Survivors of Childhood and Adolescent Cancer (eBook)

Foreword 7
Acknowledgements 9
Contents 11
Chapter 1 Overview 23
Chapter 2 Algorithms of Late Effects 27
Chapter 3 Facilitating Assessment of Late Effects by Organ System 39
Chemotherapy 39
Other Terms 40
Chapter 4 Central Nervous System Effects 57
4.1 Introduction 57
4.2 Pathophysiology 57
4.2.1 Pre- and Post-Natal Brain Development 57
4.2.2 Disease Considerations 58
4.2.3 Radiation 59
4.2.4 Intrathecal Chemotherapy 61
4.2.5 Systemic Chemotherapy 61
4.3 Clinical Presentations 62
4.4 Moderators and Mediators of Central Nervous System Outcomes 64
4.5 Prevention and Intervention 65
4.5.1 Prevention: Primary and Secondary 65
4.5.2 Interventions 68
4.6 Future Directions 68
References 69
Chapter 5 Neuroendocrine Complications of Cancer Therapy 73
5.1 Pathophysiology 74
5.1.1 Normal Hypothalamic–Pituitary Axis 74
5.1.2 Injury of the Hypothalamic–Pituitary Axis in Patients with Cancer 76
5.1.3 Contribution of Radiation to Hypothalamic–Pituitary Axis Injury 78
5.2 Clinical Manifestations 82
5.2.1 GH Deficiency 82
5.2.2 LH or FSH Deficiency 82
5.2.3 Precocious or Rapid Tempo Puberty 85
5.2.4 TSH Deficiency 86
5.2.5 ACTH Deficiency 88
5.2.6 Hyperprolactinemia 88
5.2.7 Diabetes Insipidus 88
5.2.8 Osteopenia 88
5.2.9 Hypothalamic Obesity 88
5.3 Detection and Screening 89
5.3.1 Signs and Symptoms Prompting Immediate Evaluation 89
5.3.2 Surveillance of Asymptomatic Patients 89
5.3.3 GH Deficiency 89
5.3.4 LH or FSH Deficiency 89
5.3.5 Precocious Puberty 90
5.3.6 TSH Deficiency 91
5.3.7 ACTH Deficiency 91
5.3.8 Hyperprolactinemia 92
5.3.9 Diabetes Insipidus 92
5.3.10 Osteopenia 92
5.3.11 Hypothalamic Obesity 92
5.4 Management of Established Problems 93
5.4.1 GH Deficiency 93
5.4.2 LH or FSH Deficiency 95
5.4.3 Precocious Puberty 96
5.4.4 Hypothyroidism 96
5.4.5 ACTH Deficiency 97
5.4.6 Hyperprolactinemia 98
5.4.7 Diabetes Insipidus 98
5.4.8 Osteopenia 98
5.4.9 Hypothalamic Obesity 99
References 99
Chapter 6 Ocular Complications Due to Cancer Treatment 103
6.1 Introduction 104
6.2 Eyelids, Periorbital Skin and Tear Film 104
6.2.1 Anatomy and Physiology 104
6.2.2 Acute Radiation Effects 105
6.2.3 Chronic Radiation Effects 105
6.2.4 Chemotherapy 106
6.2.5 Medical and Nursing Management 106
6.3 Conjunctiva 107
6.3.1 Anatomy and Physiology 107
6.3.2 Acute Radiation Effects 107
6.3.3 Chronic Radiation Effects 107
6.3.4 Chemotherapy 107
6.3.5 Medical and Nursing Management 107
6.4 Cornea 108
6.4.1 Anatomy and Physiology 108
6.4.2 Acute Radiation Effects 108
6.4.3 Chronic Radiation Effects 108
6.4.4 Chemotherapy 109
6.4.5 Medical and Nursing Management 109
6.5 Lens 109
6.5.1 Anatomy and Physiology 109
6.5.2 Acute Radiation Effects 109
6.5.3 Chronic Radiation Effects 109
6.5.4 Chemotherapy 110
6.5.5 Medical and Nursing Management 110
6.6 Uvea: Iris,Ciliary Body and Choroid 111
6.6.1 Anatomy and Physiology 111
6.6.2 Acute Radiation Effects 111
6.6.3 Chronic Radiation Effects 111
6.6.4 Chemotherapy 111
6.6.5 Medical and Nursing Management 111
6.7 Sclera 112
6.7.1 Anatomy and Physiology 112
6.7.2 Acute Radiation Effects 112
6.7.3 Chronic Radiation Effects 112
6.7.4 Chemotherapy 112
6.7.5 Medical and Nursing Management 112
6.8 Optic Nerve and Retina 112
6.8.1 Anatomy and Physiology 112
6.8.2 Acute Radiation Effects 112
6.8.3 Chronic Radiation Effects 112
6.8.4 Chemotherapy 113
6.8.5 Medical and Nursing Management 114
6.9 Orbital Bones and Tissue 114
6.9.1 Anatomy and Physiology 114
6.9.2 Acute Radiation Effects 114
6.9.3 Chronic Radiation Effects 114
6.9.4 Chemotherapy 115
6.9.5 Medical and Nursing Management 115
