherapy combination for
nasophary ngeal carcinoma in children: radiotherapy dose adaptation after chemotherapy
response to minimize late effects. Pediatr Blood Cancer. 2008;50(4):849–853.
165 Liu T. Issues in the management of nasophary ngeal carcinoma. Crit Rev Oncol Hematol.
1999;31(1):55–69.
166 Itami J, Anzai Y, Nemoto K, et al. Prognostic factors for local control in nasophary ngeal
cancer (NPC): analy sis by multivariate proportional hazard models. Radiother Oncol.
1991;21(4):233–239.
167 Sham J, Choy D, Kwong PW, et al. Radiotherapy for nasophary ngeal carcinoma:
shielding the pituitary may improve therapeutic ratio. Int J Radiat Oncol Biol Phys.
1994;29(4):699–704.
168 O’Meara WP, Lee N. Advances in nasophary ngeal carcinoma. Curr Opin Oncol.
2005;17(3):225–230.
169 Fang F-M, Tsai W-L, Chen H-C, et al. Intensity -modulated or conformal radiotherapy
improves the quality of life of patients with nasophary ngeal carcinoma: comparisons of four
radiotherapy techniques. Cancer. 2007;109(2):313–321.
170 Lee N, Xia P, Quivey JM, et al. Intensity -modulated radiotherapy in the treatment of
nasophary ngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys.
2002;53(1):12–22.
173 Hitchcock YJ, Tward JD, Szabo A, et al. Relative contributions of radiation and cisplatin-
based chemotherapy to sensorineural hearing loss in head-and-neck cancer patients. Int J
Radiat Oncol Biol Phys. 2009;73(3):779–788.
174 Guo Q, Cui X, Lin S, et al. Locoregionally advanced nasophary ngeal carcinoma in
childhood and adolescence: analy sis of 95 patients treated with combined chemotherapy and
intensity -modulated radiotherapy. Head Neck. 2015;1–8.
175 Ipekci SH, Cakir M, Kiy ici A, et al. Radiotherapy -induced hy popituitarism in
nasophary ngeal carcinoma: the tip of an iceberg. Exp Clin Endocrinol Diabetes.
2015;123(7):411–418.
176 Teo PM, Leung SF, Chan AT, et al. Final report of a randomized trial on altered-
fractionated radiotherapy in nasophary ngeal carcinoma prematurely terminated by
significant increase in neurologic complications. Int J Radiat Oncol Biol Phys.
2000;48(5):1311–1322.
179 Jen YM, Hsu WL, Chen CY, et al. Different risks of sy mptomatic brain necrosis in NPC
patients treated with different altered fractionated radiotherapy techniques. Int J Radiat Oncol
Biol Phys. 2001;51(2):344–348.
180 Arush MW, Stein ME, Rosenblatt E, et al. Advanced nasophary ngeal carcinoma in the
y oung: the Northern Israel Oncology Center experience, 1973–1991. Pediatr Hematol Oncol.
1995;12(3):271–276.
181 Werner-Wasik M, Winkler P, Uri A, et al. Nasophary ngeal carcinoma in children. Med
Pediatr Oncol. 1996;26(5):352–358.
182 Strojan P, Benedik MD, Kragelj B, et al. Combined radiation and chemotherapy for
advanced undifferentiated nasophary ngeal carcinoma in children. Med Pediatr Oncol.
1997;28(5):366–369.
183 Sahraoui S, Acharki A, Benider A, et al. Nasophary ngeal carcinoma in children under 15
y ears of age: a retrospective review of 65 patients. Ann Oncol. 1999;10(12):1499–1502.
184 Zubizarreta PA, D’Antonio G, Raslawski E, et al. Nasophary ngeal carcinoma in childhood
and adolescence: a single-institution experience with combined therapy. Cancer.
2000;89(3):690–695.
185 Wormald R, Lennon P, O’Dwy er TP. Ectopic olfactory neuroblastoma: report of four
cases and a review of the literature. Eur Arch Otorhinolaryngol. 2011;268(4):555–560.
186 Benoit MM, Bhattachary y a N, Faquin W, et al. Cancer of the nasal cavity in the pediatric
population. Pediatrics. 2008;121(1):e141–e145.
187 Silva EG, Butler JJ, Mackay B, et al. Neuroblastomas and neuroendocrine carcinomas of
the nasal cavity : a proposed new classification. Cancer. 1982;50(11):2388–2405.
188 Bellizzi AM, Bourne TD, Mills SE, et al. The cy tologic features of sinonasal
undifferentiated carcinoma and olfactory neuroblastoma. Am J Clin Pathol. 2008;129(3):367–
376.
190 Hy ams VJ, Batsakis JG, Micheals L. Tumors of the upper respiratory tract and ear. Atlas
Tumor Pathol. 1998;99:240–248.
191 Tajudeen BA, Arshi A, Suh JD, et al. Importance of tumor grade in
esthesioneuroblastoma survival: a population-based analy sis. JAMA Otolaryngol Head Neck
Surg. 2014;140(12):1124–1129.
193 Koike K, Jay G, Hartley JW, et al. Activation of retrovirus in transgenic mice: association
with development of olfactory neuroblastoma. J Virol. 1990;64(8):3988–3991.
194 Sorensen PH, Wu JK, Berean KW, et al. Olfactory neuroblastoma is a peripheral
primitive neuroectodermal tumor related to Ewing sarcoma. Proc Natl Acad Sci U S A.
1996;93(3):1038–1043.
195 Resto VA, Eisele DW, Forastiere A, et al. Esthesioneuroblastoma: the Johns Hopkins
experience. Head Neck. 2000;22(6):550–558.
196 Ebersold MJ, Olsen KD, Foote RL. Esthesioneublastoma. In: Kay e AH, Laws ER, eds.
Brain Tumors: An Encyclopedic Approach. New York, NY: Churchill Livingstone; 1995:825–
838.
199 Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma: a clinical analy sis of 17
cases. Cancer. 1976;37(3):1571–1576.
201 Foote RL, Morita A, Ebersold MJ, et al. Esthesioneuroblastoma: the role of adjuvant
radiation therapy. Int J Radiat Oncol Biol Phys. 1993;27(4):835–842.
203 Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analy sis and
review. Lancet Oncol. 2001;2(11):683–690.
204 Eich HT, Hero B, Staar S, et al. Multimodality therapy including radiotherapy and
chemotherapy improves event-free survival in stage C esthesioneuroblastoma. Strahlenther
Onkol. 2003;179(4):233–240.
205 Oskouian RJ, Jane JA, Dumont AS. Esthesioneuroblastoma: clinical presentation,
radiological, and pathological features, treatment, review of the literature, and the University
of Virginia experience. Neurosurg Focus. 2002;12(5):e4.
206 Gil Z, Patel SG, Cantu G, et al. Outcome of craniofacial surgery in children and
adolescents with malignant tumors involving the skull base: an international collaborative
study. Head Neck. 2009;31(3):308–317.
207 Eden BV, Debo RF, Larner JM, et al. Esthesioneuroblastoma. Long-term outcome and
patterns of failure—the University of Virginia experience. Cancer. 1994;73(10):2556–2562.
208 Sny derman CH, Kassam AB. Endoscopic techniques for pathology of the anterior cranial
fossa and ventral skull base. J Am Coll Surg. 2006;202(3):563.
209 Batra PS, Citardi MJ, Worley S, et al. Resection of anterior skull base tumors: comparison
of combined traditional and endoscopic techniques. Am J Rhinol. 2005;19(5):521–528.
210 Devaiah AK, Andreoli MT. Treatment of esthesioneuroblastoma: a 16-y ear meta-
analy sis of 361 patients. Laryngoscope. 2009;119(7):1412–1416.
211 Ow TJ, Hanna EY, Roberts DB, et al. Optimization of long-term outcomes for patients
with esthesioneuroblastoma. Head Neck. 2014;36(4):524–530.
213 Polin RS, Sheehan JP, Chenelle AG, et al. The role of preoperative adjuvant treatment in
the management of esthesioneuroblastoma: the University of Virginia experience.
Neurosurgery. 1998;42(5):1029–1037.
215 Ganly I, Patel SG, Singh B, et al. Craniofacial resection for malignant paranasal sinus
tumors: report of an International Collaborative Study. Head Neck. 2005;27(7):575–584.
218 Benfari G, Fusconi M, Ciofalo A, et al. Radiotherapy alone for local tumour control in
esthesioneuroblastoma. Acta Otorhinolaryngol Ital. 2008;28(6):292–297.
219 Noh OK, Lee S, Yoon SM, et al. Radiotherapy for esthesioneuroblastoma: is elective
nodal irradiation warranted in the multimodality treatment approach? Int J Radiat Oncol Biol
Phys. 2011;79(2):443–449.
220 Stieber VW, Munley M. Central nervous sy stem tumors. In: Mundt AJ, Roeske JC, eds.
Intensity-Modulated Radiation Therapy (IMRT):A Clinical Perspective. 1st ed. Ontario,
Canada: BC Decker Inc; 2005:231–263.
221 Zabel A, Thilmann C, Zuna I, et al. Comparison of forward planned conformal radiation
therapy and inverse planned intensity modulated radiation therapy for
esthesioneuroblastoma. Br J Radiol. 2002;75(892):356–361.
222 Suit H, Urie M. Proton beams in radiation therapy. J Natl Cancer Inst. 1992;84(3):155–
164.
224 Unger F, Haselsberger K, Walch C, et al. Combined endoscopic surgery and radiosurgery
as treatment modality for olfactory neuroblastoma (esthesioneuroblastoma). Acta Neurochir
(Wien). 2005;147(6):595–601; discussion 601–602.
225 Eich HT, Müller R-P, Micke O, et al. Esthesioneuroblastoma in childhood and
adolescence. Better prognosis with multimodal treatment? Strahlenther Onkol.
2005;181(6):378–384.
226 Fitzek MM, Thornton AF, Varvares M, et al. Neuroendocrine tumors of the sinonasal tract.
Results of a prospective study incorporating chemotherapy, surgery, and combined proton-
photon radiotherapy. Cancer. 2002;94(10):2623–2634.
227 Sheehan JM, Sheehan JP, Jane JA, et al. Chemotherapy for esthesioneuroblastomas.
Neurosurg Clin N Am. 2000;11(4):693–701.
228 McElroy EA, Buckner JC, Lewis JE. Chemotherapy for advanced
esthesioneuroblastoma: the May o Clinic experience. Neurosurgery. 1998;42(5):1023–1027;
discussion 1027–1028.
230 Buehrlen M, Zwaan CM, Granzen B, et al. Multimodal treatment, including interferon
beta, of nasophary ngeal carcinoma in children and y oung adults: preliminary results from
the prospective, multicenter study NPC-2003-GPOH/DCOG. Cancer. 2012;118(19):4892–
4900.
232 Elkon D, Hightower SI, Lim ML, et al. Esthesioneuroblastoma. Cancer. 1979;44(3):1087–
1094.
234 O’Connor TA, McLean P, Juillard GJ, et al. Olfactory neuroblastoma. Cancer.
1989;63(12):2426–2428.
236 Bachar G, Goldstein DP, Shah M, et al. Esthesioneuroblastoma: the Princess Margaret
Hospital experience. Head Neck. 2008;30(12):1607–1614.
237 Gosepath J, Spix C, Talebloo B, et al. Incidence of childhood cancer of the head and neck
in Germany. Ann Oncol. 2007;18(10):1716–1721.
238 Schwartz I, Hughes C, Brigger MT. Pediatric head and neck malignancies: incidence and
trends, 1973–2010. Otolaryngol Head Neck Surg. 2015;152(6):1127–1132.
239 Cesmebasi A, Gabriel A, Niku D, et al. Pediatric head and neck tumors: an intra-
demographic analy sis using the SEER* database. Med Sci Monit. 2014;20:2536–2542.
240 Bentz BG, Hughes CA, Lüdemann JP, et al. Masses of the salivary gland region in
children. Arch Otolaryngol Head Neck Surg. 2000;126(12):1435–1439.
241 Callender DL, Frankenthaler RA, Luna MA, et al. Salivary gland neoplasms in children.
Arch Otolaryngol Head Neck Surg. 1992;118(5):472–476.
242 Jaques DA, Krolls SO, Chambers RG. Parotid tumors in children. Am J Surg.
1976;132(4):469–471.
243 Krolls SO, Trodahl JN, Boy ers RC. Salivary gland lesions in children. A survey of 430
cases. Cancer. 1972;30(2):459–469.
244 Kaste SC, Hedlund G, Pratt CB. Malignant parotid tumors in patients previously treated
for childhood cancer: clinical and imaging findings in eight cases. Am J Roentgenol.
1994;162(3):655–659.
246 Klijanienko J, Vielh P, Batsakis JD, et al. Salivary gland tumours. Monogr Clin Cytol.
2000;15:III–XII, 1–138.
248 Rutigliano DN, Mey ers P, Ghossein RA, et al. Mucoepidermoid carcinoma as a
secondary malignancy in pediatric sarcoma. J Pediatr Surg. 2007;42(7):E9–E13.
249 Henze M, Hittel JP. [Mucoepidermoid carcinoma of the salivary glands after high dosage
radiotherapy ]. Laryngorhinootologie. 2001;80(5):253–256.
250 Védrine PO, Coffinet L, Temam S, et al. Mucoepidermoid carcinoma of salivary glands
in the pediatric age group: 18 clinical cases, including 11 second malignant neoplasms. Head
Neck. 2006;28(9):827–833.
251 Thorvaldsson SE, Beahrs OH, Woolner LB, et al. Mucoepidermoid tumors of the major
salivary glands. Am J Surg. 1970;120(4):432–438.
253 Spiro RH. Changing trends in the management of salivary tumors. Semin Surg Oncol.
1995;11(3):240–245.
254 Armstrong JG, Harrison LB, Thaler HT, et al. The indications for elective treatment of
the neck in cancer of the major salivary glands. Cancer. 1992;69(3):615–619.
255 Thariat J, Vedrine P-O, Temam S, et al. The role of radiation therapy in pediatric
mucoepidermoid carcinomas of the salivary glands. J Pediatr. 2013;162(4):839–843.
256 Ellington CL, Goodman M, Kono SA, et al. Adenoid cy stic carcinoma of the head and
neck: incidence and survival trends based on 1973–2007 surveillance, epidemiology, and end
results data. Cancer. 2012;118(18):4444–4451.
257 Elluru RG, Friess MR, Richter GT, et al. Multicenter evaluation of the effectiveness of
sy stemic propranolol in the treatment of airway hemangiomas. Otolaryngol Head Neck Surg.
2015;153(3):452–460.
258 Raol N, Metry D, Edmonds J, et al. Propranolol for the treatment of subglottic
hemangiomas. Int J Pediatr Otorhinolaryngol. 2011;75(12):1510–1514.
259 Chatrath P, Black M, Jani P, et al. A review of the current management of infantile
subglottic haemangioma, including a comparison of CO(2) laser therapy versus
tracheostomy. Int J Pediatr Otorhinolaryngol. 2002;64(2):143–157.
260 Benjamin B. Treatment of infantile subglottic hemangioma with radioactive gold grain.
Ann Otol Rhinol Laryngol. 1978;87(1 Pt 1):18–21.
261 Munitiz V, Parrilla P, Ortiz A, et al. High risk of malignancy in familial Barrett’s
esophagus: presentation of one family. J Clin Gastroenterol. 2008;42(7):806–809.
262 DuVall GA, Walden DT. Adenocarcinoma of the esophagus complicating Cornelia de
Lange sy ndrome. J Clin Gastroenterol. 1996;22(2):131–133.
263 Shahi UP, Sudarsan, Dattagupta S, et al. Carcinoma oesophagus in a 14 y ear old child:
report of a case and review of literature. Trop Gastroenterol. 1989;10(4):225–228.
264 Perch SJ, Soffen EM, Whittington R, et al. Esophageal sarcomas. J Surg Oncol.
1991;48(3):194–198.
265 Bourque MD, Spigland N, Bensoussan AL, et al. Esophageal leiomy oma in children: two
case reports and review of the literature. J Pediatr Surg. 1989;24(10):1103–1107.
266 Vade A, Nolan J. Posterior mediastinal teratoma involving the esophagus. Gastrointest
Radiol. 1989;14(2):106–108.
267 Wright JR, Ky riakos M, DeSchry ver-Kecskemeti K. Malignant fibrous histiocy toma of
the stomach. A report and review of malignant fibrohistiocy tic tumors of the alimentary tract.
Arch Pathol Lab Med. 1988;112(3):251–258.
268 Jaeger HJ, Schmitz-Stolbrink A, Albrecht M, et al. Gastric leiomy osarcoma in a child.
Eur J Radiol. 1996;23(2):111–114.
269 Siegel S, Hay s D, Romansky S, et al. Carcinoma of the stomach in childhood. Cancer.
1976;38(4):1781–1784.
271 Subbiah V, Varadhachary G, Herzog CE, et al. Gastric adenocarcinoma in children and
adolescents. Pediatr Blood Cancer. 2011;57(3):524–527.
273 Cam S. Risk of gastric cancer in children with Helicobacter pylori infection. Asian Pac J
Cancer Prev. 2014;15(22):9905–9908.
274 Durham MM, Gow KW, Shehata BM, et al. Gastrointestinal stromal tumors arising from
the stomach: a report of three children. J Pediatr Surg. 2004;39(10):1495–1409.
276 Park J, Rubinas TC, Fordham LA, et al. Multifocal gastrointestinal stromal tumor (GIST)
of the stomach in an 11-y ear-old girl. Pediatr Radiol. 2006;36(11):1212–1214.
277 Li P, Wei J, West A, et al. Epithelioid gastrointestinal stromal tumor of the stomach with
liver metastases in a 12-y ear-old girl: aspiration cy tology and molecular study. Pediatr Dev
Pathol. 2002;5(4):386–394.
278 Dishop M, Kuruvilla S. Primary and metastatic lung tumors in the pediatric population: a
review and 25-y ear experience at a large children’s hospital. Arch Pathol Lab Med.
2008;132(7):1079–1103.
279 Mahour GH, Isaacs H, Chang L. Primary malignant tumors of the stomach in children. J
Pediatr Surg. 1980;15(5):603–608.
281 Hancock B, Lorenzo M Di. Childhood primary pulmonary neoplasms. J Pediatr Surg.
1993;28(9):1133–1136.
285 Priest JR, Watterson J, Strong L, et al. Pleuropulmonary blastoma: a marker for familial
disease. J Pediatr. 1996;128(2):220–224.
286 Messinger YH, Stewart DR, Priest JR, et al. Pleuropulmonary blastoma: a report on 350
central pathology -confirmed pleuropulmonary blastoma cases by the International
Pleuropulmonary Blastoma Registry. Cancer. 2015;121(2):276–285.
287 Lee H, Goo J, Kim K, et al. Pulmonary blastoma: radiologic findings in five patients. Clin
Imaging. 2004;28(2):113–118.
289 Mut Pons R, Muro Velilla MD, Sangüesa Nebot C, et al. Pleuropulmonary blastoma in
children: imaging findings and clinical patterns. Radiologia. 2008;50(6):489–494.
290 Priest JR, McDermott MB, Bhatia S, et al. Pleuropulmonary blastoma: a clinicopathologic
study of 50 cases. Cancer. 1997;80(1):147–161.
291 Priest J, Magnuson J. Cerebral metastasis and other central nervous sy stem complications
of pleuropulmonary blastoma. Pediatr Blood Cancer. 2007;49(3):266–273.
