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

Version 5.0 - October 2018

Website: www.survivorshipguidelines.org
Copyright 2018 © Children’s Oncology GroupAll rights reserved worldwide

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers
Version 5.0 – October 2018www.survivorshipguidelines.org
Copyright 2018 © Children’s Oncology GroupAll rights reserved worldwide
Generously supported byWith special appreciation to
Jocelyn M. York, BA,
Institute for Cancer Outcomes and Survivorship
University of Alabama at Birmingham
Birmingham, AL
for editing and typesettingContents
Introductory Materials

Page

Section #

Page

Sex

Therapeutic Agent

Potential Late Effect

Abstract

x

14

18

Female Alkylating Agents

Disclaimer and Notice of Proprietary Rights

xi

15

20

Alkylating AgentsAcute myeloid leukemia; Myelodysplasia

Contributors - Panel of Experts

xii

16

21

Alkylating Agents

Pulmonary fibrosis

Contributors - Task Force Membership 2013-2018

xiii

17

22

Alkylating Agents

Cataracts

Contributors - Guideline Development Task Force - Initial Versions

xviii

18

23

Alkylating Agents

Urinary tract toxicity

Contributors - Health Link Authors

xviii

19

24

Alkylating Agents

Bladder malignancy

Preface

xix

20

25

Alkylating Agents

Renal toxicity

Instructions for Use

xxiii

21

26

Heavy Metals

Ototoxicity

New to Version 5.0

xxvi

22

28

Heavy Metals

Peripheral sensory neuropathy

23

29

Heavy Metals

Renal toxicity

2430

Antimetabolites

Neurocognitive deficits

25

31

Antimetabolites

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

26

32

Antimetabolites

Hepatic dysfunction; Sinusoidal
obstruction syndrome (SOS)27

33

Antimetabolites

Reduced bone mineral density (BMD)2835

Antimetabolites

No known renal late effects (methotrexate)

2936

Antimetabolites

Hepatic dysfunction

30

37

Antimetabolites

Neurocognitive deficits

31

38

Antimetabolites

Clinical leukoencephalopathy

32

39

Anthracycline Antibiotics

Acute myeloid leukemia

33

40

Anthracycline Antibiotics

Cardiac toxicity

34

42

Anti-Tumor Antibiotics

Pulmonary toxicity

35

44

Anti-Tumor Antibiotics

No known late effects (dactinomycin)

36

45

Corticosteroids

Reduced bone mineral density (BMD)

47

Corticosteroids

Osteonecrosis (avascular necrosis)

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
accessBlood/Serum Products
7

8

Diagnosed prior to 1972

Chronic hepatitis B

89Diagnosed prior to 1993

Chronic hepatitis C

910

Diagnosed between 1977
and 1985

HIV infection

Chemotherapy

Reduced ovarian follicular pool

Any Chemotherapy

Dental abnormalities

37

Male

Alkylating Agents

Testicular hormonal dysfunction

38

48

Corticosteroids

Cataracts

14

Male

Alkylating Agents

Impaired spermatogenesis

39

49

Enzymes

No known late effects (asparaginase)16

Female Alkylating Agents

Ovarian hormone deficiencies

40

50

Plant Alkaloids

Peripheral sensory or motor neuropathy

10

11

11

12

12
13

COG LTFU Guidelines – Page v

Version 5.0 – October 2018

Contents (cont)Section #

Page

41

51

42

Sex

52

Therapeutic Agent

Potential Late Effect

Plant Alkaloids
Epipodophyllotoxins

Section #Page

Vasospastic attacks (Raynaud's
phenomenon)

