Long-Term Follow-Up
Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers

Version 6.0 - October 2023

Website: www.survivorshipguidelines.org
Copyright 2023 © Children’s Oncology GroupAll rights reserved worldwide

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers
Version 6.0 – October 2023

www.survivorshipguidelines.org
Copyright 2023 © Children’s Oncology GroupAll rights reserved worldwide
Generously supported byWith special appreciation to
Anna DeVine, RN, BSN, CPN, CPHON
Oncology-Survivorship
St. Jude Children’s Research Hospitalfor editing and typesetting

Contents
Introductory Materials

Page

Section #

Page

Sex

Therapeutic Agent

Potential Late Effect

x

13

14

Male

Alkylating Agents

Impaired spermatogenesis

Disclaimer and Notice of Proprietary Rights

xi

14

16

Female Alkylating Agents

Ovarian hormone deficiencies

Contributors - Panel of Experts

xii

15

18

Female Alkylating Agents

Diminished ovarian reserve (DOR)

Contributors - Task Force Membership 2019-2023

xv

16

20

Alkylating AgentsAcute myeloid leukemia; Myelodysplasia

Contributors - Guideline Development Task Force - Initial Versions

xx

17

21

Alkylating Agents

Pulmonary fibrosis

Preface

xxi

18

22

Alkylating Agents

Cataracts

Instructions for Use

xxvi

19

23

Alkylating Agents

Urinary tract toxicity

New to Version 6.0

xxviii

20

24

Alkylating Agents

Bladder malignancy

Abbreviations and parameters

xxxi

21

25

Alkylating Agents

Renal toxicity

22

26

Heavy Metals

Ototoxicity

23

28

Heavy Metals

Peripheral sensory neuropathy

24

29

Heavy Metals

Renal toxicity

25

30

Antimetabolites

Neurocognitive deficits

26

31

Antimetabolites

No known late effects (cytarabine [lowdose IV, IO, IT, SQ])

27

32

Antimetabolites

Hepatic dysfunction; Sinusoidal
obstruction syndrome (SOS)28

33

Antimetabolites

No known BMD late effects (methotrexate)

29

34

Antimetabolites

No known renal late effects (methotrexate)3035Antimetabolites

Hepatic dysfunction

3136

Antimetabolites

Neurocognitive deficits

32

37

Antimetabolites

Clinical leukoencephalopathy

33

38

Anthracycline Antibiotics

Acute myeloid leukemia

Abstract

Section #

Page

Sex

Therapeutic Agent

Potential Late Effect

Any Cancer Experience1

1

Any Cancer Experience

Adverse psychosocial/quality of life
effects

2

3

Any Cancer Experience

Mental health disorders

3

4

Any Cancer Experience

Risky behaviors

45

Any Cancer Experience

Psychosocial disability due to pain

5

6

Any Cancer Experience

Fatigue; Sleep problems

6

7

Any Cancer Experience

Limitations in healthcare and insurance
access7

8

Any Cancer Experience

Subsequent malignancy/Risk ofmalignancy in offspring

Blood/Serum Products
89Diagnosed prior to 1972

Chronic hepatitis B

34

39

Anthracycline Antibiotics

Cardiac toxicity

910

Diagnosed prior to 1993

Chronic hepatitis C

35

41

Anti-Tumor Antibiotics

Pulmonary toxicity

10

11

Diagnosed between 1977
and 1985

HIV infection

36

42

Anti-Tumor Antibiotics

No known late effects (dactinomycin)

37

43

Corticosteroids

Reduced bone mineral density (BMD)

Chemotherapy
11

12

12

13

Male

38

45

Corticosteroids

Osteonecrosis (avascular necrosis)

Any Chemotherapy

Dental abnormalities

39

46

Corticosteroids

Cataracts

Alkylating Agents

Testicular hormonal dysfunction

40

47

Enzymes

No known late effects (asparaginase)

COG LTFU Guidelines – Page v

Version 6.0 - October 2023

Table of Contents

Contents (cont)Section #

Page

41

48

Sex

Therapeutic Agent

Potential Late EffectSection #Page

Plant Alkaloids

Peripheral sensory or motor neuropathy

68

Sex

Therapeutic Agent

Potential Late Effect78

Neck/Thyroid

Thyroid cancer

79

Neck/Thyroid

Hypothyroidism

42

49

Plant Alkaloids

Vasospastic attacks (Raynaud's
phenomenon)

69
70

80

Neck/Thyroid

Hyperthyroidism

43

50

Epipodophyllotoxins

Acute myeloid leukemia

71

81

Neck/Thyroid

Carotid artery disease

72

82

Neck/Thyroid

Subclavian artery disease73

83

Female Breast

Breast cancer

74

84

Female Breast

Breast tissue hypoplasia

75

85

Lungs

Pulmonary toxicity

76

86

Lungs

Lung cancer

77

87

Heart

Cardiac toxicity

78

89

SpleenFunctional asplenia

79

90

GI/Hepatic System

Esophageal stricture

80

91

GI/Hepatic System

Impaired glucose metabolism/Diabetes
mellitus

Radiation
44

52

All Fields

Subsequent benign or malignant neoplasm
occurring in or near radiation field

45

53

All Fields

Dermatologic toxicity

46

54

Brain/Cranium

Brain tumor (benign or malignant)

47

55

Brain/Cranium

Neurocognitive deficits

48

57

Brain/Cranium

Clinical leukoencephalopathy

49

58

Brain/Cranium

Cerebrovascular complications

50

59

Brain/Cranium

Craniofacial abnormalities

51

60

Brain/Cranium

Chronic sinusitis

52

61

Neuroendocrine Axis

Overweight; Obesity

81

92

GI/Hepatic System

Dyslipidemia

53

63

Neuroendocrine Axis

Growth hormone deficiency

82

93

GI/Hepatic System

Hepatic toxicity

54

64

Male

Neuroendocrine Axis

Precocious puberty

83

94

GI/Hepatic System

Cholelithiasis

55

65

Female Neuroendocrine Axis

Precocious puberty

84

95

GI/Hepatic System

Bowel obstruction

56

66

Neuroendocrine Axis

Hyperprolactinemia

85

96

GI/Hepatic System

Chronic enterocolitis; Fistula; Strictures

57

67

Neuroendocrine Axis

Central hypothyroidism

86

97

GI/Hepatic System

Colorectal cancer

58

68

Male

Neuroendocrine Axis

Gonadotropin deficiency

87

98

Urinary Tract

Renal toxicity

59

69

Female Neuroendocrine Axis

Gonadotropin deficiency

88

99

Urinary Tract

Urinary tract toxicity

60

70

Neuroendocrine Axis

Central adrenal insufficiency

89

100

Urinary Tract

Bladder malignancy

61

71

Eye

Cataracts

90

101

Male

Male Reproductive System

Testicular hormonal dysfunction

62

72

Eye

Ocular toxicity

91

102

Male

Male Reproductive System

Impaired spermatogenesis

63

73

Ear

Ototoxicity

92

103

Ovarian hormone deficiencies

64

74

Oral Cavity

Xerostomia; Salivary gland dysfunction

Female Female Reproductive
System65

75

Oral Cavity

Dental abnormalities; Temporomandibular
joint dysfunction

93

104

Female Female Reproductive
SystemDiminished ovarian reserve

66

76

Oral Cavity

Osteoradionecrosis of the jaw

94

106

Uterine vascular insufficiency

67

77

Neck/Thyroid

Thyroid nodules

Female Female Reproductive
System

COG LTFU Guidelines – Page vi

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Table of Contents

Contents (cont)Section #

Page

Sex

Therapeutic Agent

95

107

Female Female Reproductive
System

96

108

97

109

98

110

Potential Late EffectSection #

Page

Sex

Vaginal fibrosis/stenosis

119

134

Female Hysterectomy

Musculoskeletal System

Musculoskeletal growth problems

120

135

Laparotomy

Adhesions; Bowel obstruction

Musculoskeletal System

Scoliosis/Kyphosis

121

136

Limb Sparing Procedure

Musculoskeletal System

Radiation-induced fracture

Complications related to limb sparing
procedure

Nephrectomy

Hydrocele; Renal toxicity

Hematopoietic Cell Transplant (HCT)

Therapeutic Agent

Potential Late EffectPelvic floor dysfunction; Urinary
incontinence; Sexual dysfunction

122

137

Male

Auto HCT

Acute myeloid leukemia; Myelodysplasia

123

138

Female Nephrectomy

HCT

Solid tumors

124

139

Neurosurgery-Brain

Neurocognitive deficits

Female HCT

Solid tumors

125

140

Neurosurgery-Brain

Motor and/or sensory deficits

HCT

Hepatic toxicity

126

141

Neurosurgery-Brain

Seizures

HCT

Osteonecrosis (avascular necrosis)

127

142

Neurosurgery-Brain

Hydrocephalus; Shunt malfunction

117

HCT

Reduced bone mineral density (BMD)

128

143

Neurosurgery-Brain

Overweight; Obesity

105

119

HCT

Renal toxicity

129

144

Neurosurgery-Brain

Diabetes insipidus

106

120

With Chronic GVHD

Dermatologic toxicity

130

145

Neurosurgery-Spinal Cord

Neurogenic bladder; Urinary incontinence

107

121

With Chronic GVHD

Xerophthalmia (keratoconjunctivitis sicca)

131

146

Neurosurgery-Spinal Cord

Neurogenic bowel; Fecal incontinence

108

122

With Chronic GVHD

Oral toxicity

132

147

Male

Neurosurgery-Spinal Cord

Psychosexual dysfunction

109

123

With Chronic GVHD

Pulmonary toxicity

133

148

Female Neurosurgery-Spinal Cord

Psychosexual dysfunction

110

124

With Chronic GVHD

Immunologic complications

134

149

111

125

With CURRENTLY ACTIVE
Chronic GVHD

Functional asplenia

135

150

Female Oophoropexy

Oophoropexy-related complications

136

151

Female Oophorectomy (Unilateral)

Ovarian hormone deficiencies

112

127

With Chronic GVHD

Esophageal stricture

137

152

Female Oophorectomy (Unilateral)

Diminished ovarian reserve

113

128

Female With Chronic GVHD

Vulvar scarring; Vaginal fibrosis/stenosis

138

153

Female Oophorectomy (Bilateral)

114

129

With Chronic GVHD

Ovarian hormone deficiencies; Loss ofovarian follicular pool

139

154

Male

Orchiectomy (Unilateral,
Partial)Testicular hormonal dysfunction

140

155

Male

Orchiectomy (Unilateral,
Partial)Impaired spermatogenesis

141

156

Male

Orchiectomy (Bilateral)

Testosterone deficiency; Azoospermia

142

157

Pelvic Surgery; Cystectomy

Urinary incontinence; Urinary tract
obstruction

99

112

100

113

Male

101

114

102

115

103

116

104

Neurosurgery-Spinal Cord

Joint contractures

Surgery
115

130

Amputation

Amputation-related complications

116

131

Central Venous Catheter

Thrombosis; Vascular insufficiency;
Infection of retained cuff or line tract;
Post-thrombotic syndrome

117

132

Cystectomy

Cystectomy-related complications

118

133

Enucleation

Impaired cosmesis; Poor prosthetic fit;
Orbital hypoplasia

COG LTFU Guidelines – Page vii

Renal toxicity

Scoliosis/Kyphosis

Version 6.0 - October 2023

Table of Contents

Contents (cont)Section #

Page

Sex

143

158

144

159

Male

145

160

Male

146

161

Female Pelvic Surgery; Cystectomy

147

162

Splenectomy

Asplenia

148

163

Thoracic Surgery

149

164

150
151

General Health Screening

Therapeutic Agent

Potential Late EffectPelvic Surgery; Cystectomy

Fecal incontinence

164

179

General Health Screening

Pelvic Surgery; Cystectomy

Psychosexual dysfunction

165

180

General Health Vaccinations

Pelvic Surgery; Cystectomy

Sexual dysfunction (anatomic); Infertility

Appendix I: Materials for Clinical Application of LTFU Guidelines

Sexual dysfunction

Reference Materials

2

Abbreviations

3

Pulmonary dysfunction

Chemotherapy Agents

5

Thoracic Surgery

Scoliosis/Kyphosis

Radiation Fields Defined

6

165

Thyroidectomy

Hypothyroidism

Radiation Dose Calculations

9

166

Partial Thyroidectomy

Hypothyroidism

Guideline Radiation Sections by Field

10

Guideline Radiation Sections by Potential Impact

11

Total Body Irradiation (TBI) Related Potential Late Effects

14

Other Therapeutic Models

Page

152

167

Systemic Radiation (I-131)

Lacrimal duct atrophy

153

168

Systemic Radiation (I-131)

Hypothyroidism

154

169

Systemic Radiation (I-131)

Xerostomia; Salivary gland dysfunction;
Chronic sialadenitis

155

170

Systemic Radiation (MIBG)

Hypothyroidism

156

171

Systemic Radiation (MIBG)

Thyroid nodules

157

172

Systemic Radiation (MIBG)

Thyroid cancer

Instructions

20

158

173

Bioimmunotherapy

Insufficient information available
regarding late effects

Template for Summary of Cancer Treatment (Abbreviated)

22

Template for Summary of Cancer Treatment (Comprehensive)

23

Key for Completing Summary of Cancer Treatment (Comprehensive)

25

159
160

174
175

BCR-ABL tyrosine kinase
inhibitors
BCR-ABL tyrosine kinase
inhibitors

Appeal Letter Following Denial of Insurance Claims for Survivorship Care176

Other targeted biologic
therapies

Insufficient information available
regarding late effects

162

177

B-cell directed antibodybased therapies

Immunologic complications

163

178

Other antibody-based
immune therapies(antibody drug
conjugates)

Insufficient information available
regarding late effects

Template for Letter from Patient, Parent, or Guardian17

Template for Letter from Long-Term Follow-Up Clinician

18

Patient-Specific Guideline Identification Tool

Hypothyroidism

161

16

Summary of Cancer Treatment

Growth attenuation

COG LTFU Guidelines – Page viii

15

Instructions

19

31

Instructions

32

Patient-Specific Guideline Identification Tool (Version 5.0)

33

Section Number Comparison - COG LTFU Guidelines Version 6.0 vs 5.0

39

Appendix II: Health Links (Patient Education Materials)

Page

Health Links

x

Health Links Index by Title

3

Version 6.0 - October 2023

Table of Contents

Long-Term
Follow-Up
Guidelines
for Survivors of Childhood,
Adolescent, and Young Adult Cancers

Introductory
Materials
Version 6.0
October 2023

Abstract
Release date:

October 2023

Status:Updated from Version 5.0 incorporating modifications based on recommendations from the Children’s Oncology Group’s Long-Term Follow-Up Guideline Core Committee andits associated multidisciplinary Task Forces.

Overview:

These risk-based, exposure-related clinical practice guidelines provide recommendations for screening and management of late effects in survivors of pediatric malignancies.
(“Pediatric malignancies” are defined as those malignancies commonly associated with the pediatric population that may arise during childhood, adolescence or young
adulthood.) A complementary set of patient education materials, known as “Health Links” accompany the guidelines in order to enhance patient follow-up visits and broaden
the application of these guidelines. Additional accompanying materials include detailed instructions, templates for cancer treatment summary forms, a radiation reference
guide, and a tool to assist in identifying guideline applicability for individual survivors based on therapeutic exposures. The information provided in these guidelines isimportant for primary healthcare providers in the fields of pediatrics, oncology, internal medicine, family practice, and gynecology, as well as subspecialists in many fields.
Implementation of these guidelines is intended to increase awareness of potential late effects and to standardize and enhance follow-up care provided to survivors of pediatricmalignancies throughout their lifespan.

Source:Version 6.0 of the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, and related Health Links, canbe downloaded in their entirety from www.survivorshipguidelines.org.

Suggested Citations for COG Long-Term Follow-Up Guidelines
Guidelines
Children’s Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers, Version 6.0. Monrovia, CA: Children’s Oncology Group; October
2023; Available on-line: www.survivorshipguidelines.org.
Guidelines Methodology
Landier W, Bhatia S, Eshelman DA, Forte KJ, Sweeney T, Hester AL, Darling J, Armstrong FD, Blatt J, Constine LS, Freeman CR, Friedman DL, Green DM, Marina N, Meadows AT, Neglia JP,
Oeffinger KC, Robison LL, Ruccione KS, Sklar CA, Hudson MM. 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(24):4979-90.
Health Links Background and Application
Eshelman D, Landier W, Sweeney T, Hester AL, Forte K, Darling J & Hudson MM. Facilitating care for childhood cancer survivors: integrating Children’s Oncology Group long-term follow-up
guidelines and health links in clinical practice. J Pediatr Oncol Nurs 2004; 21(5): 271-280.

COG LTFU Guidelines – Page x

Version 6.0 - October 2023

Table of Contents

Disclaimer and Notice of Proprietary Rights
Introduction to Late Effects Guidelines and Health Links: The Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers and accompanying Health
Links were developed by the Children’s Oncology Group as a collaborative effort of the Late Effects Committee and Nursing Discipline and are maintained and updated by the Children’s Oncology
Group’s Long-Term Follow-Up Guidelines Core Committee and its associated Task Forces.
For Informational Purposes Only: The information and contents of each document or series of documents made available by the Children’s Oncology Group relating to late effects of cancer
treatment and care or containing the title Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers or the title Health Link, whether available in print
or electronic format (including any digital format, e-mail transmission, or download from the website), shall be known hereinafter as “Informational Content”. All Informational Content is for
informational purposes only. The Informational Content is not intended to substitute for medical advice, medical care, diagnosis or treatment obtained from a physician or healthcare provider.
To cancer survivors (if children, their parents or legal guardians): Please seek the advice of a physician or other qualified healthcare provider with any questions you may have regarding a
medical condition and do not rely on the Informational Content. The Children’s Oncology Group is a research organization and does not provide individualized medical care or treatment.
To physicians and other healthcare providers: The Informational Content is not intended to replace your independent clinical judgment, medical advice, or to exclude other legitimate criteria
for screening, health counseling, or intervention for specific complications of childhood cancer treatment. Neither is the Informational Content intended to exclude other reasonable alternative
follow-up procedures. The Informational Content is provided as a courtesy, but not intended as a sole source of guidance in the evaluation of childhood cancer survivors. The Children’s
Oncology Group recognizes that specific patient care decisions are the prerogative of the patient, family, and healthcare provider.
No endorsement of any specific tests, products, or procedures is made by Informational Content, the Children’s Oncology Group, or affiliated party or member of the Children’s Oncology Group.
No Claim to Accuracy or Completeness: While the Children’s Oncology Group has made every attempt to assure that the Informational Content is accurate and complete as of the date of
publication, no warranty or representation, express or implied, is made as to the accuracy, reliability, completeness, relevance, or timeliness of such Informational Content.
No Liability on Part of Children’s Oncology Group and Related Parties/Agreement to Indemnify and Hold Harmless the Children’s Oncology Group and Related Parties: No liability is
assumed by the Children’s Oncology Group or any affiliated party or member thereof for damage resulting from the use, review, or access of the Informational Content. You agree to the following
terms of indemnification: (i) “Indemnified Parties” include authors and contributors to the Informational Content, all officers, directors, representatives, employees, agents, and members of theChildren’s Oncology Group and affiliated organizations; (ii) by using, reviewing, or accessing the Informational Content, you agree, at your own expense, to indemnify, defend and hold harmless
Indemnified Parties from any and all losses, liabilities, or damages (including attorneys’ fees and costs) resulting from any and all claims, causes of action, suits, proceedings, or demands related
to or arising out of use, review or access of the Informational Content.
Proprietary Rights: The Informational Content is subject to protection under the copyright law and other intellectual property law in the United States and worldwide. The Children’s Oncology
Group retains exclusive copyright and other right, title, and interest to the Informational Content and claims all intellectual property rights available under law. You hereby agree to help theChildren’s Oncology Group secure all copyright and intellectual property rights for the benefit of the Children’s Oncology Group by taking additional action at a later time, action which could
include signing consents and legal documents and limiting dissemination or reproduction of Informational Content.

COG LTFU Guidelines – Page xi

Version 6.0 - October 2023

Table of Contents

Contributors
Panel of Experts
The following members of the Children’s Oncology Group Long-Term Follow-Up (LTFU) Guidelines Core Committee participated in comprehensive review and scoring of Version 6.0 of the Children’s Oncology Group Long-Term
Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:

CORE COMMITTEE
Smita Bhatia, MD, MPH
Co-Chair, COG LTFU Guidelines Core Committee
Professor and Vice Chair, Pediatrics
Director, Institute for Cancer Outcomes and SurvivorshipChildren’s Hospital of Alabama
University of Alabama at Birmingham
Birmingham, AL
Louis S. Constine, MD, FASTRO, FACR
The Philip Rubin Professor of Radiation Oncology and Pediatrics
Vice Chair, Department of Radiation Oncology
Director, The Judy DiMarzo Cancer Survivorship Program
James P. Wilmot Cancer institute
University of Rochester Medical Center
Rochester, NY

Saro Armenian, DO, MPH
Professor, Departments of Pediatrics and Population Sciences
Director, Center for Survivorship and Outcomes
City of Hope Comprehensive Cancer Center
Duarte, CA
Melissa A. Acquazzino, MD, MS
Associate Professor, Pediatrics
Medical Director Pediatric Cancer Survivorship Clinic
University of Nebraska Medical Center andChildren’s Hospital & Medical Center
Omaha, NE
Johnnie K. Bass, AuD, PhD
Research Audiologist, Rehabilitation Services
St. Jude Children’s Research Hospital
Memphis, TN

COG LTFU Guidelines – Page xii

Matthew J. Ehrhardt, MD, MS
Co-Chair, COG LTFU Guidelines Core Committee
Associate Member, Department of Oncology
St. Jude Children’s Research Hospital
Memphis, TN
Danielle N. Friedman, MD, MS
Co-Chair, COG LTFU Guidelines Core Committee
Associate Member, Department of Pediatrics
Director, Pediatric Survivorship Fellowship
Memorial Sloan Kettering Cancer Center
New York, NY

Alicia Kunin-Batson, PhD
Associate Professor, Pediatrics
Associate Director of Research
Clinical Behavioral Neuroscience
University of Minnesota Medical School
Minneapolis, MN
Daniel C. Bowers, MD
Professor, Pediatrics and Neurological Surgery
Director, After the Cancer Experience Program
UT Southwestern Medical School
Dallas, TX
Sharon Castellino, MD, MSc
Professor of Pediatrics
Emory University
Director, Leukemia/Lymphoma Program
Aflac Cancer and Blood Disorders Center
Children’s Healthcare of Atlanta
Atlanta, GA
Table of Contents

Melissa M. Hudson, MD
Co-Chair, COG LTFU Guidelines Core Committee
Member, Department of Oncology
Co-Leader, Cancer Control & Survivorship Program
Director, Cancer Survivorship Division and After Completion of
Therapy Program
St. Jude Children’s Research Hospital
Memphis, TN
Wendy Landier, PhD, CRNP
Co-Chair, COG LTFU Guidelines Core Committee
Professor, Pediatrics
Deputy Director, Institute for Cancer Outcomes and Survivorship
School of Medicine, University of Alabama at Birmingham
Birmingham, AL
Kay W. Chang, MD
Professor, Department of Otolaryngology
Stanford University School of Medicine
Palo Alto, CA
Wassim Chemaitilly, MD
Clinical Director, Division of Endocrinology and Diabetes
UPMC Children’s Hospital of Pittsburgh
Professor of Pediatrics
University of Pittsburgh School of Medicine
Pittsburgh, PA
Ming Hui Chen, MD, MMSc, FACC, FASE
Associate Professor of Pediatrics
Director, Cardiovascular Health for Cancer Survivors Program
Boston Children’s Hospital
Dana Farber Cancer Institute
Harvard Medical School
Boston, MA
Version 6.0 - October 2023

Contributors
Panel of Experts continued
The following members of the Children’s Oncology Group Long-Term Follow-Up (LTFU) Guidelines Core Committee participated in comprehensive review and scoring of Version 6.0 of the Children’s Oncology Group
Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:

Eric J. Chow, MD, MPH
Associate Professor, Pediatrics
Director, Cancer Survivor Program
University of Washington School of Medicine
Seattle Children’s Hospital
Seattle, WA
Douglas Cipkala, MDChildren’s Center for Cancer and Blood Disorders
Peyton Manning Children’s Hospital at Ascension St. Vincent
Assistant Clinical Professor Marian University College of Osteopathic
Medicine
Indianapolis, IN
Laurie E. Cohen, MD
Professor of Pediatrics
Chief, Division of Pediatric Endocrinology and Diabetes
Associate Director, Reassessment and Evaluation After Cancer
Treatment (REACT) Clinic
The Children’s Hospital at Montefiore
Albert Einstein College of Medicine
Bronx, NY
Karen E. Effinger, MS, MD
Associate Professor Pediatrics
Medical Director, Cancer Survivor Program
Emory University
Children’s Healthcare of Atlanta
Atlanta, GA
Natia Esiashvili, MD
Professor, Chief Quality Officer, Department of Radiation Oncology
Emory University
Atlanta, GA

Paul G. Fisher, MD, MHS
Interim Chair, Department of Neurology and Neurological Sciences
Professor, Neurology and Pediatrics
Stanford University
Palo Alto, CA
Kayla L. Foster, MD, MPH
Assistant Professor, Pediatrics
Texas Children’s Cancer and Hematology Centers
Baylor College of Medicine
Houston, TX
M. Monica Gramatges, MD, PhD
Associate Professor, Pediatrics
Associate Chief, Oncology
Texas Children’s Cancer and Hematology Center
Baylor College of Medicine
Houston, TX
Daniel M. Green, MD
Member, Departments of Oncology and Epidemiology and Cancer
Control
St. Jude Children’s Research Hospital
Memphis, TN
Gregory M.T. Guilcher, MD, FRCPC, FAAP
Associate Professor of Oncology and Pediatrics
Pediatric Medical Director, Alberta Blood and Marrow Transplant
ProgramCumming School of Medicine, University of Calgary
Calgary, AB, Canada

COG LTFU Guidelines – Page xiii

Tara O. Henderson, MD, MPH
Arthur and Marian Edelstein Professor of Pediatrics
Chief, Cancer and Blood Diseases Service Line CCHA
Section Chief, Pediatric Hematology, Oncology and Stem Cell
Transplantation
The University of Chicago
Chicago, IL
David Hodgson, MD, MPH, FRCPC
Professor, Department of Radiation Oncology
Princess Margaret Cancer Centre, University of Toronto
Medical Director, Pediatric Oncology Group of Ontario
POGO Chair, Childhood Cancer Control, University of Toronto
Toronto, Canada
Lisa B. Kenney, MD, MPH
Senior Physician, David B. Perini Jr., Quality of Life Clinic
Dana-Farber Boston Children’s Cancer and Blood Disorders Center
Assistant Professor of Pediatrics, Harvard Medical School
Boston, MA
James Klosky, PhD, ABPP
Professor, Department of Pediatrics
Emory University School of Medicine &Director of Psychology and Neuropsychology
Aflac Cancer and Blood Disorders Center
Children’s Healthcare of Atlanta
Atlanta, GA
Kevin R. Krull, PhD, ABPP
Chair, Department of Psychology and Biobehavioral Sciences
St. Jude Children’s Research Hospital
Memphis, TN

Version 6.0 - October 2023

Table of Contents

Contributors
Panel of Experts continued
The following members of the Children’s Oncology Group Long-Term Follow-Up (LTFU) Guidelines Core Committee participated in comprehensive review and scoring of Version 6.0 of the Children’s Oncology Group
Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:

Lillian R. Meacham, MD
Professor of Pediatrics
Emory University
Chair for Cancer Survivorship
Director of the Fertility Preservation andReproductive Health ProgramChildren’s Healthcare of Atlanta
Atlanta, GA
Cesar A. Migliorati, DDS, MS, PhD
Professor, Oral Medicine
Department of Oral and Maxillofacial Diagnostic Sciences
University of Florida College of Dentistry
Gainesville, Florida
Daniel A. Mulrooney, MD, MS
Associate Member, Department of Oncology
Deputy Director, After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, TN
Paul C. Nathan, MD, MSc, FRCPC
Professor, Paediatrics and Health Policy, Management & Evaluation
Director, Aftercare Program
The Hospital for Sick Children
University of Toronto
Toronto, Ontario, Canada

Kirsten K. Ness, PT, PhD
Member, Department of Epidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TN
Kevin C. Oeffinger, MD
Professor, Medicine and Community and Family Medicine
Director, Center for Onco-Primary Care and Supportive Care andSurvivorship Center
Duke University Medical Center
Durham, NC
Linda Rivard, RN, BSN, CPON
Survivorship Coordinator/P.O.S.T. Clinic
Patient Advocate
Pediatric Hematology/Oncology
Advocate Children’s Hospital
Oak Lawn, IL
Fiona Schulte, PhD
Associate Professor, Department of Oncology, Division of
Psychosocial Oncology
Cumming School of Medicine, University of Calgary
Hematology, Oncology and Transplant Program
Alberta Children’s Hospital
Calgary, Canada

COG LTFU Guidelines – Page xiv

Ami J. Shah, MD
Clinical Professor of Pediatrics
Division of Hematology/Oncology/Stem Cell Transplantation andRegenerative Medicine
Stanford School of Medicine
Lucile Packard Children’s Hospital
Palo Alto, CA
Sheri L. Spunt, MD, MBA
Endowed Professor of Pediatric Cancer
Department of Pediatrics
Stanford University School of Medicine
Stanford, CA
Stephanie Smith, MD, MPH
Instructor, Pediatric Oncology
Lucile Packard Children’s Hospital Stanford
Stanford University School of Medicine
Palo Alto, CA
Nicole Ullrich, MD, PhD, MMSci
Professor, Neurology
Director of Neurologic NeuroOncology
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Harvard Medical School
Boston, MA

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Contributors
Task Force Membership 2019-2023
Task Force

Task Force Members

COG Institution

Expertise

Auditory

Douglas A. Cipkala, MD, Chair
Pinki Prasad, MD, MPH, Silo Leader
Tambra R. Dahlheimer, RN, CPNP, CNP
Kristin Knight, MS, CCC-A, FAAA
Etan Orgel, MD
Catherine Woodman, MD
Torunn I. Yock, MD

Saint Vincent Hospital and Health Care Center
Children’s Hospital New Orleans
University of Minnesota, Masonic Cancer Center
Oregon Health and Science University
Keck School of Medicine, University of Southern California
Massachusetts General Hospital Cancer Center
University of Iowa College of Medicine

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Audiology
Pediatric Hematology Oncology
Radiation Oncology
Family Medicine

Endocrine:
Bone Mineral Density

Wassim Chemaitilly, MD, Chair
Jill H. Simmons, MD, Silo Leader
Nathalie Alos, MD
Sue Kaste, DO
Sogol Mostoufi-Moab, MD, MSCE
Susan V. Shannon, RN, MSN, CPNP, CPON
Linda M. Vrooman, MD, MSc

Children’s Hospital of Philadelphia UMPC
Vanderbilt University Medical Center
Université de Montréal
St. Jude Children’s Research HospitalChildren’s Hospital of Philadelphia UMPC
Miller Children’s and Women’s Hospital Long BeachDana-Farber/Harvard Cancer Center

Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Radiology
Pediatric Oncology & Endocrinology
Pediatric Hematology Oncology
Pediatric Hematology Oncology

CardiovascularMatthew J. Ehrhardt, MD, MS, Chair
Joy M. Fulbright, MD, Silo Leader
Anne Blaes, MD
Rachel Conyers, MD
Kasey J. Leger, MD
Hari Narayan, MD
Thomas Walwyn, MBBS

St. Jude Children’s Research HospitalChildren’s Mercy Hospitals and Clinics
University of Minnesota/Masonic Cancer Center
Royal Children’s Hospital, Melbourne
Seattle Children’s Hospital
University of California San Diego
Perth Children’s Hospital

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Oncology
Hematopoietic Cell Transplantation and Pediatric Oncology
Pediatric Hematology Oncology
Pediatric Cardiology
Pediatric Hematology Oncology

Clinical Care Translation

Melissa Acquazzino, MD, MS, Co-Chair
Kayla Foster, MD, MPH, Co-Chair
Shekinah Andrews, FNP
Roma Bhuta, DO, MPH
Ashlee Blumhoff, APRN-CNP
Leeann Carmichael, DNP, APN, FNP-BC, CPHON
Casey DeBais, MSN, APRN, FNP-BC, CPHON
Amelia Derosa, RN, BSN, CPON
Deirdre Fischer, MEd
Beth Fisher, DNP, APRN, CPNP, CPON, CHPPN
Sarah Ford, MS, PA-C
Julie Nichols, RN, BSN
Linda S. Rivard, RN, BSN, CPON
Daniel Smith, RN, DNP, FNP
S. Ashley Speckhart, MD
Katheryn Tomlinson, RN, BSN
Angela Yarbrough, DNP, APRN, FNP-BC, CPHON
Christine S Yun, MSN, PNP, CPON

Children’s Hospital and Medical Center of Omaha
Baylor College of Medicine, Texas Children’s Hospital
St. Jude Children’s Research Hospital
Rhode Island Hospital, Hasbro Children’s Hospital
Sanford USD Medical Center - Sioux Falls
St. Jude Children’s Research Hospital
University of Chicago Medicine, Comer Children’s Hospital
Memorial Sloan Kettering Cancer Center
Advocate Children’s HospitalChildren’s Hospital of Georgia
St. Jude Children’s Research HospitalChildren’s Hospital of Wisconsin
Advocate Children’s Hospital-Oak Lawn
St. Jude Children’s Research Hospital
Maine Medical Center, Maine Children’s Cancer ProgramChildren’s Hospital of Wisconsin
MD Anderson Cancer Center
Children’s Hospital of Orange County

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology

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Contributors
Task Force Membership 2019-2023 (cont)
Task Force

Task Force Members

COG Institution

Expertise

Endocrine:
ObesityInsulin Resistance

Wassim Chemaitilly, MD, Chair
Emily S. Tonorezos, MD, MPH, Silo Leader
Rusha Bhandari, MD, MS
Smita Dandekar, MD
Stephanie Dixon, MD
Adam J. Esbenshade, MD, MSci
Heather D. Escoto, MD
Cheng-Chia Fred Wu, MD, PhD

Children’s Hospital of Philadelphia UPMC
National Cancer Institute
City of HopePenn State Children’s
St. Jude Children’s Research Hospital
Vanderbilt University/Ingram Cancer Center
Saint Vincent Hospital and Health Care Center
Columbia University Medical Center

Pediatric Endocrinology
Internal Medicine
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Radiation Oncology

Endocrine:
Ovarian

Wassim Chemaitilly, MD, Chair
Ksenya Shliakhtsitsava, MD, Silo Leader
Leslie Appiah, MD
Kari Bjornard, MD
Serena Chan, MD, FACOG
Brooke Cherven, PhD, MPH, RN, CPON
Sobenna George, MD
Stacey Marjerrison, MD
Sripriya Raman, MD
Christine Yu, MDChildren’s Hospital of Philadelphia UPMCUT Southwestern/Simmons Cancer Center-Dallas
Colorado Children’s
Indiana University
Children’s Hospital of Pittsburgh-UPMC
Children’s Healthcare of Atlanta
Children’s Healthcare of Atlanta - Egleston
McMaster Children’s Hamilton, OntarioChildren’s Hospital of Pittsburgh of UPMC
St. Jude Children’s Research Hospital

Pediatric Endocrinology
Pediatric Hematology Oncology
Pediatric and Adolescent Gynecology
Pediatric Hematology Oncology
Gynecology
Nursing Research
Pediatric Endocrinology
Pediatric Hematology Oncology
Pediatric Endocrinology
Endocrinology

Endocrine:
Pituitary
AdrenalThyroid

Wassim Chemaitilly, MD, Chair
Angela Delaney, MD
Nursen Gurtunca, MD
Maya Lodish, MD, MHSc
Alfonso Hoyos-Martinez, MD, FAAP
Joel Thompson, MD
Jonathan Wasserman, MD, PhD
Gregory C. Wheeler, MBBS, FRANZCRAngela Yarbrough, DNP, APRN, FNP-BC, CPHONKevin Yuen, MD

Children’s Hospital of Philadelphia UPMC
St. Jude Children’s Research HospitalChildren’s Hospital of Pittsburgh
UCSF
Baylor College of Medicine, Texas Children’s Hospital
Mercy-Kansas City
Sick Kids, Toronto
Royal Children’s Hospital and Monash Medical Center
MD Anderson
Oregon Health and Science University

Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Hematology Oncology
Pediatric Endocrinology
Radiation Oncology
Pediatric Hematology Oncology
Endocrinology

Endocrine:
Testicular

Wassim Chemaitilly, MD, Chair
Zoltan Antal, MD, Silo Leader
Laurie E. Cohen, MD
Sarah Hensley, MD
Vincent Horne, MD
Lisa B. Kenney, MD, MPH
Lillian R. Meacham, MD
Leena Nahata, MD
Megan Pruett, MSN, CPNP

Children’s Hospital of Philadelphia UPMC
Memorial Sloan Kettering Cancer Center
Dana-Farber/Harvard Cancer Center
Children’s Hospital of Richmond at VCU
Baylor College of Medicine, Texas Children’s HospitalDana-Farber/Harvard Cancer Center
Children’s Healthcare of Atlanta - Egleston
Nationwide Children’s HospitalChildren’s Healthcare of Atlanta

Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Hematology Oncology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Endocrinology

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Table of Contents

Contributors
Task Force Membership 2019-2023 (cont)
Task Force

Task Force Members

COG Institution

Expertise

Endocrine:
Testicular continued

Denise Rokitka, MD, MPH
Seth Rotz, MD
Jenna Sopfe, MD

Roswell Park Comprehensive Care Center
Cleveland Clinic
Children’s Hospital Colorado

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology

Gastrointestinal
Hepatic

Karen E. Effinger, MD, MS, Chair
Kathy J. Ruble, RN, CRNP, PhD, AOCN, Silo Leader
Sahaja Acharya, MD
Jennifer Burgis, MD
Sharon M. Castellino, MD, MSc
Cathleen M. Cook, MD
John K. Petty, MD
Julia O’Malley Stepenske, RN, BSN, CPON

Children’s Healthcare of Atlanta - Egleston
Johns Hopkins University
Johns Hopkins University
Lucile Packard Children’s Hospital Stanford University
Children’s Healthcare of Atlanta - Egleston
East Carolina University
Wake Forest University Health Sciences
Advocate Children’s Hospital-Park Ridge

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Radiation Oncology
Pediatric Gastroenterology/ Hepatology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Surgery
Pediatric Hematology Oncology

Hematopoietic Cell Transplantation
ImmuneDermatologic

Greg Guilcher, MD, FRCPC, FAAP, Chair
Hesham Eissa, MD, Silo Leader
Lesleigh Abbott, MD, FRCPC
Lynnette Anderson, RN, MSN, CPNP
Eric J. Chow, MD, MPH
Tal Schechter-Finkelstein, MD
Lisa Hackney, MD
Jennifer T. Huang, MD
Wendy G. Pelletier, MSW, RSW
Shanti Ramachandran, MBBS, FRACP, MPaeds
Linda S. Rivard, RN, BSN, CPON
Ami J. Shah, MD
Lena Winestone, MD, MS
Kenneth Wong, MD

University of Calgary, Alberta Children’s HospitalChildren’s Hospital Colorado
University of Ottawa
Children’s Hospital of Wisconsin
Seattle Children’s Hospital
University of Toronto
Case Western
Dana-Farber/Harvard Cancer Center
Alberta Children’s Hospital
Perth Children’s Hospital
Advocate Children’s Hospital-Oak Lawn
Lucile Packard Children’s Hospital Stanford University
UCSF
University of Southern California

Pediatric Oncology
Hematopoietic Cell Transplantation and Pediatric Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Hematopoietic Cell Transplantation
Pediatric Hematology Oncology
Pediatric Dermatology
Social Work
Hematopoietic Cell Transplantation
Pediatric Hematology Oncology
Hematopoietic Cell Transplantation
Pediatric Hematology Oncology
Radiation Oncology

Musculoskeletal

Douglas A. Cipkala, MD, Chair
Rozalyn Rodwin, MD, Silo Leader
LaVette S. Bowles, MN, NPc
Jill Cannoy, PT, DPT
Colleen Coulter, PT, DPT, PhD, PCS
Madhu Gowda, MD
Winston W. Huh, MD
Jill L. Lee, MSN, CPNP-AC, CPON
Valerae O. Lewis, MD
Anita Mahajan, MD
Lor Randall, MD, FACS
Carmen Wilson, PhD
Lauren Zeitlinger, DO

Ascension Hospital System Indianapolis
Yale School of Medicine
Mattel Children’s Hospital UC
Children’s Healthcare of Atlanta
Children’s Healthcare of Atlanta - Egleston
Children’s Hospital of Richmond at VCU
MD Anderson Cancer Center
University of Minnesota/Masonic Cancer Center
MD Anderson Cancer Center
Mayo Clinic
UC Davis
St. Jude Children’s Research Hospital
Orthopedic Specialties of Central PA - UPMC

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Family Medicine
Physical Therapy
Physical Therapy
Pediatric Hematology Oncology
Pediatric Oncology
Pediatric Hematology Oncology
Orthopedic Oncology
Radiation Oncology
Orthopedic Oncology
Epidemiology
Orthopedic Surgery

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Table of Contents

Contributors
Task Force Membership 2019-2023 (cont)
Task Force

Task Force Members

COG Institution

Expertise

Neurocognitive

Alicia Kunin-Batson, PhD, Chair
Ellen van der Plas, PhD, Silo Leader
Yin Ting Cheung, PhD
Lisa Jacola, PhD, ABPP-CN
Katharine Rae Lange, MD
Kim Raghubar, PhD

University of Minnesota/Masonic Cancer Center
University of Arkansas, Arkansas Children’s Hospital
Chinese University of Hong Kong
St. Jude Children’s Research Hospital
Hackensack Meridian Children’s Health
Texas Children’s Hospital/Baylor College of Medicine

Neuropsychology
Cognitive Neuroscience
Pharmacoepidemiology
Pediatric Neuropsychology
Pediatric Hematology Oncology
Neuropsychology

Neurologic

Douglas A. Cipkala, MD, Chair
Zsila S. Sadighi, MD, Silo Leader
Eugenia Chang, MD
Jessica Goodman, MD
Fatema Malbari, MD
Susan McGovern, MD, PhD
Neha Patel, MD
Suzanne M. Russo, MD

Ascension Hospital System Indianapolis
University of Texas, MD Anderson
St. Luke’s Children’s Cancer Institute
Peyton Manning Children’s Hospital
Texas Children’s Hospital/Baylor College of Medicine
University of Texas, MD Anderson
Cleveland Clinic
UH Seidman Cancer Center

Pediatric Hematology Oncology
Pediatric Neuro-Oncology/Neurology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Neuro-Oncology/Neurology
Radiation Oncology
Pediatric Neuro-Oncology
Radiation Oncology

New Agents

Stephanie Smith, MD, MPH, Chair
Maya Lodish, MD, MHSc, Silo Leader
Neel S. Bhatt, MD, MBBS, MPH
Sharon M. Castellino, MD, MSc
Matthew J. Ehrhardt, MD, MS
Michael Gleason, MD, MSPH
Brinda Mehta, MBBS
Esther Adebayo-Olojo, PhD, MS, RPh
Serina Patel, MD
Robert Raphael, MD
Jessica Sun, MD

Lucile Packard Children’s Hospital Stanford University
UCSF
Seattle Children’s HospitalChildren’s Healthcare of Atlanta - Egleston
St. Jude Children’s Research Hospital
Texas Children’s Hospital/Baylor College of Medicine
Children’s Hospital of Illinois
New York (NYU/LIU)
Children’s Hospital/London Health Sciences Center
UCSF
Duke University

Medicine and Pediatrics
Pediatric Endocrinology
Pediatric Hematology Oncology
Pediatric Gastroenterology/Hepatology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pharmacy
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology

OcularDouglas A. Cipkala, MD, Chair
Pinki K. Prasad, MD, MPH, Silo Leader
Charline Boente, MD

Saint Vincent Hospital and Health Care Center
Children’s Hospital New Orleans
Indiana University, Riley Hospital for Children

Pediatric Oncology
Pediatric Oncology
Pediatric Opthalmology

Oral/Dental

Karen E. Effinger, MD, MS, Chair
Kathy J. Ruble, RN, CPNP, PhD, Silo Leader
Zachary Abramson, MD, DMD
Sahaja Acharya, MD
Cathleen M. Cook, MD
Julia O’Malley Stepenske, RN, BSN, CPON
Nathaniel Treister, DMD, DMSc
Rebecca Williams, DMD

Children’s Healthcare of Atlanta - Egleston
Johns Hopkins University/Sidney Kimmel Cancer Center
St. Jude Children’s Research Hospital
Johns Hopkins University
East Carolina University
Advocate Children’s Hospital-Park Ridge
Dana-Farber/Harvard Cancer Center
Perth Children’s Hospital

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Maxillofacial Imaging
Radiation Oncology
Pediatric Hematology Oncology
Family Medicine
Oral/Dental Medicine
Pediatric Oral/Dental Medicine

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Table of Contents

Contributors
Task Force Membership 2019-2023 (cont)
Task Force

Task Force Members

COG Institution

Expertise

Psychosocial

Fiona Schulte, PhD, Chair
Rebecca Foster, PhD, Silo Leader
Tara M. Brinkman, PhD
Katie Devine, PhD, MPH
Kristin Foster, DNP, C-PNP, C-PMHNP
Cynthia Karlson, PhD
Jordan Gilleland Marchak, PhD, ABPP
Sunnye Mayes, PhD, ABPP
Sapna Oberoi, MBBS, MD, DM
Wendy G. Pelletier, MSW, RSW
Karen Long-Traynor, PhD
Victoria W. Willard, PhD

University of Calgary, Alberta Children’s Hospital
Washington University, St. Louis Children’s Hospital
St. Jude Children’s Research Hospital
Rutgers Cancer Institute of New Jersey
University of Iowa Hospitals and Clinics
University of Mississippi Medical Center
Children’s Healthcare of Atlanta
University of Louisville, Norton Children’s Cancer Institute
Max Rady School of Medicine, University of Manitoba
Alberta Children’s Hospital
Rutgers Cancer Institute of New Jersey
St. Jude Children’s Research Hospital

Psychology
Pediatric Psychology
Pediatric Psychology
Pediatric Hematology Oncology
Pediatric Psychology
Pediatric Psychology
Pediatric Psychology
Pediatric Psychology
Pediatric Hematology Oncology
Social Work
Clinical Psychology
Pediatric Psychology

Pulmonary

Matthew J. Ehrhardt, MD, MS, Chair
Neel S. Bhatt, MD, MBBS, MPH, Silo Leader
Jennifer E. Agrusa, MD, MS
Aarati Didwania, MD
Mary Frances McAleer, MD, PhD
Daniel Weiner, MD

St. Jude Children’s Research Hospital
Seattle Children’s Hospital
University of Michigan, C. S. Mott Children’s HospitalNorthwestern University Feinberg School of Medicine
MD Anderson
Children’s Hospital of Pittsburgh, UPMC

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Internal Medicine
Radiation Oncology
Pediatric Pulmonology

Subsequent Malignant Neoplasms

Danielle N. Friedman, MD, MS, Co-Chair
Monica M. Gramatges, MD, PhD, Co-Chair
Dana Barnea, MD
Taumoha Ghosh, MD
Tara O. Henderson, MD, MPH
David Hodgson, MD, MPH, FRCPC
Lenat Joffe, MD
Katharine Rae Lange, MD
Chaya Moskowitz, PhD
Paul C. Nathan, MD, MSc, FRCPCKevin C. Oeffinger, MD
Kenneth Roberts, MD
Omar Shakeel, MD
Stephanie Smith, MD, MPH
Eugene Suh, MD
Tara Suntum, MD
Lucie M. Turcotte, MD, Silo Leader
Tung Wynn, MD
Alia Zaidi, MD

Memorial Sloan Kettering Cancer Center
Texas Children’s Hospital/Baylor College of Medicine
Memorial Sloan Kettering Cancer Center
University of Miami
University of Chicago Comprehensive Cancer Center
University of Toronto
Columbia University
Hackensack Meridian Children’s Health
Memorial Sloan Kettering Cancer Center
Hospital for Sick Children
Duke University Medical Center
Yale University School of Medicine/Smillow Cancer Hospital
Texas Children’s Hospital/Baylor College of Medicine
Lucile Packard Children’s Hospital Stanford University
Loyola University Medical Center
Medstar Georgetown University Hospital
University of Minnesota/Masonic Cancer Center
University of Florida
St. Jude Children’s Research Hospital

Pediatric Hematology Oncology
Pediatric Hematology Oncology
Internal Medicine
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Radiation Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Biostatistics, Survivorship
Pediatric Hematology Oncology
Family Medicine
Radiation Oncology
Pediatric Hematology Oncology
Medicine and Pediatrics
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology

COG LTFU Guidelines – Page xix

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Contributors
Task Force Membership 2019-2023 (cont)
Task Force

Task Force Members

COG Institution

Expertise

Urinary Tract

Karen E. Effinger, MD, MS, Chair
Kathleen Kieran, MD, MS, Silo Leader
Kala Kamdar, MD
Anne Crowley Mauck, RN, MSN, CPNP
Kerry M. Moss, MD
Daniel A. Mulrooney, MD, MS
Jonathan C. Routh, MD, MPH
Sheri L. Spunt, MD

Children’s Healthcare of Atlanta - Egleston
Seattle Children’s Hospital
Texas Children’s Hospital/Baylor College of Medicine
Virginia Commonwealth University/Massey Cancer Center
Connecticut Children’s Medical Center
St. Jude Children’s Research Hospital
Duke University Medical Center
Lucile Packard Children’s Hospital Stanford University

Pediatric Hematology Oncology
Pediatric Urology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Hematology Oncology
Pediatric Urology
Pediatric Hematology Oncology

Contributors
Guideline Development Task Force - Initial Versions
The Children’s Oncology Group Nursing Discipline and Late Effects Committee collaboratively developed the initial versions (1.0, 1.1, and 1.2) of the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors ofChildhood, Adolescent, and Young Adult Cancers. The following individuals comprised the original Guideline Development Task Force:
Development Task Force
Melissa M. Hudson, MD, Task Force Co-Chair, St. Jude Children’s Research Hospital, Memphis, TN
Wendy Landier, PhD, CPNP, Task Force Co-Chair, Children’s Hospital of Alabama, Birmingham, AL
Joan Darling, PhD, COG Patient Advocate Committee, Lincoln, NE
Kathy Forte, RN, MS, CPNP, Children’s Healthcare of Atlanta - Egleston, Atlanta, GA
Allison Hester, RN, MSN, CPNP, Arkansas Children’s Hospital, Little Rock, AR
Debra A. Kent, RN, MSN, CPNP, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Teresa Sweeney, RN, MSN, CPNP, St. Jude Children’s Research Hospital, Memphis, TN

Special Acknowledgment:
Smita Bhatia, MD, MPH, Children’s Hospital of Alabama, Birmingham, AL for her leadership in overseeing
the initial development of the COG LTFU Guidelines as Chair of the COG Late Effects Committee, and for her
continued oversight of all content in all versions of the COG LTFU Guidelines
Louis S. “Sandy” Constine, MD, University of Rochester, Rochester, NY for his in-depth expert review andextensive contributions to all radiation-related sections in all versions of the COG LTFU Guidelines

COG LTFU Guidelines – Page xx

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Table of ContentsPreface
Overview

Goal

The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood,
Adolescent, and Young Adult Cancers (COG LTFU Guidelines) are risk-based, exposurerelated clinical practice guidelines for screening and management of late effects resulting
from therapeutic exposures used during treatment for pediatric malignancies. “Late effects”
are defined as therapy-related complications or adverse effects that persist or arise after
completion of treatment for a pediatric malignancy. “Pediatric malignancies” are defined as
those malignancies commonly associated with the pediatric population that may arise duringchildhood, adolescence, or young adulthood.

Implementation of these guidelines is intended to increase quality of life and decrease
complication-related healthcare costs for pediatric cancer survivors by providing standardized
and enhanced follow-up care throughout the lifespan that:

These guidelines represent a statement of consensus from a panel of experts in the lateeffects of pediatric cancer treatment. The guidelines are both evidence-based (utilizing
established associations between therapeutic exposures and late effects to identify highrisk categories) and grounded in the collective clinical experience of experts (matching themagnitude of the risk with the intensity of the screening recommendations).

Focus

Since therapeutic interventions for a specific pediatric malignancy may vary considerably
based on the patient’s age, presenting features, and treatment era, a therapy-based design
was chosen to permit modular formatting of the guidelines by therapeutic exposure.
Importantly, the recommended periodic screening underscores the use of a thorough history
and physical examination (H&P) as the primary assessment for cancer-related treatment
effects. In regard to the screening recommendations outlined for the 165 therapeutic
exposures in the COG LTFU Guidelines:•

113 (68%) are derived primarily from the H&P, of which 91 (55%) rely solely on the H&P
and 22 (13%) rely on the H&P plus a baseline diagnostic study (e.g., lab, imaging)•

44 (27%) include periodic laboratory, diagnostic imaging, or other testing•

8 (5%) recommend no screening (agents with no known late effects)

Interventions exceeding minimal screening are provided for consideration in individuals withpositive screening tests. Medical citations supporting the association of each late effect witha specific therapeutic exposure are included. Patient education materials complementing theguidelines have been organized into Health Links that feature health protective counselingon 45 topics, enhancing patient follow-up visits and broadening application of the guidelines.
Additional accompanying materials include detailed instructions, templates for cancer
treatment summary forms, a radiation reference guide, a tool to assist in identifying guideline
applicability for individual survivors based on therapeutic exposures, and templates for letters
appealing denied insurance claims.

a.

Promotes healthy lifestylesb.

Provides for ongoing monitoring of health statusc.

Facilitates early identification of late effectsd.

Provides timely intervention for late effects

These guidelines are intended for use beginning two or more years following thecompletion of cancer therapy, and provide a framework for ongoing late effects monitoringin childhood cancer survivors; however, these guidelines are not intended to provide
guidance for follow-up of the pediatric cancer survivor’s primary disease.
Target Population
The recommendations for periodic screening evaluations provided in the COG LTFU Guidelines
are appropriate for asymptomatic survivors of childhood, adolescent, or young adult cancers
who present for routine exposure-related medical follow-up. More extensive evaluations
are presumed, as clinically indicated, for survivors presenting with signs and symptoms
suggesting illness or organ dysfunction.
Intended Users
The COG LTFU Guidelines were developed as a resource for clinicians who provide ongoinghealthcare to survivors of pediatric malignancies. The information within these guidelines isimportant for clinicians (e.g., physicians, nurse practitioners, physician assistants, nurses) in
the fields of pediatrics, oncology, internal medicine, family practice, and gynecology, as well as
subspecialists in many fields (e.g., endocrinology, cardiology, pulmonology). A basic knowledgeof ongoing issues related to the long-term follow-up needs of this patient population isassumed. Healthcare professionals who do not regularly care for survivors of pediatricmalignancies are encouraged to consult with a pediatric oncology long-term follow-up center
if any questions or concerns arise when reviewing or using these guidelines.
Although the information within the guidelines will certainly prove valuable to the survivors
themselves, at this time the only version available is targeted to healthcare professionals.
Therefore, survivors who choose to review these guidelines are strongly encouraged to do so

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Table of ContentsPreface (cont)with the assistance of a healthcare professional knowledgeable about long-term follow-up
care for survivors of childhood, adolescent, and young adult cancers. This is important in orderto put the recommendations in perspective, avoid over-testing, address potential anxieties, andprovide a comprehensive evaluation of the survivor’s health status. The Children’s Oncology
Group itself does not provide individualized treatment advice to survivors or their families, andstrongly recommends discussing this information with a qualified medical professional.

the draft, including focused review of selected guideline sections. Revisions were made basedon these recommendations. The revised draft was then sent out to additional multidisciplinary
experts for further review. A total of 62 individuals participated in the review process. The
guidelines subsequently underwent comprehensive review and scoring by a panel of experts inthe late effects of pediatric malignancies, comprised of multidisciplinary representatives fromthe COG Late Effects Committee.

Developer

In a parallel effort led by the Nursing Clinical Practice Subcommittee, complementary patient
education materials (Health Links) were developed. Each Health Link underwent two levels ofreview; first by the Nursing Clinical Practice Subcommittee to verify accuracy of content andrecommendations, and then by members of the Late Effects Committee (to provide expert
medical review) and Patient Advocacy Committee (to provide feedback regarding presentationof content to the lay public).

The COG LTFU Guidelines were developed as a collaborative effort of the Children’s Oncology
Group Nursing Discipline and Late Effects Committee and are maintained and updated by
the Children’s Oncology Group’s Long-Term Follow-Up Guidelines Core Committee and its
associated Task Forces. All Children’s Oncology Group members have complied with the
COG conflict of interest policy, which requires disclosure of any potential financial or otherconflicting interests.
Evidence Collection
Pertinent information from the published medical literature over the past 20 years (updated asof October 2023) was retrieved and reviewed during the development and updating of theseguidelines. For each therapeutic exposure, a complete search was performed via MEDLINE(National Library of Medicine, Bethesda, MD). Keywords included “childhood cancer therapy,”“complications,” and “late effects,” combined with keywords for each therapeutic exposure.
References from the bibliographies of selected articles were used to broaden the search.
Methods
In 2002, the leadership of the Children’s Oncology Group Late Effects Committee and Nursing
Discipline appointed a 7-member task force, with representation from the Late Effects
Committee, Nursing Discipline, and Patient Advocacy Committee. The task force was convened
to review and summarize the medical literature and develop a draft of clinical practiceguidelines to direct long-term follow-up care for pediatric cancer survivors. The task force
followed a modified version of the guideline development process established by the National
Comprehensive Cancer Network (NCCN), integrating available literature with expert opinion
using reiterative feedback loops.
The original draft went through several iterations within the task force prior to initial review.
Multidisciplinary experts in the field, including nurses, physicians (pediatric oncologists
and other subspecialists), patient advocates, behavioral specialists, and other healthcare
professionals, were then recruited by the task force to provide an extensive, targeted review of

Pre-Release Review
The initial version of the guidelines (Version 1.0 – Children’s Oncology Group Late Effects
Screening Guidelines) was released to the Children’s Oncology Group membership in March
2003 for a six-month trial period. This allowed for initial feedback from the COG membership,
resulting in additional review and revision of the guidelines by the Late Effects Committee prior
to public release.
Revisions
The guidelines were initially released to the public (Version 1.1 – Childhood Cancer Survivor
Long-Term Follow-Up Guidelines ) on the Children’s Oncology Group Website in September
2003. Following this release, clarification regarding the applicability of the guidelines to theadolescent and young adult populations of cancer survivors was requested. In response,
additional minor modifications were made and the title of the guidelines was changed. A
revised version (Version 1.2 – Long-Term Follow-Up Guidelines for Survivors of Childhood,
Adolescent, and Young Adult Cancers ) was released to the public on the Children’s Oncology
Group Website in March 2004.
In order to keep the guidelines current and clinically meaningful, the COG Late Effects
Committee organized multidisciplinary task forces in March 2004. These task forces arecharged with the responsibility for monitoring the medical literature in regard to specificsystem-related clinical topics relevant to the guidelines (e.g., cardiovascular, neurocognitive,
fertility/reproductive), providing periodic reports to the COG Outcomes and Survivorship
Committee, and recommending revisions to the guidelines and their associated healtheducation materials and references (including the addition of therapeutic exposures) as new

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Table of ContentsPreface (cont)information becomes available. Task force members are assigned according to their respective
areas of expertise and clinical interest and membership is updated every 5 years. A list ofthese task forces and their membership is included in the “Contributors” section of thisdocument, reflecting contributions and recommendations relevant to the current release of
these guidelines (Version 6.0 – October 2023).
All revisions proposed by the task forces were evaluated by a panel of experts, and if
accepted, assigned a score (see “Scoring Explanation” section of Preface). Proposed revisions
that were rejected by the expert panel were returned with explanation to the relevant task
force chair. If desired, task force chairs were given an opportunity to respond by providing
additional justification and resubmitting the rejected task force recommendation(s) for further
consideration by the expert panel.

were assigned according to a modified version of the National Comprehensive Cancer Network“Categories of Consensus,” as follows:
Category Statement of Consensus
1

There is uniform consensus of the panel that:
1. There is high-level evidence linking the late effect with the therapeutic
exposure
2. The screening recommendation is appropriate based on the collective
clinical experience of panel members

2A

There is uniform consensus of the panel that:
1. There is lower-level evidence linking the late effect with the therapeutic
exposure
2. The screening recommendation is appropriate based on the collective
clinical experience of panel members

2B

There is non-uniform consensus of the panel that:
1. There is lower-level evidence linking the late effect with the therapeutic
exposure
2. The screening recommendation is appropriate based on the collective
clinical experience of panel members

3

There is major disagreement that the recommendation is appropriate.

