PEDIATRIC ONCOLOGY

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PEDIATRIC ONCOLOGY

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Survivors

of Childhood and

Adolescent Cancer

123

Second Edition

With 49 Figures and 61 Tables

Cindy L. Schwartz · Wendy L. Hobbie Louis S. Constine · Kathleen S. Ruccione (Eds.)

A Multidisciplinary Approach

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Cindy L. Schwartz

The Sidney Kimmel Cancer Center at Johns Hopkins

Johns Hopkins Hospital 600 North Wolfe Street Baltimore, MD 21287-5001 USA

Phone: 410-955-7385 E-mail: schwaci@jhmi.edu

Wendy L. Hobbie

Childrens Hospital of Philadelphia Division of Oncology

34^thSt. & Civic Ctr. Blvd.

Philadelphia, PA 19104 USA

E-mail: hobbie@email.chop.edu

Louis S. Constine

University of Rochester Medical Center Radiation Oncology and Pediatrics 601 Elmwood Avenue/Box 647 Rochester, NY 14642

USA

E-mail: louis_constine@urmc.rochester.edu

Kathleen S. Ruccione

Childrens Hospital Los Angeles Center for Cancer and Blood Diseases 4650 Sunset Boulevard

Los Angeles, CA 90027 USA

E-mail: kruccione@chla.usc.edu

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microﬁlm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law.

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Medical Editor: Dr. Julia Heidelmann, Heidelberg, Germany Desk Editor: Meike Stoeck, Heidelberg, Germany

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Springer Berlin Heidelberg NewYork ISSN 1613-5318

Originally published in 1994 by Mosby-Year Book, Inc., St. Louis, Missouri, USA

Title: Survivors of Childhood Cancer:

Assessment and Management 00_Schwartz_Titelei 03.02.2005 15:25 Uhr Seite IV

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To the memory of those children for whom our knowledge

was insufﬁcient;

to those children who have been cured but must approach adult life

with the residua of treatment;

and to the children of the future

who will beneﬁt from scientiﬁc advances that may limit

treatment toxicity

so as to truly approachre cure.

V

Dedication

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It was not long ago that clinicians would say, “study the late complications of cancer treatments we give to children? You must be joking! We can start worrying about that when we start curing them! Meanwhile, cure must be our only aim.” These practitioners were only partially correct in what seemed to be a glaring truth, for, in fact, increasing numbers of children were beginning to survive their malignancy, and the long-term consequences of therapy would soon become critical.

It is well to remember that the delayed consequences of a cancer treatment delivered to developing organisms were first studied long ago. It has been 100 years since Perthes reported in 1903 that growth was impaired in juvenile creatures (chicks) that were irradiated [6]. During radiation therapy, strategies to circumvent this problem were set in motion, with the judicious placement of treatment fields as a first step [5].

It was not, however, until the 1940s that chemical agent-induced remissions of childhood leukemia and responses of solid tumors, such as nephroblastoma, were reported [2,3]. The focus, nonetheless, remained the same, and rightly so: namely, ﬁnding how best to integrate surgery, radiation and, later, chemotherapy in ways that would cure cancer. As strides were made with increasingly successful combined modality regimens, short-term toxicities began to become the ob- ject of study, and soon they were identiﬁed. Contin- ued advances in treatment resulted in dramatic in- creases in long-term survival, drawing attention to late effects.

The ﬁrst large-scale meeting to deal with issues related to toxicity was convened by the National Cancer Institute in 1975 [7]. Pediatric oncology had not been idle prior to this, of course, as several papers present-

ed at the 1975 meeting revealed. Among them was one based on data collected by the Late Effects Study Group, an international consortium that consisted initially of five, then ten, pediatric centers. This was the first large scale, cooperative unit of its kind, or- ganized specifically for the purpose of studying the late effects of cancer therapy (the study of delayed complications had been included as part of the orig- inal design in the National Wilms Tumor Study launched in 1969) [1]. These historical notes demon- strate that the epidemiologic, statistical and record- keeping mechanisms necessary for studying long- term survivors effectively were in the process of being established decades before the meeting in 1975.

History is ﬁne, but one may still wonder: why should we study the late effects that might follow treatment of children 30 years ago? Those treatments are now antiquated, if not obsolete. The answer is that these patients must be followed for a lifetime to as- certain the true late effects of their therapies, and this is important regardless of what is being used today.

The reason is because, even though treatments have been reﬁned, it does not follow that the lower doses of radiation therapy or of the various chemotherapeutic agents currently used are free of potential late effects.

Consider the cardiotoxic anthracyclines, for example.

While it is true that no congestive heart failure ex- cesses have been noted in patients given the current low doses of doxorubicin speciﬁed in certain current Wilms tumor treatment regimens [4], the follow-up of these patients is relatively short, a maximum of twenty years. What will happen in the next twenty years? Will 40-, 50- and 60-year olds who received therapy decades before show latent damage?

The evolution of late effect studies has been ex- tremely useful in working out in considerable detail

VII

Foreword

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VIII Foreword

practical and efficient research methods and techniques. Just as the treatments used in the past and those currently used have benefited from the early studies, so, too, will future treatments benefit from current studies. It is very likely that in the future many of the therapies will be completely new or very different from any currently in the armamentarium.