68
69

Acute myeloid leukemia

Radiation

Sex

Therapeutic Agent

Potential Late Effect85

Neck/Thyroid

Hypothyroidism

87

Neck/Thyroid

Hyperthyroidism

70

88

Neck/Thyroid

Carotid artery disease

71

89

Neck/Thyroid

Subclavian artery disease72

90

Female Breast

Breast cancer

73

91

Female Breast

Breast tissue hypoplasia

74

92

Lungs

Pulmonary toxicity

75

93

Lungs

Lung cancer

76

94

Heart

Cardiac toxicity

77

96

SpleenFunctional asplenia

78

98

GI/Hepatic System

Esophageal stricture

79

99

GI/Hepatic System

Impaired glucose metabolism/diabetes
mellitus

43

54

All Fields

Secondary benign or malignant neoplasm
occurring in or near radiation field

44

56

All Fields

Dermatologic toxicity

45

57

Brain/Cranium

Brain tumor (benign or malignant)46

58

Brain/Cranium

Neurocognitive deficits

47

59

Brain/Cranium

Clinical leukoencephalopathy

48

60

Brain/Cranium

Cerebrovascular complications

49

61

Brain/Cranium

Craniofacial abnormalities

50

62

Brain/Cranium

Chronic sinusitis

51

63

Neuroendocrine Axis

Overweight; Obesity

80

100

GI/Hepatic System

Dyslipidemia

52

65

Neuroendocrine Axis

Growth hormone deficiency

81

101

GI/Hepatic System

Hepatic toxicity

53

67

Male

Neuroendocrine Axis

Precocious puberty

82

102

GI/Hepatic System

Cholelithiasis

54

68

Female Neuroendocrine Axis

Precocious puberty

83

103

GI/Hepatic System

Bowel obstruction

55

69

Neuroendocrine Axis

Hyperprolactinemia

84

104

GI/Hepatic System

Chronic enterocolitis; Fistula; Strictures

56

70

Neuroendocrine Axis

Central hypothyroidism

85

105

GI/Hepatic System

Colorectal cancer

57

71

Male

Neuroendocrine Axis

Gonadotropin deficiency

86

107

Urinary Tract

Renal toxicity

58

73

Female Neuroendocrine Axis

Gonadotropin deficiency

87

108

Urinary Tract

Urinary tract toxicity

59

75

Neuroendocrine Axis

Central adrenal insufficiency

88

109

Urinary Tract

Bladder malignancy

60

76

Eye

Cataracts

89

110

Male

Male Reproductive System

Testicular hormonal dysfunction

61

77

Eye

Ocular toxicity

90

111

Male

Male Reproductive System

Impaired spermatogenesis

62

78

Ear

Ototoxicity

91

113

80

Oral Cavity

Xerostomia; Salivary gland dysfunction

Female Female Reproductive
SystemOvarian hormone deficiencies

63
64

81

Oral Cavity

Dental abnormalities; Temporomandibular
joint dysfunction

92

114

Female Female Reproductive
SystemReduced ovarian follicular pool

65

82

Oral Cavity

Osteoradionecrosis of the jaw

93

116

Female Female Reproductive
SystemUterine vascular insufficiency

66

83

Neck/Thyroid

Thyroid nodules

94

117

84

Neck/Thyroid

Thyroid cancer

Female Female Reproductive
SystemVaginal fibrosis/stenosis

67

COG LTFU Guidelines – Page vi

Version 5.0 – October 2018

Contents (cont)Section #

Page

95

Sex

Therapeutic Agent

Potential Late EffectSection #

Page

118

Musculoskeletal System

Musculoskeletal growth problems

119

96

119

97

120

Musculoskeletal System

Scoliosis/Kyphosis

Musculoskeletal System

Radiation-induced fracture

Hematopoietic Cell Transplant (HCT)
98

122

99

123

Male

Sex

Therapeutic Agent

Potential Late Effect149

Laparotomy

Adhesions; Bowel obstruction

120

150

Limb Sparing Procedure

Complications related to limb sparing
procedure

121

151

Male

Nephrectomy

Hydrocele; Renal toxicity

122

153

Female Nephrectomy

Renal toxicity

Auto HCT

Acute myeloid leukemia; Myelodysplasia

HCT

Solid tumors

123

155

Neurosurgery-Brain

Neurocognitive deficits

Solid tumors

124

156

Neurosurgery-Brain

Motor and/or sensory deficits

Hepatic toxicity

125

157

Neurosurgery-Brain

Seizures

158

Neurosurgery-Brain

Hydrocephalus; Shunt malfunction

100

124

Female HCT

101

126

HCT

102

128

HCT

Osteonecrosis (avascular necrosis)

126

103

129

HCT

Reduced bone mineral density (BMD)

127

159

Neurosurgery-Brain

Overweight; Obesity

104

131

HCT

Renal toxicity

128

160

Neurosurgery-Brain

Diabetes insipidus

161

Neurosurgery-Spinal Cord

Neurogenic bladder; Urinary incontinence

105

132

With Chronic GVHD

Dermatologic toxicity

129

106

133

With Chronic GVHD

Xerophthalmia (keratoconjunctivitis sicca)

130

162

Neurosurgery-Spinal Cord

Neurogenic bowel; Fecal incontinence

163

Male

Neurosurgery-Spinal Cord

Psychosexual dysfunction

Female Neurosurgery-Spinal Cord

Psychosexual dysfunction

107

134

With Chronic GVHD

Oral toxicity

131

108

136

With Chronic GVHD

Pulmonary toxicity

132

164

109

137

With Chronic GVHD

Immunologic complications

133

165

134

166

Female Oophoropexy

Oophoropexy-related complications

Neurosurgery-Spinal Cord

Scoliosis/Kyphosis

110

138

With CURRENTLY ACTIVE
Chronic GVHD

Functional asplenia

135

167

Female Oophorectomy (Unilateral)