292 Granata C, Gambini C, Carlini C, et al. Pleuropulmonary blastoma. Eur J Pediatr Surg.
11(4),2001,271–273.
294 Senac MO Jr, Wood BP, Isaacs H, et al. Pulmonary blastoma: a rare childhood
malignancy. Radiology. 1991;179(3):743–746.
295 Ozkay nak MF, Ortega JA, Laug W, et al. Role of chemotherapy in pediatric pulmonary
blastoma. Med Pediatr Oncol. 1990;18(1):53–56.
296 Baraniy a J, Desai S, Kane S, et al. Pleuropulmonary blastoma. Med Pediatr Oncol.
1999;32(1):52–56.
301 Madafferi S, Catania VD, Accinni A, et al. Endobronchial tumor in children: unusual
finding in recurrent pneumonia, report of three cases. World J Clin Pediatr. 2015;4(2):30–34.
302 Yu Y, Song Z, Chen Z, et al. Chinese pediatric and adolescent primary tracheobronchial
tumors: a hospital-based study. Pediatr Surg Int. 2011;27(7):721–726.
303 Shorter NA, Glick RD, Klimstra DS, et al. Malignant pancreatic tumors in childhood and
adolescence: the memorial sloan-kettering experience, 1967 to present. J Pediatr Surg.
2002;37(6):887–892.
304 Perez E, Gutierrez J, Koniaris L, et al. Malignant pancreatic tumors: incidence and
outcome in 58 pediatric patients. J Pediatr Surg. 2009;44(1):197–203.
305 Nasher O, Hall NJ, Sebire NJ, et al. Pancreatic tumours in children: diagnosis, treatment
and outcome. Pediatr Surg Int. 2015;31(9):831–835.
306 Dall’igna P, Cecchetto G, Bisogno G, et al. Pancreatic tumors in children and adolescents:
the Italian TREP project experience. Pediatr Blood Cancer. 2010;54(5):675–680.
307 Murakami T, Ueki K, Kawakami H, et al. Pancreatoblastoma: case report and review of
treatment in the literature. Med Pediatr Oncol. 1996;27(3):193–197.
312 Chung EM, Travis MD, Conran RM. Pancreatic tumors in children: radiologic-pathologic
correlation. Radiographics. 2006;26(4):1211–1238.
314 Xu C, Zhong L, Wang Y, et al. Clinical analy sis of childhood pancreatoblastoma arising
from the tail of the pancreas. J Pediatr Hematol Oncol. 2012;34(5):e177–e181.
315 Bien E, Godzinski J, Dall’igna P, et al. Pancreatoblastoma: a report from the European
cooperative study group for paediatric rare tumours (EXPeRT). Eur J Cancer.
2011;47(15):2347–2352.
316 de Bree E, Askoxy lakis J, Giannikaki E, et al. Secretory carcinoma of the male breast.
Ann Surg Oncol. 2002;9(7):663–667.
317 Shannon C, Smith IE. Breast cancer in adolescents and y oung women. Eur J Cancer.
2003;39(18):2632–2642.
318 Gutierrez JC, Housri N, Koniaris LG, et al. Malignant breast cancer in children: a review
of 75 patients. J Surg Res. 2008;147(2):182–188.
319 Chung EM, Cube R, Hall GJ, et al. From the archives of the AFIP: breast masses in
children and adolescents: radiologic-pathologic correlation. Radiographics. 2009;29(3):907–
931.
320 Rogers DA, Lobe TE, Rao BN, et al. Breast malignancy in children. J Pediatr Surg.
1994;29(1):48–51.
321 Liu W, Tang Y, Gao L, et al. Nasophary ngeal carcinoma in children and adolescents - a
single institution experience of 158 patients. Radiat Oncol. 2014;9(1):274.
322 Eskelinen M, Vainio J, Tuominen L, et al. Carcinoma of the breast in children. Eur J
Pediatr Surg. 2008;45(1):52–55.
323 Templeman C, Hertweck SP. Breast disorders in the pediatric and adolescent patient.
Obstet Gynecol Clin North Am. 2000;27(1):19–34.
324 Krausz T, Jenkins D, Grontoft O, et al. Secretory carcinoma of the breast in adults:
emphasis on late recurrence and metastasis. Histopathology. 1989;14(1):25–36.
325 Richard G, Hawk JC, Baker AS, et al. Multicentric adult secretory breast carcinoma:
DNA flow cy tometric findings, prognostic features, and review of the world literature. J Surg
Oncol. 1990;44(4):238–244.
326 Bond SJ, Buchino JJ, Nagaraj HS, et al. Sentinel ly mph node biopsy in juvenile secretory
carcinoma. J Pediatr Surg. 2004;39(1):120–121.
327 Kasper ME, Parsons JT, Mancuso AA, et al. Radiation therapy for juvenile angiofibroma:
evaluation by CT and MRI, analy sis of tumor regression, and selection of patients. Int J
Radiat Oncol Biol Phys. 1993;25(4):689–694.
328 Murphy JJ, Morzaria S, Gow KW, et al. Breast cancer in a 6-y ear-old child. J Pediatr
Surg. 2000;35(5):765–767.
1 Langerhans P. Uber die nerven der menschlichen haut. Arch Pathol Anat. 1868;44:325–327.
3 Egeler RM, Zantinga AR, Coppes MJ. Paul Langerhans Jr. (1847–1888): a short life, y et two
epony mic legacies. Med Pediatr Oncol. 1994;22:129–132.
4 Egeler RM. The Langerhans cell histiocy tosis X files revealed. Br J Hematol. 2002;116:3–9.
7 Lieberman PH, Jones CR, Dargeon HWK, et al. A reappraisal of eosinophilic granuloma of
bone, Hand–Schuller–Christian sy ndrome and Letterer–Siwe sy ndrome. Medicine.
1969;48:375–400.
8 Otani E, Ehrlich J. Solitary eosinophilic granuloma of bone simulating primary neoplasm.
Am J Pathol. 1940;16:479–490.
10 Banchereau J. The long arm of the immune sy stem. Sci Am. 2002;287:52–59.
11 Mahmoud HH, Wang WC, Murphy SB. Cy closporine therapy for advanced Langerhans
cell histiocy tosis. Blood. 1991;77:721–725.
13 Hurwitz CA, Faquin WC. A 15-y ear-old boy with a retro-orbital mass and impaired vision.
N Engl J Med. 2002;146:513–520.
14 Pinkkus GS, Lones MA, Matsumara F, et al. Langerhans cell histiocy tosis:
immunohistochemical expression of fascin, a dendritic cell marker. Am J Clin Pathol.
2002;118:335–343.
16 Castleman B, McNeely BU. Case records of the Massachusetts General Hospital, case 17-
1970. N Engl J Med. 1970;282:917–925.
17 Velez-Yanguas MC, Warrier RP. Langerhans’ cell histiocy tosis. Orthop Clin North Am.
1996;27:615–623.
18 Willman CL, Busque L, Griffith BB, et al. Langerhans cell histiocy tosis (histiocy tosis X): a
clonal proliferative disease. N Engl J Med. 1994;331:154–160.
19 Cotter FE, Pritchard J. Clonality in Langerhans cell histiocy tosis. BMJ. 1995;310:74–75.
21 Egeler RM, Nesbit ME. Langerhans cell histiocy tosis and other disorders of monocy te–
histiocy te lineage. Crit Rev Oncol Hematol. 1995;18:9–35.
22 French Langerhans’ Cell Histiocy tosis Study Group. A multicentre retrospective survey of
Langerhans’ cell histiocy tosis. 348 cases observed between 1983 and 1993. Arch Dis Child.
1996;75:17–24.
23 Raney RB Jr, D’Angio GJ. Langerhans’ cell histiocy tosis (histiocy tosis X): experience at
the Children’s Hospital of Philadelphia, 1970–1984. Med Pediatr Oncol. 1989;17:20–28.
24 Starling KA, Donaldson MH, Haggard ME, et al. Therapy of histiocy tosis X with
vincristine, vinblastine, and cy clophosphamide. Am J Dis Child. 1972;123:105–110.
25 McLelland DJ, Broadbent V, Yeomans E, et al. Langerhans cell histiocy tosis: the case for
conservative treatment. Arch Dis Child. 1990;65:301–303.
26 Golpanian S, Tashiro J, Gerth DJ, et al. Pediatric histicy stosis in the United States:
incidence and outcomes. J Surg Res. 2014;190:221–229.
28 Willis B, Ablin A, Weinberg V, et al. Disease course and late sequelae of Langerhans’ cell
histiocy tosis: 25-y ear experience at the University of California, San Francisco. J Clin Oncol.
1996;14:2073–2082.
29 Gadner H, Heitger A, Grois N, et al. Treatment strategy for disseminated Langerhans cell
histiocy tosis. Med Pediatr Oncol. 1994;23:72–80.
30 Selch MT, Parker RG. Radiation therapy in the management of Langerhans cell
histiocy tosis. Med Pediatr Oncol. 1990;18:97–102.
31 Kilpatrick SE, Wenger DE, Gilchrist GS, et al. Langerhans’ cell histiocy tosis (histiocy tosis
X) of bone. A clinopathologic analy sis of 263 pediatric and adult cases. Cancer.
1995;76:2471–2484.
32 Broadbent V, Heaf D, Pritchard J, et al. Occult multisy stem involvement in histiocy tosis X
(HX). Med Pediatr Oncol. 1986;14:113.
35 Lipton J. The pathogenesis, diagnosis, and treatment of histiocy tosis sy ndromes. Pediatr
Dermatol. 1983;1:112–120.
37 Dagenais M, Pharoah MJ, Sikorski PA. The radiographic characteristics of histiocy tosis X.
Oral Surg Oral Med Oral Pathol. 1992;74:230–236.
38 Slater JM, Swarm OJ. Eosinophilic grenuloma of bone. Med Pediatr Oncol. 1980;8:151–
164.
40 Kriz J, Eich HT, Bruns F, et al. Radiotherapy in Langerhans cell histiocy tosis – a rare
indication in a rare disease. Radiation Oncology. 2013;8:233–239.
43 Dhull AK, Aggarwal S, Kaushal V, Singh S. Into the wild world of eosinophilic granuloma.
BMJ Case Report 2013 Nov 19: 2013. pii: bcr2013200522. doi: 10.1136/bcr-2013-200522
44 Mey er JS, Harty MP, Mahboudi S, et al. Langerhans cell histiocy tosis: presentation and
evolution of radiologic findings with clinical correlation. Radiographics. 1995;15:1135–1146.
48 Minehan KJ, Chen MG, Zimmerman D, et al. Radiation therapy for diabetes insipidus
caused by Langerhans cell histiocy tosis. Int J Radiat Oncol Biol Phys. 1992;23:519–524.
49 Dunger DB, Broadbent V, Yeoman E, et al. The frequency and natural history of diabetes
insipidus in children with Langerhans’ cell histiocy tosis. N Engl J Med. 1989;321:1157–1162.
50 Seo P. Cases from the Osler medical service of Johns Hopkins University. Am J Med.
2002;112:667–669.
51 Pittman T, Grant J, Darling C, et al. An eight-month-old boy with a skull mass. Pediatr
Neurosurg. 2002;37:100–104.
52 Gerrard MP, Hendry MM, Eden OB. Comparison of radiographic and scintigraphic
assessment of skeletal lesions in histiocy tosis X. Med Pediatr Oncol. 1986;14:113.
54 Onal C, Oy mak E, Rey han M, et al. Multifocal soft tissue Langerhans’ cell histiocy tosis
treated with PET-CT based conformal radiotherapy. Jpn J Radiol. 2015. doi: 10.1007/s11604-
015-0466-6.
55 Hay ward J, Packer R, Finlay J. Central nervous sy stem and Langerhans’ cell histiocy tosis.
Med Pediatr Oncol. 1990;18:325–328.
56 Chellapandian D, Shaikl F, Van den Bos C, et al. Management and outcome of patients with
Langerhans cell histiocy tosis and single-bone CNS-risk lesions: a multi-institutional
retrospective study. Pediat Blood Cancer. 2015;62:2162–2166. doi: 10.1002/pbc.25645.
57 Rube J, Para SDL, Pickren JW. Histiocy tosis X with involvement of brain. Cancer.
1967;20:486–492.
58 Cai S, Zhang S, Liu X, et al. Solitary Langerhans cell histiocy tosis of frontal lobe: a case
report and literature review. Clin J Cancer Res. 2014;26:211–214.
59 Hund E, Steiner HH, Jansen O, et al. Treatment of cerebral Langerhans cell histiocy tosis.
J Neurol Sci. 1999;171:145–152.
60 Broadbent V, Gadner H. Current therapy for Langerhans cell histiocy tosis. Hematol Oncol
Clin North Am. 1998;12:327–338.
61 Allen CE, McKain KL. Langerhans’ cell histiocy tosis: a review of past, current and future
therapies. Drugs Today. 2007;43:627–643.
62 Greenberger JS, Crocker AC, Vawter G, et al. Results of treatment of 127 patients with
sy stemic histiocy tosis (Letterer–Siwe sy ndrome, Schuller–Christian sy ndrome and multifocal
eosinophilic granuloma). Medicine. 1981;60:311–338.
64 Scaglietti O, Marchetti PG, Bartolozzi P. Final results obtained in the treatment of bone
cy sts with methy lprednisolone acetate (Depo Medrol) and a discussion of the results achieved
in other bone lesions. Clin Orthop. 1982;165;33–42.
66 Ruff S, Chapman GK, Tay lor TKF, et al. The evolution of eosinophilic granuloma of bone:
a case report. Skeletal Radiol. 1983;10:37–39.
69 Wirtschafter JD, Nesbit ME, Anderson P, et al. Intralesional methy lprednisolone for
Langerhans’ cell histiocy tosis of the orbit and cranium. J Pediatr Ophthalmol Stabismus.
1987;24:194–197.
70 Jones LR, Toth BB, Cangir A. Treatment for solitary eosinophilic granuloma of the
mandible by steroid injection: report of a case. J Oral Maxillofac Surg. 1989;47:306–309.
71 Kindy -Degnan NA, Laflamme P, Duprat G, et al. Interlesional steroid in the treatment of
an orbital eosinophilic granuloma [letter]. Arch Ophthalmol. 1992;12:811–814.
72 Egeler RM, Thompson RC Jr, Voute PA, et al. Inralesional infiltration of corticosteroids in
localized Langerhans’ cell histiocy tosis. J Pediatr Orthop. 1992;12:811–814.
73 Lahey ME, Hey n RM, Newton WA Jr, et al. Histiocy tosis X: clinical trial of chlorambucil:
a report from Children’s Cancer Study Group. Med Pediatr Oncol. 1979;7:197–203.
75 Berry DH, Gresik M, May bee D, et al. Histiocy tosis in bone only. Med Pediatr Oncol.
1990;18:292–294.
76 McGaran MH, Spady HA. Eosinophilic granuloma of bone. A study of 28 cases. J Bone
Joint Surg. 1960;42A:979–992.
77 Sartoris DJ, Parker BR. Histiocy tosis X: rate and pattern of resolution of osseous lesions.
Radiology. 1984;152:679–684.
78 Alexander JE, Seibert JJ, Berry DH, et al. Prognostic factors for healing of bone lesions in
histiocy tosis X. Pediatr Radiol. 1988;18:326–332.
81 Smith JH, Fulton L, O’Brien JM. Spontaneous regression of orbital Langerhans cell
granulomatosis in a three-y ear-old girl. Am J Ophthalmol. 1999;128:119–121.
82 Minkov M. Multisy stem Langerhans cell histiocy tosis in children: current treatment and
future directions. Paediatr Drugs. 2011;13:75–86.
89 Fowles JV, Bobechnkio WP. Solitary eosinophilic granuloma in bone. J Bone St Surg (Br).
1970;52-B:238–243.
90 Lindenbaum B, Gettes NI. Solitary eosinophilic granuloma of the cervical region—a case
report. Clin Orthop. 1970;68:112–114.
92 Rodrigues RJ, Lewis HH. Eosinophilic granuloma of bone—review of literature and case
presentation. Clin Orthop Relat Res. 1971;77:183–192.
94 Metha DN, Romani GV, Chatterjee AK, et al. Eosinophilic granuloma of the temporal
bone. J Laryn Otol. 1974;88:185–191.
96 Sweet RM, Kornblut AD, Hy ams VJ. Eosinophilic granuloma in the temporal bone.
Laryngoscope. 1979;89:1545–1552.
99 Wester SM, Beabout JW, Unmi KK, et al. Langerhans’ cell granulomatosis (histiocy tosis X)
of bone in adults. Am J Surg Pathol. 1982;6:413–416.
100 Shelby JH, Sweet RM. Eosinophilic granuloma of the temporal bone: medical and
surgical management in the pediatric patient. South Med J. 1983;76(1):65–70.
101 Rawlings CE III, Wilkins RH. Solitary eosinophilic granuloma of the skull. Neurosurgery.
1984;15:155–161.
102 Hauk HK, Ahlendorf W. Strahlentherapie eines eosinophilen Granulomas mit multiplen
Kochenherden. Radiobiol Radiother. 1986;27:436–440.
103 Anonsen CK, Donaldson SS. Langerhans’ cell histiocy tosis of the head and neck.
Laryngoscope. 1987;97:537–542.
104 Selch MT, Fu YS. Regressing aty pical histiocy tosis: a case report of control following low
dose radiotherapy therapy. Int J Radiat Oncol Biol Phys. 1987;13:1739–1745.
105 Mackenzie WG, Morton KS. Eosinophilic granuloma of bone. Can J Surg. 1988;31:264–
267.
107 Wiegel T, Sommer K, Knop J, et al. Radiotherapy of solitary and multiple eosinophilic
granulomas of bone (stage 1). Strahlenther Onkol. 1991;167(7):403–406.
108 El-Say ed S, Brewin TB. Histiocy tosis X: does radiotherapy still have a role? Clin Oncol
(R Coll Radiol). 1992;4(1):27–31.
109 Fiorillo A, Sadile F, DeChiara C, et al. Bone lesions in Langerhans’ cell histiocy tosis. Clin
Pediatr Oncol. 1993;32:118–120.
110 Irving RM, Broadbent V, Jones NS. Langerhans’ cell histiocy tosis in childhood:
management of head and neck manifestations. Laryngoscope. 1994;104:64–70.
111 Floman Y, Bar-On E, Mosheiff R, et al. Eosinophilic granuloma of the spine.
Laryngoscope. 1987;97(5):537–542.
113 Braier J, Chantada G, Rosso D, et al. Langerhans’ cell histiocy tosis: retrospective
evaluation of 125 patients at a single institution. Pediatr Hematol Oncol. 1999;16:377–385.
115 Ghanem I, Tolo VT, D’Ambra P, et al. Langerhans cell histiocy tosis of bone in children
and adolescents. J Pediatr Orthop. 2003;23(1):124–130.
116 Sarkar S, Singh M, Nag D, et al. A case report of unifocal Langerhans’ cell histiocy tosis or
eosinophilic granuloma. J Indian Med Assoc. 2007;105:218–220.
117 Saliba I, Sidani K, El Fata F, et al. Langerhans’ cell histiocy tosis of the temporal bone in
children. Int J Pediatr Otorhinolaryngol. 2008;72:775–786.
119 Kindy -Degnan NA, Laflamme P, Duprat G, et al. Intralesional steroid in the treatment of
an orbital eosinophilic granuloma [letter]. Arch Ophthalmol. 1991;109:617–628.