The established epidemiologic and statistical techniques used to measure outcomes, and the means of tracking long-term survivors for late follow-up ex- aminations, will be invaluable as the years roll by.

For, no matter how new the treatments, it is likely that there will always be side effects, at least until the ultimate discovery of the “magic bullets” that affect sin- gularly and precisely only the malignant cells, leaving nearby normal cells unscathed.

Let us not lose sight of the reason these studies are pursued: it is to inform the survivors themselves and their families of what to expect as the years go by.

This volume brings together relevant invaluable material in a practical, easily understood form, with information extracted from the thousands of articles dealing with the chronic adversities of therapy. A re- cent survey showed that more than twenty-five hun- dred articles concerned with late effects have been published in the last five years alone. The readers of this volume, therefore, owe the editors a debt of grat- itude for enlisting the multi-disciplinary array of contributing authors. Physicians, nurses, experts from other professions and lay persons all have as- sisted in condensing and bringing order out of this very complex matrix of information. These outstand- ing authorities offer up-to-date information on many different topics related to the late effects of juvenile cancer treatments. Together, they afford the reader a comprehensive, definitive overview of this com- pelling aspect of pediatric oncology.

The ultimate goal of pediatric oncology has been – and remains – to ensure not only the health, but also the psychosocial and economic well-being of children cured of malignant diseases. Parents have ques- tions concerning all these issues, and what the future holds for their sons and daughters. So do the young men and women who themselves were treated suc- cessfully for cancer years before.

This book provides answers to their many ques- tions.

Giulio J. D’Angio, MD

Hospital of the University of Pennsylvania, Radiation Oncology, 2 Donner Building, 3400 Spruce Street, Philadelphia, PA 19104–4238

References

1. Evans AE, Norkool P, Evans I, Breslow N, D’Angio GJ. Late effects of treatment for Wilms tumor. A report from the Na- tional Wilms Tumor Study Group. Cancer 1991; 67:331–336 2. Farber S, Diamond LK, Mercer RD, et al. Temporary remis-

sions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin).

NEJM 1948; 328:787–793

3. Farber S, Toch R, Sears EM, Pinkel D. Advances in chemotherapy in cancer in man. Adv Cancer Res 1956; 4:1 4. Green DM, Grigoriev YA, Nan B, et al. Congestive heart fail-

ure after treatment for Wilms tumor. A report from the National Wilms Tumor Study Group. J Clin Oncol 2001;

19:1926–1934

5. Neuhauser, EBD, Wittenborg MH, Berman CZ, Cohen J.

Irradiation effects of roentgen therapy on the growing spine. Radiology 1952; 59:637–650

6. Perthes G. Ueber den Einﬂuss der Roentgen-Strahlen auf epithelial Gewebe insbensondere auf das Carcinom. Archiv Fuer Klinische Chirurgie 1903; 71:955–982

7. Proceedings of the National Cancer Institute Conference on the Delayed Consequences of Cancer Therapy. Proven and Potential. Cancer 1976; 37:999–1936

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IX

Ten years ago we embarked on the mission of creat- ing a text that would foster a more complete under- standing of the long-term toxicity of cancer therapy.

Although progress has been impressive in the last decade, and long-term survivorship programs have been established at most pediatric oncology institu- tions, we still are on a journey toward the goal of optimizing the quality of survival for children with cancer.

Our personal families have matured in the years since the ﬁrst edition was written. The joy we receive from observing the achievements of our children (Jaffa, Adam, Tali, Jonathan, Sarah, Alysia, Joshua and Daniel) encourage our work to provide all children with the chance for a healthy life, ﬁlled with opportu- nity. Our spouses (Howard, Danny and Sally) contin- ue to be the unwavering supports that have enabled this work to proceed. As we have struggled to nurture our children, we are also even more appreciative of the role our own parents (Ruth, Jerry, Catrine, Michael, Mike, Nancy and Louis) have played in our efforts to reach our goals.

Indeed, it is often parents who are the greatest advocates for their children, and this is particularly true

for children with cancer. We may provide advice, but it is they who sit at the bedside after hours during the child’s therapy, and it is they who, once the child is cured, help him or her tackle the world. Their success is now visible in the new cohort of advocates: the survivors themselves. One in 500 young adults had cancer before the age of 20. These young adults not only support each other, they work together to ensure an even better future for those now affected.

In the previous edition we thanked our own men- tors for teaching us the importance of long-term survivorship and for supporting our efforts. Just as parents nurture their children and are proud to watch them engage the future, we are proud to acknowledge our appreciation of the many young physicians, nurses, social workers and others who are focused on im- proving the lives of survivors of childhood and adolescent cancer. We hope that this second edition of our text will provide them with the background to achieve even greater success. With their collective in- telligence, dedication and caring, we know that children diagnosed with cancer in the next era can look forward to happier and more productive lives than ever before.