Plan for Updates
The multidisciplinary task forces described above will continue to monitor the literature andreport to the COG Long-Term Follow-Up Guideline Core Committee during each guideline
review/update cycle. Periodic revisions to these guidelines are planned as new information
becomes available, and at least every 5 years. Clinicians are advised to check the Children’s
Oncology Group website periodically for the latest updates and revisions to the guidelines,
which will be posted at www.survivorshipguidelines.org.
Scoring Explanation
These guidelines represent a statement of consensus from a multidisciplinary panel ofexperts in the late effects of pediatric cancer treatment. The guidelines outline minimum
recommendations for specific health screening evaluations in order to detect potential lateeffects arising as a result of therapeutic exposures received during treatment of childhood,adolescent, and young adult cancers.
Each score relates to the strength of the association of the identified late effect withthe specific therapeutic exposure based on current literature, and is coupled with arecommendation for periodic health screening based on the collective clinical experience ofthe panel of experts. This is due to the fact that there are no randomized clinical trials (andnone forthcoming in the foreseeable future) on which to base recommendations for periodic
screening evaluations in this population; therefore, the guidelines should not be misconstrued
as representing conventional “evidence-based clinical practice guidelines” or “standards ofcare”.
Each item was scored based on the level of evidence currently available to support it. Scores

Uniform consensus: Near-unanimous agreement of the panel with some possible neutral positions.
Non-uniform consensus: The majority of panel members agree with the recommendation; however, there
is recognition among panel members that, given the quality of evidence, clinicians may choose to adopt
different approaches.
High-level evidence: Evidence derived from high quality case control or cohort studies.
Lower-level evidence: Evidence derived from non-analytic studies, case reports, case series, and clinicalexperience.

All “Category 1” recommendations reflect uniform consensus among the reviewers.
“Category 2” recommendations are designated as “2A” (there is uniformity of consensus
among the reviewers regarding strength of evidence and appropriateness of the screening
recommendation) or “2B” (there is non-uniform consensus among the reviewers regarding
strength of evidence and appropriateness of the screening recommendation).
Rather than submitting recommendations representing major disagreements, items scoredas “Category 3” were either deleted or revised by the panel of experts to provide at least a“Category 2B” score for all recommendations included in the guidelines.

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Table of ContentsPreface (cont)
Recommendations and Rationale
Screening and follow-up recommendations are organized by therapeutic exposure andincluded throughout the guidelines. Pediatric cancer survivors represent a relatively small but
growing population at high risk for various therapy-related complications. Although several
well-conducted studies on large populations of childhood cancer survivors have demonstrated
associations between specific exposures and late effects, the size of the survivor populationand the rate of occurrence of late effects does not allow for clinical studies that would assess
the impact of screening recommendations on the morbidity and mortality associated with thelate effect. Therefore, scoring of each exposure reflects the expert panel’s assessment of thelevel of literature support linking the therapeutic exposure with the late effect coupled with anassessment of the appropriateness of the recommended screening modality in identifying thepotential late effect based on the panel’s collective clinical experience.
Potential Benefits and Harms
Potential benefits of implementing these guidelines into clinical practice include earlier
identification of and intervention for late onset therapy-related complications in this at-risk
population, potentially reducing or ameliorating the impact of late complications on the healthstatus of survivors. In addition, ongoing healthcare that promotes healthy lifestyle choices andprovides ongoing monitoring of health status is important for all cancer survivors.
Potential harms of guideline implementation include increased patient anxiety related toenhanced awareness of possible complications, as well as the potential for false-positive
screening evaluations, leading to unnecessary further workup. In addition, costs of longterm follow-up care may be prohibitive for some survivors, particularly those lacking
health insurance, or those with insurance that does not cover the recommended screening
evaluations.
Patient Preferences
Ultimately, as with all clinical guidelines, decisions regarding screening and clinicalmanagement for any specific patient should be individually tailored, taking into consideration
the patient’s treatment history, risk factors, co-morbidities, and lifestyle. These guidelines are
therefore not intended to replace clinical judgment or to exclude other reasonable alternative
follow-up procedures. The Children’s Oncology Group recognizes that specific patient caredecisions are the prerogative of the patient, family, and healthcare provider.

provided to survivors of pediatric malignancies throughout the lifespan. Considerations in thisregard include the practicality and efficiency of applying these broad guidelines in individual
clinical situations. Studies to address guideline implementation and refinement are a toppriority of the COG Long-Term Follow-Up Guideline Core Committee; studies of feasibility ofguideline use have been reported in limited institutions and others are currently underway.
Issues being addressed include description of anticipated barriers to application of therecommendations in the guidelines and development of review criteria for measuring changes
in care when the guidelines are implemented. Additional concerns surround the lack of current
evidence establishing the efficacy of screening for late complications in pediatric cancer
survivors. While most clinicians believe that ongoing surveillance for these late complications
is important in order to allow for early detection and intervention for complications that may
arise, development of studies addressing the efficacy of this approach is imperative in order todetermine which screening modalities are optimal for asymptomatic survivors.
In addition, the clinical utility of this lengthy document has also been a top concern of the
COG Long-Term Follow-Up Guideline Core Committee. While recognizing that the length anddepth of these guidelines is important in order to provide clinically-relevant, evidence-based
recommendations and supporting health education materials, clinician time limitations andthe effort required to identify the specific recommendations relevant to individual survivors
have been identified as barriers to their clinical application. Therefore, the COG Long-Term
Follow-Up Guideline Core Committee has partnered with the Baylor School of Medicine todevelop a web-based interface, known as “Passport for Care,” that generates individualized
exposure-based recommendations from these guidelines in a clinician-focused format for easeof patient-specific application of the guidelines in the clinical setting. The Passport for Care®
application is available to Children’s Oncology member institutions at no cost. For additional
information, please contact Monica Gramatges, MD, PhD (gramatge@bcm.edu) or Susan
Krause (skrause@texaschildrens.org ).
Funding SourceThis work was supported by the Children’s Oncology Group Chair’s Grant (U10 CA098543) andthe National Clinical Trials Network Group Operations Center Grant (U10 CA180886) from the
National Cancer Institute. The Version 6.0 update, including typesetting, was supported by the
St. Baldrick’s Foundation.

Implementation Considerations
Implementation of these guidelines is intended to standardize and enhance follow-up care
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Instructions for Use
Guideline Organization

System/Score

The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood,
Adolescent, and Young Adult Cancers are organized according to therapeutic exposures,arranged by column as follows:
Section Number

Unique identifier for each guideline section.

Therapeutic Agent

Therapeutic intervention for malignancy, including chemotherapy,
radiation, surgery, blood/serum products, hematopoietic celltransplant, and other therapeutic modalities.

Potential Late
Effects

Most common late treatment complications associated with specified
therapeutic intervention.

Periodic
Evaluations

Recommended screening evaluations, including health history,
physical examination, laboratory evaluation, imaging, andpsychosocial assessment. Recommendation for minimum frequency
of periodic evaluations is based on risk factors and magnitude of risk,
as supported by the medical literature and/or the combined clinicalexperience of the reviewers and panel of experts.

Health Counseling/
Further
Considerations

Health Links: Health education materials developed specifically toaccompany these guidelines. Title(s) of Health Link(s) relevant toeach guideline section are referenced in this column. Health Link
documents are included in Appendix II, and are also available on the
COG website at www.survivorshipguidelines.org.

Body system (e.g., auditory, musculoskeletal) most relevant to eachguideline section.
Score assigned by expert panel representing the strength of datafrom the literature linking a specific late effect with a therapeutic
exposure coupled with an assessment of the appropriateness of thescreening recommendation based on collective clinical experience.
See “Scoring Explanation” in the Preface for more information.

Additional
Information

Patient and cancer/treatment factors, pre-morbid/co-morbid
health conditions, and health behaviors that may increase risk fordeveloping the complication and additional information pertinent to
the late effects or its evaluation (previously known as “Info Links”)

References

References are listed immediately following each guideline
section. Included are medical citations that provide evidence forthe association of the therapeutic intervention with the specifictreatment complication and/or evaluation of predisposing risk factors.
In addition, some general review articles have been included in the
Reference section for clinician convenience.

Resources: Books and websites that may provide the clinician withadditional relevant information.
Counseling: Suggested patient counseling regarding measures
to prevent/reduce risk or promote early detection of the potential
treatment complication.
Potential Considerations for Further Testing and Intervention:
Recommendations for further diagnostic evaluations beyond
minimum screening for individuals with positive history and/or physical examination findings or positive screening tests,
recommendations for consultation and/or referral, andrecommendations for management of exacerbating or predisposing
conditions.
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Instructions for Use (cont)
Using the COG LTFU Guidelines to Develop Individualized Screening Recommendations
In order to accurately derive individualized screening recommendations for a specific childhood
cancer survivor using the Children’s Oncology Group Long-Term Follow-Up Guidelines for
Survivors of Childhood, Adolescent, and Young Adult Cancers, the following procedure should
be followed. (Note: For ease of use, a Patient-Specific Guideline Identification Tool has beendeveloped to streamline the following process and is included in Appendix I).
1.

Obtain the survivor’s Cancer Treatment Summary (see templates for comprehensive
and abbreviated summaries in Appendix 1). Note: In order to generate accurate exposure-based follow-up recommendations from these guidelines, the following information
regarding the survivor’s diagnosis and treatment is required, at minimum:

Cancer Treatment: Radiation• Names of all radiation field(s) treated– For list of radiation fields addressed by these guidelines (Sections 44-98), see “Radiation” portionof the Patient-Specific Guideline Identification Tool in Appendix I– For definition of radiation fields, see “Radiation Fields Defined" in Appendix I• For head/brain, neck, chest, abdomen, spine (whole, cervical, thoracic) radiation and TBI, total dose(in Gy):– Total radiation dose to each field (should include boost dose, if given)– To convert cGy or rads to Gy, divide dose by 100 (example: 2400 cGy = 2400 rads = 24 Gy)

Demographics

Cancer Treatment: Hematopoietic Cell Transplant(s)• Name• Sex• Date of birth• Whether or not the survivor underwent a HCT, and if so:– Transplant type (autologous vs allogeneic)– Chronic graft-versus-host disease (cGVHD) status (no history of cGVHD, history of cGVHD,
currently active cGVHD)

Cancer Diagnosis

Cancer Treatment: Surgery• Diagnosis• Date of diagnosis• Date cancer therapy was completed• Names of all surgical procedures.
– For list of surgical procedures addressed by these guidelines (Sections 115–151), see “Surgery”
portion of the Patient-Specific Guideline Identification Tool in Appendix I

Cancer Treatment: Chemotherapy• Names of all chemotherapy agents received– For a list of chemotherapy agents addressed by these guidelines (Sections 11-43), see the“Chemotherapy” portion of the Patient-Specific Guideline Identification Tool in Appendix I.
– For generic and brand names of chemotherapy agents, see Chemotherapy Agents in Appendix I.
• Cumulative dose of all anthracycline chemotherapy received (i.e., doxorubicin, daunorubicin,
idarubicin, mitoxantrone and epirubicin)– See Section 34 of Guidelines for anthracycline isotoxic dose-equivalent conversion.
– For doses in mg/kg, multiply by 30 to obtain equivalent dosing in mg/m2 (example: 2 mg/kg = 60
mg/m2).
• For carboplatin, whether any dose was myeloablative (i.e., given as conditioning for HCT)• For cytarabine and methotrexate:– Route of administration (i.e., IV, IM, SQ, PO, IT, IO)– If IV, designation of “high dose” (any single dose ≥ 1000 mg/m2) versus “standard dose” (allsingle doses < 1000 mg/m2)

Cancer Treatment: Other Therapeutic Modalities• Whether or not the survivor received radioiodine therapy (I-131 thyroid ablation), systemic MIBG (intherapeutic doses), or other novel agents (Sections 152-163)

2.

COG LTFU Guidelines – Page xxvi

Compile a list of guideline sections relevant to the survivor based off the list generated instep 1.
•

Sections 1 - 7: Applicable to all survivors•

Section 8: Survivors diagnosed before 1972•

Section 9: Survivors diagnosed before 1993•

Section 10: Survivors diagnosed between 1977 and 1985•

Section 11: All survivors who received chemotherapy•

Sections 12-43: For survivors who received chemotherapy, include relevant sections•

Sections 44, 45, 96: All survivors who received radiation
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Instructions for Use (cont)1.

•

Sections 46 - 95, 97- 98: For survivors who received radiation, include relevant
sections

information, please contact Monica Gramatges, MD, PhD (gramatge@bcm.edu) or Susan
Krause (skrause@texaschildrens.org ).

•Sections 100 - 105: All survivors who underwent HCT

We are hopeful that this revised version of the Children’s Oncology Group Long-Term FollowUp Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers will enhance
the follow-up care provided to this unique group of cancer survivors. If you have questions,suggestions, or concerns regarding use of these guidelines, please contact:–

Section 100 is for males only–

Section 101 is for females only•

Section 99: For survivors who underwent autologous HCT•

Sections 106 - 114: For survivors who underwent allogeneic HCT, include relevant
sections•

Sections 115 - 151: For survivors who underwent surgery, include relevant sections•

Sections 152 - 163: For survivors who received other therapeutic modalities, include
relevant sections•

Section 164-165: Applicable to all survivors

Review all guideline sections generated in the list above, and develop a plan for screening the individual survivor, taking into consideration the survivor’s relevant risk factors,
current health, co-morbidities, health-related behaviors and preferences.

Note: The above procedure is applicable to generation of follow-up guidelines from the current
version of this document; however, the COG Long-Term Follow-Up Guidelines Core Committee
recognizes that as new evidence becomes available and these guidelines are updated,additional details regarding the childhood cancer survivor’s therapeutic exposures may berequired in order to generate comprehensive recommendations. Therefore, we strongly advisethat a comprehensive treatment summary be prepared for each childhood cancer survivor,
including a record of all therapeutic exposures with applicable dates, details of administration,and cumulative doses of all agents, including those not currently addressed by theseguidelines.

Co-Chairs, COG Long-Term Follow-Up Guidelines Core Committee:
Matthew J. Ehrhardt, MD, MS
St. Jude Children’s Research Hospital
Memphis, TN(901) 595-5913
matt.ehrhardt@stjude.org

Danielle N. Friedman, MD, MS
Memorial Sloan Kettering Cancer Center
New York, NY(212) 639-7376
friedmad@mskcc.org

Melissa M. Hudson, MD
St. Jude Children’s Research Hospital
Memphis, Tennessee(901) 595-4781
melissa.hudson@stjude.org

Louis S. “Sandy” Constine, MD
University of Rochester Medical Center
Rochester, NY(585) 275-5622
louis_constine@urmc.rochester.edu

Wendy Landier, PhD, CPNP
Children’s Hospital of Alabama
University of Alabama at Birmingham
Birmingham, Alabama(205) 638-2120
wlandier@peds.uab.edu

Smita Bhatia, MD, MPH
Children’s Hospital of Alabama
University of Alabama at Birmingham
Birmingham, Alabama(205) 638-2120
sbhatia@peds.uab.edu

The COG Long-Term Follow-Up Guidelines Core Committee recognizes that the time required
to identify patient-specific recommendations from these guidelines is significant, and has been
identified as a barrier to clinical use. Therefore, COG has partnered with the Baylor School of
Medicine to develop a web-based interface, known as “Passport for Care,” that generates
individualized exposure-based recommendations from these guidelines in a clinician-focusedformat for ease of patient-specific application in the clinical setting. The Passport for Care®
application is available to Children’s Oncology member institutions at no cost. For additional
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New to Version 6.0
All guideline sections have been reviewed by the Long-Term Follow-Up Guidelines Task Forces
and modifications have been made per their recommendations and with the approval of theExpert Panel. The most significant modifications are detailed below.
Simplification
A continued overall goal of Version 6.0 of the COG Long-Term Follow-Up Guidelines is tosimplify the format and content of the guidelines in order to focus on clinically relevant
content, reduce the burden of medical record data abstraction necessary to determine tailored
recommendations for survivors, reduce the complexity of guideline application to individual
survivors, and better align COG’s screening recommendations with those of the International
Guideline Harmonization Group. Version 6.0 therefore features the following modifications:•

Guideline navigation has been simplified through the use of hyperlinks. Hyperlinks aredenoted with blue text and assist in moving more easily through the guideline contents.
Additionally, there is often a hyperlink at the bottom of most pages to direct the user backto a section or the guideline table of contents.

•

Simplification of design/format with a focus on clinical information that drives screening•

Continuation of defined and simplified radiation fields–

All radiation fields from Version 5.0 are still mapped to body parts–

In most cases, knowing the general area of the body that received radiation is now
all that is necessary in order to generate tailored radiation-related recommendations
for survivors–••

It is not necessary to know or record specific radiation doses (with a few exceptions)Radiation dose cut-offs largely eliminated–Emerging evidence indicates that some late effects (e.g., breast and colorectal
cancers) are occurring below the previously determined minimum dose thresholds–

The dose cut-offs that remain are for late effects that require screening beyond thehistory and physical examination and for which evidence indicates that there is a low
risk of developing the late effect below the radiation threshold

All Risk Factors and Highest Risk Factors have been moved to Additional Information

Revisions have been made to Counseling and Potential Considerations in most sections•

References have been updated in all applicable sections•

Secondary malignancy has been renamed Subsequent throughout the guidelines•

References to veno-occlusive disease (VOD) has been removed throughout the guidelines
and replaced with the current sinusoidal obstruction syndrome (SOS) term•

Templates remain in Appendix I to assist with drafting appeal letters for denied insurance
claimsNew Sections/Late Effects
The following new sections/late effects have been added:•

Subsequent malignancy and/or Risk of malignancy in offspring related to any cancer
experience (section 7)•

Hypothyroidism related to (partial) Thyroidectomy (section 151)•

Xerostomia and/or Salivary gland dysfunction and/or Chronic sialadenitis related toradioiodine therapy (I-131 thyroid ablation) (section 154)•

Growth attenuation related to BCR-ABL tyrosine kinase inhibitors (section 159)•

Hypothyroidism related to BCR-ABL tyrosine kinase inhibitors (section 160)•

Insufficient information regarding late effects from Other targeted biologic therapies(section 161)•

Immunologic complications related to B-cell directed antibody-based therapies (section
162)•

Insufficient information regarding late effects from Other antibody-based immune
therapies (section 163)•

General health screening regarding vaccinations (section 165)

Sections/Late Effects Removed
The following sections or late effects have been removed from Version 6.0 of the COG LTFU
Guidelines:

General Updates••

Some History and Physical Exam elements have been reworded for consistency between
sections•

Clinical leukoencephalopathy related to high dose cytarabine (section 24 of Version 4.0)•

Lymphoma related to HCT (section 106 of Version 4.0)

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New to Version 6.0 (cont)•

Renal toxicity related to methotrexate (section 28 changed to “No Known Renal Late
Effects” in Version 5.0)•

Reduced bone mineral density related to methotrexate (section 27 changed to “No Known
BMD Late Effects” in Version 6.0)•

The Cancer Screening Guidelines Sections (156-164 in Version 5.0) for average risk
individuals have been removed due to inconsistencies across cooperative groups andpractice standards, as well as timing alignment with suggested changes and publication.
Your health care providers will offer guidance based on current recommendations andguidelines.

•

Reduced ovarian follicular pool renamed as Diminished ovarian reserve (DOR) (15, 93, 137)•

Secondary benign or malignant neoplasm occurring in or near radiation field renamed as
Subsequent benign or malignant neoplasm occurring in or near radiation field (44)

Newly Combined Sections
These sections from Version 5.0 have been combined into one section (164) in Version 6.0:
Breast cancer screening guidelines standard risk (previous section 156)•

Cervical cancer screening guidelines standard risk (previous section 157)•

Colorectal cancer screening guidelines standard risk (previous section 158)•

Endometrial cancer screening guidelines standard risk (previous section 159)•

Lung cancer screening guidelines standard risk (previous section 160)•

Oral cancer screening guidelines standard risk (previous section 161)•

Prostate cancer screening guidelines standard risk (previous section 162)•

Skin cancer screening guidelines standard risk (previous section 163)•

Testicular cancer screening guidelines standard risk (previous section 164)

New Potential Late Effects Subcategories Added•

Subsequent malignancy (section 7)•

Risk of malignancy in offspring (section 7)•

Altered skin pigmentation (section 106)

Guidelines for Genetic Risk Assessment for Cancer Predisposition (Section 7)
There is risk for subsequent malignancy and/or malignancy in offspring based on genetic
predisposition which warrants further assessment based on the determined risk factors.
Screening for Decreased Bone Mineral Density after Methotrexate (Section 28)

Late Effects Renamed•

Major Screening Changes
Guidelines for Genetic Risk Assessment for Cancer Predisposition (7)Screening for Decreased Bone Mineral Density after Methotrexate (28)
Cardiomyopathy Screening (34, 77)
Cancer Screening for Average Risk Individuals (previously 156-164)

No association has been found concerning decreased BMD and methotrexate; screening is nolonger recommended, but the section remains for reference
Cardiomyopathy Screening (Sections 34, 77)• Echocardiogram screening is not recommended for individuals with both <15Gy radiationdose (with potential impact to heart) and a cumulative doxorubicin equivalent anthracycline
dose <100 mg/m2• Anthracycline dose conversion of mitoxantrone changed to “multiply total dose x 10”
versus the previous recommendation to multiply the total dose x 4
Cancer Screening for Average Risk Individuals
The Average Risk Cancer screening guidelines (Version 5.0 sections 156-164) have been
removed and replaced with a combined screening guideline section (164) for average risk
individuals. Patients with high risk needs related to their cancer treatment are meticulously
addressed in their specific sections. Standard risk patients should consult with their healthcare
provider for general health maintenance based on age and gender. High risk patients are thosewith a history of the following exposure(s):• Breast cancer: radiation (TBI, chest, axilla) review section 73• Cervical cancer: HCT review section 100• Colorectal cancer: radiation (TBI, abdominal, pelvic, spinal [lumbar, sacral, whole]) review
section 85• Lung cancer: radiation (TBI, chest, axilla) review section 75• Oral cancer: radiation (TBI, head/brain, neck) review section 43 and/or GVHD should review
section 107• Skin cancer: radiation review section 44, with a history of HCT review section 100/101,
and/or with a history of cGVHD review section 106

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New to Version 6.0 (cont)
Additional Screening Change Highlights••

Testicular hormonal dysfunction related to alkylating agents and/or testicular radiation:
Screening with AM testosterone in high-risk patients starting at age 18 years is
recommended (12, 90)
Cyclophosphamide equivalent dose calculator (CED) has been added to assist in
determining high risk status (12, 13, 14, 15, 92, 93)•

Cataracts related to corticosteroids, alkylating agents, and/or radiation recommends a
yearly evaluation by an ophthalmologist or optometrist (18, 39, 61)•

Reduced bone mineral density related to steroids and HCT: Adjustments for gender andmenopause status regarding z-score, as well as the age metric changing from 20 to
50 years old. Guidelines for follow up are indicated with a specific algorithm for ease of
implementation. Vitamin D recommendations updated to reflect AAP guidelines with age
specific parameters (37, 104)•

Monthly breast “self-exam” is no longer recommended (73)General Recommendations Regarding Use of the Simplified COG LTFU Guidelines, V 6.0•

The COG Long-Term Follow-Up Guidelines are designed to offer general guidance and are
not meant to provide or replace the medical advice or judgment of clinicians caring forindividual survivors.

•

The recommendations in Version 6.0 of these Guidelines rely more extensively on history
and physical examination and less on screening evaluations, when compared to prior
Guideline versions.

•

We recognize that recommendations for over-screening may occur (primarily due toelimination of radiation dose-cutoffs and simplification of radiation fields); however,additional screening will generally result in recommendations for components of thehistory and physical examination only.

•

It is important for clinicians to recognize that not all survivors may be at-risk for all lateeffects that are associated with the broader exposure categories in Version 6.0; forexample, survivors with radiation fields that are known to be limited to a specific targetedarea within a broader field. Thus, if clinicians have more detailed information that supports
refraining from a specific screening for a particular patient, clinical judgment should be
used to guide the individual evaluation.

•

Since a number of previously recommended screening evaluations are now to beconsidered based on findings from the history and physical examination, cliniciansneed to carefully discern which history and physical examination findings should trigger
further evaluations. Additional, more intensive screening and/or diagnostic workup arerecommended for any survivors for whom the clinician believes there is reason to suspect
the presence of a late effect.

•

If clinicians have more detailed information that supports additional screening (orrefraining from screening), clinicians are encouraged to modify their recommendations
for individual survivors based on their knowledge of that survivor’s specific therapeutic
exposures during treatment and their current clinical status.

Health Links•

The Health Links have been modified to reflect all Version 6.0 Guideline changes.

•

Five Health Links have been renamed:
Diet and Physical Activity is now Staying Healthy through Nutrition and Physical Activity
Educational Issues is now School After Cancer Treatment
Emotional Issues is now Mental Health After Cancer Treatment
Female Health Issues after Cancer Treatment is now Ovarian and Reproductive Health afterCancer Treatment
Male Health Issues after Cancer Treatment is now Testicular and Reproductive Health afterCancer Treatment•

Two new Health Links for Version 6.0:
Vaccines after Treatment for Cancer Survivors Treated with Hematopoietic Cell Transplant(HCT)
Vaccines after Treatment for Cancer Survivors Treated with Chemotherapy and/or Radiation(Non-HCT)

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Abbreviations & Parameters
Abbreviation

Definition

Abbreviation

Definition

Abbreviation

Definition

AAP

American Academy of Pediatrics

COG

Children’s Oncology GroupHCV

Hepatitis C virus

ABR

Auditory brainstem response

CRT

Cranial radiation therapy

HDL

High-density lipoproteins

ACIP

Advisory Committee on Immunization
PracticesCT

Computed tomography

HIB

Haemophilus influenzae type B

CVRF

Cardiovascular risk factors

ACS

American Cancer Society

HIV

Human immunodeficiency virusdB

DecibelAHA

American Heart Association

HLA

Human leukocyte antigen

DES

Diethylstilbestrol

ALL

Acute lymphoblastic leukemia

HNPCC

Hereditary nonpolyposis colorectal cancer

DI

Diabetes Insipidus

ALT

Alanine aminotransferase

HPF

High power field

DLCO

Diffusion capacity of carbon monoxide

AMH

Anti-Mullerian hormone

HPV

Human papillomavirus

DOR

Diminished ovarian reserve

AML

Acute myeloid leukemia

htHeightDTI

Diffusion-tensor imaging

AST

Aspartate aminotransferase

Hz

Hertz

DWI

Diffusion-weighted imaging

ATG

Anti-thymocyte globulin

IBD

Inflammatory bowel disease

DXA

Dual energy x-ray absorptiometryATM

Ataxia telangiectasia cancer susceptibility
gene (located on chromosome 11)

K

Potassium

ECHO

Echocardiogram

I-131

Iodine 131 radioisotope

AVN

Avascular necrosis

EKG

Electrocardiogram

IgA

Immunoglobulin A

BMD

Bone mineral density

EIA

Enzyme immunoassay

IL-2

Interleukin-2

BMI

Body mass index

FAP

Familial adenomatous polyposis

IM

Intramuscular

BRCA1

Breast cancer susceptibility gene 1 (locatedon chromosome 17)

FM

Frequency modulated

IMRTIntensity-modulated radiation therapy

FNA

Fine needle aspiration

IO

Intra-Ommaya

FNH

Focal nodular hyperplasia

IQIntelligence quotient

FSH

Follicle stimulating hormone

IT

Intrathecal

Granulocyte colony stimulating factor

IU

International unit

BRCA2

Breast cancer susceptibility gene 2 (locatedon chromosome 13)

BUN

Blood urea nitrogen

G-CSF

Ca

CalciumGH

Growth hormone

IV

Intravenous

CAD

Coronary artery disease

GI

Gastrointestinal

IVIG

Intravenous immunoglobulin

Complete blood count

gm

Gram

kg

Kilogram

CCG

Children’s Cancer GroupGVHD

Graft versus host disease

KUB

Kidneys, ureters, bladder radiograph

CDC

Centers for Disease Control

Gy

Gray

LH

Luteinizing hormone

cGVHD

Chronic graft versus host disease

HbA1c

Hemoglobin A1c

LV

Left ventricular

Chloride

HBcAb

Hepatitis B core antibodym

Square meter

Central nervous system

HBsAg

Hepatitis B surface antigen

MDS

Myelodysplastic syndrome

Carbon dioxide

HCT

Hematopoietic cell transplant

MIBG

Iodine-131-meta-iodobenzylguanidine

CBC

Cl
CNS
CO2

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Abbreviations & Parameters (cont.)
Abbreviation

Definition

Abbreviation

Definitionmg

Milligram

SCUBA

Mg

Magnesium

Self-contained underwater breathingapparatus

MMF

Mycophenolate mofetil

SD

Standard deviation

MOPP

Mechlorethamine, Oncovin, Procarbazine,
Prednisone

SOS

Sinusoidal obstruction syndrome

SQ

SubcutaneousMR

Magnetic resonance

STLI

Subtotal lymphoid irradiation

MRA

Magnetic resonance angiography

T4

Thyroxine

MRI

Magnetic resonance imaging

TBI

Total body irradiation

Na

SodiumTLI

Total lymphoid irradiation

NF1

Neurofibromin 1 (neurofibromatosis)
cancer susceptibility gene (located on
chromosome 17)

TPN

Total parenteral nutrition

TSH

Thyroid stimulating hormone

U

Units

USPSTF

United States Preventive Services Task
Force

V-A

Ventriculoatrial

VOD

Veno-occlusive disease

V-P

Ventriculoperitoneal

V-V

Ventriculovenus

VZIG

Varicella zoster immunoglobulin

WAGR

Wilms tumor, aniridia, genitourinary
anomalies, range of developmental delays

wt

WeightNHL

Non-Hodgkin lymphoma

NSAIDs

Non-steroidal anti-inflammatory drugs

p53

Cancer susceptibility gene associated withfamilial cancers (located on chromosome
17)

PAP

Papanicolaou

PCR

Polymerase chain reaction

PFTs

Pulmonary function tests

PNET

Primitive neuroectodermal tumor

PNS

Peripheral nervous systemPOBy mouth

PO4

Phosphate

PSA

Prostate specific antigen

PUVA

Psoralen plus ultraviolet-A radiation

QTc

Corrected QT interval

RB1

Retinoblastoma cancer susceptibility gene(located on chromosome 13)

RBC

Red blood cell

RUQ

Right upper quadrant

Parameters commonly referenced in the guidelines≥1000 mg/m2

High dose methotrexate<1000mg/m

Standard dose methotrexate22≥1000 mg/m

High dose cytarabine

2<1000mg/m

Standard dose cytarabine

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Long-Term
Follow-Up
Guidelines
for Survivors of Childhood,
Adolescent, and Young Adult Cancers

Guidelines
Version 6.0
October 2023

ANY CANCER EXPERIENCESec #Therapeutic
Exposure

Potential
Late Effects

1

Any Cancer Experience

Adverse psychosocial/qualityof life effects
Social withdrawal
Educational problems
Relationship problems
Under-employment/
Unemployment
Dependent living

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORYHEALTH LINKS
Psychosocial assessment with attention to: Introduction to Long-Term Follow-Up• Educational and/or vocational progress Mental Health• Social withdrawal
School After Treatment
YearlyRESOURCES‘Childhood Cancer Survivors: A Practical Guide to Your Future,’ by Nancy Keene,
Wendy Hobbie & Kathy Ruccione, Childhood Cancer Guides, 2012
‘Educating the Child with Cancer: A Guide for Parents and Teachers,’ edited by
Ruth Hoffman, American Childhood Cancer Organization, 2013
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Preference should be given to self vs. proxy report.
Psychological consultation in patients with emotional difficulties related tocancer experience, including physical deformities or chronic disabilities.
Social work consultation.
Refer as indicated to school liaison in community or cancer center (psychologist,social worker, school counselor) to facilitate acquisition of educational or
vocational resources.
Refer as indicated for neuropsychological evaluation.
Assess social determinants of health including economic stability, education
access and quality, health care access and quality, neighborhood andbuilt environment, and social and community context (https://health.gov/
healthypeople/objectives-and-data/social-determinants-health).
SYSTEM = Psychosocial
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at diagnosis, family history of depression, anxiety, or mental illness, lower household income, lower educational attainment, school withdrawal, race/ethnicity- Cancer/Treatment factors: Bone tumor, CNS tumor, CNS-directed therapy, history of HCT- Pre-morbid/Co-morbid medical conditions: Premorbid learning or emotional difficulties, chronic conditions after cancer treatment (e.g., obesity, endocrine, pulmonary, cardiac conditions) are associated with increased risk forneurocognitive difficulties, and/or increased symptom burden (e.g., pain, fatigue) including neurocognitive problems

References
Barrera M, Shaw AK, Speechley KN, et al: Educational and social late effects of childhood cancer and related clinical, personal, and familial characteristics. Cancer 104:1751-60, 2005
Bernard F, Auquier P, Herrmann I, et al: Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study. Bone Marrow Transplant 49:709-16, 2014
Boman KK, Lindblad F, Hjern A: Long-term outcomes of childhood cancer survivors in Sweden: a population-based study of education, employment, and income. Cancer 116:1385-91, 2010
Brinkman TM, Bass JK, Li Z, et al: Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study. Cancer 121:4053-61, 2015
Brinkman TM, Krasin MJ, Liu W, et al: Long-term neurocognitive functioning and social attainment in adult survivors of pediatric CNS tumors: results from the St Jude Lifetime Cohort Study. J Clin Oncol 34:1358-67, 2016
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ANY CANCER EXPERIENCE (CONT)
Section 1 References (cont)
Brinkman TM, Ullrich NJ, Zhang N, et al: Prevalence and predictors of prescription psychoactive medication use in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Cancer Surviv 7:104-14,
2013
de Blank PM, Fisher MJ, Lu L, et al: Impact of vision loss among survivors of childhood central nervous system astroglial tumors. Cancer 122:730-9, 2016
Devine KA, Christen S, Mulder RL, et al: Recommendations for the surveillance of education and employment outcomes in survivors of childhood, adolescent, and young adult cancer: a report from the International Late Effects ofChildhood Cancer Guideline Harmonization Group. Cancer 1;128(13):2405-2419, 2022
Edelmann MN, Daryani VM, Bishop MW, et al: Neurocognitive and patient-reported outcomes in adult survivors of childhood osteosarcoma. JAMA Oncol 2(2):201-8, 2016
Font-Gonzalez A, Feijen EL, Sieswerda E, et al: Social outcomes in adult survivors of childhood cancer compared to the general population: linkage of a cohort with population registers. Psycho-Oncol 25:933-41, 2016
Hornquist L, Rickardsson J, Lannering B, et al: Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence: population-based outcomes compared with the general population. Neuro Oncol 17:73340, 2015
Iijima M, Liu W, Panetta JC, et al. Association between obesity and neurocognitive function in survivors of childhood acute lymphoblastic leukemia treated only with chemotherapy. Cancer 127(17):3202-3213, 2021
Janson C, Leisenring W, Cox C, et al: Predictors of marriage and divorce in adult survivors of childhood cancers: a report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 18:2626-35, 2009
Kinahan KE, Sharp LK, Seidel K, et al: Scarring, disfigurement, and quality of life in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30:2466-74, 2012
Kirchhoff AC, Krull KR, Ness KK, et al: Occupational outcomes of adult childhood cancer survivors: A report from the Childhood Cancer Survivor Study. Cancer 117:3033-44, 2011
Kirchhoff AC, Leisenring W, Krull KR, et al: Unemployment among adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Med Care 48:1015-25, 2010
Kunin-Batson A, Kadan-Lottick N, Zhu L, et al: Predictors of independent living status in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 57:1197-203, 2011
Lancashire ER, Frobisher C, Reulen RC, et al: Educational attainment among adult survivors of childhood cancer in Great Britain: a population-based cohort study. J Natl Cancer Inst 102:254-70, 2010
Lown EA, Phillips F, Schwartz LA, et al: Psychosocial follow-up in survivorship as a standard of care in pediatric oncology. Pediatr Blood Cancer 62 Suppl 5:S514-84, 2015
Lund LW, Schmiegelow K, Rechnitzer C, et al: A systematic review of studies on psychosocial late effects of childhood cancer: structures of society and methodological pitfalls may challenge the conclusions. Pediatr Blood Cancer
56:532-43, 2011
Mitby PA, Robison LL, Whitton JA, et al: Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 97:1115-26,
2003
Rueegg CS, Gianinazzi ME, Rischewski J, et al: Health-related quality of life in survivors of childhood cancer: the role of chronic health problems. J Cancer Surviv 7:511-22, 2013
Schulte F, Kunin-Batson AS, Olson-Bullis BA, et al: Social attainment in survivors of pediatric central nervous system tumors: a systematic review and meta-analysis from the Children’s Oncology Group. J Cancer Surviv 13(6):921931, 2019
Stokke J, Sung L, Gupta A, et al: Systematic review and meta-analysis of objective and subjective quality of life among pediatric, adolescent, and young adult bone tumor survivors. Pediatr Blood Cancer 62:1616-29, 2015
Wengenroth L, Rueegg CS, Michel G, et al: Life partnerships in childhood cancer survivors, their siblings, and the general population. Pediatr Blood Cancer 61:538-45, 2014

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ANY CANCER EXPERIENCE (CONT)Sec #2Therapeutic
Exposure
Any Cancer Experience

Potential
Late Effects
Mental health disorders
Depression
Anxiety
Post-traumatic stressSuicidal behavior

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Psychosocial assessment with attention to:• Depression• Anxiety• Post-traumatic stress• Suicidal ideation
YearlyHEALTH LINKS
Mental HealthRESOURCES‘Childhood Cancer Survivors: A Practical Guide to Your Future,’ by Nancy Keene, Wendy
Hobbie & Kathy Ruccione, Childhood Cancer Guides, 2012
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Preference should be given to self vs. proxy report.
Psychological consultation in patients with emotional difficulties related to cancer
experience, including physical deformities or chronic disabilities.
Appropriate psychotropic medications, as clinically indicated.
Evaluation of parent for posttraumatic stress.
Assess social determinants of health including economic stability, education access andquality, health care access and quality, neighborhood and built environment, and socialand community context (https://health.gov/healthypeople/objectives-and-data/social-determinants-health).
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Female sex, family history of depression, anxiety, or mental illness, lower household income, lower educational attainment, especially school withdrawal, unemployment, not in a relationship, poor social support, perceived poor physical health, no health insurance or public health insurance- Cancer/Treatment factors: CNS tumor, CNS-directed therapy, history of HCT- Pre-morbid/Co-morbid medical conditions: Chronic pain, scarring or physical disfigurement, permanent hair loss, premorbid learning or emotional difficulties, sleep/fatigue issues, substance misuse

References
Allen J, Willard VW, Klosky JL, et al: Posttraumatic stress-related psychological functioning in adult survivors of childhood cancer. J Cancer Survivorship 12(2),216–223, 2018
Brinkman TM, Li C, Vannatta K, et al: Behavioral, social, and emotional symptom comorbidities and profiles in adolescent survivors of childhood cancer: a report From the Childhood Cancer Survivor Study. J Clin Oncol 1;34(28):3417-25, 2016
Brinkman TM, Zhu L, Zeltzer LK, et al: Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Br J Cancer 109:1373-81, 2013
Cunningham SJ, Patton M, Schulte F, et al: Worry about somatic symptoms as a sign of cancer recurrence: prevalence and associations with fear of recurrence and quality of life in survivors of childhood cancer. Psycho-onc 30(7),1077–1085, 2021
Kinahan KE, Sharp LK, Seidel K, et al: Scarring, disfigurement, and quality of life in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30:2466-74, 2012
Klosky JL, Krull KR, Kawashima T, et al: Relations between posttraumatic stress and posttraumatic growth in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Health Psychol 33:878-82, 2014
Korhonen LM, Taskinen M, Rantanen M, et al: Suicides and deaths linked to risky health behavior in childhood cancer patients: a Nordic population-based register study. Cancer 125(20):3631-8, 2019
Lown EA, Phillips F, Schwartz LA, et al: Psychosocial follow-up in survivorship as a standard of care in pediatric oncology. Pediatr Blood Cancer 62 Suppl 5:S514-84, 2015
Michel G, Rebholz CE, von der Weid NX, et al: Psychological distress in adult survivors of childhood cancer: the Swiss Childhood Cancer Survivor Study. J Clin Oncol 28:1740-8, 2010
Oancea SC, Brinkman TM, Ness KK, et al: Emotional distress among adult survivors of childhood cancer. J Cancer Surviv 8:293-303, 2014
Prasad PK, Hardy KK, Zhang N, et al: Psychosocial and neurocognitive outcomes in adult survivors of adolescent and early young adult cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 33:2545-52, 2015
Recklitis CJ, Diller LR, Li X, et al: Suicide ideation in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 28:655-61, 2010
Shah SS, Dellarole A, Peterson EC, et al: Long-term psychiatric outcomes in pediatric brain tumor survivors. Childs Nerv Syst 31:653-63, 2015
Stuber ML, Meeske KA, Krull KR, et al: Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer. Pediatrics 125:e1124-34, 2010
Zebrack BJ, Landier W: The perceived impact of cancer on quality of life for post-treatment survivors of childhood cancer. Qual Life Res 20:1595-608, 2011
Zebrack BJ, Stuber ML, Meeske KA, et al: Perceived positive impact of cancer among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Psycho-Oncol 21:630-9, 2012

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ANY CANCER EXPERIENCE (CONT)Sec #Therapeutic
Exposure

Potential
Late Effects

3

Any Cancer Experience

Risky behaviors
Behaviors known to increase
the likelihood of subsequentillness or injury

Periodic Evaluation
HISTORY
Psychosocial assessment
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Mental HealthRESOURCES‘Childhood Cancer Survivors: A Practical Guide to Your Future,’ by Nancy Keene,
Wendy Hobbie & Kathy Ruccione, Childhood Cancer Guides, 2012www.smokefree.gov
www.cancer.org/healthy/stay-away-from-tobacco
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Psychological consultation in patients with emotional difficulties related tocancer experience.
Assess social determinants of health including economic stability, education
access and quality, health care access and quality, neighborhood andbuilt environment, and social and community context (https://health.gov/
healthypeople/objectives-and-data/social-determinants-health).
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Adolescent/Young adult at diagnosis or follow-up, male sex, lower household income, lower educational attainment, rural neighborhood, psychological distress

References
Buchanan N, Leisenring W, Mitby PA, et al: Behaviors associated with ultraviolet radiation exposure in a cohort of adult survivors of childhood and adolescent cancer: a report from the Childhood Cancer Survivor Study. Cancer 115:4374-84, 2009
Frobisher C, Lancashire ER, Reulen RC, et al: Extent of alcohol consumption among adult survivors of childhood cancer: the British Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 19:1174-84, 2010
Gibson TM, Liu W, Armstrong GT, et al: Longitudinal smoking patterns in survivors of childhood cancer: an update from the Childhood Cancer Survivor Study. Cancer 121:4035-43, 2015
Howell CR, Wilson CL, Yasui Y, et al: Neighborhood effect and obesity in adult survivors of pediatric cancer: a report from the St. Jude lifetime cohort study. Int J Cancer 147(2),338–349, 2020
Ji X, Cummings JR, Mertens AC, et al: Substance use, substance use disorders, and treatment in adolescent and young adult cancer survivors-results from a national survey. Cancer 127(17),3223–3231, 2021
Klosky JL, Howell CR, Li Z, et al: Risky health behavior among adolescents in the Childhood Cancer Survivor Study cohort. J Pediatr Psychol 37:634-46, 2012
Milam J, Slaughter R, Meeske K, et al: Substance use among adolescent and young adult cancer survivors. Psycho-Oncol 25:1357-1362, 2016
Oancea SC, Gurney JG, Ness KK, et al: Cigarette smoking and pulmonary function in adult survivors of childhood cancer exposed to pulmonary-toxic therapy: results from the St. Jude Lifetime Cohort Study. Cancer Epidemiol Biomarkers Prev
23:1938-43, 2014
Pinto S, Fresneau B, Hounsossou HC, et al: Identifying clusters of health risk behaviors and their predictors in adult survivors of childhood cancer: a report from the French Childhood Cancer Survivor Study. Psychooncology, 29(10),1595-1603,
2020
Sundberg KK, Lampic C, Arvidson J, et al: Sexual function and experience among long-term survivors of childhood cancer. Eur J Cancer 47:397-403, 2011

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ANY CANCER EXPERIENCE (CONT)Sec #Therapeutic
Exposure

Potential
Late Effects

4

Any Cancer Experience

Psychosocial disability due
to painHealth Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Psychosocial assessment
YearlyHEALTH LINKS
Chronic Pain after Childhood Cancer
RESOURCES‘Childhood Cancer Survivors: A Practical Guide to Your Future,’ by Nancy Keene,
Wendy Hobbie & Kathy Ruccione, Childhood Cancer Guides, 2012
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Psychological consultation in patients with chronic pain.
Appropriate psychotropic medications, as clinically indicated.
Referral to pain rehabilitation clinic.
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Female sex- Cancer/Treatment factors: CNS tumor, Hodgkin lymphoma, sarcoma/bone diagnosis, radiation to bone/joint, vincristine exposure- Pre-morbid/Co-morbid medical conditions: History of osteonecrosis, depression, anxiety, sleep/fatigue issues, severe/life threatening chronic medical conditions

References
Karlson CW, Alberts NM, Liu W, et al: Longitudinal pain and pain interference in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 15;126(12):2915-2923, 2020
Lu Q, Krull KR, Leisenring W, et al: Pain in long-term adult survivors of childhood cancers and their siblings: a report from the Childhood Cancer Survivor Study. Pain 152:2616-24, 2011
Ness KK, Hudson MM, Jones KE, et al: Effect of temporal changes in therapeutic exposure on self-reported health status in childhood cancer survivors. Ann Intern Med 166:89-98, 2017
Schulte FSM, Patton M, Alberts NM, et al: Pain in long-term survivors of childhood cancer: A systematic review of the current state of knowledge and a call to action from the Children’s Oncology Group. Cancer 1;127(1):35-44, 2021
Tonning Olsson I, Alberts NM, Li C, et al: Pain and functional outcomes in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort study. Cancer 15;127(10):1679-1689, 2021

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ANY CANCER EXPERIENCE (CONT)Sec #Therapeutic
Exposure5

Any Cancer Experience

Potential
Late Effects
FatigueSleep problems

Periodic Evaluation
HISTORY
Psychosocial assessment
YearlyHealth Counseling/
Further Considerations
RESOURCES‘Childhood Cancer Survivors: A Practical Guide to Your Future,’ by Nancy Keene,
Wendy Hobbie & Kathy Ruccione, Childhood Cancer Guides, 2012
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Screen for physical sources of fatigue, such as anemia, sleep disturbances,
nutritional deficiencies, cardiomyopathy, pulmonary fibrosis, hypothyroidism, orother endocrinopathies.
Referral to specialties such as endocrinology, sleep lab/study, or nutrition as
indicated.
Referral to psychology for behavioral intervention for emotional difficulties
contributing to sleep/fatigue issues.
Refer as indicated for cognitive-behavior therapy for insomnia.
Assess social determinants of health including economic stability, education
access and quality, health care access and quality, neighborhood andbuilt environment, and social and community context (https://health.gov/
healthypeople/objectives-and-data/social-determinants-health).
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Female sex- Cancer/Treatment factors: CNS tumor (e.g., craniopharyngioma), pulmonary radiation- Pre-morbid/Co-morbid medical conditions: Depression, anxiety, obesity, sleep/fatigue issues, pain

References
Christen S, Roser K, Mulder RL, et al: Recommendations for the surveillance of cancer-related fatigue in childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. J Cancer Surviv 14(6):923-938, 2020
Jacobsen PB: Assessment of fatigue in cancer patients. J Natl Cancer Inst Monogr:93-7, 2004
Lawrence DP, Kupelnick B, Miller K, et al: Evidence report on the occurrence, assessment, and treatment of fatigue in cancer patients. J Natl Cancer Inst Monogr:40-50, 2004
Mulrooney DA, Ness KK, Neglia JP, et al: Fatigue and sleep disturbance in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS). Sleep 31:271-81, 2008
Rosen G, Brand SR: Sleep in children with cancer: case review of 70 children evaluated in a comprehensive pediatric sleep center. Support Care Cancer 19:985-94, 2011
Verberne LM, Maurice-Stam H, Grootenhuis MA, et al: Sleep disorders in children after treatment for a CNS tumour. J Sleep Res 21:461-9, 2012
Zeller B, Loge JH, Kanellopoulos A, et al: Chronic fatigue in long-term survivors of childhood lymphomas and leukemia: persistence and associated clinical factors. J Pediatr Hematol Oncol 36:438-44, 2014
Zhou ES, Vrooman LM, Manley PE, et al: Adapted delivery of cognitive-behavioral treatment for insomnia in adolescent and young adult cancer survivors: a pilot study. Behav Sleep Med 15:288-301, 2017

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ANY CANCER EXPERIENCE (CONT)Sec #Therapeutic
Exposure

Potential
Late Effects

6

Any Cancer Experience

Limitations in healthcare andinsurance access

Periodic Evaluation
HISTORY
Psychosocial assessment with attention to
healthcare and insurance accessYearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Finding and Paying for Healthcare
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Social work consultation.
Healthcare and insurance access may differ by country and/or state.
Assess social determinants of health including economic stability, education
access and quality, health care access and quality, neighborhood andbuilt environment, and social and community context (https://health.gov/
healthypeople/objectives-and-data/social-determinants-health).
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Lower household income, lower educational attainment, unemployment

References
Caplin DA, Smith KR, Ness KK, et al: Effect of population socioeconomic and health system factors on medical care of childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Adolesc Young Adult Oncol 6:7482, 2017
Fiala MA. Disparities in health care affordability among childhood cancer survivors persist following the Affordable Care Act. Pediatr Blood Cancer 68(12):e29370, 2021
Huang IC, Bhakta N, Brinkman TM, et al: Determinants and consequences of financial hardship among adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. J Natl Cancer Inst 111(2):189-200, 2019
Nathan PC, Greenberg ML, Ness KK, et al: Medical care in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 26:4401-9, 2008
Park ER, Kirchhoff AC, Nipp RD, et al: Assessing health insurance coverage characteristics and impact on health care cost, worry, and access: a report from the Childhood Cancer Survivor Study. JAMA Intern Med 177(12):1855-1858,2017
Park ER, Kirchhoff AC, Zallen JP, et al: Childhood Cancer Survivor Study participants’ perceptions and knowledge of health insurance coverage: implications for the Affordable Care Act. J Cancer Surviv 6:251-9, 2012

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ANY CANCER EXPERIENCE (CONT)Sec #Therapeutic
Exposure

7

Any Cancer Experience

Potential
Late Effects
Subsequent malignancy
Risk of malignancy inoffspring

Table 1

Solid Tumor
Adrenocortical carcinoma
Desmoid tumor
Endolymphatic sac tumor
Gastrointestinal stromal tumor
Malignant peripheral nerve sheath tumor
Medullary thyroid cancer
Osteosarcoma
Ovarian Sertoli cell or Sertoli-Leydig cell tumor
Paraganglioma
Pheochromocytomaw

Periodic Evaluation
HISTORY
Strongly consider assessment for cancer
predisposition in the following settings:• Any tumor listed in Table 1• Any bilateral cancer• >1 primary cancer• ≥1 first degree relative(s) with cancer• Other concerning family history including consanguinity• Diagnosis of adult-type cancer in a child(basal cell carcinoma, breast, colon,
gastrointestinal, ovarian, etc.)• Diagnosis of cancer predisposition syndrome in a relative

Solid Tumor (cont)Pleuropulmonary blastoma
Renal cell carcinoma
Rhabdoid tumor
Schwannoma
CNS Tumor
Atypical teratoid rhabdoid tumor
Choroid plexus carcinoma
Ciliary body medullo-ephithelioma
Hemangioblastoma
Optic pathway glioma

Health Counseling/
Further Considerations
RESOURCES
McGill Interactive Pediatric OncoGenetic Guidelines: www.mipogg.com
National Society of Genetic Counselors: www.nsgc.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
For patients who may be at risk for cancer predisposition by history, or with ahistory of one of the cancer types listed in Table 1, consider:• Referral to genetic counseling or clinical genetics• Referral for preconception/prenatal counseling
SYSTEM = SMNSCORE = 1

CNS Tumor (cont)Pineoblastoma
Pituitary blastoma
Retinoblastoma
Sub-ependymomal giant cell astrocytoma
Non-Malignant/Other
Cystic nephroma
Juvenile myelomonocytic leukemia
Meningioma
Myelodysplastic syndrome

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
Common cancers for which there is increased risk for underlying predisposition under specific clinical scenarios include:- AML with personal or family history of cytopenias or chronic infections, monosomy 7, short stature, microcephaly, other congenital anomalies, or 3 or more café au lait macules- B-cell ALL with low hypodiploid cytogenetics (32-39 chromosomes)- Embryonal rhabdomyosarcoma diagnosed <4 years old, diffuse anaplasia or botryoid subtype, or in genitourinary location- Medulloblastoma of SHH or WNT subtypes, or diagnosed <3 years old if subtype unknown- Hepatoblastoma with family history of GI cancer/polyps, or with features of hemihyperplasia/overgrowth syndrome- Wilms tumor diagnosed <2 years old with GU anomalies (including history of undescended testicle or hypospadias), hemihyperplasia/overgrowth, or other syndromic features

References
Goudie C, Witkowski L, Cullinan N, et al: Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes. JAMA Oncol 1;7(12):1806-1814, 2021
Jongmans MC, Loeffen JL, Waanders E, et al: Recognition of genetic predisposition in pediatric cancer patients: an easy-to-use selection tool. Eur J Med Genet 59(3):116-25, 2016
Ripperger T, Bielack SS, Borkhardt A, et al: Childhood cancer predisposition syndromes-a concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J
Med Genet A173(4):1017-1037, 2017
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BLOOD/SERUM PRODUCTS
Sec #Therapeutic
Exposure

8

Diagnosed prior to 1972

Potential
Late Effects
Chronic hepatitis B

Periodic Evaluation

Health Counseling/
Further Considerations

SCREENING
Hepatitis B surface antigen (HBsAg)
Hepatitis B core antibody (anti-HBc or
HBcAb)
Once in patients who received treatment forcancer prior to 1972
Note: Date may vary for international patientsHEALTH LINKS
Hepatitis
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Screen for viral hepatitis in patients with persistently abnormal liver function
regardless of transfusion history.
Gastroenterology or hepatology consultation for patients with chronic hepatitis.
Hepatitis A and B immunization in at-risk patients lacking immunity.
SYSTEM = Immune
SCORE = 1w

Additional Information

Exposure to blood/serum products prior to initiation of hepatitis B screening of blood supply (1972 in the United States - dates may differ in other countries) is associated with risk of chronic hepatitis B.
Since the vast majority of patients received some type of blood product during childhood cancer treatment, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did notreceive any blood or blood products.
Relevant exposures include packed red cells, whole blood, granulocytes, platelets, fresh frozen plasma, cryoprecipitate, IVIG, VZIG, factor concentrate, and allogeneic marrow, cord blood, or stem cells.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Living in hyperendemic areas- Cancer/Treatment factors: Chronic immunosuppression- Health behaviors: History of IV drug use, unprotected sex, multiple partners, high-risk sexual behavior, sexually transmitted infections, tattoos, body piercing

References
Castellino S, Muir A, Shah A, et al: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr Blood Cancer 54:663-9, 2010
Locasciulli A, Alberti A, Rossetti F, et al: Acute and chronic hepatitis in childhood leukemia: a multicentric study from the Italian Pediatric Cooperative Group for Therapy of Acute Leukemia (AIL-AIEOP). Med Pediatr Oncol 13:203-6,
1985
Willers E, Webber L, Delport R, et al: Hepatitis B--a major threat to childhood survivors of leukaemia/lymphoma. J Trop Pediatr 47:220-5, 2001
Zou S, Stramer SL, Dodd RY: Donor testing and risk: current prevalence, incidence, and residual risk of transfusion-transmissible agents in US allogeneic donations. Transfus Med Rev 26:119-28, 2012

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BLOOD/SERUM PRODUCTS (CONT)Sec #Therapeutic
Exposure

9

Diagnosed prior to 1993

Potential
Late Effects
Chronic hepatitis C

Periodic Evaluation
SCREENING
Hepatitis C antibody
Once in patients who received treatment forcancer prior to 1993
Note: Date may vary for international patients
Hepatitis C PCR (to establish chronic
infection)
Once in patients with positive Hepatitis C
antibody

Health Counseling/
Further Considerations
HEALTH LINKS
Hepatitis
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Screen for viral hepatitis in patients with persistently abnormal liver function
regardless of transfusion history.
PCR testing for HCV in immunosuppressed patients who are negative for
antibody.
Gastroenterology or hepatology consultation for management of patients withchronic hepatitis.
Hepatitis A and B immunization in at-risk patients lacking immunity.
SYSTEM = Immune
SCORE = 1w

Additional Information

Exposure to blood/serum products prior to initiation of hepatitis C screening of blood supply (1993 in the United States [considering the more reliable EIA-2 screening was released in the U.S. in 1992] - dates may differ in othercountries) is associated with risk of chronic hepatitis C.
Since the vast majority of patients received some type of blood product during childhood cancer treatment, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did notreceive any blood or blood products.
Relevant exposures include packed red cells, whole blood, granulocytes, platelets, fresh frozen plasma, cryoprecipitate, IVIG, VZIG, factor concentrates, and allogeneic marrow, cord blood, or stem cells.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Living in hyperendemic areas- Cancer/Treatment factors: Chronic immunosuppression, exposure to blood/serum products prior to 1986 (when surrogate screening of blood donors with ALT was initiated and donors with self-reported high-risk behaviors
were deferred)- Health behaviors: History of IV drug use, unprotected sex, multiple partners, high-risk sexual behavior, sexually transmitted infections, tattoos, body piercing

References
Bardi E, Mulder RL, van Dalen EC, et al. Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
Cancer Treat Rev 100:102296, 2021
Castellino S, Lensing S, Riely C, et al: The epidemiology of chronic hepatitis C infection in survivors of childhood cancer: an update of the St Jude Children’s Research Hospital hepatitis C seropositive cohort. Blood 103:2460-6, 2004
Castellino S, Muir A, Shah A, et al: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr Blood Cancer 54:663-9, 2010
Cesaro S, Bortolotti F, Petris MG, et al: An updated follow-up of chronic hepatitis C after three decades of observation in pediatric patients cured of malignancy. Pediatr Blood Cancer 55:108-12, 2010
Green DM, Wang M, Krasin MJ, et al. Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Hepatol 69(1):94-106, 2019
Lansdale M, Castellino S, Marina N, et al: Knowledge of hepatitis C virus screening in long-term pediatric cancer survivors: a report from the Childhood Cancer Survivor Study. Cancer 116:974-82, 2010
Locasciulli A, Testa M, Pontisso P, et al: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 90:4628-33, 1997
Peffault de Latour R, Levy V, Asselah T, et al: Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 103:1618-24, 2004
Psaros Einberg A, Ekman AT, Söderhäll S, et al. Prevalence of chronic hepatitis C virus infection among childhood cancer survivors in Stockholm, Sweden. Acta Oncol, 58(7):997-1002, 2019

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BLOOD/SERUM PRODUCTS (CONT)
Sec #
10

Therapeutic
Exposure

Potential
Late Effects

Diagnosed between 1977 HIV infection
and 1985

Periodic Evaluation

Health Counseling/
Further Considerations

SCREENING
HIV testingOnce in patients who received treatment forcancer between 1977 and 1985
Note: Date may vary for international patients

COUNSELING
Standard counseling regarding safer sex, universal precautions and high-risk
behaviors that exacerbate risk.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
HIV/Infectious diseases specialist consultation for patients with chronic infection.
SYSTEM = Immune
SCORE = 1w

Additional Information

Exposure to blood/serum products prior to initiation of HIV screening of blood supply (between 1977 and 1985 in the United States - dates may differ in other countries) is associated with risk of HIV infection.
Since the vast majority of patients received some type of blood product during childhood cancer treatment, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did notreceive any blood or blood products.
Relevant exposures include packed red cells, whole blood, granulocytes, platelets, fresh frozen plasma, cryoprecipitate, IVIG, VZIG, factor concentrates, and allogeneic marrow, cord blood, or stem cells.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Health behaviors: History of IV drug use, unprotected sex, multiple partners, high-risk sexual behavior, sexually transmitted infections, tattoos, body piercing