6.10 Conclusion 115
References 115
Chapter 7 Head and Neck 117
7.1 Introduction 117
7.2 Pathophysiology 117
7.2.1 Normal Organ Development 117
7.2.2 Organ Damage and Developmental Effects of Cytotoxic Therapy 118
7.3 Clinical Manifestation of Late Effects 120
7.3.1 Skin and Mucous Membranes 120
7.3.2 Bone and Connective Tissue 121
7.3.3 Salivary Glands and Taste Buds 122
7.3.4 Teeth 123
7.3.5 Ear 124
7.4 Detection and Screening 124
7.5 Management of Established Problems and Rehabilitation 126
7.5.1 Oral Cavity 126
7.5.2 Bone and Connective Tissue Disease 126
7.5.3 Ears 126
References 127
Chapter 8 Adverse Effects of Cancer Treatment on Hearing 131
8.1 Introduction 131
8.2 Pathophysiology 131
8.2.1 Normal Anatomy and Physiology 131
8.2.2 Ototoxic Effects of Tumor and Therapy: Risk Factors and Incidence 133
8.2.3 Preventive Measures 136
8.3 Clinical Manifestations 139
8.3.1 Clinical Manifestations of Ototoxicity Related to Surgery or Tumor 139
8.3.2 Clinical Manifestations of Radiation-Related Ototoxicity 139
8.3.3 Clinical Manifestations of Ototoxicity Related to Pharmacologic Agents 139
8.4 Detection and Screening 140
8.4.1 Auditory Screening 140
8.4.2 Diagnostic Audiometry 140
8.4.3 Guidelines for Audiologic Monitoring 140
8.5 Management of Established Problems 142
8.5.1 Hearing Aids 142
8.5.2 Other Assistive Devices 142
8.5.3 Cochlear Implants 143
8.5.4 Communication Methods 143
8.5.5 Community and Educational Resources 143
8.6 Conclusion 143
References 144
Chapter 9 The Thyroid Gland 147
9.1 Pathophysiology 147
9.2 Clinical Manifestations 148
9.2.1 Hypothyroidism 148
9.2.2 Hyperthyroidism 151
9.2.3 Thyroid Nodules 151
9.3 Detection and Screening 152
9.4 Management 152
References 153
Chapter 10 Cardiovascular Effects of Cancer Therapy 155
10.1 Pathophysiology 156
10.1.1 Normal Organ Development 156
10.1.2 Changes Induced by Cytotoxic Therapy 156
10.2 Clinical Manifestations 160
10.2.1 Anthracyclines 160
10.2.2 Radiation 164
10.3 Detection and Screening 169
10.3.1 Assessment of Myocardial and Valvular Function 170
10.3.2 Assessment of Dysrhythmias/Conduction Abnormalities 170
10.3.3 Assessment of Coronary Artery Disease Risk Factors 171
10.3.4 Exercise Stress Testing 171
10.3.5 Invasive Procedures 171
10.3.6 Recommendations from Personal Experience 172
10.4 Preventive Measures 172
10.4.1 During Therapy 172
10.4.2 Post Therapy 173
10.5 Management of Established Problems 173
10.5.1 Cardiomyopathy, Congestive Heart Failure and Ventricular Arrhythmia 174
10.5.2 Coronary Artery Disease 175
10.5.3 Valvular Disease 176
10.5.4 Pericarditis 176
10.5.5 Other Problems 176
References 177
Chapter 11 Pulmonary Effects of Antineoplastic Therapy 183
11.1 Pathophysiology 183
11.1.1 Development of the Lung 183
11.1.2 Pathophysiologic Changes Induced by Cytotoxic Therapy 184
11.2 Clinical Manifestations 187
11.2.1 Long-Term Effect in Pediatric Population 187
11.2.2 Radiotherapy: Clinical Presentations 188
11.2.3 Chemotherapy: Clinical Manifestations 190
11.2.4 Chemotherapy–Chemotherapy Interactions 193
11.2.5 Radiation and Chemotherapy Combinations: Interaction and Tolerance 193
11.3 Detection and Screening 193
11.3.1 Measurable Endpoints 194
11.4 Management of Established Pulmonary Toxicity Induced by Cytotoxic Therapy 196
11.4.1 Precautions for Minimizing Potential Complications 196
11.4.2 Preventative Therapy 196
11.4.3 Therapy for Established Toxicity 197
11.5 Future Studies 197
References 198
Chapter 12 Late Gastrointestinal and Hepatic Effects 203
12.1 Introduction 203
12.2 Pathophysiology 204
12.2.1 Upper and Lower Gastrointestinal Tract 204