Acknowledgements

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1 Overview. . . 1

Cindy L. Schwartz, Wendy L. Hobbie, Louis S. Constine, Kathleen S. Ruccione 2 Algorithms of Late Effects by Disease. . . 5

Cindy L. Schwartz, Wendy L. Hobbie, Louis S. Constine 3 Facilitating Assessment of Late Effects by Organ System . . . 17

Cindy L. Schwartz, Wendy L. Hobbie, Louis S. Constine Chemotherapy. . . 17

Other Terms . . . 18

4 Central Nervous System Effects. . . 35

Nina S. Kadan-Lottick, Joseph P. Neglia 4.1 Introduction . . . 35

4.2 Pathophysiology . . . 35

4.2.1 Pre- and Post-Natal Brain Development . . 35

4.2.2 Disease Considerations . . . 36

4.2.3 Radiation . . . 37

4.2.4 Intrathecal Chemotherapy . . . 39

4.2.5 Systemic Chemotherapy . . . 39

4.3 Clinical Presentations . . . 40

4.4 Moderators and Mediators of Central Nervous System Outcomes . . . 42

4.5 Prevention and Intervention . . . 43

4.5.1 Prevention: Primary and Secondary . . . 43

4.5.2 Interventions . . . 46

4.6 Future Directions . . . 46

References . . . 47

5 Neuroendocrine Complications of Cancer Therapy . . . 51

Wing Leung, Susan R. Rose, Thomas E. Merchant 5.1 Pathophysiology . . . 52

5.1.1 Normal Hypothalamic–Pituitary Axis . . . . 52

5.1.1.1 Growth Hormone. . . 53

5.1.1.2 Gonadotropins . . . 53

5.1.1.3 Thyroid-Stimulating Hormone . . . 54

5.1.1.4 Adrenocorticotropin . . . 54

5.1.1.5 Prolactin . . . 54

5.1.2 Injury of the Hypothalamic–Pituitary Axis in Patients with Cancer . . . 56

5.1.3 Contribution of Radiation to Hypothalamic–Pituitary Axis Injury . . . 56

5.2 Clinical Manifestations . . . 60

5.2.1 GH Deﬁciency . . . 60

5.2.2 LH or FSH Deﬁciency . . . 60

5.2.3 Precocious or Rapid Tempo Puberty . . . 63

5.2.4 TSH Deﬁciency . . . 64

5.2.5 ACTH Deﬁciency . . . 66

5.2.6 Hyperprolactinemia . . . 66

5.2.7 Diabetes Insipidus . . . 66

5.2.8 Osteopenia . . . 66

5.2.9 Hypothalamic Obesity . . . 66

5.3 Detection and Screening . . . 67

5.3.1 Signs and Symptoms Prompting Immediate Evaluation . . . 67

5.3.2 Surveillance of Asymptomatic Patients . . . 67

5.3.5 Precocious Puberty . . . 68

5.3.6 TSH Deﬁciency . . . 69

5.3.10 Osteopenia . . . 70

5.3.11 Hypothalamic Obesity . . . 70 XI

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5.4 Management of Established Problems . . . 71

5.4.3 Precocious Puberty . . . 74

5.4.4 Hypothyroidism . . . 74

5.4.8 Osteopenia . . . 76

5.4.9 Hypothalamic Obesity . . . 77

6 Ocular Complications due to Cancer Treatment. . . 81

Michael Ober, Camille A. Servodidio, David Abramson 6.1 Introduction . . . 82

6.2 Eyelids, Periorbital Skin and Tear Film . . . 82

6.2.1 Anatomy and Physiology . . . 82

6.2.2 Acute Radiation Effects . . . 83

6.2.3 Chronic Radiation Effects . . . 83

6.2.4 Chemotherapy . . . 84

6.2.5 Medical and Nursing Management . . . 84

6.3 Conjunctiva . . . 85

6.4 Cornea . . . 86

6.5 Lens . . . 87

6.6 Uvea: Iris, Ciliary Body and Choroid . . . 89

6.7 Sclera . . . 90

6.8 Optic Nerve and Retina . . . 90

6.9 Orbital Bones and Tissue . . . 92

6.10 Conclusion . . . 93

7 Head and Neck . . . 95

Arnold C. Paulino, Mary Koshy, Della Howell 7.1 Introduction . . . 95

7.2.1 Normal Organ Development . . . 95

7.2.2 Organ Damage and Developmental Effects of Cytotoxic Therapy . . . 96

7.2.2.1 Skin and Mucous Membranes . . . . 96

7.2.2.2 Bone and Connective Tissue . . . 97

7.2.2.3 Salivary Glands and Taste Buds. . . . 97

7.2.2.4 Teeth . . . 97

7.2.2.5 Ear. . . 98

7.3 Clinical Manifestation of Late Effects . . . 98

7.3.1 Skin and Mucous Membranes . . . 98

7.3.2 Bone and Connective Tissue . . . 99

7.3.3 Salivary Glands and Taste Buds . . . 100

7.3.4 Teeth . . . 101

7.3.5 Ear . . . 102

7.5 Management of Established Problems and Rehabilitation . . . 104

7.5.1 Oral Cavity . . . 104

7.5.2 Bone and Connective Tissue Disease . . . . 104

7.5.3 Ears . . . 104

8 Adverse Effects of Cancer Treatment on Hearing . . . 109

Wendy Landier, Thomas E. Merchant 8.1 Introduction . . . 109

8.2.1 Normal Anatomy and Physiology . . . 109

8.2.2 Ototoxic Effects of Tumor and Therapy: Risk Factors and Incidence . . . 111

8.2.2.1 Surgery and Tumor . . . 111

8.2.2.2 Radiation Therapy . . . 112

8.2.2.3 Pharmacologic Therapy . . . 113

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8.3.1 Clinical Manifestations of Ototoxicity Related to Surgery or Tumor . . . 117