References
Zou S, Stramer SL, Dodd RY: Donor testing and risk: current prevalence, incidence, and residual risk of transfusion-transmissible agents in US allogeneic donations. Transfus Med Rev 26:119-28, 2012

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CHEMOTHERAPY
Sec #
11

w

Therapeutic
Exposure
Any Chemotherapy

ANY CHEMOTHERAPY
Potential
Late Effects

Dental abnormalities
Tooth/Root agenesis
Root thinning/shortening
Enamel dysplasia
Microdontia
Ectopic molar eruption
Dental caries

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Oral exam
YearlySCREENING
Dental exam and cleaning
Every 6 months

HEALTH LINKS
Dental Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Regular dental care including fluoride applications.
Baseline panorex prior to dental procedures to evaluate root development.
SYSTEM = Dental
SCORE
Ectopic Molar Eruption = 2A
All Else = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Any patient who had not developed permanent dentition at time of cancer therapy, younger age at treatment, especially age <5 years- Cancer/Treatment factors: Any radiation treatment involving the oral cavity or salivary glands

References
Busenhart DM, Erb J, Rigakos G, et al: Adverse effects of chemotherapy on the teeth and surrounding tissues of children with cancer: a systematic review with meta-analysis. Oral Oncol 83:64-72, 2018
Effinger KE, Migliorati CA, Hudson MM, et al: Oral and dental late effects in survivors of childhood cancer: a Children’s Oncology Group report. Support Care Cancer 22:2009-19, 2014
Goho C: Chemoradiation therapy: effect on dental development. Pediatr Dent 15:6-12, 1993
Hsieh SG, Hibbert S, Shaw P, et al: Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy. Cancer 117:2219-27, 2011
Immonen E, Nikkilä A, Peltomäki T, et al: Late adverse effects of childhood acute lymphoblastic leukemia treatment on developing dentition. Pediatr Blood Cancer 68(9), 2021
Kaste SC, Goodman P, Leisenring W, et al: Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study. Cancer 115:5817-27, 2009
Ko Y, Park K, Kim JY: Effect of anticancer therapy on ectopic eruption of permanent first molars. Pediatr Dent 35:530-3, 2013
Proc P, Szczepanska J, Skiba A, et al: Dental anomalies as late adverse effect among young children treated for cancer. Cancer Res Treat 48:658-67, 2016
Shum M, Mahoney E, Naysmith K, et al. Associations between childhood cancer treatment and tooth agenesis. N Z Med J 133(1523):41-54, 2020
Sonis AL, Tarbell N, Valachovic RW, et al: Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities. Cancer 66:2645-52, 1990

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CHEMOTHERAPYSec #12(male)

ALKYLATING AGENTS

Therapeutic
Exposure

Potential
Late Effects

Classical Alkylating AgentsBusulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa
Heavy Metals
Carboplatin
Cisplatin
Non-Classical Alkylators
Dacarbazine (DTIC)
Temozolomide

Testicular hormonal dysfunction
Testosterone deficiency/
insufficiency
Delayed/Arrested puberty

HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal emissions,libido)Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyMonitor growth until mature
YearlySCREENING
AM testosterone in high risk patients startingat 18 years

Commonly used alkylators can be converted to a cyclophosphamide equivalent dose by using: CED (mg/m2)=
1.0 (cumulative cyclophosphamide dose (mg/m2)) + 0.244 (cumulative ifosfamide dose (mg/m2)) +0.857 (cumulative procarbazine dose (mg/m2)) + 14.286 (cumulative chlorambucil dose (mg/m2)) +15 (cumulative BCNU dose (mg/m2)) + 16 (cumulative CCNU dose (mg/m2)) + 40 (cumulative melphalan dose (mg/m2)) +50 (cumulative thiotepa dose (mg/m2)) + 100 (cumulative nitrogen mustard dose (mg/m2)) +8.823 (cumulative busulfan dose (mg/m2))w

Health Counseling/
Further Considerations

Periodic Evaluation
HEALTH LINKS

Testicular and Reproductive Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Testosterone insufficiency or deficiency requiring hormone replacement after alkylating
agents only is rare.
Endocrine referral for the following:• No signs of puberty by age 14 years• Failure of pubertal progression• Adults with low AM testosterone levels
Periodic re-evaluation of testosterone in males with low normal testosterone as they age
or if they become symptomatic.
Bone density evaluation in androgen deficient patients.
Consider assessment of fertility status prior to initiation of testosterone replacement
therapy.
SYSTEM = Reproductive (Male)SCOREClassical Alkylating Agents = 1
Heavy Metals = 2A
Non-Classical Alkylators = 2A

Additional Information

Testicular volume is not a reliable indicator of pubertal onset/stage in boys treated with alkylating agents and/or direct testicular radiotherapy.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Testicular cancer, higher cumulative doses of alkylators (especially cyclophosphamide dose ≥20 gm/m2 or ifosfamide ≥60 gm/m2), combinations of alkylators, combination with MOPP, cyclophosphamide as conditioning for HCT, in combination with radiation (to abdomen/pelvis, testes [especially dose ≥20 Gy], brain/cranium [neuroendocrine axis], or TBI), and unilateral orchiectomy- Health behaviors: Tobacco/Marijuana use

References
Brignardello E, Felicetti F, Castiglione A, et al: Gonadal status in long-term male survivors of childhood cancer. J Cancer Res Clin Oncol 142:1127-32, 2016
Chemaitily W, Liu Q, van Iersel L, et al: Leydig cell function in male survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J Clin Oncol 37:3018-31, 2019
Hamre H, Kiserud CE, Ruud E, et al: Gonadal function and parenthood 20 years after treatment for childhood lymphoma: a cross-sectional study. Pediatr Blood Cancer 59:271-7, 2012
Kenney LB, Antal Z, Ginsberg JP, et al: Improving male reproductive health after childhood, adolescent, and young adult cancer: progress and future directions for survivorship research. J Clin Oncol 36:2160-68, 2018
Kenney LB, Laufer MR, Grant FD, et al: High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 91:613-21, 2001
Lopez R, Plat G, Bertrand Y, et al: Testosterone deficiency in men surviving childhood acute leukemia after treatment with hematopoietic stem cell transplantation or testicular radiation: an L.E.A. study. Bone Marrow Transplant 56(6):1422-1425, 2021
Mostafi-Moab S, Seidel K, Leisenring WM, et al: Endocrine abnormalities in aging survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. J Clin Oncol 34:3240-47, 2016
Practice Committee of American Society for Reproductive Medicine: Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 98:294-301, 2012
Skinner R, Mulder RL, Kremer LC, et al: Recommendations for gonadotoxiity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guidelines Harmonization Group in collaboration with the PanCareSurFup Consortium, Lancet Oncol 18:e75-90, 2017
Sprauten M, Brydoy M, Haugnes HS, et al: Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 32:571-8, 2014
Williams D, Crofton PM, Levitt G: Does ifosfamide affect gonadal function? Pediatr Blood Cancer 50:347-51, 2008

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CHEMOTHERAPYSec #13(male)

ALKYLATING AGENTS (CONT)

Therapeutic
Exposure

Potential
Late Effects

Classical Alkylating
AgentsBusulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa
Heavy Metals
Carboplatin
Cisplatin
Non-Classical Alkylators
Dacarbazine (DTIC)
Temozolomide

Impaired spermatogenesis
Reduced fertility
Oligospermia
Azoospermia
Infertility

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyCommonly used alkylators can be converted to a cyclophosphamide equivalent dose by using: CED (mg/m2)=
1.0 (cumulative cyclophosphamide dose (mg/m2)) + 0.244 (cumulative ifosfamide dose (mg/m2)) +0.857 (cumulative procarbazine dose (mg/m2)) + 14.286 (cumulative chlorambucil dose (mg/m2)) +15 (cumulative BCNU dose (mg/m2)) + 16 (cumulative CCNU dose (mg/m2)) + 40 (cumulative melphalan dose (mg/m2)) +50 (cumulative thiotepa dose (mg/m2)) + 100 (cumulative nitrogen mustard dose (mg/m2)) +8.823 (cumulative busulfan dose (mg/m2))w

Health Counseling/
Further Considerations
HEALTH LINKS
Testicular and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Need for contraception.
Fertility recovery can be seen in the early years after completion of therapy andoccasionally thereafter.
Review previous fertility preservation counseling/interventions.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
For sexually mature patients who desire information about potential future
fertility: semen analysis (optimal) and/or FSH and inhibin B (alternative if
unable or unwilling to provide semen sample).
Reproductive endocrinology/urology referral for infertility evaluation andconsultation regarding assisted reproductive technologies.
Alkylating agent doses that cause gonadal dysfunction show individual variation.
Germ cell function (spermatogenesis) is impaired at lower doses compared to
Leydig cell (testosterone production) function.
Prepubertal status at treatment does not protect from gonadal injury in males.
SYSTEM = Reproductive (Male)SCOREClassical Alkylating Agents = 1
Heavy Metals = 2A
Non-Classical Alkylators = 2A

Additional Information

Testicular volume is not a reliable indicator of pubertal onset/stage in boys treated with alkylating agents and/or direct testicular radiotherapy.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents)- Cancer/Treatment factors: Testicular cancer, higher cumulative doses of alkylators (especially busulfan ≥600 mg/m2, cyclophosphamide ≥4 gm/m2, CED >4 gm/m2, ifosfamide ≥50 gm/m2), and cisplatin >488 mg/m2, combinations ofalkylators, MOPP ≥3 cycles, cyclophosphamide as conditioning for HCT, in combination with radiation to abdomen/pelvis, testes, brain/cranium (neuroendocrine axis), or TBI, genitourinary surgery- Pre-morbid/Co-morbid medical conditions: Obesity, ejaculatory dysfunction, history of sexually transmitted infections, cGVHD- Health behaviors: Tobacco/Marijuana use

References
Chow EJ, Stratton KL, Leisenring WM, et al: Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 17:567-76,
2016
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 2:571-7, 1984
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CHEMOTHERAPY

ALKYLATING AGENTS (CONT)

Section 13 References (cont)Eskenazi B, Wyrobek AJ, Sloter E, et al: The association of age and semen quality in healthy men. Hum Reprod 18:447-454, 2003
Green DM, Kawashima T, Stovall M, et al: Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 28:332-9, 2010
Green DM, Liu W, Kutteh WH, et al: Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. Lancet Oncol 15:1215-23, 2014
Green DM, Zhu L, Zhang N, et al: Lack of specificity of plasma concentrations of inhibin B and follicle-stimulating hormone for identification of azoospermic survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. J Clin
Oncol 31:1324-8, 2013
Kenney LB, Antal Z, Ginsberg JP, et al: Improving male reproductive health after childhood, adolescent, and young adult cancer: progress and future directions for survivorship research. J Clin Oncol 36:2160-68, 2018
Loren AW, Mangu PB, Beck LN, et al: Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 31:2500-10, 2013
Meistrich ML, Chawla SP, Da Cunha MF, et al: Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 63:2115-23, 1989
Nudell DM, Monoski MM, Lipshultz LI: Common medications and drugs: how they affect male fertility. Urol Clin N Am 29:965-+, 2002
Practice Committee of American Society for Reproductive Medicine: Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 98:294-301, 2012
Romerius P, Stahl O, Moell C, et al: High risk of azoospermia in men treated for childhood cancer. Int J Androl 34:69-76, 2011
Sprauten M, Brydoy M, Haugnes HS, et al: Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 32:571-8, 2014

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CHEMOTHERAPYSec #14(female)ALKYLATING AGENTS (CONT)

Therapeutic
Exposure

Potential
Late Effects

Classical Alkylating
AgentsBusulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa
Heavy Metals
Carboplatin
Cisplatin
Non-Classical Alkylators
Dacarbazine (DTIC)
Temozolomide

Ovarian hormone deficiencies
Delayed puberty
Arrested pubertyPremature ovarian
insufficiency/Prematuremenopause

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Menstrual history
Sexual function (vaginal dryness, libido)
Menopausal symptoms
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyMonitor growth until mature
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive Health
COUNSELING
Higher cumulative doses of alkylating agents with or without radiation may
increase risk. Dose can be estimated using CED dose calculation.
Adverse impact of ovarian hormone deficiencies on growth, bone mineralization,
cardiovascular disease and sexual dysfunction.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH and estradiol and/or endocrine/gynecology referral for patients with:• No signs of puberty by age 13 years• Failure of pubertal progression• Abnormal menstrual patterns or menopausal symptoms• Ovarian hormone deficiency/insufficiency to weigh risks and benefits of hormonal replacement therapy
Bone density evaluation in patients with ovarian hormone deficiencies.

Commonly used alkylators can be converted to a cyclophosphamide equivalent dose by using: CED (mg/m2)=
1.0 (cumulative cyclophosphamide dose (mg/m2)) + 0.244 (cumulative ifosfamide dose (mg/m2)) +0.857 (cumulative procarbazine dose (mg/m2)) + 14.286 (cumulative chlorambucil dose (mg/m2)) +15 (cumulative BCNU dose (mg/m2)) + 16 (cumulative CCNU dose (mg/m2)) + 40 (cumulative melphalan dose (mg/m2)) +50 (cumulative thiotepa dose (mg/m2)) + 100 (cumulative nitrogen mustard dose (mg/m2)) +8.823 (cumulative busulfan dose (mg/m2))w

SYSTEM = Reproductive (Female)
SCORE
Classical Alkylating Agents = 1
Heavy Metals = 2B
Non-Classical Alkylators = 2A

Additional Information

Alkylating agent doses that cause gonadal dysfunction show individual variation. Females can typically maintain gonadal function at higher cumulative doses than males.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Older age at treatment- Cancer/Treatment factors: Higher cumulative doses of alkylators or combinations of alkylators, combination with radiation to abdomen/pelvis, lumbar or sacral spine (from ovarian scatter), or brain/cranium (neuroendocrineaxis), any alkylators combined with pelvic radiation or TBI- Health behaviors: Smoking

References
Afify Z, Shaw PJ, Clavano-Harding A, et al: Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. Bone Marrow Transplant 25:1087-92, 2000
Armstrong GT, Whitton JA, Gajjar A, et al: Abnormal timing of menarche in survivors of central nervous system tumors: a report from the Childhood Cancer Survivor Study. Cancer 115:2562-70, 2009
Chemaitilly W, Li Z, Krasin MJ, et al: Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab 102(7):2242-50, 2017
Chemaitilly W, Mertens AC, Mitby P, et al: Acute ovarian failure in the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 91:1723-8, 2006
Levine JM, Whitton JA, Ginsberg JP, et al: Nonsurgical premature menopause and reproductive implications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 124(5):1044-52, 2018
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Section 14 References (cont)Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol 31:1239-47, 2013
Molinari S, Parissone F, Evasi V, et al: Serum anti-Mullerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment.
Eur J Endocrinol 185:717-728, 2021
Overbeek A, van den Berg M, van Leeuwen F, et al: Chemotherapy-related late adverse effects on ovarian function in female survivors of childhood and young adult cancer: a systematic review. Cancer Treatment Reviews 53:10-24, 2017
Sklar CA, Mertens AC, Mitby P, et al: Premature menopause in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 98:890-6, 2006
Wallace WH, Shalet SM, Crowne EC, et al: Gonadal dysfunction due to cis-platinum. Med Pediatr Oncol 17:409-13, 1989

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Sec #15(female)Therapeutic
ExposureClassical Alkylating AgentsBusulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa
Heavy Metals
Carboplatin
Cisplatin
Non-Classical Alkylators
Dacarbazine (DTIC)
Temozolomide

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Diminished Ovarian Reserve(DOR)
Infertility

HISTORY
Menstrual and pregnancy history
Hormonal therapy
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyCommonly used alkylators can be converted to a cyclophosphamide equivalent dose by using: CED (mg/m2)=
1.0 (cumulative cyclophosphamide dose (mg/m2)) + 0.244 (cumulative ifosfamide dose (mg/m2)) +0.857 (cumulative procarbazine dose (mg/m2)) + 14.286 (cumulative chlorambucil dose (mg/m2)) +15 (cumulative BCNU dose (mg/m2)) + 16 (cumulative CCNU dose (mg/m2)) + 40 (cumulative melphalan dose (mg/m2)) +50 (cumulative thiotepa dose (mg/m2)) + 100 (cumulative nitrogen mustard dose (mg/m2)) +8.823 (cumulative busulfan dose (mg/m2))w

Health Counseling/
Further Considerations

Periodic Evaluation
HEALTH LINKS

Ovarian and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
Livestrong Foundation: www.livestrong.org/what-we-do/program/fertility
Oncofertility Consortium: https://oncofertility.msu.edu
COUNSELING
Need for contraception.
Review previous fertility preservation counseling/interventions.
Fertility recovery can be seen in the early years after the completion of therapy andoccasionally thereafter.
Potential for shorter period of fertility in family planning. Those with DOR should consider
discussing reproductive health options with a reproductive endocrinologist or fertility
specialist.
Higher cumulative doses of alkylating agents with or without radiation may increase risk.
Dose can be estimated using CED dose calculation.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH and estradiol for patients with menstrual cycle dysfunction suggestive of premature
ovarian insufficiency or those who desire information about potential for future fertility.
AMH to assess for diminished ovarian reserve.
Reproductive endocrinology referral for antral follicle count, ovarian reserve evaluationand consultation regarding assisted reproductive technologies in at-risk patients who
desire information about potential fertility and interventions to preserve future fertility.
Alkylating agent doses that cause gonadal dysfunction show individual variation. Females
can typically maintain gonadal function at higher cumulative doses than males.
SYSTEM = Reproductive (Female)
SCORE
Classical Alkylating Agents = 1
Heavy Metals = 2B
Non-Classical Alkylators = 2A

Additional Information

AMH may be low in the presence of normal FSH. AMH should be interpreted relative to age-specific reference ranges. FSH is lowered and AMH may be lowered by concurrent hormonal contraceptive use.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Older age at treatment- Cancer/Treatment factors: Higher cumulative doses of alkylators or combinations of alkylators, combination with radiation to abdomen/pelvis, lumbar or sacral spine (from ovarian scatter), or brain, cranium (neuroendocrineaxis), any alkylators combined with pelvic radiation or TBI- Health behaviors: Smoking
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Section 15 References (cont)Chemaitilly W, Li Z, Krasin MJ, et al. Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab 102(7):2242-50, 2017
Gracia CR, Sammel MD, Freeman E, et al: Impact of cancer therapies on ovarian reserve. Fertil Steril 97:134-40 e1, 2012
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 27:2677-2685, 2009
Hamre H, Kiserud CE, Ruud E, et al: Gonadal function and parenthood 20 years after treatment for childhood lymphoma: a cross-sectional study. Pediatr Blood Cancer 59:271-7, 2012
Krawczuk-Rybak M, Leszczynska E, Poznanska M, et al: Anti-Mullerian hormone as a sensitive marker of ovarian function in young cancer survivors. Int J Endocrinol 2013:125080, 2013
Levine JM, Kelvin JF, Quinn GP, et al: Infertility in reproductive-age female cancer survivors. Cancer 121:1532-9, 2015
Levine JM, Whitton JA, Ginsberg JP, et al. Nonsurgical premature menopause and reproductive implications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 124(5):1044-52, 2018
Lunsford AJ, Whelan K, McCormick K, et al: Anti-Mullerian hormone as a measure of reproductive function in female childhood cancer survivors. Fertil Steril 101:227-31, 2014
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Nyström A, Mörse H, Nordlöf H, et al. Anti-müllerian hormone compared with other ovarian markers after childhood cancer treatment. Acta Oncol 58(2):218-24, 2019
Overbeek A, van den Berg M, van Leeuwen F, et al. Chemotherapy-related late adverse effects on ovarian function in female survivors of childhood and young adult cancer: a systematic review. Cancer Treatment Reviews 53:10-24,
2017
Thomas-Teinturier C, Allodji RS, Svetlova E, et al: Ovarian reserve after treatment with alkylating agents during childhood. Hum Reprod 30:1437-46, 2015

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CHEMOTHERAPY
Sec #
16

w

Therapeutic
ExposureClassical Alkylating
AgentsBusulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa
Heavy Metals
Carboplatin
Cisplatin
Non-Classical Alkylators
Dacarbazine (DTIC)
Temozolomide

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Acute myeloid leukemia(AML)
Myelodysplasia (MDS)

Periodic Evaluation
HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after exposure to agent
PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure to agent

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.
SYSTEM = SMN
SCOREClassical Alkylating Agents = 1
Heavy Metals = 2A
Non-Classical Alkylators = 2A

Additional Information

There is negligible benefit to obtaining a screening CBC in the absence of clinical signs and symptoms for AML/MDS.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Less than 10 years since exposure to agent, higher cumulative alkylator dose or combination of alkylators, autologous HCT. Note melphalan and mechlorethamine are more potent leukemogens thancyclophosphamide.
- Pre-morbid/Co-morbid medical conditions: Evidence is conflicting that splenectomy modifies risk for AML/MDS

References
Allodji RS, Schwartz B, Veres C, et al: Risk of subsequent leukemia after a solid tumor in childhood: impact of bone marrow radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 93:658-67, 2015
Bhatia S: Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol 40:666-75, 2013
Bhatia S, Krailo MD, Chen Z, et al: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a report from the Children’s Oncology Group. Blood 109:46-51, 2007
Eichenauer DA, Thielen I, Haverkamp H, et al: Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 123:1658-64, 2014
Greene MH, Harris EL, Gershenson DM, et al: Melphalan may be a more potent leukemogen than cyclophosphamide. Ann Intern Med 105:360-7, 1986
Hijiya N, Ness KK, Ribeiro RC, et al: Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer 115:23-35, 2009
Koontz MZ, Horning SJ, Balise R, et al: Risk of therapy-related secondary leukemia in Hodgkin lymphoma: the Stanford University experience over three generations of clinical trials. J Clin Oncol 31:592-8, 2013
Landier W, Armenian SH, Lee J, et al: Yield of screening for long-term complications using the Children’s Oncology Group long-term follow-up guidelines. J Clin Oncol 30:4401-8, 2012
Nottage K, Lanctot J, Li Z, et al: Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study. Blood 117:6315-8, 2011
Rihani R, Bazzeh F, Faqih N, et al: Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer 116:4385-94, 2010

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Sec #
17

w

Therapeutic
ExposureClassical Alkylating
AgentsBusulfan
Carmustine (BCNU)
Lomustine (CCNU)

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Pulmonary fibrosis

Periodic Evaluation
HISTORY
Cough
Wheezing
Shortness of breath
Dyspnea on exertion
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patients withabnormal results or progressive pulmonary
dysfunction

Health Counseling/
Further Considerations
HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco avoidance/Smoking cessation/Environmental tobacco smoke.
Influenza and Pneumococcal vaccinations.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Pulmonary consultation for patients with symptomatic pulmonary dysfunction.
Pulmonary consultation for survivors who desire to SCUBA dive (due to potential
undiagnosed pulmonary toxicities, and limited data to guide safe diving
recommendations for individuals treated with pulmonary toxic therapy).
SYSTEM = Pulmonary
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher cumulative doses, especially BCNU ≥600 mg/m2 and busulfan ≥500 mg (transplant doses), combination with bleomycin, combination with chest radiation or TBI- Pre-morbid/Co-morbid medical conditions: Atopic history- Health behaviors: Smoking, inhaled illicit drug use

References
Dietz AC, Chen Y, Yasui Y, et al: Risk and impact of pulmonary complications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 122:3687-3696, 2016
Green DM, Zhu L, Wang M, et al: Pulmonary function after treatment for childhood cancer. A report from the St. Jude Lifetime Cohort Study (SJLIFE). Ann Am Thorac Soc 13:1575-85, 2016
Huang TT, Hudson MM, Stokes DC, et al: Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest 140:881-901, 2011
Lohani S, O’Driscoll BR, Woodcock AA: 25-year study of lung fibrosis following carmustine therapy for brain tumor in childhood. Chest 126:1007, 2004
Tetrault JM, Crothers K, Moore BA, et al: Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med 167:221-8, 2007
van Hulst RA, Rietbroek RC, Gaastra MT, et al: To dive or not to dive with bleomycin: a practical algorithm. Aviat Space Environ Med 82:814-8, 2011
Wolff AJ, O’Donnell AE: Pulmonary effects of illicit drug use. Clin Chest Med 25:203-16, 2004

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18

w

Therapeutic
ExposureClassical Alkylating
AgentsBusulfan

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Cataracts

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Visual changes (decreased acuity, halos,
diplopia)
YearlyPHYSICAL
Visual acuity
Funduscopic exam
YearlySCREENING
Evaluation by ophthalmologist or
optometrist
YearlyHEALTH LINKS
Cataracts
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ophthalmology consultation as clinically indicated.
Refer patients with visual deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate acquisition of
educational resources.
SYSTEM = Ocular
SCORE = 2B

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with corticosteroids, combination with TBI, cranial, orbital, or eye radiation, longer interval since treatment

References
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 168:518-25, 2015
Saglio F, Zecca M, Pagliara D, et al: Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study. Bone Marrow Transplant 55,1918–1927, 2020Socie G, Salooja N, Cohen A, et al: Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101:3373-85, 2003

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Sec #
19

Therapeutic
ExposureClassical Alkylating
AgentsCyclophosphamide
Ifosfamide

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Urinary tract toxicity
Hemorrhagic cystitis
Bladder fibrosis
Dysfunctional voiding
Vesicoureteral reflux
Hydronephrosis

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Bladder Health
COUNSELING
Promptly report dysuria or gross hematuria.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urinalysis, urine culture, spot urine calcium/creatinine ratio for patients withpositive history.
Ultrasound of kidneys and bladder for patients with microscopic hematuria(defined as >5 RBC/HPF on at least 2 occasions).
Nephrology or urology referral for patients with culture-negative microscopic
hematuria AND abnormal ultrasound and/or abnormal calcium/creatinine ratio.
Urology referral for patients with culture-negative macroscopic hematuria,
incontinence, or dysfunctional voiding.
SYSTEM = Urinary
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher cumulative doses (decreased incidence with Mesna), especially cyclophosphamide dose ≥3 gm/m2, combination with pelvic radiation, especially pelvic radiation dose ≥30 Gy- Health behaviors: Alcohol use, smoking

References
Dieffenbach BV, Liu Q, Murphy AJ, et al: Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer 155:216-226, 2021
Green DM, Wang M, Krasin M, et al: Kidney function after treatment for childhood cancer: a report from the St. Jude Lifetime Cohort Study. J Am Soc Nephrol 32(4):983-993, 2021
Hale GA, Marina NM, Jones-Wallace D, et al: Late effects of treatment for germ cell tumors during childhood and adolescence. J Pediatr Hematol Oncol 21:115-22, 1999
Heyn R, Raney RB, Jr., Hays DM, et al: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 10:614-23, 1992
Jerkins GR, Noe HN, Hill D: Treatment of complications of cyclophosphamide cystitis. J Urol 139:923-5, 1988
Kooijmans EC, Bökenkamp A, Tjahjadi NS, et al: Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer. Cochrane Database Syst Rev 11;3(3), 2019
Lima MV, Ferreira FV, Macedo FY, et al: Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis. Cancer Chemother Pharmacol 59:643-50, 2007
Stillwell TJ, Benson RC, Jr.: Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer 61:451-7, 1988
Stillwell TJ, Benson RC, Jr., Burgert EO, Jr.: Cyclophosphamide-induced hemorrhagic cystitis in Ewing’s sarcoma. J Clin Oncol 6:76-82, 1988

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Sec #
20

Therapeutic
ExposureClassical Alkylating
AgentsCyclophosphamide

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Bladder malignancy

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Bladder Health
COUNSELING
Promptly seek medical attention for dysuria or gross hematuria.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urinalysis, urine culture, spot urine calcium/creatinine ratio for patients withpositive history.
Ultrasound of kidneys and bladder for patients with microscopic hematuria(defined as >5 RBC/HPF on at least 2 occasions).
Nephrology or urology referral for patients with culture-negative microscopic
hematuria AND abnormal ultrasound.
Urology referral for patients with culture-negative macroscopic hematuria.
SYSTEM = SMNSCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with pelvic radiation- Health behaviors: Alcohol use, smoking

References
Chou R, Dana T: Screening adults for bladder cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 153:461-8, 2010
Chou WH, McGregor B, Schmidt A, et al: Cyclophosphamide-associated bladder cancers and considerations for survivorship care: A systematic review. Urol Oncol 39(10):678-685, 2021
Kersun LS, Wimmer RS, Hoot AC, et al: Secondary malignant neoplasms of the bladder after cyclophosphamide treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer 42:289-91, 2004
Pedersen-Bjergaard J, Ersboll J, Hansen VL, et al: Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin’s lymphoma. N Engl J Med 318:1028-32, 1988
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 52:439-46, 2009
Travis LB, Curtis RE, Glimelius B, et al: Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst 87:524-30, 1995

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Sec #
21

Therapeutic
ExposureClassical Alkylating
AgentsIfosfamide

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Renal toxicity
Glomerular injury
Renal insufficiency
Hypertension
Tubular injury (renal tubularacidosis, Fanconi syndrome,
hypophosphatemic rickets)

Periodic Evaluation
PHYSICAL
Blood pressure
YearlySCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Kidney Health
Cardiovascular Risk Factors
COUNSELINGIn patients with salt-wasting tubular dysfunction, educate that low magnesium
levels potentiate coronary atherosclerosis.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTIONElectrolyte supplements for patients with persistent electrolyte wasting.
Nephrology consultation for patients with hypertension or progressive renal
insufficiency.
SYSTEM = Urinary
SCORE = 1w

Additional Information

Ifosfamide-related renal toxicity typically occurs during the acute treatment phase and improves or progresses over time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <4 years- Cancer/Treatment factors: Tumor infiltration of kidney(s), nephrectomy, higher cumulative dose, especially ifosfamide dose ≥60 grams/m2, combination with other nephrotoxic agents (e.g., cisplatin, carboplatin, aminoglycosides, amphotericin, immunosuppressants, methotrexate, radiation impacting the kidney), renal radiation dose ≥15 Gy- Pre-morbid/Co-morbid medical conditions: Pre-existing renal impairment, congenital absence of kidney

References
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 32:93-6, 1999
Ceremuzynski L, Gebalska J, Wolk R, et al: Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. J Intern Med 247:78-86, 2000
Dekkers IA, Blijdorp K, Cransberg K, et al: Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 8:922-9, 2013
Ho PT, Zimmerman K, Wexler LH, et al: A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer 76:2557-64, 1995
Langer T, Stohr W, Bielack S, et al: Late effects surveillance system for sarcoma patients. Pediatr Blood Cancer 42:373-9, 2004
Loebstein R, Atanackovic G, Bishai R, et al: Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children. J Clin Pharmacol 39:454-61, 1999
Skinner R, Cotterill SJ, Stevens MC: Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children’s Cancer Study Group. Br J Cancer 82:1636-45, 2000
Skinner R, Sharkey IM, Pearson AD, et al: Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol 11:173-90, 1993
Stohr W, Paulides M, Bielack S, et al: Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 48:447-52, 2007

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Sec #
22

Therapeutic
Exposure
Heavy Metals
Carboplatin (myeloablative
doses)
Cisplatin

HEAVY METALS
Potential
Late Effects

Ototoxicity
Sensorineural hearing loss
Tinnitus
Vertigo

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORY
Hearing difficulties (with/withoutbackground noise)
Tinnitus
VertigoYearlyPHYSICAL
Otoscopic exam
YearlySCREENING
Complete audiological evaluation byaudiologist
Yearly, for patients ages ≤5 years

HEALTH LINKS
Hearing Loss
School After Treatment
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Additional testing with high frequency audiometry at >8000 Hz is recommended
if equipment is available.
Audiology consultation for any survivor who has symptoms suggestive of
hearing loss, tinnitus, or abnormal pure tone audiometry results showing a lossof more than 15 dB absolute threshold level (1000-8000 Hz).
Ongoing follow-up with audiology for patients with hearing loss.
Otolaryngology consultation in patients with chronic infection, cerumen
impaction, or other anatomical problems exacerbating or contributing tohearing loss.
Speech and language therapy for patients with hearing loss.
Pure tone audiometry testing at 1000-8000 Refer patients with auditory deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate acquisition ofHz
educational resources.
Every 2 years, for patients ages 6-12 years,
Specialized
evaluation for specific needs and/or preferential classroom seating,then every 5 years beginning at age 13 years
FM amplification system, and other educational assistance as indicated.
SYSTEM = Auditory
SCORE = 1w

Additional Information

Myeloablative doses of carboplatin are given as conditioning for HCT and are typically ≥1500 mg/m2.
A “complete audiological evaluation” includes pure tone air and bone conduction, speech audiometry, and tympanometry for both ears.
Frequency-specific auditory brainstem response can be performed if the above is inconclusive.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Age <4 years at treatment- Cancer/Treatment factors: CNS neoplasm, cumulative cisplatin dose ≥360 mg/m2, high dose cisplatin (i.e., 40 mg/m2 per day x 5 days per course), carboplatin conditioning for HCT, combination with cranial/ear radiation or
ototoxic drugs (e.g., aminoglycosides, loop diuretics), cisplatin administered AFTER cranial/ear radiation, combination with radiation involving ear ≥30 Gy- Pre-morbid/Co-morbid medical conditions: Chronic otitis, cerumen impaction, renal dysfunction, cerebrospinal fluid shunt

References
Bass JK, Knight KR, Yock TI, et al: Evaluation and management of hearing loss in survivors of childhood and adolescent cancers: a report from the Children’s Oncology Group. Pediatr Blood Cancer 63:1152-62, 2016
Bertolini P, Lassalle M, Mercier G, et al: Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss. J Pediatr Hematol Oncol 26:649-55, 2004
Clemens E, de Vries AC, Pluijm SF, et al: Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study. Eur J Cancer 69:77-85, 2016
Clemens E, van den Heuvel-Eibrink MM, Mulder RL, et al: Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer
Guideline Harmonization Group in collaboration with the PanCare Consortium. The Lancet Onc 20(1):e29-e41, 2019
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 120:e1229-36, 2007
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Section 22 References (cont)
Heitzer AM, Villagran AM, Raghubar K, et al: Effect of sensorineural hearing loss on neurocognitive and adaptive functioning in survivors of pediatric embryonal brain tumor. J Neuro-Onc 146(1):147-56, 2020
Knight KR, Chen L, Freyer D, et al: Group-wide, prospective study of ototoxicity assessment in children receiving cisplatin chemotherapy (ACCL05C1): a report from the Children’s Oncology Group. J Clin Oncol 35:440-445, 2017
Knight KR, Kraemer DF, Neuwelt EA: Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 23:8588-96, 2005
Knight KR, Kraemer DF, Winter C, et al: Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol
25:1190-5, 2007
Kushner BH, Budnick A, Kramer K, et al: Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer 107:417-22, 2006
Weiss A, Sommer G, Kasteler R, et al: Long-term auditory complications after childhood cancer: a report from the Swiss Childhood Cancer Survivor Study. Pediatr Blood Cancer 64(2):364-73, 2017
Weiss A, Sommer G, Schindera C, et al: Hearing loss and quality of life in survivors of paediatric CNS tumours and other cancers. Qual Life Res 28(2):515-521, 2019

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Therapeutic
Exposure
Heavy Metals
Carboplatin
Cisplatin

HEAVY METALS (CONT)
Potential
Late Effects

Peripheral sensory
neuropathy
Paresthesias
Dysesthesias

Periodic Evaluation
HISTORY
Paresthesias
Dysesthesias
Yearly, until 2 to 3 years after therapy, monitor
yearly if symptoms persist
PHYSICAL
Neurologic exam
Yearly, until 2 to 3 years after therapy, monitor
yearly if symptoms persist

Health Counseling/
Further Considerations
HEALTH LINKS
Peripheral Neuropathy
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Physical therapy referral for patients with symptomatic neuropathy.
Physical and occupational therapy assessment of hand function.
Treat with effective agent for neuropathic pain (e.g., gabapentin or amitriptyline).
SYSTEM = PNSSCORE = 2A

Additional Information

Acute toxicities most commonly occur and usually improve or resolve prior to patients entry to long-term follow-up.
Neuropathy can persist after treatment and is typically not late in onset.
Studies of adults treated during childhood support higher prevalence of deficits than previously appreciated.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Cumulative cisplatin dose ≥300 mg/m2, combination with vincristine, taxanes, gemcitabine

References
Ness KK, Jones KE, Smith WA, et al: Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: results from the St. Jude Lifetime Cohort Study. Arch Phys Med
Rehabil 94:1451-7, 2013

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Therapeutic
Exposure
Heavy Metals
Carboplatin
Cisplatin

HEAVY METALS (CONT)
Potential
Late Effects

Renal toxicity
Glomerular injury
Renal insufficiency
Hypertension
Tubular injury (renal tubularacidosis, Fanconi syndrome,
hypophosphatemic rickets)

Periodic Evaluation
PHYSICAL
Blood pressure
YearlySCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Kidney Health
Cardiovascular Risk Factors
COUNSELINGIn patients with salt-wasting tubular dysfunction, educate that low magnesium
levels potentiate coronary atherosclerosis.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTIONElectrolyte supplements for patients with persistent electrolyte wasting.
Nephrology consultation for patients with hypertension or progressive renal
insufficiency.
SYSTEM = Urinary
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Nephrectomy, combination with other nephrotoxic agents (e.g., aminoglycosides, amphotericin, immunosuppressants, methotrexate, radiation impacting the kidney), cisplatin dose ≥200 mg/m2,
renal radiation dose ≥15 Gy- Pre-morbid/Co-morbid medical conditions: Diabetes mellitus, hypertension, congenital absence of kidney

References
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 32:93-6, 1999
Bianchetti MG, Kanaka C, Ridolfi-Luthy A, et al: Persisting renotubular sequelae after cisplatin in children and adolescents. Am J Nephrol 11:127-30, 1991
Ceremuzynski L, Gebalska J, Wolk R, et al: Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. J Intern Med 247:78-86, 2000
Hutchison FN, Perez EA, Gandara DR, et al: Renal salt wasting in patients treated with cisplatin. Ann Intern Med 108:21-5, 1988
Jimenez-Triana CA, Castelan-Martinez OD, Rivas-Ruiz R, et al: Cisplatin nephrotoxicity and longitudinal growth in children with solid tumors: a retrospective cohort study. Medicine (Baltimore) 94:e1413, 2015
Liao F, Folsom AR, Brancati FL: Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 136:480-90, 1998
Stohr W, Paulides M, Bielack S, et al: Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system. Pediatr Blood Cancer 48:140-7, 2007von der Weid NX, Erni BM, Mamie C, et al: Cisplatin therapy in childhood: renal follow up 3 years or more after treatment. Swiss Pediatric Oncology Group. Nephrol Dial Transplant 14:1441-4, 1999

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ANTIMETABOLITESTherapeutic
Exposure

Potential
Late Effects

Antimetabolites
Cytarabine (high dose IV)

Neurocognitive deficits
Functional deficits in:• Executive function (planningand organization)• Sustained attention• Memory (particularly visual,sequencing, temporal
memory)• Processing speed• Visual-motor integration• Fine motor dexterity
Learning deficits in math andreading (particularly reading
comprehension)
Diminished IQ
Behavioral change

Periodic Evaluation
HISTORY
Educational and/or vocational progress
YearlySCREENING
Referral for formal neuropsychologicalevaluation
Baseline at entry into long-term follow-up,
then periodically as clinically indicatedfor patients with evidence of impaired
educational or vocational progress

Health Counseling/
Further Considerations
HEALTH LINKS
School After Treatment
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Referral to school liaison in community or cancer center (psychologist, social
worker, school counselor) to facilitate acquisition of educational resources and/or social skills training.
Psychotropic medication (e.g., stimulants) or evidence-based rehabilitation
training. Caution—lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended.
Referral to community services for vocational rehabilitation or for services fordevelopmentally disabled.
SYSTEM = CNSSCORE = 2A

Additional Information

Formal neuropsychological evaluation includes tests of processing speed, computer-based attention, visual motor integration, memory, comprehension of verbal instructions, verbal fluency, executive function and planning.
Neurocognitive deficits in survivors of leukemia and lymphoma are more frequently related to information processing (e.g., slow processing speed, attention problems). Extent of deficit depends on age at treatment, intensity of treatment, and time since treatment. New and progressive deficits may emerge over time.
Acute toxicity predominates if cytarabine is administered systemically as a single agent. Cytarabine may contribute to late neurotoxicity if combined with high dose or intrathecal methotrexate and/or cranial radiation.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <3 years, female sex, family history of learning or attention problems- Cancer/Treatment factors: CNS leukemia/lymphoma, relapsed leukemia/lymphoma treated with CNS-directed therapy, longer elapsed time since therapy, combination with corticosteroids, methotrexate (IT, IO, high dose IV),
radiation dose ≥24 Gy, TBI, especially single fraction TBI (10 Gy), cranial radiation- Pre-morbid/Co-morbid medical conditions: Pre-morbid learning or attention problems

References
Ehrhardt MJ, Mulrooney DA, Li C, et al: Neurocognitive, psychosocial, and quality-of-life outcomes in adult survivors of childhood non-Hodgkin lymphoma. Cancer 124(2):417-25, 2018
Hardy KK, Embry L, Kairalla JA, et al: Neurocognitive functioning of children treated for high-risk b-acute lymphoblastic leukemia randomly assigned to different methotrexate and corticosteroid treatment strategies: a report from thechildren’s oncology group. J Clin Oncol 35(23):2700-7 2017
Kadan-Lottick NS, Zeltzer LK, Liu Q, et al: Neurocognitive functioning in adult survivors of childhood non-central nervous system cancers. J Natl Cancer Inst 102:881-93, 2010

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ANTIMETABOLITES (CONT)

Therapeutic
Exposure

Potential
Late Effects

Antimetabolites
Cytarabine (low dose IV)
Cytarabine IO
Cytarabine IT
Cytarabine SQ

No known late effects

Periodic Evaluation

Health Counseling/
Further Considerations
SYSTEM = No Known Late Effects
SCORE = 1

Additional Information

Acute toxicities predominate, from which the majority of patients recover without sequelae.

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ANTIMETABOLITES (CONT)

Therapeutic
Exposure

Potential
Late Effects

Antimetabolites
Mercaptopurine (6MP)
Thioguanine (6TG)

Hepatic dysfunction
Sinusoidal obstruction
syndrome (SOS)

Periodic Evaluation
PHYSICAL
Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly
YearlySCREENING
ALT
AST
Bilirubin
Baseline at entry into long-term follow-up,
repeat as clinically indicated.

Health Counseling/
Further Considerations
HEALTH LINKS
Liver Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Platelet count for evaluation of hypersplenism and prothrombin time for
evaluation of hepatic synthetic function in patients with abnormal liver
screening tests.
Screen for viral hepatitis in patients with persistently abnormal liver function or
any patient transfused prior to 1993.
Gastroenterology/Hepatology consultation in patients with persistent liver
dysfunction.
Hepatitis A and B immunization in at-risk patients lacking immunity.
SYSTEM = GI/Hepatic
SCORE = 2A

Additional Information

Acute toxicities predominate from which the majority of patients recover without sequelae.
Delayed hepatic dysfunction may occur after a history of acute SOS, presenting as portal hypertension with liver biopsy indicating nodular regenerative hyperplasia, fibrosis, or siderosis.
Patients treated on CCG-1952, Regimens B1 and B2, received 6TG in place of 6MP during maintenance therapy.
Acute hepatotoxicity (manifesting as SOS) occurred in about 25% of patients.
Portal hypertension was identified as a late complication of 6TG in a small subset of patients (see Broxson et al., 2005).
Outcomes are detailed in Stork et al., 2010.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Pre-morbid/Co-morbid medical conditions: Viral hepatitis (especially chronic viral hepatitis), previous SOS, siderosis

References
Bardi E, Mulder RL, van Dalen EC, et al. Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Cancer Treat Rev 100:102296, 2021
Broxson EH, Dole M, Wong R, et al: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 44:226-31,
2005
Castellino S, Muir A, Shah A, et al: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr Blood Cancer 54:663-9, 2010
Green DM, Wang M, Krasin MJ, et al. Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Hepatol 69(1):94-106, 2019
Piel B, Vaidya S, Lancaster D, et al: Chronic hepatotoxicity following 6-thioguanine therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 125:410-1; author reply 412, 2004
Rawat D, Gillett PM, Devadason D, et al: Long-term follow-up of children with 6-thioguanine-related chronic hepatoxicity following treatment for acute lymphoblastic leukaemia. J Pediatr Gastroenterol Nutr 53:478-9, 2011
Stork LC, Matloub Y, Broxson E, et al: Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children’s Oncology Group CCG-1952
clinical trial. Blood 115:2740-8, 2010

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Therapeutic
Exposure
Antimetabolites
Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate POw

ANTIMETABOLITES (CONT)
Potential
Late Effects

Periodic Evaluation

No known bone mineraldensity (BMD) late effects

Health Counseling/
Further Considerations
SYSTEM = No Known BMD Late Effects
SCORE = 2B

References

Siegel DA, Claridy M, Mertens A, et al: Risk factors and surveillance for reduced bone mineral density in pediatric cancer survivors. Pediatr Blood Cancer 64(9), 2017
van Atteveld JE, Mulder RL, van den Heuvel-Eibrink MM, et al. Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects ofChildhood Cancer Guideline Harmonization Group. Lancet Diabetes Endocrinol 9(9):622-637, 2021
van Atteveld JE, Pluijm SMF, Ness KK, et al: Prediction of low and very low bone mineral density among adult survivors of childhood cancer. J Clin Oncol 37(25):2217-25, 2019

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Therapeutic
Exposure
Antimetabolites

ANTIMETABOLITES (CONT)
Potential
Late Effects

Periodic Evaluation

No known renal late effects

SYSTEM = No Known Renal Late Effects
SCORE = 2A

Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate POw

Health Counseling/
Further Considerations

Additional Information

Acute toxicities predominate, from which the majority of patients recover without sequelae.
Renal injury from other events (aminoglycoside exposure, tumor lysis) may make patients more vulnerable.

References
Dekkers IA, Blijdorp K, Cransberg K, et al: Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 8:922-9, 2013
Mulder RL, Knijnenburg SL, Geskus RB, et al: Glomerular function time trends in long-term survivors of childhood cancer: a longitudinal study. Cancer Epidemiol Biomarkers Prev 22:1736-46, 2013
Yetgin S, Olgar S, Aras T, et al: Evaluation of kidney damage in patients with acute lymphoblastic leukemia in long-term follow-up: value of renal scan. Am J Hematol 77:132-9, 2004

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Therapeutic
Exposure
Antimetabolites

Potential
Late Effects
Hepatic dysfunction

Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate POw

ANTIMETABOLITES (CONT)Periodic Evaluation
PHYSICAL
Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly
YearlySCREENING
ALT
AST
Bilirubin
Baseline at entry into long-term follow-up,
repeat as clinically indicated.

Health Counseling/
Further Considerations
HEALTH LINKS
Liver Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Platelet count for evaluation of hypersplenism and prothrombin time for
evaluation of hepatic synthetic function in patients with abnormal liver
screening tests.
Screen for viral hepatitis in patients with persistently abnormal liver function or
any patient transfused prior to 1993.
Gastroenterology/hepatology consultation in patients with persistent liver
dysfunction.
Hepatitis A and B immunization in at-risk patients lacking immunity.
SYSTEM = GI/Hepatic
SCORE = 2A

Additional Information

Acute toxicities predominate from which the majority of patients recover without sequelae.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Abdominal radiation, treatment before 1970
- Pre-morbid/Co-morbid medical conditions: Viral hepatitis (especially chronic viral hepatitis)

References
Bardi E, Mulder RL, van Dalen EC, et al. Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Cancer Treat Rev 100:102296, 2021
Castellino S, Muir A, Shah A, et al: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr Blood Cancer 54:663-9, 2010
Dietz AC, Seidel K, Leisenring WM, et al: Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol 20(10):1420-1431, 2019
Green DM, Wang M, Krasin MJ, et al. Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Hepatol 69(1):94-106, 2019
McIntosh S, Davidson DL, O’Brien RT, et al: Methotrexate hepatotoxicity in children with leukemia. J Pediatr 90:1019-21, 1977

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Therapeutic
Exposure
Antimetabolites
Methotrexate (high dose IV)
Methotrexate IO
Methotrexate ITw

ANTIMETABOLITES (CONT)
Potential
Late Effects

Neurocognitive deficits
Functional deficits in:• Executive function (planningand organization)• Sustained attention• Memory (particularly visual,sequencing, temporal
memory)• Processing speed• Visual-motor integration• Fine motor dexterity
Learning deficits in math andreading (particularly reading
comprehension)
Diminished IQ
Behavioral change

Periodic Evaluation
HISTORY
Educational and/or vocational progress
YearlySCREENING
Referral for formal neuropsychologicalevaluation
Baseline at entry into long-term follow-up,
then periodically as clinically indicatedfor patients with evidence of impaired
educational or vocational progress

Health Counseling/
Further Considerations
HEALTH LINKS
School After Treatment
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Referral to school liaison in community or cancer center (psychologist, social
worker, school counselor) to facilitate acquisition of educational resources and/or social skills training.
Psychotropic medication (e.g., stimulants) or evidence-based rehabilitation
training. Caution—lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended.
Referral to community for vocational rehabilitation or for services fordevelopmentally disabled.
SYSTEM = CNSSCORE = 1

Additional Information

Formal neuropsychological evaluation includes tests of processing speed, computer-based attention, visual motor integration, memory, comprehension of verbal instructions, verbal fluency, executive function and planning.
Neurocognitive deficits in survivors of leukemia and lymphoma are more frequently related to information processing (e.g., slow processing speed, attention problems). Extent of deficit depends on age at treatment, intensity of treatment, and time since treatment. New and progressive deficits may emerge over time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <3 years, female sex, family history of learning or attention problems- Cancer/Treatment factors: CNS leukemia/lymphoma, relapsed leukemia/lymphoma treated with CNS-directed therapy, longer elapsed time since therapy, combination with corticosteroids, cytarabine (high dose IV), TBI, especially single fraction TBI (10 Gy), or CRT especially ≥24 Gy- Pre-morbid/Co-morbid medical conditions: Pre-morbid learning or attention problems

References
Cheung YT, Sabin ND, Reddick WE, et al: Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal
analysis. Lancet Haematol 3(10):e456-e66, 2016
Ehrhardt MJ, Mulrooney DA, Li C, et al: Neurocognitive, psychosocial, and quality-of-life outcomes in adult survivors of childhood non-Hodgkin lymphoma. Cancer 124(2):417-25, 2018
Hardy KK, Embry L, Kairalla JA, et al: Neurocognitive functioning of children treated for high-risk B-acute lymphoblastic leukemia randomly assigned to different methotrexate and corticosteroid treatment strategies: a report from the children’s
oncology group. J Clin Oncol 35(23):2700-7, 2017
Iuvone L, Mariotti P, Colosimo C, et al: Long-term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia. Cancer 95:2562-70, 2002
Jacola LM, Edelstein K, Liu W, et al: Cognitive, behaviour, and academic functioning in adolescent and young adult survivors of childhood acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study. Lancet Psychiatry3(10):965-72, 2016
Jacola LM, Krull KR, Pui CH, et al: Longitudinal assessment of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy protocol. J Clin Oncol 34:1239-47, 2016
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 lymphoblastic leukemia. Blood 114:1746-52, 2009
Krull KR, Cheung YT, Liu W, et al: Chemotherapy pharmacodynamics and neuroimaging and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 34(22):2644-53, 2016
Riva D, Giorgi C, Nichelli F, et al: Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 59:48-53, 2002
van der Plas E, Qiu W, Nieman BJ, et al: Sex-specific associations between chemotherapy, chronic conditions and neurocognitive impairment in ALL survivors: A report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 4;113(5):588-596,
2021
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Exposure
Antimetabolites
Methotrexate (high dose IV)
Methotrexate IO
Methotrexate ITw

ANTIMETABOLITES (CONT)
Potential
Late Effects

Clinical leukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures

Periodic Evaluation
HISTORY
Cognitive, motor and/or sensory deficits
Seizures
Other neurologic symptoms
YearlyPHYSICAL
Neurologic exam
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Brain CT or Brain MRI with MRA as clinically indicated with preferred study
based on intracranial lesion to be evaluated:• Calcifications: CT• White matter: MRI with DTI• Microvascular injury: Gadolinium-enhanced MRI with DWI
Neurology consultation and follow-up as clinically indicated.
SYSTEM = CNSSCORE = 1

Additional Information

Clinical leukoencephalopathy may present with or without imaging abnormalities (e.g., leukoencephalopathy, cerebral lacunes, cerebral atrophy, dystrophic calcifications, mineralizing microangiopathy).
Transient white matter anomalies may follow radiotherapy and high dose chemotherapy for medulloblastoma/PNET, may mimic tumor recurrence, and signify risk of persistent neurologic sequelae.
Neuroimaging changes do not always correlate with degree of cognitive dysfunction.
Prospective studies are needed to define the dose/effect relationship of neurotoxic agents.
New deficits may emerge over time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: CNS leukemia/lymphoma, relapsed leukemia/lymphoma treated with CNS-directed therapy, combination with cytarabine (high dose IV), dexamethasone, CRT especially ≥24 Gy

References
Hertzberg H, Huk WJ, Ueberall MA, et al: CNS late effects after ALL therapy in childhood. Part I: Neuroradiological findings in long-term survivors of childhood ALL--an evaluation of the interferences between morphology andneuropsychological performance. The German Late Effects Working Group. Med Pediatr Oncol 28:387-400, 1997
Matsumoto K, Takahashi S, Sato A, et al: Leukoencephalopathy in childhood hematopoietic neoplasm caused by moderate-dose methotrexate and prophylactic cranial radiotherapy--an MR analysis. Int J Radiat Oncol Biol Phys
32:913-8, 1995
Ness KK, Hudson MM, Pui CH, et al: Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: associations with physical performance and chemotherapy doses. Cancer 118:828-38, 2012

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Therapeutic
Exposure

ANTHRACYCLINE ANTIBIOTICS
Potential
Late Effects

Anthracycline Antibiotics Acute myeloid leukemia
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone

Periodic Evaluation
HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after exposure to agent
PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure to agent

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.
SYSTEM = SMNSCORE = 1

Additional Information

Although mitoxantrone technically belongs to the anthraquinone class of anti-tumor antibiotics, it is related to the anthracycline family.
There is negligible benefit to obtaining a screening CBC in the absence of clinical signs and symptoms of AML.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Less than 5 years since exposure to agent, autologous HCT- Pre-morbid/Co-morbid medical conditions: Evidence is conflicting that splenectomy modifies risk for AML

References
Bhatia S: Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol 40:666-75, 2013
Bhatia S, Krailo MD, Chen Z, et al: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a report from the Children’s Oncology Group. Blood 109:46-51, 2007
Eichenauer DA, Thielen I, Haverkamp H, et al: Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 123:1658-64, 2014
Felix CA: Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol 36:525-35, 2001
Hijiya N, Ness KK, Ribeiro RC, et al: Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer 115:23-35, 2009
Koontz MZ, Horning SJ, Balise R, et al: Risk of therapy-related secondary leukemia in Hodgkin lymphoma: the Stanford University experience over three generations of clinical trials. J Clin Oncol 31:592-8, 2013
Landier W, Armenian SH, Lee J, et al: Yield of screening for long-term complications using the Children’s Oncology Group long-term follow-up guidelines. J Clin Oncol 30:4401-8, 2012
Le Deley MC, Leblanc T, Shamsaldin A, et al: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Societe Francaise d’Oncologie
Pediatrique. J Clin Oncol 21:1074-81, 2003
Nottage K, Lanctot J, Li Z, et al: Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study. Blood 117:6315-8, 2011
Rihani R, Bazzeh F, Faqih N, et al: Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer 116:4385-94, 2010

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ANTHRACYCLINE ANTIBIOTICS (CONT)

Therapeutic
Exposure

Potential
Late Effects

Anthracycline Antibiotics
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone

Cardiac toxicity
Cardiomyopathy
Subclinical left ventricular
dysfunction
Congestive heart failure
Arrhythmia

Dose Conversion
Use the following formulas
to convert to doxorubicin
isotoxic equivalents prior to
calculating total cumulative
anthracycline dose.
To estimate cumulative
anthracycline dose in doxorubicin
isotoxic equivalents
1.0 x (doxorubicin total dose) +0.5 x (daunorubicin total dose) +0.67 x (epirubicin total dose) +5.0 x (idarubicin total dose) +10.0 x (mitoxantrone total dose)

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Shortness of breath
Dyspnea on exertion
Orthopnea
Chest pain
Palpitations
If under 25 yrs: nausea, vomiting
YearlyPHYSICAL
Blood pressure
Cardiac exam
YearlySCREENING
Echo (or comparable imaging to evaluate
cardiac function)
RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM
Anthracycline
Dose*
None ot <100mg/m2

Radiation
Dose**

Recommended
Frequency

None to <15Gy

No screening

15Gy to <30Gy
None to <100mg/m2
Every 5 years≥100 to <250mg/m²
None to <15Gy≥100 to <250mg/m²≥15Gy
None to Any≥30Gy
Every 2 years≥ 250mg/m²
None to Any*Based on doxorubicin isotonic equivalent dose.
**Based on radiation dose with potential impact to heart(radiation to chest, abdomen, spine [thoracic, whole], TBI).
See section 77.