120 Kieffer SA, Nesbit ME, D’Angio GJ. Vertebra plane due to histiocy tosis X: serial studies.
Acta Radiol. 1969;8:241–250.
121 Alston RD, Tatevossian RG, McNanny RJ, et al. Incidence and survival of childhood
Langerhans cell histiocy tosis in Northwest England from 1954 to 1998. Pediatr Blood Cancer.
2007;48(5):555–560.
122 Matus-Ridley M, Raney RB Jr, Thawerani H, et al. Histiocy tosis X in children: patterns of
disease and results of treatment. Med Pediatr Oncol. 1983;11:99–105.
123 Greenberger JS, Cassady JR, Jaffe N, et al. Radiation therapy in patients with
histiocy tosis: management of diabetes insipidus and bone lesions. Int J Radiat Oncol Biol
Phys. 1979;5:1749–1755.
124 Braier J, Rosso D, Pollano D, et al. Sy mptomatic bone Langerhans cell histiocy tosis
treated at diagnosis or after reactivation with indomethacin alone. J Pediatr Hematol Oncol.
2014, on-line
125 Broadbent V, Chu AC. Langerhans cell histiocy tosis. In: Plowman PN, Pinkerson CR, eds.
Paediatric Oncology: Clinical Practices and Controversies. 2nd ed. London, England:
Chapman & Hall; 1997:546–560.
126 Grois N, Potschger U, Prosch H, et al. DALHX-and LCH1 and 11 Study Committee.
Pediatr Blood Cancer. 2006;46(2):228–233.
127 Demiral AN. The role of radiotherapy in the management of diabetes insipidus caused
by Langerhans cell histiocy tosis. J BUON. 2002;7:217–219.
128 Nezelof C, Barbey S, Gane P, et al. Histiocy tosis X: a proliferation disorder of the
Langerhans’ cell sy stem. Med Pediatr Oncol. 1986;14:108–109.
129 Berry DH, Gresik MV, Humphrey GB, et al. Natural history of histiocy tosis X: a
Pediatric Oncology Group study. Med Pediatr Oncol. 1986;14:1–5.
130 Raney RB Jr. Chemotherapy for children with aggressive fibromatosis and Langerhans’
cell histiocy tosis. Clin Orthop. 1991;262:58–63.
132 West WO. Velban as treatment for disseminated eosinophilic granuloma of bone: follow-
up note after seventeen y ears. J Bone Joint Surg Am. 1984;66:1128.
133 Katz BZ. Treatment for multisy stem Langerhans’ cell histocy tosis. J Pediatr.
2002;140:280.
134 Ceci A, DeTerlizzi M, Colella R, et al. Langerhans cell histiocy tosis in childhood: results
from the Italian Cooperative AIEOP-CNR-H.X. 1983 study. Med Pediatr Oncol.
1993;21:259–264.
135 Gadner H, Grois N, Arico M, et al. A randomized trial of treatment for multisy stem
Langerhans cell histiocy tosis. J Pediatr. 2001;138:728–734.
136 Gadner H, Grois N, Pötschger U, et al. Improved outcome in multisy stem Langerhans
cell histiocy tosis is associated with therapy intensification. Blood. 2008;111(5):2556–2562.
137 Satter EK, High WA. Langerhans cell histiocy tosis: a review of the current
recommendations of the Histiocy te Society. Pediatr Dermatol. 2008;25(3):291–295.
138 Rodriguez-Galindo C, Kelly P, Jeng M, et al. Treatment of children with Langerhans cell
histiocy tosis with 2-chlorodeoxy adenosine. Am J Hematol. 2002;69:179–184.
139 Hampshire AP, Saven A. Update of cladribine in the treatment of adults with
Langerhans-cell histiocy tosis. J Clin Oncol. 2004;22(145):6602.
140 Sheehan MP, Atherton DJ, Broadbent V, et al. Topical nitrogen mustard: an effective
treatment for cutaneous Langerhans cell histiocy tosis. J Pediatr. 1991;119:317–321.
141 May ou SC, Chu AC, Munro DD, et al. Langerhans cell histiocy tosis: excellent response to
etoposide. Clin Exp Dermatol. 1991;16:292–294.
142 Concepcion W, Esquivel CO, Terry A, et al. Liver transplantation in Langerhans’ cell
histiocy tosis (histiocy tosis X). Semin Oncol. 1991;8:24–28.
143 Gurthery SL, Heubi JE. Liver involvement in childhood histiocy tic sy ndromes. Curr Opin
Gastroenterol. 2001;17(5):474–478.
144 Conter V, Reciputo A, Arrigo C, et al. Bone marrow transplantation for refractory
Langerhans’ cell histiocy tosis. Haematologica. 1996;81:468–471.
145 Greinix HT, Storb R, Sanders JE, et al. Marrow transplantation for treatment of
multisy stem progressive Langerhans’ cell histiocy tosis. Bone Marrow Transplant. 1992;10:39–
44.
146 Morgan G. My eloablative therapy and bone marrow transplantation for Langerhans’ cell
histiocy tosis. Br J Cancer. 1994;23(suppl):552–553.
147 Suminoe A, Matsuzaki A, Hattari H, et al. Unrelated cord blood transplantation for an
infant with chemotherapy -resistant progressive Langerhans cell histiocy tosis. J Pediatr
Hematol Oncol. 2001;23:633–636.
150 Lai CC, Huang WC, Chang SN. Successful treatment of refractory Langerhans cell
histiocy tosis by allogeneic peripheral blood stem cell transplantation. Pediatr Transplant.
2008;12(1):99–104.
151 Childs DS Jr, Kennedy RLJ. Reticuloendotheliosis of children: treatment with roentgen
ray s. Radiology. 1951;57:653–661.
152 Cassady JR. Current role of radiation therapy in the management of histiocy tosis X.
Hematol Oncol Clin North Am 1987; 1: 123-129.
153 Komp DM. Therapeutic strategies for Langerhans cell histiocy tosis. J Pediatr.
1991;119:274–275.
154 Ransom JL, Morris P, John RG, et al. Neuropsy chological late sequelae of histiocy tosis X
[abstract]. Pediatr Res. 1978;12:47.
155 McClelland J, Pritchard J, Chu AC. Current controversies. Hematol Oncol Clin North Am.
1987;1:147–162.
156 Nandurf VR, Barelile P, Pritchard J, et al. Growth and endocrine disorders in multisy stem
Langerhans’ cell histiocy tosis. Clin Endocrinol. 2000;53:509–515.
157 Haupt R, Nanduri V, Calevo MG, et al. Permanent consequences in Langerhans cell
histiocy tosis patients: a pilot study from the Histiocy te Society —Late Effects Study Group.
Pediatr Blood Cancer. 2004;42:483–484.
158 Egeler RM, Neglia JP, Puccetti DM, et al. The association of Langerhans’ cell
histiocy tosis with malignant neoplasms. Cancer. 1993;71:865–874.
159 Haupt R, Fears TR, Rosso P, et al. Increased risk of secondary leukemia after single-agent
treatment with etoposide for Langerhans’ cell histiocy tosis. Pediatr Hematol Oncol.
1994;11:499–507.
160 Richter MP, D’ANgio GJ. The role of radiation therapy in the management of children
with histiocy tosis X. Am J Pediatr Hematol Oncol. 1981;8:24–28.
2 Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children:
a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69:412–422.
3 Mulliken JB, Enjolras O. Congenital hemangiomas and infantile hemangioma: missing links.
J Am Acad Dermatol. 2004;50:875–882.
4 Lawley LP, Cerimele F, Weiss SW, et al. Expression of Wilms tumor 1 gene distinguishes
vascular malformations from proliferative endothelial lesions. Arch Dermatol.
2005;141:1297–1300.
5 Coffin CM, Dehner LP. Vascular tumors in children and adolescents: a clinicopathologic
study of 228 tumors in 222 patients. Pathol Annu. 1993;28(pt 1):97–120.
6 North PE, Waner M, Buckmiller L, et al. Vascular tumors of infancy and childhood: bey ond
capillary hemangioma. Cardiovasc Pathol. 2006;15:303–317.
7 Ogino I, Torikai K, Kobay asi S, et al. Radiation therapy for life- or function-threatening
infant hemangioma. Radiology. 2001;218:834–839.
10 Furst CJ, Lundell M, Holm LE, et al. Cancer incidence after radiotherapy for skin
hemangioma: a retrospective cohort study in Sweden. J Natl Cancer Inst. 1988;80:1387–1392.
11 Furst CJ, Silfversward C, Holm LE. Mortality in a cohort of radiation treated childhood skin
hemangiomas. Acta Oncol. 1989;28:789–794.
12 Lindberg S, Karlsson P, Arvidsson B, et al. Cancer incidence after radiotherapy for skin
haemangioma during infancy. Acta Oncol. 1995;34:735–740.
13 Lundell M, Hakulinen T, Holm LE. Thy roid cancer after radiotherapy for skin
hemangioma in infancy. Radiat Res. 1994;140:334–339.
14 Lundell M, Holm LE. Risk of solid tumors after irradiation in infancy. Acta Oncol.
1995;34:727–734.
15 Lundell M, Mattsson A, Hakulinen T, et al. Breast cancer after radiotherapy for skin
hemangioma in infancy. Radiat Res. 1996;145:225–230.
18 Furst CJ, Lundell M, Holm LE. Radiation therapy of hemangiomas, 1909–1959—a cohort
based on 50 y ears of clinical practice at Radiumhemmet, Stockholm. Acta Oncol.
1987;26:33–36.
20 Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med.
1999;341:173–181.
21 Nakay ama H. Clinical and histological studies of the classification and the natural course
of the strawberry mark. J Dermatol. 1981;8:277–291.
22 Finn MC, Glowacki J, Mulliken JB. Congenital vascular lesions: clinical application of a new
classification. J Pediatr Surg. 1983;18:894–900.
26 Batta K, Goody ear HM, Moss C, et al. Randomised controlled study of early pulsed dy e
laser treatment of uncomplicated childhood haemangiomas: results of a 1-y ear analy sis.
Lancet. 2002;360:521–527.
29 Nord KM, Kandel J, Lefkowitch JH, et al. Multiple cutaneous infantile hemangiomas
associated with hepatic angiosarcoma: case report and review of the literature. Pediatrics.
2006;118:e907–e913.
30 Dey rup AT, Miettinen M, North PE, et al. Pediatric cutaneous angiosarcomas: a
clinicopathologic study of 10 cases. Am J Surg Pathol. 2011;35:70–75.
32 Mutalik SS, Bathi RJ, Naikmasur VG. Sturge–Weber sy ndrome: phy sician’s dream;
surgeon’s enigma. N Y State Dent J. 2009;75:44–45.
35 Huang WJ, Creath CJ. Klippel–Trenaunay –Weber sy ndrome: literature review and case
report. Pediatr Dent. 1994;16:231–235.
36 Nozaki T, Nosaka S, Miy azaki O, et al. Sy ndromes associated with vascular tumors and
malformations: a pictorial review. Radiographics. 2013;33:175–195.
38 Raco A, Ciappetta P, Artico M, et al. Vertebral hemangiomas with cord compression: the
role of embolization in five cases. Surg Neurol. 1990;34:164–168.
39 Dutton SC, Plowman PN. Paediatric haemangiomas: the role of radiotherapy. Br J Radiol.
1991;64:261–269.
40 Schild SE, Buskirk SJ, Frick LM, et al. Radiotherapy for large sy mptomatic hemangiomas.
Int J Radiat Oncol Biol Phys. 1991;21:729–735.
41 Sealy R, Barry L, Buret E, et al. Cavernous haemangioma of the head and neck in the
adult. J R Soc Med. 1989;82:198–202.
42 Kim MS, Park K, Kim JH, et al. Gamma knife radiosurgery for orbital tumors. Clin Neurol
Neurosurg. 2008;110:1003–1007.
43 Rades D, Bajrovic A, Alberti W, et al. Is there a dose-effect relationship for the treatment
of sy mptomatic vertebral hemangioma? Int J Radiat Oncol Biol Phys. 2003;55:178–181.
44 Unni KK, Ivins JC, Beabout JW, et al. Hemangioma, hemangiopericy toma, and
hemangioendothelioma (angiosarcoma) of bone. Cancer. 1971;27:1403–1414.
54 Sanlialp I, Karnak I, Tany el FC, et al. Sclerotherapy for ly mphangioma in children. Int J
Pediatr Otorhinolaryngol. 2003;67:795–800.
56 Acevedo JL, Shah RK, Brietzke SE. Nonsurgical therapies for ly mphangiomas: a
sy stematic review. Otolaryngol Head Neck Surg. 2008;138:418–424.
58 Kandil A, Rostom AY, Mourad WA, et al. Successful control of extensive thoracic
ly mphangiomatosis by irradiation. Clin Oncol (R Coll Radiol). 1997;9:407–411.
61 Johnson DW, Klazy nski PT, Gordon WH, et al. Mediastinal ly mphangioma and
chy lothorax: the role of radiotherapy. Ann Thorac Surg. 1986;41:325–328.
62 Tai PT, Jewell LD. Case report: mesenteric mixed haemangioma and ly mphangioma;
report of a case with 10 y ear follow-up after radiation treatment. Br J Radiol. 1995;68:657–
661.
64 Pearce MS, Parker L, Cotterill SJ, et al. Skin cancer in children and y oung adults: 28 y ears’
experience from the Northern Region Young Person’s Malignant Disease Registry, UK.
Melanoma Res. 2003;13:421–426.
65 Scalvenzi M, Francia MG, Falleti J, et al. Basal cell carcinoma with fibroepithelioma-like
histology in a healthy child: report and review of the literature. Pediatr Dermatol.
2008;25:359–363.
67 Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with
nevoid basal cell carcinoma sy ndrome. Am J Med Genet. 1997;69:299–308.
68 Lo Muzio L. Nevoid basal cell carcinoma sy ndrome (Gorlin sy ndrome). Orphanet J Rare
Dis. 2008;3:32.
69 Hughes JR, O’Donnell PJ, Pembroke AC. Basal cell carcinoma arising in a naevus
sebaceous in a 5-y ear-old girl. Clin Exp Dermatol. 1995;20:177.
72 Perkins JL, Liu Y, Mitby PA, et al. Nonmelanoma skin cancer in survivors of childhood and
adolescent cancer: a report from the childhood cancer survivor study. J Clin Oncol.
2005;23:3733–3741.
73 Schwartz JL, Kopecky KJ, Mathes RW, et al. Basal cell skin cancer after total-body
irradiation and hematopoietic cell transplantation. Radiat Res. 2009;171:155–163.
74 Amlashi SF, Riffaud L, Brassier G, et al. Nevoid basal cell carcinoma sy ndrome: relation
with desmoplastic medulloblastoma in infancy —a population-based study and review of the
literature. Cancer. 2003;98:618–624.
76 Robbins JH, Kraemer KH, Lutzner MA, et al. Xeroderma pigmentosum—an inherited
diseases with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Ann
Intern Med. 1974;80:221–248.
77 Sakata K, Aoki Y, Kumakura Y, et al. Radiation therapy for patients with xeroderma
pigmentosum. Radiat Med. 1996;14:87–90.
78 Pratt CB, George SL, Green AA, et al. Carcinomas in children—clinical and demographic
characteristics. Cancer. 1988;61: 1046–1050.
79 Lange JR, Palis BE, Chang DC, et al. Melanoma in children and teenagers: an analy sis of
patients from the National Cancer Data Base. J Clin Oncol. 2007;25:1363–1368.
80 Strouse JJ, Fears TR, Tucker MA, et al. Pediatric melanoma: risk factor and survival
analy sis of the surveillance, epidemiology and end results database. J Clin Oncol.
2005;23:4735–4741.
81 Downard CD, Rapkin LB, Gow KW. Melanoma in children and adolescents. Surg Oncol.
2007;16:215–220.
82 Swetter SM. Dermatological perspectives of malignant melanoma. Surg Clin North Am.
2003;83:77–95, vi.
83 Dennis LK. Analy sis of the melanoma epidemic, both apparent and real: data from the
1973 through 1994 surveillance, epidemiology, and end results program registry. Arch
Dermatol. 1999;135:275–280.
84 Hall HI, Miller DR, Rogers JD, et al. Update on the incidence and mortality from
melanoma in the United States. J Am Acad Dermatol. 1999;40:35–42.
86 Austin MT, Xing Y, Hay es-Jordan AA, et al. Melanoma incidence rises for children and
adolescents: an epidemiologic review of pediatric melanoma in the United States. J Pediatr
Surg. 2013;48:2207–2213.
87 Hamre MR, Chuba P, Bakhshi S, et al. Cutaneous melanoma in childhood and adolescence.
Pediatr Hematol Oncol. 2002;19:309–317.
88 Campbell LB, Kreicher KL, Gittleman HR, et al. Melanoma incidence in children and
adolescents: decreasing trends in the United States. J Pediatr. 2015;166:1505–1513.
90 Whiteman DC, Valery P, McWhirter W, et al. Risk factors for childhood melanoma in
Queensland, Australia. Int J Cancer. 1997;70:26–31.
91 Fears TR, Bird CC, Guerry Dt, et al. Average midrange ultraviolet radiation flux and time
outdoors predict melanoma risk. Cancer Res. 2002;62:3992–3996.
92 Loria D, Matos E. Risk factors for cutaneous melanoma: a case-control study in Argentina.
Int J Dermatol. 2001;40:108–114.
93 Kaskel P, Sander S, Kron M, et al. Outdoor activities in childhood: a protective factor for
cutaneous melanoma? Results of a case-control study in 271 matched pairs. Br J Dermatol.
2001;145:602–609.
94 Wiecker TS, Luther H, Buettner P, et al. Moderate sun exposure and nevus counts in
parents are associated with development of melanocy tic nevi in childhood: a risk factor study
in 1,812 kindergarten children. Cancer. 2003;97:628–638.
95 Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published studies. Int J
Cancer. 1997;73:198–203.
96 Siskind V, Aitken J, Green A, et al. Sun exposure and interaction with family history in risk
of melanoma, Queensland, Australia. Int J Cancer. 2002;97:90–95.
97 Whiteman DC, Whiteman CA, Green AC. Childhood sun exposure as a risk factor for
melanoma: a sy stematic review of epidemiologic studies. Cancer Causes Control.
2001;12:69–82.
101 Livestro DP, Kaine EM, Michaelson JS, et al. Melanoma in the y oung: differences and
similarities with adult melanoma: a case-matched controlled analy sis. Cancer. 2007;110:614–
624.
102 Jen M, Murphy M, Grant-Kels JM. Childhood melanoma. Clin Dermatol. 2009;27:529–
536.
103 Melnik MK, Urdaneta LF, Al-Jurf AS, et al. Malignant melanoma in childhood and
adolescence. Am Surg. 1986;52: 142–147.
104 Ferrari A, Bono A, Baldi M, et al. Does melanoma behave differently in y ounger
children than in adults? A retrospective study of 33 cases of childhood melanoma from a
single institution. Pediatrics. 2005;115:649–654.
105 Cordoro KM, Gupta D, Frieden IJ, et al. Pediatric melanoma: results of a large cohort
study and proposal for modified ABCD detection criteria for children. J Am Acad Dermatol.
2013;68:913–925.
106 Reintgen DS, Vollmer R, Seigler HF. Juvenile malignant melanoma. Surg Gynecol Obstet.
1989;168:249–253.