8.3.2 Clinical Manifestations of Radiation-Related Ototoxicity . . . 117

8.3.3 Clinical Manifestations of Ototoxicity Related to Pharmacologic Agents. . . 117

8.4.1 Auditory Screening . . . 118

8.4.2 Diagnostic Audiometry . . . 118

8.4.2.1 Pure Tone Audiometry . . . 118

8.4.2.2 Brainstem Auditory-Evoked Response . . . 118

8.4.3 Guidelines for Audiologic Monitoring . . . 118

8.5 Management of Established Problems . . . 120

8.5.1 Hearing Aids . . . 120

8.5.2 Other Assistive Devices . . . 120

8.5.3 Cochlear Implants . . . 121

8.5.4 Communication Methods . . . 121

8.5.5 Community and Educational Resources . . 121

8.6 Conclusion . . . 121

9 The Thyroid Gland . . . 125

Tithi Biswas, Louis S. Constine, Cindy L. Schwartz 9.1 Pathophysiology . . . 125

9.2.1 Hypothyroidism . . . 126

9.2.2 Hyperthyroidism . . . 129

9.2.3 Thyroid Nodules . . . 129

9.4 Management . . . 130

10 Cardiovascular Effects of Cancer Therapy . . . 133

M. Jacob Adams, Sarah A. Duffy, Louis S. Constine, Steven E. Lipshultz 10.1 Pathophysiology . . . 134

10.1.2 Changes Induced by Cytotoxic Therapy . 134 10.1.2.1 Anthracyclines . . . 134

10.1.2.2 Cyclophosphamide . . . 135

10.1.2.3 Radiation . . . 135

10.2 Clinical Manifestations . . . 138

10.2.1 Anthracyclines . . . 138

10.2.1.1 Spectrum of Anthracycline Damage. . . 138

10.2.1.2 Risk Factors for Anthracycline- Induced Cardiotoxicity . . . 140

10.2.2 Radiation . . . 142

10.2.2.1 Coronary Artery Disease and Mortality from All Cardiac Causes. . . 144

10.2.2.2 Pericarditis . . . 145

10.2.2.3 Cardiomyopathy . . . 145

10.2.2.4 Valvular Disease. . . 146

10.2.2.5 Dysrhythmia/ Conduction Abnormalities . . . . 146

10.3 Detection and Screening . . . 147

10.3.1 Assessment of Myocardial and Valvular Function . . . 148

10.3.2 Assessment of Dysrhythmias/ Conduction Abnormalities . . . 148

10.3.3 Assessment of Coronary Artery Disease Risk Factors . . . 149

10.3.4 Exercise Stress Testing . . . 149

10.3.5 Invasive Procedures . . . 149

10.3.6 Recommendations from Personal Experience . . . 150

10.4 Preventive Measures . . . 150

10.4.1 During Therapy . . . 150

10.4.2 Post Therapy . . . 151

10.5 Management of Established Problems . . . 151

10.5.1 Cardiomyopathy, Congestive Heart Failure and Ventricular Arrhythmia . 152 10.5.2 Coronary Artery Disease . . . 153

10.5.3 Valvular Disease . . . 154

10.5.4 Pericarditis . . . 154

10.5.5 Other Problems . . . 154

11 Pulmonary Effects of Antineoplastic Therapy. . . 161

Andrea S. Hinkle, Cindy Proukou, Yuhchyau Chen 11.1 Pathophysiology . . . 161

11.1.1 Development of the Lung . . . 161

11.1.2 Pathophysiologic Changes Induced by Cytotoxic Therapy . . . 162

11.2.1 Long-Term Effect in Pediatric Population . . . 165

11.2.2 Radiotherapy: Clinical Presentations . . . 166

11.2.2.1 Subacute Radiation Pneumonitis. 166 11.2.2.2 Radiation Fibrosis . . . 166

11.2.2.3 Radiation Tolerance Doses and Tolerance Volumes . . . 167

11.2.3 Chemotherapy: Clinical Manifestations . . 168

11.2.4 Chemotherapy– Chemotherapy Interactions . . . 171

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11.3.1 Measurable Endpoints . . . 172

11.4 Management of Established Pulmonary Toxicity Induced by Cytotoxic Therapy . . . 174

11.4.1 Precautions for Minimizing Potential Complications . 174 11.4.2 Preventative Therapy . . . 175

11.4.3 Therapy for Established Toxicity . . . 175

11.5 Future Studies . . . 175

12 Late Gastrointestinal and Hepatic Effects . . . 181

M.M. Hudson 12.1 Introduction . . . 181

12.2 Pathophysiology . . . 182

12.2.1 Upper and Lower Gastrointestinal Tract . 182 12.2.1.1 Normal Anatomy and Physiology. 182 12.2.1.2 Organ Damage Induced by Cytotoxic Therapy . . . 182