EKG (include evaluation of QTc interval)
Baseline at entry into long-term follow-up, repeat
as clinically indicated

HEALTH LINKS

Heart Health
Cardiovascular Risk Factors
Nutrition and Physical Activity
COUNSELING
Traditional CVRFs significantly increase survivors’ risk of cardiomyopathy. Counsel
regarding the importance of maintaining blood pressure, BMI, lipids, and glucose levels
within goal ranges per general population guidelines.
Regarding exercise:• Exercise is generally safe and encouraged for patients with normal LV systolic function• Consult cardiology for survivors with asymptomatic cardiomyopathy to define physicalactivity limits and precautions.
• Consider cardiology consultation to define physical activity limits and precautions forhigh risk survivors (i.e., those requiring an echo every 2 years) who plan to participate
in intensive exercise.
If QTc interval is prolonged: Caution use of QTc prolonging medications (e.g., tricyclic
anti-depressants, antifungals, macrolide antibiotics, metronidazole).
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Cardiac MRI as an adjunct imaging modality when echo images are suboptimal.
Cardiology consultation in patients with subclinical abnormalities on screening
evaluations, LV dysfunction, dysrhythmia, or prolonged QTc interval.
For patients who are pregnant or planning to become pregnant, additional cardiology
evaluation is indicated in patients who received:• ≥250 mg/m2 anthracyclines• ≥30 Gy chest radiation, or• Anthracycline (any dose) combined with chest radiation (≥15 Gy)• Evaluation should include a baseline echo (pre- or early-pregnancy). For those without
prior abnormalities and with normal pre- or early-pregnancy baseline echos, follow-up
echos may be obtained at the provider’s discretion. Those with a history of systolic
dysfunction or with pre- or early-pregnancy systolic dysfunction are at highest risk for
pregnancy-associated cardiomyopathy, and should be monitored periodically during
pregnancy, labor and delivery due to increased risk for heart failure.
SYSTEM = Cardiovascular
SCORE = 1w

Additional Information

Although mitoxantrone is an anthraquinone, it is related to the anthracycline family and is included in this section because of its cardiotoxic potential.
Childhood cancer survivors exhibit clinical and subclinical toxicity at lower levels than adults. In patients with abnormal LV systolic function, certain conditions (such as isometric exercise and viral infections) have been anecdotally
reported to precipitate cardiac decompensation. Prospective studies are needed to better define the contribution of these factors to cardiac disease risk.
Abdominal symptoms (nausea, emesis) may be seen more frequently than exertional dyspnea or chest pain in younger patients.
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Exertional intolerance is an uncommon presentation of left ventricular dysfunction in patients <25 years old.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Age <5 years at time of treatment, genetic variants associated with increased anthracycline-induced cardiotoxicity- Cancer/Treatment factors: Combined with radiation involving the heart, higher cumulative anthracycline doses (≥550 mg/m2 in patients ≥18 years at time of treatment, ≥250 mg/m2 in patients <18 years at time of treatment), chest radiation ≥15 Gy chest radiation combined with ≥100 mg/m2 anthracycline, longer time since treatment- Pre-morbid/Co-morbid medical conditions: Obesity, congenital heart disease, hypertension, diabetes mellitus, dyslipidemia. For female patients, pregnancy if systolic function is abnormal pre-pregnancy- Health behaviors: Smoking, drug use (e.g., cocaine, diet pills, ephedra, mahuang)

References
Armstrong GT, Oeffinger KC, Chen Y, et al: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 31:3673-80, 2013
Armstrong GT, Plana JC, Zhang N, et al: Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 30:2876-84, 2012
Blanco JG, Sun CL, Landier W, et al: Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes-a report from the Children’s Oncology Group. J Clin Oncol 30:1415-21, 2012
Chen Y, Chow EJ, Oeffinger KC, et al: Traditional cardiovascular risk factors and individual prediction of cardiovascular events in childhood cancer survivors. J Natl Cancer Inst 112:3,256-265, 2020
Chow EJ, Chen Y, Kremer LC, et al: Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol 33:394-402, 2015
Ehrhardt MJ, Leerink JM, Mulder RL, et al: Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects ofChildhood Cancer Guideline Harmonization Group. Lancet Oncol 24(3):e108-e120, 2023
Ehrhardt MJ, Ward ZJ, Liu Q, et al: Cost-effectiveness of the International Late Effects of Childhood Cancer Guideline Harmonization Group screening guidelines to prevent heart failure in survivors of childhood cancer. J Clin Oncol
38(33):3851-3862, 2020
Feijen EA, Leisenring WM, Stratton KL, et al: Derivation of anthracycline and anthraquinone equivalence ratios to doxorubicin for late-onset cardiotoxicity. JAMA Oncol Jun 5(6):864-871, 2019
Feijen EA, Leisenring WM, Stratton KL, et al: Equivalence ratio for daunorubicin to doxorubicin in relation to late heart failure in survivors of childhood cancer. J Clin Oncol 33:3774-80, 2015
Haddy N, Diallo S, El-Fayech C, et al: Cardiac diseases following childhood cancer treatment: cohort study. Circulation 133:31-8, 2016
Hines MR, Mulrooney DA, Hudson MM, et al: Pregnancy-associated cardiomyopathy in survivors of childhood cancer. J Cancer Surviv 10:113-21, 2016
Leger KJ, Cushing-Haugen K, Hansen JA, et al: Clinical and genetic determinants of cardiomyopathy risk among hematopoietic cell transplantation survivors. Biol Blood Marrow Transplant 22(6):1094-1101, 2016
Lipshultz SE, Adams MJ, Colan SD, et al: Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 128:1927-95, 2013
Mulrooney DA, Armstrong GT, Huang S, et al: Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study. Ann Intern Med 164:93-101, 2016
Mulrooney DA, Hyun G, Ness KK, et al: Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort. BMJ 368:l6794, 2020
Spewak MB, Williamson RS, Mertens AC, et al: Yield of screening echocardiograms during pediatric follow-up in survivors treated with anthracyclines and cardiotoxic radiation. Pediatr Blood Cancer 64(6), 2017van Dalen EC, van der Pal HJ, Kok WE, et al: Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42:3191-8, 2006
van Dalen EC, van der Pal HJ, van den Bos C, et al: Clinical heart failure during pregnancy and delivery in a cohort of female childhood cancer survivors treated with anthracyclines. Eur J Cancer 42:2549-53, 2006
van der Pal HJ, van Dalen EC, van Delden E, et al: High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 30:1429-37, 2012

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Therapeutic
Exposure
Anti-Tumor Antibiotics
Bleomycin

ANTI-TUMOR ANTIBIOTICS
Potential
Late Effects

Pulmonary toxicity
Pulmonary fibrosis
Interstitial pneumonitis
Acute respiratory distresssyndrome (very rare)

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Cough
Wheezing
Shortness of breath
Dyspnea on exertion
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up, repeat
as clinically indicated in patients with abnormal
results or progressive pulmonary dysfunction

HEALTH LINKS
Pulmonary HealthBleomycin AlertRESOURCES
www.smokefree.gov
COUNSELING
Notify healthcare providers of history of bleomycin therapy and risk of worsening fibrosis
with high oxygen exposure such as during general anesthesia.
Administration of high concentrations of oxygen may result in chronic progressive
pulmonary fibrosis.
Tobacco avoidance/smoking cessation/environmental tobacco smoke.
Influenza and Pneumococcal vaccinations.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Pulmonary consultation for patients with symptomatic pulmonary dysfunction.
Pulmonary consultation for survivors who desire to SCUBA dive (due to potential
undiagnosed pulmonary toxicities, and limited data to guide safe diving
recommendations for individuals treated with pulmonary toxic therapy).
SYSTEM = Pulmonary
SCORE
ARDS = 2B
All Else = 1wAdditional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Pulmonary toxicity- Cancer/Treatment factors: Higher cumulative dose, especially bleomycin dose ≥400 U/m2 (pulmonary function deficits observed at doses as low as 60-100 U/m2 in children on formal pulmonary function testing), combination with busulfan,
carmustine (BCNU), or lomustine (CCNU), combination with chest radiation, or TBI- Pre-morbid/Co-morbid medical conditions: Renal dysfunction, high dose oxygen support such as during general anesthesia- Health behaviors: Smoking, inhaled illicit drug use

References
Armenian SH, Landier W, Francisco L, et al: Long-term pulmonary function in survivors of childhood cancer. J Clin Oncol 33:1592-600, 2015
De A, Kamath S, Wong K, et al: Correlation of pulmonary function abnormalities with dose volume histograms in children treated with lung irradiation. Pediatr Pulmonol 50:596-603, 2015
Dietz AC, Chen Y, Yasui Y, et al: Risk and impact of pulmonary complications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 122:3687-3696, 2016
Green DM, Zhu L, Wang M, et al: Pulmonary function after treatment for childhood cancer. A report from the St. Jude Lifetime Cohort Study (SJLIFE). Ann Am Thorac Soc 13:1575-85, 2016
Huang TT, Hudson MM, Stokes DC, et al: Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest 140:881-901, 2011
Hudson MM, Ness KK, Gurney JG, et al: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371-2381, 2013
Mulder RL, Thonissen NM, van der Pal HJ, et al: Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 66:1065-71, 2011
Tetrault JM, Crothers K, Moore BA, et al: Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med 167:221-8, 2007
van Hulst RA, Rietbroek RC, Gaastra MT, et al: To dive or not to dive with bleomycin: a practical algorithm. Aviat Space Environ Med 82:814-8, 2011
Wolff AJ, O’Donnell AE: Pulmonary effects of illicit drug use. Clin Chest Med 25:203-16, 2004
Zorzi AP, Yang CL, Dell S, et al: Bleomycin-associated lung toxicity in childhood cancer survivors. J Pediatr Hematol Oncol 37:e447-52, 2015

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ANTI-TUMOR ANTIBIOTICS (CONT)

Therapeutic
Exposure

Potential
Late Effects

Anti-Tumor Antibiotics
Dactinomycin

No known late effects

Periodic Evaluation

Health Counseling/
Further Considerations
SYSTEM = No Known Late Effects
SCORE = 1

Additional Information

Dactinomycin has been associated with acute SOS, from which the majority of patients recover without sequelae.

References
Green DM, Norkool P, Breslow NE, et al: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms’ Tumor Study. J Clin Oncol 8:1525-30,
1990

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Therapeutic
Exposure
Corticosteroids
Dexamethasone
Prednisone

CORTICOSTEROIDS
Potential
Late Effects

Reduced bone mineral density(BMD)
Defined as Z-score >2 SD below
the mean in male survivors <50
years old and premenopausal
women or T-score >1 SD below
the mean in male survivors >50
years old and postmenopausal
women

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Bone density evaluation (DXA)
Adjust for height-age Z-score in survivors <age
20 years*Baseline BMD at entry into long-term follow-up (2to 5 years after completion of therapy) with thefollowing recommended actions:• If Z-score >1 SD above the mean (normal),repeat at 25 years of age when peak bone mass
should be achieved• Between these two measurements and thereafter, screen as clinically indicated based on BMD
and ongoing risk assessment• If Z-score >2 SD below the mean, referral to (orconsultation of) a bone health specialist• If Z-score >1 and <2 SD below the mean,evaluation for endocrine defects (e.g., hypogonadism or GH deficiency) and consultation with abone health specialist for further evaluation andinterpretation of findings as clinically indicated.
Repeat DXA after 2 years and thereafter as clinically indicated based on BMD change (i.e., BMD
decline is greater than the DXA least significant
change) and ongoing risk assessment

HEALTH LINKS

Bone HealthRESOURCES
National Osteoporosis Foundation: www.nof.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ensure the AAP recommended minimum daily intake of vitamin D (400 IU/day) for infants<12 months, 600 IU/day for those age 12 months through age 70 years, 800 IU/day for
those >70 years
Ensure adequate dietary calcium (see table in the “Bone Health” Health Link for ageappropriate recommendations). Supplements may be necessary if there are dietary
restrictions.
Use caution regarding calcium supplementation in patients with history of renal lithiasis.
Advocate for regular weight-bearing exercises such as running and jumping.
Treat exacerbating or predisposing conditions (e.g., hormonal replacement therapy
for hypogonadism, GH deficiency, correction of chronic metabolic acidosis that could
accelerate bone loss).
Endocrine consultation for patients with osteoporosis or history of multiple fractures
for pharmacologic interventions (e.g., bisphosphonates, calcitonin, selective estrogen
receptor modulators).
SYSTEM = Musculoskeletal
SCORE = 2B

*Pediatric Z-score calculator adjusted forheight age: https://zscore.research.chop.edu/
calcpedbonedens.phpw

Additional Information

The World Health Organization definition of osteoporosis in adults is based on comparison of a measured BMD of young adults at peak bone age and defined as a T-score.
A T-score is the number of standard deviations the BMD measurement is above or below the mean.
Current definitions of osteopenia (T-scores between 1.0 and 2.5 SD below the mean) and osteoporosis (T-scores >2.5 SD below the mean) were developed primarily in the context of postmenopausal women. In this population,T-scores have a well-validated correlation with fracture risk that increases with age.
The fracture risk associated with T-scores in younger populations, including cancer survivors with treatment-related hypogonadism, has not been established.
T-scores are not appropriate to assess skeletal health in pediatric patients who have not achieved peak adult bone mass.
Pediatric BMD reference data sets calculate Z-scores based on age and gender.
A Z-score is the number of standard deviations the measurement is above or below the age-matched mean BMD.
The fracture risk in pediatric patients with low BMD for chronologic age based on Z-scores has not been established.
There are no defined standards for referral or treatment of low BMD in children.

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Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Caucasian race, lower weight/BMI. Both genders are at risk.
- Cancer/Treatment factors: Corticosteroids (especially prolonged therapy, e.g., for cGVHD), higher cumulative corticosteroid dose (especially ≥9 gm/m2), cranial/craniospinal radiation, HCT, or TBI.
- Pre-morbid/Co-morbid medical conditions: GH deficiency, hypogonadism/delayed puberty, hyperthyroidism- Health behaviors: Intake of calcium and vitamin D, intake of alcohol and carbonated beverages, weight bearing exercise, smoking

References
Bischoff-Ferrari HA: Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol 624:55-71, 2008
Chaiban J, Muwakkit S, Arabi A, et al: Modeling pathways for low bone mass in children with malignancies. J Clin Densitom 12:441-9, 2009
Esbenshade AJ, Sopfe J, Zhao Z, et al: Screening for vitamin D insufficiency in pediatric cancer survivors. Pediatr Blood Cancer 61:723-8, 2014
Kaste SC, Qi A, Smith K, et al: Calcium and cholecalciferol supplementation provides no added benefit to nutritional counseling to improve bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL). Pediatr
Blood Cancer 61:885-93, 2014
Landier W, Armenian SH, Lee J, et al: Yield of screening for long-term complications using the Children’s Oncology Group long-term follow-up guidelines. J Clin Oncol 30:4401-8, 2012
Leonard MB: Assessment of bone health in children and adolescents with cancer: promises and pitfalls of current techniques. Med Pediatr Oncol 41:198-207, 2003
Mostoufi-Moab S, Brodsky J, Isaacoff EJ, et al: Longitudinal assessment of bone density and structure in childhood survivors of acute lymphoblastic leukemia without cranial radiation. J Clin Endocrinol Metab 97:3584-92, 2012
NIH Office of Dietary Supplements: Vitamin D health professionals fact sheet. Accessed March 16, 2023: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional
Polgreen LE, Petryk A, Dietz AC, et al: Modifiable risk factors associated with bone deficits in childhood cancer survivors. BMC Pediatr 12:40, 2012
The International Society for Clinical Densitometry. 2019 ISCD official positions. Accessed March 2023: https://iscd.org/learn/official-positions
van Leeuwen BL, Kamps WA, Jansen HW, et al: The effect of chemotherapy on the growing skeleton. Cancer Treat Rev 26:363-76, 2000
Wasilewski-Masker K, Kaste SC, Hudson MM, et al: Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics 121:e705-13, 2008
Wilson CL, Dilley K, Ness KK, et al: Fractures among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 118:5920-8, 2012
Zemel BS, Leonard MB, Kelly A, et al: Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab 95:1265-73, 2010

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Therapeutic
Exposure
Corticosteroids
Dexamethasone
Prednisone

CORTICOSTEROIDS (CONT)
Potential
Late Effects

Osteonecrosis (avascularnecrosis)

Periodic Evaluation
HISTORY
Joint pain
Swelling
Immobility
Limited range of motion
YearlyPHYSICAL
Musculoskeletal exam
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Osteonecrosis
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
MRI as clinically indicated.
Orthopedic consultation in patients with positive imaging and/or symptoms ofosteonecrosis.
Physical therapy evaluation (for non-pharmacologic pain management, range of
motion, strengthening, stretching, functional mobility).
SYSTEM = Musculoskeletal
SCORE = 1

Additional Information

Osteonecrosis typically occurs during the acute treatment phase; may progress over time or resolve.
Multifocal osteonecrosis is significantly more common (3:1) than unifocal.
Symptomatic lesions confer the greatest risk for collapse.
Dexamethasone is associated with a greater risk than prednisone, especially for patients with ALL ≥10 years of age at time of exposure.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Being pubertal or post-pubertal at time of treatment, genetic polymorphisms- Cancer/Treatment factors: High dose radiation to any bone, orthovoltage radiation (commonly used before 1970) due to delivery of greater dose to skin and bones, TBI, prolonged immunosuppression (e.g., for cGVHD)- Pre-morbid/Co-morbid medical conditions: Sickle cell disease, cGVHD

References
Elmantaser M, Stewart G, Young D, et al: Skeletal morbidity in children receiving chemotherapy for acute lymphoblastic leukaemia. Arch Dis Child 95:805-9, 2010
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 26:3038-45, 2008
Karimova EJ, Rai SN, Ingle D, et al: MRI of knee osteonecrosis in children with leukemia and lymphoma: Part 2, clinical and imaging patterns. AJR Am J Roentgenol 186:477-82, 2006
Karol SE, Yang W, Van Driest SL, et al: Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood 126:1770-6, 2015
Kawedia JD, Kaste SC, Pei D, et al: Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood 117:2340-7; quiz 2556, 2011
Mattano LA, Jr., Devidas M, Nachman JB, et al: Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961
randomised cohort trial. Lancet Oncol 13:906-15, 2012
Mattano LA, Jr., Sather HN, Trigg ME, et al: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol 18:3262-72, 2000
Ojala AE, Paakko E, Lanning FP, et al: Osteonecrosis during the treatment of childhood acute lymphoblastic leukemia: a prospective MRI study. Med Pediatr Oncol 32:11-7, 1999
Plesa M, Gagné V, Glisovic S, et al: Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia. Pharmacogenomics J 19(1):33-41, 2019
Relling MV, Yang W, Das S, et al: Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. J Clin Oncol 22:3930-6, 2004
te Winkel ML, Pieters R, Hop WC, et al: Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia. J Clin Oncol 29:4143-50, 2011

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Therapeutic
Exposure
Corticosteroids
Dexamethasone
Prednisone

CORTICOSTEROIDS (CONT)
Potential
Late Effects

Cataracts

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Visual changes (decreased acuity, halos,
diplopia)
YearlyPHYSICAL
Visual acuity
Funduscopic exam
YearlySCREENING
Evaluation by ophthalmologist or
optometrist
YearlyHEALTH LINKS
Cataracts
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ophthalmology consultation as clinically indicated.
Refer patients with visual deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate acquisition of
educational resources.
SYSTEM = Ocular
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with busulfan, combination with TBI, cranial, orbital or eye radiation, longer interval since treatment

References
Alloin AL, Barlogis V, Auquier P, et al: Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study. Br J Haematol 164:94100, 2014
Benyunes MC, Sullivan KM, Deeg HJ, et al: Cataracts after bone marrow transplantation: long-term follow-up of adults treated with fractionated total body irradiation. Int J Radiat Oncol Biol Phys 32:661-70, 1995

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Therapeutic
Exposure
Enzymes
Asparaginase

ENZYMES
Potential
Late Effects

Periodic Evaluation

No known late effects

Health Counseling/
Further Considerations
SYSTEM = No Known Late Effects
SCORE = 1

Additional Information

Acute toxicities predominate, from which the majority of patients recover without sequelae.

References
Duval M, Suciu S, Ferster A, et al: Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children’s Leukemia Group phase 3 trial. Blood 99:2734-9, 2002
Parsons SK, Skapek SX, Neufeld EJ, et al: Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Blood 89:1886-95, 1997

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Therapeutic
Exposure
Plant Alkaloids
Vinblastine
Vincristine

PLANT ALKALOIDS
Potential
Late Effects

Peripheral sensory or motor
neuropathy
Areflexia
Weakness
Foot drop
Paresthesias
Dysesthesias

Periodic Evaluation
HISTORY
Areflexia
Weakness
Foot drop
Paresthesias
Dysesthesias
Yearly, until 2 to 3 years after therapy, monitor
yearly if symptoms persist
PHYSICAL
Neurologic exam
Yearly, until 2 to 3 years after therapy, monitor
yearly if symptoms persist

Health Counseling/
Further Considerations
HEALTH LINKS
Peripheral Neuropathy
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Physical therapy referral for patients with symptomatic neuropathy.
Physical and occupational therapy assessment of hand function.
Treat with effective agent for neuropathic pain (e.g., gabapentin or amitriptyline).
SYSTEM = PNSSCORE = 2A

Additional Information

Acute toxicities most commonly occur and usually improve or resolve prior to patients entering long-term follow-up.
Neuropathy can persist after treatment and is typically not late in onset.
Studies of adults treated during childhood support higher prevalence of deficits than previously appreciated.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with platinum chemotherapy, gemcitabine, taxanes- Pre-morbid/Co-morbid medical conditions: Anorexia, severe weight loss, Charcot-Marie-Tooth disease

References
Chauvenet AR, Shashi V, Selsky C, et al: Vincristine-induced neuropathy as the initial presentation of Charcot-Marie-Tooth disease in acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Pediatr Hematol Oncol 25:31620, 2003
Lehtinen SS, Huuskonen UE, Harila-Saari AH, et al: Motor nervous system impairment persists in long-term survivors of childhood acute lymphoblastic leukemia. Cancer 94:2466-73, 2002
Ness KK, Jones KE, Smith WA, et al: Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: results from the St. Jude Lifetime Cohort Study. Arch Phys Med
Rehabil 94:1451-7, 2013

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CHEMOTHERAPY
Sec #
42

Therapeutic
Exposure
Plant Alkaloids
Vinblastine
Vincristine

PLANT ALKALOIDS (CONT)
Potential
Late Effects

Vasospastic attacks(Raynaud’s phenomenon)

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Vasospasms of hands, feet, nose, lips,
cheeks, or earlobes related to stress orcold temperatures
YearlyPHYSICAL
Physical exam of affected area
As clinically indicated

HEALTH LINKS
Raynaud’s Phenomenon
COUNSELING
Wear appropriate protective clothing in cold environments.
Symptoms may be exacerbated by medications/chemicals that cause
vasoconstriction (e.g., pseudoephedrine, stimulants), illicit drugs (e.g., cocaine),and nicotine.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Vasodilating medications (calcium-channel blockers, alpha blockers) for
patients with frequent, severe vasospastic attacks unresponsive to behavioral
management.
SYSTEM = PNSSCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Pre-morbid/Co-morbid medical conditions: Smoking, illicit drug use, use of vasoconstricting medications/substances, exposure to repetitive vibration

References
Bokemeyer C, Berger CC, Kuczyk MA, et al: Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 14:2923-32, 1996
Doll DC, Ringenberg QS, Yarbro JW: Vascular toxicity associated with antineoplastic agents. J Clin Oncol 4:1405-17, 1986
Vogelzang NJ, Bosl GJ, Johnson K, et al: Raynaud’s phenomenon: a common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med 95:288-92, 1981

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w

Therapeutic
Exposure
Epipodophyllotoxins
Etoposide (VP16)
Teniposide (VM26)

EPIPODOPHYLLOTOXINS
Potential
Late Effects

Acute myeloid leukemia (AML)

Periodic Evaluation
HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after exposure to agent
PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure to agent

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.
SYSTEM = SMNSCORE = 1

Additional Information

Epipodophyllotoxin administration schedules have been modified since approximately 1990 to reduce the risk of AML.
There is negligible benefit to obtaining a screening CBC in the absence of clinical signs and symptoms for AML.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Weekly or twice weekly administration, <5 years since exposure to agent, autologous HCT- Pre-morbid/Co-morbid medical conditions: Evidence is conflicting that splenectomy modifies risk for AML

References
Eichenauer DA, Thielen I, Haverkamp H, et al: Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 123:1658-64, 2014
Hijiya N, Ness KK, Ribeiro RC, et al: Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer 115:23-35, 2009
Koontz MZ, Horning SJ, Balise R, et al: Risk of therapy-related secondary leukemia in Hodgkin lymphoma: the Stanford University experience over three generations of clinical trials. J Clin Oncol 31:592-8, 2013
Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors. Blood 95:1588-93, 2000
Landier W, Armenian SH, Lee J, et al: Yield of screening for long-term complications using the Children’s Oncology Group long-term follow-up guidelines. J Clin Oncol 30:4401-8, 2012
Le Deley MC, Leblanc T, Shamsaldin A, et al: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Societe Francaise d’Oncologie
Pediatrique. J Clin Oncol 21:1074-81, 2003
Nottage K, Lanctot J, Li Z, et al: Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study. Blood 117:6315-8, 2011
Pui CH, Relling MV, Rivera GK, et al: Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia 9:1990-6, 1995
Rihani R, Bazzeh F, Faqih N, et al: Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer 116:4385-94, 2010
Sanford NN, Miao R, Wang H, et al: Characteristics and predictors for secondary leukemia and myelodysplastic syndrome in Ewing and osteosarcoma survivors. Int J Radiat Oncol Biol Phys 103(1):52-61, 2019
Smith MA, Rubinstein L, Anderson JR, et al: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17:569-77, 1999

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RADIATIONINSTRUCTIONS

Determining Applicability of Radiation Sections for Specific Patients Based on
Exposure

Guideline Radiation Sections by Field
Applicable guideline sections indicated in bold/dark blue; M=Male; F=Female

The radiation sections of the COG Long-Term Follow-Up Guidelines (Sections 44-98) areorganized by anatomic region from the head downward. In this current version of the
COG LTFU Guidelines, the radiation fields are still simplified and categorized by anatomic
region, as follows:-

Head/Brain
Neck
Chest
AxillaAbdomenPelvisTesticularSpine (cervical, thoracic, lumbar, sacral, whole)
Skin/soft tissues/bones/extremities
TBI

64, 65, 66*, 67,
68, 69, 70, 71, 79

The Guideline sections applicable to each radiation field are listed on the accompanying
diagram.
Traditional and combined radiation fields (e.g., mantle, mediastinal, para-aortic, etc.) aredefined in Appendix I and mapped to the anatomic fields specified above, as follows:-

46, 47, 48, 49, 50, 51, 52,
53, 54M, 55F, 56, 57, 58M,
59F, 60*, 61, 62, 63*, 63,
65, 66*, 67, 68, 69, 70, 71

44, 45, 46,
47, 48, 53,
58M, 59F,
61, 64, 65,
67, 68, 69,
73F, 74F,
75, 76, 80,
81, 86, 87,
91M, 92F,
93F, 94F, 96

72, 77*, 79, 97
44,
44,
45,
45,
96,
96,
98
97

Whole Spine

Radiation Fields Defined, Table: Appendix I, pages 6-7
Radiation Fields Defined, Diagram: Appendix I, page 8

Radiation Dose Calculations: Appendix I, page 9

Guideline Radiation Sections by Potential Impact, Table: Appendix I, pages 11-12
Guideline Radiation Sections by Potential Impact, Diagram: Appendix I, page 13
Total Body Irradiation (TBI) Related Potential Late Effects: Appendix I, page 14

Use the “Patient-Specific Guideline Identification Tool” in Appendix I (pages 32-37) todetermine specific screening guidelines by section number for individual patients.
COG LTFU Guidelines – Page 51

73F, 74F,
75, 76

77*, 78*, 79,
80, 81, 82,
83, 84, 85,
86, 87, 97

84, 85, 86, 97

Further details regarding radiation impact by organ systems, with associated potential lateeffects, are also available in Appendix I, as follows:-

72, 73F,
74F, 75, 76,
77*, 79, 97

64, 65, 66*, 67,
68, 69, 70, 71, 72,
77*, 79, 84, 85,
86, 88, 89, 92F,
93F, 94F, 97,

Five sections of these Guidelines (Sections 60, 63, 66, 77, 78) include minimum dose
specifications. These five Guideline sections are applicable only to patients who received
radiation to any of the relevant fields at a total dose higher than the specified minimum
dose. Instructions regarding calculating combined radiation doses are available asfollows:-

64, 65, 66*,
67, 68, 69, 70,
71, 72, 79

84, 85, 86, 88,
89, 92F, 93F,
94F, 95F

84, 85, 86, 88, 89
92F, 93F, 94F

90M, 91M*Minimum dose
specifications apply.
For instructions andexamples regarding
radiation dose
calculations, refer to“Radiation Dose
Calculations” in COG
Long-Term Follow-Up
Guidelines Appendix I
Reference Materials.
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RADIATION
Sec #
44

ALL FIELDS

Therapeutic
Exposure

Potential
Late Effects

Any Radiation (Including
TBI)

Subsequent benign ormalignant neoplasm
occurring in or nearradiation field
Such as dysplastic nevi, skincancer (basal cell carcinoma,squamous cell carcinoma),bone malignancies, oral
cancerPeriodic Evaluation
HISTORY
Skin lesions
Changing moles (asymmetry, bleeding,increasing size, indistinct borders)
Bone pain (especially in irradiated field)
Persistent thickening or lump of soft tissue
or boneYearlyPHYSICAL
Skin self exam
Monthly
Inspection and palpation of skin and soft
tissues in irradiated field(s)Dermatologic exam of irradiated fields
Palpation of bones in irradiated field
Yearlyw

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
Skin Health
COUNSELING
Promptly seek medical attention for symptoms (e.g., bone pain, bone mass,
persistent fevers).
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
See relevant guideline sections to determine screening for specific radiation
fields.
Dermatology consultation for evaluation and monitoring of atypical nevi.
Diagnostic imaging in patients as clinically indicated.
Surgical and/or oncology consultation as clinically indicated.
SYSTEM = SMNSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, adolescent at treatment [bone malignancies]- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy (bone malignancies), large radiation treatment volumes, alkylating agent exposure, orthovoltage radiation (commonly used before 1970) due to delivery ofgreater dose to skin and bones- Pre-morbid/Co-morbid medical conditions: Predisposing mutation (e.g., p53, NF1), bilateral or familial retinoblastoma (implying RB1 likely pathogenic variant), Gorlin syndrome (nevoid basal cell carcinoma syndrome)- Health behaviors: Sun exposure, tanning booths

References
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 29:3056-64, 2011
Baker KS, Leisenring WM, Goodman PJ, et al: Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood 133(26):2790-2799, 2019
Bhatia S, Louie AD, Bhatia R, et al: Solid cancers after bone marrow transplantation. J Clin Oncol 19:464-71, 2001
Bright CJ, Hawkins MM, Winter DL, et al: Risk of Soft-Tissue Sarcoma Among 69 460 Five-Year Survivors of Childhood Cancer in Europe. J Natl Cancer Inst 110(6):649-660, 2018
Henderson TO, Rajaraman P, Stovall M, et al: Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 84:224-30, 2012
Inskip PD, Sigurdson AJ, Veiga L, et al: Radiation-related new primary solid cancers in the Childhood Cancer Survivor Study: comparative radiation dose response and modification of treatment effects. Int J Radiat Oncol Biol Phys
94:800-7, 2016
Reulen RC, Frobisher C, Winter DL, et al: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA 305:2311-9, 2011
Schaapveld M, Aleman BM, van Eggermond AM, et al: Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. N Engl J Med 373:2499-511, 2015
Schwartz B, Benadjaoud MA, Clero E, et al: Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment. Radiat Environ Biophys 53:381-90, 2014
Teepen JC, Kok JL, Kremer LC, et al: Long-Term Risk of Skin Cancer Among Childhood Cancer Survivors: A DCOG-LATER Cohort Study. J Natl Cancer Inst 111(8):845-853, 2019
Turcotte LM, Liu Q, Yasui Y, et al: Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015. JAMA 317(8):814-824, 2017
Turcotte LM, Whitton JA, Friedman DL, et al: Risk of subsequent neoplasms during the fifth and sixth decades of life in the Childhood Cancer Survivor Study cohort. J Clin Oncol 33:3568-75, 2015
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RADIATION
Sec #
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w

ALL FIELDS (CONT)

Therapeutic
Exposure

Potential
Late Effects

Any Radiation (Including
TBI)

Dermatologic toxicity otherthan neoplasms
Permanent alopecia
Altered skin pigmentation
Telangiectasias
Fibrosis

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Dermatologic exam of irradiated fields
YearlyHEALTH LINKS
Skin Health
SYSTEM = Dermatologic
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: Total radiation dose ≥40 Gy, especially ≥50 Gy, large dose fractions (e.g., ≥2 Gy per fraction), orthovoltage radiation (commonly used before 1970) due to delivery of greater dose to skin and bones

References
Alsner J, Andreassen CN, Overgaard J: Genetic markers for prediction of normal tissue toxicity after radiotherapy. Semin Radiat Oncol 18:126-35, 2008
Kinahan KE, Sharp LK, Seidel K, et al: Scarring, disfigurement, and quality of life in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30:2466-74, 2012
Lawenda BD, Gagne HM, Gierga DP, et al: Permanent alopecia after cranial irradiation: dose-response relationship. Int J Radiat Oncol Biol Phys 60:879-87, 2004
Marcus RB, Esiashivilli N: Musculoskeletal, integument, in Schwartz CL, Hobbie WL, Constine LS, et al (eds): Survivors of Childhood and Adolescent Cancer: A Multidisciplinary Approach (ed 3). Switzerland, Springer International
Publishing, 2015, pp 297-324
Rannan-Eliya YF, Rannan-Eliya S, Graham K, et al: Surgical interventions for the treatment of radiation-induced alopecia in pediatric practice. Pediatr Blood Cancer 49:731-6, 2007
Rogers S, Donachie P, Sugden E, et al: Comparison of permanent hair loss in children with standard risk PNETS of the posterior fossa following radiotherapy alone or chemotherapy and radiotherapy after surgical resection. Pediatr
Blood Cancer 57:1074-6, 2011

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POTENTIAL IMPACT TO
BRAIN/CRANIUM

RADIATION
Sec #
46

w

Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Brain tumor (benign ormalignant)Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Headaches
Vomiting
Cognitive, motor or sensory deficits
Seizures and other neurologic symptoms
YearlyPHYSICAL
Neurologic exam
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Brain MRI as clinically indicated for symptomatic patients.
Brain MRI every other year for patients with neurofibromatosis beginning 2 years
after radiation therapy.
Neurosurgical consultation for tissue diagnosis and/or resection.
Neuro-oncology consultation for medical management.
SYSTEM = SMNSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <6 years- Cancer/Treatment factors: Higher radiation dose (risk of subsequent CNS tumor after cranial radiation increases in a dose-dependent fashion)- Pre-morbid/Co-morbid medical conditions: Neurofibromatosis, ataxia telangiectasia

References
Bowers DC, Moskowitz CS, Chou JF, et al: Morbidity and Mortality Associated With Meningioma After Cranial Radiotherapy: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 35(14):1570-1576, 2017
Bowers DC, Verbruggen LC, Kremer LCM, et al: Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late
Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 22(5):e196-e206, 2021
Friedman DL, Whitton J, Leisenring W, et al: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102:1083-95, 2010
Kok JL, Teepen JC, van Leeuwen FE, et al: Risk of benign meningioma after childhood cancer in the DCOG-LATER cohort: contributions of radiation dose, exposed cranial volume, and age. Neuro Oncol 21(3):392-403, 2019
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 98:1528-37, 2006
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 24:2570-5, 2006
Taylor 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 28:5287-93, 2010
Walter AW, Hancock ML, Pui CH, et al: Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol 16:3761-7, 1998

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BRAIN/CRANIUM (CONT)RADIATION
Sec #
47

w

Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Neurocognitive deficits
Functional deficits in:• Executive function (planningand organization)• Sustained attention• Memory (particularly visual,sequencing, temporal
memory)• Processing speed• Visual-motor integration• Fine motor dexterity• Language• Academic fluency
Learning deficits in math andreading (particularly reading
comprehension)
Diminished IQ
Behavioral change

Periodic Evaluation
HISTORY
Educational and/or vocational progress
YearlySCREENING
Referral for formal neuropsychologicalevaluation
Baseline at entry into long-term follow-up,
then periodically as clinically indicatedfor patients with evidence of impaired
educational or vocational progress

Health Counseling/
Further Considerations
HEALTH LINKS
School After Treatment
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Referral to school liaison in community or cancer center (psychologist, social
worker, school counselor) to facilitate acquisition of educational resources and/or social skills training.
Psychotropic medication (e.g., stimulants) or evidence-based rehabilitation
training. Caution—lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended.
Referral to community services for vocational rehabilitation or for services fordevelopmentally disabled.
SYSTEM = CNSSCORE = 1

Additional Information

Formal neuropsychological evaluation includes tests of processing speed, computer-based attention, visual motor integration, memory, comprehension of verbal instructions, verbal fluency, executive function and planning.
Neurocognitive deficits in survivors of leukemia and lymphoma are more frequently related to information processing (e.g., slow processing speed, attention problems). Neurocognitive deficits in brain tumor survivors treated withhigher doses of cranial radiation are more global (significant decline in IQ). Extent of deficit depends on age at treatment, intensity of treatment, and time since treatment. New or progressive deficits may emerge over time.
Note: academic fluency is defined as the ability to correctly complete multiple simple academic problems (e.g., reading words, simple math equations) within a limited amount of time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <3 years, female sex, family history of learning or attention problems- Cancer/Treatment factors: Primary CNS tumor, CNS leukemia/lymphoma, relapsed leukemia/lymphoma treated with CNS-directed therapy, head/neck tumors with brain in radiation field, temporal lobe field including hippocampus (without hippocampal sparing), higher radiation dose, larger radiation field, greater cortical volumes, cranial radiation in combination with TBI, lack of volume-sparing radiation techniques (e.g., proton beam therapy),
combination with corticosteroids, methotrexate (IT, IO, high dose IV), cytarabine (high dose IV), longer elapsed time since therapy- Pre-morbid/Co-morbid medical conditions: Pre-morbid learning or attention problems, sleep disturbance, seizures, hydrocephalus, CRT-induced ototoxicity, chronic conditions (e.g., endocrine, cardiopulmonary, frailty)

References
Acharya S, Wu S, Ashford JM, et al: Association between hippocampal dose and memory in survivors of childhood or adolescent low-grade glioma: a 10-year neurocognitive longitudinal study. Neurooncol 21(9),1175-1183, 2019
Ali JS, Ashford JM, Swain MA, et al: Predictors of cognitive performance among infants treated for brain tumors: findings from a multisite, prospective, longitudinal trial. J Clin Oncol 39(21),2350-2358, 2021
Bass JK, Liu W, Banerjee P, et al: Association of hearing impairment with neurocognition in survivors of childhood cancer. JAMA Oncol 6(9),1363-1371, 2020
Brinkman TM, Krasin MJ, Liu W, et al: Long-term neurocognitive functioning and social attainment in adult survivors of pediatric CNS tumors: results from the St Jude Lifetime Cohort Study. J Clin Oncol 34:1358-67, 2016
Cheung YT, Brinkman TM, Li C, et al: Chronic health conditions and neurocognitive function in aging survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 110(4),411-419, 2018Child AE, Warren EA, Grosshans DR, et al: Long-term cognitive and academic outcomes among pediatric brain tumor survivors treated with proton versus photon radiotherapy. Pediatr Blood Cancer 68(9),e29125, 2021
Dixon SB, Chen Y, Yasui Y, et al: Reduced morbidity and mortality in survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study. J Clin Oncol 38(29),3418-3429, 2020
Eaton BR, Fong GW, Ingerski LM, et al: Intellectual functioning among case-matched cohorts of children treated with proton or photon radiation for standard-risk medulloblastoma. Cancer 127(20),3840-3846, 2021
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BRAIN/CRANIUM (CONT)RADIATION
Section 47 References (cont)Goda JS, Dutta D, Krishna U, et al: Hippocampal radiotherapy dose constraints for predicting long-term neurocognitive outcomes: mature data from a prospective trial in young patients with brain tumors. Neurooncol 22(11),16771685, 2020
Heitzer AM, Villagran AM, Raghubar K, et al: Effect of sensorineural hearing loss on neurocognitive and adaptive functioning in survivors of pediatric embryonal brain tumor. Journal of Neurooncol 146(1),147-156, 2020
Kahalley LS, Conklin HM, Tyc VL, et al: Slower processing speed after treatment for pediatric brain tumor and acute lymphoblastic leukemia. Psycho-Oncol 22:1979-86, 2013
Kahalley LS, Peterson R, Ris MD, et al: Superior intellectual outcomes after proton radiotherapy compared with photon radiotherapy for pediatric medulloblastoma. J Clin Oncol 38(5),454-461, 2020
Kahalley LS, Ris MD, Grosshans DR, et al: Comparing intelligence quotient change after treatment with proton versus photon radiation therapy for pediatric brain tumors. J Clin Oncol 34(10),1043-1049, 2016
Krull KR, Brinkman TM, Li C, et al: Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: a report from the St Jude Lifetime Cohort Study. J Clin Oncol 31:4407-15, 2013
Krull KR, Li C, Phillips NS, et al: Growth hormone deficiency and neurocognitive function in adult survivors of childhood acute lymphoblastic leukemia. Cancer 125(10),1748-1755, 2019
Michalski JM, Janss AJ, Vezina LG, et al: Children’s oncology group phase III trial of reduced-dose and reduced-volume radiotherapy with chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 39(24),26852697, 2021
Mulrooney DA, Hyun G, Ness KK, et al: The changing burden of long-term health outcomes in survivors of childhood acute lymphoblastic leukaemia: a retrospective analysis of the St Jude Lifetime Cohort Study. Lancet Haematol
6(6),e306-e316, 2019
Olivier TW, Bass JK, Ashford JM, et al: Cognitive implications of ototoxicity in pediatric patients with embryonal brain tumors. J Clin Oncol 37(18),1566-1575, 2019
Orgel E, O’Neil SH, Kayser K, et al: Effect of sensorineural hearing loss on neurocognitive functioning in pediatric brain tumor survivors. Pediatr Blood Cancer 63(3),527-534, 2016
Tsang DS, Kim L, Liu ZA, et al: Intellectual changes after radiation for children with brain tumors: which brain structures are most important? Neurooncol 23(3),487-497, 2021
van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12),e28723, 2020
Weusthof K, Luttich P, Regnery S, et al: Neurocognitive outcomes in pediatric patients following brain irradiation. Cancers 13(14), 2021
Williams AM, Krull KR, Howell CR, et al: Physiologic frailty and neurocognitive decline among young-adult childhood cancer survivors: a prospective study from the st jude lifetime cohort. J Clin Oncol 39(31),3485-3495, 2021
Zureick AH, Evans CL, Niemierko A, et al: Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors. Cancer 124(10),2238-2245, 2018

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POTENTIAL IMPACT TO
BRAIN/CRANIUM (CONT)RADIATION
Sec #
48

w

Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Clinical leukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures

Periodic Evaluation
HISTORY
Cognitive, motor and/or sensory deficits
Seizures
Other neurologic symptoms
YearlyPHYSICAL
Neurologic exam
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Brain CT or Brain MRI with MRA as clinically indicated with preferred study
based on intracranial lesion to be evaluated:• Calcifications: CT• White matter: MRI with DTI• Microvascular injury: Gadolinium-enhanced MRI with DWI
Neurology consultation and follow-up as clinically indicated.
SYSTEM = CNSSCORE = 1

Additional Information

Clinical leukoencephalopathy may present with or without imaging abnormalities (e.g., leukoencephalopathy, cerebral lacunes, cerebral atrophy, dystrophic calcifications, mineralizing microangiopathy).
Transient white matter anomalies may follow radiotherapy and high dose chemotherapy for medulloblastoma/PNET, may mimic tumor recurrence, and signify risk of persistent neurologic sequelae.
Neuroimaging changes do not always correlate with degree of cognitive dysfunction.
Prospective studies are needed to define the dose/effect relationship of neurotoxic agents.
New deficits may emerge over time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: CNS leukemia/lymphoma, relapsed leukemia/lymphoma treated with CNS-directed therapy, longer elapsed time since therapy, higher radiation dose, especially ≥24 Gy or fraction dose ≥3 Gy, larger
radiation field, greater cortical volumes, combination with dexamethasone, methotrexate (IT, IO, high dose IV), cytarabine (high dose IV)

References
Faraci M, Lanino E, Dini G, et al: Severe neurologic complications after hematopoietic stem cell transplantation in children. Neurology 59:1895-904, 2002
Faraci M, Morana G, Bagnasco F, et al: Magnetic resonance imaging in childhood leukemia survivors treated with cranial radiotherapy: a cross sectional, single center study. Pediatr Blood Cancer 57:240-6, 2011
Hertzberg H, Huk WJ, Ueberall MA, et al: CNS late effects after ALL therapy in childhood. Part I: Neuroradiological findings in long-term survivors of childhood ALL--an evaluation of the interferences between morphology andneuropsychological performance. The German Late Effects Working Group. Med Pediatr Oncol 28:387-400, 1997
King TZ, Wang L, Mao H: Disruption of white matter integrity in adult survivors of childhood brain tumors: correlates with long-term intellectual outcomes. PLoS One 10:e0131744, 2015
Kingma A, Mooyaart EL, Kamps WA, et al: Magnetic resonance imaging of the brain and neuropsychological evaluation in children treated for acute lymphoblastic leukemia at a young age. Am J Pediatr Hematol Oncol 15:231-8, 1993
Matsumoto K, Takahashi S, Sato A, et al: Leukoencephalopathy in childhood hematopoietic neoplasm caused by moderate-dose methotrexate and prophylactic cranial radiotherapy--an MR analysis. Int J Radiat Oncol Biol Phys
32:913-8, 1995
Reddick WE, Taghipour DJ, Glass JO, et al: Prognostic factors that increase the risk for reduced white matter volumes and deficits in attention and learning for survivors of childhood cancers. Pediatr Blood Cancer 61:1074-9, 2014

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Sec #
49

w

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Cerebrovascularcomplications
StrokeMoyamoyaOcclusive cerebral
vasculopathy
Cavernomas

Periodic Evaluation
HISTORY
Hemiparesis
Hemiplegia
Weakness
Aphasia
YearlyPHYSICAL
Neurologic exam
YearlyHealth Counseling/
Further Considerations
COUNSELING
Importance of controlling health conditions known to increase cardiovascularand stroke risk (e.g., hypertension, diabetes, dyslipidemia).
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Brain MRI with DWI with MRA as clinically indicated.
Neurology/Neurosurgery consultation and follow-up.
Physical and occupational therapy as clinically indicated.
Revascularization procedures as indicated for moyamoya.
SYSTEM = CNSSCORE = 1

Additional Information

Moyamoya syndrome is the complete occlusion of ≥1 of the three major cerebral vessels with the development of small, immature collateral vessels, and reflects an attempt to revascularize the ischemic portion of the brain.
Cavernomas are a common late effect of cranial radiation, but the majority of patients with cavernomas are asymptomatic.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Parasellar tumor, radiation dose ≥18 Gy, especially ≥50 Gy, supra-sellar radiation, circle of Willis in radiation field- Pre-morbid/Co-morbid medical conditions: Down syndrome, sickle cell disease, neurofibromatosis

References
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 24:5277-82, 2006
Burn S, Gunny R, Phipps K, et al: Incidence of cavernoma development in children after radiotherapy for brain tumors. J Neurosurg 106:379-83, 2007
Campen CJ, Kranick SM, Kasner SE, et al: Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke 43:3035-40, 2012
Faraci M, Morana G, Bagnasco F, et al: Magnetic resonance imaging in childhood leukemia survivors treated with cranial radiotherapy: a cross sectional, single center study. Pediatr Blood Cancer 57:240-6, 2011
Haddy N, Mousannif A, Tukenova M, et al: Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality. Brain 134:1362-72, 2011
Hall MD, Bradley JA, Rotondo RL, et al: Risk of radiation vasculopathy and stroke in pediatric patients treated with proton therapy for brain and skull base tumors. Int J Radiat Oncol Biol Phys 101(4):854-859, 2018
Morris B, Partap S, Yeom K, et al: Cerebrovascular disease in childhood cancer survivors: a Children’s Oncology Group report. Neurology 73:1906-13, 2009
Mueller S, Fullerton HJ, Stratton K, et al: Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 86:649-55, 2013
Passos J, Nzwalo H, Marques J, et al: Late cerebrovascular complications after radiotherapy for childhood primary central nervous system tumors. Pediatr Neurol 53:211-5, 2015
Ullrich NJ, Robertson R, Kinnamon DD, et al: Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 68:932-8, 2007
Wu YH, Chang FC, Liang ML, et al: Incidence and long-term outcome of postradiotherapy moyamoya syndrome in pediatric patients with primary brain tumors: a single institute experience in Taiwan. Cancer Med 5:2155-60, 2016
Yeom KW, Lober RM, Partap S, et al: Increased focal hemosiderin deposition in pediatric medulloblastoma patients receiving radiotherapy at a later age. J Neurosurg Pediatr 12:444-51, 2013

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Sec #
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w

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Craniofacial abnormalities

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORYRESOURCES
Psychosocial assessment with attention to: FACES—The National Craniofacial Association: www.faces-cranio.org• Educational and/or vocational progress
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION• Depression
Reconstructive craniofacial surgical consultation.
• Anxiety
Consultation with psychologist in patients with adjustment disorders related to• Post-traumatic stressfacial asymmetry/deformity.
• Social withdrawal
YearlySYSTEM = Musculoskeletal
SCORE = 1
PHYSICAL
Craniofacial abnormalities
YearlyAdditional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <5 years- Cancer/Treatment factors: Higher radiation dose, especially dose ≥30 Gy

References
Frascino AV, Fava M, Collassanti MDS, Odone-Filho V. Impact of Pediatric Hematopoietic Stem-Cell Transplantation on Craniofacial Growth. Clinics 75, 2020
Kaste SC, Chen G, Fontanesi J, et al: Orbital development in long-term survivors of retinoblastoma. J Clin Oncol 15:1183-9, 1997
Kinahan KE, Sharp LK, Seidel K, et al: Scarring, disfigurement, and quality of life in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30:2466-74, 2012
Mattos VD, Ferman S, Araújo Magalhães DM, et al: Dental and craniofacial alterations in long-term survivors of childhood head and neck rhabdomyosarcoma. Oral Surg Oral Med Oral Pathol Oral Radiol 127(4),272-281, 2019
Schoot RA, Slater O, Ronckers CM, et al: Adverse events of local treatment in long-term head and neck rhabdomyosarcoma survivors after external beam radiotherapy or AMORE treatment. Eur J Cancer 51:1424-34, 2015
Shildkrot Y, Kirzhner M, Haik BG, et al: The effect of cancer therapies on pediatric anophthalmic sockets. Ophthalmology 118:2480-6, 2011

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Sec #
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w

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Chronic sinusitis

Periodic Evaluation
HISTORY
Rhinorrhea, postnasal discharge
History of URIs
YearlyPHYSICAL
Nasal and sinus exam
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CT scan of sinuses as clinically indicated.
Otolaryngology consultation as clinically indicated.
SYSTEM = Immune
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Radiation dose to sinuses ≥30 Gy, radiomimetic chemotherapy (e.g., doxorubicin, dactinomycin)- Pre-morbid/Co-morbid medical conditions: Atopic history, hypogammaglobulinemia, underlying immunodeficiency

References
Chang CC, Chen MK, Wen YS, et al: Effects of radiotherapy for nasopharyngeal carcinoma on the paranasal sinuses: study based on computed tomography scanning. J Otolaryngol 29:23-7, 2000
Huang WH, Liu CM, Chao TK, et al: Middle meatus bacteriology of acute rhinosinusitis in patients after irradiation of nasopharynx. Am J Rhinol 21:286-8, 2007
Indelicato DJ, Rotondo RL, Mailhot Vega RB, et al: 45 GyRBE for group III orbital embryonal rhabdomyosarcoma. Acta Oncol 58(10):1404-1409, 2019
Lockney NA, Friedman DN, Wexler LH, et al: Late toxicities of intensity-modulated radiation therapy for head and neck rhabdomyosarcoma. Pediatr Blood Cancer 63(9):1608-14, 2016

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POTENTIAL IMPACT TO
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Sec #52

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Overweight
Obesity

Periodic Evaluation
PHYSICAL
HeightWeight
BMI
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Nutrition and Physical Activity
Cardiovascular Risk Factors
COUNSELING
Obesity-related health risks.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluate for other co-morbid conditions, including dyslipidemia, hypertension,and impaired glucose metabolism.
Refer to dietitian for nutrition education and weight management.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Definition of Overweight: Age 2-20 years BMI for age ≥85th to <95th percentile. Age ≥21 years BMI ≥25-29.9.
Definition of Obesity: Age 2-20 years BMI for age ≥95th percentile. Age ≥21 years BMI ≥30.
BMI=wt(kg)/ht(m2). BMI calculator available on-line at: www.nhlbi.nih.gov/guidelines/obesity/BMI/bmicalc.htm. Growth charts for patients <21 years of age available on-line at: www.cdc.gov/growthcharts.
Overweight/Obesity may occur in a constellation of conditions known as metabolic syndrome.
Definitions of metabolic syndrome generally include a combination of central (abdominal) obesity with at least 2 or more of the following: elevated blood pressure, atherogenic dyslipidemia (elevated triglycerides, reduced HDLcholesterol), and abnormal glucose metabolism.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <4 years, female sex- Cancer/Treatment factors: Higher cranial radiation dose (especially ≥18 Gy), surgery in supra-sellar region, corticosteroids (especially prolonged therapy, e.g., for cGVHD)- Pre-morbid/Co-morbid medical conditions: GH deficiency, hypothyroidism, hypogonadism, inability to exercise

References
Alberti KG, Eckel RH, Grundy SM, et al: Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute;
American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640-5, 2009
Brennan BM, Rahim A, Blum WF, et al: Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf) 50:163-9, 1999
Constine LS, Woolf PD, Cann D, et al: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87-94, 1993
Cooksey R, Wu SY, Klesse L, et al: Metabolic syndrome is a sequela of radiation exposure in hypothalamic obesity among survivors of childhood brain tumors. J Investig Med 67(2):295-302, 2019
Dalton VK, Rue M, Silverman LB, et al: Height and weight in children treated for acute lymphoblastic leukemia: relationship to CNS treatment. J Clin Oncol 21:2953-60, 2003
Faienza MF, Delvecchio M, Giordano P, et al: Metabolic syndrome in childhood leukemia survivors: a meta-analysis. Endocrine 49:353-60, 2015
Garmey EG, Liu Q, Sklar CA, et al: Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 26:4639-45,
2008
Howell CR, Wilson CL, Yasui Y,et al: Neighborhood effect and obesity in adult survivors of pediatric cancer: a report from the St. Jude Lifetime Cohort Study. Int J Cancer 147(2):338-49, 2020
Lustig RH, Rose SR, Burghen GA, et al: Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr 135:162-8, 1999
Meacham LR, Chow EJ, Ness KK, et al: Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 19:170-81, 2010
Nathan PC, Jovcevska V, Ness KK, et al: The prevalence of overweight and obesity in pediatric survivors of cancer. J Pediatr 149:518-25, 2006
Nottage KA, Ness KK, Li C, et al: Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia - From the St. Jude Lifetime Cohort. Br J Haematol 165:364-74, 2014
Oeffinger KC, Adams-Huet B, Victor RG, et al: Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 27:3698-704, 2009
Oudin C, Simeoni MC, Sirvent N, et al: Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. Blood 117:4442-8, 2011
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Section 52 References (cont)

Razzouk BI, Rose SR, Hongeng S, et al: Obesity in survivors of childhood acute lymphoblastic leukemia and lymphoma. J Clin Oncol 25:1183-9, 2007
Reilly JJ, Ventham JC, Newell J, et al: Risk factors for excess weight gain in children treated for acute lymphoblastic leukaemia. Int J Obes Relat Metab Disord 24:1537-41, 2000
Steffens M, Beauloye V, Brichard B, et al: Endocrine and metabolic disorders in young adult survivors of childhood acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL). Clin Endocrinol (Oxf) 69:819-27, 2008
Steinberger J, Daniels SR, Eckel RH, et al: Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the
Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation 119:628-47, 2009
Talvensaari KK, Lanning M, Tapanainen P, et al: Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab 81:3051-5, 1996
Warner JT, Evans WD, Webb DK, et al: Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol 38:165-72, 2002
Weiss R, Dziura J, Burgert TS, et al: Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362-74, 2004
Wilson CL, Liu W, Yang JJ, et al: Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. Cancer 121:2262-70, 2015
Withycombe JS, Post-White JE, Meza JL, et al: Weight patterns in children with higher risk ALL: A report from the Children’s Oncology Group (COG) for CCG 1961. Pediatr Blood Cancer 53:1249-54, 2009

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POTENTIAL IMPACT TO
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Sec #53

Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Growth hormone deficiency

Periodic Evaluation
HISTORY
Assessment of nutritional status
Every 6 months until growth is completed,then yearly
PHYSICAL
Tanner staging
Every 6 months until sexually mature
HeightWeightBMI
Every 6 months until growth is completed,then yearly

Health Counseling/
Further Considerations
HEALTH LINKS
Growth Hormone Deficiency
Hypopituitarism
RESOURCES
Magic Foundation for Children’s Growth: www.magicfoundation.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Growth velocity can be assessed using dedicated charts or electronic medical
record tools if available.
Consider bone density testing in patients who are GH deficient.
Evaluate thyroid function in any poorly growing child.
Endocrine consultation for:• Dose ≥30 Gy• Poor growth for age or stage of puberty as evidenced by persistent decline
in growth velocity and change in percentile rankings on growth chart, weight<3rd percentile on growth chart• Discuss risks/benefits of adult GH replacement
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Growth charts available on-line at www.cdc.gov/growthcharts/ and www.who.int/tools/child-growth-standards/standards
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: Surgery in supra-sellar region, higher radiation dose (especially ≥18 Gy), pretransplant radiation (especially CRT), ≥12 Gy fractionated, TBI given in single fraction (especially ≥ 10Gy)

References
Brownstein CM, Mertens AC, Mitby PA, et al: Factors that affect final height and change in height standard deviation scores in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin
Endocrinol Metab 89:4422-7, 2004
Cattoni A, Clarke E, Albanese A. The predictive value of insulin-like growth factor 1 in irradiation-dependent growth hormone deficiency in childhood cancer survivors. Horm Res Paediatr 90(5):314-325, 2018
Clement SC, Schouten-van Meeteren AY, Boot AM, et al: Prevalence and risk factors of early endocrine disorders in childhood brain tumor survivors: a nationwide, multicenter study. J Clin Oncol 34(36):4362-70, 2016
Frisk P, Arvidson J, Gustafsson J, et al: Pubertal development and final height after autologous bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant 33:205-10, 2004
Indelicato DJ, Ioakeim-Ioannidou M, Bradley JA, et al: Proton therapy for pediatric ependymoma: mature results from a bicentric study. Int J Radiat Oncol Biol Phys 1;110(3):815-820, 2021
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 29:4776-80, 2011
Mostoufi-Moab S, Seidel K, Leisenring WM, et al: Endocrine abnormalities in aging survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 20;34(27):3240-7, 2016
Raman S, Grimberg A, Waguespack SG, et al: Risk of neoplasia in pediatric patients receiving growth hormone therapy--a report from the pediatric endocrine society drug and therapeutics committee. J Clin Endocrinol Metab 100:2192-203, 2015
Shalitin S, Gal M, Goshen Y, et al: Endocrine outcome in long-term survivors of childhood brain tumors. Horm Res Paediatr 76:113-22, 2011
Sklar CA, Antal Z, Chemaitilly W, et al: Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 1;103(8):2761-2784, 2018
van Iersel L, Li Z, Srivastava DK, et al: Hypothalamic-pituitary disorders in childhood cancer survivors: prevalence, risk factors and long-term health outcomes. J Clin Endocrinol Metab 1;104(12):6101-6115, 2019van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12):e28723, 2020

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POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATIONSec #54

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Precocious puberty(male)

Periodic Evaluation
PHYSICAL
HeightWeightTanner staging
Testicular volume by Prader orchidometer
Yearly until sexually mature

Health Counseling/
Further Considerations
HEALTH LINKS
Precocious Puberty
RESOURCES
Magic Foundation for Children’s Growth: www.magicfoundation.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH, LH, testosterone, as clinically indicated in patients with signs of accelerated
pubertal progression and growth.
X-ray for bone age in rapidly growing children.
Growth velocity can be assessed using dedicated charts or electronic medical
record tools if available.
Endocrine consultation for suspected precocious puberty (males <9 years).
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Testicular volume is not a reliable indicator of pubertal onset/stage in boys treated with alkylating agents and/or direct testicular radiotherapy.
Affected children may present with accelerated linear growth but this could mask co-existing GH deficiency.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: Tumor near hypothalamus and/or optic pathways, radiation doses ≥18 Gy- Pre-morbid/Co-morbid medical conditions: History of hydrocephalus

References
Chemaitilly W, Merchant TE, Li Z, et al: Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes. Clin Endocrinol (Oxf) 84:36171, 2016
Clement SC, Schouten-van Meeteren AY, Boot AM, et al: Prevalence and risk factors of early endocrine disorders in childhood brain tumor survivors: a nationwide, multicenter study. J Clin Oncol 34(36):4362-70, 2016
Darzy KH: Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab 5:88-99, 2009
Gan HW, Phipps K, Aquilina K, et al: Neuroendocrine morbidity after pediatric optic gliomas: a longitudinal analysis of 166 children over 30 years. J Clin Endocrinol Metab 100:3787-99, 2015
Oberfield SE, Soranno D, Nirenberg A, et al: Age at onset of puberty following high dose central nervous system radiation therapy. Arch Pediatr Adolesc Med 150:589-92, 1996
Ogilvy-Stuart AL, Clayton PE, Shalet SM: Cranial irradiation and early puberty. J Clin Endocrinol Metab 78:1282-6, 1994
Quigley C, Cowell C, Jimenez M, et al: Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. N Engl J Med 321:143-51, 1989
Sklar CA, Antal Z, Chemaitilly W, et al: Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 1;103(8):2761-2784, 2018
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995
van Iersel L, Li Z, Srivastava DK, et al: Hypothalamic-pituitary disorders in childhood cancer survivors: prevalence, risk factors and long-term health outcomes. J Clin Endocrinol Metab 1;104(12):6101-6115, 2019van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12):e28723, 2020

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POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #55

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Precocious puberty(female)Periodic Evaluation
PHYSICAL
HeightWeightTanner staging
Yearly until sexually mature

Health Counseling/
Further Considerations
HEALTH LINKS
Precocious Puberty
RESOURCES
Magic Foundation for Children’s Growth: www.magicfoundation.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH, LH, estradiol, as clinically indicated in patients with signs of accelerated
pubertal progression and growth.
X-ray for bone age in rapidly growing children.
Growth velocity can be assessed using dedicated charts or electronic medical
record tools if available.
Endocrine consultation for suspected precocious puberty (females <8 years).
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Affected children may present with accelerated linear growth but this could mask co-existing GH deficiency.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: Tumor near hypothalamus and/or optic pathways, radiation doses ≥18 Gy- Pre-morbid/Co-morbid medical conditions: History of hydrocephalus

References
Armstrong GT, Whitton JA, Gajjar A, et al: Abnormal timing of menarche in survivors of central nervous system tumors: a report from the Childhood Cancer Survivor Study. Cancer 115:2562-70, 2009
Chemaitilly W, Merchant TE, Li Z, et al: Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes. Clin Endocrinol (Oxf) 84:36171, 2016
Clement SC, Schouten-van Meeteren AY, Boot AM, et al: Prevalence and risk factors of early endocrine disorders in childhood brain tumor survivors: a nationwide, multicenter study. J Clin Oncol 34(36):4362-70, 2016
Darzy KH: Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab 5:88-99, 2009
Gan HW, Phipps K, Aquilina K, et al: Neuroendocrine morbidity after pediatric optic gliomas: a longitudinal analysis of 166 children over 30 years. J Clin Endocrinol Metab 100:3787-99, 2015
Oberfield SE, Soranno D, Nirenberg A, et al: Age at onset of puberty following high dose central nervous system radiation therapy. Arch Pediatr Adolesc Med 150:589-92, 1996
Ogilvy-Stuart AL, Clayton PE, Shalet SM: Cranial irradiation and early puberty. J Clin Endocrinol Metab 78:1282-6, 1994
Quigley C, Cowell C, Jimenez M, et al: Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. N Engl J Med 321:143-51, 1989
Sklar CA, Antal Z, Chemaitilly W, et al: Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 1;103(8):2761-2784, 2018
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995
van Iersel L, Li Z, Srivastava DK, et al: Hypothalamic-pituitary disorders in childhood cancer survivors: prevalence, risk factors and long-term health outcomes. J Clin Endocrinol Metab 1;104(12):6101-6115, 2019van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12):e28723, 2020

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POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #56

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Hyperprolactinemia

Periodic Evaluation
HISTORY
Decreased libido
Galactorrhea
Menstrual history
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Hyperprolactinemia
RESOURCES
Magic Foundation for Children’s Growth: www.magicfoundation.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Prolactin level in patients with galactorrhea or decreased libido, or in femaleswith amenorrhea.
CT evaluation of sella turcica for pituitary adenoma in patients withhyperprolactinemia.
Endocrine consultation for patients with hyperprolactinemia or galactorrhea.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose (≥40 Gy, especially ≥50 Gy), surgery or tumor in hypothalamic area

References
Constine LS, Woolf PD, Cann D, et al: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87-94, 1993
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995

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Sec #
57

w

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Central hypothyroidism

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening
during periods of rapid growth
PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening
during periods of rapid growth
SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growth

HEALTH LINKS
Thyroid Problems
Hypopituitarism
COUNSELINGFor females, thyroid levels prior to attempting pregnancy and periodicallythroughout pregnancy.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
If dose ≥30 Gy refer to endocrinologist for ongoing management, given risk ofmultiple hormone deficiencies. If endocrinology care is not readily available,
screen as indicated, and refer to endocrinologist for thyroid hormone
replacement.
SYSTEM = Endocrine/Metabolic
SCORE = 1

Additional Information

Central hypothyroidism includes thyroid-releasing and TSH deficiency.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy, may occur at lower doses with longer follow-up, surgery or tumor in supra-sellar area.