12.3 Clinical Manifestations 206
12.3.1 Radiation 206
12.3.2 Chemotherapy 208
12.3.3 Surgery 208
12.3.4 Bone Marrow Transplant 208
12.4 Detection and Screening 209
12.5 Management of Established Problems 213
12.3 Hepatobiliary Tree 214
12.3.1 Pathophysiology 214
12.3.2 Clinical Manifestations 215
12.3.3 Detection and Screening 219
12.3.4 Management 219
References 220
Chapter 13 The Ovary 225
13.1 Pathophysiology 225
13.1.1 Normal Organ Development 225
13.1.2 Organ Damage Induced by Cytotoxic Therapy 226
13.1.3 Cytotoxic Effects of Radiotherapy 226
13.1.4 Cytotoxic Effects of Chemotherapy 227
13.2 Clinical Manifestations 227
13.2.1 Effects of Radiotherapy on Ovarian Function 227
13.2.2 Effects of Chemotherapy on Ovarian Function 227
13.2.3 Effects of Radiotherapy and Chemotherapy on Reproductive Outcomes 228
13.3 Detection and Screening 229
13.4 Management of Established Problems 231
13.4.1 Prevention Strategies 231
13.4.2 Management of Delayed Puberty 232
13.4.3 Management of Infertility 233
13.4.4 Management of Pregnancy and Delivery 233
13.4.5 Management of Premature Menopause 233
13.5 Summary 233
References 234
Chapter 14 The Testes 237
14.1 Introduction 237
14.2 Pathophysiology 237
14.2.1 Overview of Normal Gonadal Development 237
14.2.2 Anatomy of Normal Testis 238
14.2.3 Hypothalamic-Pituitary-Testicular Axis 238
14.2.4 Normal Developmental Stages 239
14.3 Cytotoxic Effects of Therapy 240
14.3.1 Cytotoxic Effects of Chemotherapy 240
14.3.2 Cytotoxic Effects of Testicular Irradiation 241
14.4 Clinical Manifestations 242
14.4.1 Effects of Chemotherapy 242
14.4.2 Effects of Radiation 244
14.5 Detection and Screening 248
14.5.1 Assessment of Testicular Function 248
14.6 Management of Established Problems 249
14.6.1 Prevention of Testicular Damage 249
14.6.2 Method to Minimize Testicular Radiation Dose 249
References 250
Chapter 15 Genitourinary 253
15.1 Introduction 253
15.2 Pathophysiology 254
15.2.1 Normal Organ Development 254
15.2.2 Organ Damage and Developmental Problems 254
15.2.3 Surgery 254
15.2.4 Radiation Therapy 255
15.2.5 Chemotherapy 256
15.3 Clinical Manifestations 257
15.3.1 Kidney 257
15.3.2 Bladder 259
15.3.3 Prostate 259
15.3.4 Vagina 259
15.3.5 Uterus 259
15.3.6 Ureter 260
15.3.7 Urethra 260
15.4 Detection and Screening 260
15.4.1 Evaluation of Overt Sequelae 260
15.4.2 Screening for Preclinical Injury 260
15.4.3 Guidelines for Follow-up of Asymptomatic Patients 261
15.4.4 Management of Established Problems 261
15.5 Conclusion 262
References 263
Chapter 16 Musculoskeletal, Integument, Breast 265
16.1 Introduction 265
16.2 Musculoskeletal 266
16.2.1 Pathophysiology 266
16.2.2 Clinical Manifestations 269
16.2.3 Impact of Aging 274
16.2.4 Detection/Screening 274
16.2.5 Management of Established Problems 280
16.3 Integument and Breast 284
16.3.1 Pathophysiology 284
16.3.3 Clinical Manifestations 286
16.3.4 Detection/Screening 288
16.3.5 Management of Established Problems 288
References 289
Chapter 17 Hematopoietic Stem Cell Transplantation 293
17.1 Conditioning 293
17.2 Endocrine System 294
17.2.1 Growth 294
17.2.2 Thyroid 295
17.2.3 Diabetes and Metabolic Syndrome 295
17.2.4 Reproductive 296
17.3 Pulmonary 297
17.4 Cardiac 297
17.5 Renal 298
17.6 Ocular 298
17.7 Dental 298
17.8 Ototoxicity 298
17.9 Bone Mineral Density 299
17.10 Neuropsychologic 299
17.11 Other Issues Post HSCT 299
17.11.1 Chronic GVHD 299
17.11.2 Clinical Features 300
17.11.3 Evaluation and Therapy 300
17.12 Immune Reconstitution and Re-Immunization 301
17.12.1 Reimmunization After HSCT 301
17.13 Secondary Malignancies 301
References 302