12.3.1 Radiation . . . 184

12.3.3 Surgery . . . 186

12.3.4 Bone Marrow Transplant . . . 186

12.3 Hepatobiliary Tree . . . 192

12.3.1 Pathophysiology . . . 192

12.3.1.1 Normal Anatomy and Physiology. 192 12.3.1.2 Changes Induced by Cytotoxic Therapy . . . 192

12.3.2 Clinical Manifestations . . . 193

12.3.2.1 Radiation . . . 194

12.3.2.2 Chemotherapy . . . 194

12.3.2.3 Hepatic Veno-Occlusive Disease . 194 12.3.2.4 Bone Marrow Transplant . . . 195

12.3.2.5 Transfusion-Acquired Chronic Hepatitis . . . 195

12.3.2.6 Other Late Hepatobiliary Complications. . . 196

12.3.3 Detection and Screening . . . 197

12.3.4 Management . . . 197

13 The Ovary . . . 203

Debra L. Friedman 13.1 Pathophysiology . . . 203

13.1.2 Organ Damage Induced by Cytotoxic Therapy . . . 204

13.1.3 Cytotoxic Effects of Radiotherapy . . . 204

13.1.4 Cytotoxic Effects of Chemotherapy . . . . 205

13.2.1 Effects of Radiotherapy on Ovarian Function . . . 205

13.2.2 Effects of Chemotherapy on Ovarian Function . . . 205

13.2.3 Effects of Radiotherapy and Chemotherapy on Reproductive Outcomes . . . 206

13.4.1 Prevention Strategies . . . 209

13.4.2 Management of Delayed Puberty . . . 210

13.4.3 Management of Infertility . . . 211

13.4.4 Management of Pregnancy and Delivery . 211 13.4.5 Management of Premature Menopause . 211 13.5 Summary . . . 211

14 The Testes . . . 215

Jill P. Ginsberg, Amit Maity 14.1 Introduction . . . 215

14.2.1 Overview of Normal Gonadal Development . . . 215

14.2.2 Anatomy of Normal Testis . . . 216

14.2.3 Hypothalamic-Pituitary-Testicular Axis . . 216

14.2.4 Normal Developmental Stages . . . 217

14.3 Cytotoxic Effects of Therapy . . . 218

14.3.1 Cytotoxic Effects of Chemotherapy . . . . 218

14.3.2 Cytotoxic Effects of Testicular Irradiation . 219 14.4 Clinical Manifestations . . . 220

14.4.1 Effects of Chemotherapy . . . 220

14.4.1.1 Treatment-Induced Leydig Cell Failure from Chemotherapy . . . 221

14.4.2 Effects of Radiation . . . 222

14.4.2.1 Leydig Cell Function Following Radiotherapy . . . 223

14.4.2.2 Testicular Function Following Total Body Irradiation. . . 224

14.4.2.3 Summary . . . 225

14.5.1 Assessment of Testicular Function . . . 226

14.6.1 Prevention of Testicular Damage . . . 227

14.6.2 Method to Minimize Testicular Radiation Dose . . . 227

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15 Genitourinary . . . 231

Lawrence Marks, Nicole Larrier 15.1 Introduction . . . 231

15.2.2 Organ Damage and Developmental Problems . . . 232

15.2.3 Surgery . . . 232

15.2.4 Radiation Therapy . . . 233

15.2.4.1 Kidney. . . 233

15.2.4.2 Bladder, Ureter and Urethra. . . . 233

15.2.4.3 Prostate, Uterus and Vagina. . . . 234

15.2.5.1 Kidney. . . 234

15.2.5.2 Bladder . . . 234

15.3.1 Kidney . . . 235

15.3.1.1 Surgery . . . 235

15.3.1.2 Radiation . . . 235

15.3.1.3 Chemotherapy . . . 235

15.3.1.4 Aging Effects . . . 237

15.3.2 Bladder . . . 237

15.3.2.1 Surgery . . . 237

15.3.2.2 Radiation . . . 237

15.3.2.3 Chemotherapy . . . 237

15.3.3 Prostate . . . 237

15.3.4 Vagina . . . 237

15.3.5 Uterus . . . 237

15.3.6 Ureter . . . 238

15.3.7 Urethra . . . 238

15.4.1 Evaluation of Overt Sequelae . . . 238

15.4.2 Screening for Preclinical Injury . . . 238

15.4.3 Guidelines for Follow-up of Asymptomatic Patients . . . 239

15.4.4 Management of Established Problems . . 239

15.4.4.1 Therapy . . . 239

Kidney . . . 239

Bladder . . . 240

Ureter and Urethra . . . 240

Prostate, Vagina and Uterus. . . 240

Rehabilitation. . . 240

15.5 Conclusion . . . 240

16 Musculoskeletal, Integument, Breast^{. . 243}

Robert B. Marcus, Jr., Matthew R. DiCaprio, Dieter M. Lindskog, Brian E. McGrath, Kathy Gamble, Mark Scarborough 16.1 Introduction . . . 243

16.2 Musculoskeletal . . . 244

16.2.1.1 Normal Organ Development . . . 244

16.2.1.2 Organ Damage Induced by Cytotoxic Therapy . . . 244

16.2.2.1 Bone. . . 248

Bone Density Changes . . . 248

Physeal Injury. . . 248

Pathologic Fractures . . . 250

Osteonecrosis. . . 250

16.2.2.2 Muscle. . . 250

16.2.3 Impact of Aging . . . 252

16.2.4 Detection/Screening . . . 252

16.2.4.1 Spinal Sequelae. . . 253

16.2.4.2 Limb Length Discrepancy. . . 253

16.2.4.3 Other Bony Sequelae . . . 257

16.2.4.4 Muscle. . . 257

16.2.5.1 Management . . . 258

16.2.5.2 Rehabilitation. . . 261

16.3 Integument and Breast . . . 262

16.3.1.1 Brief Overview of Normal Organ Development. . 262

Skin . . . 262

Breast. . . 262

16.3.2.2 Organ Damage Induced by Cytotoxic Therapy . . . 262

Skin . . . 262

16.3.4 Detection/Screening . . . 266

16.3.5.1 Management and Rehabilitation. 266 References . . . 267

17 Hematopoietic Stem Cell Transplantation. . . 271

Nancy Bunin, Constance DiDomenico, Virginia Guzikowski 17.1 Conditioning . . . 271