References
Aldrich KD, Horne VE, Bielamowicz K, et al: Comparison of hypothyroidism, growth hormone deficiency, and adrenal insufficiency following proton and photon radiotherapy in children with medulloblastoma. J Neurooncol 155(1):93100, 2021
Huang S, Wang X, Hu C, et al: Hypothalamic-pituitary-thyroid dysfunction induced by intensity-modulated radiotherapy (IMRT) for adult patients with nasopharyngeal carcinoma. Med Oncol 30:710, 2013
Inskip PD, Veiga LHS, Brenner AV, et al: Hypothyroidism after radiation therapy for childhood cancer: a report from the Childhood Cancer Survivor Study. Radiat Res 190(2):117-132, 2018
Lando A, Holm K, Nysom K, et al: Thyroid function in survivors of childhood acute lymphoblastic leukaemia: the significance of prophylactic cranial irradiation. Clin Endocrinol (Oxf) 55:21-5, 2001
Sklar CA, Antal Z, Chemaitilly W, et al: Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 1;103(8):2761-2784, 2018
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995
van Iersel L, Li Z, Srivastava DK, et al: Hypothalamic-pituitary disorders in childhood cancer survivors: prevalence, risk factors and long-term health outcomes. J Clin Endocrinol Metab 1;104(12):6101-6115, 2019van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12):e28723, 2020
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POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #58(male)

Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Gonadotropin deficiency
LH and FSH deficiency

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyMonitor growth until mature
YearlyHEALTH LINKS
Testicular and Reproductive HealthHypopituitarism
RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Need for contraception.
Spermatogenesis can be induced with gonadotropins in men withhypogonadotropic hypogonadism.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH, LH, testosterone as clinically indicated in patients with delayed/arrested
puberty and/or clinical signs and symptoms of testosterone deficiency.
If dose ≥30 Gy refer to endocrinologist for ongoing management, given risk ofmultiple hormone deficiencies. If endocrinology care is not readily available,
screen as indicated, and refer to endocrinologist for thyroid hormone
replacement.
Hormonal replacement therapy for hypogonadal patients.
Refer to reproductive endocrinology as clinically indicated for infertility
evaluation and consultation regarding assisted reproductive technologies.
BMD testing in patients who are gonadotropin deficient.
SYSTEM = Reproductive (Male)SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy, may occur at lower doses with longer follow-up, surgery or tumor in supra-sellar area

References
Darzy KH: Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab 5:88-99, 2009
Gleeson HK, Shalet SM: The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer 11:589-602, 2004
Kenney LB, Cohen LE, Shnorhavorian M, et al: Male reproductive health after childhood, adolescent, and young adult cancers: a report from the Children’s Oncology Group. J Clin Oncol 30:3408-16, 2012
Schmiegelow M, Lassen S, Poulsen HS, et al: Gonadal status in male survivors following childhood brain tumors. J Clin Endocrinol Metab 86:2446-52, 2001
Sklar CA, Antal Z, Chemaitilly W, et al: Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 1;103(8):2761-2784, 2018
van Iersel L, Li Z, Srivastava DK, et al: Hypothalamic-pituitary disorders in childhood cancer survivors: prevalence, risk factors and long-term health outcomes. J Clin Endocrinol Metab 1;104(12):6101-6115, 2019van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12):e28723, 2020

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POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #59(female)Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Gonadotropin deficiency
LH and FSH deficiency

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Menstrual history
Sexual function (vaginal dryness, libido)
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyMonitor growth until mature
YearlyHEALTH LINKS
Ovarian and Reproductive HealthHypopituitarism
RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Need for contraception.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH, LH, estradiol as clinically indicated in patients with delayed or arrested
puberty, irregular menses, primary or secondary amenorrhea, or clinical signs
and symptoms of estrogen deficiency.
If dose ≥30 Gy refer to endocrinologist for ongoing management, given risk ofmultiple hormone deficiencies. If endocrinology care is not readily available,
screen as indicated, and refer to endocrinologist for thyroid hormone
replacement.
Hormonal replacement therapy for hypogonadal patients.
Refer to reproductive endocrinology as clinically indicated for infertility
evaluation and consultation regarding assisted reproductive technologies.
BMD testing in patients who are gonadotropin deficient.
SYSTEM = Reproductive (Female)
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy, may occur at lower doses with longer follow-up, surgery or tumor in supra-sellar area

References
Chemaitilly W, Li Z, Huang S, et al: Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort Study. J Clin Oncol 33:492-500, 2015
Chow EJ, Friedman DL, Yasui Y, et al: Timing of menarche among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 50:854-8, 2008
Darzy KH: Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab 5:88-99, 2009
Gleeson HK, Shalet SM: The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer 11:589-602, 2004
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 27:2677-2685, 2009
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol 31:1239-47, 2013
Mills JL, Fears TR, Robison LL, et al: Menarche in a cohort of 188 long-term survivors of acute lymphoblastic leukemia. J Pediatr 131:598-602, 1997
Sklar CA, Antal Z, Chemaitilly W, et al: Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 1;103(8):2761-2784, 2018
van Iersel L, Li Z, Srivastava DK, et al: Hypothalamic-pituitary disorders in childhood cancer survivors: prevalence, risk factors and long-term health outcomes. J Clin Endocrinol Metab 1;104(12):6101-6115, 2019van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12):e28723, 2020
Wo JY, Viswanathan AN: Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys 73:1304-12, 2009
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POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #60

Therapeutic
Exposure

Potential
Late Effects

Head/Brain
TBI(TBI is included for
cumulative dose
calculation purposes
only; this section is notapplicable to patients
who received TBI alone.)

Central adrenal insufficiency

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORY
If dose ≥30 Gy:
Failure to thrive
Anorexia
Dehydration
Hypoglycemia
Lethargy
Unexplained hypotension
YearlySCREENING
If dose ≥30 Gy:
8 AM cortisol
Yearly, refer to endocrinology for further
testing if level <13 mcg/dL or <365 nmol/L

HEALTH LINKS
Central Adrenal Insufficiency
Hypopituitarism
RESOURCES
Magic Foundation for Children’s Growth: www.magicfoundation.org
COUNSELING
Need for corticosteroid replacement therapy and stress dosing.
Obtain medical alert bracelet or card.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
If dose ≥30 Gy refer to endocrinologist for ongoing management, given risk ofmultiple hormone deficiencies. If endocrinology care is not readily available,
screen as indicated, and refer to endocrinologist for thyroid hormone
replacement.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Cortisol secretion follows a circadian rhythm. Levels should be drawn as close as possible to 8AM and before 9 AM.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy, may occur at lower doses with longer follow-up, surgery or tumor in supra-sellar area
- Pre-morbid/Co-morbid medical conditions: History of another hypothalamic-pituitary endocrinopathy

References
Aldrich KD, Horne VE, Bielamowicz K, et al: Comparison of hypothyroidism, growth hormone deficiency, and adrenal insufficiency following proton and photon radiotherapy in children with medulloblastoma. J Neurooncol 155(1):93100, 2021
Clement SC, Schouten-van Meeteren AY, Boot AM, et al: Prevalence and risk factors of early endocrine disorders in childhood brain tumor survivors: a nationwide, multicenter study. J Clin Oncol 34(36):4362-70, 2016
Darzy KH: Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab 5:88-99, 2009
Follin C, Wiebe T, Moell C, et al: Moderate dose cranial radiotherapy causes central adrenal insufficiency in long-term survivors of childhood leukaemia. Pituitary 17:7-12, 2014
Gleeson HK, Shalet SM: The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer 11:589-602, 2004
Kazlauskaite R, Evans AT, Villabona CV, et al: Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 93:4245-53, 2008
Patterson BC, Truxillo L, Wasilewski-Masker K, et al: Adrenal function testing in pediatric cancer survivors. Pediatr Blood Cancer 53:1302-7, 2009
Sklar CA, Antal Z, Chemaitilly W, et al: Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 1;103(8):2761-2784, 2018
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995
van Iersel L, van Santen HM, Potter B, et al: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67(12):e28723, 2020

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POTENTIAL IMPACT TO
EYE

RADIATION
Sec #
61

w

Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Cataracts

Periodic Evaluation
HISTORY
Visual changes (decreased acuity, halos,
diplopia)
YearlyPHYSICAL
Visual acuity
Funduscopic exam
YearlySCREENING
Evaluation by ophthalmologist or
optometrist
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Cataracts
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Refer patients with visual deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate acquisition of
educational resources.
SYSTEM = Ocular
SCORE = 1

Additional Information

Radiation-related ocular complications other than cataracts are generally associated only with orbital/eye radiation or higher dose CRT.
Patients with a history of an ocular tumor (e.g., retinoblastoma) are at higher risk for late-onset ocular complications and should receive ongoing follow-up by an ophthalmologist at least annually, and more frequently if clinicallyindicated.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Radiation dose ≥10 Gy, especially ≥15 Gy, radiation fraction dose ≥2 Gy, TBI dose ≥2 Gy in single fraction, TBI dose ≥5 Gy fractionated, especially ≥10 Gy, cranial/orbital/eye radiation combined with
TBI, radiation combined with corticosteroids or busulfan, longer interval since treatment

References
Allodji RS, Diallo I, El-Fayech C, et al: Association of radiation dose to the eyes with the risk for cataract after nonretinoblastoma solid cancers in childhood. JAMA Ophthalmol 134(4):390-7, 2016
Chodick G, Sigurdson AJ, Kleinerman RA, et al: The risk of cataract among survivors of childhood and adolescent cancer: a report from the Childhood Cancer Survivor Study. Radiat Res 185:366-74, 2016
Fahnehjelm KT, Tornquist AL, Olsson M, et al: Visual outcome and cataract development after allogeneic stem-cell transplantation in children. Acta Ophthalmol Scand 85:724-33, 2007
Ferry C, Gemayel G, Rocha V, et al: Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies. Bone Marrow Transplant 40:219-24, 2007
Gurney JG, Ness KK, Rosenthal J, et al: Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood: results from the Bone Marrow Transplant Survivor
study. Cancer 106:1402-8, 2006
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 168:518-25, 2015
Socie G, Salooja N, Cohen A, et al: Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101:3373-85, 2003
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 52:136774, 2002
van Kempen-Harteveld ML, Struikmans H, Kal HB, et al: Cataract after total body irradiation and bone marrow transplantation: degree of visual impairment. Int J Radiat Oncol Biol Phys 52:1375-80, 2002
Zierhut D, Lohr F, Schraube P, et al: Cataract incidence after total-body irradiation. Int J Radiat Oncol Biol Phys 46:131-5, 2000

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POTENTIAL IMPACT TO
EYE (CONT)RADIATION
Sec #
62

w

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Ocular toxicity
Orbital hypoplasia
Lacrimal duct atrophy
Xerophthalmia(keratoconjunctivitis sicca)
Keratitis
Telangiectasias
Retinopathy
Optic chiasm neuropathy
Enophthalmos
Chronic painful eye
Maculopathy
Papillopathy
Glaucoma

Periodic Evaluation
HISTORY
Visual changes (decreased acuity, halos,
diplopia)
Dry eye
Persistent eye irritation
Excessive tearing
Light sensitivity
Poor night vision
Painful eye
YearlyPHYSICAL
Visual acuity
Funduscopic exam
YearlySCREENING
Evaluation by ophthalmologist or
optometrist
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Eye HealthRESOURCESFACES—The National Craniofacial Association: www.faces-cranio.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Refer patients with visual deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate acquisition of
educational resources.
SYSTEM = Ocular
SCORE = 1

Additional Information

Radiation-related ocular complications other than cataracts are generally associated only with orbital/eye radiation or higher dose CRT.
Patients with a history of an ocular tumor (e.g., retinoblastoma) are at higher risk for late-onset ocular complications and should receive ongoing opthalmology follow-up at least annually, and more frequently if clinically indicated.
Reduced visual acuity may be associated with cataracts, retinal damage, and optic nerve damage.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy, higher daily fraction dose, especially fraction dose ≥2 Gy, radiomimetic chemotherapy (e.g., doxorubicin, dactinomycin), problems related to tearing- Pre-morbid/Co-morbid medical conditions: cGVHD (xerophthalmia only)

References
Albrecht F, Wolters H, Ziert Y, et al: Evaluation of treatment-associated eye toxicity after irradiation in childhood and adolescence-results from the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK). Strahlenther Onkol 197(8):700-710, 2021
Jeganathan VS, Wirth A, MacManus MP: Ocular risks from orbital and periorbital radiation therapy: a critical review. Int J Radiat Oncol Biol Phys 79:650-9, 2011
Mayo C, Martel MK, Marks LB, et al: Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 76:S28-35, 2010
Oberlin O, Rey A, Anderson J, et al: Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment--results of an international workshop. J Clin Oncol 19:197-204, 2001
Shields CL, Shields JA, Cater J, et al: Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108:2116-21, 2001
Tinkle CL, Pappo A, Wu J, et al: Efficacy and safety of limited-margin conformal radiation therapy for pediatric rhabdomyosarcoma: long-term results of a phase 2 study. Int J Radiat Oncol Biol Phys 107(1):172-180, 2020
Whelan KF, Stratton K, Kawashima T, et al: Ocular late effects in childhood and adolescent cancer survivors: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 54:103-9, 2010

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POTENTIAL IMPACT TO
EARRADIATION
Sec #63

Therapeutic
Exposure

Potential
Late Effects

Head/Brain
TBI(TBI is included for
cumulative dose
calculation purposes
only; this section is notapplicable to patients
who received TBI alone.)

Ototoxicity
Tympanosclerosis
Otosclerosis
Eustachian tube dysfunction
Conductive hearing loss
Sensorineural hearing loss
Tinnitus
Vertigo

Periodic Evaluation
HISTORY
If dose ≥30 Gy:
Hearing difficulties (with/withoutbackground noise)
Tinnitus
VertigoYearlyPHYSICAL
If dose ≥30 Gy:
Otoscopic exam
YearlySCREENING
If dose ≥30 Gy:
Complete audiological evaluation byaudiologist
Yearly, for patients ages ≤5 years
Pure tone audiometry testing at 1000-8000
Hz
Every 2 years, for patients ages 6-12, thenevery 5 years beginning at age 13 years

w

Health Counseling/
Further Considerations
HEALTH LINKS
Hearing Loss
School After Treatment
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Additional testing with high frequency audiometry at >8000 Hz is recommended
if equipment is available.
Audiology consultation for any survivor who has symptoms suggestive of
hearing loss, tinnitus, or abnormal pure tone audiometry results showing a lossof more than 15 dB absolute threshold level (1000-8000 Hz).
Ongoing follow-up with audiology for patients with hearing loss.
Otolaryngology consultation in patients with chronic infection, cerumen
impaction, or other anatomical problems exacerbating or contributing tohearing loss.
Speech and language therapy for patients with hearing loss.
Refer patients with auditory deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate acquisition of
educational resources.
Specialized evaluation for specific needs and/or preferential classroom seating,
FM amplification system, and other educational assistance as indicated.
SYSTEM = Auditory
SCORE = 1

Additional Information

A “complete audiological evaluation” includes pure tone air and bone conduction, speech audiometry, and tympanometry for both ears.
Frequency-specific auditory brainstem response can be performed if the above is inconclusive.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: All hearing loss types: higher radiation dose; sensorineural hearing loss/tinnitus: CNS neoplasm, conventional (non-conformal) radiation, combination with other ototoxic agents (cisplatin, carboplatin, aminoglycosides, loop diuretics), radiation administered prior to platinum chemotherapy- Pre-morbid/Co-morbid medical conditions: All hearing loss types: chronic otitis, chronic cerumen impaction; sensorineural hearing loss/tinnitus: cerebrospinal fluid shunt

References
Bass JK, Hua CH, Huang J, et al: Hearing loss in patients who received cranial radiation therapy for childhood cancer. J Clin Oncol 34:1248-55, 2016
Bass JK, Knight KR, Yock TI, et al: Evaluation and management of hearing loss in survivors of childhood and adolescent cancers: a report from the Children’s Oncology Group. Pediatr Blood Cancer 63:1152-62, 2016
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 72:892-9, 2008
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 52:599-605, 2002
Khan A, Budnick A, Barnea D, et al: Hearing loss in adult survivors of childhood cancer treated with radiotherapy. Children 5(5):59, 2018
Low WK, Toh ST, Wee J, et al: Sensorineural hearing loss after radiotherapy and chemoradiotherapy: a single, blinded, randomized study. J Clin Oncol 24:1904-9, 2006
Meijer AJM, Clemens E, Hoetink AE, et al: Tinnitus during and after childhood cancer: a systematic review. Crit Rev Oncol Hematol 135:1-7, 2019
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 58:1194-207, 2004
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POTENTIAL IMPACT TO
ORAL CAVITY

RADIATION
Sec #
64

w

Therapeutic
Exposure

Potential
Late Effects

Head/Brain
Neck
Spine (cervical, whole)
TBI

Xerostomia
Salivary gland dysfunction

Periodic Evaluation
HISTORY
Xerostomia (dry mouth)YearlyPHYSICAL
Oral exam
YearlySCREENING
Dental exam and cleaning
Every 6 months

Health Counseling/
Further Considerations
HEALTH LINKS
Dental Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Supportive care with saliva substitutes, moistening agents, and sialagogues(e.g., pilocarpine).
Regular dental care including fluoride applications.
SYSTEM = Dental
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Head and neck radiation involving the parotid gland, higher proportion of one gland or both salivary glands in the radiation field, higher radiation doses, radiomimetic chemotherapy (e.g.,doxorubicin, dactinomycin)- Pre-morbid/Co-morbid medical conditions: cGVHD

References
Bolling T, Weege J, Eich HT, et al: Acute and late side effects to salivary glands and oral mucosa after head and neck radiotherapy in children and adolescents. Results of the “Registry for the evaluation of side effects after radiotherapy in childhood and adolescence.” Head Neck 37:1137-41, 2015
Dahllof G, Bagesund M, Remberger M, et al: Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol 33:327-31, 1997
Dahllof G, Bagesund M, Ringden O: Impact of conditioning regimens on salivary function, caries-associated microorganisms and dental caries in children after bone marrow transplantation. A 4-year longitudinal study. Bone Marrow
Transplant 20:479-83, 1997
Effinger KE, Migliorati CA, Hudson MM, et al: Oral and dental late effects in survivors of childhood cancer: a Children’s Oncology Group report. Support Care Cancer 22:2009-19, 2014
Jensen SB, Pedersen AM, Vissink A, et al: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 18:1061-79, 2010
Jensen SB, Pedersen AM, Vissink A, et al: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18:1039-60, 2010
Kaste SC, Goodman P, Leisenring W, et al: Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study. Cancer 115:5817-27, 2009
Milgrom SA, van Luijk P, Pino R, et al: Salivary and dental complications in childhood cancer survivors treated with radiation therapy to the head and neck: a Pediatric Normal Tissue Effects in the Clinic (PENTEC) comprehensive
review. Int J Radiat Oncol Biol Phys S0360-3016(21)00443, 2021
Qiu WZ, Peng XS, Xia HQ, et al: A retrospective study comparing the outcomes and toxicities of intensity-modulated radiotherapy versus two-dimensional conventional radiotherapy for the treatment of children and adolescentnasopharyngeal carcinoma, J Cancer Res Clin Oncol 143(8):1563-1572, 2017

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POTENTIAL IMPACT TO
ORAL CAVITY (CONT)RADIATION
Sec #
65

w

Therapeutic
Exposure
Head/Brain
Neck
Spine (cervical, whole)
TBI

Potential
Late Effects
Dental abnormalities
Tooth/root agenesis
Root thinning/shortening
Enamel dysplasia
Microdontia
Ectopic molar eruption
Dental caries
Periodontal disease
Malocclusion
Temporomandibular joint
dysfunction

Periodic Evaluation
PHYSICAL
Oral exam
YearlySCREENING
Dental exam and cleaning
Every 6 months

Health Counseling/
Further Considerations
HEALTH LINKS
Dental Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Regular dental care including fluoride applications.
Baseline panorex prior to dental procedures to evaluate root development.
Consultation with orthodontist experienced in management of irradiatedchildhood cancer survivors.
SYSTEM = Dental
SCORE
Ectopic Molar Eruption = 2A
All Else = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <5 years, Gorlin syndrome (nevoid basal cell carcinoma syndrome)- Cancer/Treatment factors: Higher radiation dose (especially ≥10 Gy)

References
Dahllof G, Jonsson A, Ulmner M, et al: Orthodontic treatment in long-term survivors after pediatric bone marrow transplantation. Am J Orthod Dentofacial Orthop 120:459-65, 2001
Effinger KE, Migliorati CA, Hudson MM, et al: Oral and dental late effects in survivors of childhood cancer: a Children’s Oncology Group report. Support Care Cancer 22:2009-19, 2014
Goho C: Chemoradiation therapy: effect on dental development. Pediatr Dent 15:6-12, 1993
Kaste SC, Goodman P, Leisenring W, et al: Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study. Cancer 115:5817-27, 2009
Ko Y, Park K, Kim JY: Effect of anticancer therapy on ectopic eruption of permanent first molars. Pediatr Dent 35:530-3, 2013
Krasin MJ, Wiese KM, Spunt SL, et al: Jaw dysfunction related to pterygoid and masseter muscle dosimetry after radiation therapy in children and young adults with head-and-neck sarcomas. Int J Radiat Oncol Biol Phys 82:355-60,
2012
Milgrom SA, van Luijk P, Pino R, et al: Salivary and dental complications in childhood cancer survivors treated with radiation therapy to the head and neck: a Pediatric Normal Tissue Effects in the Clinic (PENTEC) comprehensive
review. Int J Radiat Oncol Biol Phys S0360-3016(21)00443, 2021
Qiu WZ, Peng XS, Xia HQ, et al: A retrospective study comparing the outcomes and toxicities of intensity-modulated radiotherapy versus two-dimensional conventional radiotherapy for the treatment of children and adolescentnasopharyngeal carcinoma, J Cancer Res Clin Oncol 143(8):1563-1572, 2017
Sonis AL, Tarbell N, Valachovic RW, et al: Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities. Cancer 66:2645-52, 1990

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POTENTIAL IMPACT TO
ORAL CAVITY (CONT)RADIATION
Sec #
66

w

Therapeutic
Exposure
Head/Brain
Neck
Spine (cervical, whole)
TBI(TBI is included for
cumulative dose
calculation purposes
only; this section is notapplicable to patients
who received TBI alone.)

Potential
Late Effects
Osteoradionecrosis of thejaw

Periodic Evaluation
HISTORY
If dose ≥40 Gy:
Impaired or delayed healing following
dental work
Persistent jaw pain or swelling
TrismusYearlyPHYSICAL
If dose ≥40 Gy:
Impaired wound healing
Jaw swelling
TrismusAs clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Osteoradionecrosis
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Imaging studies (x-ray, CT scan and/or MRI) may assist in making diagnosis.
Biopsy may be needed to confirm diagnosis.
Hyperbaric oxygen treatments pre- or post-mandibular surgery to facilitate
healing.
SYSTEM = Dental
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Radiation dose ≥40 Gy (especially ≥50 Gy)

References
Ashamalla HL, Ames JW, Uri A, et al: Hyperbaric oxygen in the management of osteoradionecrosis. Med Pediatr Oncol 27:48-53, 1996
Effinger KE, Migliorati CA, Hudson MM, et al: Oral and dental late effects in survivors of childhood cancer: a Children’s Oncology Group report. Support Care Cancer 22:2009-19, 2014
Mercado CE, Little SB, Mazewski C, et al: Mandibular condyle erosion and sclerosis in pediatric patients treated with radiotherapy to the head and neck region. Pediatr Blood Cancer 61:1479-80, 2014

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POTENTIAL IMPACT TO
NECK/THYROIDRADIATION
Sec #67

Therapeutic
Exposure
Head/Brain
Neck
Spine (cervical, whole)
TBI

Potential
Late Effects
Thyroid nodules

Periodic Evaluation
PHYSICAL
Thyroid exam
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ultrasound for evaluation of palpable nodule(s).
FNA as clinically indicated.
Endocrine and/or surgical consultation for further management.
SYSTEM = SMNSCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, female sex- Cancer/Treatment factors: Thyroid gland directly in radiation field, TBI

References
Bhatti P, Veiga LH, 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 174:741-52, 2010
Clement SC, Kremer LCM, Verburg FA, et al: Balancing the benefits and harms of thyroid cancer surveillance in survivors of childhood, adolescent and young adult cancer: Recommendations from the International Late Effects ofChildhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 63:28-39, 2018
Clement SC, Lebbink CA, Klein Hesselink MS, et al: Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study. Eur J Endocrinol183(2):169-180, 2020
Lubin JH, Adams MJ, Shore R, et al: Thyroid cancer Following Childhood Low-Dose Radiation Exposure: A Pooled Analysis of Nine Cohorts. J Clin Endocrinol Metab 1;102(7):2575-2583, 2017
Metzger ML, Howard SC, Hudson MM, et al: Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma. Pediatr Blood Cancer 46:314-9, 2006
Sklar C, Whitton J, Mertens A, et al: Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85:3227-32, 2000
Vivanco M, Dalle JH, Alberti C, et al: Malignant and benign thyroid nodules after total body irradiation preceding hematopoietic cell transplantation during childhood. Eur J Endocrinol 167:225-33, 2012

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POTENTIAL IMPACT TO
NECK/THYROID (CONT)RADIATION
Sec #68

Therapeutic
Exposure
Head/Brain
Neck
Spine (cervical, whole)
TBI

Potential
Late Effects
Thyroid cancer

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Thyroid exam
YearlyHEALTH LINKS
Thyroid Problems
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ultrasound for evaluation of palpable nodule(s).
FNA as clinically indicated.
Endocrine and/or surgical consultation for further management.
SYSTEM = SMNSCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: >5 years after irradiation, highest risk is between 10-30 Gy, thyroid gland directly in radiation field, TBI, alkylating agents

References
Bhatti P, Veiga LH, 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 174:741-52, 2010
Cohen A, Rovelli A, Merlo DF, et al: Risk for secondary thyroid carcinoma after hematopoietic stem-cell transplantation: an EBMT Late Effects Working Party Study. J Clin Oncol 25:2449-54, 2007
Clement SC, Kremer LCM, Verburg FA, et al: Balancing the benefi ts and harms of thyroid cancer surveillance in survivors of childhood, adolescent and young adult cancer: Recommendations from the International Late Effects ofChildhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 63:28-39, 2018
Clement SC, Lebbink CA, Klein Hesselink MS, et al: Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study. Eur J Endocrinol183(2):169-180, 2020
de Vathaire F, Haddy N, Allodji RS, et al: Thyroid radiation dose and other risk factors of thyroid carcinoma following childhood cancer. J Clin Endocrinol Metab 100:4282-90, 2015
Inskip PD: Thyroid cancer after radiotherapy for childhood cancer. Med Pediatr Oncol 36:568-73, 2001
Lubin JH, Adams MJ, Shore R, et al: Thyroid cancer Following Childhood Low-Dose Radiation Exposure: A Pooled Analysis of Nine Cohorts. J Clin Endocrinol Metab 1;102(7):2575-2583, 2017
Veiga LH, Bhatti P, Ronckers CM, et al: Chemotherapy and thyroid cancer risk: a report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 21:92-101, 2012
Veiga LH, Holmberg E, Anderson H, et al: Thyroid Cancer after Childhood Exposure to External Radiation: An Updated Pooled Analysis of 12 Studies. Radiat Res 185:473-84, 2016

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POTENTIAL IMPACT TO
NECK/THYROID (CONT)RADIATION
Sec #
69

w

Therapeutic
Exposure
Head/Brain
Neck
Spine (cervical, whole)
TBI

Potential
Late Effects
Hypothyroidism

Periodic Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed mood
Menstrual Irregularity
Yearly, consider more frequent screening during
periods of rapid growth
PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening during
periods of rapid growth
SCREENING
TSHFree T4
Yearly, consider more frequent screening during
periods of rapid growth

Health Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
COUNSELINGFor females, thyroid levels prior to attempting pregnancy and periodically throughout
pregnancy.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Endocrine consultation for thyroid hormone replacement.
SYSTEM = Endocrine/Metabolic
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Female sex- Cancer/Treatment factors: Radiation dose ≥10 Gy (especially radiation dose ≥20 Gy), thyroid gland directly in radiation field, TBI

References
Aldrich KD, Horne VE, Bielamowicz K, et al: Comparison of hypothyroidism, growth hormone deficiency, and adrenal insufficiency following proton and photon radiotherapy in children with medulloblastoma. J Neurooncol 155(1):93-100, 2021
Chemaitilly W, Li Z, Brinkman TM, et al: Primary hypothyroidism in childhood cancer survivors: prevalence, risk factors, and long-term consequences. Cancer 1;128(3):606-614, 2022
Cheuk DK, Billups CA, Martin MG, et al: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117:197-206, 2011
Clement SC, Schouten-van Meeteren AY, Boot AM, et al: Prevalence and risk factors of early endocrine disorders in childhood brain tumor survivors: a nationwide, multicenter study. J Clin Oncol 34(36):4362-70, 2016
Katsanis E, Shapiro RS, Robison LL, et al: Thyroid dysfunction following bone marrow transplantation: long-term follow-up of 80 pediatric patients. Bone Marrow Transplant 5:335-40, 1990
Massimino M, Gandola L, Pignoli E, et al: TSH suppression as a possible means of protection against hypothyroidism after irradiation for childhood Hodgkins lymphoma. Pediatr Blood Cancer 57:166-8, 2011
Mostoufi-Moab S, Seidel K, Leisenring WM, et al: Endocrine abnormalities in aging survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 20;34(27):3240-7, 2016
Sanders JE: Endocrine complications of high dose therapy with stem cell transplantation. Pediatr Transplant 8 Suppl 5:39-50, 2004
Sklar C, Boulad F, Small T, et al: Endocrine complications of pediatric stem cell transplantation. Front Biosci 6:G17-22, 2001
Sklar CA, Kim TH, Ramsay NK: Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med 73:688-94, 1982
Vatner RE, Niemierko A, Misra M, et al: Endocrine deficiency as a function of radiation dose to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. J Clin Oncol 36(28):2854-62, 2018
Vogelius IR, Bentzen SM, Maraldo MV, et al: Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis. Cancer 117:5250-60, 2011

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POTENTIAL IMPACT TO
NECK/THYROID (CONT)RADIATION
Sec #
70

w

Therapeutic
Exposure
Head/Brain
Neck
Spine (cervical, whole)

Potential
Late Effects
Hyperthyroidism

Periodic Evaluation
HISTORY
Heat intolerance
Tachycardia
Palpitations
Weight loss
Emotional lability
Muscular weakness
Hyperphagia
YearlyPHYSICAL
Eyes
Skin
Thyroid
Cardiac
Neurologic
YearlySCREENING
TSHFree T4
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Endocrine consultation for medical management.
SYSTEM = Endocrine/Metabolic
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy

References
Constine LS, Donaldson SS, McDougall IR, et al: Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer 53:878-83, 1984
DeGroot LJ: Effects of irradiation on the thyroid gland. Endocrinol Metab Clin North Am 22:607-15, 1993
Mostoufi-Moab S, Seidel K, Leisenring WM, et al: Endocrine abnormalities in aging survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 20;34(27):3240-7, 2016
Perz JB, Marin D, Szydlo RM, et al: Incidence of hyperthyroidism after unrelated donor allogeneic stem cell transplantation. Leuk Res 31:1433-6, 2007
Sklar C, Boulad F, Small T, et al: Endocrine complications of pediatric stem cell transplantation. Front Biosci 6:G17-22, 2001
Sklar C, Whitton J, Mertens A, et al: Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85:3227-32, 2000

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POTENTIAL IMPACT TO
NECK/THYROID (CONT)RADIATION
Sec #71

Therapeutic
Exposure

Potential
Late Effects

Head/Brain
Neck
Spine (cervical, whole)

Carotid artery disease

Periodic Evaluation
HISTORY
Memory impairment
YearlyPHYSICAL
Blood pressure
Diminished carotid pulses
Carotid bruits
Abnormal neurologic exam (compromise ofblood flow to brain)
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Cardiovascular Risk Factors
Nutrition and Physical Activity
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Optimize CVRFs, including blood pressure, lipid profile, and blood glucose.
Doppler ultrasound of carotid vessels as clinically indicated. Refer to cardiology
if abnormal.
MRI with DWI with MRA and cardiovascular surgery consultation as clinicallyindicated.
For survivors who received ≥40 Gy radiation to the neck: Color Doppler
ultrasound 10 years after completion of radiation therapy as a baseline. Referto cardiologist if abnormal.
SYSTEM = Cardiovascular
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: ≥40 Gy radiation dose
- Pre-morbid/Co-morbid medical conditions: Hypertension, diabetes mellitus, hypercholesterolemia, smoking

References
Bowers DC, McNeil DE, Liu Y, et al: Stroke as a late treatment effect of Hodgkin’s disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol 23:6508-15, 2005
De Bruin ML, Dorresteijn LD, van’t Veer MB, et al: Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst 101:928-37, 2009
Hull MC, Morris CG, Pepine CJ, et al: Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA 290:2831-7, 2003
Jonas DE, Feltner C, Amick HR, et al: Screening for asymptomatic carotid artery stenosis: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 161(5):336-46, 2014
Meeske KA, Siegel SE, Gilsanz V, et al: Premature carotid artery disease in pediatric cancer survivors treated with neck irradiation. Pediatr Blood Cancer 53:615-21, 2009
Morris B, Partap S, Yeom K, et al: Cerebrovascular disease in childhood cancer survivors: a Children’s Oncology Group report. Neurology 73:1906-13, 2009
Qureshi AI, Alexandrov AV, Tegeler CH, et al: Guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary Practice Guidelines Committee of the American Society of
Neuroimaging; cosponsored by the Society of Vascular and Interventional Neurology. J Neuroimaging 17:19-47, 2007
van Leeuwen-Segarceanu EM, Bos WJ, Dorresteijn LD, et al: Screening Hodgkin lymphoma survivors for radiotherapy induced cardiovascular disease. Cancer Treat Rev 37:391-403, 2011
van Leeuwen-Segarceanu EM, Dorresteijn LD, Vogels OJ, et al: Arterial stiffness is increased in Hodgkin lymphoma survivors treated with radiotherapy. Leuk Lymphoma 54:1734-41, 2013
Zaletel LZ, Popit M, Zaletel M: Is carotid stiffness a possible surrogate for stroke in long-term survivors of childhood cancer after neck radiotherapy? Radiol Oncol 52(2):136-142, 2018

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POTENTIAL IMPACT TO
NECK/THYROID (CONT)RADIATION
Sec #72

Therapeutic
Exposure
Neck
Chest
Spine (thoracic, whole)

Potential
Late Effects
Subclavian artery disease

Periodic Evaluation
PHYSICAL
Blood pressure in both arms (checking for
wide blood pressure variation)
Diminished brachial and radial pulses
Pallor of upper extremities
Coolness of skin
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Cardiovascular Risk Factors
Nutrition and Physical Activity
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Optimize CVRFs, including blood pressure, lipid profile, and blood glucose.
Doppler ultrasound of carotid vessels as clinically indicated. Refer to cardiology
if abnormal.
MRI with DWI with MRA and cardiovascular surgery consultation as clinicallyindicated.
For survivors who received ≥40 Gy radiation to the neck: Color Doppler
ultrasound 10 years after completion of radiation therapy as a baseline. Referto cardiologist if abnormal.
SYSTEM = Cardiovascular
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: ≥40 Gy radiation dose
- Pre-morbid/Co-morbid medical conditions: Hypertension, diabetes mellitus, hypercholesterolemia

References
Bowers DC, McNeil DE, Liu Y, et al: Stroke as a late treatment effect of Hodgkin’s disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol 23:6508-15, 2005
Hull MC, Morris CG, Pepine CJ, et al: Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA 290:2831-7, 2003
van Leeuwen-Segarceanu EM, Bos WJ, Dorresteijn LD, et al: Screening Hodgkin lymphoma survivors for radiotherapy induced cardiovascular disease. Cancer Treat Rev 37:391-403, 2011
van Leeuwen-Segarceanu EM, Dorresteijn LD, Vogels OJ, et al: Arterial stiffness is increased in Hodgkin lymphoma survivors treated with radiotherapy. Leuk Lymphoma 54:1734-41, 2013

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POTENTIAL IMPACT TO
BREAST

RADIATION
Sec #73(female)Therapeutic
Exposure
Chest
AxillaTBI

Potential
Late Effects
Breast cancer

Periodic Evaluation
PHYSICAL
Clinical breast exam
Yearly, beginning at puberty until age 25, thenevery 6 months
SCREENING
Mammogram
Yearly, beginning 8 years after radiation or atage 25, whichever occurs lastHealth Counseling/
Further Considerations
HEALTH LINKS
Breast Cancer
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery and/or oncology consultation as clinically indicated.
SYSTEM = SMNSCORE = 1

Breast MRI
Yearly, as an adjunct to mammography
beginning 8 years after radiation or at age
25, whichever occurs lastw

Additional Information

Mammography is limited in its ability to evaluate the premenopausal breast.
MRI is now recommended as an adjunct to mammography in women treated with chest radiation for childhood cancer, similar to screening of other populations at high risk for breast cancer (e.g., premenopausal known or likely
carriers of pathogenic or likely pathogenic variant of known penetrance).
The upper age limit at which mammography and breast MRI should be used for breast cancer surveillance has not been established.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Family history of breast cancer- Cancer/Treatment factors: Higher radiation dose, especially ≥10 Gy, longer time since radiation (>5 years). Note decreased risk in women treated with alkylating agents of sufficient dose to ablate ovarian function, althoughannual surveillance is still recommended.
- Pre-morbid/Co-morbid medical conditions: Personal history of BRCA1, BRCA2, ATM or p53 mutation or in absence of personal genetic testing, known BRCA mutation in first degree relative

References
Bhatia S, Robison LL, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 334:745-51, 1996
Ehrhardt MJ, Howell CR, Hale K, et al: Subsequent Breast Cancer in Female Childhood Cancer Survivors in the St Jude Lifetime Cohort Study (SJLIFE). J Clin Oncol 37(19):1647-1656, 2019Friedman 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 111:939-44, 2008
Henderson TO, Amsterdam A, Bhatia S, et al: Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med 152:444-55; W144-54, 2010
Henderson TO, Moskowitz CS, Chou JF, et al: Breast cancer risk in childhood cancer survivors without a history of chest radiotherapy: a report from the Childhood Cancer Survivor Study. J Clin Oncol 34:910-8, 2016
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 120:3722-30, 2014
Moskowitz CS, Chou JF, Wolden SL, et al: Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol 32:2217-23, 2014
Moskowitz CS, Ronckers CM, Chou JF, et al: Development and Validation of a Breast Cancer Risk Prediction Model for Childhood Cancer Survivors Treated With Chest Radiation: A Report From the Childhood Cancer Survivor Study and the Dutch
Hodgkin Late Effects and LATER Cohorts. J Clin Oncol 39(27):3012-3021, 2021
Mulder RL, Hudson MM, Bhatia S, et al: Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group. J Clin Oncol
38(35):4194-4207, 2020
Ng AK, Garber JE, Diller LR, et al: Prospective study of the efficacy of breast magnetic resonance imaging and mammographic screening in survivors of Hodgkin lymphoma. J Clin Oncol 31:2282-8, 2013
Schaapveld M, Aleman BM, van Eggermond AM, et al: Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. N Engl J Med 373:2499-511, 2015
Travis LB, Hill DA, Dores GM, et al: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290:465-75, 2003
Yeh JM, Lowry KP, Schechter CB, et al: Benefits, Harms, and Cost-Effectiveness of Breast Cancer Screening for Survivors of Childhood Cancer Treated With Chest Radiation: A Comparative Modeling Study. Ann Intern Med 173(5):331-341, 2020

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POTENTIAL IMPACT TO
BREAST (CONT)RADIATION
Sec #74(female)w

Therapeutic
Exposure
Chest
AxillaTBI

Potential
Late Effects
Breast tissue hypoplasia

Periodic Evaluation
PHYSICAL
Clinical breast exam
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgical consultation for breast reconstruction after completion of growth.
SYSTEM = Reproductive (Female)
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Prepubertal at time of treatment- Cancer/Treatment factors: Radiation dose ≥10 Gy to prepubertal breast bud (especially dose ≥20 Gy)

References
Furst CJ, Lundell M, Ahlback SO, et al: Breast hypoplasia following irradiation of the female breast in infancy and early childhood. Acta Oncol 28:519-23, 1989
Johnston K, Vowels M, Carroll S, et al: Failure to lactate: a possible late effect of cranial radiation. Pediatr Blood Cancer 50:721-2, 2008
Lo AC, Ronckers C, Aznar MC, et al: Breast hypoplasia and decreased lactation from radiation therapy in survivors of pediatric malignancy: a PENTEC comprehensive review. Int J Radiat Oncol Biol Phys 6:S0360-3016(21)02725-5,
2021
Macklis RM, Oltikar A, Sallan SE: Wilms’ tumor patients with pulmonary metastases. Int J Radiat Oncol Biol Phys 21:1187-93, 1991

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POTENTIAL IMPACT TOLUNGSRADIATION
Sec #
75

w

Therapeutic
Exposure
Chest
AxillaTBI

Potential
Late Effects
Pulmonary toxicity
Pulmonary fibrosis
Interstitial pneumonitis
Restrictive lung disease
Obstructive lung disease

Periodic Evaluation
HISTORY
Cough
Wheezing
Shortness of breath
Dyspnea on exertion
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patients withabnormal results or progressive pulmonary
dysfunction

Health Counseling/
Further Considerations
HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco and environmental tobacco smoke avoidance/Smoking cessation.
Influenza and Pneumococcal vaccinations.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Pulmonary consultation for patients with symptomatic pulmonary dysfunction.
Pulmonary consultation for survivors who desire to SCUBA dive (due to potential
undiagnosed pulmonary toxicities, and limited data to guide safe diving
recommendations for individuals treated with pulmonary toxic therapy).
SYSTEM = Pulmonary
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at irradiation- Cancer/Treatment factors: Radiation dose >10 Gy, especially ≥15 Gy, TBI ≥6 Gy in single fraction, TBI ≥12 Gy fractionated, chest radiation combined with TBI, radiation combined with bleomycin, busulfan, carmustine (BCNU),
or lomustine (CCNU), radiomimetic chemotherapy (e.g., doxorubicin, dactinomycin)- Pre-morbid/Co-morbid medical conditions: Atopic history- Health behaviors: Smoking, inhaled illicit drug use

References
Armenian SH, Landier W, Francisco L, et al: Long-term pulmonary function in survivors of childhood cancer. J Clin Oncol 33:1592-600, 2015
Dietz AC, Chen Y, Yasui Y, et al: Risk and impact of pulmonary complications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 122:3687-3696, 2016
Green DM, Zhu L, Wang M, et al: Pulmonary function after treatment for childhood cancer. A report from the St. Jude Lifetime Cohort Study (SJLIFE). Ann Am Thorac Soc 13:1575-85, 2016
Huang TT, Hudson MM, Stokes DC, et al: Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest 140:881-901, 2011
Hudson MM, Ness KK, Gurney JG, et al: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371-2381, 2013
Mulder RL, Thonissen NM, van der Pal HJ, et al: Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 66:1065-71, 2011
Tetrault JM, Crothers K, Moore BA, et al: Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med 167:221-8, 2007
van Hulst RA, Rietbroek RC, Gaastra MT, et al: To dive or not to dive with bleomycin: a practical algorithm. Aviat Space Environ Med 82:814-8, 2011
Venkatramani R, Kamath S, Wong K, et al: Correlation of clinical and dosimetric factors with adverse pulmonary outcomes in children after lung irradiation. Int J Radiat Oncol Biol Phys 86:942-8, 2013
Wolff AJ, O’Donnell AE: Pulmonary effects of illicit drug use. Clin Chest Med 25:203-16, 2004

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POTENTIAL IMPACT TO
LUNGS (CONT)RADIATION
Sec #
76

w

Therapeutic
Exposure
Chest
AxillaTBI

Potential
Late Effects
Lung cancer

Periodic Evaluation
HISTORY
Cough
Wheezing
Shortness of breath
Dyspnea on exertion
YearlyPHYSICAL
Pulmonary Exam
YearlySCREENING
Spiral CT Scan
Discuss the benefits and risks/harms of spiral
CT scanning for patients at highest risk (i.e.,smokers)

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Imaging and surgery and/or oncology consultation as clinically indicated.
SYSTEM = SMNSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Workplace exposure to asbestos, arsenic, radiation, second hand smoke (in non-smokers)- Health behaviors: Smoking, especially 30 pack-years or more

References
Ghosh T, Chen Y, Dietz AC, et al: Lung Cancer as a Subsequent Malignant Neoplasm in Survivors of Childhood Cancer. Cancer Epidemiol Biomarkers Prev 30(12):2235-2243, 2021
Holmqvist AS, Chen Y, Berano Teh J, et al: Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-Identification of high-risk populations to guide surveillance: A report from the Late Effects Study Group.
Cancer 125(8):1373-1383, 2019
Moyer VA, U. S. Preventive Services Task Force: Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160:330-8, 2014
National Lung Screening Trial Research Team, Church TR, Black WC, et al: Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 368:1980-91, 2013
Schaapveld M, Aleman BM, van Eggermond AM, et al: Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. N Engl J Med 373:2499-511, 2015
Smith RA, Andrews KS, Brooks D, et al: Cancer screening in the United States, 2017: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin 67:100-121, 2017
Swerdlow AJ, Higgins CD, Smith P, et al: Second cancer risk after chemotherapy for Hodgkin’s lymphoma: a collaborative British cohort study. J Clin Oncol 29:4096-104, 2011
Wattson DA, Hunink MG, DiPiro PJ, et al: Low-dose chest computed tomography for lung cancer screening among Hodgkin lymphoma survivors: a cost-effectiveness analysis. Int J Radiat Oncol Biol Phys 90:344-53, 2014

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POTENTIAL IMPACT TO
HEARTRADIATION
Sec #77

Therapeutic
Exposure
Chest
AbdomenSpine (thoracic, whole)
TBI(TBI is included for
cumulative dose calculation
purposes only; this section
is not applicable to patients
who received TBI <15 Gy
alone.)

Potential
Late Effects
Cardiac toxicity
Cardiomyopathy
Subclinical left ventricular
dysfunction
Congestive heart failure
Pericarditis
Pericardial fibrosis
Valvular disease
Atherosclerotic heart disease
Myocardial infarction
Arrhythmia

Periodic Evaluation
HISTORY
If dose ≥15 Gy:
Shortness of breath
Dyspnea on exertion
Orthopnea
Chest pain
Palpitations
If under 25 yrs: abdominal symptoms (nausea,
vomiting)
YearlyPHYSICAL
If dose ≥15 Gy:
Blood pressure
Cardiac exam
YearlySCREENING
Echo (or comparable imaging to evaluate
cardiac anatomy and function)
RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM
Anthracycline
Dose*
None to <100mg/m2

Radiation
Dose**

Recommended
Frequency

None to <15Gy

No screening

None to <100mg/m2
15Gy to <30Gy
Every 5 years≥100 to <250mg/m²
None to <15Gy≥100 to <250mg/m²≥15Gy
None to Any≥30Gy
Every 2 years≥ 250mg/m²
None to Any*Based on doxorubicin isotonic equivalent dose. See doseconversion instructions in section 34.
**Based on radiation dose with potential impact to heart (radiation to chest, abdomen, spine [thoracic, whole], TBI).

If dose ≥15 Gy:
EKG (include evaluation of QTc interval)
Baseline at entry into long-term follow-up, repeat
as clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Heart Health
Cardiovascular Risk Factors
Nutrition and Physical Activity
Dental Health
COUNSELING
Traditional CVRFs significantly increase survivors’ risk of cardiomyopathy. Counsel
regarding the importance of maintaining blood pressure, BMI, lipids, and glucose levels
within goal ranges per general population guidelines.
Regarding exercise:• Exercise is generally safe and encouraged for patients with normal LV systolic function• Consult cardiology for survivors with asymptomatic cardiomyopathy to define physicalactivity limits and precautions.
• Consider cardiology consultation to define physical activity limits and precautions forhigh risk survivors (i.e., those requiring an echo every 2 years) who plan to participate
in intensive exercise.
If QTc interval is prolonged: Caution use of QTc prolonging medications (e.g., tricyclic
anti-depressants, antifungals, macrolide antibiotics, metronidazole).
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Cardiac MRI as an adjunct imaging modality when echo images are suboptimal.
Cardiology consultation in patients with subclinical abnormalities on screening
evaluations, LV dysfunction, dysrhythmia, or prolonged QTc interval.
Cardiology consultation (5 to 10 years after radiation) may be reasonable to evaluate risk
for coronary artery disease in survivors who received ≥30 Gy chest radiation alone or≥15 Gy chest radiation plus anthracycline.
In survivors with valvular disorders: Consult cardiologist to advise regarding need for
endocarditis prophylaxis.
Female patients only: For patients who are pregnant or planning to become pregnant,additional cardiology evaluation is indicated in patients who received:• ≥250 mg/m2 anthracyclines• ≥30 Gy chest radiation, or• Anthracycline (any dose) combined with chest radiation (≥15 Gy)• Evaluation should include a baseline echo (pre- or early-pregnancy). For those without
prior abnormalities and with normal pre- or early-pregnancy baseline echos, follow-up
echos may be obtained at the provider’s discretion. Those with a history of systolic
dysfunction or with pre- or early-pregnancy systolic dysfunction are at highest risk for
pregnancy-associated cardiomyopathy, and should be monitored periodically during
pregnancy and during labor and delivery due to increased risk for heart failure.
SYSTEM = Cardiovascular
SCORE = 1

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POTENTIAL IMPACT TO
HEART (CONT)RADIATION
Additional Information

Exertional intolerance is an uncommon presentation of LV dysfunction in patients <25 years old.
Abdominal symptoms (nausea, emesis) may be observed more frequently than exertional dyspnea or chest pain in younger patients.
The AHA now limits their recommendation regarding endocarditis prophylaxis only to patients whose cardiac conditions are associated with the highest risk of adverse outcome, which includes, but is not limited to the following four
categories: (1) prosthetic heart valves, (2) previous history of infective endocarditis, (3) certain patients with congenital heart disease, and (4) valvulopathy following cardiac transplantation.
Survivors diagnosed with heart valve disorders should discuss the need for endocarditis prophylaxis with their cardiologist. See Wilson et al. (2007) for specifics.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at irradiation, especially age <5 years, family history of dyslipidemia, CAD- Cancer/Treatment factors: Radiation dose ≥20 Gy to chest, TBI, anteriorly-weighted radiation fields, lack of subcarinal shielding, combined with radiomimetic chemotherapy (e.g., doxorubicin, dactinomycin), doses ≥15 Gy inpatients who have received ≥100 mg/m2 of anthracyclines, doses ≥30 Gy in patients who have not received anthracyclines, longer time since treatment- Pre-morbid/Co-morbid medical conditions: Obesity, congenital heart disease, hypertension, diabetes mellitus, dyslipidemia. For female patients, premature ovarian failure (untreated), pregnancy if systolic function is abnormal pre-pregnancy- Health behaviors: Smoking, drug use (e.g., cocaine, diet pills, ephedra, mahuang)

References
Armstrong GT, Joshi VM, Ness KK, et al: Comprehensive echocardiographic detection of treatment-related cardiac dysfunction in adult survivors of childhood cancer: results from the St. Jude Lifetime Cohort Study. J Am Coll Cardiol
65:2511-22, 2015
Armstrong GT, Oeffinger KC, Chen Y, et al: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 31:3673-80, 2013
Blanco JG, Sun CL, Landier W, et al: Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children’s Oncology Group. J Clin Oncol 30:1415-21, 2012
Chow EJ, Chen Y, Hudson MM, et al: Prediction of ischemic heart disease and stroke in survivors of childhood cancer. J Clin Oncol 36:44-52, 2018
Chow EJ, Chen Y, Kremer LC, et al: Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol 33:394-402, 2015
Christiansen JR, Hamre H, Massey R, et al: Left ventricular function in long-term survivors of childhood lymphoma. Am J Cardiol 114:483-90, 2014
Ehrhardt MJ, Leerink JM, Mulder RL, et al: Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects ofChildhood Cancer Guideline Harmonization Group. Lancet Oncol 24(3):e108-e120, 2023
Ehrhardt MJ, Ward ZJ, Liu Q, et al: Cost-effectiveness of the International Late Effects of Childhood Cancer Guideline Harmonization Group screening guidelines to prevent heart failure in survivors of childhood cancer. J Clin Oncol
38(33):3851-3862, 2020
Haddy N, Diallo S, El-Fayech C, et al: Cardiac diseases following childhood cancer treatment: cohort study. Circulation 133:31-8, 2016
Hines MR, Mulrooney DA, Hudson MM, et al: Pregnancy-associated cardiomyopathy in survivors of childhood cancer. J Cancer Surviv 10:113-21, 2016
Mulrooney DA, Armstrong GT, Huang S, et al: Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study. Ann Intern Med 164:93-101, 2016
Mulrooney DA, Hyun G, Ness KK, et al: Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort. BMJ 368:l6794, 2020
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 55:1145-52, 2010
Swerdlow AJ, Higgins CD, Smith P, et al: Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst 99:206-14, 2007
van Dalen EC, van der Pal HJ, van den Bos C, et al: Clinical heart failure during pregnancy and delivery in a cohort of female childhood cancer survivors treated with anthracyclines. Eur J Cancer 42:2549-53, 2006
van der Pal HJ, van Dalen EC, van Delden E, et al: High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 30:1429-37, 2012
van Nimwegen FA, Schaapveld M, Janus CP, et al: Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk. JAMA Intern Med 175:1007-17, 2015
Wilson W, Taubert KA, Gewitz M, et al: Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group.
Circulation 116:1736-54, 2007

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POTENTIAL IMPACT TO
SPLEENRADIATION
Sec #78

Therapeutic
Exposure

Potential
Late Effects

AbdomenTBI(TBI is included for
cumulative dose calculation
purposes only; this section
is not applicable to patients
who received TBI alone.)

Functional asplenia
At risk for life-threatening infection
with encapsulated organisms(e.g., Haemophilus influenzae,
Streptococcus pneumoniae,
meningococcus)

Periodic Evaluation
PHYSICAL
If radiation dose ≥40 Gy:
Physical exam at time of febrile illness toevaluate degree of illness and potential
source of infection
When febrile T ≥101°F (38.3°C)
SCREENING
If dose ≥40 Gy:
Blood culture
When febrile T ≥101°F (38.3°C)

Health Counseling/
Further Considerations
HEALTH LINKS
Splenic Precautions
COUNSELING
Risk of life-threatening infections with encapsulated organisms.
Risk of malaria and tick-borne diseases if living in or visiting endemic areas.
Obtain medical alert bracelet/card noting functional asplenia.
Discuss importance of immunization with Pneumococcal, Meningococcal (including
serotype B), Influenza and HIB vaccines according to current ACIP recommendations.
For further details regarding antibiotic prophylaxis and immunizations, see current editionof AAP Red Book.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Administer a long-acting, broad-spectrum parenteral antibiotic (e.g., ceftriaxone) inpatients with T ≥101°F (38.3°C) or other signs of serious illness and continue close
medical monitoring while awaiting blood culture results.
Hospitalize and broaden antimicrobial coverage (e.g., addition of vancomycin) undercertain circumstances, such as the presence of marked leukocytosis, neutropenia, or
significant change from baseline CBC, toxic clinical appearance, fever ≥104°F (40°C),
meningitis, pneumonia, or other serious focus of infection, signs of septic shock, orprevious history of serious infection.
Discuss with dental provider potential need for antibiotic prophylaxis based on planned
procedure.
SYSTEM = Immune
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, larger volume of spleen in treatment field, include documentation of splenic radiation dose exposure in the survivor’s treatment summary.