Chapter 18 Second Malignancies Following Treatment for Childhood Cancer 305
18.1 Introduction 305
18.2 Radiation 306
18.2.1 Breast Cancer 307
18.2.2 Other Radiation-Associated SMNs 308
18.3 Chemotherapy and Secondary Leukemia 309
18.4 Bone Marrow Transplant 310
18.5 Genetic Predisposition 310
18.5.1 Retinoblastoma 310
18.5.2 Neurofibromatosis 312
18.5.3 Li–Fraumeni Syndrome 312
18.5.4 Other Predisposing Conditions 313
18.6 Summary 313
References 313
Chapter 19 Psychological Aspects of Long-Term Survivorship 317
19.1 Psychological Symptoms in Childhood Cancer Survivors 318
19.1.1 Depression and Behavioral Disorders 318
19.1.2 Posttraumatic Stress 318
19.2 Quality of Life and Functional Impact of Cancer 320
19.3 Effects on Social Development 320
19.3.1 Social Consequences for Survivors of Non-CNS Malignancies 321
19.3.2 Social Consequences for Survivors of CNS Malignancies 321
19.3.3 Social Consequences for Survivors’ Family Members 322
19.4 Implications for the Provision of Follow-Up Care 322
19.5 Research and Practice: Developing Interventions Targeting Psychological Late Effects 323
19.6 Conclusion 324
References 324
Chapter 20 Legal Issues 327
20.1 Introduction 327
20.2 The Scope of Cancer-Based Employment Problems 327
20.2.1 The Types of Employment Problems Encountered by Cancer Survivors 328
20.2.2 The Numbers of Cancer Survivors Who Encounter Employment Problems 328
20.3 Why Cancer Survivors Face Employment Problems 329
20.4 How to Combat Cancer-Based Discrimination 330
20.4.1 When Cancer-Based Discrimination is Illegal 330
20.4.2 How to Avoid Becoming a Victim of Discrimination 332
20.4.3 Fighting Back Against Discrimination 333
20.5 Health Insurance 335
20.5.1 The Impact of Cancer on Health Insurance 335
20.5.2 Cancer Patients’ Health Insurance Rights 336
20.5.3 How to Challenge a Denied Claim 338
20.6 Right to Education 339
20.6.1 Individuals with Disabilities Education Act 339
20.6.2 Americans with Disabilities Act 339
20.7 Conclusion 340
Appendix 340
References 341
Chapter 21 Methodological Issues in the Study of Survivors of Childhood Cancer 343
21.1 Introduction 343
21.1.1 Childhood Cancer Survivor Study 344
21.2 Methodological Issues Relevant to Survivor Studies 344
21.2.1 Selection of Study Subjects 344
21.2.2 Protection of Human Subjects 345
21.2.3 Bias, Confounding, Matching 345
21.2.4 Exposure Assessment 346
21.2.5 Outcome Assessment 346
21.2.6 Need for External Comparisons 347
21.2.7 Importance of Thorough Recruitment and Follow-up 347
21.2.8 Use of Molecular Tools 348
21.3 Types of Epidemiologic Study Designs 348
21.3.1 Descriptive Studies 349
21.3.2 Analytic Studies 349
21.4 Conclusion 352
References 352
Chapter 22 Transition Issues 355
22.1 Risk-Based Healthcare for Survivors 355
22.1.1 Risk-Based Healthcare: Definition and Rationale 355
22.2 First Transition Period: From Acute Cancer Care to Long-Term Follow-up 358
22.2.1 Models of Care for Follow-up During Childhood 358
22.2.2 Current Status of Risk-Based Healthcare During Childhood 359
22.2.3 Barriers to Transitioning Survivors to Childhood Follow-up 359
22.2.4 Methods to Facilitate Transition and Risk-Based Healthcare of Survivors in Their Childhood Years 359
22.3 Second Transition Period: Young Adulthood 360
22.3.1 Models of Care for Young Adult Survivors 360
22.3.2 Current Status of Risk-Based Healthcare for Young Adult Survivors 361
22.3.3 Barriers to Transitioning Survivors to Young Adult Follow-up 362
22.3.4 Methods to Facilitate Transition and Risk-Based Healthcare for Survivors in their Young Adult Years 363
References 365
Subject Index 367