17.2 Endocrine System . . . 272

17.2.1 Growth . . . 272

17.2.2 Thyroid . . . 273

17.2.3 Diabetes and Metabolic Syndrome . . . . 273

17.2.4 Reproductive . . . 274

17.3 Pulmonary . . . 275

17.4 Cardiac . . . 275

17.5 Renal . . . 276

17.6 Ocular . . . 276

17.7 Dental . . . 276

17.8 Ototoxicity . . . 276

17.9 Bone Mineral Density . . . 277

17.10 Neuropsychologic . . . 277

17.11 Other Issues Post HSCT . . . 277

17.11.1 Chronic GVHD . . . 277

17.11.2 Clinical Features . . . 278

17.11.3 Evaluation and Therapy . . . 278 00_Schwartz_Titelei 03.02.2005 15:25 Uhr Seite XV

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XVI Contents

17.12 Immune Reconstitution

and Re-Immunization . . . 279

17.12.1 Reimmunization After HSCT . . . 279

17.13 Secondary Malignancies . . . 279

18 Second Malignancies Following Treatment for Childhood Cancer. . . 283

Barbara Anne Hieb, Susan K. Ogle, Anna T. Meadows 18.1 Introduction . . . 283

18.2 Radiation . . . 284

18.2.1 Breast Cancer . . . 285

18.2.2 Other Radiation-Associated SMNs . . . 286

18.2.2.1 Skin Cancer . . . 286

18.2.2.2 Thyroid Cancer . . . 286

18.2.2.3 Sarcomas of Bone. . . 286

18.2.2.4 Secondary CNS Tumors. . . 287

18.3 Chemotherapy and Secondary Leukemia . . . . 287

18.4 Bone Marrow Transplant . . . 288

18.5 Genetic Predisposition . . . 288

18.5.1 Retinoblastoma . . . 288

18.5.2 Neuroﬁbromatosis . . . 290

18.5.3 Li–Fraumeni Syndrome . . . 290

18.5.4 Other Predisposing Conditions . . . 291

18.6 Summary . . . 291

19 Psychological Aspects of Long-Term Survivorship . . . 295

Mary T. Rourke, Anne E. Kazak 19.1 Psychological Symptoms in Childhood Cancer Survivors . . . 296

19.1.1 Depression and Behavioral Disorders . . . 296

19.1.2 Posttraumatic Stress . . . 296

19.2 Quality of Life and Functional Impact of Cancer . . . 298

19.3 Effects on Social Development . . . 299

19.3.1 Social Consequences for Survivors of Non-CNS Malignancies . . 299

19.3.2 Social Consequences for Survivors of CNS Malignancies . . . 299

19.3.3 Social Consequences for Survivors’ Family Members . . . 300

19.4 Implications for the Provision of Follow-Up Care . . . 300

19.5 Research and Practice: Developing Interventions Targeting Psychological Late Effects . . . 301

19.6 Conclusion . . . 302

20 Legal Issues. . . 305

Barbara Hoffman 20.1 Introduction . . . 305

20.2 The Scope of Cancer-Based Employment Problems . . . 305

20.2.1 The Types of Employment Problems Encountered by Cancer Survivors . . . 306

20.2.2 The Numbers of Cancer Survivors Who Encounter Employment Problems . 306 20.3 Why Cancer Survivors Face Employment Problems . . . 307

20.4 How to Combat Cancer-Based Discrimination . . 308

20.4.1 When Cancer-Based Discrimination is Illegal . . . 308

20.4.1.1 Americans with Disabilities Act. . 308

20.4.1.2 Family and Medical Leave Act . . 308

20.4.1.3 Employee Retirement and Income Security Act . . . 309

20.4.1.4 Federal Executive Order on Genetic Information. . . 309

20.4.1.5 State Employment Rights Laws. . 310

20.4.2 How to Avoid Becoming a Victim of Discrimination . . . 310

20.4.3 Fighting Back Against Discrimination . . . 311

20.5 Health Insurance . . . 313

20.5.1 The Impact of Cancer on Health Insurance . . . 313

20.5.2 Cancer Patients’ Health Insurance Rights . 314 20.5.2.1 Federal Health Insurance Laws . . 314

Americans with Disabilities Act . . . 314

Health Insurance Portability and Accountability Act . . . 314

Comprehensive Omnibus Budget Reconciliation Act. . . 315

Employee Retirement and Income Security Act 315 20.5.2.2 State Insurance Laws . . . 316