107 Gari LM, Rivers JK, Kopf AW. Melanomas arising in large congenital nevocy tic nevi: a
prospective study. Pediatr Dermatol. 1988;5:151–158.
108 Marghoob AA, Schoenbach SP, Kopf AW, et al. Large congenital melanocy tic nevi and
the risk for the development of malignant melanoma—a prospective study. Arch Dermatol.
1996;132:170–175.
109 Pratt CB, Palmer MK, Thatcher N, et al. Malignant melanoma in children and
adolescents. Cancer. 1981;47:392–397.
110 Rao BN, Hay es FA, Pratt CB, et al. Malignant melanoma in children: its management and
prognosis. J Pediatr Surg. 1990;25:198–203.
111 Rodriguez-Galindo C, Pappo AS, Kaste SC, et al. Brain metastases in children with
melanoma. Cancer. 1997;79:2440–2445.
113 Barnhill RL, Flotte TJ, Fleischli M, et al. Cutaneous melanoma and aty pical Spitz tumors in
childhood. Cancer. 1995;76:1833–1845.
115 Helm KF, Schwartz RA, Janniger CK. Juvenile melanoma (Spitz nevus). Cutis.
1996;58:35–39.
117 Conti EM, Cercato MC, Gatta G, et al. Childhood melanoma in Europe since 1978: a
population-based survival study. Eur J Cancer. 2001;37:780–784.
118 Jemal A, Devesa SS, Fears TR, et al. Cancer surveillance series: changing patterns of
cutaneous malignant melanoma mortality rates among whites in the United States. J Natl
Cancer Inst. 2000;92:811–818.
119 Saenz NC, Saenz-Badillos J, Busam K, et al. Childhood melanoma survival. Cancer.
1999;85:750–754.
120 Davidoff AM, Cirrincione C, Seigler HF. Malignant melanoma in children. Ann Surg
Oncol. 1994;1:278–282.
121 Essner R. Surgical treatment of malignant melanoma. Surg Clin North Am. 2003;83:109–
156.
123 Wagner JD, Gordon MS, Chuang TY, et al. Current therapy of cutaneous melanoma.
Plast Reconstr Surg. 2000;105:1774–1799; quiz 1800–1801.
125 Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision margins in high-risk malignant
melanoma. N Engl J Med. 2004;350:757–766.
126 Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative
ly mphatic mapping and sentinel ly mphadenectomy for early -stage melanoma: a multicenter
trial—Multicenter Selective Ly mphadenectomy Trial Group. Ann Surg. 1999;230:453–463;
discussion 463–465.
127 Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analy sis of 17,600
melanoma patients: validation of the American Joint Committee on Cancer melanoma
staging sy stem. J Clin Oncol. 2001;19:3622–3634.
128 Bleicher RJ, Essner R, Foshag LJ, et al. Role of sentinel ly mphadenectomy in thin
invasive cutaneous melanomas. J Clin Oncol. 2003;21:1326–1331.
129 Essner R, Chung MH, Bleicher R, et al. Prognostic implications of thick (>or=4-mm)
melanoma in the era of intraoperative ly mphatic mapping and sentinel ly mphadenectomy.
Ann Surg Oncol. 2002;9:754–761.
130 Bisseck M, Shen P, Pranikoff T. Sentinel ly mph node biopsy in a y oung child with thick
cutaneous melanoma. Oncology (Williston Park). 2003;17:1003–1005; discussion 1006–1010.
131 Gibbs P, Moore A, Robinson W, et al. Pediatric melanoma: are recent advances in the
management of adult melanoma relevant to the pediatric population. J Pediatr Hematol
Oncol. 2000;22:428–432.
132 Toro J, Ranieri JM, Havlik RJ, et al. Sentinel ly mph node biopsy in children and
adolescents with malignant melanoma. J Pediatr Surg. 2003;38:1063–1065.
133 Zuckerman R, Maier JP, Guiney WB Jr, et al. Pediatric melanoma: confirming the
diagnosis with sentinel node biopsy. Ann Plast Surg. 2001;46:394–399.
134 Gow KW, Rapkin LB, Olson TA, et al. Sentinel ly mph node biopsy in the pediatric
population. J Pediatr Surg. 2008;43:2193–2198.
135 Hay es FA, Green AA. Malignant melanoma in childhood: clinical course and response to
chemotherapy. J Clin Oncol. 1984;2:1229–1234.
136 Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy
of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial
EST 1684. J Clin Oncol. 1996;14:7–17.
137 Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in
high-risk melanoma: first analy sis of intergroup trial E1690/S9111/C9190. J Clin Oncol.
2000;18:2444–2458.
138 Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly
prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in
patients with resected stage IIB-III melanoma: results of intergroup trial
E1694/S9512/C509801. J Clin Oncol. 2001;19:2370–2380.
139 Navid F, Furman WL, Fleming M, et al. The feasibility of adjuvant interferon alpha-2b in
children with high-risk melanoma. Cancer. 2005;103:780–787.
140 Shah NC, Gerstle JT, Stuart M, et al. Use of sentinel ly mph node biopsy and high-dose
interferon in pediatric patients with high-risk melanoma: the Hospital for Sick Children
experience. J Pediatr Hematol Oncol. 2006;28:496–500.
141 Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for
patients with metastatic melanoma: analy sis of 270 patients treated between 1985 and 1993. J
Clin Oncol. 1999;17:2105–2116.
142 Allen I, Kupelnick B, Kumashiro M, et al. Efficacy of interleukin-2 in the treatment of
metastatic melanoma: sy stematic review and meta-analy sis. Cancer Ther. 1998;1:168–173.
143 Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group S0008: a phase III
trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus
interleukin-2 and interferon in patients with high-risk melanoma—an intergroup study of
cancer and leukemia Group B, Children’s Oncology Group, Eastern Cooperative Oncology
Group, and Southwest Oncology Group. J Clin Oncol. 2014;32:3771–3778.
144 Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-
mutated melanoma. N Engl J Med. 2014;371:1867–1876.
145 Long GV, Stroy akovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus
BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–1888.
146 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients
with metastatic melanoma. N Engl J Med. 2010;363:711–723.
147 Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously
untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526.
148 Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab
in untreated melanoma. N Engl J Med. 2015;372:2006–2017.
149 Dewey DL. The radiosensitivity of melanoma cells in culture. Br J Radiol. 1971;44:816–
817.
150 Geara FB, Ang KK. Radiation therapy for malignant melanoma. Surg Clin North Am.
1996;76:1383–1398.
151 Overgaard J. The role of radiotherapy in recurrent and metastatic malignant melanoma:
a clinical radiobiological study. Int J Radiat Oncol Biol Phys. 1986;12:867–872.
152 Konefal JB, Emami B, Pilepich MV. Analy sis of dose fractionation in the palliation of
metastases from malignant melanoma. Cancer. 1988;61:243–246.
153 Clark WH Jr, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior
of primary human malignant melanomas of the skin. Cancer Res. 1969;29:705–727.
154 Francken AB, Accortt NA, Shaw HM, et al. Prognosis and determinants of outcome
following locoregional or distant recurrence in patients with cutaneous melanoma. Ann Surg
Oncol. 2008;15:1476–1484.
155 Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous
and noncutaneous melanoma: a summary of 84,836 cases from the past decade—The
American College of Surgeons Commission on Cancer and the American Cancer Society.
Cancer. 1998;83:1664–1678.
156 Leiter U, Buettner PG, Eigentler TK, et al. Prognostic factors of thin cutaneous
melanoma: an analy sis of the central malignant melanoma registry of the german
dermatological society. J Clin Oncol. 2004;22:3660–3667.
1 Ries LAG, Smith MA, Gurney JG, et al. Cancer incidence and survival among children and
adolescents: United States SEER Program 1975–1995, National Cancer Institute, SEER
Program. NIH Pub. No. 99-4649, Bethesda, MD; 1999:1–15.
2 Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of
childhood cancer. N Engl J Med. 2006;355:1572–1582.
3 Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-y ear survivors of childhood
cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009:27:2328–
2338.
4 Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-y ear survivors
of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100:1368–
1379.
5 Cohen L, Creditor M. Iso-effect tables for tolerance of irradiated normal human tissues. Int
J Radiat Oncol Biol Phys. 1983;9:233–241.
6 Rubin P, Cassarett GW. Clinical Radiation Pathology, Vols I and II. Philadelphia, PA: WB
Saunders; 1968.
7 Krasin MJ, Constine LS, Friedman DL, et al. Radiation-related treatment effects across the
age spectrum: differences and similarities, or what the old and y oung can learn from each
other. Semin Radiat Oncol. 2010;20:21–29.
8 Wallace WH, Kelsey TW. Human ovarian reserve from conception to menopause. PLoS
One. 2010;5:e8772.
9 Wallace WH, Thomson AB, Saran F, et al. Predicting age of ovarian failure after radiation
to a field that includes the ovaries. Int J Radiat Oncol Biol Phys. 2005;62:738–744.
10 Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer
survivor study. J Clin Endocrinol Metab. 2006;91:1723–1728.
11 Ogilvy -Stuart AL, Clark DJ, Wallace WH, et al. Endocrine deficit after fractionated total
body irradiation. Arch Dis Child. 1992;67:1107–1110.
12 Dobbing J, Sands J. The quantitative growth and development of the human brain. Arch Dis
Child. 1963;48:757–767.
13 Marks JE, Wong J. The risk of cerebral radionecrosis in relation to dose, time, and
fractionation—a follow-up study. Prog Exp Tumor Res. 1985;29:210–218.
15 Torcuator R, Zuniga R, Mohan YS, et al. Initial experience with bevacizumab treatment for
biopsy confirmed cerebral radiation necrosis. J Neurooncol. 2009;94:63–68.
16 Duffner PK, Cohen ME. Long-term consequences of CNS treatment for childhood cancer.
Part II: clinical consequences. Pediatr Neurol. 1991;7:237–242.
17 Griffin TW. White matter necrosis, microangiopathy and intellectual abilities in survivors
of childhood leukemia—association with central nervous sy stem irradiation and methotrexate
therapy. In: Gilbert HA, Kagan AR, eds. Radiation Damage to the Nervous System. New York,
NY: Raven Press; 1980:155–174.
18 Hertzberg H, Huk W, Ueberall M, et al. CNS late effects after ALL therapy in childhood.
Part I: neuroradiological findings in long-term survivors of childhood ALL. Med Pediatr
Oncol. 1997;28:387–400.
19 Duffner PK, Cohen ME. The long-term effects of central nervous sy stem therapy on
children with brain tumors. Neurol Clin. 1991;9:479–495.
20 Palmer SL, Goloubeva O, Reddick WE, et al. Patterns of intellectual development among
survivors of pediatric medulloblastoma: a longitudinal analy sis. J Clin Oncol. 2001;19:2302–
2308.
21 Reddick W, White H, Glass J, et al. Developmental model relating white matter volume to
neurocognitive deficits in pediatric brain tumor survivors. Cancer. 2003;97:2523–2529.
23 Ris MD, Packer R, Goldwein J, et al. Intellectual outcome after reduced-dose radiation
therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study.
J Clin Oncol. 2001;19:3470–3476.
24 Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsy chologic functioning of survivors of
childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal
irradiation: a Pediatric Oncology Group study. J Clin Oncol. 1998;16:1723–1728.
25 Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with medulloblastomas
with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy : a Children’s
Cancer Group study. J Clin Oncol. 1999;17:2127–2136.
26 Merchant TE, Schreiber JE, Wu S, et al. Critical combinations of radiation dose and
volume predict intelligence quotient and academic achievement scores after craniospinal
irradiation in children with medulloblastoma. Int J Radiat Oncol Biol Phys. 2014;90:554–561.
27 Meadows AT, Gordon J, Massari DJ. Declines in IQ scores and cognitive dy sfunctions in
children with acute ly mphocy tic leukemia treated with cranial irradiation. Lancet.
1981;2:1015–1018.
29 Kingma A, Van Dommelen RI, Mooy aart EL, et al. No major cognitive impairment in
y oung children with acute ly mphoblastic leukemia using chemotherapy only : a prospective
longitudinal study. J Pediatr Hematol Oncol. 2002;24:106–114.
30 Waber DP, Shapiro BL, Carpentieri SC, et al. Excellent therapeutic efficacy and minimal
late neurotoxicity in children treated with 18 gray of cranial radiation therapy for high-risk
acute ly mphoblastic leukemia: a 7-y ear follow-up study of the Dana–Farber Cancer Institute
Consortium protocol 87-01. Cancer. 2001;92:15–22.
32 Brown RT, Madan-Swain A, Pais R, et al. Chemotherapy for acute ly mphocy tic leukemia:
cognitive and academic sequelae. J Pediatr. 1992;121:885–889.
34 Butler RW, Hill JM, Steinherz PG, et al. Neuropsy chologic effects of cranial irradiation,
intrathecal methotrexate, and sy stemic methotrexate in childhood cancer. J Clin Oncol.
1994;12:2621–2629.
35 Kaleita TA, Reaman GH, MacLean WE, et al. Neurodevelopmental outcome of infants
with acute ly mphoblastic leukemia: a Children’s Cancer Group report. Cancer. 1999;85:1859–
1865.
36 Hill DE, Ciesielski KT, Sethre-Hofstad L, et al. Visual and verbal short-term memory
deficits in childhood leukemia survivors after intrathecal chemotherapy. J Pediatr Psychol.
1997;22:861–870.
39 Jones AM. Transient radiation my elopathy (with reference to Lhermitte’s sign of electrical
paresthesia). Br J Radiol. 1964;37:727–744.
42 Wara W, Phillips T, Sheline G, et al. Radiation tolerance of the spinal cord. Cancer.
1975;35:1558–1562.
43 Marcus R, William R. The incidence of my elitis after irradiation of the cervical spinal
cord. Int J Radiat Oncol Biol Phys. 1990;19:3–8.
44 Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors
of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study.
J Clin Oncol. 2006;24:5277–5282.
45 De Bruin ML, Dorresteijn LD, van’t Veer MB, et al. Increased risk of stroke and transient
ischemic attack in 5-y ear survivors of Hodgkin ly mphoma. J Natl Cancer Inst. 2009;101:928–
937.
46 Mitchell WG, Fishman LS, Miller JH, et al. Stroke as a late sequel of cranial irradiation for
childhood brain tumors. J Child Neurol. 1991;6:128–133.
47 Schwartz CL, Hobbie WL, Constine LS. Facilitated assessment of chronic treatment by
sy mptom and organ sy stems. In: Schwartz CL, Hobbie WL, Constine LS, et al., eds. Survivors
of Child and Adolescent Cancer: A Multi-Disciplinary Approach. Berlin, Germany : Springer;
2015:17–34.
48 Brinkman TM, Zhu L, Zeltzer LK, et al. Longitudinal patterns of psy chological distress in
adult survivors of childhood cancer. Br J Cancer. 2013;109:1373–1381.
49 Brinkman TM, Zhang N, Recklitis CJ, et al. Suicide ideation and associated mortality in
adult survivors of childhood cancer. Cancer. 2014;120:271–277.
50 Krull KR, Huang S, Gurney JG, et al. Adolescent behavior and adult health status in
childhood cancer survivors. J Cancer Surviv. 2010;4:210–217.
51 Zebrack BJ, Zeltzer LK, Whitton J, et al. Psy chological outcomes in long-term survivors of
childhood leukemia, Hodgkin ly mphoma, and non-Hodgkin’s ly mphoma: a report from the
Childhood Cancer Survivor Study. Pediatrics. 2002;110:42–52.
52 Mulrooney DA, Mertens AC, Neglia JP, et al. Fatigue and sleep disturbance in survivors of
childhood cancer: a report from the Childhood Cancer Survivor Study. Proc Annu Meet Am
Soc Clin Oncol. 2003;22:761.
53 Pai AL, Kazak AE. Pediatric medical traumatic stress in pediatric oncology : family
sy stems interventions. Curr Opin Pediatr. 2006;18:558–562.
54 Santacroce SJ, Lee YL. Uncertainty, posttraumatic stress, and health behavior in y oung
adult childhood cancer survivors. Nurs Res. 2006;55:259–266.
55 Kazak AE, Rourke MT, Alderfer MA, et al. Evidence-based assessment, intervention and
psy chosocial care in pediatric oncology : a blueprint for comprehensive services across
treatment. J Pediatr Psychol. 2007;32:1099–1110.
56 Kazak AE, Alderfer M, Rourke MT, et al. Posttraumatic stress disorder (PTSD) and
posttraumatic stress sy mptoms (PTSS) in families of adolescent childhood cancer survivors. J
Pediatr Psychol. 2004;29:211–219.
57 Kazak AE, Boeving CA, Alderfer MA, et al. Posttraumatic stress sy mptoms during
treatment in parents of children with cancer. J Clin Oncol. 2005;23:7405–7410.
58 Patino-Fernandez AM, Pai AL, Alderfer M, et al. Acute stress in parents of children newly
diagnosed with cancer. Pediatr Blood Cancer. 2008;50:289–292.
59 Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of health outcomes
among adults treated for childhood cancer. JAMA. 2013;309:2371–2381.
60 Merchant TE, Rose SR, Bosley C, et al. Growth hormone secretion after conformal
radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol.
2011;29:4776–4780.
61 Sklar C, Mertens A, Walter A, et al. Final height after treatment for childhood acute
ly mphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2499 centigray s
of cranial irradiation. J Pediatr. 1993;123:59–64.
62 Chow EJ, Friedman DL, Yasui Y, et al. Decreased adult height in survivors of childhood
acute ly mphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr.
2007;150:370–375.
63 Sanders JE. Endocrine problems in children after bone marrow transplant for hematologic
malignancies. Bone Marrow Transplant. 1991;8:2–4.
64 Wingard JR, Plotnick LP, Freemer CS, et al. Growth in children after bone marrow
transplantation: busulfan plus cy clophosphamide versus cy clophosphamide plus total body
irradiation. Blood. 1992;79:1068–1073.
65 Huma Z, Boulad F, Black P, et al. Growth in children after bone marrow transplantation for
acute leukemia. Blood. 1995;86:819–824.
66 Sklar CA, Mertens AC, Mitby P, et al. Risk of disease recurrence and second neoplasms in
survivors of childhood cancer treated with growth hormone: a report from the Childhood
Cancer Survivor Study. J Clin Endocrinol Metab. 2002;87:3136–3141.
68 Leung W, Rose SR, Zhou Y, et al. Outcomes of growth hormone replacement therapy in
survivors of childhood acute ly mphoblastic leukemia. J Clin Oncol. 2002;20:2959–2964.
69 Shalet SM, Brennan BM. Puberty in children with cancer. Horm Res. 2002;57:39–42.
70 Shalet SM, Crowne EC, Didi MA, et al. Irradiation-induced growth failure. Baillieres Clin
Endocrinol Metab. 1992;6:513–526.
72 Constine LS, Woolf PD, Cann D, et al. Hy pothalamic–pituitary dy sfunction after radiation
for brain tumors. N Engl J Med. 1993;328:87–94.
74 Gurney JG, Kadan-Lottick NS, Packer RJ. Endocrine and cardiovascular late effects
among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer.
2003;97:663–673.
75 Constine LS, Donaldson SS, McDougall IR, et al. Thy roid dy sfunction after radiotherapy in
children with Hodgkin ly mphoma. Cancer. 1984;53:878–883.
76 Paulino AC. Hy pothy roidism in children with medulloblastoma: a comparison of 3600 and
2340 cGy craniospinal radiotherapy. Int J Radiat Oncol Biol Phys. 2002;53:543–547.