References
Castagnola E, Fioredda F: Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes. Eur J Haematol 71:319-26, 2003
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Morb Mortal Wkly Rep 61:816-9, 2012
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 62:521-4, 2013
Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Barnett ED, Lynfield R, et al (eds): Red Book: 2021 Report of the Committee on Infectious Diseases (ed 32). Itasca, IL, American
Academy of Pediatrics, 2021, pp 67-105
Guilcher GMT, Rivard L, Huang JT, et al: Immune function in childhood cancer survivors: a Children’s Oncology Group review. Lancet Child Adolesc Health 5(4):284-294, 2021
Mbaeyi SA, Bozio CH, Duffy J, et al: Meningococcal vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 69(9);1-41, 2020
Mourtzoukou EG, Pappas G, Peppas G, et al: Vaccination of asplenic or hyposplenic adults. Br J Surg 95:273-80, 2008
Price VE, Blanchette VS, Ford-Jones EL: The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am 21:697-710, viii-ix, 2007
Smets F, Bourgois A, Vermylen C, et al: Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine. Vaccine 25:5278-82, 2007
Spelman D, Buttery J, Daley A, et al: Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J 38:349-56, 2008

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POTENTIAL IMPACT TO
GI/HEPATIC SYSTEMRADIATION
Sec #79

Therapeutic
Exposure

Potential
Late Effects

Neck
Esophageal stricture
Chest
AbdomenSpine (cervical, thoracic,
whole)

Periodic Evaluation
HISTORY
Dysphagia
HeartburnYearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery and/or gastroenterology consultation for symptomatic patients.
SYSTEM = GI/Hepatic
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Radiation dose ≥30 Gy (increased risk with higher radiation dose, especially ≥40 Gy)- Pre-morbid/Co-morbid medical conditions: Gastroesophageal reflux, history of Candida esophagitis, gut GVHD

References
Asdahl PH, Oeffinger KC, Albieri V, et al. Esophageal disease among childhood cancer survivors - a report from the Childhood Cancer Survivors Study. Pediatr Blood Cancer 68(8):e29043, 2021
Lal DR, Foroutan HR, Su WT, et al: The management of treatment-related esophageal complications in children and adolescents with cancer. J Pediatr Surg 41:495-9, 2006
Mahboubi S, Silber JH: Radiation-induced esophageal strictures in children with cancer. Eur Radiol 7:119-22, 1997
Rodriguez ML, Martin MM, Padellano LC, et al: Gastrointestinal toxicity associated to radiation therapy. Clin Transl Oncol 12:554-61, 2010

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POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #80

Therapeutic
Exposure
Abdomen
TBI

Potential
Late Effects
Impaired glucose
metabolism/Diabetes
mellitus

Periodic Evaluation
SCREENING
Fasting blood glucose OR HbA1c
Every 2 years

Health Counseling/
Further Considerations
HEALTH LINKS
Nutrition and Physical Activity
Cardiovascular Risk Factors
COUNSELING
Obesity-related health risks.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Endocrine consultation
Evaluate for other co-morbid conditions, including dyslipidemia, hypertension,and overweight/obesity.
Refer to dietitian for blood sugar management.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Impaired glucose metabolism may occur as a part of a constellation of conditions known as metabolic syndrome.
Definitions of metabolic syndrome generally include a combination of central (abdominal) obesity and ≥2 of the following: elevated blood pressure, atherogenic dyslipidemia (elevated triglycerides, reduced HDL cholesterol), abnormal
glucose metabolism.
Note: Patients who received TBI may develop features of metabolic syndrome without associated obesity.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Family history of diabetes mellitus, pregnancy- Cancer/Treatment factors: Prolonged corticosteroid therapy (e.g., for cGVHD)- Pre-morbid/Co-morbid medical conditions: Obesity

References
Baker KS, Ness KK, Steinberger J, et al: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplantation Survivor Study. Blood 109:1765-72, 2007
Chow EJ, Simmons JH, Roth CL, et al: Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with total body irradiation. Biol Blood Marrow Transplant 16:1674-81, 2010de Vathaire F, El-Fayech C, Ben Ayed FF, et al: Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 13:1002-10, 2012Friedman DN, Moskowitz CS, Hilden P, et al: Radiation dose and volume to the pancreas and subsequent risk of diabetes mellitus: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 112(5):525-32, 2020
Hoffmeister PA, Storer BE, Sanders JE: Diabetes mellitus in long-term survivors of pediatric hematopoietic cell transplantation. J Pediatr Hematol Oncol 26:81-90, 2004
Lorini R, Cortona L, Scaramuzza A, et al: Hyperinsulinemia in children and adolescents after bone marrow transplantation. Bone Marrow Transplant 15:873-7, 1995
Meacham LR, Chow EJ, Ness KK, et al: Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 19:170-81, 2010
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 169:1381-8, 2009
Mostoufi-Moab S, Seidel K, Leisenring WM, et al: Endocrine abnormalities in aging survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 34(27):3240-7, 2016
Shalitin S, Phillip M, Stein J, et al: Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant 37:1109-17, 2006
Taskinen M, Saarinen-Pihkala UM, Hovi L, et al: Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet 356:993-7, 2000

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POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #81

Therapeutic
Exposure
Abdomen
TBI

Potential
Late Effects
Dyslipidemia

Periodic Evaluation
SCREENING
Fasting lipid profile
Every 2 years

Health Counseling/
Further Considerations
HEALTH LINKS
Nutrition and Physical Activity
Cardiovascular Risk Factors
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluate for other co-morbid conditions, including hypertension, impaired
glucose metabolism, and overweight/obesity.
Refer to dietitian.
SYSTEM = Endocrine/Metabolic
SCORE
Abdominal Radiation = 2A
TBI = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Family history of dyslipidemia- Cancer/Treatment factors: Prolonged corticosteroid therapy (e.g., for cGVHD)

References
Bajwa R, Skeens M, Garee A, et al: Metabolic syndrome and endocrine dysfunctions after HSCT in children. Pediatr Transplant 16:872-8, 2012
Baker KS, Ness KK, Steinberger J, et al: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplantation Survivor Study. Blood 109:1765-72, 2007
Chow EJ, Simmons JH, Roth CL, et al: Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with total body irradiation. Biol Blood Marrow Transplant 16:1674-81, 2010
Daniels SR, Greer FR, Committee on Nutrition: Lipid screening and cardiovascular health in childhood. Pediatrics 122:198-208, 2008
Felicetti F, D’Ascenzo F, Moretti C, et al: Prevalence of cardiovascular risk factors in long-term survivors of childhood cancer: 16 years follow up from a prospective registry. Eur J Prev Cardiol 22:762-70, 2015
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 169:1381-8, 2009
Oudin C, Simeoni MC, Sirvent N, et al: Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. Blood 117:4442-8, 2011
Shalitin S, Phillip M, Stein J, et al: Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant 37:1109-17, 2006
Taskinen M, Saarinen-Pihkala UM, Hovi L, et al: Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet 356:993-7, 2000
van Waas M, Neggers SJ, Uitterlinden AG, et al: Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors. Eur J Cancer 49:668-75, 2013

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POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #
82

w

Therapeutic
Exposure
AbdomenPotential
Late Effects
Hepatic toxicity
Hepatic fibrosis
Cirrhosis
FNH

Periodic Evaluation
PHYSICAL
Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly
YearlySCREENING
ALT
AST
Bilirubin
Baseline at entry into long-term follow-up,
repeat as clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Liver Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Platelet count for evaluation of hypersplenism and prothrombin time for
evaluation of hepatic synthetic function in patients with abnormal liver
screening tests.
Screen for viral hepatitis in patients with persistently abnormal liver function or
any patient transfused prior to 1993.
Gastroenterology/Hepatology consultation in patients with persistent liver
dysfunction.
Hepatitis A and B immunization in at-risk patients lacking immunity.
SYSTEM = GI/Hepatic
SCORE = 1

Additional Information

FNH is a benign change that represents a scar in the liver.
FNH is usually an asymptomatic finding noted on MRI or ultrasound of the liver.
Continued observation or biopsy may be indicated depending on individual patient factors and imaging features.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose to liver, especially ≥30 Gy, or to larger volume- Pre-morbid/Co-morbid medical conditions: Chronic hepatitis, history of SOS- Health behaviors: Alcohol use (in relation to hepatic fibrosis and cirrhosis)

References
Bardi E, Mulder RL, van Dalen EC, et al: Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Cancer Treat Rev 100:102296, 2021
Castellino S, Muir A, Shah A, et al: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr Blood Cancer 54:663-9, 2010
Green DM, Wang M, Krasin MJ, et al: Serum alanine aminotransferase elevations in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Hepatol 69(1):94-106, 2019
Mulder RL, van Dalen EC, Van den Hof M, et al: Hepatic late adverse effects after antineoplastic treatment for childhood cancer. Cochrane Database Syst Rev:CD008205, 2011
Pan CC, Kavanagh BD, Dawson LA, et al: Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 76:S94-100, 2010
Pillon M, Carucci NS, Mainardi C, et al: Focal nodular hyperplasia of the liver: an emerging complication of hematopoietic SCT in children. Bone Marrow Transplant 50:414-9, 2015
Smith EA, Salisbury S, Martin R, et al: Incidence and etiology of new liver lesions in pediatric patients previously treated for malignancy. AJR Am J Roentgenol 199:186-91, 2012

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GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #
83

w

Therapeutic
Exposure
AbdomenPotential
Late Effects
Cholelithiasis

Periodic Evaluation
HISTORY
Colicky abdominal pain related to fatty
food intake
Excessive flatulence
YearlyPHYSICAL
Epigastric or RUQ tenderness
Positive Murphy’s sign
As clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gallbladder ultrasound in patients with chronic abdominal pain.
SYSTEM = GI/Hepatic
SCORE = 2B

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Family history of cholelithiasis- Cancer/Treatment factors: Radiation dose ≥30 Gy, abdominal surgery, abdominal radiation, TPN, HCT- Pre-morbid/Co-morbid medical conditions: Ileal conduit, obesity, pregnancy

References
Castellino S, Muir A, Shah A, et al: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr Blood Cancer 54:663-9, 2010
Dieffenbach BV, Li N, Madenci AL, et al: Incidence of and risk factors for late cholecystectomy in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer 133:4-13, 2020
Hoffmeister PA, Storer BE, McDonald GB, et al: Gallstones in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up. J Pediatr Hematol Oncol 36:484-90, 2014
Mahmoud H, Schell M, Pui CH: Cholelithiasis after treatment for childhood cancer. Cancer 67:1439-42, 1991

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POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #
84

w

Therapeutic
Exposure
AbdomenPelvisSpine (lumbar, sacral,whole)

Potential
Late Effects
Bowel obstruction

Periodic Evaluation
HISTORY
Abdominal pain
Distension
Vomiting
Constipation
YearlyPHYSICAL
Tenderness
Abdominal guarding
Distension
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Imaging as clinically indicated for suspected obstruction.
Surgical consultation in patients unresponsive to medical management.
SYSTEM = GI/Hepatic
SCORE = 1

Additional Information

Bowel obstruction is rarely seen in individuals treated with abdominal radiation who have not had abdominal surgery.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Abdominal surgery, radiation dose ≥20 Gy (especially ≥45 Gy). Obstruction may occur in people who received lower doses of abdominal radiation during childhood.

References
Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109-22, 1991
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 33:2893-900, 2015
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 46:1239-46, 2000

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POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #85

Therapeutic
Exposure
AbdomenPelvisSpine (lumbar, sacral,whole)

Potential
Late Effects
Chronic enterocolitis
FistulaStrictures

Periodic Evaluation
HISTORY
NauseaVomiting
Abdominal pain
Diarrhea
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Serum protein and albumin in patients with chronic diarrhea or fistula.
Surgical and/or gastroenterology consultation.
SYSTEM = GI/Hepatic
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Abdominal surgery, radiation dose ≥30 Gy (particularly radiation dose ≥45 Gy), higher radiation dose to bowel

References
Donaldson SS, Jundt S, Ricour C, et al: Radiation enteritis in children. A retrospective review, clinicopathologic correlation, and dietary management. Cancer 35:1167-78, 1975
Heyn R, Raney RB, Jr., Hays DM, et al: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 10:614-23, 1992
Madenci AL, Dieffenbach BV, Liu Q, et al. Late-onset anorectal disease and psychosocial impact in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 125(21):3873-3881, 2019
Raney B, Jr., Heyn R, Hays DM, et al: Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup Rhabdomyosarcoma Study Committee. Cancer
71:2387-94, 1993
Rodriguez ML, Martin MM, Padellano LC, et al: Gastrointestinal toxicity associated to radiation therapy. Clin Transl Oncol 12:554-61, 2010

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POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #86

Therapeutic
Exposure
AbdomenPelvisSpine (lumbar, sacral,whole)
TBI

Potential
Late Effects
Colorectal cancer

Periodic Evaluation

Health Counseling/
Further Considerations

SCREENING
HEALTH LINKS
Regular screening selected from the options
Colorectal Cancer
below based on informed decision-making
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
between patient and provider
Gastroenterology, surgery and/or oncology consultation as clinically indicated.
Beginning 5 years after radiation or at age 30 years(whichever occurs last)
SYSTEM = SMN
Radiation-Related Colorectal Cancer
SCORE = 2A
Screening Options
Test

Frequency

Multitarget stool DNA test*

Every 3 years

Colonoscopy

Every 5 years*Positive result should be followed up with timely
colonoscopy.
Note: Colonoscopy is considered the gold standard forcolorectal cancer screening in high-risk populations;however, recognizing that not all survivors are willing or able
to undergo colonoscopy, multitarget stool DNA testing isdeemed a reasonable alternative. Alternative stool-based
testing (i.e., annual fecal immunochemical testing (FIT) or
high-sensitivity guaiac-based fecal occult blood testing) oralternative structural examination (i.e., every 5 year CT
colonography or flexible sigmoidoscopy) may also be
considered if colonoscopy or multitarget stool DNA testing
are not feasible or acceptable to the survivor. All positive
results from these alternative testing methods should be
followed up with timely colonoscopy.
w

Additional Information

Participation in screening remains poor in the cancer survivor population, with >70% of at-risk survivors unscreened (see Daniel et al. 2015); thus it is important for clinicians to engage survivors in informed decision-making, weighing risks andbenefits of the available options, and selecting an option that is acceptable to the survivor and likely to result in successful completion of timely periodic screening.
For patients at high risk due to personal or family history or hereditary syndromes predisposing to colorectal cancer, more intensive and earlier screening is recommended (see Giardiello et al. 2014, Kahl et al. 2016, Lieberman et al. 2012, andSyngal et al. 2015).
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Current age ≥45 years, family history of colorectal cancer or polyps in first degree relative- Cancer/Treatment factors: Hepatoblastoma, gastrointestinal malignancy, higher radiation dose, especially ≥20 Gy, combination with chemotherapy (especially alkylators)- Pre-morbid/Co-morbid medical conditions: Obesity, ulcerative colitis, adenomatous polyps, familial polyposis- Health behaviors: High fat/low fiber diet

References
Daniel CL, Kohler CL, Stratton KL, et al: Predictors of colorectal cancer surveillance among survivors of childhood cancer treated with radiation: a report from the Childhood Cancer Survivor Study. Cancer 121:1856-63, 2015
Henderson TO, Oeffinger KC, Whitton J, et al: Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med 156:757-66, W-260, 2012
Hodgson DC, Koh ES, Tran TH, et al: Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin lymphoma. Cancer 110:2576-86, 2007
Nottage K, McFarlane J, Krasin MJ, et al: Secondary colorectal carcinoma after childhood cancer. J Clin Oncol 30:2552-8, 2012
Teepen JC, de Vroom SL, van Leeuwen FE, et al: Risk of subsequent gastrointestinal cancer among childhood cancer survivors: A systematic review. Cancer Treat Rev 43:92-103, 2016

Teepen JC, Kok JL, van Leeuwen FE, et al: Colorectal adenomas and cancers after childhood cancer treatment: A DCOG-LATER Record Linkage Study. J Natl Cancer Inst 110(7):758-767, 2018
Tukenova M, Diallo I, Anderson H, et al: Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study. Int J Radiat Oncol Biol Phys 82:e383-90, 2012
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POTENTIAL IMPACT TO
URINARY TRACTRADIATION
Sec #
87

w

Therapeutic
Exposure
Abdomen
TBI

Potential
Late Effects
Renal toxicity
Glomerular injury
Renal insufficiency
Hypertension

Periodic Evaluation
PHYSICAL
Blood pressure
YearlySCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Kidney Health
Cardiovascular Risk Factors
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Nephrology consultation for patients with hypertension or progressive renal
insufficiency.
SYSTEM = Urinary
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Bilateral Wilms tumor, nephrectomy, radiomimetic chemotherapy (e.g., doxorubicin, dactinomycin), combination with other nephrotoxic agents (e.g., cisplatin, carboplatin, ifosfamide, aminoglycosides, amphotericin, immunosuppressants), radiation dose ≥10 Gy, especially dose ≥15 Gy, TBI ≥6 Gy in single fraction, TBI ≥12 Gy fractionated, TBI combined with radiation to the kidney- Pre-morbid/Co-morbid medical conditions: Diabetes mellitus, hypertension, congenital absence of kidney

References
Dekkers IA, Blijdorp K, Cransberg K, et al: Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 8:922-9, 2013
Delgado J, Cooper N, Thomson K, et al: The importance of age, fludarabine, and total body irradiation in the incidence and severity of chronic renal failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 12:75-83, 2006
Dieffenbach BV, Liu Q, Murphy AJ, et al: Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer 155:216-226, 2021
Fels LM, Bokemeyer C, van Rhee J, et al: Evaluation of late nephrotoxicity in long-term survivors of Hodgkin’s disease. Oncology 53:73-8, 1996
Frisk P, Bratteby LE, Carlson K, et al: Renal function after autologous bone marrow transplantation in children: a long-term prospective study. Bone Marrow Transplant 29:129-36, 2002
Green DM, Wang M, Krasin M, et al: Kidney function after treatment for childhood cancer: a report from the St. Jude Lifetime Cohort Study. J Am Soc Nephrol 32(4):983-993, 2021
Gronroos MH, Bolme P, Winiarski J, et al: Long-term renal function following bone marrow transplantation. Bone Marrow Transplant 39:717-23, 2007
Knijnenburg SL, Jaspers MW, van der Pal HJ, et al: Renal dysfunction and elevated blood pressure in long-term childhood cancer survivors. Clin J Am Soc Nephrol 7:1416-27, 2012
Lawton CA, Cohen EP, Murray KJ, et al: Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant 20:1069-74, 1997
Miralbell R, Bieri S, Mermillod B, et al: Renal toxicity after allogeneic bone marrow transplantation: the combined effects of total-body irradiation and graft-versus-host disease. J Clin Oncol 14:579-85, 1996
Ritchey ML, Green DM, Thomas PR, et al: Renal failure in Wilms’ tumor patients: a report from the National Wilms’ Tumor Study Group. Med Pediatr Oncol 26:75-80, 1996
Tarbell NJ, Guinan EC, Niemeyer C, et al: Late onset of renal dysfunction in survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys 15:99-104, 1988

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POTENTIAL IMPACT TO
URINARY TRACT (CONT)RADIATION
Sec #88

Therapeutic
Exposure
PelvisSpine (sacral, whole)

Potential
Late Effects
Urinary tract toxicity
Hemorrhagic cystitis
Bladder fibrosis
Dysfunctional voiding
Vesicoureteral reflux
Hydronephrosis

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Bladder Health
COUNSELING
Promptly report dysuria or gross hematuria.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urinalysis, urine culture, spot urine calcium/creatinine ratio for patients withpositive history.
Ultrasound of kidneys and bladder for patients with microscopic hematuria(defined as >5 RBC/HPF on at least 2 occasions).
Nephrology or urology referral for patients with culture-negative microscopic
hematuria AND abnormal ultrasound and/or abnormal calcium/creatinine ratio.
Urology referral for patients with culture-negative macroscopic hematuria,
incontinence, or dysfunctional voiding.
SYSTEM = Urinary
SCORE
Hemorrhagic cystitis = 2A
All Else = 1wAdditional Information

The bladder is included in the left and right flank/hemiabdomen treatment fields only if the fields extended below the iliac crest.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, especially ≥30 Gy to entire bladder, ≥45 Gy to portion of bladder, combination with cyclophosphamide, ifosfamide or vincristine

References
Hale GA, Marina NM, Jones-Wallace D, et al: Late effects of treatment for germ cell tumors during childhood and adolescence. J Pediatr Hematol Oncol 21:115-22, 1999
Levy A, Martelli H, Fayech C, et al: Late toxicity of brachytherapy after female genital tract tumors treated during childhood: Prospective evaluation with a long-term follow-up. Radiother Oncol 117:206-12, 2015
Marks LB, Carroll PR, Dugan TC, et al: The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys 31:1257-80, 1995
Piver MS, Rose PG: Long-term follow-up and complications of infants with vulvovaginal embryonal rhabdomyosarcoma treated with surgery, radiation therapy, and chemotherapy. Obstet Gynecol 71:435-7, 1988
Raney B, Jr., Heyn R, Hays DM, et al: Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup Rhabdomyosarcoma Study Committee. Cancer
71:2387-94, 1993
Soler R, Macedo A, Jr., Bruschini H, et al: Does the less aggressive multimodal approach of treating bladder-prostate rhabdomyosarcoma preserve bladder function? J Urol 174:2343-6, 2005
Stillwell TJ, Benson RC, Jr.: Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer 61:451-7, 1988
Stillwell TJ, Benson RC, Jr., Burgert EO, Jr.: Cyclophosphamide-induced hemorrhagic cystitis in Ewing’s sarcoma. J Clin Oncol 6:76-82, 1988
Yeung CK, Ward HC, Ransley PG, et al: Bladder and kidney function after cure of pelvic rhabdomyosarcoma in childhood. Br J Cancer 70:1000-3, 1994

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POTENTIAL IMPACT TO
URINARY TRACT (CONT)RADIATION
Sec #89

Therapeutic
Exposure
PelvisSpine (sacral, whole)

Potential
Late Effects
Bladder malignancy

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Bladder Health
COUNSELING
Promptly seek medical attention for dysuria or gross hematuria.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urinalysis, urine culture, spot urine calcium/creatinine ratio for patients withpositive history.
Ultrasound of kidneys and bladder for patients with microscopic hematuria(defined as >5 RBC/HPF on at least 2 occasions).
Nephrology or urology referral for patients with culture-negative microscopic
hematuria AND abnormal ultrasound.
Urology referral for patients with culture-negative macroscopic hematuria.
SYSTEM = SMNSCORE = 2Aw

Additional Information

The bladder is included in the left and right flank/hemiabdomen treatment fields only if the fields extended below iliac crest.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with cyclophosphamide or ifosfamide- Health behaviors: Alcohol use, smoking

References
Chou R, Dana T: Screening adults for bladder cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 153:461-8, 2010
Kersun LS, Wimmer RS, Hoot AC, et al: Secondary malignant neoplasms of the bladder after cyclophosphamide treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer 42:289-91, 2004
Pedersen-Bjergaard J, Ersboll J, Hansen VL, et al: Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin’s lymphoma. N Engl J Med 318:1028-32, 1988
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 52:439-46, 2009
Travis LB, Curtis RE, Glimelius B, et al: Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst 87:524-30, 1995

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POTENTIAL IMPACT TO
MALE REPRODUCTIVE SYSTEMRADIATION
Sec #90

Therapeutic
Exposure
Testes(male)

Potential
Late Effects
Testicular hormonal
dysfunction
Testosterone deficiency/
insufficiency
Delayed/Arrested puberty

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyMonitor growth until mature
YearlySCREENING
AM testosterone in high risk patients
starting at 18 years

w

Health Counseling/
Further Considerations
HEALTH LINKS
Testicular and Reproductive Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Testosterone insufficiency or deficiency requiring hormone replacement after
alkylating agents only is rare.
Endocrine referral for the following:• No signs of puberty by age 14 years• Failure of pubertal progression• Adults with low AM testosterone levels
Periodic re-evaluation of testosterone in males with low normal testosterone asthey age or if they become symptomatic.
Bone density evaluation in androgen deficient patients.
Consider assessment of fertility status prior to initiation of testosterone
replacement therapy.
SYSTEM = Reproductive (Male)SCORE = 1

Additional Information

Testicular volume is not a reliable indicator of pubertal onset/stage in boys treated with alkylating agents and/or direct testicular radiotherapy.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Testicular cancer, testicular irradiation combined with head/brain irradiation, testicular dose ≥12 Gy, combination with alkylating agents, combination with cyclophosphamide conditioning for HCT,
combination with unilateral orchiectomy

References
Chemaitily W, Liu Q, van Iersel L, et al: Leydig cell function in male survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J Clin Oncol 37:3018-31, 2019
Greenfield DM, Walters SJ, Coleman RE, et al: Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab 92:3476-82, 2007
Kenney LB, Antal Z, Ginsberg JP, et al: Improving male reproductive health after childhood, adolescent, and young adult cancer: progress and future directions for survivorship research. J Clin Oncol 36:2160-68, 2018
Leung W, Hudson MM, Strickland DK, et al: Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 18:3273-9, 2000
Lopez R, Plat G, Bertrand Y, et al: Testosterone deficiency in men surviving childhood acute leukemia after treatment with hematopoietic stem cell transplantation or testicular radiation: an L.E.A. study. Bone Marrow Transplant56(6):1422-1425, 2021
Mostafi-Moab S, Seidel K, Leisenring WM, et al: Endocrine abnormalities in aging survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. J Clin Oncol 34:3240-47, 2016
Petersen PM, Giwercman A, Daugaard G, et al: Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis. J Clin Oncol 20:1537-43, 2002
Skinner R, Mulder RL, Kremer LC, et al: Recommendations for gonadotoxiity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guidelines
Harmonization Group in collaboration with the PanCareSurFup Consortium, Lancet Oncol 18:e75-90, 2017
Sklar CA, Robison LL, Nesbit ME, et al: Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer Study Group. J Clin Oncol 8:1981-7, 1990
Sprauten M, Brydoy M, Haugnes HS, et al: Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 32:571-8,
2014
Wilhelmsson M, Vatanen A, Borgstrom B, et al: Adult testicular volume predicts spermatogenetic recovery after allogeneic HSCT in childhood and adolescence. Pediatr Blood Cancer 61:1094-100, 2014

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POTENTIAL IMPACT TO
MALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #91(male)

Therapeutic
Exposure
TestesTBI

Potential
Late Effects
Impaired spermatogenesis
Reduced fertility
Oligospermia
Azoospermia
Infertility

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyHEALTH LINKS

Testicular and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Need for contraception.
Review previous fertility preservation counseling/interventions.
Fertility recovery can be seen in the early years after completion of therapy andoccasionally thereafter.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
For sexually mature patients who desire information about potential future fertility:
semen analysis (optimal) and/or FSH and inhibin B (alternative if unable orunwilling to provide semen sample).
Reproductive endocrinology/urology referral for infertility evaluation and consultation
regarding assisted reproductive technologies.
SYSTEM = Reproductive (Male)SCORE = 1w

Additional Information

Testicular volume is not a reliable indicator of pubertal onset/stage in boys treated with alkylating agents and/or direct testicular radiotherapy.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents)- Cancer/Treatment factors: Testicular cancer, fractionated small doses greater risk than single large doses, radiation dose to testes (up to 6 Gy azoospermia may be transient, ≥6 Gy azoospermia likely permanent and especially testiculardose ≥20 Gy), combination with alkylating agents, genitourinary surgery- Pre-morbid/Co-morbid medical conditions: Obesity, ejaculatory dysfunction, history of sexually transmitted infections, cGVHD- Health behaviors: Tobacco/Marijuana use

References
Anserini P, Chiodi S, Spinelli S, et al: Semen analysis following allogeneic bone marrow transplantation. Additional data for evidence-based counselling. Bone Marrow Transplant 30:447-51, 2002
Couto-Silva AC, Trivin C, Thibaud E, et al: Factors affecting gonadal function after bone marrow transplantation during childhood. Bone Marrow Transplant 28:67-75, 2001
Green DM, Kawashima T, Stovall M, et al: Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 28:332-9, 2010
Grigg AP, McLachlan R, Zaja J, et al: Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant 26:1089-95, 2000
Howell SJ, Shalet SM: Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr:12-7, 2005
Jacob A, Barker H, Goodman A, et al: Recovery of spermatogenesis following bone marrow transplantation. Bone Marrow Transplant 22:277-9, 1998
Kenney LB, Antal Z, Ginsberg JP, et al: Improving male reproductive health after childhood, adolescent, and young adult cancer: progress and future directions for survivorship research. J Clin Oncol 36:2160-68, 2018
Rovo A, Tichelli A, Passweg JR, et al: Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently absence of chronic GvHD. Blood
108:1100-5, 2006
Sklar CA, Robison LL, Nesbit ME, et al: Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer Study Group. J Clin Oncol 8:1981-7, 1990
Sprauten M, Brydoy M, Haugnes HS, et al: Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 32:571-8, 2014

Wasilewski-Masker K, Seidel KD, Leisenring W, et al: Male infertility in long-term survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. J Cancer Surviv 8:437-47, 2014
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POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEMRADIATION
Sec #92(female)Therapeutic
Exposure
PelvisSpine (sacral, whole)
TBI

Potential
Late Effects
Ovarian hormone deficiencies
Delayed puberty
Arrested pubertyPremature ovarian
insufficiency/Prematuremenopause

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Menstrual history
Sexual function (vaginal dryness, libido)
Menopausal symptoms
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyMonitor growth until mature
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive Health
COUNSELING
Review previous fertility preservation counseling/interventions.
Higher cumulative doses of alkylating agents with or without radiation may
increase risk. Dose can be estimated using CED dose calculation located in
section 14.
Adverse impact of ovarian hormone deficiencies on growth, bone mineralization,
cardiovascular disease and sexual dysfunction.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH and estradiol and/or endocrine/gynecology referral for patients with:• No signs of puberty by age 13 years• Failure of pubertal progression• Abnormal menstrual patterns or menopausal symptoms• Ovarian hormone deficiency/insufficiency to weigh risks and benefits of hormonal replacement therapy
Bone density evaluation in patients with ovarian hormone deficiencies.
SYSTEM = Reproductive (Female)
SCORE = 1w

Additional Information

The ovaries are included in the left and right flank/hemiabdomen treatment fields only if the fields extended below the iliac crest.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Older age at irradiation- Cancer/Treatment factors: Radiation dose ≥5 Gy if pubertal (especially ≥10 Gy), dose ≥10 Gy if prepubertal (especially ≥15 Gy), combination with alkylating agent chemotherapy, longer time since treatment, combination withcyclophosphamide conditioning for HCT- Health behaviors: Smoking

References
Chemaitilly W, Li Z, Krasin MJ, et al: Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab 102(7):2242-50, 2017
Chemaitilly W, Mertens AC, Mitby P, et al: Acute ovarian failure in the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 91:1723-8, 2006
Couto-Silva AC, Trivin C, Thibaud E, et al: Factors affecting gonadal function after bone marrow transplantation during childhood. Bone Marrow Transplant 28:67-75, 2001
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 27:2374-81, 2009
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Molinari S, Parissone F, Evasi V, et al: Serum anti-Mullerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal
assessment. Eur J Endocrinol 185:717-728, 2021
Roshandel R, van Dijk M, Overbeek A, et al: LATER-VEVO Study Group. Female reproductive function after treatment of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 68(4):e28894, 2021
Sklar CA, Mertens AC, Mitby P, et al: Premature menopause in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 98:890-6, 2006
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POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #93(female)Therapeutic
Exposure
PelvisSpine (sacral, whole)
TBI

Potential
Late Effects
Diminished Ovarian Reserve(DOR)
Infertility

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Menstrual and pregnancy history
Hormonal Therapy
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyHEALTH LINKS

Ovarian and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
Livestrong Foundation: www.livestrong.org/what-we-do/program/fertility
Oncofertility Consortium: https://oncofertility.msu.edu
COUNSELING
Need for contraception.
Review previous fertility preservation counseling/interventions.
Fertility recovery can be seen in the early years after the completion of therapy andoccasionally thereafter.
Potential for shorter period of fertility in family planning. Those with DOR should consider
discussing reproductive health options with a reproductive endocrinologist or fertility
specialist.
Higher cumulative doses of alkylating agents with or without radiation may increase risk.
Dose can be estimated using CED dose calculation located in section 15.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH and estradiol for patients with menstrual cycle dysfunction suggestive of premature
ovarian insufficiency or those who desire information about potential for future fertility.
AMH to assess for diminished ovarian reserve.
Reproductive endocrinology referral for antral follicle count, ovarian reserve evaluationand consultation regarding assisted reproductive technologies in at-risk patients who
desire information about potential fertility and interventions to preserve future fertility.
SYSTEM = Reproductive (Female)
SCORE = 1w

Additional Information

The ovaries are included in the left and right flank/hemiabdomen treatment fields only if the fields extended below the iliac crest.
AMH may be low in the presence of normal FSH. AMH should be interpreted relative to age-specific reference ranges. FSH is lowered and AMH may be lowered by concurrent hormonal contraceptive use.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Older age at irradiation- Cancer/Treatment factors: Radiation dose ≥5 Gy if pubertal (especially ≥10 Gy), radiation dose ≥10 Gy if prepubertal (especially ≥15 Gy), combination with alkylating agent chemotherapy, longer time since treatment, combination with cyclophosphamide conditioning for HCT- Health behaviors: Smoking

References
Chemaitilly W, Li Z, Krasin MJ, et al: Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab 102(7):2242-50, 2017
Couto-Silva AC, Trivin C, Thibaud E, et al: Factors affecting gonadal function after bone marrow transplantation during childhood. Bone Marrow Transplant 28:67-75, 2001
Gao W, Liang JX, Yan Q: Exposure to radiation therapy is associated with female reproductive health among childhood cancer survivors: a meta-analysis study. J Assist Reprod Genet 32:1179-86, 2015
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POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Section 93 References (cont)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 27:2677-2685, 2009
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 27:2374-81, 2009
Levine JM, Kelvin JF, Quinn GP, et al: Infertility in reproductive-age female cancer survivors. Cancer 121:1532-9, 2015
Lie Fong S, Laven JS, Hakvoort-Cammel FG, et al: Assessment of ovarian reserve in adult childhood cancer survivors using anti-Mullerian hormone. Hum Reprod 24:982-90, 2009
Lunsford AJ, Whelan K, McCormick K, et al: Anti-Mullerian hormone as a measure of reproductive function in female childhood cancer survivors. Fertil Steril 101:227-31, 2014
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Sudour H, Chastagner P, Claude L, et al: Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors. Int J Radiat Oncol Biol Phys 76:867-73, 2010

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POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #94(female)Therapeutic
Exposure
PelvisSpine (sacral, whole)
TBI

Potential
Late Effects

Periodic Evaluation

Uterine vascular insufficiency HISTORY
Resulting in adverse pregnancy Pregnancy
outcomes such as:Childbirth history• Spontaneous abortion
Yearly for women of reproductive age• Neonatal death• Low-birth weight infant• Fetal malposition• Premature labor

Health Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
High-level ultrasound evaluation of genitourinary tract after pubertal
development as clinically indicated in patients contemplating pregnancy.
High-risk obstetrical care during pregnancy.
SYSTEM = Reproductive (Female)
SCORE = 2Bw

Additional Information

The uterus is included in the left and right flank/hemiabdomen treatment fields only if the fields extended below iliac crest.
10% of girls with Wilms tumor have congenital uterine anomalies.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Wilms tumor and associated Mullerian anomalies (i.e., agenesis, hypoplasia), prepubertal at time of treatment- Cancer/Treatment factors: TBI, higher radiation dose to pelvis, radiation dose ≥30 Gy

References
Gao W, Liang JX, Yan Q: Exposure to radiation therapy is associated with female reproductive health among childhood cancer survivors: a meta-analysis study. J Assist Reprod Genet 32:1179-86, 2015
Green DM, Lange JM, Peabody EM, et al: Pregnancy outcome after treatment for Wilms tumor: a report from the national Wilms tumor long-term follow-up study. J Clin Oncol 28:2824-30, 2010
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Rozen G, Rogers P, Chander S, et al: Clinical summary guide: reproduction in women with previous abdominopelvic radiotherapy or total body irradiation. Hum Reprod Open 25(4):hoaa045, 2020
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 98:1453-61, 2006
Signorello LB, Mulvihill JJ, Green DM, et al: Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 376:624-30, 2010
van de Loo LEXM, van den Berg MH, Overbeek A, et al: Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors. Fertil Steril 111(2):372-380, 2019
Winther JF, Boice JD, Jr., Svendsen AL, et al: Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors. J Clin Oncol 26:4340-6, 2008

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POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #95

Therapeutic
Exposure
PelvisPotential
Late Effects
Vaginal fibrosis/stenosis(female)w

Periodic Evaluation
HISTORY
Psychosocial assessment
Dyspareunia
Post-coital bleeding
Difficulty with tampon insertion
Vaginal dryness
Vulvar pain/tenderness
Vulvovaginal burning or pruritus
Dysuria
YearlyPHYSICAL
Exam of external genitalia
YearlyHealth Counseling/
Further Considerations
COUNSELING
Avoid frequent contact with irritants (e.g., bubble bath, wet wipes and soaps).
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation for management.
Psychological consultation in patients with emotional difficulties.
SYSTEM = Reproductive (Female)
SCORE = 2A

Additional Information

The vagina is included in the left and right flank/hemiabdomen treatment fields only if the fields extended below iliac crest.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Vaginal tumor or pelvic tumor adjacent to vagina, radiation dose ≥50 Gy if postpubertal (especially dose ≥55 Gy), radiation dose ≥25 Gy if prepubertal (especially dose ≥35 Gy)- Pre-morbid/Co-morbid medical conditions: cGVHD

References
Flamant F, Gerbaulet A, Nihoul-Fekete C, et al: Long-term sequelae of conservative treatment by surgery, brachytherapy, and chemotherapy for vulval and vaginal rhabdomyosarcoma in children. J Clin Oncol 8:1847-53, 1990
Gaillard P, Krasin MJ, Laningham FH, et al: Hematometrocolpos in an adolescent female treated for pelvic Ewing sarcoma. Pediatr Blood Cancer 50:157-60, 2008
Levy A, Martelli H, Fayech C, et al: Late toxicity of brachytherapy after female genital tract tumors treated during childhood: Prospective evaluation with a long-term follow-up. Radiother Oncol 117:206-12, 2015
Magne N, Oberlin O, Martelli H, et al: Vulval and vaginal rhabdomyosarcoma in children: update and reappraisal of Institut Gustave Roussy brachytherapy experience. Int J Radiat Oncol Biol Phys 72:878-83, 2008
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Schover LR: Sexuality and fertility after cancer. Hematology Am Soc Hematol Educ Program:523-7, 2005
Spunt SL, Sweeney TA, Hudson MM, et al: Late effects of pelvic rhabdomyosarcoma and its treatment in female survivors. J Clin Oncol 23:7143-51, 2005

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POTENTIAL IMPACT TO
MUSCULOSKELETAL SYSTEMRADIATION
Sec #
96

w

Therapeutic
Exposure

Potential
Late Effects

Any Radiation (Including
TBI)

Musculoskeletal growth
problems
Hypoplasia
Fibrosis
Reduced or uneven growth
Shortened trunk height (trunkradiation)
Limb length discrepancy(extremity radiation)

Periodic Evaluation
PHYSICAL
HeightWeightYearlySitting height
Yearly for patients who had trunk radiation

Health Counseling/
Further Considerations
COUNSELING
Increased risk of fractures in weight-bearing irradiated bones.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Orthopedic consultation for any deficit noted in growing child.
Plastic surgery consult for reconstruction.
SYSTEM = Musculoskeletal
SCORE = 1

Limb lengths
Yearly for patients who had extremity radiation

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially prepubertal at treatment- Cancer/Treatment factors: Higher cumulative radiation dose, especially dose ≥20 Gy, larger radiation treatment field, higher radiation dose per fraction, orthovoltage radiation (commonly used before 1970) due to delivery ofgreater dose to skin and bones, epiphysis in treatment field

References
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 150:370-5, 375 e1, 2007
Chow EJ, Liu W, Srivastava K, et al: Differential effects of radiotherapy on growth and endocrine function among acute leukemia survivors: a Childhood Cancer Survivor Study report. Pediatr Blood Cancer 60:110-5, 2013
Fletcher BD: Effects of pediatric cancer therapy on the musculoskeletal system. Pediatr Radiol 27:623-36, 1997
Gawade PL, Hudson MM, Kaste SC, et al: A systematic review of selected musculoskeletal late effects in survivors of childhood cancer. Curr Pediatr Rev 10:249-62, 2014
Hogeboom CJ, Grosser SC, Guthrie KA, et al: Stature loss following treatment for Wilms tumor. Med Pediatr Oncol 36:295-304, 2001
Linsenmeier C, Thoennessen D, Negretti L, et al: Total body irradiation (TBI) in pediatric patients. A single-center experience after 30 years of low-dose rate irradiation. Strahlenther Onkol 186:614-20, 2010
Merchant TE, Nguyen L, Nguyen D, et al: Differential attenuation of clavicle growth after asymmetric mantle radiotherapy. Int J Radiat Oncol Biol Phys 59:556-61, 2004
Noorda EM, Somers R, van Leeuwen FE, et al: Adult height and age at menarche in childhood cancer survivors. Eur J Cancer 37:605-12, 2001
Probert JC, Parker BR: The effects of radiation therapy on bone growth. Radiology 114:155-62, 1975
Rohde RS, Puhaindran ME, Morris CD, et al: Complications of radiation therapy to the hand after soft tissue sarcoma surgery. J Hand Surg Am 35:1858-63, 2010

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POTENTIAL IMPACT TO
MUSCULOSKELETAL SYSTEM (CONT)RADIATION
Sec #97

Therapeutic
Exposure
Chest
AbdomenSpine (thoracic, lumbar,
whole)

Potential
Late Effects
Scoliosis/Kyphosis

Periodic Evaluation

Health Counseling/
Further Considerations

PHYSICALHEALTH LINKS
Exam of back/spine
Scoliosis and Kyphosis
Yearly until growth completed, may need more POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
frequent assessment during puberty or if
Spine films in patients with clinically apparent curve.
curve detected
Orthopedic consultation as indicated based on physical and/or radiographic
exam.
SYSTEM = Musculoskeletal
SCORE = 1w

Additional Information

With contemporary treatment approaches, scoliosis is infrequently seen as a consequence of radiation unless the patient has also undergone surgery to the hemithorax, abdomen or spine.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at irradiation- Cancer/Treatment factors: Paraspinal malignancies, hemithoracic, abdominal or spinal surgery, hemithoracic or abdominal radiation, radiation of only a portion of (rather than whole) vertebral body, radiation doses ≥20 Gy(lower doses for infants), orthovoltage radiation (commonly used before 1970)- Pre-morbid/Co-morbid medical conditions: Neurofibromatosis

Referencesde Jonge T, Slullitel H, Dubousset J, et al: Late-onset spinal deformities in children treated by laminectomy and radiation therapy for malignant tumours. Eur Spine J 14:765-71, 2005
Gawade PL, Hudson MM, Kaste SC, et al: A systematic review of selected musculoskeletal late effects in survivors of childhood cancer. Curr Pediatr Rev 10:249-62, 2014
Interiano RB, Kaste SC, Li C, et al: Associations between treatment, scoliosis, pulmonary function, and physical performance in long-term survivors of sarcoma. J Cancer Surviv 11(5),553–561, 2017Laverdiere C, Liu Q, Yasui Y, et al: Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 101:1131-40, 2009
Marcus RB, Esiashivilli N: Musculoskeletal, Integument, in Schwartz CL, Hobbie WL, Constine LS, et al (eds): Survivors of Childhood and Adolescent Cancer: A Multidisciplinary Approach. Switzerland, Springer International Publishing,
2015, pp pp. 297-324
Oshiro Y, Mizumoto M, Pan H, et al: Spinal changes after craniospinal irradiation in pediatric patients. Pediatr Blood Cancer 67(12):e28728, 2020
Paulino AC, Mayr NA, Simon JH, et al: Locoregional control in infants with neuroblastoma: role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys 52:1025-31, 2002
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 46:1239-46, 2000

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POTENTIAL IMPACT TO
MUSCULOSKELETAL SYSTEM (CONT)RADIATION
Sec #98

Therapeutic
Exposure
Any Radiation (notincluding TBI)

Potential
Late Effects
Radiation-induced fracture

Periodic Evaluation
PHYSICAL
Pain, swelling, deformity of bone
As clinically indicatedHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTIONRadiograph of affected bone as clinically indicated.
Orthopedic evaluation as clinically indicated.
SYSTEM = Musculoskeletal
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: History of surgery to cortex of bone, radiation dose ≥40 Gy, radiation dose ≥50 Gy to bone

References
Blaes AH, Lindgren B, Mulrooney DA, et al: Pathologic femur fractures after limb-sparing treatment of soft-tissue sarcomas. J Cancer Surviv 4:399-404, 2010
Cannon CP, Lin PP, Lewis VO, et al: Management of radiation-associated fractures. J Am Acad Orthop Surg 16:541-9, 2008
Im C, Li N, Moon W, et al: Genome-wide association studies reveal novel locus with sex-/therapy-specific fracture risk effects in childhood cancer survivors. J Bone Miner Res 36(4):685-695, 2021
Paulino AC: Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 60:265-74, 2004

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HEMATOPOIETIC CELL TRANSPLANT

INSTRUCTIONS

Hematopoietic Cell Transplant Introductory Information•

Complications after HCT have multifactorial etiologies, including prior therapy forprimary malignancy, intensity of transplant conditioning, stem cell product (e.g.,marrow, cord blood, peripheral stem cells), donor (e.g., autologous, allogeneic,
unrelated), quality of donor to recipient match, complications of the transplant
process (immunosuppression and GVHD), complications in the post-transplant period,
underlying disease, host genetic factors, and lifestyle behaviors.

Total Body Irradiation (TBI) Related Potential Late Effects
SectionNumberSex

Potential Late Effect

44

Both

Subsequent benign or malignant neoplasm occurring in ornear radiation field

45

Both

Dermatologic toxicity

46

Both

Brain tumor (benign or malignant)

47

Both

Neurocognitive deficits•

This section includes late treatment complications that may be observed inhematopoietic cell transplant recipients not covered elsewhere in these guidelines.

•

Refer to other sections of these guidelines for specific details related to latecomplications of radiation and of specific chemotherapeutic agents.

48

Both

Clinical leukoencephalopathy

53

Both

Growth hormone deficiency•

For HCT follow-up recommendations from the European Group for Blood and Marrow
Transplantation, Center for International Blood and Marrow Transplant Research, and
the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT),
see: Majhail NS, Rizzo JD, Lee SJ, et al: Recommended screening and preventive
practices for long-term survivors after hematopoietic cell transplantation. Bone
Marrow Transplant 47:337-41, 2012.

58

Male

Gonadotropin deficiency

59

FemaleGonadotropin deficiency

61

Both

Cataracts

64

Both

Xerostomia; Salivary gland dysfunction

65

Both

Dental abnormalities; Temporomandibular joint dysfunction

For the Children’s Oncology Group Report regarding late effects surveillance
recommendations among survivors of childhood hematopoietic cell transplantation,see: Chow EJ, Anderson L, Baker KS, et al: Late Effects Surveillance
Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation:
A Children’s Oncology Group Report. Biol Blood Marrow Transplant 22:782-95, 2016.

67

Both

Thyroid nodules

68

Both

Thyroid cancer

69

Both

Hypothyroidism

73

FemaleBreast cancer

74

FemaleBreast tissue hypoplasia

75

Both

Pulmonary toxicity

76

Both

Lung cancer

80

Both

Impaired glucose metabolism/diabetes mellitus

81

Both

Dyslipidemia

86

Both

Colorectal cancer

87

Both

Renal toxicity

91

Male

Impaired spermatogenesis

92

FemaleOvarian hormone deficiencies

93

FemaleDiminished ovarian reserve

94

FemaleUterine vascular insufficiency

96

Both

Musculoskeletal growth problems•

Total Body Irradiation (TBI) Related Potential Late Effects•

The complete list of potential late effects and associated Guideline section numbers
are included on the accompanying table for clinician convenience when evaluating
patients who received TBI. For details regarding each potential late effect andindicated screening, please refer to the relevant section within the Guidelines.

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HEMATOPOIETIC CELL TRANSPLANT
Sec #
99

w

Therapeutic
Exposure

Potential
Late Effects

Autologous
Hematopoietic Cell
Transplant (HCT)Acute myeloid leukemia(AML)
Myelodysplasia (MDS)

Periodic Evaluation
HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after transplant
PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after transplant

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.
SYSTEM = SMNSCORE = 1

Additional Information

There is negligible benefit to obtaining a screening CBC in the absence of clinical signs and symptoms for AML/MDS.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Older age at transplant- Cancer/Treatment factors: Radiation therapy, alkylating agent chemotherapy, epipodophyllotoxins, anthracyclines, history of non-Hodgkin and Hodgkin lymphoma, peripheral blood stem cells as the stem cell source- Pre-morbid/Co-morbid medical conditions: Evidence is conflicting that splenectomy modifies risk for AML/MDS

References
Allodji RS, Schwartz B, Veres C, et al: Risk of subsequent leukemia after a solid tumor in childhood: impact of bone marrow radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 93:658-67, 2015
Baker KS, DeFor TE, Burns LJ, et al: New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol 21:1352-8, 2003
Bhatia S: Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol 40:666-75, 2013
Bhatia S, Ramsay NK, Steinbuch M, et al: Malignant neoplasms following bone marrow transplantation. Blood 87:3633-9, 1996
Danner-Koptik KE, Majhail NS, Brazauskas R, et al: Second malignancies after autologous hematopoietic cell transplantation in children. Bone Marrow Transplant 48:363-8, 2013
Kalaycio M, Rybicki L, Pohlman B, et al: Risk factors before autologous stem-cell transplantation for lymphoma predict for secondary myelodysplasia and acute myelogenous leukemia. J Clin Oncol 24:3604-10, 2006
Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors. Blood 95:1588-93, 2000
Landier W, Armenian SH, Lee J, et al: Yield of screening for long-term complications using the Children’s Oncology Group long-term follow-up guidelines. J Clin Oncol 30:4401-8, 2012
Pole JD, Darmawikarta D, Gassas A, et al: Subsequent malignant neoplasms in pediatric cancer patients treated with and without hematopoietic SCT. Bone Marrow Transplant 50:721-6, 2015
Rihani R, Bazzeh F, Faqih N, et al: Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer 116:4385-94, 2010

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HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
100
(male)

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Solid tumors
Such as basal cell carcinoma,
melanoma, liver cancer

Periodic Evaluation
PHYSICAL
Skin self exam
Monthly
Dermatologic exam
Abdominal exam
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
COUNSELING
Importance of sun protection measures.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Dermatology and/or oncology consultation as clinically indicated.
SYSTEM = SMNSCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at transplant- Cancer/Treatment factors: Radiation therapy (especially TBI), second HCT, umbilical cord blood HCT, haploidentical HCT, unrelated donor transplant, HLA mismatch, T-cell depletion, ATG- Pre-morbid/Co-morbid medical conditions: Hepatitis C infection, cGVHD, Fanconi anemia, primary immune deficiency

References
Baker KS, DeFor TE, Burns LJ, et al: New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol 21:1352-8, 2003
Bhatia S, Louie AD, Bhatia R, et al: Solid cancers after bone marrow transplantation. J Clin Oncol 19:464-71, 2001
Bhatia S, Ramsay NK, Steinbuch M, et al: Malignant neoplasms following bone marrow transplantation. Blood 87:3633-9, 1996
Curtis RE, Metayer C, Rizzo JD, et al: Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood 105:3802-11, 2005
Curtis RE, Rowlings PA, Deeg HJ, et al: Solid cancers after bone marrow transplantation. N Engl J Med 336:897-904, 1997
Leisenring W, Friedman DL, Flowers ME, et al: Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol 24:1119-26, 2006
Majhail NS, Brazauskas R, Rizzo JD, et al: Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood 117:316-22, 2011
Pole JD, Darmawikarta D, Gassas A, et al: Subsequent malignant neoplasms in pediatric cancer patients treated with and without hematopoietic SCT. Bone Marrow Transplant 50:721-6, 2015
Rizzo JD, Curtis RE, Socie G, et al: Solid cancers after allogeneic hematopoietic cell transplantation. Blood 113:1175-83, 2009
Schwartz JL, Kopecky KJ, Mathes RW, et al: Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation. Radiat Res 171:155-63, 2009
Socie G, Curtis RE, Deeg HJ, et al: New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 18:348-57, 2000
Witherspoon RP, Fisher LD, Schoch G, et al: Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 321:784-9, 1989

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HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
101
(female)Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Solid tumors
Such as basal cell carcinoma,
melanoma, liver cancer, cervicalcancerPeriodic Evaluation
PHYSICAL
Skin self exam
Monthly
Dermatologic exam
Abdominal exam
YearlyPelvic exam
Every 3-5 years beginning at age 21 years (see“Screening” below for specific recommendations)
SCREENING
Cervical PAP smear
Cervical cancer screening should begin at age 21
years
Women: 21 to 29 years: PAP test every 3 years.
Women: 30 to 65 years: HPV and PAP test every 5
years (optimal), or PAP test alone every 3 years(alternative).
Women: >65 years: No testing for cervical cancer ifnormal screening results in past 10 years.

w

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Subsequent Cancers
COUNSELING
Importance of sun protection measures.
Safer sexual practices to reduce HPV transmission.
Importance of HPV vaccination.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Dermatology, gynecology and/or oncology consultation as clinically indicated.
HPV vaccination per current recommendations.
SYSTEM = SMNSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at transplant- Cancer/Treatment factors: Radiation therapy (especially TBI), second HCT, umbilical cord blood HCT, haploidentical HCT, unrelated donor transplant, HLA mismatch, T-cell depletion, ATG- Pre-morbid/Co-morbid medical conditions: Hepatitis C infection, HPV infection, cGVHD, Fanconi anemia, primary immune deficiency

References
Baker KS, DeFor TE, Burns LJ, et al: New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol 21:1352-8, 2003
Bhatia S, Louie AD, Bhatia R, et al: Solid cancers after bone marrow transplantation. J Clin Oncol 19:464-71, 2001
Bhatia S, Ramsay NK, Steinbuch M, et al: Malignant neoplasms following bone marrow transplantation. Blood 87:3633-9, 1996
Curtis RE, Metayer C, Rizzo JD, et al: Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood 105:3802-11, 2005
Curtis RE, Rowlings PA, Deeg HJ, et al: Solid cancers after bone marrow transplantation. N Engl J Med 336:897-904, 1997Friedman 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 111:939-44, 2008
Leisenring W, Friedman DL, Flowers ME, et al: Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol 24:1119-26, 2006
Majhail NS, Brazauskas R, Rizzo JD, et al: Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood 117:316-22, 2011
Ojha RP, Tota JE, Offutt-Powell TN, et al: Human papillomavirus-associated subsequent malignancies among long-term survivors of pediatric and young adult cancers. PLoS One 8:e70349, 2013
Pole JD, Darmawikarta D, Gassas A, et al: Subsequent malignant neoplasms in pediatric cancer patients treated with and without hematopoietic SCT. Bone Marrow Transplant 50:721-6, 2015
Rizzo JD, Curtis RE, Socie G, et al: Solid cancers after allogeneic hematopoietic cell transplantation. Blood 113:1175-83, 2009
Schwartz JL, Kopecky KJ, Mathes RW, et al: Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation. Radiat Res 171:155-63, 2009
Socie G, Curtis RE, Deeg HJ, et al: New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 18:348-57, 2000
Witherspoon RP, Fisher LD, Schoch G, et al: Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 321:784-9, 1989
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Sec #
102

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Hepatic toxicity
Chronic hepatitis
Cirrhosis
Iron overload
Cholelithiasis
FNH

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly
YearlySCREENING
ALT
AST
Bilirubin
Ferritin
Baseline at entry into long-term follow-up,
repeat as clinically indicated

HEALTH LINKS
Liver Health
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Platelet count to evaluate hypersplenism and prothrombin time fto evaluate
hepatic synthetic function in patients with abnormal liver screening tests.
Screen for viral hepatitis in patients with persistently abnormal liver function or
any patient transfused prior to 1993.
PCR testing for HCV in immunosuppressed patients negative for antibody.
Gastroenterology/Hepatology consultation in patients with persistent liver
dysfunction or known hepatitis.
Hepatitis A and B immunization in at-risk patients lacking immunity.
T2* MRI for evaluation of liver iron content.
Liver biopsy in patients with evidence of excessive liver iron content (based onclinical context and magnitude of elevation).
Phlebotomy or chelation therapy for treatment of iron overload.
SYSTEM = GI/Hepatic
SCORE = 1w

Additional Information

FNH is a benign change that represents a scar in the liver.
FNH is usually an asymptomatic finding noted on MRI or ultrasound of the liver.
Continued observation or biopsy may be indicated depending on individual patient factors and imaging features.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: History of multiple transfusions, radiation to the liver, antimetabolite therapy- Pre-morbid/Co-morbid medical conditions: cGVHD, viral hepatitis, history of SOS, chronic hepatitis C with siderosis, steatosis, cholelithiasis- Health behaviors: Alcohol use (in relation to hepatic fibrosis and cirrhosis)

References
Castellino S, Muir A, Shah A, et al: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr Blood Cancer 54:663-9, 2010
Hoffmeister PA, Storer BE, McDonald GB, et al: Gallstones in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up. J Pediatr Hematol Oncol 36:484-90, 2014
Masetti R, Colecchia A, Rondelli R, et al: Benign hepatic nodular lesions after treatment for childhood cancer. J Pediatr Gastroenterol Nutr 56:151-5, 2013
McDonald GB: Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology 51:1450-60, 2010
McKay PJ, Murphy JA, Cameron S, et al: Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. Bone Marrow Transplant 17:63-6, 1996
Mulder RL, van Dalen EC, Van den Hof M, et al: Hepatic late adverse effects after antineoplastic treatment for childhood cancer. Cochrane Database Syst Rev:CD008205, 2011
Peffault de Latour R, Levy V, Asselah T, et al: Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 103:1618-24, 2004
Pillon M, Carucci NS, Mainardi C, et al: Focal nodular hyperplasia of the liver: an emerging complication of hematopoietic SCT in children. Bone Marrow Transplant 50:414-9, 2015
Schempp A, Lee J, Kearney S, et al: Iron overload in survivors of childhood cancer. J Pediatr Hematol Oncol 38(1):27-31, 2016

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w

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Osteonecrosis (avascularnecrosis)

Periodic Evaluation
HISTORY
Joint pain
Swelling
Immobility
Limited range of motion
YearlyPHYSICAL
Musculoskeletal exam
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Osteonecrosis
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
MRI as clinically indicated.
Orthopedic consultation in patients with positive imaging and/or symptoms ofosteonecrosis.
Physical therapy evaluation (for non-pharmacologic pain management, range of
motion, strengthening, stretching, functional mobility).
SYSTEM = Musculoskeletal
SCORE = 1

Additional Information

Osteonecrosis typically occurs during the acute treatment phase, may progress over time or resolve.
Multifocal osteonecrosis is significantly more common (3:1) than unifocal.
Symptomatic lesions confer the greatest risk for collapse.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Being pubertal or post-pubertal at time of transplant- Cancer/Treatment factors: Corticosteroids (dexamethasone effect is more potent than prednisone), other immunosuppressants, prolonged immunosuppressive therapy (e.g., for cGVHD), TBI, high dose radiation to any bone,allogeneic HCT > autologous HCT- Pre-morbid/Co-morbid medical conditions: Sickle cell disease, cGVHD, pre-transplant osteonecrosis

References
Campbell S, Sun CL, Kurian S, et al: Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation. Cancer 115:4127-35, 2009
Faraci M, Calevo MG, Lanino E, et al: Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica 91:1096-9, 2006
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 26:3038-45, 2008
Karimova EJ, Wozniak A, Wu J, et al: How does osteonecrosis about the knee progress in young patients with leukemia?: a 2- to 7-year study. Clin Orthop Relat Res 468:2454-9, 2010
Kuhlen M, Bader P, Sauer M, et al: Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial. Br J Haematol 183(1):104-109, 2018
Leung W, Ahn H, Rose SR, et al: A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86:215-24, 2007
Mattano LA, Jr., Sather HN, Trigg ME, et al: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol 18:3262-72, 2000
Schulte CM, Beelen DW: Avascular osteonecrosis after allogeneic hematopoietic stem-cell transplantation: diagnosis and gender matter. Transplantation 78:1055-63, 2004
Sun CL, Francisco L, Kawashima T, et al: Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood 116:3129-39; quiz 3377, 2010

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HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
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Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Reduced bone mineral density(BMD)
Defined as Z-score >2 SD below
the mean in male survivors <50
years old and premenopausal
women or T-score >1 SD below
the mean in male survivors >50
years old and postmenopausal
women

Periodic Evaluation
SCREENING
Bone density evaluation (DXA)
Adjust for height-age Z-score in survivors <age
20 years*Baseline BMD at entry into long-term follow-up (2to 5 years after completion of therapy) with thefollowing recommended actions:• If Z-score >1 SD above the mean (normal),repeat at 25 years of age when peak bone mass
should be achieved• Between these two measurements and thereafter, screen as clinically indicated based on BMD
and ongoing risk assessment• If Z-score >2 SD below the mean, referral to (orconsultation of) a bone health specialist• If Z-score >1 and <2 SD below the mean,evaluation for endocrine defects (e.g., hypogonadism or GH deficiency) and consultation with abone health specialist for further evaluation andinterpretation of findings as clinically indicated.
Repeat DXA after 2 years and thereafter as clinically indicated based on BMD change (i.e., BMD
decline is greater than the DXA least significant
change) and ongoing risk assessment

Health Counseling/
Further Considerations
HEALTH LINKS
Bone HealthRESOURCES
National Osteoporosis Foundation: www.nof.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ensure the AAP recommended minimum daily intake of vitamin D (400 IU/day) for infants<12 months, 600 IU/day for those aged 12 months through aged 70 years, 800 IU/day
for those >70 years
Ensure adequate dietary calcium (see table in the “Bone Health” Health Link for ageappropriate recommendations). Supplements may be necessary if there are dietary
restrictions.
Use caution regarding calcium supplementation in patients with history of renal lithiasis.
Advocate for regular weight-bearing exercises such as running and jumping.
Treat exacerbating or predisposing conditions (e.g., hormonal replacement therapy
for hypogonadism, GH deficiency, correction of chronic metabolic acidosis that could
accelerate bone loss).
Endocrine consultation for patients with osteoporosis or history of multiple fractures
for pharmacologic interventions (e.g., bisphosphonates, calcitonin, selective estrogen
receptor modulators).
SYSTEM = Musculoskeletal
SCORE = 2B

*Pediatric Z-score calculator adjusted forheight age: https://zscore.research.chop.edu/
calcpedbonedens.phpw

Additional Information

The World Health Organization definition of osteoporosis in adults is based on comparison of a measured BMD of young adults at peak bone age and defined as a T-score.
A T-score is the number of standard deviations the BMD measurement is above or below the mean.
Current definitions of osteopenia (T-scores between 1.0 and 2.5 SD below the mean) and osteoporosis (T-scores >2.5 SD below the mean) were developed primarily in the context of postmenopausal women. In this population, T-scores have awell-validated correlation with fracture risk that increases with age.
The fracture risk associated with T-scores in younger populations, including cancer survivors with treatment-related hypogonadism, has not been established.
T-scores are not appropriate to assess skeletal health in pediatric patients who have not achieved peak adult bone mass.
Pediatric BMD reference data sets calculate Z-scores based on age and gender.
A Z-score is the number of standard deviations the measurement is above or below the age-matched mean BMD.
The fracture risk in pediatric patients with low bone density for chronologic age based on Z-scores has not been established.
There are no defined standards for referral or treatment of low BMD in children.