Chapter 12 Late Gastrointestinal and Hepatic Effects (p. 181-182)

M. M. Hudson

12.1 Introduction ,

Radiation and speci.c chemotherapeutic agents may produce gastrointestinal (GI) or hepatic toxicity that is acute and transient in the majority of patients, but may be delayed and persistent. It should be noted, however, that these relatively uncommon late gastrointestinal and hepatic complications are potentially life threatening and capable of severely compromising quality of life. Although the most common malignancies that can be complicated by GI and hepatic injury are abdominal sarcomas (rhabdomyosarcoma and other soft tissue sarcomas), a limited number of reports describe GI complications observed in pediatric patients with genitourinary solid tumors or in those with lymphoma who underwent staging laparotomy [1–8].

Not surprisingly, the severity of GI tract and hepatic toxicity is related to the speci.c treatment modality and intensity employed, multimodal therapy confers additive risks. Other comorbid conditions, for example, transfusion-acquired hepatitis or graft versus host disease (GVHD), may enhance risk [9–17]. Many reports describe complications resulting from now outdated treatment modalities. As a result, the current paucity of literature about long-term gastrointestinal outcomes may be due to the low frequency of these complications after contemporary therapy. However, longterm outcomes after veno-occlusive disease, chronic graft-versus-host disease and transfusion-acquired hepatitis remain to be established, as these conditions have been associated with subclinical liver dysfunction that may predispose aging childhood cancer survivors to clinically signi.cant liver disease [11, 16–20].

This chapter will summarize complications involving the GI tract and hepatobiliary tree observed following treatment for childhood cancer in the context of normal organ pathophysiology. These sequelae may develop after a variety of therapeutic interventions, for example, radiation, chemotherapy, surgery or bone marrow transplantation,or they may result from supportive therapies such as blood product transfusion. Guidelines for monitoring predisposed childhood cancer survivors and recommendations for health-protective, risk-reducing counseling will also be provided.

12.2 Pathophysiology

12.2.1 Upper and Lower Gastrointestinal Tract

12.2.1.1 Normal Anatomy and Physiology

The upper GI tract extends from the oropharynx to the ileocecal valve and includes the esophagus, stomach and small intestine. The esophagus is a distensible tube lined by an inner mucosa of squamous epithelium, surrounded by a submucosa, a muscularis externa (composed of both striated and smooth muscle) and an outermost connective tissue layer. The neurovascular supply and mucous glands, which are located primarily in submucosa, open into the lumen of the esophagus.

The lower esophageal sphincter prevents esophageal injury from re.ux of gastric contents, while the epithelium and mucous glands protect against peptic injury. Salivation and esophageal peristalsis also protect the esophageal mucosa by facilitating acid clearance. Located inferior to the left hemidiaphragm, the stomach is anatomically divided into the cardia, fundus, body and antrum. A thick, muscular-walled pylorus forms a sphincter that connects the gastric antrum to the duodenum. The stomach is lined by an inner mucosa of columnar epithelium that is surrounded by a submucosa and an outer muscularis comprised of longitudinal and circular smooth muscle. Gastric mucosal glands secrete mucus, hydrochloric acid or hormones that regulate gastric secretions and motility.