20.5.3 How to Challenge a Denied Claim . . . 316

20.6 Right to Education . . . 317

20.6.1 Individuals with Disabilities Education Act 317 20.6.2 Americans with Disabilities Act . . . 317

20.7 Conclusion . . . 318

Appendix . . . 318

References . . . 319 00_Schwartz_Titelei 03.02.2005 15:25 Uhr Seite XVI

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XVII Contents

21 Methodological Issues in the Study

of Survivors of Childhood Cancer . . . . 321

Ann C. Mertens, Yutaka Yasui 21.1 Introduction . . . 321

21.1.1 Childhood Cancer Survivor Study . . . 322

21.2 Methodological Issues Relevant to Survivor Studies . . . 322

21.2.1 Selection of Study Subjects . . . 322

21.2.2 Protection of Human Subjects . . . 323

21.2.3 Bias, Confounding, Matching . . . 323

21.2.4 Exposure Assessment . . . 324

21.2.5 Outcome Assessment . . . 324

21.2.5.1 Conﬁrmation of Key Medical Events. . . 325

21.2.6 Need for External Comparisons . . . 325

21.2.7 Importance of Thorough Recruitment and Follow-up . . . 325

21.2.7.1 Tracing Techniques . . . 325

21.2.8 Use of Molecular Tools . . . 326

21.3 Types of Epidemiologic Study Designs . . . 326

21.3.1 Descriptive Studies . . . 327

21.3.2 Analytic Studies . . . 327

21.3.2.1 Case-Control Study . . . 327

21.3.2.2 Cohort Study . . . 328

21.3.2.4 Nested Case-Control Design . . . 328

21.3.2.5 Case-Cohort Design. . . 329

21.3.2.6 Intervention Studies . . . 329

21.4 Conclusion . . . 330

22 Transition Issues . . . 333

Kevin C. Oefﬁnger, Debra A. Eshelman 22.1 Risk-Based Healthcare for Survivors . . . 333

22.1.1 Risk-Based Healthcare: Deﬁnition and Rationale . . . 333

22.2 First Transition Period: From Acute Cancer Care to Long-Term Follow-up . . . 336

22.2.1 Models of Care for Follow-up During Childhood . . . 336

22.2.2 Current Status of Risk-Based Healthcare During Childhood . . . 337

22.2.3 Barriers to Transitioning Survivors to Childhood Follow-up . . . 337

22.2.4 Methods to Facilitate Transition and Risk-Based Healthcare of Survivors in Their Childhood Years . . . 337

22.3 Second Transition Period: Young Adulthood . . . 338

22.3.1 Models of Care for Young Adult Survivors 338 22.3.2 Current Status of Risk-Based Healthcare for Young Adult Survivors . . . 339

22.3.3 Barriers to Transitioning Survivors to Young Adult Follow-up . . . 340

22.3.4 Methods to Facilitate Transition and Risk-Based Healthcare for Survivors in their Young Adult Years . . . 341

Subject Index . . . 345 00_Schwartz_Titelei 03.02.2005 15:25 Uhr Seite XVII

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David Abramson M.D., F.A.C.S.

Clinical Professor of Ophthalmology Weill Cornell Medical Center

New York-Presbyterian Hospital, 70 East 66th Street New York, NY 10021, USA

M. Jacob Adams MD, MPH Assistant Professor of Community and Preventive Medicine

The University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue

Box 644, Rochester, NY 14642, USA

Tithi Biswas

Department of Radiation Oncology University of Rochester School of Medicine and Dentistry, Strong Memorial Hospital/

The University of Rochester Medical Center 601 Elmwood Avenue, Box 647, Rochester NY 14642, USA

Nancy Bunin

Professor of Pediatrics

The Children’s Hospital of Philadelphia 34^thStreet and Civic Center Blvd.

Philadelphia, PA 19104-4399, USA

Yuhchyau Chen

Associate Professor of Radiation Oncology University of Rochester School of Medicine and Dentistry, Strong Memorial Hospital/

Louis S. ConstineMD

Professor of Radiation Oncology and Pediatrics University of Rochester School of Medicine and Dentistry, Strong Memorial Hospital/

Matthew R. DiCaprioMD Department of Orthopedics

University of Florida Health Science Center Gainesville, Florida, USA

Constance DiDomenicoMSN, CRNP Professor of Pediatrics

Sarah A. DuffyMS

Senior Research Associate

Department of Pediatrics, University

of Miami School of Medicine, P.O Box 016820 Miami, Florida 33101, USA

Debra A. Eshelman RN, MSN, CPNP

University of Texas Southwestern Medical Center at Dallas, TX, and Children’s Medical Center Dallas, TX, the After the Cancer Experience (ACE) Young Adult Program, 6263 Harry Hines Blvd.

Dallas, TX 75390-9067, USA

XIX

Contributors

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XX Contributors

Debra L. Friedman

Children’s Hospital and Regional Medical Center

Assistant Professor

Children’s Hospital & Regional Medical Ctr 4800 Sand Point Way NE; Mailstop 6d-1 Seattle, WA 98105, USA

Kathy GambleRN

Pediatric Hematology/Oncology

Jill P. GinsbergMD

Children’s Hospital of Philadelphia 34^th& Civic Center Blvd.

4^thFloor, Wood Building Philadelphia, PA 19104, USA

Virginia GuzikowskiMSN, CRNP The Children’s Hospital of Philadelphia 34^thStreet and Civic Center Blvd.