77 Constine LS, Rubin P, Woolf PD, et al. Hy perprolactinemia and hy pothy roidism following
cy totoxic therapy for central nervous sy stem malignancies. J Clin Oncol. 1987;5:1841–1851.
78 Samaan NA, Vieto R, Schultz PN, et al. Hy pothalamic pituitary and thy roid dy sfunction
after radiotherapy to the head and neck. Int J Radiat Oncol Biol Phys. 1982;8:1857–1867.
79 Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thy roid in survivors of Hodgkin
ly mphoma: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab.
2000;85:3227–3232.
81 Oberfield SE, Chin D, Uli N, et al. Endocrine late effects of childhood cancers. J Pediatr.
1997;131(1 pt 2):S37–S41.
83 Chow EJ, Friedman DL, Stovall M, et al. Risk of thy roid dy sfunction and subsequent
thy roid cancer among survivors of acute ly mphoblastic leukemia: a report from the
Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2009:53:432–437.
84 Borgstrom B, Bolme P. Thy roid function in children after allogeneic bone marrow
transplantation. Bone Marrow Transplant. 1994;13:59–64.
85 Laughton SJ, Merchant TE, Sklar CA, et al. Endocrine outcomes for children with
embry onal brain tumors after risk-adapted craniospinal and conformal primary -site
irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin
Oncol. 2008;26(7):1112–1118.
86 Hancock SL, Cox RS, McDougall IR. Thy roid diseases after treatment of Hodgkin
ly mphoma. N Engl J Med. 1991;325:599–605.
87 Petersen M, Keeling CA, McDougall IR. Hy perthy roidism with low radioiodine uptake
after head and neck irradiation for Hodgkin ly mphoma. J Nucl Med. 1989;30:255–257.
88 Donaldson SS. Effects of irradiation on skeletal growth and development. In: Green DM,
D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer. New York, NY: Wiley -Liss;
1992:63–70.
89 Hogeboom CJ, Grosser SC, Guthrie KA, et al. Stature loss following treatment for Wilms
tumor. Med Pediatr Oncol. 2001;36:295–304.
90 Riseborough EJ, Grabias SL, Burton RI, et al. Skeletal alterations following irradiation for
Wilms’ tumor. J Bone Joint Surg. 1976;58A:526–536.
91 Paulino AC, Wen BC, Brown CK, et al. Late effects in children treated with radiation
therapy for Wilms’ tumor. Int J Radiat Oncol Biol Phys. 2000;46:1239–1246.
92 Silverman CL, Thomas PR, McAlister WH, et al. Slipped femoral capital epiphy sis in
irradiated children: dose, volume, and age relationships. Int J Radiat Oncol Biol Phys.
1981;7:1357–1363.
93 Fletcher BD, Crom DB, Krance RA, et al. Radiation-induced bone abnormalities after
bone marrow transplantation for childhood leukemia. Radiology. 1994;191:231–235.
95 French D, Hamilton LH, Mattano LA Jr, et al. A PAI-1 (SERPINE1) poly morphism
predicts osteonecrosis in children with acute ly mphoblastic leukemia: a report from the
Children’s Oncology Group. Blood. 2008;111:4496–4499.
96 Sala A, Mattano LA Jr, Barr RD. Osteonecrosis in children and adolescents with cancer—
an adverse effect of sy stemic therapy. Eur J Cancer. 2007;43:683–689.
97 Mattano LA Jr, Sather HN, Trigg ME, et al. Osteonecrosis as a complication of treating
acute ly mphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin
Oncol. 2000;18:3262–3272.
98 Gay non PS, Lustig RH. The use of glucocorticoids in acute ly mphoblastic leukemia of
childhood. Molecular, cellular, and clinical considerations. J Pediatr Hematol Oncol.
1995;17:1–12.
99 Strauss AJ, Su JT, Dalton VM, et al. Bony morbidity in children treated for acute
ly mphoblastic leukemia. J Clin Oncol. 2001;19:3066–3072.
100 Morris LL, Cassady JR, Jaffe N. Sternal changes following mediastinal irradiation for
childhood Hodgkin ly mphoma. Radiology. 1975;115:701–705.
101 Murphy s FD, Blount WP. Cartilaginous exostoses following irradiation. J Bone Joint Surg.
1981;44:662–668.
102 Rutherford H, Dodd GD. Complications of radiation therapy : growing bone. Semin
Roentgenol. 1974;9:15–27.
103 Jaffe N, Toth BB, Hoar RE, et al. Dental and maxillo-facial abnormalities in long-term
survivors of childhood cancer: effects of treatment with chemotherapy and radiation to the
head and neck. Pediatrics. 1984;73:816–823.
104 Goldwein JW. Effects of radiation therapy on skeleton growth in childhood. Clin Orthop.
1991;262:101–107.
105 Kaste SC, Jones-Wallace D, Rose SR, et al. Bone mineral decrements in survivors of
childhood acute ly mphoblastic leukemia: frequency of occurrence and risk factors for their
development. Leukemia. 2001;15:728–734.
106 Kadan-Lottick N, Marshall JA, Baron AE, et al. Normal bone mineral density after
treatment for childhood acute ly mphoblastic leukemia diagnosed between 1991 and 1998. J
Pediatr. 2001;138:898–904.
107 Bhatia S, Ramsay NK, Weisdorf D, et al. Bone mineral density in patients undergoing
bone marrow transplantation for my eloid malignancies. Bone Marrow Transplant.
1998;22(1):87–90.
108 Ny som K, Holm K, Michaelsen KF, et al. Bone mass after allogeneic BMT for childhood
leukaemia or ly mphoma. Bone Marrow Transplant. 2000;25:191–196.
109 Oeffinger KC, Mertens AC, Sklar CA, et al. Obesity in adult survivors of childhood acute
ly mphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol.
2003;21:1359–1365.
110 Warner JT, Evans WD, Webb DK, et al. Body composition of long-term survivors of
acute ly mphoblastic leukaemia. Med Pediatr Oncol. 2002;38:165–172.
111 Reilly JJ, Kelly A, Ness P, et al. Premature adiposity rebound in children treated for acute
ly mphoblastic leukemia. J Clin Endocrinol Metab. 2001;86:2775–2778.
112 Chow EJ, Pihoker C, Hunt K, et al. Obesity and hy pertension among children after
treatment for acute ly mphoblastic leukemia. Cancer. 2007:110:2313–2320.
113 Gurney JG, Ness KK, Sibley SD, et al. Metabolic sy ndrome and growth hormone
deficiency in adult survivors of childhood acute ly mphoblastic leukemia. Cancer.
2006;107:1303–1312.
114 Oeffinger KC. Are survivors of acute ly mphoblastic leukemia (ALL) at increased risk of
cardiovascular disease? Pediatr Blood Cancer. 2008;50(2 suppl):462–468.
115 Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors and major cardiac
events among adult survivors of childhood cancer. J Clin Oncol. 2013;31:3673–3680.
116 Smith WA, Li C, Nottage KA, et al. Lifesty le and metabolic sy ndrome in adult survivors
of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Cancer.
2014;120:2742–2750.
117 Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease
after treatment of Hodgkin ly mphoma. JAMA. 1993;270:1949–1955.
118 King V, Constine LS, Clark D, et al. Sy mptomatic coronary artery disease after mantle
irradiation for Hodgkin ly mphoma. Int J Radiat Oncol Biol Phys. 1996;36:881–889.
119 Adams MJ, Lipshultz S, Schwartz C, et al. Radiation associated cardiovascular disease:
manifestations and management. Semin Radiat Oncol. 2003;13:346–356.
120 Haddy N, Diallo S, El-Fay ech C, et al. Cardiac diseases following childhood cancer
treatment: cohort Study. Circulation. 2016;133:31–38.
121 Darby SC, Cutter DJ, Boerma M, et al. Radiation-related heart disease: current
knowledge and future prospects. Int J Radiat Oncol Biol Phys. 2010;76:656–665.
122 Armstrong GT, Joshi VM, Ness KK, et al. Comprehensive echocardiographic detection of
treatment-related cardiac dy sfunction in adult survivors of childhood cancer: results from the
St. Jude Lifetime Cohort Study. J Am Coll Cardiol. 2015;65:2511–2522.
123 Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among
survivors of childhood cancer. JAMA. 2010;304:172–179.
124 Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling,
life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol.
2014;32:1218–1227.
125 Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult
survivors of childhood and adolescent cancer: retrospective analy sis of the Childhood Cancer
Survivor Study cohort. BMJ. 2009;339:b4606.
126 Schellong G, Riepenhausen M, Bruch C, et al. Late valvular and other cardiac diseases
after different doses of mediastinal radiotherapy for Hodgkin disease in children and
adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian
DAL-HD studies. Pediatr Blood Cancer. 2010;55:1145–1152.
127 Green DM, Gingell RL, Pearce J, et al. The effect of mediastinal irradiation on cardiac
function of patients treated during childhood and adolescence for Hodgkin ly mphoma. J Clin
Oncol. 1987;5:239–245.
128 Mauch PM, Weinstein H, Botnick L, et al. An evaluation of long-term survival and
treatment complications in children with Hodgkin ly mphoma. Cancer. 1983;51:925–932.
130 Creutzig U, Diekamp S, Zimmerman M, et al. Longitudinal evaluation of early and late
anthracy cline cardiotoxicity in children with AML. Pediatr Blood Cancer. 2007;48:651–662.
131 Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of
Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol. 2004;22:3139–3148.
132 Adams MJ, Lipshultz SE. Pathophy siology of anthracy cline- and radiation-associated
cardiomy opathies: implications for screening and prevention. Pediatr Blood Cancer.
2005;44:600–606.
133 Lipshultz SE, Alvarez JA, Scully RE. Anthracy cline associated cardiotoxicity in survivors
of childhood cancer. Heart. 2008;94:525–533.
134 Hudson MM. Anthracy cline cardiotoxicity in long-term survivors of childhood cancer:
the light is not at the end of the tunnel. Pediatr Blood Cancer. 2007;48:649–650.
135 Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and higher drug dose as risk factors
for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med.
1995;332:1738–1743.
136 Wouters KA, Kremer LC, Miller TL, et al. Protecting against anthracy cline-induced
my ocardial damage: a review of the most promising strategies. Br J Haematol.
2005;131:561–578.
137 Herman EH, Zhang J, Rifai N, et al. The use of serum levels of cardiac troponin T to
compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-
induced cardiotoxicity. Cancer Chemother Pharmacol. 2001;48:297–304.
138 Barry E, Alvarez JA, Scully RE, et al. Anthracy cline-induced cardiotoxicity : course,
pathophy siology, prevention and management. Expert Opin Pharmacother. 2007;8:1039–
1058.
139 Swain SM, Whaley F, Gerber M. Cardioprotection with dexrazoxane for doxorubicin-
containing therapy in advanced breast cancer. J Clin Oncol. 1997;15:1318–1332.
140 Venturini M, Michelotti A, Del Mastro L, et al. Multicenter randomized controlled clinical
trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women
receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol. 1996;14:3112–
3120.
141 Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute
my eloid leukemia/my elody splastic sy ndrome and other secondary malignancies in pediatric
Hodgkin’s disease. J Clin Oncol. 2007;25:493–500.
142 Barry EV, Vrooman LM, Dahlberg SE, et al. Absence of secondary malignant neoplasms
in children with high-risk acute ly mphoblastic leukemia treated with dexrazoxane. J Clin
Oncol. 2008;26:1106–1111.
145 Chow EJ, Chen Y, Kremer LC, et al. Individual prediction of heart failure among
childhood cancer survivors. J Clin Oncol. 2015;33:394–402.
146 Carlson RG, May field WR, Norman S, et al. Radiation-associated valvular disease. Chest.
1991;99:538–545.
147 Jakacki R, Goldwein J, Larsen R, et al. Cardiac dy sfunction following spinal irradiation
during childhood. J Clin Oncol. 1993;11:1033–1038.
148 Cohen SI, Bharati S, Glass J, et al. Radiotherapy as a cause of complete atrioventricular
block as Hodgkin ly mphoma: an electrophy siological–pathological correlation. Arch Intern
Med. 1981;141:676–679.
150 Hancock SL, Hoppe RT, Horning SJ, et al. Intercurrent death after Hodgkin’s disease
therapy in radiotherapy and adjuvant MOPP trials. Ann Intern Med. 1988;109:183–189.
151 Rubin P, Finkelstein JN, Siemann DW, et al. Predictive biochemical assay s for late
radiation effects. Int J Radiat Oncol Biol Phys. 1986;12:469–476.
152 Fry er CJH, Fitzpatrick PJ, Rider WD, et al. Radiation pneumonitis: experience following a
large single dose of radiation. Int J Radiat Oncol Biol Phys. 1978;4:931–936.
153 Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor
Study cohort: a review of published findings. J Clin Oncol. 2009;27:2339–2355.
154 Mertens AC, Yasui Y, Liu Y. Pulmonary complications in survivors of childhood and
adolescent cancer. Cancer. 2002;95:2431–2441.
155 McDonald S, Rubin P, Phillips T, et al. Injury to the lung from cancer therapy : clinical
sy ndromes, measurable endpoints, and potential scoring sy stems. Int J Radiat Oncol Biol
Phys. 1995;31:1187–1203.
156 Bradley JI, Zoberi I, Wasserman TH. Thoracic radiotherapy : complications and injury to
normal tissue. Prin Prac Radiat Oncol Updates. 2002;3:1–16.
157 Armenian SH, Landier W, Francisco L, et al. Long-term pulmonary function in survivors
of childhood cancer. J Clin Oncol. 2015;33:1592–600.
159 Fry er C, Hutchinson RJ, Krailo M, et al. Efficacy and toxicity of 12 courses of ABVD
chemotherapy followed by low-dose regional radiation in advanced Hodgkin ly mphoma in
children: a report from the Children’s Cancer Study Group. J Clin Oncol. 1990;8:1971–1980.
160 Marina NM, Greenwald CA, Fairclough DL, et al. Serial pulmonary function studies in
children treated for newly diagnosed Hodgkin ly mphoma with mantle radiotherapy plus
cy cles of cy clophosphamide, vincristine, and procarbazine alternating with cy cles of
doxorubicin, bleomy cin, vinblastine, and dacarbazine. Cancer. 1995;75:1706–1711.
161 Oguz A, Tay fun T, Citak EC, et al. Long-term pulmonary function in survivors of
childhood Hodgkin disease and non-Hodgkin ly mphoma. Pediatr Blood Cancer. 2007;49:699–
703.
162 Cerveri I, Fulgoni P, Giorgiani G. Lung function abnormalities after bone marrow
transplantation in children: has the trend recently changed? Chest. 2001;120:1900–1906.
163 Keane T, van Dy ke J, Rider W. Idiopathic interstitial pneumonia following bone marrow
transplantation: the relationship with total body irradiation. Int J Radiat Oncol Biol Phys.
1981;7:1365–1370.
164 Bolling T. Pulmonary effects of antineoplastic therapy : whole lung irradiation in patients
with exclusively pulmonary metastases of Ewing tumors—toxicity analy sis and treatment
results of the EICESS-92 trial. Strahlenther Onkol. 2008;184:193–197.
165 Miller RW, Fusner JE, Fink RJ, et al. Pulmonary function abnormalities in long-term
survivors of childhood cancer. Med Pediatr Oncol. 1986;14:202–207.
166 Wohl ME, Griscom NT, Traggis DG, et al. Effects of therapeutic irradiation delivered in
early childhood upon subsequent lung function. Pediatrics. 1975;55:507–516.
167 Motosue MS, Zhu L, Srivastava K, et al. Pulmonary function after whole lung irradiation
in pediatric patients with solid malignancies. Cancer. 2012;118:1450–1456.
169 Lushbaugh CC, Casarett GW. The effects of gonadal irradiation in clinical radiation
therapy : a review. Cancer. 1976;37:1111–1120.
170 Wallace WHB, Shalet SM, Crowne EC, et al. Ovarian failure following abdominal
irradiation in childhood: natural history and prognosis. Clin Oncol. 1989;1:75–79.
171 Halperin EC. Concerning the spinal component of the craniospinal irradiation field for
central nervous sy stem malignancies. Int J Radiat Oncol Biol Phys. 1993;26:357–362.
173 By rne J, Mulvihill JJ, My ers MH, et al. Effects of treatment on fertility in long-term
survivors of childhood or adolescent cancer. N Engl J Med. 1987;317:1315–1321.
174 Green DM, Kawashima T, Stovall M, et al. Fertility of female survivors of childhood
cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27:2677–2685.
175 Green DM, Sklar CA, Boice JD Jr, et al. Ovarian failure and reproductive outcomes after
childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol.
2009;27:2374–2381.
176 Sklar CA, Kim TH, Williamson JF, et al. Ovarian function after successful bone marrow
transplantation in post-menarchal females. Med Pediatr Oncol. 1983;11:361–364.
177 Sanders JE, Buckner CD, Leonard JM, et al. Late effects on gonadal function of
cy clophosphamide, total-body irradiation, and marrow transplantation. Transplantation.
1983;36:252–255.
178 Fürst CJ, Lundell M, Ahlbäck SO, et al. Breast hy poplasia following irradiation of the
female breast in infancy and early childhood. Acta Oncol. 1989;28:519–523.
179 Macklis RM, Oltikar A, Sallan SE. Wilms’ tumor patients with pulmonary metastases. Int J
Radiat Oncol Biol Phys. 1991;21:1187–1193.
180 Izard M. Ley dig cell function and radiation: a review of the literature. Radiother Oncol.
1995;34:1–8.
181 Thomson AB, Critchley HO, Kelnar CJ, et al. Late reproductive sequelae following
treatment of childhood cancer and options for fertility preservation. Best Pract Res Clin
Endocrinol Metab. 2002;16:311–334.
182 Heller GC. Effects on the germinal epithelium in radiobiological factors in manned space
flight. In: Langham WH, ed. NRC Publication 1487. Washington, DC: National Academy of
Sciences, National Research Council; 1967:124–133.
183 Sklar CA, Robison LL, Nesbit ME, et al. Effects of radiation on testicular function in long-
term survivors of childhood acute ly mphoblastic leukemia: a report from the Children’s
Cancer Study Group. J Clin Oncol. 1990;8:1981–1987.
184 Bokemey er C, Schmoll HJ, van Rhee J, et al. Long-term gonadal toxicity after therapy
for Hodgkin’s and non-Hodgkin’s ly mphoma. Ann Hematol. 1994;68:105–110.
185 Hobbie WL, Ginsberg JP, Ogle SK, et al. Fertility in males treated for Hodgkin’s disease
with COPP/ABV hy brid. Pediatr Blood Cancer. 2005;44:193–196.
186 Longhi A, Macchiagodena M, Vitali G, et al. Fertility in male patients treated with
neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol. 2003;25:292–296.
187 Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatr
Blood Cancer. 2008;50:347–351.
188 van Casteren NJ, van der Linden GH, Hakvoort-Cammel FG, et al. Effect of childhood
cancer treatment on fertility markers in adult male long-term survivors. Pediatr Blood
Cancer. 2009;52:108–112.
189 By rne J, Fears TR, Mills JL, et al. Fertility of long-term male survivors of acute
ly mphoblastic leukemia diagnosed during childhood. Pediatr Blood Cancer. 2004;42:364–372.