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HEMATOPOIETIC CELL TRANSPLANT (CONT)
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Caucasian race, lower weight/BMI.
- Cancer/Treatment factors: Corticosteroids (especially prolonged therapy, e.g., for cGVHD), CRT, craniospinal radiation, HCT/TBI- Pre-morbid/Co-morbid medical conditions: GH deficiency, hypogonadism/delayed puberty, hyperthyroidism, central and primary hypogonadism- Health behaviors: Intake of calcium and vitamin D, intake of alcohol and carbonated beverages, lack of weight bearing exercise, smoking

References
Bischoff-Ferrari HA: Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol 624:55-71, 2008
Buxbaum NP, Robinson C, Sinaii N, et al: Impaired bone mineral density in pediatric patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant 24(7):1415-23, 2018
Chemaitilly W, Li Z, Krasin MJ, et al: Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab 102(7):2242-50, 2017
Chemaitilly W, Sklar CA: Endocrine complications of hematopoietic stem cell transplantation. Endocrinol Metab Clin North Am 36:983-98; ix, 2007
Cho WK, Ahn MB, Lee JW, et al: Low bone mineral density in adolescents with leukemia after hematopoietic stem cell transplantation: prolonged steroid therapy for GvHD and endocrinopathy after hematopoietic stem cell transplantation might bemajor concerns? Bone Marrow Transplant 52(1):144-6, 2017
Kaste SC, Shidler TJ, Tong X, et al: Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant 33:435-41, 2004
Klopfenstein KJ, Clayton J, Rosselet R, et al: Prevalence of abnormal bone density of pediatric patients prior to blood or marrow transplant. Pediatr Blood Cancer 53:675-7, 2009
Landier W, Armenian SH, Lee J, et al: Yield of screening for long-term complications using the Children’s Oncology Group long-term follow-up guidelines. J Clin Oncol 30:4401-8, 2012
Le Meignen M, Auquier P, Barlogis V, et al: Bone mineral density in adult survivors of childhood acute leukemia: impact of hematopoietic stem cell transplantation and other treatment modalities. Blood 118:1481-9, 2011
McDonald L, Luke J, Jude V, et al: Development of an evidence-based clinical guideline for age-appropriate screening, prevention, and management of bone abnormalities in children post-hematopoietic stem cell transplant. J Pediatr Oncol Nurs
30:78-89, 2013
NIH Office of Dietary Supplements: Vitamin D health professionals fact sheet. Accessed March 16, 2023: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional
Polgreen LE, Petryk A, Dietz AC, et al: Modifiable risk factors associated with bone deficits in childhood cancer survivors. BMC Pediatr 12:40, 2012
Ruble K: Skeletal complications after bone marrow transplant in childhood. J Pediatr Oncol Nurs 25:79-85, 2008
The International Society for Clinical Densitometry. 2019 ISCD official positions. Accessed March 2023: https://iscd.org/learn/official-positions
Tylavsky FA, Smith K, Surprise H, et al: Nutritional intake of long-term survivors of childhood acute lymphoblastic leukemia: evidence for bone health interventional opportunities. Pediatr Blood Cancer 55:1362-9, 2010
van Atteveld JE, Mulder RL, van den Heuvel-Eibrink MM, et al. Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood
Cancer Guideline Harmonization Group. Lancet Diabetes Endocrinol 9(9):622-637, 2021
Zemel BS, Leonard MB, Kelly A, et al: Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab 95:1265-73, 2010

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HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
105

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Renal toxicity
Glomerular injury
Renal insufficiency
Hypertension
Tubular injury (renal tubularacidosis, Fanconi syndrome,
hypophosphatemic rickets)

Periodic Evaluation
PHYSICAL
Blood pressure
YearlySCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Kidney Health
Cardiovascular Risk Factors
COUNSELINGIn patients with salt-wasting tubular dysfunction, educate that low magnesium
levels potentiate coronary atherosclerosis.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTIONElectrolyte supplements for patients with persistent electrolyte wasting.
Nephrology consultation for patients with hypertension or progressive renal
insufficiency.
SYSTEM = Urinary
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Older age- Cancer/Treatment factors: Chronic cyclosporine use, TBI- Pre-morbid/Co-morbid medical conditions: Acute kidney injury within 6 months of HCT, history of cGVHD

References
Abboud I, Porcher R, Robin M, et al: Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15:1251-7, 2009
Al-Hazzouri A, Cao Q, Burns LJ, et al: Similar risks for chronic kidney disease in long-term survivors of myeloablative and reduced-intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 14:658-63, 2008
Ando M, Ohashi K, Akiyama H, et al: Chronic kidney disease in long-term survivors of myeloablative allogeneic haematopoietic cell transplantation: prevalence and risk factors. Nephrol Dial Transplant 25:278-82, 2010
Ceremuzynski L, Gebalska J, Wolk R, et al: Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. J Intern Med 247:78-86, 2000
Choi M, Sun CL, Kurian S, et al: Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation. Cancer 113:1580-7, 2008
Ellis MJ, Parikh CR, Inrig JK, et al: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8:2378-90, 2008
Esiashvili N, Chiang KY, Hasselle MD, et al: Renal toxicity in children undergoing total body irradiation for bone marrow transplant. Radiother Oncol 90:242-6, 2009
Gerstein J, Meyer A, Sykora KW, et al: Long-term renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT). Strahlenther Onkol 185:751-5, 2009
Hoffmeister PA, Hingorani SR, Storer BE, et al: Hypertension in long-term survivors of pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant 16:515-24, 2010
Majhail NS, Challa TR, Mulrooney DA, et al: Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 15:1100-7, 2009
Nieder ML, McDonald GB, Kida A, et al: National Cancer Institute-National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatrichematopoietic cell transplantation: long-term organ damage and dysfunction. Biol Blood Marrow Transplant 17:1573-84, 2011

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Therapeutic
Exposure

Potential
Late Effects

Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Dermatologic toxicity
Permanent alopecia
Nail dystrophy
Vitiligo
Sclerodermatous changes
Squamous cell carcinoma of
the skin
Melanoma
Altered skin pigmentation

Periodic Evaluation
PHYSICAL
Skin self exam
Every 3 months
Hair (alopecia)
Nails (dystrophy)
Skin (vitiligo, atypical and changing skinlesions, sclerodermatous changes)
YearlyWITH CHRONIC GVHD
Health Counseling/
Further Considerations
HEALTH LINKS
Skin Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery, dermatology, and/or oncology consultation as clinically indicated.
SYSTEM = Dermatologic
SCORE = 1

Additional Information

Dermatologic toxicity is more common in presence of active cGVHD; effects may persist after cGVHD resolves.

References
Antin JH: Clinical practice. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med 347:36-42, 2002
Curtis RE, Metayer C, Rizzo JD, et al: Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood 105:3802-11, 2005
Huang JT, Duncan CN, Boyer D, et al: Nail dystrophy, edema, and eosinophilia: harbingers of severe chronic GVHD of the skin in children. Bone Marrow Transplant 49:1521-7, 2014
Kinahan KE, Sharp LK, Seidel K, et al: Scarring, disfigurement, and quality of life in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30:2466-74, 2012
Leisenring W, Friedman DL, Flowers ME, et al: Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol 24:1119-26, 2006
Sanli H, Akay BN, Arat M, et al: Vitiligo after hematopoietic cell transplantation: six cases and review of the literature. Dermatology 216:349-54, 2008
Skert C, Patriarca F, Sperotto A, et al: Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica 91:258-61, 2006
Vajdic CM, Mayson E, Dodds AJ, et al: Second cancer risk and late mortality in adult Australians receiving allogeneic hematopoietic stem cell transplantation: a population-based cohort study. Biol Blood Marrow Transplant 22:949-56,
2016
Zuo RC, Naik HB, Steinberg SM, et al: Risk factors and characterization of vitiligo and alopecia areata in patients with chronic graft-vs-host disease. JAMA Dermatol 151:23-32, 2015

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Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Potential
Late Effects

Periodic Evaluation

Xerophthalmia
HISTORY(keratoconjunctivitis sicca) Dry eyes (burning, itching, foreign bodysensation, inflammation)
YearlyPHYSICAL
Eye exam
YearlySCREENING
Evaluation by ophthalmologist or
optometrist
YearlyWITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations
HEALTH LINKS
Eye Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Supportive care with artificial tears.
SYSTEM = Ocular
SCORE = 1

Additional Information

Xerophthalmia is more common in presence of active cGVHD; effects may persist after cGVHD resolves.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Cranial radiation, higher radiation dose, especially ≥30 Gy, radiation fraction ≥2 Gy, radiomimetic chemotherapy (e.g., doxorubicin, dactinomycin)

References
Espana EM, Shah S, Santhiago MR, et al: Graft versus host disease: clinical evaluation, diagnosis and management. Graefes Arch Clin Exp Ophthalmol 251:1257-66, 2013
Ng JS, Lam DS, Li CK, et al: Ocular complications of pediatric bone marrow transplantation. Ophthalmology 106:160-4, 1999
Riemens A, te Boome L, Imhof S, et al: Current insights into ocular graft-versus-host disease. Curr Opin Ophthalmol 21:485-94, 2010
Shikari H, Antin JH, Dana R: Ocular graft-versus-host disease: a review. Surv Ophthalmol 58:233-51, 2013
Socie G, Salooja N, Cohen A, et al: Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101:3373-85, 2003
Suh DW, Ruttum MS, Stuckenschneider BJ, et al: Ocular findings after bone marrow transplantation in a pediatric population. Ophthalmology 106:1564-70, 1999
Townley JR, Dana R, Jacobs DS: Keratoconjunctivitis sicca manifestations in ocular graft versus host disease: pathogenesis, presentation, prevention, and treatment. Semin Ophthalmol 26:251-60, 2011
Westeneng AC, Hettinga Y, Lokhorst H, et al: Ocular graft-versus-host disease after allogeneic stem cell transplantation. Cornea 29:758-63, 2010

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Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Potential
Late Effects
Oral toxicity
Xerostomia
Salivary gland dysfunction
Dental caries
Periodontal disease
Oral cancer (squamous cell
carcinoma)

Periodic Evaluation
HISTORY
Xerostomia
YearlyPHYSICAL
Oral exam
YearlySCREENING
Dental exam and cleaning
Every 6 months

WITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations
HEALTH LINKS
Dental Health
COUNSELING
Safer sexual practices to reduce HPV transmission.
Importance of HPV vaccination.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Supportive care with saliva substitutes, moistening agents, and sialagogues(pilocarpine).
Regular dental care including fluoride applications and intraoral malignancy
screening.
Head and neck/otolaryngology consultation as indicated.
HPV vaccination per current recommendations.
SYSTEM = Dental
SCORE = 1w

Additional Information

Oral-dental late effects are more common in presence of active cGVHD; effects may persist after cGVHD resolves.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Use of azathioprine for cGVHD management, head and neck radiation involving the parotid gland, higher radiation dose, especially ≥30 Gy, radiomimetic chemotherapy (e.g., doxorubicin,
dactinomycin)- Pre-morbid/Co-morbid medical conditions: High grade of cGVHD, Fanconi anemia, dyskeratosis congenita, HPV infection

References
Alter BP, Giri N, Savage SA, et al: Cancer in dyskeratosis congenita. Blood 113:6549-57, 2009
American Academy of Pediatric Dentistry: Guideline on dental management of pediatric patients receiving chemotherapy, hematopoietic cell transplantation, and/or radiation. Pediatr Dent 35:E185-93, 2013
Bhatia S, Louie AD, Bhatia R, et al: Solid cancers after bone marrow transplantation. J Clin Oncol 19:464-71, 2001
Brocklehurst P, Kujan O, O’Malley LA, et al: Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev:CD004150, 2013
Chaturvedi AK, Graubard BI, Broutian T, et al: Effect of prophylactic human papillomavirus (HPV) vaccination on oral HPV infections among young adults in the United States. J Clin Oncol 36:262-267, 2018
Curtis RE, Metayer C, Rizzo JD, et al: Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood 105:3802-11, 2005
Dahllof G, Bagesund M, Remberger M, et al: Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol 33:327-31, 1997
Effinger KE, Migliorati CA, Hudson MM, et al: Oral and dental late effects in survivors of childhood cancer: a Children’s Oncology Group report. Support Care Cancer 22:2009-19, 2014
Elad S, Raber-Durlacher JE, Brennan MT, et al: Basic oral care for hematology-oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of
Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT). Support Care Cancer 23:223-36, 2015
Gawade PL, Hudson MM, Kaste SC, et al: A systematic review of dental late effects in survivors of childhood cancer. Pediatr Blood Cancer 61:407-16, 2014
Guchelaar HJ, Vermes A, Meerwaldt JH: Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment. Support Care Cancer 5:281-8, 1997
Masserot C, Peffault de Latour R, Rocha V, et al: Head and neck squamous cell carcinoma in 13 patients with Fanconi anemia after hematopoietic stem cell transplantation. Cancer 113:3315-22, 2008
Meier JK, Wolff D, Pavletic S, et al: Oral chronic graft-versus-host disease: report from the International Consensus Conference on clinical practice in cGVHD. Clin Oral Investig 15:127-39, 2011
Ojha RP, Tota JE, Offutt-Powell TN, et al: Human papillomavirus-associated subsequent malignancies among long-term survivors of pediatric and young adult cancers. PLoS One 8:e70349, 2013
Treister NS, Woo SB, O’Holleran EW, et al: Oral chronic graft-versus-host disease in pediatric patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11:721-31, 2005
van der Pas-van Voskuilen IG, Veerkamp JS, Raber-Durlacher JE, et al: Long-term adverse effects of hematopoietic stem cell transplantation on dental development in children. Support Care Cancer 17:1169-75, 2009
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Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Potential
Late Effects
Pulmonary toxicity
Bronchiolitis obliterans
Chronic bronchitis
Bronchiectasis

Periodic Evaluation
HISTORY
Cough
Wheezing
Shortness of breath
Dyspnea on exertion
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patients withabnormal results or progressive pulmonary
dysfunction

WITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations
HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco and Environmental tobacco smoke avoidance/Smoking cessation.
Influenza and Pneumococcal vaccinations.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Pulmonary consultation for patients with symptomatic pulmonary dysfunction.
Pulmonary consultation for survivors who desire to SCUBA dive (due to potential
undiagnosed pulmonary toxicities, and limited data to guide safe diving
recommendations for individuals treated with pulmonary toxic therapy).
SYSTEM = Pulmonary
SCORE = 1

Additional Information

Pulmonary late effects are more common in presence of active cGVHD; effects may persist after cGVHD resolves.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Prolonged immunosuppression related to cGVHD, chest radiation, TBI, pulmonary toxic chemotherapy (e.g., busulfan, bleomycin, carmustine [BCNU], lomustine [CCNU])- Health behaviors: Smoking, inhaled illicit drug use

References
Dietz AC, Chen Y, Yasui Y, et al: Risk and impact of pulmonary complications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 122:3687-3696, 2016
Gower WA, Collaco JM, Mogayzel PJ, Jr.: Lung function and late pulmonary complications among survivors of hematopoietic stem cell transplantation during childhood. Paediatr Respir Rev 11:115-22, 2010
Huang TT, Hudson MM, Stokes DC, et al: Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest 140:881-901, 2011
Inaba H, Yang J, Pan J, et al: Pulmonary dysfunction in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Cancer 116:2020-30, 2010
Madanat-Harjuoja LM, Valjento S, Vettenranta K, et al: Pulmonary function following allogeneic stem cell transplantation in childhood: a retrospective cohort study of 51 patients. Pediatr Transplant 18:617-24, 2014
Nakasone H, Onizuka M, Suzuki N, et al: Pre-transplant risk factors for cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia after hematopoietic cell transplantation. Bone Marrow Transplant 48:1317-23,
2013
Nishio N, Yagasaki H, Takahashi Y, et al: Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children. Bone Marrow Transplant 44:303-8, 2009
Uhlving HH, Bang CL, Christensen IJ, et al: Lung function after allogeneic hematopoietic stem cell transplantation in children: a longitudinal study in a population-based cohort. Biol Blood Marrow Transplant 19:1348-54, 2013
van Hulst RA, Rietbroek RC, Gaastra MT, et al: To dive or not to dive with bleomycin: a practical algorithm. Aviat Space Environ Med 82:814-8, 2011
Yoshihara S, Yanik G, Cooke KR, et al: Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic
stem cell transplantation. Biol Blood Marrow Transplant 13:749-59, 2007

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Therapeutic
Exposure

Potential
Late Effects

Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Immunologic complications
Secretory IgA deficiency
Hypogammaglobulinemia
Decreased B cells
T cell dysfunction
Chronic infections (e.g.,
conjunctivitis, sinusitis, andbronchitis)

WITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Chronic conjunctivitis
Chronic sinusitis
Chronic bronchitis
Recurrent or unusual infections
SepsisYearlyPHYSICAL
Eye exam
Nasal exam
Pulmonary exam
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Administer pneumocystis jirovecii pneumonia prophylaxis, consider antibiotic
prophylaxis for encapsulated organisms, and anti-viral and anti-fungal
prophylaxis in patients with active cGVHD for duration of immunosuppressive
therapy.
Immunize with inactivated vaccines for all patients according to publishedguidelines; postponing vaccination in patients with GVHD is not recommended
with the exception of live vaccines.
Immunology or infectious diseases consultation for assistance with managementof infections.
Some patients with hypogammaglobulinemia require lifelong IgG replacement.
SYSTEM = Immune
SCORE = 1

Additional Information

Immunologic complications related to cGVHD may persist or resolve over time. Immunologic abnormalities may persist for up to 20 years post transplant.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Pre-morbid/Co-morbid medical conditions: Active cGVHD, prolonged immunosuppression related to cGVHD and its treatment

References
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 61:816-9, 2012
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 62:521-4, 2013
Engelhard D, Cordonnier C, Shaw PJ, et al: Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey. Br J Haematol 117:444-50, 2002
Guilcher GMT, Rivard L, Huang JT, et al: Immune function in childhood cancer survivors: a Children’s Oncology Group review. Lancet Child Adolesc Health 5(4):284-294, 2021
Majhail NS, Rizzo JD, Lee SJ, et al: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplant 47:337-41, 2012
Maury S, Mary JY, Rabian C, et al: Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients. Br J Haematol 115:630-41, 2001
Mbaeyi SA, Bozio CH, Duffy J, et al: Meningococcal vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 69(9);1-41, 2020
Nordoy T, Kolstad A, Endresen P, et al: Persistent changes in the immune system 4-10 years after ABMT. Bone Marrow Transplant 24:873-8, 1999
Perkins JL, Chen Y, Harris A, et al: Infections among long-term survivors of childhood and adolescent cancer: a report from the Childhood Cancer Survivor Study. Cancer 120:2514-21, 2014
Robin M, Porcher R, De Castro Araujo R, et al: Risk factors for late infections after allogeneic hematopoietic stem cell transplantation from a matched related donor. Biol Blood Marrow Transplant 13:1304-12, 2007
Storek J, Gooley T, Witherspoon RP, et al: Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol 54:131-8, 1997
Tomblyn M, Chiller T, Einsele H, et al: Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15:1143-238, 2009

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Sec #
111

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT) with
CURRENTLY ACTIVE
cGVHD

Potential
Late Effects
Functional asplenia
At risk for life-threatening infection
with encapsulated organisms(e.g., Haemophilus influenzae,
Streptococcus pneumoniae,
meningococcus)

Periodic Evaluation
PHYSICAL
Physical exam at time of febrile illness toevaluate degree of illness and potential
source of infection
When febrile T ≥101°F (38.3°C) as indicated forpatients with active cGVHD
SCREENING
Blood culture
When febrile T ≥101°F (38.3°C) as indicated forpatients with active cGVHD

WITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations
HEALTH LINKS
Splenic Precautions
COUNSELING
Risk of life-threatening infections with encapsulated organisms.
Risk associated with malaria and tick-borne diseases if living in or visiting endemicareas.
Obtain medical alert bracelet/card noting functional asplenia.
Discuss importance of immunization with Pneumococcal, Meningococcal (including
serotype B), Influenza and HIB vaccines according to current ACIP recommendations.
For further details regarding antibiotic prophylaxis and immunizations, see current editionof AAP Red Book.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Antibiotic prophylaxis for encapsulated organisms and bacteremia/endocarditis
prophylaxis for duration of immunosuppressive therapy for cGVHD (see: American
Academy of Pediatric Dentistry, Guideline on Antibiotic Prophylaxis for Dental Patients at
Risk for Infection).
Administer a long-acting, broad-spectrum parenteral antibiotic (e.g., ceftriaxone) inpatients with T ≥101°F (38.3°C) or other signs of serious illness and continue close
medical monitoring while awaiting blood culture results.
Hospitalize and broaden antimicrobial coverage (e.g., addition of vancomycin) undercertain circumstances, such as the presence of marked leukocytosis, neutropenia, or
significant change from baseline CBC, toxic clinical appearance, fever ≥104°F (40°C),
meningitis, pneumonia, or other serious focus of infection, signs of septic shock, orprevious history of serious infection.
SYSTEM = Immune
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Splenic radiation, ongoing immunosuppression- Pre-morbid/Co-morbid medical conditions: Hypogammaglobulinemia

References
American Academy of Pediatric Dentistry Clinical Affairs Committee, American Academy of Pediatric Dentistry Council on Clinical Affairs: Guideline on antibiotic prophylaxis for dental patients at risk for infection. Chicago, IL, American
Academy of Pediatric Dentistry, 2011
Castagnola E, Fioredda F: Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes. Eur J Haematol 71:319-26,
2003
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 61:816-9, 2012
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 62:521-4, 2013
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HEMATOPOIETIC CELL TRANSPLANT

WITH CHRONIC GVHD (CONT)

Section 111 References (cont)Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Barnett ED, Lynfield R, et al (eds): Red Book: 2021 Report of the Committee on Infectious Diseases(ed 32). Itasca, IL, American Academy of Pediatrics, 2021, pp 67-105
Engelhard D, Cordonnier C, Shaw PJ, et al: Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey. Br J Haematol 117:444-50, 2002
Guilcher GMT, Rivard L, Huang JT, et al: Immune function in childhood cancer survivors: a Children’s Oncology Group review. Lancet Child Adolesc Health 5(4):284-294, 2021
Mbaeyi SA, Bozio CH, Duffy J, et al: Meningococcal vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 69(9);1-41, 2020
Mourtzoukou EG, Pappas G, Peppas G, et al: Vaccination of asplenic or hyposplenic adults. Br J Surg 95:273-80, 2008
Price VE, Blanchette VS, Ford-Jones EL: The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am 21:697-710, viii-ix, 2007
Smets F, Bourgois A, Vermylen C, et al: Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine. Vaccine 25:5278-82, 2007
Spelman D, Buttery J, Daley A, et al: Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J 38:349-56, 2008

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Sec #
112

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Potential
Late Effects
Esophageal stricture

WITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Dysphagia
HeartburnYearlyHEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery and/or gastroenterology consultation for symptomatic patients.
SYSTEM = GI/Hepatic
SCORE = 1w

Additional Information

Esophageal stricture related to cGVHD is generally not reversible over time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Radiation involving the esophagus, radiation dose ≥30 Gy (increased risk with higher radiation dose, particularly dose ≥40 Gy)- Pre-morbid/Co-morbid medical conditions: Gastroesophageal reflux, candida esophagitis, gut GVHD

References
Lal DR, Foroutan HR, Su WT, et al: The management of treatment-related esophageal complications in children and adolescents with cancer. J Pediatr Surg 41:495-9, 2006
Stemmelin GR, Pest P, Peters RA, et al: Severe esophageal stricture after autologous bone marrow transplant. Bone Marrow Transplant 15:1001-2, 1995
Williams M: Gastrointestinal manifestations of graft-versus-host disease: diagnosis and management. AACN Clin Issues 10:500-6, 1999

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(female)w

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Potential
Late Effects
Vulvar scarring
Vaginal fibrosis/stenosis

Periodic Evaluation
HISTORY
Psychosocial assessment
Dyspareunia
Post-coital bleeding
Difficulty with tampon insertion
Vaginal dryness
Vulvar pain/tenderness
Vulvovaginal burning or pruritus
Dysuria
YearlyPHYSICAL
Exam of genitalia for lichen planus-likefeatures, erosions, fissures, ulcers
YearlyWITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations
COUNSELING
Avoid frequent contact with irritants (bubble bath, wet wipes and soaps).
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation for management.
Psychological consultation in patients with emotional difficulties.
SYSTEM = Reproductive (Female)
SCORE = 1

Additional Information

Vulvovaginal cGVHD is rare before the onset of puberty, but should be considered beyond thelarche.
Estrogen deficiency and infection (HPV/HSV, yeast, bacteria and other recognized gynecological pathogens) should be ruled out before a diagnosis of genital cGVHD is made.
Vaginal fibrosis/stenosis related to cGVHD is generally not reversible over time.
Physical examination should be done with each assessment for cGVHD to detect vulvar lesions before vaginal stenosis develops.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Pelvic radiation

References
Carpenter PA, Kitko CL, Elad S, et al: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group
Report. Biol Blood Marrow Transplant 21:1167-87, 2015
Costantini S, Di Capua E, Bosi S, et al: The management of severe vaginal obstruction from genital chronic graft-versus-host disease: diagnosis, surgical technique and follow-up. Minerva Ginecol 58:11-6, 2006
Duncan CN, Majhail NS, Brazauskas R, et al: Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol
Blood Marrow Transplant 21:151-8, 2015
Frey Tirri B, Hausermann P, Bertz H, et al: Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD. Bone Marrow Transplant 50:3-9, 2015
Gifford G, Sim J, Horne A, et al: Health status, late effects and long-term survivorship of allogeneic bone marrow transplantation: a retrospective study. Intern Med J 44:139-47, 2014
Hirsch P, Leclerc M, Rybojad M, et al: Female genital chronic graft-versus-host disease: importance of early diagnosis to avoid severe complications. Transplantation 93:1265-9, 2012
Jagasia MH, Greinix HT, Arora M, et al: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol
Blood Marrow Transplant 21:389-401 e1, 2015
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Smith Knutsson E, Bjork Y, Broman AK, et al: Genital chronic graft-versus-host disease in females: a cross-sectional study. Biol Blood Marrow Transplant 20:806-11, 2014
Tauchmanova L, Selleri C, Di Carlo C, et al: Estrogen-progestogen induced hematocolpometra following allogeneic stem cell transplant. Gynecol Oncol 93:112-5, 2004
Zantomio D, Grigg AP, MacGregor L, et al: Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management. Bone Marrow Transplant 38:567-72, 2006

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w

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT) withany history of cGVHD

Potential
Late Effects
Joint contractures

Periodic Evaluation
PHYSICAL
Musculoskeletal exam
YearlyWITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Consultation with physical therapy, rehabilitation medicine/physiatrist.
SYSTEM = Musculoskeletal
SCORE = 1

Additional Information

Joint contractures related to cGVHD are generally not reversible over time.

References
Antin JH: Clinical practice. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med 347:36-42, 2002
Beredjiklian PK, Drummond DS, Dormans JP, et al: Orthopaedic manifestations of chronic graft-versus-host disease. J Pediatr Orthop 18:572-5, 1998
Carpenter PA: Late effects of chronic graft-versus-host disease. Best Pract Res Clin Haematol 21:309-31, 2008
Flowers ME, Parker PM, Johnston LJ, et al: Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial.
Blood 100:415-9, 2002

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SURGERYSec #115

AMPUTATION

Therapeutic
Exposure
Amputation

Potential
Late Effects
Amputation-related
complications
Impaired cosmesis
Functional and activity limitations
Residual limb integrity problems
Pain
Increased energy expenditure
Impaired quality of life
Psychological maladjustment

Periodic Evaluation
HISTORY
Phantom pain
Functional, activity, and fitness limitations
YearlyPHYSICAL
Residual limb integrity
YearlySCREENING
Prosthetic evaluation
Every 6 months until skeletally mature, then yearly

Health Counseling/
Further Considerations
HEALTH LINKS
Amputation
COUNSELING
Skin checks
Signs of poor prosthetic fit
Residual limb and prosthetic hygiene
Physical fitness
Importance of maintaining a healthy weight and lifestyle.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Physical therapy consultation as needed per changing physical status such as weightgain or gait training with a new prosthesis, and for non-pharmacological pain
management.
Occupational therapy consultation as needed to assist with activities of daily living.
Psychological/social work consultation to assist with emotional difficulties related to body
image, marriage, pregnancy, parenting, employment, insurance, depression, sexual
health, or high-risk behaviors (e.g., alcohol or tobacco use).
Vocational counseling/training to identify vocations that will not produce/exacerbate
functional limitations.
SYSTEM = Musculoskeletal
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Skeletally immature/growing children- Cancer/Treatment factors: Hemipelvectomy site of amputation (trans-femur amputation, trans-tibia amputation)- Pre-morbid/Co-morbid medical conditions: Obesity, diabetes, poor residual limb healing

References
Aulivola B, Hile CN, Hamdan AD, et al: Major lower extremity amputation: outcome of a modern series. Arch Surg 139:395-9; discussion 399, 2004
Bekkering WP, Vliet Vlieland TP, Koopman HM, et al: Functional ability and physical activity in children and young adults after limb-salvage or ablative surgery for lower extremity bone tumors. J Surg Oncol 103:276-82, 2011
Eiser C, Darlington AS, Stride CB, et al: Quality of life implications as a consequence of surgery: limb salvage, primary and secondary amputation. Sarcoma 5:189-95, 2001
Eiser C, Grimer RJ: Quality of life in survivors of a primary bone tumour: a systematic review. Sarcoma 3:183-90, 1999
Fernandez-Pineda I, Hudson MM, Pappo AS, et al: Long-term functional outcomes and quality of life in adult survivors of childhood extremity sarcomas: a report from the St. Jude Lifetime Cohort Study. J Cancer Surviv 11(1):1-12, 2017
Griesser MJ, Gillette B, Crist M, et al: Internal and external hemipelvectomy or flail hip in patients with sarcomas: quality-of-life and functional outcomes. Am J Phys Med Rehabil 91:24-32, 2012
Lown EA, Hijiya N, Zhang N, et al: Patterns and predictors of clustered risky health behaviors among adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 122(17):2747-2756, 2016
Nagarajan R, Mogil R, Neglia JP, et al: Self-reported global function among adult survivors of childhood lower-extremity bone tumors: a report from the Childhood Cancer Survivor Study (CCSS). J Cancer Surviv 3:59-65, 2009
Nagarajan R, Neglia JP, Clohisy DR, et al: Education, employment, insurance, and marital status among 694 survivors of pediatric lower extremity bone tumors: a report from the Childhood Cancer Survivor Study. Cancer 97:2554-64, 2003
Ottaviani G, Robert RS, Huh WW, et al: Sociooccupational and physical outcomes more than 20 years after the diagnosis of osteosarcoma in children and adolescents: limb salvage versus amputation. Cancer 119:3727-36, 2013
Renard AJ, Veth RP, Schreuder HW, et al: Function and complications after ablative and limb-salvage therapy in lower extremity sarcoma of bone. J Surg Oncol 73:198-205, 2000
Stokke J, Sung L, Gupta A, et al: Systematic review and meta-analysis of objective and subjective quality of life among pediatric, adolescent, and young adult bone tumor survivors. Pediatr Blood Cancer 62:1616-29, 2015

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SURGERYCENTRAL VENOUS CATHETERSec #Therapeutic
Exposure

Potential
Late Effects

116

Central venous catheter

Thrombosis
Vascular insufficiency
Infection of retained cuff orline tract
Post-thrombotic syndromew

Periodic Evaluation
HISTORY
Tenderness or swelling at previous
catheter site
YearlyPHYSICAL
Venous stasis
Swelling
Tenderness at previous catheter site
YearlyHealth Counseling/
Further Considerations
SYSTEM = Cardiovascular
SCORE = 2A

References

Kuhle S, Spavor M, Massicotte P, et al: Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost 6:589-94, 2008
Polen E, Weintraub M, Stoffer C, et al: Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors: A prospective cohort study. Pediatr Blood Cancer 62:285-290, 2015
Revel-Vilk S, Menahem M, Stoffer C, et al: Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors is associated with a history of obstruction. Pediatr Blood Cancer 55:153-6, 2010
Wilimas JA, Hudson M, Rao B, et al: Late vascular occlusion of central lines in pediatric malignancies. Pediatrics 101:E7, 1998

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Sec #
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w

CYSTECTOMY

Therapeutic
Exposure
Cystectomy

Potential
Late Effects
Cystectomy-related
complications
Asymptomatic bacteriuria
Chronic urinary tract infection
Renal dysfunction
Vesicoureteral reflux
Hydronephrosis
Reservoir calculi
Spontaneous neobladderperforation
Vitamin B12/Folate/Carotene
deficiency (patients with ileal
enterocystoplasty only)

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Vitamin B12 level
Yearly, starting 5 years after cystectomy(patients with ileal enterocystoplasty only)
Evaluation by urologist
YearlyHEALTH LINKS
Cystectomy
Kidney Health
SYSTEM = Urinary
SCORE
Reservoir calculi = 2A
Vitamin B12/folate/carotene deficiency = 2B
All Else = 1

Additional Information

All potential late effects for pelvic surgery apply to cystectomy (see also sections 141-145).
Reservoir calculi are stones in the neobladder (a reservoir for urine usually constructed of ileum/colon).

References
Castagnetti M, Angelini L, Alaggio R, et al: Oncologic outcome and urinary function after radical cystectomy for rhabdomyosarcoma in children: role of the orthotopic ileal neobladder based on 15-year experience at a single center. J
Urol 191:1850-5, 2014
DeFoor W, Tackett L, Minevich E, et al: Risk factors for spontaneous bladder perforation after augmentation cystoplasty. Urology 62:737-41, 2003
Hautmann RE, de Petriconi R, Gottfried HW, et al: The ileal neobladder: complications and functional results in 363 patients after 11 years of followup. J Urol 161:422-7; discussion 427-8, 1999
Hensle TW, Bingham J, Lam J, et al: Preventing reservoir calculi after augmentation cystoplasty and continent urinary diversion: the influence of an irrigation protocol. BJU Int 93:585-7, 2004
Inouye BM, Shah BB, Massanyi EZ, et al: Urologic complications of major genitourinary reconstruction in the exstrophy-epispadias complex. J Pediatr Urol 10:680-7, 2014
Jahnson S, Pedersen J: Cystectomy and urinary diversion during twenty years--complications and metabolic implications. Eur Urol 24:343-9, 1993
Kalloo NB, Jeffs RD, Gearhart JP: Long-term nutritional consequences of bowel segment use for lower urinary tract reconstruction in pediatric patients. Urology 50:967-71, 1997
Metcalfe PD, Casale AJ, Kaefer MA, et al: Spontaneous bladder perforations: a report of 500 augmentations in children and analysis of risk. J Urol 175:1466-70; discussion 1470-1, 2006
Raney B, Jr., Heyn R, Hays DM, et al: Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup Rhabdomyosarcoma Study Committee. Cancer
71:2387-94, 1993
Rosenbaum DH, Cain MP, Kaefer M, et al: Ileal enterocystoplasty and B12 deficiency in pediatric patients. J Urol 179:1544-7; discussion 1547-8, 2008
Sim HG, Lau WK, Cheng CW: A twelve-year review of radical cystectomies in Singapore General Hospital. Ann Acad Med Singapore 31:645-50, 2002
Stewart D, Inouye BM, Goldstein SD, et al: Pediatric surgical complications of major genitourinary reconstruction in the exstrophy-epispadias complex. J Pediatr Surg 50:167-70, 2015

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ENUCLEATION

Therapeutic
Exposure
Enucleation

Potential
Late Effects
Impaired cosmesis
Poor prosthetic fit
Orbital hypoplasia

Periodic Evaluation
SCREENING
Evaluation by ocularist
YearlyEvaluation by ophthalmologist
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Eye Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Psychological consultation in patients with emotional difficulties related tocosmetic and visual impairment.
Vocational rehabilitation referral as clinically indicated.
SYSTEM = Ocular
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at enucleation- Cancer/Treatment factors: Combination with radiation

References
Chojniak MM, Chojniak R, Testa ML, et al: Abnormal orbital growth in children submitted to enucleation for retinoblastoma treatment. J Pediatr Hematol Oncol 34:e102-5, 2012
Kaste SC, Chen G, Fontanesi J, et al: Orbital development in long-term survivors of retinoblastoma. J Clin Oncol 15:1183-9, 1997
Shildkrot Y, Kirzhner M, Haik BG, et al: The effect of cancer therapies on pediatric anophthalmic sockets. Ophthalmology 118:2480-6, 2011

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HYSTERECTOMY

Therapeutic
Exposure
Hysterectomy(female)Potential
Late Effects
Pelvic floor dysfunction
Urinary incontinence
Sexual dysfunction

Periodic Evaluation
HISTORY
Psychosocial assessment
Urinary leakage
Abdominal pain
Dyspareunia
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive Health
COUNSELING
Potential for biologic parenthood using gestational surrogate.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Reproductive endocrinology consultation for patients wishing to pursue
pregnancy via gestational surrogate.
Female pelvic medicine and reconstructive surgery consultation for patients withurinary complaints after hysterectomy.
SYSTEM = Reproductive (Female)
SCORE = 2Aw

Additional Information

For patients who also underwent oophorectomy, see also: sections 136-137 (unilateral oophorectomy) or section 138 (bilateral oophorectomy).
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Pelvic radiation

References
Benedetti-Panici P, Zullo MA, Plotti F, et al: Long-term bladder function in patients with locally advanced cervical carcinoma treated with neoadjuvant chemotherapy and type 3-4 radical hysterectomy. Cancer 100:2110-7, 2004
Jensen PT, Groenvold M, Klee MC, et al: Early-stage cervical carcinoma, radical hysterectomy, and sexual function. A longitudinal study. Cancer 100:97-106, 2004
Laterza RM, Sievert KD, de Ridder D, et al: Bladder function after radical hysterectomy for cervical cancer. Neurourol Urodyn 34:309-15, 2015
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Skjeldestad FE, Hagen B: Long-term consequences of gynecological cancer treatment on urinary incontinence: a population-based cross-sectional study. Acta Obstet Gynecol Scand 87:469-75, 2008

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w

LAPAROTOMY

Therapeutic
Exposure
Laparotomy

Potential
Late Effects
Adhesions
Bowel obstruction

Periodic Evaluation
HISTORY
Abdominal pain
Distension
Vomiting
Constipation
YearlyPHYSICAL
Tenderness
Abdominal guarding
Distension
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Imaging as clinically indicated for suspected obstruction.
Surgical consultation for patients unresponsive to medical management.
SYSTEM = GI/Hepatic
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combined with radiation

References
Cooke-Barber J, Scorletti F, Rymeski B, et al. Long-term follow-up of surgical outcomes for patients with Wilms tumor and neuroblastoma. Cancer 127(17):3232-3238, 2021
Jockovich M, Mendenhall NP, Sombeck MD, et al: Long-term complications of laparotomy in Hodgkin’s disease. Ann Surg 219:615-21; discussion 621-4, 1994
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 33:2893-900, 2015
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 46:1239-46, 2000
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 192:63-8; quiz 146, 2001

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LIMB SPARING PROCEDURE

Sec #Therapeutic
Exposure

Potential
Late Effects

121

Limb sparing procedure

Conditions related to limb
sparing procedure
Functional and activity
limitations
Contractures
Chronic infection
Chronic pain
Limb length discrepancy
Increased energy expenditure
Fibrosis
Prosthetic malfunction(loosening, non-union,
fracture) requiring revision,
replacement or amputation
Impaired quality of life
Complications with pregnancy/
delivery (in female patientswith internal hemipelvectomy)w

Periodic Evaluation
HISTORY
Functional and activity limitations
YearlyPHYSICAL
Residual limb integrity
YearlySCREENING
Radiograph of affected limb
YearlyEvaluation by orthopedic surgeon (ideallyby an orthopedic oncologist)
Every 6 months until skeletally mature, thenyearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Limb Sparing Procedures
COUNSELING
Potential need to discuss antibiotic prophylaxis prior to dental and invasive
procedures with their treating dentist/orthopedic surgeon.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Physical therapy consultation as needed per changes in functional status (suchas post-lengthening, revisions, life changes such as pregnancy), and for nonpharmacological pain management.
Psychological consultation as needed to assist with emotional difficulties related
to body image, marriage, pregnancy, parenting, employment, insurance,
depression or sexual health.
Vocational counseling/training to identify vocations that will not produce/
exacerbate functional limitations.
SYSTEM = Musculoskeletal
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at surgery, being skeletally immature, rapid growth spurt- Cancer/Treatment factors: Tibial endoprosthesis, use of biologic material (allograft or autograft) for reconstruction, radiation to extremity- Pre-morbid/Co-morbid medical conditions: Obesity, endoprosthetic infection, history of poor healing, infection of reconstruction- Health behaviors: High level of physical activity (associated with higher risk loosening), low level of physical activity (associated with higher risk of contractures or functional limitations)

References
American Academy of Orthopedic Surgeons, American Dental Association: Prevention of orthopaedic implant infection in patients undergoing dental procedures. Rosemont, IL, American Academy of Orthopedic Surgeons, 2012
Eiser C, Darlington AS, Stride CB, et al: Quality of life implications as a consequence of surgery: limb salvage, primary and secondary amputation. Sarcoma 5:189-95, 2001
Groundland JS, Ambler SB, Houskamp LDJ, et al: Surgical and functional outcomes after limb-preservation surgery for tumor in pediatric patients: a systematic review. J Bone J Surg 4(2):1-13, 2016
Nagarajan R, Mogil R, Neglia JP, et al: Self-reported global function among adult survivors of childhood lower-extremity bone tumors: a report from the Childhood Cancer Survivor Study (CCSS). J Cancer Surviv 3:59-65, 2009
Nagarajan R, Neglia JP, Clohisy DR, et al: Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications? J Clin Oncol 20:4493-501, 2002
Ottaviani G, Robert RS, Huh WW, et al: Sociooccupational and physical outcomes more than 20 years after the diagnosis of osteosarcoma in children and adolescents: limb salvage versus amputation. Cancer 119:3727-36, 2013
Portney DA, Bi AS, Christian RA, et al: Outcomes of expandable prostheses for primary bone malignancies in skeletally immature patients: a systematic review and pooled data analysis. J Pediatr Orthop 40(6):e487-e497, 2020
Stokke J, Sung L, Gupta A, et al: Systematic review and meta-analysis of objective and subjective quality of life among pediatric, adolescent, and young adult bone tumor survivors. Pediatr Blood Cancer 62:1616-29, 2015
Tsuda Y, Tsoi K, Stevenson JD, et al: Extendable endoprostheses in skeletally immature patients: a study of 124 children surviving more than 10 years after resection of bone sarcomas. J Bone Joint Surg Am 15;102(2):151-162, 2020
Wright EH, Gwilym S, Gibbons CL, et al: Functional and oncological outcomes after limb-salvage surgery for primary sarcomas of the upper limb. J Plast Reconstr Aesthet Surg 61:382-7, 2008

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NEPHRECTOMY

Therapeutic
Exposure
Nephrectomy(male)

Potential
Late Effects
Hydrocele
Renal toxicity
Proteinuria
Hyperfiltration
Renal insufficiency
Hypertension

Periodic Evaluation
PHYSICAL
HeightWeightBMI
Blood pressure
YearlyTesticular exam to evaluate for hydrocele
YearlySCREENING
BUN
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicated
Urine dipstick for protein
Creatinine with calculated eGFR*
Yearlyw

Health Counseling/
Further Considerations
HEALTH LINKS
Single Kidney Health
Kidney Health
Cardiovascular Risk Factors
COUNSELING
Counsel mononephric survivors regarding sports and activity safety, stressing
the importance of physical fitness, and proper use of seatbelts (i.e., wearing
lap belts around hips, not waist). Consideration should be given to survivor
health status, current kidney health (position, size, function), and acceptabilityof unlikely risk of sports-related renal injury to the survivor and/or family.
Use NSAIDs with caution.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Nephrology consultation for patients with hypertension, proteinuria, or
progressive renal insufficiency.
SYSTEM = Urinary
SCORE = 1

Additional Information

Surgery-induced renal atrophy (vanishing kidney) is a rare complication reported in survivors who have undergone retroperitoneal tumor resections. Once this diagnosis is established, annual screening should include evaluations
recommended for children treated with nephrectomy.
*eGFR Calculator available at: https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/laboratory-evaluation/glomerular-filtration-rate-calculators/recommended
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Bilateral Wilms tumor, other nephrotoxic therapy (e.g., cisplatin, carboplatin, ifosfamide, aminoglycosides, amphotericin, immunosuppressants, methotrexate, radiation impacting the kidneys)- Pre-morbid/Co-morbid medical conditions: Denys-Drash syndrome, WAGR syndrome, hypospadias, cryptorchidism

References
Bailey S, Roberts A, Brock C, et al: Nephrotoxicity in survivors of Wilms’ tumours in the North of England. Br J Cancer 87:1092-8, 2002
Breslow NE, Collins AJ, Ritchey ML, et al: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174:1972-5, 2005
Cozzi DA, Ceccanti S, Frediani S, et al: Renal function adaptation up to the fifth decade after treatment of children with unilateral renal tumor: a cross-sectional and longitudinal study. Pediatr Blood Cancer 60:1534-8, 2013
Dieffenbach BV, Liu Q, Murphy AJ, et al: Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer 155:216-226, 2021
Ginsberg JP, Hobbie WL, Ogle SK, et al: Prevalence of and risk factors for hydrocele in survivors of Wilms tumor. Pediatr Blood Cancer 42:361-3, 2004
Green DM, Wang M, Krasin M, et al: Kidney function after treatment for childhood cancer: a report from the St. Jude Lifetime Cohort Study. J Am Soc Nephrol 32(4):983-993, 2021
Grinsell MM, Showalter S, Gordon KA, et al: Single kidney and sports participation: perception versus reality. Pediatrics 118:1019-27, 2006
Hubertus J, Gunther B, Becker K, et al: Development of hypertension is less frequent after bilateral nephron sparing surgery for bilateral Wilms tumor in a long-term survey. J Urol 193:262-6, 2015
Johnson B, Christensen C, Dirusso S, et al: A need for reevaluation of sports participation recommendations for children with a solitary kidney. J Urol 174:686-9; discussion 689, 2005
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 46:1239-46, 2000
Ritchey ML, Green DM, Thomas PR, et al: Renal failure in Wilms’ tumor patients: a report from the National Wilms’ Tumor Study Group. Med Pediatr Oncol 26:75-80, 1996
Sharp DS, Ross JH, Kay R: Attitudes of pediatric urologists regarding sports participation by children with a solitary kidney. J Urol 168:1811-4; discussion 1815, 2002
Srinivas M, Agarwala S, Padhy AK, et al: Somatic growth and renal function after unilateral nephrectomy for Wilms’ tumor. Pediatr Surg Int 14:185-8, 1998
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NEPHRECTOMY (CONT)

Therapeutic
Exposure
Nephrectomy(female)Potential
Late Effects
Renal toxicity
Proteinuria
Hyperfiltration
Renal insufficiency
Hypertension

Periodic Evaluation
PHYSICAL
HeightWeightBMI
Blood pressure
YearlySCREENING
BUN
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicated
Urine dipstick for protein
Creatinine with calculated eGFR*
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Single Kidney Health
Kidney Health
Cardiovascular Risk Factors
COUNSELING
Counsel mononephric survivors regarding sports and activity safety, stressing
the importance of physical fitness, and proper use of seatbelts (i.e., wearing
lap belts around hips, not waist). Consideration should be given to survivor
health status, current kidney health (position, size, function), and acceptabilityof unlikely risk of sports-related renal injury to the survivor and/or family.
Use NSAIDs with caution.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Nephrology consultation for patients with hypertension, proteinuria, or
progressive renal insufficiency.
SYSTEM = Urinary
SCORE = 1w

Additional Information

Surgery-induced renal atrophy (vanishing kidney) is a rare complication reported in survivors who have undergone retroperitoneal tumor resections. Once this diagnosis is established, annual screening should include evaluations
recommended for children treated with nephrectomy.
*eGFR Calculator available at: https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/laboratory-evaluation/glomerular-filtration-rate-calculators/recommended
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Bilateral Wilms tumor, other nephrotoxic therapy (e.g., cisplatin, carboplatin, ifosfamide, aminoglycosides, amphotericin, immunosuppressants, methotrexate, radiation impacting the kidneys)- Pre-morbid/Co-morbid medical conditions: Denys-Drash syndrome, WAGR syndrome

References
Bailey S, Roberts A, Brock C, et al: Nephrotoxicity in survivors of Wilms’ tumours in the North of England. Br J Cancer 87:1092-8, 2002
Breslow NE, Collins AJ, Ritchey ML, et al: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174:1972-5, 2005
Cozzi DA, Ceccanti S, Frediani S, et al: Renal function adaptation up to the fifth decade after treatment of children with unilateral renal tumor: a cross-sectional and longitudinal study. Pediatr Blood Cancer 60:1534-8, 2013
Dieffenbach BV, Liu Q, Murphy AJ, et al: Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer 155:216-226, 2021
Green DM, Wang M, Krasin M, et al: Kidney function after treatment for childhood cancer: a report from the St. Jude Lifetime Cohort Study. J Am Soc Nephrol 32(4):983-993, 2021
Grinsell MM, Showalter S, Gordon KA, et al: Single kidney and sports participation: perception versus reality. Pediatrics 118:1019-27, 2006
Hubertus J, Gunther B, Becker K, et al: Development of hypertension is less frequent after bilateral nephron sparing surgery for bilateral Wilms tumor in a long-term survey. J Urol 193:262-6, 2015
Johnson B, Christensen C, Dirusso S, et al: A need for reevaluation of sports participation recommendations for children with a solitary kidney. J Urol 174:686-9; discussion 689, 2005
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 46:1239-46, 2000
Ritchey ML, Green DM, Thomas PR, et al: Renal failure in Wilms’ tumor patients: a report from the National Wilms’ Tumor Study Group. Med Pediatr Oncol 26:75-80, 1996
Sharp DS, Ross JH, Kay R: Attitudes of pediatric urologists regarding sports participation by children with a solitary kidney. J Urol 168:1811-4; discussion 1815, 2002
Srinivas M, Agarwala S, Padhy AK, et al: Somatic growth and renal function after unilateral nephrectomy for Wilms’ tumor. Pediatr Surg Int 14:185-8, 1998

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Neurosurgery-Brainw

NEUROSURGERY—BRAIN
Potential
Late Effects
Neurocognitive deficits
Functional deficits in:• Executive function (planningand organization)• Sustained attention• Memory (particularly visual,sequencing, temporal
memory)• Processing speed• Visual-motor integration
Learning deficits in math andreading (particularly reading
comprehension)
Diminished IQ
Behavioral change

Periodic Evaluation
HISTORY
Educational and/or vocational progress
YearlySCREENING
Referral for formal neuropsychologicalevaluation
Baseline at entry into long-term follow-up,
then periodically as clinically indicatedfor patients with evidence of impaired
educational or vocational progress

Health Counseling/
Further Considerations
HEALTH LINKS
School After Treatment
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Referral to school liaison in community or cancer center (psychologist, social
worker, school counselor) to facilitate acquisition of educational resources and/or social skills training.
Psychotropic medication (e.g., stimulants) or evidence-based rehabilitation
training. Caution—lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended.
Referral to community services for vocational rehabilitation or for services fordevelopmentally disabled.
SYSTEM = CNSSCORE = 1

Additional Information

Formal neuropsychological evaluation includes tests of processing speed, computer-based attention, visual motor integration, memory, comprehension of verbal instructions, verbal fluency, executive function and planning.
Neurocognitive deficits vary with extent of surgery, postoperative complications and location. Neurosensory deficits (i.e., vision, hearing) due to tumor or its therapy may complicate neurocognitive outcomes. Extent of deficit depends
on age at treatment, intensity of treatment, and time since treatment. New and progressive deficits may emerge over time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Younger age at treatment, especially age <3 years, family history of learning or attention problems- Cancer/Treatment factors: Primary CNS tumor, extent and location of resection, longer elapsed time since therapy, combination with methotrexate (IT, IO, high dose IV), cytarabine (high dose IV), radiation dose ≥24 Gy to wholebrain, radiation dose ≥40 Gy to local fields, TBI, CRT- Pre-morbid/Co-morbid medical conditions: Pre-morbid learning or attention problems, hydrocephalus/history of shunt placement, seizures, posterior fossa syndrome, CNS infection, neurologic and pulmonary conditions

References
Aarsen FK, Paquier PF, Arts WF, et al: Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood. J Clin Oncol 27:3526-32, 2009
Armstrong GT, Conklin HM, Huang S, et al: Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol 13:223-34, 2011
Carpentieri SC, Waber DP, Pomeroy SL, et al: Neuropsychological functioning after surgery in children treated for brain tumor. Neurosurgery 52:1348-56; discussion 1356-7, 2003
Catsman-Berrevoets CE, Aarsen FK: The spectrum of neurobehavioural deficits in the posterior fossa syndrome in children after cerebellar tumour surgery. Cortex 46:933-46, 2010
Mulhern RK, Merchant TE, Gajjar A, et al: Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 5:399-408, 2004
Reimers TS, Ehrenfels S, Mortensen EL, et al: Cognitive deficits in long-term survivors of childhood brain tumors: Identification of predictive factors. Med Pediatr Oncol 40:26-34, 2003
Williams AM, Cheung YT, Hyun G, et al. Childhood neurotoxicity and brain resilience to adverse events during adulthood. Ann Neurol 89(3):534-545, 2021

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Neurosurgery-Brainw

NEUROSURGERY—BRAIN (CONT)
Potential
Late Effects
Motor and/or sensory deficits
Paralysis
Movement disorders
AtaxiaEye problems (ocularnerve palsy, gaze paresis,
nystagmus, papilledema, optic
atrophy)

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Paralysis
Movement problems
AtaxiaEye problems
YearlyPHYSICAL
Neurologic exam
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluation by neurologist for persistent neurologic symptoms.
Speech, physical, and occupational therapy in patients with persistent deficits.
Evaluation by physiatrist/rehabilitation medicine specialist in patients with motor
dysfunction.
Ophthalmology evaluation as clinically indicated.
SYSTEM = CNSSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Primary CNS tumor, skull base tumors, optic pathway tumor, hypothalamic tumor, supra-sellar tumor (eye problems)- Pre-morbid/Co-morbid medical conditions: Hydrocephalus

References
Elliott RE, Hsieh K, Hochm T, et al: Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children. J Neurosurg Pediatr 5:30-48, 2010
Jane JA, Jr., Prevedello DM, Alden TD, et al: The transsphenoidal resection of pediatric craniopharyngiomas: a case series. J Neurosurg Pediatr 5:49-60, 2010
Kotecha RS, Jacoby P, Cole CH, et al: Morbidity in survivors of child and adolescent meningioma. Cancer 119:4350-7, 2013
Lo AC, Howard AF, Nichol A, et al: Long-term outcomes and complications in patients with craniopharyngioma: the British Columbia Cancer Agency experience. Int J Radiat Oncol Biol Phys 88:1011-8, 2014
Pietila S, Korpela R, Lenko HL, et al: Neurological outcome of childhood brain tumor survivors. J Neurooncol 108:153-61, 2012
Robertson PL, Muraszko KM, Holmes EJ, et al: Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children’s Oncology Group. J Neurosurg 105:444-51,
2006
Sonderkaer S, Schmiegelow M, Carstensen H, et al: Long-term neurological outcome of childhood brain tumors treated by surgery only. J Clin Oncol 21:1347-51, 2003
Ullrich NJ, Pomeroy SL, Kapur K, et al: Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors. Epilepsia 56:1599-604, 2015
Wibroe M, Cappelen J, Castor C, et al: Cerebellar mutism syndrome in children with brain tumours of the posterior fossa. BMC Cancer 17:439, 2017
Yano S, Kudo M, Hide T, et al: Quality of life and clinical features of long-term survivors surgically treated for pediatric craniopharyngioma. World Neurosurg 85:153-62, 2016

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Neurosurgery-Brainw

NEUROSURGERY—BRAIN (CONT)
Potential
Late Effects
Seizures

Periodic Evaluation
HISTORY
SeizuresYearlyPHYSICAL
Neurologic exam
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluation by neurologist as clinically indicated.
SYSTEM = CNSSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Primary CNS tumor, methotrexate (IV, IT, IO)

References
Kotecha RS, Jacoby P, Cole CH, et al: Morbidity in survivors of child and adolescent meningioma. Cancer 119:4350-7, 2013
Lo AC, Howard AF, Nichol A, et al: Long-term outcomes and complications in patients with craniopharyngioma: the British Columbia Cancer Agency experience. Int J Radiat Oncol Biol Phys 88:1011-8, 2014
Pietila S, Korpela R, Lenko HL, et al: Neurological outcome of childhood brain tumor survivors. J Neurooncol 108:153-61, 2012
Sonderkaer S, Schmiegelow M, Carstensen H, et al: Long-term neurological outcome of childhood brain tumors treated by surgery only. J Clin Oncol 21:1347-51, 2003
Ullrich NJ, Pomeroy SL, Kapur K, et al: Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors. Epilepsia 56:1599-604, 2015
Yano S, Kudo M, Hide T, et al: Quality of life and clinical features of long-term survivors surgically treated for pediatric craniopharyngioma. World Neurosurg 85:153-62, 2016

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Neurosurgery-Brainw

NEUROSURGERY—BRAIN (CONT)
Potential
Late Effects
Hydrocephalus
Shunt malfunction

Periodic Evaluation
HISTORY
Headaches
Nausea/Vomiting
AtaxiaIrritability
Drowsiness
YearlyPHYSICAL
Neurologic exam
YearlySCREENING
Abdominal x-ray
After pubertal growth spurt for patients withshunts to assure distal shunt tubing inperitoneum

Health Counseling/
Further Considerations
COUNSELING
Educate patient/family regarding potential symptoms of shunt malfunction.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluation by neurosurgeon for patients with shunts.
Per the American Academy of Pediatric Dentistry endocarditis prophylaxis
guidelines, antibiotic prophylaxis prior to dental work is indicated for survivors
with V-A and V-V shunts, but not for survivors with V-P shunts.
SYSTEM = CNSSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Primary CNS tumor

References
American Academy of Pediatric Dentistry Clinical Affairs Committee, American Academy of Pediatric Dentistry Council on Clinical Affairs: Guideline on antibiotic prophylaxis for dental patients at risk for infection. Chicago, IL, American
Academy of Pediatric Dentistry, 2011
Kotecha RS, Jacoby P, Cole CH, et al: Morbidity in survivors of child and adolescent meningioma. Cancer 119:4350-7, 2013
Lo AC, Howard AF, Nichol A, et al: Long-term outcomes and complications in patients with craniopharyngioma: the British Columbia Cancer Agency experience. Int J Radiat Oncol Biol Phys 88:1011-8, 2014
Pietila S, Korpela R, Lenko HL, et al: Neurological outcome of childhood brain tumor survivors. J Neurooncol 108:153-61, 2012
Ullrich NJ, Pomeroy SL, Kapur K, et al: Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors. Epilepsia 56:1599-604, 2015
Yano S, Kudo M, Hide T, et al: Quality of life and clinical features of long-term survivors surgically treated for pediatric craniopharyngioma. World Neurosurg 85:153-62, 2016

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SURGERYSec #128

NEUROSURGERY—BRAIN (CONT)

Therapeutic
Exposure
Neurosurgery-Brain(applies only toneurosurgery withpotential to affect the
hypothalamic-pituitaryaxis)