Barbara Anne HiebMSN, CRNP

Andrea S. HinkleMD

Division of Pediatric Hematology/Oncology Golisano Children’s at Strong

University of Rochester Medical Center Box 777, 601 Elmwood Ave

Rochester, NY 14642, USA

Wendy L. Hobbie

Children’s Hospital of Philadelphia Division of Oncology

34^thSt. & Civic Ctr. Blvd.

Philadelphia, PA 19104, USA

Barbara Hoffman, J.D.

9 Madison Drive, Princeton Junction NJ 08550, USA

Della HowellMD

Department of Pediatrics

Division of Hematology/Oncology Emory University and Children’s

Healthcare of Atlanta, Atlanta, GA 30322, USA

Melissa Hudson

St. Jude Children’s Research Hospital Memphis Pediatric hematology/oncology

332 North Lauderdale Street Memphis, Tn 38105, USA

Anne E. KazakPhD, ABPP

Childrens Hospital of Philadelphia Division of Oncology

324 South 34^thStreet Philadelphia, PA 19104, USA

Mary KoshyMD

Department of Radiation Oncology Emory University and Emory Clinic Atlanta, GA 30322, USA

Wendy LandierRN, MSN, CPNP, CPON Pediatric Nurse Practitioner

City of Hope National Medical Center, Duarte California, Assistant Clinical Professor UCLA School of Nursing, Los Angeles California, 1500 E. Duarte Rd., MOB-4, Duarte CA 91010-3000, USA

Dieter M. LindskogMD Department of Orthopedics

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XXI Contributors

Steven E. LipshultzMD

Professor and Chairman of Pediatrics Professor of Public Health and Epidemiology Professor of Medicine, University of Miami School of Medicine, P.O Box 016820

Miami, Florida 33101, USA

Wing Leung

St. Jude Children’s Research Hospital Memphis Hematology/Oncology

332 North Lauderdale Street Memphis, Tn 38105, USA

Nina S. Kadan-LottickMD, MSPH

Assistant Professor, Pediatrics Department of Pediatrics, Section of Pediatric Hematology- Oncology, Yale University School of Medicine 333 Cedar St, LMP 2073, New Haven, CT 06520

Amit MaityMD

Department of Radiation Oncology Hospital of the University of Pennsylvania 195 John Morgan Building

University of Pennsylvania School of Medicine 3620 Hamilton Walk

Philadelphia, PA 19104, USA

Robert B. Marcus, Jr.MD

Department of Radiation Oncology Emory Healthcare, 1365 Clifton Road Atlanta, GA 30322, USA

Lawrence MarksMD

Box 3085 Duke Univ Med Ctr Durham NC 27710, USA

Brian E. McGrathMD Department of Orthopedics

State University of New York at Buffalo 100 High Street, Buffalo, NY 14203, USA

Anna T. MeadowsMD

Children’s Hospital of Philadelphia 34^th& Civic Center Blvd.

4^thFloor Wood Building Philadelphia, PA 19104, USA

Thomas E. MerchantDO, PhD

Chief, Division of Radiation Oncology Department of Radiologic Sciences St. Jude Children’s Research Hospital

Memphis, Tennessee, 332 North Lauderdale Street Memphis, TN 38105, USA

Ann MertensPhD Department of Pediatrics University of Minnesota MMC 715, 420 Delaware St, SE, Minneapolis, MN 55455, USA

Joseph P. Neglia MD

Division of Pediatric Hem/Onc Room D 557 Mayo Bldg./MMC 484 420 Delaware St., SE

Minneapolis, MN 55455, USA

Michael OberMD

(e-mail: obermike@aol.com) Fellow, Vitreo-Retinal Surgery Columbia College of Physicians

and Surgeons, Edward S. Harkness Eye Institute 635 West 165th Street, New York, NY 10032, USA

Kevin C. OefﬁngerMD

Department of Family Practice and Community Medicine, University of Texas Southwestern Medical Center at Dallas, 6263 Harry Hines Blvd.

Dallas, TX 75390-9067, USA

Susan K. OgleMSN, CRNP

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XXII Contributors

Arnold C. PaulinoMD

Department of Radiation Oncology, A1300 1365 Clifton Road, N.E., Atlanta, GA 30322, USA

Cindy ProukouRN, CPNP Special Care Nursery Highland Hospital 1000 South Avenue Rochester, NY 14620, USA

Susan R. RoseMD

Professor of Pediatrics and Endocrinology Cincinnati Children’s Hospital Medical Center and University of Cincinnati

3333 Burnet Avenue

Cincinnati, Ohio 45229-3039, USA

Mary T. RourkePhD

Kathleen S. RuccioneMPH, RN Childrens Hospital Los Angeles Center for Cancer and Blood Diseases 4650 Sunset Boulevard

Los Angeles, CA 90027, USA

Mark ScarboroughMD Department of Orthopedics

Cindy L. SchwartzMD

The Sidney Kimmel Cancer Center at Johns Hopkins

Johns Hopkins Hospital 600 North Wolfe Street

Baltimore, MD 21287-5001, USA

Camille A. ServodidioRN, MPH

70 East 66th Street, New York, NY 10021, USA

Yutaka YasuiPhD

Cancer Prevention Research Program Division of Public Health Sciences Fred Hutchinson Cancer Research Center P.O. Box 19024, 1100 Fairview Ave. N., MP702 Seattle, WA 98109-1024, USA

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