190 Shalet SM, Horner A, Akrned SR, et al. Ley dig cell damage after testicular irradiation for
acute ly mphoblastic leukemia. Med Pediatr Oncol. 1985;13:65–68.
191 Brauner R, Catlabiano P, Rappaport R, et al. Ley dig cell insufficiency after testicular
irradiation for acute ly mphoblastic leukemia. Horm Res. 1988;30:111–114.
192 Sanders JE. Effects of bone marrow transplantation on reproductive function. In: Green
DM, D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer. New York, NY: Wiley -
Liss; 1992:95–102.
193 Critchley HO, Bath LE, Wallace WH. Radiation damage to the uterus: review of the
effects of treatment of childhood cancer. Hum Fertil. 2002;5:61–66.
194 Green DM, Whitton JA, Stovall M. Pregnancy outcome of partners of male survivors of
childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol.
2003;21:716–721.
195 Green DM, Peabody EM, Nan B. Pregnancy outcome after treatment for Wilms tumor:
a report from the National Wilms Tumor Study Group. J Clin Oncol. 2002;20:2506–2513.
196 Winther JF, Boice JD Jr, Svendsen AL, et al. Spontaneous abortion in a Danish population-
based cohort of childhood cancer survivors. J Clin Oncol. 2008;26:4340–4346.
197 Signorello LB, Cohen SS, Bosetti C, et al. Female survivors of childhood cancer: preterm
birth and low birth weight among their children. J Natl Cancer Inst. 2006;98:1453–1461.
198 By rne J, Rasmussen SA, Steinhorn SC. Genetic disease in offspring of long term
surivivors of childhood and adolescent cancer. Am J Hum Genet. 1998;62:45–52.
201 Bath LE, Hamish W, Wallace B, et al. Late effects of the treatment of childhood cancer
on the female reproductive sy stem and the potential for fertility preservation. Int J Obstet
Gynaecol. 2002;109(2):107–114.
202 Agarwal A. Semen banking in patients with cancer: 20-y ear experience. Int J Androl.
2000;23(suppl 2):16–19.
204 Muller J, Sonksen J, Sommer P, et al. Cry opreservation of semen from pubertal boy s with
cancer. Med Pediatr Oncol. 2000;34:191–194.
206 Pfeifer S, Coutifaris C. Reproductive technologies 1998: options available for the cancer
patient. Med Pediatr Oncol. 1999;33:34–40.
207 Donnez J, Godin P, Qu J, et al. Gonadal cry opreservation in the y oung patient with
gy naecological malignancy. Curr Opin Obstet Gynecol. 2000;12:1–9.
208 Newton H. The cry opreservation of ovarian tissue as a strategy for preserving the
fertility of cancer patients. Hum Reprod Update. 1998;4:237–247.
209 Hansen M, Kurinczuk JJ, Bower C, et al. The risk of major birth defects after
intracy toplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725–730.
210 Bonduelle M, Liebaers I, Deketelaere V, et al. Neonatal data on a cohort of 2889 infants
born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999). Hum Reprod.
2002;17:671–694.
211 Simpson JL, Lamb DJ. Genetic effects of intracy toplasmic sperm injection. Semin
Reprod Med. 2001;19:239–249.
212 Serafini P. Outcome and follow-up of children born after IVF-surrogacy. Hum Reprod
Update. 2001;7:23–27.
213 Ericson A, Kallen B. Congenital malformations in infants born after IVF: a population-
based study. Hum Reprod. 2001;16:504–509.
214 Sankila R, Olsen JH, Anderson H, et al. Risk of cancer among offspring of childhood-
cancer survivors. N Engl J Med. 1998;338:1339–1344.
215 Friedman DL, Kadan-Lottick N, Liu Y, et al. History of cancer among first-degree
relatives of childhood cancer survivors: a report from the Childhood Cancer Survivor Study.
Proc Annu Meet Am Soc Clin Oncol. 2001:433a.
216 Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys. 1995;31:1249–
1256.
217 Smith GR, Thomas PR, Ritchey M, et al. Long-term renal function in patients with
irradiated bilateral Wilms tumor. National Wilms’ Tumor Study Group. Am J Clin Oncol.
1998;21:58–63.
218 Breslow NE, Takashima JR, Ritchey ML, et al. Renal failure in the Deny s–Drash and
Wilms’ tumor–aniridia sy ndromes. Cancer Res. 2000;60:4030–4032.
219 Tarbell N, Guinan E, Neimey er C, et al. Late onset of renal dy sfunction in survivors of
bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1988;15:99–104.
220 Lonnerholm G, Carlson K, Bratteby LE, et al. Renal function after autologous bone
marrow transplantation. Bone Marrow Transplant. 1991;8:129–134.
222 Patzer L, Hempel L, Ringelmann F, et al. Renal function after conditioning therapy for
bone marrow transplantation in childhood. Med Pediatr Oncol. 1997;28:274–283.
223 Bianchetti MG, Kanaka C, Ridolfi-Luthy A, et al. Persisting renotubular sequelae after
cisplatin in children and adolescents. Am J Nephrol. 1991;11:127–130.
224 Mey er WH, Pratt CB, Poquette CA. Carboplatin/ifosfamide window therapy for
osteosarcoma: results of the St Jude Children’s Research Hospital OS-91 trial. J Clin Oncol.
2001;19:171–182.
225 Stern JW, Bunin N. Prospective study of carboplatin-based chemotherapy for pediatric
germ cell tumors. Med Pediatr Oncol. 2002;39:163–167.
228 Skinner R, Pearson AD, English MW, et al. Risk factors for ifosfamide nephrotoxicity in
children. Lancet. 1996;348:578–580.
229 McCune JS, Friedman DL, Schuetze S, et al. Influence of age upon ifosfamide-induced
nephrotoxicity. Pediatr Blood Cancer. 2004;42:427–432.
230 Riachy E, Krauel L, Rich BS, et al. Risk factors and predictors of severity score and
complications of pediatric hemorrhagic cy stitis. J Urol. 2014;191:186–192.
231 Ritchey M, Ferrer F, Shearer P, et al. Late effects on the urinary bladder in patients
treated for cancer in childhood: a report from the Children’s Oncology Group. Pediatr Blood
Cancer. 2009;52:439–446.
233 Donaldson SS, Jundt S, Ricour C, et al. Radiation enteritis in children. Cancer.
1975;35:1167–1178.
234 Emami B, Ly man J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation.
Int J Radiat Oncol Biol Phys. 1991;21:109–122.
235 Madenci AL, Fisher S, Diller LR, et al. Intestinal obstruction in survivors of childhood
cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2015;33:2893–2900.
236 Neville KA, Cohn RJ, Steinbeck KS, et al. Hy perinsulinemia, impaired glucose tolerance,
and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin
Endocrinol Metab. 2006;91:4401–4407.
237 Meacham LR, Sklar CA, Li S, et al. Diabetes mellitus in long-term survivors of childhood
cancer. Increased risk associated with radiation therapy : a report for the Childhood Cancer
Survivor Study. Arch Intern Med. 2009:169:1381–1388.
238 de Vathaire F, El-Fay ech C, Ben Ay ed FF, et al. Radiation dose to the pancreas and risk of
diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol.
2012;13:1002–1010.
239 van Nimwegen FA, Schaapveld M, Janus CP, et al. Risk of diabetes mellitus in long-term
survivors of Hodgkin ly mphoma. J Clin Oncol. 2014;32:3257–3263.
240 Ingold JA, Reed GB, Kaplan HS, et al. Radiation hepatitis. Am J Roentgenol. 1963;93:200–
208.
241 Hasegawa S, Horibe K, Kawabe T, et al. Veno-occlusive disease of the liver after
allogeneic bone marrow transplantation in children with hematologic malignancies:
incidence, onset time and risk factors. Bone Marrow Transplant. 1998;22:1191–1197.
242 Ortega J, Donaldson S, Percy S, et al. Venoocclusive disease of the liver after
chemotherapy with vincristine, actinomy cin D, and cy clophosphamide for the treatment of
rhabdomy osarcoma—a report of the Intergroup Rhabdomy osarcoma Study Group. Cancer.
1997;79:2435–2439.
243 Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the liver. Semin Radiat
Oncol. 2001;11:240–246.
244 Thomas PRM, Tefft M, D’Angio GJ, et al. Acute toxicities associated with radiation in the
second National Wilms’ Tumor Study. J Clin Oncol. 1988;6:1694–1698.
245 Nanda SK, Schachat AP. Ocular complications following radiation therapy to the orbit.
In: Green DM, D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer. New York,
NY: Wiley -Liss; 1992:11–22.
246 Wara W, Irvine A, Neger R, et al. Radiation retinopathy. Int J Radiat Oncol Biol Phys.
1979;5:81–83.
247 Hilliard L, Berkow R, Watterson J, et al. Retinal toxicity associated with cisplatin and
etoposide in pediatric patients. Med Pediatr Oncol. 1997;28:310–313.
248 Parsons J, Fitzgerald C, Hood C, et al. The effects of irradiation of the ey e and optic
nerve. Int J Radiat Oncol Biol Phys. 1983;9:609–622.
249 Paulino AC, Simon JH, Zhen W, et al. Long-term effects in children treated with
radiotherapy for head and neck rhabdomy osarcoma. Int J Radiat Oncol Biol Phys.
2000;48:1489–1495.
250 Merriam G, Focht E. Radiation dose to the lens in treatment of tumors of the ey e and
adjacent structures: possibilities of cataract formation. Radiology. 1958;71:357–369.
251 Britten M, Halman K, Meredith W. Radiation cataract: new evidence on radiation dosage
to the lens. Br J Radiol. 1966;39:612–617.
252 Otake M, Schull WJ. A review of forty -five y ears study of Hiroshima and Nagasaki
atomic bomb survivors radiation cataract. J Radiat Res. 1991;32:283–293.
253 Belkacemi Y, Labopin M, Vernant JP, et al. Cataracts after total body irradiation and bone
marrow transplantation in patients with acute leukemia in complete remission: a study of the
European Group for Blood and Marrow Transplantation. Int J Radiat Biol Oncol Phys.
1998;41:659–668.
254 van Kempen-Harteveld ML, Belkacemi Y, Kal HB, et al. Dose–effect relationship for
cataract induction after single-dose total body irradiation and bone marrow transplantation for
acute leukemia. Int J Radiat Oncol Biol Phys. 2002;52:1367–1374.
255 van Kempen-Harteveld ML, Struikmans H, Kal HB. Cataract after total body irradiation
and bone marrow transplantation: degree of visual impairment. Int J Radiat Oncol Biol Phys.
2002;52:1375–1380.
256 Zierhut D, Lohr F, Schraube P. Cataract incidence after total-body irradiation. Int J Radiat
Oncol Biol Phys. 2000;46:131–135.
257 Horwitz M, Auquier P, Barlogis V, et al. Incidence and risk factors for cataract after
haematopoietic stem cell transplantation for childhood leukaemia: an LEA study. Br J
Haematol. 2015;168:518–525.
258 McCormick B, Ellsworth R, Abramson D, et al. Results of external beam radiation for
children with retinoblastoma: a comparison of two techniques. J Pediatr Ophthalmol
Strabismus. 1989;26:239–243.
259 Brooks HL Jr, Mey er D, Shields JA, et al. Removal of radiation-induced cataracts in
patients treated for retinoblastoma. Arch Ophthalmol. 1990;108:1701–1708.
262 Shields CL, Honavar SG, Shields JA, et al. Factors predictive of recurrence of retinal
tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma.
Arch Ophthalmol. 2002;120:460–464.
263 Shields CL, Meadows AT, Leahey AM, et al. Continuing challenges in the management of
retinoblastoma with chemotherapy. Retina. 2004;24:849–862.
264 Shields CL, Mashay ekhi A, Cater J, et al. Chemoreduction for retinoblastoma: analy sis of
tumor control and risks for recurrence in 457 tumors. Trans Am Ophthalmol Soc. 2004;102:35–
45.
265 Shields CL, Mashay ekhi A, Au AK, et al. The international classification of
retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280.
266 Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomy osarcoma: survival
and late effects of treatment—results of an international workshop. J Clin Oncol.
2001;19:197–204.
267 Adler M, Hawke M, Bergern G, et al. Radiation effects on the external auditory canal. J
Otolaryngol. 1985;14:226.
268 Huang E, The BS, Strother DR. Intensity -modulated radiation therapy for pediatric
medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys.
2002;52:599–605.
269 Merchant TE, Gould CJ, Xiong X, et al. Early neuro-otologic effects of three-
dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol Biol Phys.
2004;58:1194–1207.
270 McHaney VA, Thibadoux G, Hay es FA, et al. Hearing loss in children receiving cisplatin
chemotherapy. J Pediatr. 1983;10:314–317.
271 Landier W. Hearing loss related to ototoxicity in children with cancer. J Pediatr Oncol
Nurs. 1998;15:195–206.
272 Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al. Analy sis of ototoxicity in y oung
children receiving carboplatin in the context of conservative management of unilateral or
bilateral retinoblastoma. Pediatr Blood Cancer. 2009;52:637–643.
273 Dean JB, Hay ashi SS, Albert CM, et al. Hearing loss in pediatric oncology patients
receiving carboplatin-containing regimens. J Pediatr Hematol Oncol. 2008;30:130–134.
274 Kushner BH, Budnick A, Kramer K, et al. Ototoxicity from high-dose use of platinum
compounds in patients with neuroblastoma. Cancer. 2006;107:417–422.
275 Maguire A, Craft A, Evans R, et al. The long-term effects of treatment on the dental
condition of children surviving malignant disease. Cancer. 1987;60:2570–2575.
277 Dahllof G, Barr M, Balme P, et al. Disturbances in dental development after total body
irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol.
1988;65:41–44.
278 Kaste S, Hopkins K, Crom D, et al. Dental abnormalities in children treated for acute
ly mphoblastic leukemia. Leukemia. 1997;11:792–796.
279 Fromm M, Littman P, Raney B, et al. Late effects after treatment of twenty children with
soft tissue sarcomas of the head and neck. Cancer. 1986;57:2070–2076.
280 Bucker J, Fleming T, Fuller L, et al. Preliminary observations on the effect of mantle field
radiotherapy on salivary flow rates in patients with Hodgkin ly mphoma. J Dent Res.
1988;6:518–521.
281 Marks J, Davis C, Gottsman V, et al. The effects of radiation on parotid salivary function.
Int J Radiat Oncol Biol Phys. 1981;7:1013–1019.
282 Jensen SB, Pedersen AM, Vissink A, et al. A sy stematic review of salivary gland
hy pofunction and xerostomia induced by cancer therapies: management strategies and
economic impact. Support Care Cancer. 2010;18:1061–1079.
283 Johnson J, Ferretti G, Nethery J, et al. Oral pilocarpine for post-irradiation xerostomia in
patients with head and neck cancer. N Engl J Med. 1993;329:390–395.
284 Yeazel MW, Gurney JG, Oeffinger KC, et al. An examination of the dental utilization
practices of adult survivors of childhood cancer: a report from the Childhood Cancer Survivor
Study. J Public Health Dent. 2004;64:50–54.
285 Hendry J. The cellular basis of long-term marrow injury after irradiation. Radiother
Oncol. 1985;3:331–338.
286 Storb R, Deeg HJ, Applebaum FR, et al. Total-body irradiation in bone marrow
transplantation. In: Browne D, ed. Treatment of Radiation Injuries. New York, NY: Plenum
Press; 1990:29–33.
288 Sachs E, Goris M, Glatstein E, et al. Bone marrow regeneration following large field
irradiation. Influence of volume, age, dose and time. Cancer. 1978;42:1057–1065.
289 Cristy M. Active bone marrow distribution as a function of age in humans. Phys Med
Biol. 1981;26:389–400.
1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
2 Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling, life-
threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol.
2014;32:1218–1227.
3 Curtis RE, Freedman DM, Ron E, et al. New malignancies among cancer survivors: SEER
cancer registries, 1973–2000, NIH Publ. No. 05-5302. Bethesda, MD: National Cancer
Institute; 2006.
5 Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47,697 patients treated
for childhood cancer in the Nordic countries. J Natl Cancer Inst. 2009;101:806–813.
6 Reulen RC, Frobisher C, Winter DL, et al. Long-term risks of subsequent primary
neoplasms among survivors of childhood cancer. JAMA. 2011;305:2311–2319.
7 Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-y ear survivors of
childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102:1083–
1095.
8 Cardous-Ubbink MC, Heinen RC, Bakker PJ, et al. Risk of second malignancies in long-term
survivors of childhood cancer. Eur J Cancer. 2007;43:351–362.
10 Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nat Rev Cancer.
2002;2:124–132.
11 Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-y ear survivors
of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100:1368–
1379.
13 Bhatia S, Yasui Y, Robison LL, et al. High risk of subsequent neoplasms continues with
extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group.
J Clin Oncol. 2003;21:4386–4394.
14 Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous
sy stem in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
J Natl Cancer Inst. 2006;98:1528–1537.
15 Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thy roid cancer after a first
tumour in childhood (the Childhood Cancer Survivor Study ): a nested case-control study.
Lancet. 2005;365:2014–2023.
16 Wong FL, Boice JDJ, Abramson DH, et al. Cancer incidence after retinoblastoma—
radiation dose and sarcoma risk. JAMA. 1997;278:1262–1267.
17 Strong LC, Stine M, Norsted TL. Cancer in survivors of childhood soft tissue sarcoma and
their relatives. J Natl Cancer Inst. 1987;79:1213–1220.
18 Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second neoplasms after
childhood Hodgkin’s disease. N Engl J Med. 1996;334:745–751.
19 Neglia JP, Meadows AT, Robison LL, et al. Second neoplasms after acute ly mphoblastic
leukemia in childhood. N Engl J Med. 1991;325:1330–1336.
20 Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow
transplantation. Blood. 1996;87:3633–3639.
21 Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated for
Hodgkin’s disease: associations with gender and radiation dose. Int J Radiat Oncol Biol Phys.
2008;72:24–33.
22 Zang EA, Wy nder EL. Differences in lung cancer risk between men and women:
examination of the evidence. J Natl Cancer Inst. 1996;88:183–192.
23 Garwicz S, Anderson H, Olsen JH, et al. Second malignant neoplasms after cancer in
childhood and adolescence: a population-based case-control study in the 5 Nordic countries.
The Nordic Society for Pediatric Hematology and Oncology. The Association of the Nordic
Cancer Registries. Int J Cancer. 2000;88:672–678.
27 Okey A, Harper P, Grant D, et al. Chemical and radiation carcinogenesis. In: Tannock I,
Hill R, eds. The Basic Science of Oncology. 3rd ed. ed. New York, NY: McGraw-Hill;
1998:166–196.
28 Haselow RE, Nesbit M, Dehner LP, et al. Second neoplasms following megavoltage
radiation in a pediatric population. Cancer. 1978;42:1185–1191.
29 Potish RA, Dehner LP, Haselow RE, et al. The incidence of second neoplasms following
megavoltage radiation for pediatric tumors. Cancer. 1985;56:1534–1537.
30 Richardson RB. Past and revised risk estimates for cancer induced by irradiation and their
influence on dose limits. Br J Radiol. 1990;63:235–245.
31 Wolden SL, Lamborn KR, Cleary SF, et al. Second cancers following pediatric Hodgkin’s
disease. J Clin Oncol. 1998;16:536–544.
32 Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent malignant neoplasms among 1641
Hodgkin’s disease patients diagnosed in childhood and adolescence: a population-based cohort
study in the five Nordic countries. J Clin Oncol. 1996;14:1442–1446.