Potential
Late Effects
Overweight
Obesity

Periodic Evaluation
PHYSICAL
HeightWeight
BMI
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Nutrition and Physical Activity
Cardiovascular Risk Factors
COUNSELING
Obesity-related health risks.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluate for central endocrinopathies, including GH deficiency, central
hypothyroidism, central adrenal insufficiency, precocious puberty, andgonadotropin deficiency.
Refer to endocrine for management of hormonal dysfunction.
Evaluate for other co-morbid conditions, including dyslipidemia, hypertension,and impaired glucose metabolism.
Refer to dietitian for weight management.
SYSTEM = Endocrine/Metabolic
SCORE = 2Aw

Additional Information

Definition of Overweight: Age 2-20 years BMI for age ≥85th to <95th percentile. Age ≥21 years BMI ≥25-29.9.
Definition of Obesity: Age 2-20 years BMI for age ≥95th percentile. Age ≥21 years BMI ≥30.
BMI=wt(kg)/ht(m2). BMI calculator available on-line at: www.nhlbi.nih.gov/guidelines/obesity/BMI/bmicalc.htm. Growth charts for patients <21 years of age available on-line at: www.cdc.gov/growthcharts.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Craniopharyngioma, tumor extension to hypothalamus, surgery in supra-sellar region- Pre-morbid/Co-morbid medical conditions: Pre-treatment obesity

References
De Vile CJ, Grant DB, Kendall BE, et al: Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted? J Neurosurg 85:73-81, 1996
Elliott RE, Hsieh K, Hochm T, et al: Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children. J Neurosurg Pediatr 5:30-48, 2010
Elliott RE, Wisoff JH: Surgical management of giant pediatric craniopharyngiomas. J Neurosurg Pediatr 6:403-16, 2010
Jane JA, Jr., Prevedello DM, Alden TD, et al: The transsphenoidal resection of pediatric craniopharyngiomas: a case series. J Neurosurg Pediatr 5:49-60, 2010
Lustig RH, Post SR, Srivannaboon K, et al: Risk factors for the development of obesity in children surviving brain tumors. J Clin Endocrinol Metab 88:611-6, 2003
Muller HL, Emser A, Faldum A, et al: Longitudinal study on growth and body mass index before and after diagnosis of childhood craniopharyngioma. J Clin Endocrinol Metab 89:3298-305, 2004
Muller HL, Gebhardt U, Faldum A, et al: Functional capacity and body mass index in patients with sellar masses--cross-sectional study on 403 patients diagnosed during childhood and adolescence. Childs Nerv Syst 21:539-45, 2005
Puget S, Garnett M, Wray A, et al: Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg 106:3-12, 2007
Sainte-Rose C, Puget S, Wray A, et al: Craniopharyngioma: the pendulum of surgical management. Childs Nerv Syst 21:691-5, 2005

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SURGERYSec #129

NEUROSURGERY—BRAIN (CONT)

Therapeutic
Exposure
Neurosurgery-Brain(applies only toneurosurgery withpotential to affect the
hypothalamic-pituitaryaxis)

Potential
Late Effects
Diabetes insipidus

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Assessment of excessive thirst/polyuria
YearlyHEALTH LINKS
Hypopituitarism
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Na, K, Cl, CO2, serum osmolality, and urine osmolality as clinically indicated if
history consistent with excessive thirst and/or polyuria.
Evaluation for other central endocrinopathies, including GH deficiency, central
hypothyroidism, central adrenal insufficiency, precocious puberty, andgonadotropin deficiency.
Refer to endocrine to manage hormonal dysfunction.
Diabetes insipidus is unlikely to occur as a late effect past two years fromtherapeutic exposure, other causes should be considered in the presence ofsymptoms.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Craniopharyngioma, extension of tumor into hypothalamus, surgery in supra-sellar region, reoperation for recurrent tumor

References
Elliott RE, Hsieh K, Hochm T, et al: Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children. J Neurosurg Pediatr 5:30-48, 2010
Jane JA, Jr., Prevedello DM, Alden TD, et al: The transsphenoidal resection of pediatric craniopharyngiomas: a case series. J Neurosurg Pediatr 5:49-60, 2010
Lawson SA, Horne VE, Golekoh MC, et al: Hypothalamic-pituitary function following childhood brain tumors: analysis of prospective annual endocrine screening. Pediatric Blood Cancer 66(5):e27631, 2019
Lo AC, Howard AF, Nichol A, et al: Long-term outcomes and complications in patients with craniopharyngioma: the British Columbia Cancer Agency experience. Int J Radiat Oncol Biol Phys 88:1011-8, 2014
Olsson DS, Andersson E, Bryngelsson IL, et al: Excess mortality and morbidity in patients with craniopharyngioma, especially in patients with childhood onset: a population-based study in Sweden. J Clin Endocrinol Metab 100:467-74,
2015
Puget S, Garnett M, Wray A, et al: Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg 106:3-12, 2007
Sainte-Rose C, Puget S, Wray A, et al: Craniopharyngioma: the pendulum of surgical management. Childs Nerv Syst 21:691-5, 2005
Vinchon M, Baroncini M, Leblond P, et al: Morbidity and tumor-related mortality among adult survivors of pediatric brain tumors: a review. Childs Nerv Syst 27:697-704, 2011
Yano S, Kudo M, Hide T, et al: Quality of life and clinical features of long-term survivors surgically treated for pediatric craniopharyngioma. World Neurosurg 85:153-62, 2016

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SURGERYSec #130

NEUROSURGERY—SPINAL CORD

Therapeutic
Exposure
Neurosurgery-Spinal
cord

Potential
Late Effects
Neurogenic bladder
Urinary incontinence

Periodic Evaluation
HISTORY
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Neurogenic Bladder
COUNSELING
Importance of adequate fluid intake, regular voiding, and seeking medical
attention for symptoms of voiding dysfunction or urinary tract infection.
Importance of compliance with recommended bladder catheterization regimen.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urologic consultation for patients with dysfunctional voiding or recurrent urinary
tract infections.
SYSTEM = CNSSCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to or compressing spinal cord or cauda equina, injury above the level of the sacrum, radiation dose ≥45 Gy to lumbar and/or sacral spine and/or cauda equina, especially radiationdose ≥50 Gy

References
Fowler CJ, Sakakibara R, Frohman EM, et al: Neurologic bladder, bowel and sexual dysfunction, in Munsat TL (ed): World Federation of Neurology Seminars in Clinical Neurology. The Netherlands, Elsevier Science B.V., 2001
Hoover M, Bowman LC, Crawford SE, et al: Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol 32:353-9, 1999
McGirt MJ, Chaichana KL, Atiba A, et al: Resection of intramedullary spinal cord tumors in children: assessment of long-term motor and sensory deficits. J Neurosurg Pediatr 1:63-7, 2008
Poretti A, Zehnder D, Boltshauser E, et al: Long-term complications and quality of life in children with intraspinal tumors. Pediatr Blood Cancer 50:844-8, 2008

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SURGERY
Sec #
131

w

NEUROSURGERY—SPINAL CORD (CONT)

Therapeutic
Exposure
Neurosurgery-Spinal
cord

Potential
Late Effects
Neurogenic bowel
Fecal incontinence

Periodic Evaluation
HISTORY
Chronic constipation
Fecal soiling
YearlyPHYSICAL
Rectal exam
As clinically indicatedHealth Counseling/
Further Considerations
COUNSELING
Benefits of adherence to bowel regimen, including adequate hydration, fiber,
laxatives/enemas as clinically indicated.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
GI consultation to establish bowel regimen for patients with chronic impaction or
fecal soiling.
SYSTEM = CNSSCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to or compressing spinal cord or cauda equina, injury above the level of the sacrum, radiation dose ≥50 Gy to bladder, pelvis, or spine

References
Fowler CJ, Sakakibara R, Frohman EM, et al: Neurologic bladder, bowel and sexual dysfunction, in Munsat TL (ed): World Federation of Neurology Seminars in Clinical Neurology. The Netherlands, Elsevier Science B.V., 2001
Hoover M, Bowman LC, Crawford SE, et al: Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol 32:353-9, 1999

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SURGERYSec #132(male)NEUROSURGERY—SPINAL CORD (CONT)

Therapeutic
Exposure
Neurosurgery-Spinal
cord

Potential
Late Effects
Psychosexual dysfunction
Erectile dysfunction
Ejaculatory dysfunction

Periodic Evaluation
HISTORY
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Testicular and Reproductive Health
COUNSELING
Use of assisted reproductive technology for sperm retrieval.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urologic consultation in patients with positive history.
SYSTEM = Reproductive (Male)SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to or compressing spinal cord or cauda equina, radiation to bladder, pelvis, or spine, radiation dose ≥55 Gy to penile bulb in adult, ≥45 Gy in prepubertal child- Pre-morbid/Co-morbid medical conditions: Testosterone deficiency/insufficiency, injury above the level of the sacrum

References
Albright TH, Grabel Z, DePasse JM, et al: Sexual and reproductive function in spinal cord injury and spinal surgery patients. Orthop Rev (Pavia) 7:5842, 2015
Fowler CJ, Sakakibara R, Frohman EM, et al: Neurologic bladder, bowel and sexual dysfunction, in Munsat TL (ed): World Federation of Neurology Seminars in Clinical Neurology. The Netherlands, Elsevier Science B.V., 2001
Kenney LB, Cohen LE, Shnorhavorian M, et al: Male reproductive health after childhood, adolescent, and young adult cancers: a report from the Children’s Oncology Group. J Clin Oncol 30:3408-16, 2012
Kubota M, Yagi M, Kanada S, et al: Long-term follow-up status of patients with neuroblastoma after undergoing either aggressive surgery or chemotherapy--a single institutional study. J Pediatr Surg 39:1328-32, 2004
Ritenour CW, Seidel KD, Leisenring W, et al: Erectile dysfunction in male survivors of childhood cancer-a report from the Childhood Cancer Survivor Study. J Sex Med 13:945-54, 2016

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SURGERYSec #133(female)w

NEUROSURGERY—SPINAL CORD (CONT)

Therapeutic
Exposure
Neurosurgery-Spinal
cord

Potential
Late Effects
Psychosexual dysfunction

Periodic Evaluation
HISTORY
Altered or diminished sensation, loss of
sensation
Dyspareunia
Medication use
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation in patients with positive history.
SYSTEM = Reproductive (Female)
SCORE = 2A

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to or compressing spinal cord or cauda equina, radiation to bladder, pelvis, or spine- Pre-morbid/Co-morbid medical conditions: Hypogonadism, vaginal fibrosis/stenosis, cGVHD, injury above the level of the sacrum

References
Bjornard KL, Howell CR, Klosky JL, et al: Psychosexual functioning of female childhood cancer survivors: a report from the St. Jude Lifetime Cohort Study. J Sex Med 17(10):1981-1994, 2020
Fowler CJ, Sakakibara R, Frohman EM, et al: Neurologic bladder, bowel and sexual dysfunction, in Munsat TL (ed): World Federation of Neurology Seminars in Clinical Neurology. The Netherlands, Elsevier Science B.V., 2001
Korse NS, Nicolai MP, Both S, et al: Discussing sexual health in spinal care. Eur Spine J 25:766-73, 2016
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Piotrowski K, Snell L: Health needs of women with disabilities across the lifespan. J Obstet Gynecol Neonatal Nurs 36:79-87, 2007

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SURGERYSec #134

NEUROSURGERY—SPINAL CORD (CONT)

Therapeutic
Exposure
Neurosurgery-Spinal
cordLaminectomy
Laminoplasty

Potential
Late Effects
Scoliosis/Kyphosis

Periodic Evaluation

Health Counseling/
Further Considerations

PHYSICALHEALTH LINKS
Exam of back/spine
Scoliosis and Kyphosis
Yearly until growth completed, may need more POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
frequent assessment during puberty or if
Spine films in patients with clinically apparent curve.
curve detected
Orthopedic consultation as indicated based on physical and/or radiographic
exam.
SYSTEM = Musculoskeletal
SCORE = 1w

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Young age (deformity can still develop even if skeletally mature at time of surgery)- Cancer/Treatment factors: Radiation to the spine, increasing number of laminae removed, especially >3 laminae removed, facetectomy, laminectomy (versus laminotomy), laminectomy without fusion, increasing number ofresections, surgery of thoracolumbar junction- Pre-morbid/Co-morbid medical conditions: Preoperative deformity

References
Anakwenze OA, Auerbach JD, Buck DW, et al: The role of concurrent fusion to prevent spinal deformity after intramedullary spinal cord tumor excision in children. J Pediatr Orthop 31:475-9, 2011de Jonge T, Slullitel H, Dubousset J, et al: Late-onset spinal deformities in children treated by laminectomy and radiation therapy for malignant tumours. Eur Spine J 14:765-71, 2005
Gawade PL, Hudson MM, Kaste SC, et al: A systematic review of selected musculoskeletal late effects in survivors of childhood cancer. Curr Pediatr Rev 10:249-62, 2014
Laverdiere C, Liu Q, Yasui Y, et al: Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 101:1131-40, 2009
McGirt MJ, Chaichana KL, Atiba A, et al: Incidence of spinal deformity after resection of intramedullary spinal cord tumors in children who underwent laminectomy compared with laminoplasty. J Neurosurg Pediatr 1:57-62, 2008
Papagelopoulos PJ, Peterson HA, Ebersold MJ, et al: Spinal column deformity and instability after lumbar or thoracolumbar laminectomy for intraspinal tumors in children and young adults. Spine 22:442-451, 1997
Paulino AC, Fowler BZ: Risk factors for scoliosis in children with neuroblastoma. Int J Radiat Oncol Biol Phys 61:865-869, 2005
Yao KC, Mcgirt MJ, Chaichana KL, et al: Risk factors for progressive spinal deformity following resection of intramedullary spinal cord tumors in children: an analysis of 161 consecutive cases. J Neurosurg 107:463-468, 2007

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SURGERYSec #135

Therapeutic
Exposure
Oophoropexy(female)w

OOPHOROPEXY
Potential
Late Effects
Oophoropexy-related
complications
Inability to conceive despite
normal ovarian function
Dyspareunia
Symptomatic ovarian cysts
Bowel obstruction
Pelvic adhesions

Periodic Evaluation
HISTORY
Inability to conceive
Dyspareunia
Abdominal pain
Pelvic pain
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation for patients with positive history.
SYSTEM = Reproductive (Female)
SCORE = 2A

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Ovarian radiation, tubo-ovarian dislocation (especially with lateral ovarian transposition)

References
Chambers SK, Chambers JT, Kier R, et al: Sequelae of lateral ovarian transposition in irradiated cervical cancer patients. Int J Radiat Oncol Biol Phys 20:1305-8, 1991
Damewood MD, Hesla HS, Lowen M, et al: Induction of ovulation and pregnancy following lateral oophoropexy for Hodgkin’s disease. Int J Gynaecol Obstet 33:369-71, 1990
Hadar H, Loven D, Herskovitz P, et al: An evaluation of lateral and medial transposition of the ovaries out of radiation fields. Cancer 74:774-9, 1994
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Terenziani M, Piva L, Meazza C, et al: Oophoropexy: a relevant role in preservation of ovarian function after pelvic irradiation. Fertil Steril 91:935 e15-6, 2009
Thibaud E, Ramirez M, Brauner R, et al: Preservation of ovarian function by ovarian transposition performed before pelvic irradiation during childhood. J Pediatr 121:880-4, 1992

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SURGERYSec #136(female)OOPHORECTOMY (UNILATERAL)

Therapeutic
Exposure
Oophorectomy
unilateral

Potential
Late Effects
Ovarian hormone deficiencies
Delayed puberty
Arrested pubertyPremature ovarian
insufficiency/Prematuremenopause

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Menstrual history
Sexual function (vaginal dryness, libido)
Menopausal symptoms
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyMonitor growth until mature
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive Health
COUNSELING
Adverse impact of ovarian hormone deficiencies on growth, bone mineralization,
cardiovascular disease and sexual dysfunction.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH and estradiol and/or endocrine/gynecology referral for patients with:• No signs of puberty by age 13 years• Failure of pubertal progression• Abnormal menstrual patterns or menopausal symptoms• Ovarian hormone deficiency/insufficiency to weigh risks and benefits of hormonal replacement therapy
Bone density evaluation in patients with ovarian hormone deficiencies.
SYSTEM = Reproductive (Female)
SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with pelvic radiation, TBI, or alkylating agents- Health behaviors: Smoking

References
Bercow A, Nitecki R, Brady PC, et al: Outcomes after fertility-sparing surgery for women with ovarian cancer: a systematic review of the literature. J Minim Invasive Gynecol 28(3):527-536.e1, 2021
Chen J, Wang FF, Zhang Y, et al: Oncological and reproductive outcomes of fertility-sparing surgery in women with early-stage epithelial ovarian carcinoma: a multicenter retrospective study. Curr Med Sci 40(4):745-752, 2020
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Thomas-Teinturier C, El Fayech C, Oberlin O, et al: Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature. Hum Reprod 28:488-95, 2013

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SURGERYSec #137(female)OOPHORECTOMY (UNILATERAL) (CONT)

Therapeutic
Exposure
Oophorectomy
unilateral

Potential
Late Effects
Diminished Ovarian Reserve(DOR)
Infertility

Periodic Evaluation
HISTORY
Menstrual and pregnancy history
Hormonal therapy
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
Livestrong Foundation: www.livestrong.org/what-we-do/program/fertility
Oncofertility Consortium: https://oncofertility.msu.edu
COUNSELING
Potential for shorter period of fertility in family planning. Those with DOR
should consider discussing reproductive health options with a reproductive
endocrinologist or fertility specialist.
Review previous fertility preservation counseling/interventions.
Need for contraception.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
FSH and estradiol for patients with menstrual cycle dysfunction suggestiveof premature ovarian insufficiency or those who desire information about
potential for future fertility.
AMH to assess for DOR.
Reproductive endocrinology referral for antral follicle count, ovarian reserve
evaluation and consultation regarding assisted reproductive technologies in atrisk patients who desire information about potential fertility and interventions
to preserve future fertility.
SYSTEM = Reproductive (Female)
SCORE = 2Aw

Additional Information

AMH may be low in the presence of normal FSH. AMH should be interpreted relative to age-specific reference ranges. FSH is lowered and AMH may be lowered by concurrent hormonal contraceptive use.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with pelvic radiation, TBI, or alkylating agents- Health behaviors: Smoking

References
Chemaitilly W, Li Z, Krasin MJ, et al. Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab 102(7):2242-50, 2017
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Thomas-Teinturier C, El Fayech C, Oberlin O, et al: Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature. Hum Reprod 28:488-95, 2013

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SURGERYSec #138(female)Therapeutic
Exposure
Oophorectomy
bilateral

OOPHORECTOMY (BILATERAL)
Potential
Late Effects

Periodic Evaluation

Ovarian hormone deficiencies SCREENING
Absence of puberty
Endocrinologic or gynecologic consultation
Loss of ovarian follicular poolfor initiation of hormonal replacement
Infertility
therapy
At age 11 years or immediately for postpubertal patients

Health Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
Livestrong Foundation www.livestrong.org/what-we-do/program/fertility
Oncofertility Consortium https://oncofertility.msu.edu
COUNSELING
Benefits of hormone replacement therapy in promoting pubertal progression,bone and cardiovascular health.
Counsel women regarding pregnancy potential with donor eggs (if intact uterus).
Review previous fertility preservation counseling/interventions.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Reproductive endocrinology referral regarding assisted reproductive
technologies.
BMD evaluation.
SYSTEM = Reproductive (Female)
SCORE = 1w

References

Candy B, Jones L, Vickerstaff V, et al: Interventions for sexual dysfunction following treatments for cancer in women. Cochrane Database of Systematic Reviews, 2016
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Rivera CM, Grossardt BR, Rhodes DJ, et al: Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 16:15-23, 2009
Schover LR: Sexuality and fertility after cancer. Hematology Am Soc Hematol Educ Program:523-7, 2005

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SURGERYSec #139(male)ORCHIECTOMY (UNILATERAL, PARTIAL)

Therapeutic
Exposure
Orchiectomy
unilateralpartialPotential
Late Effects
Testicular hormonal
dysfunction
Testosterone deficiency/
insufficiency
Delayed/Arrested puberty

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyMonitor growth until mature
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Testicular and Reproductive Health
COUNSELING
Wear athletic supporter with protective cup during athletic activities.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Testosterone insufficiency or deficiency requiring hormone replacement after
alkylating agents only is rare.
Endocrine referral for the following:• No signs of puberty by age 14 years• Failure of pubertal progression• Adults with low AM testosterone levels
Periodic re-evaluation of testosterone in males with low-normal testosterone asthey age or if they become symptomatic.
Bone density evaluation in androgen deficient patients.
Surgical placement of testicular prosthesis and ongoing monitoring for surgicalcomplications after prosthesis placement.
Psychology referral (because orchiectomy can be associated with psychologicaldistress related to altered body image).
SYSTEM = Reproductive (Male)SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents)- Cancer/Treatment factors: Testicular cancer, unilateral orchiectomy combined with pelvic or testicular radiation and/or alkylating agents, higher cumulative dose platinum chemotherapy, infradiaphragmatic radiation- Pre-morbid/Co-morbid medical conditions: Obesity, ejaculatory dysfunction, history of sexually transmitted infections- Health behaviors: Tobacco/Marijuana use

References
Bandak M, Aksglaede L, Juul A, et al: The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer. Eur J Cancer 47:2585-2591, 2011
Eberhard J, Stahl O, Cwikiel M, et al: Risk factors for post-treatment hypogonadism in testicular cancer patients. Eur J Endocrinol 158:561-570, 2008
Huddart RA, Norman A, Moynihan C, et al: Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer 93:200-207, 2005
Jacobsen KD, Fossa SD, Bjoro TP, et al: Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Eur Urol 42:229-237, 2002
Sprauten M, Brydoy M, Haugnes HS, et al: Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 32:571-8,
2014
Woo LL, Ross JH: The role of testis-sparing surgery in children and adolescents with testicular tumors. Urol Oncol 34:76-83, 2016
Yossepowitch O, Aviv D, Wainchwaig L, et al: Testicular prostheses for testis cancer survivors: patient perspectives and predictors of long-term satisfaction. J Urol 186:2249-2252, 2011

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SURGERYSec #140(male)ORCHIECTOMY (UNILATERAL, PARTIAL) (CONT)

Therapeutic
Exposure
Orchiectomy
unilateralpartialPotential
Late Effects
Impaired spermatogenesis
Reduced fertility
Oligospermia
Azoospermia
Infertility

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyPHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyHEALTH LINKS

Testicular and Reproductive HealthRESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Need for contraception.
Review previous fertility preservation counseling/interventions.
Wear athletic supporter with protective cup during athletic activities.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
For sexually mature patients who desire information about potential future fertility:
semen analysis (optimal) and/or FSH and inhibin B (alternative if unable orunwilling to provide semen sample).
Reproductive endocrinology/urology referral for infertility evaluation and consultation
regarding assisted reproductive technologies.
Surgical placement of testicular prosthesis and ongoing monitoring for surgicalcomplications after prosthesis placement.
Psychology referral (because orchiectomy can be associated with psychologicaldistress related to altered body image).
SYSTEM = Reproductive (Male)SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents)- Cancer/Treatment factors: Testicular cancer, unilateral orchiectomy combined with pelvic or testicular radiation and/or alkylating agents, higher cumulative dose platinum chemotherapy, infradiaphragmatic radiation- Pre-morbid/Co-morbid medical conditions: Obesity, ejaculatory dysfunction, history of sexually transmitted infections- Health behaviors: Tobacco/Marijuana use

References
Eskenazi B, Wyrobek AJ, Sloter E, et al: The association of age and semen quality in healthy men. Hum Reprod 18:447-454, 2003
Green DM, Zhu L, Zhang N, et al: Lack of specificity of plasma concentrations of inhibin B and follicle-stimulating hormone for identification of azoospermic survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. J Clin Oncol
31:1324-8, 2013
Huddart RA, Norman A, Moynihan C, et al: Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer 93:200-207, 2005
Jacobsen KD, Fossa SD, Bjoro TP, et al: Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Eur Urol 42:229-237, 2002
Nudell DM, Monoski MM, Lipshultz LI: Common medications and drugs: how they affect male fertility. Urol Clin N Am 29:965-73, 2002
Romerius P, Stahl O, Moell C, et al: High risk of azoospermia in men treated for childhood cancer. Int J Androl 34:69-76, 2011
Sprauten M, Brydoy M, Haugnes HS, et al: Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 32:571-8, 2014
Woo LL, Ross JH: The role of testis-sparing surgery in children and adolescents with testicular tumors. Urol Oncol 34:76-83, 2016
Yossepowitch O, Aviv D, Wainchwaig L, et al: Testicular prostheses for testis cancer survivors: patient perspectives and predictors of long-term satisfaction. J Urol 186:2249-2252, 2011
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SURGERYSec #141(male)

Therapeutic
Exposure
Orchiectomy
bilateral

ORCHIECTOMY (BILATERAL)
Potential
Late Effects
Testosterone deficiency
Absence of puberty
Azoospermia
Infertility

Periodic Evaluation
PHYSICAL
Exam of testicular prostheses
YearlySCREENING
Endocrinologic consultation for initiation of
hormonal replacement therapy
At age 11 years or immediately for postpubertal patients

Health Counseling/
Further Considerations
HEALTH LINKS
Testicular and Reproductive Health
COUNSELING
Review previous fertility preservation counseling/interventions.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgical placement of testicular prostheses and ongoing monitoring for surgicalcomplications after prostheses placement.
Psychology referral (because orchiectomy can be associated with psychologicaldistress related to altered body image).
Bone density evaluation.
SYSTEM = Reproductive (Male)SCORE = 1w

References

Herman-Giddens ME, Steffes J, Harris D, et al: Secondary sexual characteristics in boys: data from the pediatric research in office settings network. Pediatrics 130:E1058-E1068, 2012
Jacobsen KD, Fossa SD, Bjoro TP, et al: Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Eur Urol 42:229-237, 2002
Modh RA, Mulhall JP, Gilbert SM: Sexual dysfunction after cystectomy and urinary diversion. Nat Rev Urol 11:445-53, 2014
Yossepowitch O, Aviv D, Wainchwaig L, et al: Testicular prostheses for testis cancer survivors: patient perspectives and predictors of long-term satisfaction. J Urol 186:2249-2252, 2011

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SURGERYSec #142

PELVIC SURGERY

Therapeutic
Exposure
Pelvic surgery
Cystectomy

Potential
Late Effects
Urinary incontinence
Urinary tract obstruction

Periodic Evaluation
HISTORY
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHealth Counseling/
Further Considerations
COUNSELING
Importance of adequate fluid intake, regular voiding, and seeking medical
attention for symptoms of voiding dysfunction or urinary tract infection.
Importance of compliance with recommended bladder catheterization regimen.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urologic consultation for patients with dysfunctional voiding or recurrent urinary
tract infections.
SYSTEM = Urinary
SCORE = 1w

Additional Information

For patients with cystectomy, see also section 117.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Pre-morbid/Co-morbid medical conditions: Tumor adjacent to or compressing spinal cord or cauda equina, retroperitoneal node dissection, extensive pelvic dissection (e.g., bilateral ureteral re-implantation, retroperitoneal
tumor resection), radiation to the bladder, pelvis, and/or lumbar-sacral spine

References
Derikx JPM, De Backer A, van de Schoot L, et al: Long-term functional sequelae of sacrococcygeal teratoma: a national study in the Netherlands. J Pediatr Surg 42:1122-1126, 2007
Hale GA, Marina NM, Jones-Wallace D, et al: Late effects of treatment for germ cell tumors during childhood and adolescence. J Pediatr Hematol Oncol 21:115-22, 1999
Heyn R, Raney RB, Jr., Hays DM, et al: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 10:614-23, 1992
Koyle MA, Hatch DA, Furness PD, et al: Long-term urological complications in survivors younger than 15 months of advanced stage abdominal neuroblastoma. J Urol 166:1455-1458, 2001
Kremer ME, Derikx JP, van Baren R, et al: Patient-reported defecation and micturition problems among adults treated for sacrococcygeal teratoma during childhood--the need for new surveillance strategies. Pediatr Blood Cancer
63:690-4, 2016
Ozkan KU, Bauer SB, Khoshbin S, et al: Neurogenic bladder dysfunction after sacrococcygeal teratoma resection. J Urol 175:292-296, 2006
Raney B, Anderson J, Jenney M, et al: Late effects in 164 patients with rhabdomyosarcoma of the bladder/prostate region: A report from the international workshop. J Urol 176:2190-2194, 2006

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PELVIC SURGERY (CONT)

Therapeutic
Exposure
Pelvic surgery
Cystectomy

Potential
Late Effects
Fecal incontinence

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Chronic constipation
Fecal soiling
YearlyPHYSICAL
Rectal exam
As clinically indicated

COUNSELING
Benefits of adherence to bowel regimen, including adequate hydration, fiber,
laxatives/enemas as clinically indicated.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
GI consultation to establish bowel regimen for patients with chronic impaction or
fecal soiling.
SYSTEM = GI/Hepatic
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to or compressing spinal cord or cauda equina, radiation to bladder, pelvis, or spine

References
Hale GA, Marina NM, Jones-Wallace D, et al: Late effects of treatment for germ cell tumors during childhood and adolescence. J Pediatr Hematol Oncol 21:115-22, 1999
Hoover M, Bowman LC, Crawford SE, et al: Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol 32:353-9, 1999
Moore SW, Kaschula ROC, Albertyn R, et al: The outcome of solid tumors occurring in the neonatal-period. Pediatr Surg Int 10:366-370, 1995
Rao S, Azmy A, Carachi R: Neonatal tumours: a single-centre experience. Pediatr Surg Int 18:306-309, 2002

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SURGERYSec #144(male)PELVIC SURGERY (CONT)

Therapeutic
Exposure
Pelvic surgery
Cystectomy

Potential
Late Effects
Psychosexual dysfunction
Erectile dysfunction

Periodic Evaluation
HISTORY
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Testicular and Reproductive Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urologic consultation in patients with positive history.
SYSTEM = Reproductive (Male)SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to spine, retroperitoneal node dissection, retroperitoneal tumor resection, extensive presacral tumor resection, cystectomy, radical prostatectomy, radiation to bladder, pelvis, or spine,or dissection, radiation dose ≥55 Gy to penile bulb in adult, ≥45 Gy in prepubertal child- Pre-morbid/Co-morbid medical conditions: Hypogonadism

References
Brydoy M, Fossa SD, Klepp O, et al: Paternity following treatment for testicular cancer. J Natl Cancer Inst 97:1580-1588, 2005
Jacobsen KD, Ous S, Waehre H, et al: Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection. Br J Cancer 80:249-55, 1999
Macedo A, Jr., Ferreira PV, Barroso U, Jr., et al: Sexual function in teenagers after multimodal treatment of pelvic rhabdomyosarcoma: A preliminary report. J Pediatr Urol 6:605-8, 2010
Modh RA, Mulhall JP, Gilbert SM: Sexual dysfunction after cystectomy and urinary diversion. Nat Rev Urol 11:445-53, 2014
Ritenour CW, Seidel KD, Leisenring W, et al: Erectile dysfunction in male survivors of childhood cancer-a report from the Childhood Cancer Survivor Study. J Sex Med 13:945-54, 2016
Zippe C, Nandipati K, Agarwal A, et al: Sexual dysfunction after pelvic surgery. Int J Impot Res 18:1-18, 2006

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SURGERYSec #145(male)PELVIC SURGERY (CONT)

Therapeutic
Exposure
Pelvic surgery
Cystectomy

Potential
Late Effects
Sexual dysfunction(anatomic)
Retrograde ejaculation
Anejaculation
Obstructive azoospermia
Infertility

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORYHEALTH LINKS
Quality of ejaculate (frothy white urine
Testicular and Reproductive Healthwith first void after intercourse suggests COUNSELING
retrograde ejaculation)
Use of assisted reproductive technology for sperm retrieval.
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urologic consultation in patients with positive history.
SYSTEM = Reproductive (Male)SCORE = 2Aw

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to spine, retroperitoneal node dissection, retroperitoneal tumor resection, extensive presacral tumor resection, cystectomy, radical prostatectomy, radiation to bladder, pelvis, or spine,or dissection, radiation dose ≥55 Gy to penile bulb in adult, ≥45 Gy in prepubertal child- Pre-morbid/Co-morbid medical conditions: Hypogonadism

References
Brydoy M, Fossa SD, Klepp O, et al: Paternity following treatment for testicular cancer. J Natl Cancer Inst 97:1580-1588, 2005
Jacobsen KD, Ous S, Waehre H, et al: Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection. Br J Cancer 80:249-55, 1999
Macedo A, Jr., Ferreira PV, Barroso U, Jr., et al: Sexual function in teenagers after multimodal treatment of pelvic rhabdomyosarcoma: A preliminary report. J Pediatr Urol 6:605-8, 2010
Modh RA, Mulhall JP, Gilbert SM: Sexual dysfunction after cystectomy and urinary diversion. Nat Rev Urol 11:445-53, 2014
Ritenour CW, Seidel KD, Leisenring W, et al: Erectile dysfunction in male survivors of childhood cancer-a report from the Childhood Cancer Survivor Study. J Sex Med 13:945-54, 2016
Zippe C, Nandipati K, Agarwal A, et al: Sexual dysfunction after pelvic surgery. Int J Impot Res 18:1-18, 2006

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SURGERYSec #146(female)w

PELVIC SURGERY (CONT)

Therapeutic
Exposure
Pelvic surgery
Cystectomy

Potential
Late Effects
Sexual dysfunction

Periodic Evaluation
HISTORY
Altered or diminished sensation, loss of
sensation
Dyspareunia
Medication use
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Ovarian and Reproductive Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation for patients with positive history.
SYSTEM = Reproductive (Female)
SCORE = 2A

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to spine, radiation to bladder, pelvis or spine- Pre-morbid/Co-morbid medical conditions: cGVHD, hypogonadism

References
Aerts L, Enzlin P, Verhaeghe J, et al: Sexual and psychological functioning in women after pelvic surgery for gynaecological cancer. Eur J Gynaecol Oncol 30:652-6, 2009
Bjornard KL, Howell CR, Klosky JL, et al: Psychosexual functioning of female childhood cancer survivors: a report from the St. Jude Lifetime Cohort Study. J Sex Med 17(10):1981-1994, 2020
Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol
31:1239-47, 2013
Schover LR: Sexuality and fertility after cancer. Hematology Am Soc Hematol Educ Program:523-7, 2005
Spunt SL, Sweeney TA, Hudson MM, et al: Late effects of pelvic rhabdomyosarcoma and its treatment in female survivors. J Clin Oncol 23:7143-51, 2005

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SURGERYSec #147

Therapeutic
Exposure
Splenectomy

SPLENECTOMY
Potential
Late Effects
Asplenia
At risk for life-threatening infection
with encapsulated organisms(e.g., Haemophilus influenzae,
Streptococcus pneumoniae,
meningococcus)

Periodic Evaluation
PHYSICAL
Physical exam at time of febrile illness toevaluate degree of illness and potential
source of infection
When febrile T ≥101°F (38.3°C)
SCREENING
Blood culture
When febrile T ≥101°F (38.3°C)

Health Counseling/
Further Considerations
HEALTH LINKS
Splenic Precautions
COUNSELING
Risk of life-threatening infections with encapsulated organisms.
Risk of malaria and tick-borne diseases if living in or visiting endemic areas.
Obtain medical alert bracelet/card noting asplenia.
Discuss importance of immunization with Pneumococcal, Meningococcal (including
serotype B), Influenza and HIB vaccines according to current ACIP recommendations.
For further details regarding antibiotic prophylaxis and immunizations, see current editionof AAP Red Book.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Administer a long-acting, broad-spectrum parenteral antibiotic (e.g., ceftriaxone) inpatients with T ≥101°F (38.3°C) or other signs of serious illness and continue close
medical monitoring while awaiting blood culture results.
Hospitalize and broaden antimicrobial coverage (e.g., addition of vancomycin) undercertain circumstances, such as the presence of marked leukocytosis, neutropenia, or
significant change from baseline CBC, toxic clinical appearance, fever ≥104°F (40°C),
meningitis, pneumonia, or other serious focus of infection, signs of septic shock, orprevious history of serious infection.
Discuss with dental provider potential need for antibiotic prophylaxis based on planned
procedure.
SYSTEM = Immune
SCORE = 2Aw

References

Castagnola E, Fioredda F: Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes. Eur J Haematol 71:319-26, 2003
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 61:816-9, 2012
Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of theAdvisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 62:521-4, 2013
Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Barnett ED, Lynfield R, et al (eds): Red Book: 2021 Report of the Committee on Infectious Diseases (ed 32). Itasca,
IL, American Academy of Pediatrics, 2021, pp 67-105
Guilcher GMT, Rivard L, Huang JT, et al: Immune function in childhood cancer survivors: a Children’s Oncology Group review. Lancet Child Adolesc Health 5(4):284-294, 2021
Jockovich M, Mendenhall NP, Sombeck MD, et al: Long-term complications of laparotomy in Hodgkin’s disease. Ann Surg 219:615-21; discussion 621-4, 1994

Mbaeyi SA, Bozio CH, Duffy J, et al: Meningococcal vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 69(9);1-41, 2020
Mourtzoukou EG, Pappas G, Peppas G, et al: Vaccination of asplenic or hyposplenic adults. Br J Surg 95:273-80, 2008
Newland A, Provan D, Myint S: Preventing severe infection after splenectomy - Patients should know the risks, be immunised, and take prophylactic antibiotics. BMJ 331:417-418, 2005
Omlin AG, Muhlemann K, Fey MF, et al: Pneumococcal vaccination in splenectomised cancer patients. Eur J Cancer 41:1731-1734, 2005
Price VE, Blanchette VS, Ford-Jones EL: The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am 21:697-710, viii-ix, 2007
Smets F, Bourgois A, Vermylen C, et al: Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine. Vaccine 25:5278-82, 2007
Spelman D, Buttery J, Daley A, et al: Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J 38:349-56, 2008
Taylor MD, Genuit T, Napolitano LM: Overwhelming postsplenectomy sepsis and trauma: Time to consider revaccination? J Trauma 59:1482-1485, 2005
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THORACIC SURGERY

Therapeutic
ExposureThoracic surgery

Potential
Late Effects
Pulmonary dysfunction

Periodic Evaluation
HISTORY
Cough
Wheezing
Shortness of breath
Dyspnea on exertion
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patients withabnormal results or progressive pulmonary
dysfunction

Health Counseling/
Further Considerations
HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco and Environmental tobacco smoke avoidance/Smoking cessation.
Influenza and Pneumococcal vaccinations.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Pulmonary consultation for patients with symptomatic pulmonary dysfunction.
Pulmonary consultation for survivors who desire to SCUBA dive (due to potential
undiagnosed pulmonary toxicities, and limited data to guide safe diving
recommendations for individuals treated with pulmonary toxic therapy).
SYSTEM = Pulmonary
SCORE = 2A

Additional Information

Thoracic surgery includes thoractomy, chest wall surgery, rib resection, pulmonary lobectomy, pulmonary metastasectomy and pulmonary wedge resection.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Combination with pulmonary toxic therapy (e.g., bleomycin, busulfan, carmustine [BCNU], lomustine [CCNU]), combination with chest radiation and TBI- Pre-morbid/Co-morbid medical conditions: Atopic history- Health behaviors: Smoking, inhaled illicit drug use

References
Dietz AC, Chen Y, Yasui Y, et al: Risk and impact of pulmonary complications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 122:3687-3696, 2016
Green DM, Zhu L, Wang M, et al: Pulmonary function after treatment for childhood cancer. A report from the St. Jude Lifetime Cohort Study (SJLIFE). Ann Am Thorac Soc 13:1575-85, 2016
Hudson MM, Ness KK, Gurney JG, et al: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371-2381, 2013
Mulder RL, Thonissen NM, van der Pal HJ, et al: Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 66:1065-71, 2011
Tetrault JM, Crothers K, Moore BA, et al: Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med 167:221-8, 2007
van Hulst RA, Rietbroek RC, Gaastra MT, et al: To dive or not to dive with bleomycin: a practical algorithm. Aviat Space Environ Med 82:814-8, 2011
Wolff AJ, O’Donnell AE: Pulmonary effects of illicit drug use. Clin Chest Med 25:203-16, 2004

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THORACIC SURGERY (CONT)

Therapeutic
ExposureThoracic surgery

Potential
Late Effects
Scoliosis/Kyphosis

Periodic Evaluation

Health Counseling/
Further Considerations

PHYSICALHEALTH LINKS
Exam of back/spine
Scoliosis and Kyphosis
Yearly until growth completed, may need more POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
frequent assessment during puberty or if
Spine films in patients with clinically apparent curve.
curve detected
Orthopedic consultation as indicated based on physical and/or radiographic
exam.
SYSTEM = Musculoskeletal
SCORE = 2Aw

Additional Information

Thoracic surgery includes thoractomy, chest wall surgery, rib resection, pulmonary lobectomy, pulmonary metastasectomy and pulmonary wedge resection.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Patient factors: Young age (deformity can still develop even if skeletally mature at time of surgery)- Cancer/Treatment factors: Radiation to the spine, greater number of ribs resected- Pre-morbid/Co-morbid medical conditions: Preoperative deformity

References
Deschamps C, Tirnaksiz BM, Darbandi R, et al: Early and long-term results of prosthetic chest wall reconstruction. J Thorac Cardiovasc Surg 117:588-91; discussion 591-2, 1999
Dingemann C, Linderkamp C, Weidemann J, et al: Thoracic wall reconstruction for primary malignancies in children: short- and long-term results. Eur J Pediatr Surg 22:34-9, 2012
Gawade PL, Hudson MM, Kaste SC, et al: A systematic review of selected musculoskeletal late effects in survivors of childhood cancer. Curr Pediatr Rev 10:249-62, 2014
Interiano RB, Kaste SC, Li C, et al: Associations between treatment, scoliosis, pulmonary function, and physical performance in long-term survivors of sarcoma. J Cancer Surviv 11(5),553–561, 2017
Kawakami N, Winter RB, Lonstein JE, et al: Scoliosis secondary to rib resection. J Spinal Disord 7:522-7, 1994
Laverdiere C, Liu Q, Yasui Y, et al: Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 101:1131-40, 2009
Scalabre A, Parot R, Hameury F, et al: Prognostic risk factors for the development of scoliosis after chest wall resection for malignant tumors in children. J Bone Joint Surg Am 96:e10, 2014
Soyer T, Karnak I, Ciftci AO, et al: The results of surgical treatment of chest wall tumors in childhood. Pediatr Surg Int 22:135-139, 2006

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SURGERYSec #150

THYROIDECTOMY

Therapeutic
Exposure
Thyroidectomy

Potential
Late Effects
Hypothyroidism

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Endocrine consultation for initiation of
thyroid hormone replacement
Immediately

HEALTH LINKS
Thyroid Problems
COUNSELINGFor females, thyroid levels prior to attempting pregnancy and periodicallythroughout pregnancy.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information

Total thyroidectomy is associated with the risk of hypoparathyroidism. This complication generally occurs in the early postoperative period and may persist.
Patients with a history of total thyroidectomy should be monitored for signs and symptoms of hypoparathyroidism (e.g., paresthesias, muscle cramping, altered mental status, hyperreflexia, tetany, hypocalcemia, and hyperphosphatemia).

References
Diesen DL, Skinner MA: Pediatric thyroid cancer. Semin Pediatr Surg 21:44-50, 2012
La Quaglia MP, Telander RL: Differentiated and medullary thyroid cancer in childhood and adolescence. Semin Pediatr Surg 6:42-9, 1997
Lallier M, St-Vil D, Giroux M, et al: Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg 33:846-8, 1998

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THYROIDECTOMY (PARTIAL)

Therapeutic
Exposure
Thyroidectomy
partialPotential
Late Effects
Hypothyroidism

Periodic Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening
during periods of rapid growth
PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening
during periods of rapid growth
SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growth

Health Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
COUNSELINGFor females, thyroid levels prior to attempting pregnancy and periodicallythroughout pregnancy.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Endocrine consultation for thyroid hormone replacement.
SYSTEM = Endocrine/Metabolic
SCORE = 1

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Thyroid gland in radiation field

References
Chemaitilly W, Li Z, Brinkman TM, et al: Primary hypothyroidism in childhood cancer survivors: prevalence, risk factors, and long-term consequences. Cancer 1;128(3):606-614, 2022
Lallier M, St-Vil D, Giroux M, et al: Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg 33:846-8, 1998
Verloop H, Louwerens M, Schoones JW, et al: Risk of hypothyroidism following hemithyroidectomy: systematic review and meta-analysis of prognostic studies. J Clin Endocrinol Metab 97(7):2243-55, 2012
Zatelli MC, Lamartina L, Meringolo D, et al: Thyroid nodule recurrence following lobo-isthmectomy: incidence, patient’s characteristics, adn risk factors. J Endocrinol Invest 41(12):1469-1475, 2018

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Therapeutic
Exposure

Potential
Late Effects

Radioiodine therapy (I-131 Lacrimal duct atrophy
thyroid ablation)

SYSTEMIC RADIATION

Periodic Evaluation
HISTORY
Excessive tearing

Yearlyw

Health Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ophthalmology consultation as clinically indicated.
SYSTEM = Ocular
SCORE = 2A

References

Burns JA, Morgenstern KE, Cahill KV, et al: Nasolacrimal obstruction secondary to I-131 therapy. Ophthal Plast Recons 20:126-129, 2004
Morgenstern KE, Vadysirisack DD, Zhang ZX, et al: Expression of sodium iodide symporter in the lacrimal drainage system: Implication for the mechanism underlying nasolacrimal duct obstruction in I-131-treated patients. Ophthal
Plast Recons 21:337-344, 2005
Zettinig G, Hanselmayer G, Fueger BJ, et al: Long-term impairment of the lacrimal glands after radioiodine therapy: a cross-sectional study. Eur J Nucl Med Mol Imaging 29:1428-32, 2002

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Therapeutic
Exposure

Potential
Late Effects

Radioiodine therapy (I-131 Hypothyroidism
thyroid ablation)

SYSTEMIC RADIATION (CONT)
Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening during
periods of rapid growth
PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening during
periods of rapid growth
SCREENING
TSHFree T4
Yearly, consider more frequent screening during
periods of rapid growth

HEALTH LINKS

Thyroid Problems
COUNSELINGFor females, thyroid levels prior to attempting pregnancy and periodically throughout
pregnancy.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Endocrine consultation for thyroid hormone replacement.
SYSTEM = Endocrine/Metabolic
SCORE = 2A

References

Safa AM, Schumacher OP, Rodriguez-Antunez A: Long-term follow-up results in children and adolescents treated with radioactive iodine (131I) for hyperthyroidism. N Engl J Med 292:167-71, 1975
Safa AM, Skillern PG: Treatment of hyperthyroidism with a large initial dose of sodium iodide I 131. Arch Intern Med 135:673-5, 1975

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Therapeutic
Exposure

Potential
Late Effects

Radioiodine therapy (I-131 Xerostomia
thyroid ablation)
Salivary gland dysfunction
Chronic sialadenitis

SYSTEMIC RADIATION (CONT)
Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Xerostomia
YearlyPHYSICAL
Oral Exam
YearlySCREENING
Dental Exam and Cleaning
Every 6 months

HEALTH LINKS

Dental Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Supportive care with saliva substitutes, moistening agents, and sialagogues(pilocarpine).
Regular dental care including fluoride applications.
SYSTEM = Oral/Dental
SCORE

References

Albano D, Bertagna F, Panarotto MB, et al: Early and late adverse effects of radioiodine for pediatric differentiated thyroid cancer. Pediatr Blood Cancer 64(11), 2017
Clement SC, Peeters RP, Ronckers CM, et al: Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review. Cancer Treat Rev 41(10):925-34, 2015
Horvath E, Skoknic V, Majlis S, et al: Radioiodine-Induced salivary gland damage detected by ultrasonography in patients treated for papillary thyroid cancer: radioactive iodine activity and risk. Thyroid (11):1646-1655, 2020
Selvakumar T, Nies M, Klein Hesselink MS, et al: Long-term effects of radioiodine treatment on salivary gland function in adult survivors of pediatric differentiated thyroid carcinoma. J Nucl Med Nov, 2018

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Therapeutic
Exposure
Systemic MIBG (intherapeutic doses)

Potential
Late Effects
Hypothyroidism

SYSTEMIC RADIATION (CONT)Periodic Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening
during periods of rapid growth
PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening
during periods of rapid growth
SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growth

Health Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
COUNSELINGFor females, thyroid levels prior to attempting pregnancy and periodicallythroughout pregnancy.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Endocrine consultation for thyroid hormone replacement.
SYSTEM = Endocrine/Metabolic
SCORE = 1

Additional Information

MIBG used for diagnostic purposes (i.e., MIBG scanning) does NOT put patients at risk for hypothyroidism.

References
Bhandari S, Cheung NK, Kushner BH, et al: Hypothyroidism after 131I-monoclonal antibody treatment of neuroblastoma. Pediatr Blood Cancer 55:76-80, 2010
Brans B, Monsieurs M, Laureys G, et al: Thyroidal uptake and radiation dose after repetitive I-131-MIBG treatments: influence of potassium iodide for thyroid blocking. Med Pediatr Oncol 38:41-6, 2002
Picco P, Garaventa A, Claudiani F, et al: Primary hypothyroidism as a consequence of 131-I-metaiodobenzylguanidine treatment for children with neuroblastoma. Cancer 76:1662-4, 1995
van Santen HM, de Kraker J, van Eck BL, et al: High incidence of thyroid dysfunction despite prophylaxis with potassium iodide during (131)I-meta-iodobenzylguanidine treatment in children with neuroblastoma. Cancer 94:2081-9,
2002
van Santen HM, de Kraker J, van Eck BLF, et al: Improved radiation protection of the thyroid gland with thyroxine, methimazole, and potassium iodide during diagnostic and therapeutic use of radiolabeled metaiodobenzylguanidine inchildren with neuroblastoma. Cancer 98:389-396, 2003

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Therapeutic
Exposure
Systemic MIBG (intherapeutic doses)

Potential
Late Effects
Thyroid nodules

SYSTEMIC RADIATION (CONT)Periodic Evaluation
PHYSICAL
Thyroid exam
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ultrasound for evaluation of palpable nodule(s).
FNA as clinically indicated.
Endocrine and/or surgical consultation for further management.
SYSTEM = SMNSCORE = 2Aw

References

Clement SC, Kremer LCM, Verburg FA, et al: Balancing the benefits and harms of thyroid cancer surveillance in survivors of childhood, adolescent and young adult cancer: Recommendations from the International Late Effects ofChildhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 63:28-39, 2018
Clement SC, van Rijn RR, van Eck-Smit BL, et al: Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma. Eur J
Nucl Med Mol Imaging 42:706-15, 2015

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Therapeutic
Exposure
Systemic MIBG (intherapeutic doses)

Potential
Late Effects
Thyroid cancer

SYSTEMIC RADIATION (CONT)Periodic Evaluation
PHYSICAL
Thyroid exam
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ultrasound for evaluation of palpable nodule(s).
FNA as clinically indicated.
Endocrine and/or surgical consultation for further management.
SYSTEM = SMNSCORE = 2Aw

References

Clement SC, Kremer LCM, Verburg FA, et al: Balancing the benefits and harms of thyroid cancer surveillance in survivors of childhood, adolescent and young adult cancer: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 63:28-39, 2018
Clement SC, van Eck-Smit BL, van Trotsenburg AS, et al: Long-term follow-up of the thyroid gland after treatment with 131I-Metaiodobenzylguanidine in children with neuroblastoma: importance of continuous surveillance. Pediatr
Blood Cancer 60:1833-8, 2013
Clement SC, van Rijn RR, van Eck-Smit BL, et al: Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma. Eur J
Nucl Med Mol Imaging 42:706-15, 2015

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Therapeutic
Exposure

Potential
Late Effects

Bioimmunotherapy(e.g., G-CSF, IL-2,
erythropoietin)

Insufficient information
currently available
regarding late effects

BIOIMMUNOTHERAPY

Periodic Evaluation

Health Counseling/
Further Considerations
SYSTEM = No Known Late Effects
SCORE = N/Aw

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Therapeutic
Exposure
BCR-ABL tyrosine
kinase inhibitors (e.g.,
imatinib, dasatinib,
nilotinib)

Potential
Late Effects
Growth attenuation

TARGETED BIOLOGIC THERAPIES

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORY
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Parental heights at baseline
Endocrine consultation for poor growth for age or stage of puberty as evidenced
Growth rateby decline in growth velocity and change in percentile rankings on growth
Signs of puberty
chart.
YearlyNeed for systematic study of the use of GH in children on chronic TKI therapy.
PHYSICALSYSTEM = Endocrine/Metabolic
Tanner staging every 6 months until
SCORE = 2A
sexually mature
Height and weight measured at every visit,
at least every 6 months
Plot growth velocity
SCREENING
None recommended aside from History andPhysical items listed above

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Cranial/CRT, HCT, chronic steroid treatment

References
Hijiya N, Maschan A, Rizzari C, et al. A phase 2 study of nilotinib in pediatric patients with CML: long-term update on growth retardation and safety. Blood Advances 5(14):2925-2934, 2021
Lodish MB. Kinase inhibitors: adverse effects related to the endocrine system. J Clin Endocrinol Metab 98(4):1333-1342, 2013
Millot F, Guilhot J, Baruchel A, et al. Growth deceleration in children treated with imatinib for chronic myeloid leukaemia. Eur J Cancer 50(18):3206-11, 2014
Narayanan KR, Bansal D, Walia R, et al. Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis. Pediatr Blood Cancer 60(7):1148-53, 2013
Samis J, Lee P, Zimmerman D, et al. Recognizing endocrinopathies associated with tyrosine kinase inhibitor therapy in children with chronic myelogenous leukemia. Pediatr Blood Cancer (8):1332-1338, 2016
Shima H, Tokuyama M, Tanizawa A, et al. Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. J Pediatr 159(4):676-81, 2011
Walia R, Aggarwal A, Bhansali A, et al. Acquired neuro-secretory defect in growth hormone secretion due to Imatinib mesylate and the efficacy of growth hormone therapy in children with chronic myeloid leukemia. Pediatr Hematol
Oncol, 37(2):99-108, 2020

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Therapeutic
Exposure
BCR-ABL tyrosine
kinase inhibitors (e.g.,
imatinib, dasatinib,
nilotinib)

Potential
Late Effects
Hypothyroidism

TARGETED BIOLOGIC THERAPIES (CONT)Periodic Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening
during periods of rapid growth
PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening
during periods of rapid growth
SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growth

Health Counseling/
Further Considerations
HEALTH LINKS
Thyroid Problems
COUNSELINGFor females, thyroid levels prior to attempting pregnancy and periodicallythroughout pregnancy.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Other forms of thyroid dysfunction (hyperthyroidism) may occur.
Endocrine consultation for thyroid hormone replacement.
SYSTEM = Endocrine/Metabolic
SCORE = 2B

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Thyroid gland in radiation field

References
Lodish MB. Kinase Inhibitors: Adverse Effects Related to the Endocrine System. J Clin Endocrinol Metab 98(4):1333-1342, 2013
Patel S, Nayernama A, Jones SC, et al: BCR-ABL1 tyrosine kinase inhibitor-associated thyroid dysfunction: a review of cases reported to the FDA Adverse Event Reporting System and published in the literature. Am J Hematol95(12):E332-35, 2020
Samis J, Lee P, Zimmerman D, et al: Recognizing endocrinopathies associated with tyrosine kinase inhibitor therapy in children with chronic myelogenous leukemia. Pediatr Blood Cancer 63(8):1332-1338, 2016

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Therapeutic
Exposure
Other targeted biologic
therapies

Potential
Late Effects

TARGETED BIOLOGIC THERAPIES (CONT)Periodic Evaluation

Insufficient information
currently available
regarding late effects

Health Counseling/
Further Considerations
SYSTEM = No Known Late Effects
SCORE = N/Aw

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Therapeutic
Exposure

Potential
Late Effects

B-cell directed antibody- Immunologic complications
based therapies
Hypogammaglobulinemia(rituximab)

ANTIBODY-BASED IMMUNE THERAPIES

Periodic Evaluation
HISTORY
Recurrent unusual infections
SCREENING
Serum quantitative immunoglobulins
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patients withabnormal resultsw

Health Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Immunology or infectious diseases consultation for assistance with managementof infections.
Some patients with hypogammaglobulinemia require lifelong IgG replacement.
SYSTEM = Immune
SCORE = 2A

Additional Information

Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors that may increase risk.
- Cancer/Treatment factors: Prior HCT- Pre-morbid/Co-morbid medical conditions: Underlying primary immunodeficiency

References
Labrosse R, Barmettler S, Derfalvi B, et al. Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients. J Allergy Clin Immunol 148(2):523-532, 2021
Minard-Colin V, Aupérin A, Pillon M, et al. Rituximab for high-risk, mature B-Cell Non-Hodgkin’s Lymphoma in children. N Engl J Med 382(23):2207-19, 2020

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Therapeutic
Exposure
Other antibody-based
immune therapies,
including antibody
drug conjugates(e.g., blinatumomab,
brentuximab
vedotin, inotuzumab,
gemtuzumab
ozogamicin,
dinutuximab,
naxitamab,
pembrolizumab,
ipilimumab,
nivolumab,
atezolizumab)

Potential
Late Effects

ANTIBODY-BASED IMMUNE THERAPIES (CONT)Periodic Evaluation

Insufficient information
currently available
regarding late effects

Health Counseling/
Further Considerations
SYSTEM = No Known Late Effects
SCORE = N/Aw

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GENERAL HEALTH
Health Counseling/
Further Considerations

Screening
SCREENING
Refer to the Centers for Disease Control andPrevention recommendations for screening,
vaccines, and healthy choices:www.cdc.gov/cancer/dcpc/prevention

COUNSELING
Importance of general health maintenance based on age and gender, including all recommended immunizations and cancer
screening.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
General health maintenance and screening per standard recommendations for age.
Screening for hypertension, obesity, depression, tobacco use, alcohol misuse.
Certain subpopulations require screening for lipid disorders, sexually transmitted infections, and diabetes mellitus. Others require
counseling regarding the prevention of cardiovascular disease, osteoporosis, and other disorders.
See www.ahrq.gov/clinic/uspstfix.htm for specific recommendations.
Follow preventive screening recommendations for common adult-onset cancers for average risk individuals.

References
Agency for Healthcare Research and Quality: Clinical Guidelines and Recommendations: U.S. Preventive Services Task Force. www.ahrq.gov/clinic/uspstfi.htm
Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Barnett ED, Lynfield R, et al (eds): Red Book: 2021 Report of the Committee on Infectious Diseases (ed32). Itasca, IL, American Academy of Pediatrics, 2021, pp 67-105

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VACCINATIONS
Health Counseling/
Further Considerations

Screening
SCREENING
Review age-appropriate vaccination history yearly

HEALTH LINKS
Vaccines after Treatment for Cancer Survivors Treated with HCT
Vaccines after Treatment for Cancer Survivors Treated with Chemotherapy and/or Radiation (Non-HCT)
COUNSELING
For survivors who have NOT received HCT:• At entry into long-term follow-up, confirm survivors have been offered catch-up vaccinations for any that were missed during
therapy according to national or regional guidelines
For survivors who have received HCT:
• Revaccinate allogeneic and autologous HCT survivors per international guidelines and after discussing with primary HCT team
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
All cancer survivors: screen for HPV vaccination - all cancer survivors should receive the 3-dose series regardless of age at first
HPV vaccine dose.
Regarding all other immunizations, reimmunize as indicated below:
HCT patients consider current recommendations (Tomblyn et al, 2009: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103296)
Non-HCT patients, some survivors treated with conventional therapy may lose vaccine-related immunity. Shared decision-making
regarding revaccinations/boosters for previously received vaccines may include any of the following approaches:• Give boosters for all routine vaccinations• Measure antibody titres (serology check) to assess for seroprotection and boosting as needed• Observe and manage as needed. See https://www.cdc.gov/vaccines/schedules/index.html for current immunization
schedules

Additional Information
Testing of immune function and referral to immunology in survivors (other than allogeneic HCT survivors) should be considered only if there is clinical suspicion of immune dysfunction.
Allogeneic HCT recipients undergo testing of immune reconstitution at some centers, but there are no universal standards.
New therapies (eg immunotherapy such as chimeric antigen receptor T-cell therapy) may impact immunologic function in both the short and long term; challenges exist in recommending standard testing or re-vaccination in survivors
due to paucity of long-term data.

References
Guilcher, GMT, Rivard L, Huang JT, et al: Immune function in childhood cancer survivors: a Children’s Oncology Group review. Lancet Child Adolesc Health 5:284-94, 2021
Mikulska M, Cesaro S, de Lavallade H, et al: Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL7). Lancet Infect
Dis 19:e188-199, 2019
Rubin LG, Levin MJ, Ljungman P, et al: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 58:e44-100, 2014
Tomblyn M, Chiller T, Einsele H, et al: Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15:1143-238, 2009

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