34 Tucker MA, Meadows AT, Boice JDJ, et al. Leukemia after therapy with alky lating agents
for childhood cancer. J Natl Cancer Inst. 1987;78:459–464.
35 Pui CH, Ribeiro RC, Hancock ML, et al. Acute my eloid leukemia in children treated with
epipodophy llotoxins for acute ly mphoblastic leukemia. N Engl J Med. 1991;325:1682–1687.
36 Winick NJ, McKenna RW, Shuster JJ, et al. Secondary acute my eloid leukemia in children
with acute ly mphoblastic leukemia treated with etoposide. J Clin Oncol. 1993;11:209–217.
37 Sugita K, Furukawa T, Tsuchida M, et al. High frequency of etoposide (VP-16)-related
secondary leukemia in children with non-Hodgkin’s ly mphoma. Am J Pediatr Hematol Oncol.
1993;15:99–104.
38 Nguy en F, Rubino C, Guerin S, et al. Risk of a second malignant neoplasm after cancer in
childhood treated with radiotherapy : correlation with the integral dose restricted to the
irradiated fields. Int J Radiat Oncol Biol Phys. 2008;70:908–915.
39 Diallo I, Haddy N, Adjadj E, et al. Frequency distribution of second solid cancer locations
in relation to the irradiated volume among 115 patients treated for childhood cancer. Int J
Radiat Oncol Biol Phys. 2009;74:876–883.
41 Land CE. Temporal distributions of risk for radiation-induced cancers. J Chronic Dis.
1987;40:45S–57S.
42 Tucker MA, Coleman CN, Cox RS, et al. Risk of second cancers after treatment for
Hodgkin’s disease. N Engl J Med. 1988;318:76–81.
43 Smith MA, McCaffrey RP, Karp JE. The secondary leukemias: challenges and research
directions. J Natl Cancer Inst. 1996;88:407–418.
44 Hawkins MM, Wilson LM, Stovall MA, et al. Epipodophy llotoxins, alky lating agents, and
radiation and risk of secondary leukaemia after childhood cancer. Br Med J. 1992;304:951–
958.
45 Tucker MA, D’Angio GL, Boice JDJ, et al. Bone sarcomas linked to radiotherapy and
chemotherapy in children. N Engl J Med. 1987;317:588–593.
46 Hawkins MM, Wilson LM, Burton HS, et al. Radiotherapy, alky lating agents, and risk of
bone cancer after childhood cancer. J Natl Cancer Inst. 1996;88:270–278.
47 Pedersen-Bjergaard J, Erbsoll J, Hansen VL, et al. Carcinoma of the urinary bladder after
treatment with cy clophosphamide for non-Hodgkin’s ly mphoma. N Engl J Med.
1988;318:1028–1032.
48 Blay ney DW, Longo DL, Young RC, et al. Decreasing risk of leukemia with prolonged
follow-up after chemotherapy and radiotherapy for Hodgkin’s disease. N Engl J Med.
1987;316:710–714.
50 Smith SM, Le Beau MM, Huo D, et al. Clinical-cy togenetic associations in 306 patients
with therapy -related my elody splasia and my eloid leukemia: the University of Chicago
series. Blood. 2003;102:43–52.
52 Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO)
classification of the my eloid neoplasms. Blood. 2002;100:2292–2302.
53 van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiotherapy and smoking in lung
cancer following Hodgkin’s disease. J Natl Cancer Inst. 1995;87:1530–1537.
54 Shiels MS, Gibson T, Sampson J, et al. Cigarette smoking prior to first cancer and risk of
second smoking-associated cancers among survivors of bladder, kidney, head and neck, and
Stage I lung cancers. J Clin Oncol. 2014;32:3989–3995.
56 Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or my elody splastic
sy ndrome after treatment with epipodophy llotoxins. J Clin Oncol. 1999;17:569–577.
57 Karp JE, Sarkodee-Adoo CB. Therapy -related acute leukemia. Clin Lab Med. 2000;20:71–
81.
60 Lovett BD, Strumberg D, Blair IA, et al. Etoposide metabolites enhance DNA
topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints.
Biochemistry. 2001;40:1159–1170.
61 Megonigal MD, Cheung NK, Rappaport EF, et al. Detection of leukemia-associated MLL-
GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors. Proc
Natl Acad Sci U S A. 2000;97:2814–2819.
62 Felix CA, Lange BJ, Hosler MR, et al. Chromosome band 11q23 translocation breakpoints
are DNA topoisomerase II cleavage sites. Cancer Res. 1995;55:4287–4292.
63 Libura J, Slater DJ, Felix CA, et al. Therapy -related acute my eloid leukemia-like MLL
rearrangements are induced by etoposide in primary human CD34+ cells and remain stable
after clonal expansion. Blood. 2005;105:2124–2131.
64 Rowley JD, Olney HJ. International workshop on the relationship of prior therapy to
balanced chromosome aberrations in therapy -related my elody splastic sy ndromes and acute
leukemia: overview report. Genes Chromosomes Cancer. 2002;33:331–345.
65 Le Deley MC, Leblanc T, Shamsaldin A, et al. Risk of secondary leukemia after a solid
tumor in childhood according to the dose of epipodophy llotoxins and anthracy clines: a case-
control study by the Societe Francaise d’Oncologie Pediatrique. J Clin Oncol. 2003;21:1074–
1081.
68 Friedman DL, Rovo A, Leisenring W, et al. Increased risk of breast cancer among
survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the
EBMT-Late Effect Working Party. Blood. 2008;111:939–944.
69 Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and
chemotherapy among y oung women with Hodgkin disease. JAMA. 2003;290:465–475.
70 Hancock SL, Tucker MA, Hoppe RT. Breast cancer after treatment of Hodgkin’s disease. J
Natl Cancer Inst. 1993;85:25–31.
71 Metay er C, Ly nch C, Clarke EA, et al. Second cancers among long-term survivors of
Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol. 2000;18:2435–2443.
72 Henderson TO, Amsterdam A, Bhatia S, et al. Sy stematic review: surveillance for breast
cancer in women treated with chest radiation for childhood, adolescent, or y oung adult
cancer. Ann Intern Med. 2010;152:444–455.
73 Inskip PD, Robison LL, Stovall M, et al. Radiation dose and breast cancer risk in the
childhood cancer survivor study. J Clin Oncol. 2009;27:3901–3907.
74 Moskowitz CS, Chou JF, Wolden SL, et al. Breast cancer after chest radiation therapy for
childhood cancer. J Clin Oncol. 2014 32:2217–2223.
75 van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation dose, chemotherapy,
and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst.
2003;95:971–980.
76 Tay lor AJ, Little MP, Winter DL, et al. Population-based risks of CNS tumors in survivors
of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol.
2010;28:5287–5293.
77 Reulen RC, Tay lor AJ, Winter DL, et al. Long-term population-based risks of breast cancer
after childhood cancer. Int J Cancer. 2008;123:2156–2163.
78 Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for y oung
women treated for Hodgkin ly mphoma. J Natl Cancer Inst. 2005;97:1428–1437.
79 Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thy roid in survivors of Hodgkin’s
disease: data from the Childhood Cancer Survivor Study. J Clin Endocrine Metab.
2000;85:3227–3232.
80 Ronckers CM, Sigurdson AJ, Stovall M, et al. Thy roid cancer in childhood cancer
survivors: a detailed evaluation of radiation dose response and its modifiers. Radiat Res.
2006;166:618–628.
81 Bhatti P, Veiga LH, Ronckers CM, et al. Risk of second primary thy roid cancer after
radiotherapy for a childhood cancer in a large cohort study : an update from the childhood
cancer survivor study. Radiat Res. 2010;174:741–752.
82 Bhatia S, Sather HN, Pabustan OB, et al. Low incidence of second neoplasms among
children diagnosed with acute ly mphoblastic leukemia after 1983. Blood. 2002;99:4257–4264.
83 Bowers DC, Nathan PC, Constine L, et al. Subsequent neoplasms of the CNS among
survivors of childhood cancer: a sy stematic review. Lancet Oncol. 2013;14:e321–e328.
84 Pappo AS, Armstrong GT, Liu W, et al. Melanoma as a subsequent neoplasm in adult
survivors of childhood cancer: a report from the childhood cancer survivor study. Pediatr
Blood Cancer. 2013;60:461–466.
85 Little MP, de Vathaire F, Shamsaldin A, et al. Risks of brain tumour following treatment for
cancer in childhood: modification by genetic factors, radiotherapy and chemotherapy. Int J
Cancer. 1998;78:269–275.
86 Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours after
radiotherapy and antimetabolites. Lancet. 1999;354:34–39.
87 Bassal M, Mertens AC, Tay lor L, et al. Risk of selected subsequent carcinomas in survivors
of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol.
2006;24:476–483.
88 Leisenring W, Friedman DL, Flowers ME, et al. Nonmelanoma skin and mucosal cancers
after hematopoietic cell transplantation. J Clin Oncol. 2006;24:1119–1126.
89 Schwartz JL, Kopecky KJ, Mathes RW, et al. Basal cell skin cancer after total-body
irradiation and hematopoietic cell transplantation. Radiat Res. 2009;171:155–163.
90 Perkins JL, Liu Y, Mitby PA, et al. Nonmelanoma skin cancer in survivors of childhood and
adolescent cancer: a report from the childhood cancer survivor study. J Clin Oncol.
2005;23:3733–3741.
91 Braam KI, Overbeek A, Kaspers GJ, et al. Malignant melanoma as second malignant
neoplasm in long-term childhood cancer survivors: a sy stematic review. Pediatr Blood
Cancer. 2012;58:665–674.
92 Wilson CL, Ness KK, Neglia JP, et al. Renal carcinoma after childhood cancer: a report
from the childhood cancer survivor study. J Natl Cancer Inst. 2013;105:504–508.
93 Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow
transplantation for childhood acute leukemia. J Clin Oncol. 2000;18:348–357.
94 Guerin S, Dupuy A, Anderson H, et al. Radiation dose as a risk factor for malignant
melanoma following childhood cancer. Eur J Cancer. 2003;39:2379–2386.
95 Soufir N, Avril MF, Chompret A, et al. Prevalence of p16 and CDK4 germline mutations in
48 melanoma-prone families in France—The French Familial Melanoma Study Group. Hum
Mol Genet. 1998;7:209–216.
96 Bishop DT, Demenais F, Iles MM, et al. Genome-wide association study identifies three
loci associated with melanoma risk. Nat Genet. 2009;41:920–925.
97 Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term
survivors of retinoblastoma. J Natl Cancer Inst. 1993;85:1121–1128.
98 Frobisher C, Gurung PM, Leiper A, et al. Risk of bladder tumours after childhood cancer:
the British Childhood Cancer Survivor Study. BJU Int. 2010;106:1060–1069.
99 Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following
cy clophosphamide therapy for non-Hodgkin’s ly mphoma. J Natl Cancer Inst. 1995;87:524–
530.
100 Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and side
effects. N Engl J Med. 2003;348:538–549.
101 Fleitz JM, Wootton-Gorges SL, Wy att-Ashmead J, et al. Renal cell carcinoma in long-
term survivors of advanced stage neuroblastoma in early childhood. Pediatr Radiol.
2003;33:540–545.
102 Boukheris H, Stovall M, Gilbert ES, et al. Risk of salivary gland cancer after childhood
cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys.
2013;85:776–783.
104 Schneider AB, Lubin J, Ron E, et al. Salivary gland tumors after childhood radiation
treatment for benign conditions of the head and neck: dose-response relationships. Radiat Res.
1998;30:149:625.
105 Travis LB, Demark Wahnefried W, Allan JM, et al. Aetiology, genetics and prevention of
secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol. 2013;10:289–310.
106 Allan JM. Genetic susceptibility to radiogenic cancer in humans. Health Phys.
2008;95:677–686.
107 Kalow W, Ozdemir V, Tang BK, et al. The science of pharmacological variability : an
essay. Clin Pharmacol Ther. 1999;66:445–447.
108 Larson RA, Wang Y, Banerjee M, et al. Prevalence of the inactivating 609C-->T
poly morphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with
primary and therapy -related my eloid leukemia. Blood. 1999;94:803–807.
109 Berwick M, Vineis P. Markers of DNA repair and susceptibility to cancer in humans: an
epidemiologic review. J Natl Cancer Inst. 2000;92:874–897.
110 Rai R, Peng G, Li K, et al. DNA damage response: the play ers, the network and the role in
tumor suppression. Cancer Genomics Proteomics. 2007;4:99–106.
111 Felix CA, Walker AH, Lange BJ, et al. Association of CYP3A4 genoty pe with treatment-
related leukemia. Proc Natl Acad Sci U S A. 1998;95:13176–13181.
114 Bolufer P, Collado M, Barragan E, et al. Profile of poly morphisms of drug metabolizing
enzy mes and the risk of therapy -related leukaemia. Br J Haematol. 2007;136:590–596.
115 Ellis NA, Huo D, Yildiz O, et al. MDM2 SNP309 and TP53 Arg72Pro interact to alter
therapy -related acute my eloid leukemia susceptibility. Blood. 2008;112:741–749.
116 Naoe T, Takey ama K, Yokozawa T, et al. Analy sis of genetic poly morphism in NQO1,
GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy -related
leukemia/my elody splastci sy ndrome and de novo acute my eloid leukemia. Clin Cancer Res.
2000;6:4091–4095.
117 Allan JM, Wild CP, Rollingson S, et al. Poly morphism in glutathione S-transferase P1 is
associated with susceptibility to chemotherapy -induced leukemia. PNAS. 2001;98:11592–
11597.
118 Woo MH, Shuster JJ, Chen CL, et al. Gluthathione S-transferase genoty pes in children
who develop treatment-related acute my eloid malignancies. Leukemia. 2000;14.
120 Worrillow LJ, Travis LB, Smith AG, et al. An intron splice acceptor poly morphism in
hMSH2 and risk of leukemia after treatment with chemotherapeutic alky lating agents. Clin
Cancer Res. 2003;9:3012–3020.
121 Worrillow LJ, Smith AG, Scott K, et al. Poly morphic MLH1 and risk of cancer after
methy lating chemotherapy for Hodgkin ly mphoma. J Med Genet. 2008;45:142–146.
122 Jawad M, Seedhouse CH, Russell N, et al. Poly morphisms in human homeobox HLX1
and DNA repair RAD51 genes increase the risk of therapy -related acute my eloid leukemia.
Blood. 2006;108:3916–3918.
123 Allan JM, Smith AG, Wheatley K, et al. Genetic variation in XPD predicts treatment
outcome and risk of acute my eloid leukemia following chemotherapy. Blood. 2004;104:3872–
3877.
124 Seedhouse C, Bainton R, Lewis M, et al. The genoty pe distribution of the XRCC1 gene
indicates a role for base excision repair in the development of therapy -related acute
my eloblastic leukemia. Blood. 2002;100:3761–3766.
126 Guillem VM, Collado M, Terol MJ, et al. Role ofMTHFR (677, 1298) haploty pe in the risk
of developing secondary leukemia after treatment of breast cancer and hematological
malignancies. Leukemia. 2007;21:1413–1422.
127 Ding Y, Sun C-L, Li L, et al. Genetic susceptibility to therapy -related leukemia after
Hodgkin ly mphoma or non-Hodgkin ly mphoma: role of drug metabolism, apoptosis, and
DNA repair. BCJ. 2012;2:e58.
128 Knight JA, Skol AD, Shinde A, et al. Genome-wide association study to identify novel loci
associated with therapy -related my eloid leukemia susceptibility. Blood. 2009;113:5575–5582.
130 Yu CL, Tucker MA, Abramson DH, et al. Cause-specific mortality in long-term survivors
of retinoblastoma. J Natl Cancer Inst. 2009;101:581–591.
131 Best T, Li DL, Skol AD, et al. Variants at 6q21 implicate PRDM1 in the etiology of
therapy -induced second malignancies after Hodgkin’s ly mphoma. Nat Med. 2011;17:941–943.
132 Mertens AC, Mitby PA, Radloff G, et al. XRCC1 and glutathione-S-transferase gene
poly morphisms and susceptibility to radiotherapy -related malignancies in survivors of
Hodgkin disease. Cancer. 2004;101:1463–1472.
133 Bernstein JL, Haile RW, Stovall M, et al. Radiation exposure, the ATM gene, and
contralateral breast cancer in the women’s environmental cancer and radiation epidemiology
study. J Natl Cancer Inst. 2010;102:475–483.
134 Brooks JD, Teraoka SN, Reiner AS, et al. Variants in Activators and downstream targets of
ATM, radiation exposure, and contralateral breast cancer risk on the WECARE study. Hum
Mutat. 2012;33:158–164.
135 Hosking FJ, Feldman D, Bruchim R, et al. Search for inherited susceptibility to radiation-
associated meningioma by genomewide SNP linkage disequilibrium mapping. Br J Cancer.
2011;104:1049–1054.
136 Akulevich NM, Saenko VA, Rogounovitch TI, et al. Poly morphisms of DNA damage
response genes in radiation-related and sporadic papillary thy roid carcinoma. Endocr Relat
Cancer. 2009;16:491–503.
137 Bethke L, Murray A, Webb E, et al. Comprehensive analy sis of DNA repair gene variants
and risk of meningioma. J Natl Cancer Inst. 2008;100:270–276.
138 Damiola F, By rnes G, Moissonnier M, et al. Contribution of ATM and FOXE1 (TTF2) to
risk of papillary thy roid carcinoma in Belarusian children exposed to radiation. Int J Cancer.
2014;134:1659–1668.
139 Gramatges MM, Liu Q, Yasui Y, et al. Telomere content and risk of second malignant
neoplasm in survivors of childhood cancer: a report from the Childhood Cancer Survivor
Study. Clin Cancer Res. 2014;20:904–911.
140 Moll AC, Imhof SM, Schouten-Van Meeteren AY, et al. Second primary tumors in
hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on
radiation-related risk? Ophthalmology. 2001;108:1109–1114.
141 Abramson DH, Ellsworth RM, Kitchin FD, et al. Second nonocular tumors in
retinoblastoma survivors are they radiation-induced? Ophthalmology. 1984;91:1351–1355.
142 Neglia JP, Friedman DL, Yutaka Y, et al. Second malignant neoplasms in five-y ear
survivors of childhood cancer: Childhood Cancer Survivor Study. J Natl Cancer Inst.
2001;93:618–629.
143 Kleinerman RA, Tucker MA, Abramson DH, et al. Risk of soft tissue sarcomas by
individual subty pe in survivors of hereditary retinoblastoma. J Natl Cancer Inst. 2007;99:24–
31.
144 Green DM, Hy land A, Barcos MP, et al. Second malignant neoplasms after treatment for
Hodgkin’s disease in childhood or adolescence. J Clin Oncol. 2000;18:1492–1499.
145 Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast
screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75–89.
146 Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood,
adolescent, and y oung adult cancers, version 4.0. Monrovia, CA: Children’s Oncology Group;
2013. www.survivorshipguidelines.org.
147 Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices
for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow
Transplant. 2012;18:348–371.
2 Slifer KJ. A video sy stem to help children cooperate with motion control for radiation
treatment without sedation. J Pediatr Oncol Nurs. 1996;13(2):91–97.
3 Slifer KJ, Bucholtz JD, Cataldo MD. Behavioral training of motion control in y oung children
undergoing radiation treatment without sedation. J Pediatr Oncol Nurs. 1994;11(2):55–63.
4 Slifer KJ, Cataldo MF, Cataldo MD, et al. Behavior analy sis of motion control for pediatric
neuroimaging. J Appl Behav Anal. 1993;26(4):469–470.
5 Haeberli S, Grotzer MA, Niggli FK, et al. A psy choeducational intervention reduces the
need for anesthesia during radiotherapy for y oung childhood cancer patients. Radiat Oncol.
2008;3:17.
8 Sarner JB, Levine M, Davis PJ, et al. Clinical characteristics of sevoflurane in children—a
comparison with halothane. Anesthesiology. 1995;82(1):38–46.
12 Smith I, Nathanson MH, White PF. The role of sevoflurane in outpatient anesthesia. Anesth
Analg. 1995;81(suppl 6):S67–S72.
13 Grebenik CR, Ferguson C, White A. The lary ngeal mask airway in pediatric radiotherapy.
Anesthesiology. 1990;72(3):474–477.
14 Morris GN, Marjot R. Lary ngeal mask airway performance: effect of cuff deflation
during anaesthesia. Br J Anaesth. 1996;76(3):456–458.
15 Moy lan SL, Luce MA. The reinforced lary ngeal mask airway in paediatric radiotherapy.
Br J Anaesth. 1993;71(1):172.
16 Wilson IG. The lary ngeal mask airway in paediatric practice. Br J Anaesth.
1993;70(2):124–125.
17 Jacobs JR, Reves JG, Glass PS. Rationale and technique for continuous infusions in
anesthesia. Int Anesthesiol Clin. 1991;29(4):23–38.
19 Bennett JA, Bullimore JA. The use of ketamine hy drochloride anaesthesia for
radiotherapy in y oung children. Br J Anaesth. 1973;45(2):197–201.
20 Edge WG, Morgan M. Ketamine and paediatric radiotherapy. Anaesth Intensive Care.
1977;5(2):153–156.
21 Soy annwo OA, Amanor-Boadu SD, Adenipekun A, et al. Ketamine anaesthesia for y oung
children undergoing radiotherapy. West Afr J Med. 2001;20(2):136–139.
22 Cronin MM, Bousfield JD, Hewett EB, et al. Ketamine anaesthesia for radiotherapy in
small children. Anaesthesia. 1972;27(2):135–142.
23 Worrell JB, Mccune WJ. A case report: the use of ketamine and midazolam intravenous
sedation for a child undergoing radiotherapy. AANA J. 1993;61(1):99–102.
24 Menache L, Eifel PJ, Kennamer DL, et al. Twice-daily anesthesia in infants receiving
hy perfractionated irradiation. Int J Radiat Oncol Biol Phys. 1990;18(3):625–629.
26 Buehrer S, Immoos S, Frei M, et al. Evaluation of propofol for repeated prolonged deep
sedation in children undergoing proton radiation therapy. Br J Anaesth. 2007;99(4):556–560.
27 Keidan I, Perel A, Shabtai EL, et al. Children undergoing repeated exposures for radiation
therapy do not develop tolerance to propofol: clinical and bispectral index data.
Anesthesiology. 2004;100(2):251–254.
28 Seiler G, De Vol E, Khafaga Y, et al. Evaluation of the safety and efficacy of repeated
sedations for the radiotherapy of y oung children with cancer: a prospective study of 1033
consecutive sedations. Int J Radiat Oncol Biol Phys. 2001;49(3):771–783.
29 Scheiber G, Ribeiro FC, Karpienski H, et al. Deep sedation with propofol in preschool
children undergoing radiation therapy. Paediatr Anaesth. 1996;6(3):209–213.
30 Bennett SN, McNeil MM, Bland LA, et al. Postoperative infections traced to contamination
of an intravenous anesthetic, propofol. N Engl J Med. 1995;333(3):147–154.
31 Fortney JT, Halperin EC, Hertz CM, et al. Anesthesia for pediatric external beam radiation
therapy. Int J Radiat Oncol Biol Phys. 1999;44(3):587–591.
32 Daghistani D, Horn M, Rodriguez Z, et al. Prevention of indwelling central venous catheter
sepsis. Med Pediatr Oncol. 1996;26(6):405–408.
35 Shukry M, Ramadhy ani U. Dexmedetomidine as the primary sedative agent for brain
radiation therapy in a 21-month old child. Paediatr Anaesth. 2005;15(3):241–242.
36 Anghelescu DL, Burgoy ne LL, Liu W, et al. Safe anesthesia for radiotherapy in pediatric
oncology : St. Jude Children’s Research Hospital Experience, 2004–2006. Int J Radiat Oncol
Biol Phys. 2008;71(2):491–497.
37 Buchsbaum JC, McMullen KP, Douglas JG, et al. Repetitive pediatric anesthesia in a non-
hospital setting. Int J Radiat Oncol Biol Phys. 2013;85(5):1296–1300.
40 Bucholtz JD. Cost savings in pediatric monitoring during sedation for radiation therapy.
Oncol Nurs Forum. 1991;18(7):1246.
41 Bucholtz JD. Issues concerning the sedation of children for radiation therapy. Oncol Nurs
Forum. 1992;19(4):649–655.
42 ASA house of delegates, C.O.S.A.P.P. Standards for basic anesthetic monitoring (American
Society of Anesthesiologists (ASA), approved 1986 and last amended in 2004).
45 Tobias JD. Special considerations for the pediatric oncology patient. In: Berry FA, Steward
DJ, eds. Pediatrics for the Anesthesiologist. New York, NY: Churchill Livingstone; 1993:287–
303.
46 Harris EA. Sedation and anesthesia options for pediatric patients in the radiation oncology
suite. Int J Pediatr. 2010;2010:870921.
47 Keon TP. Death on induction of anesthesia for cervical node biopsy. Anesthesiology.
1981;55(4):471–472.
48 von Ungern-Sternberg BS, Boda K, Schwab C, et al. Lary ngeal mask airway is associated
with an increased risk of adverse respiratory events in children with recent upper repiratory
tract infections. Anesthesiology. 2007;107(5):714–719.
49 McFay den JG, Pelly N, Orr RJ. Sedation and anesthesia for the pediatric patient
undergoing radiation therapy. Curr Opin Anaesthesiol. 2011;24:433–438.
51 Glauber DT, Audenaert SM. Anesthesia for children undergoing craniospinal radiotherapy.
Anesthesiology. 1987;67(5):801–803.
52 Mark RJ, Bailet JW, Poen J, et al. Postirradiation sarcoma of the head and neck. Cancer.
1993;72(3):887–893.
53 Mendel P, Anaes FC, Bristow A. New methods of dealing with the complications of
panendoscopy. J Laryngol Otol. 1992;106(10):903–904.
1 Krull KR, Gioia G, Ness KK, et al. Reliability and validity of the childhood cancer survivor
study neurocognitive questionnaire. Cancer. 2008;113:2188–2197.
2 Ris MD. Lessons in pediatric neuropsy cho-oncology : what we have learned since Johnny
Gunther. J Pediatr Psychol. 2007;32:1029–1037.
3 Moore BD. Neurocognitive outcomes in survivors of childhood cancer. J Pediatr Psychol.
2005;30:51–63.
4 Mulhern RK, Reddick WE, Palmer SL, et al. Neurocognitive deficits in medulloblastoma
survivors and white matter loss. Ann Neurol. 1999;46:834–841.
5 Sugita Y, Kobay ashi S, Uegaki M, et al. [Assessment of functional status in children with
brain tumors]. No Shinkei Geka. 1987;15:643–649.
6 Mulhern RK, Hancock J, Fairclough D, et al. Neuropsy chological status of children treated
for brain tumors: a critical review and integrative analy sis. Med Pediatr Oncol. 1992;20:181–
191.
7 Dowell RE Jr, Copeland DR, Francis DJ, et al. Absence of sy nergistic effects of CNS
treatments on neuropsy chologic test performance among children. J Clin Oncol.
1991;9:1029–1036.
8 Schatz J, Kramer JH, Ablin A, et al. Processing speed, working memory, and IQ: a
developmental model of cognitive deficits following cranial radiation therapy.
Neuropsychology. 2000;14:189–200.
9 Mulhern RK, Merchant TE, Gajjar A, et al. Late neurocognitive sequelae in survivors of
brain tumors in childhood. Lancet Oncol. 2004;5:399–408.
11 Palmer SL, Gajjar A, Reddick WE, et al. Predicting intellectual outcome among children
treated with 35–40 Gy craniospinal irradiation for medulloblastoma. Neuropsychology.
2003;17:548–555.
12 Ily eskoski I, Pihko H, Wiklund T, et al. Neurologic late effects in children with malignant
brain tumors treated with surgery, radiotherapy and “8 in 1” chemotherapy. Neuropediatrics.
1996;27:124–129.
13 Mabbott DJ, Penkman L, Witol A, et al. Core neurocognitive functions in children treated
for posterior fossa tumors. Neuropsychology. 2008;22:159–168.
14 Reinhardt D, Thiele C, Creutzig U. [Neuropsy chological sequelae in children with AML
treated with or without prophy lactic CNS-irradiation]. Klin Paediatr. 2002;214:22–29.
18 Spiegler BJ, Bouffet E, Greenberg ML, et al. Change in neurocognitive functioning after
treatment with cranial radiation in childhood. J Clin Oncol. 2004;22:706–713.
19 Monleon BMC, Andreu LJA, Estelles SII, et al. [Psy chological sequelae in long term
cancer survivors]. An Esp Pediatr. 2000;3:553–560.
20 Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsy chologic functioning of survivors of
childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal
irradiation: a Pediatric Oncology Group study. J Clin Oncol. 1998;16:1723–1728.
21 Halberg FE, Wara WM, Fippin LF, et al. Low-dose craniospinal radiation therapy for
medulloblastoma. Int J Radiat Oncol Biol Phys. 1991;20:651–654.
22 Kramer JH, Crittenden MR, Halberg FE, et al. A prospective study of cognitive functioning
following low-dose cranial radiation for bone marrow transplantation. Pediatrics.
1992;90:447–449.
23 Ky ung JA, Yoo SJ, Ki WS, et al. Health-related quality of life and cognitive functioning
aton-and off-treatment periods in children aged between 6-13 y ears old with brain tumors: a
prospective longitudinal study. Yonsei Med J. 2013;54:306–314.
24 Palmer SL, Goloubeva O, Reddick WE, et al. Patterns of intellectual development in long
term survivors of pediatric medulloblastoma: a longitudinal analy sis. J Clin Oncol.
2001;19:2302–2308.
25 Askins MA, Moore BD III. Preventing neurocognitive late effects in childhood cancer
survivors. J Child Neurol. 2008;23:1160–1171.
26 Monje M. Cranial radiation therapy and damage to hippocampal neurogenesis. Dev
Disabil Res Rev. 2008;14:238–242.
27 Conklin HM, Li C, Xiong X, et al. Predicting change in academic abilities after conformal
radiation therapy for localized ependy moma. J Clin Oncol. 2008;26:3965–3970.
28 Mulhern RK, Palmer SL, Merchant TE, et al. Neurocognitive consequences of risk-
adapted therapy for childhood medulloblastoma. J Clin Oncol. 2005;20:5511–5519.
29 Mabbott DJ, Spiegler BJ, Greenberg ML, et al. Serial evaluation of academic and
behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol.
2005;23:2256–2263.
31 Shah AJ, Epport K, Azen C, et al. Progressive declines in neurocognitive function among
survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies. J
Pediatr Hematol Oncol. 2008;30:411–418.
32 Butler RW, Hill JM, Steinherz PG, et al. Neuropsy chologic effects of cranial irradiation,
intrathecal methotrexate, and sy stemic methotrexate in childhood cancer. J Clin Oncol.
1994;12:2621–2629.
33 Massimo LM, Wiley TJ, Bonassi S, et al. Longitudinal psy chosocial outcomes in two
cohorts of adult survivors from childhood acute leukaemia treated with or without cranial
radiation. Minerva Pediatr. 2006;58:1–7.
35 Mulhern RK, Palmer SL, Rddick WE, et al. Risks of y oung age for selected neurocognitive
deficits in medulloblastoma are associated with white matter loss. J Clin Oncol. 2001;19:472–
479.
36 Kiehna EN, Mulhern RK, Li C, et al. Changes in attentional performance of children and
y oung adults with localized primary brain tumors after conformal radiation therapy. J Clin
Oncol. 2006;24:5283–5290.
37 Papazoglou A, King TZ, Morris RD, et al. Attention mediates radiation’s impact on daily
living skills in children treated for brain tumors. Pediatr Blood Cancer. 2008;50:1253–1257.
38 Netson KL, Conklin HM, Wu S, et al. A 6-y ears investigation of children’s adaptive
functioning following conformal radiation therapy for localized ependy moma. Int J Radiat
Oncol Biol Phys. 2012;84:217–223.
39 Landau E, Boop FA, Conklin HM, et al. Supratentorial ependy moma: disease control,
complications, and functional outcomes after irradiation. J Radiat Oncol Biol Phys.
2013;85:e193–e199.
40 Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine,
neurocognitive and visual profiles of proton radiation for pediatric low-grade gliomas. J
Radiat Oncol Biol Phys. 2014;89:1060–1068.
42 Armstron CL, Gy ato K, Avadalla AW, et al. A crtical review of the clinical effects of the
therapeutic irradiation damage in the brain: the roots of controversy. Neuropsychol Rev.
2004;14:65–86.
44 Palmer SL, Glass JO, Li Y, et al. White matter integrity is associated with cognitive
processing in patients treated for a posterior foss brain tumor. Neuro Oncol. 2012;14:1185–
1193.
47 Whitt JK, Wells RJ, Lauria MM, et al. Cranial radiation in childhood acute ly mphocy tic
leukemia. Neuropsy chologic sequelae. Am J Dis Child. 1984;138:730–736.
48 Nelson KL, Conklin HM, Wu S, et al. Longitudinal investigation of adaptive functioning
following conformal irradiation for pediatric phary ngioma and low-grade glioma. Int J
Radiat Oncol Biol Phys. 2013;85:1301–1306.
49 Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents
surviving cancer. J Pediatr Psychol. 2005;30:65–78.
50 Tallal P, Merzenich MM, Miller SL, et al. Language learning impairments: integrating basic
science, technology, and intervention. Exp Brain Res. 1998;123:210–219.
52 Carpentieri SC, Mulhern RK, Douglas S, et al. Behavioral resiliency among children
surviving brain tumors: a longitudinal study. J Clin Child Psychol. 1993;22:236–246.
53 LeBaron S, Zeltzer PM, Zeltzer LK, et al. Assessment of quality of survival in children
with medulloblastoma and cerebellar astrocy toma. Cancer. 1988;62:179–185.
54 Mulhern RK, Carpentieri S, Shema S, et al. Factors associated with social and behavioral
problems among children recently diagnosed with brain tumor. J Pediatr Psychol.
1993;18:339–350.
55 Radcliffe J, Bennett D, Kazak AE, et al. Adjustment in childhood brain tumor survival:
child, mother, and teacher report. J Pediatr Psychol. 1996;21:529–539.
57 Vannatta K, Gerhardt CA, Wells RJ, et al. Intensity of CNS treatment for pediatric cancer:
prediction of social outcomes in survivors. Pediatr Blood Cancer. 2007;49:716–722.
60 Beneddito Monleon MC, Lopez Andreu JA, Serra Estellesl L, et al. [Psy chological
sequelae in long term cancer survivors]. An Esp Pediatr. 2000;53:553–560.
61 Ross L, Johansen C, Dalton SO, et al. Psy chitric hospitalizations among survivors of cancer
in childhood or adolescence. N Engl J Med. 2003;349:650–657.
64 Hill JM, Kornblith AB, Jones D, et al. A comparative study of the long term psy chosocial
functioning of childhood acute ly mphoblastic leukemia survivors treated by intrathecal
methotrexate with or without cranial radiation. Cancer. 1998;82:208–218.
66 Lew CC. Special needs of children. In: Dow KH, Hilderly LJ, eds. Nursing Care in
Radiation Oncology. Philadelphia, PA: Saunders; 1992:177–202.
68 Klosky JL, Ty c VL, Tong X, et al. Predicting pediatric distress during radiation therapy
procedures: the role of medical, psy chosocial, and demographic factors. Pediatrics.
2007;119:1159–1166.
70 Chiang YC, Yeh CH, Lee SC, et al. [Fatigue in pediatric oncology patients]. Hu Li Za Zhi.
2005;51:27–33.
71 Jensen SB, Pedersen AM, Vissink A, et al. A sy stematic review of salivary gland
hy pofunction and xerostomia induced by cancer therapies: prevalence, severity and impact
on quality of life. Support Care Cancer. 2010;18:1039–1060.
72 Ginsberg JP. Educational paper: the effect of cancer therapy on fertility ; the assessment of
fertility and fertility preservation options for pediatric patients. Eur J Pediatr. 2011;170:703–
708.
73 Kaley ias J, Manley P, Kothare SV, et al. Sleep disorders in children with cancer. Semin
Pediatr Neurol. 2012;19:25–34.
74 Tucker TL, Samant RS, Fitzgibbon EJ. Knowledge and utilization of pediatric radiotherapy
by paediatric oncologists. Curr Oncol. 2010;17:48–55.
75 Kreitler S, Kreitler MM. Quality of life in children. In: Kreitler S, Wey l Ben Arush M,
Martin A. eds. Pediatric Psycho-Oncology: Psychosocial Aspects and Clinical Interventions.
2nd ed. Chichester, England: Wiley -Blackwell; 2012:18–31.
76 Bucholtz JD. Comforting children during radiotherapy. Oncol Nurs Forum. 1994;21:987–
994.
77 Slifer KJ, Bucholtz JD, Cataldo MD. Behavioral training of motion control in y oung
children undergoing radiation treatment without sedation. J Pediatr Oncol Nurs. 1994;11:55–
63.
78 Garding J, Edwinson MM, Tomqvist E, et al. Caring for children undergoing radiotherapy
treatment: Swedish radiotherapy nurses’ perceptions. Eur J Oncol Nurs. 2015;19(6):660–666.
81 Klosky JL, Ty c VL, Srivastava DK, et al. Brief report: evaluation of an interactive
intervention designed to reduce pediatric distress during radiation therapy procedures. J
Pediatr Psychol. 2004;29:621–626.
82 Haeberli S, Grotzer MA, Niggli FK, et al. A psy choeducational intervention reduces the
need for anesthesia during radiotherapy for y oung childhood cancer patients. Radiat Oncol.
2008;3:17.
83 Shrimpton BJ, Willis DJ, Tongs CD, et al. Movie making as a cognitive distraction for
paeditric patients receiving radiotherapy treatment: qualitative interview study. BMJ Open.
2013;3(1).
84 Barry P, O’Callagahan C, Wheeler G, et al. Music therapy CD creation for initial pediatric
radiation therapy : a mixed methods analy sis. J Music Ther. 2010;47:233–263.
85 LeBaron S, Zeltzer L. Research on hy pnotherapy for the relief of pain, anxiety, nausea
and vomiting in children with cancer. Texas Psychol. 1985;37:12–14.
86 LeBaron S, Zeltzer LK. The role of imagery in the treatment of dy ing children and
adolescents. J Dev Behav Pediatr. 1885;6:252–258.
88 Trask CL, Welch JJ, Manley P, et al. Parental needs for information related to
neurocognitive late effects from pediatric cancer and its treatment. Pediatr Blood Cancer.
2009;52:273–279.