Ovarian hormone deficiencies

111

140

With Chronic GVHD

Esophageal stricture

136

168

Female Oophorectomy (Unilateral)

Reduced ovarian follicular pool

112

141

Female With Chronic GVHD

Vulvar scarring; Vaginal fibrosis/stenosis

137

169

Female Oophorectomy (Bilateral)

113

142

With Chronic GVHD

Ovarian hormone deficiencies; Loss ofovarian follicular pool

138

170

Male

143

Amputation

Amputation-related complications

Orchiectomy (Unilateral,
Partial)Testicular hormonal dysfunction

114
115

145

Central Venous Catheter

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

139

172

Male

Orchiectomy (Unilateral,
Partial)Impaired spermatogenesis

116

146

Cystectomy

Cystectomy-related complications

Male

117

147

Enucleation

Impaired cosmesis; Poor prosthetic fit;
Orbital hypoplasia

118

148

Joint contractures

Surgery

Female Hysterectomy

COG LTFU Guidelines – Page vii

Pelvic floor dysfunction; Urinary
incontinence; Sexual dysfunction

140

174

Orchiectomy (Bilateral)

Testosterone deficiency; Azoospermia

141

175

Pelvic Surgery; Cystectomy

Urinary incontinence; Urinary tract
obstruction

142

176

Pelvic Surgery; Cystectomy

Fecal incontinence

143

177

Pelvic Surgery; Cystectomy

Psychosexual dysfunction

Male

Version 5.0 – October 2018

Contents (cont)Section #

Page

Sex

Therapeutic Agent

Potential Late EffectAppendix I: Materials for Clinical Application of LTFU Guidelines

144

178

Male

Pelvic Surgery; Cystectomy

Sexual dysfunction (anatomic); Infertility

Reference Materials

3

Sexual dysfunction

Abbreviations

5

Asplenia

Chemotherapy Agents

7

Radiation Fields Defined

8

145

179

146

180

Female Pelvic Surgery; Cystectomy
Splenectomy

Page

147

182

Thoracic Surgery

Pulmonary dysfunction

148

183

Thoracic Surgery

Scoliosis/Kyphosis

Radiation Dose Calculations

11

Hypothyroidism

Guideline Radiation Sections by Field

12

Guideline Radiation Sections by Potential Impact

13

Total Body Irradiation (TBI) Related Potential Late Effects

16

149

184

Thyroidectomy

Other Therapeutic Models
150

185

Systemic Radiation (I-131)

Lacrimal duct atrophy

Appeal Letter Following Denial of Insurance Claims for Survivorship Care

17

151

186

Systemic Radiation (I-131)

Hypothyroidism

152

187

Systemic Radiation (MIBG)

Hypothyroidism

Instructions

19

Template for Letter from Patient, Parent, or Guardian

20

153

188

Systemic Radiation (MIBG)

Thyroid nodules

154

189

Systemic Radiation (MIBG)

Thyroid cancer

155

190

Bioimmunotherapy

Insufficient information currently available
regarding late effects of biologicalagentsCancer Screening Guidelines
156

191

FemaleBreast Cancer

157

192

FemaleCervical Cancer

158

194

159

196

160

197

161

198

162

199

163

200

164

201

Colorectal Cancer
FemaleEndometrial Cancer
Lung Cancer

Template for Letter from Long-Term Follow-Up Clinician

21

Summary of Cancer Treatment

23

Instructions

25

Template for Summary of Cancer Treatment (Abbreviated)

27

Template for Summary of Cancer Treatment (Comprehensive)28

Key for Completing Summary of Cancer Treatment (Comprehensive)

30

Patient-Specific Guideline Identification Tool

37

Instructions

39

Patient-Specific Guideline Identification Tool (Version 5.0)

40

Section Number Comparison - COG LTFU Guidelines Version 4.0 vs 5.0

45Oral Cancer
Male
Male

Prostate Cancer

Appendix II: Health Links (Patient Education Materials)

Skin Cancer

Health Links Index by Title

Testicular Cancer

Health Links

General Health Screening
165

202

COG LTFU Guidelines – Page viii

General Health Screening

Version 5.0 – October 2018

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

Introductory
Materials

Version 5.0
October 2018

Abstract
Release date:

October 2018

Status:Updated from Version 4.0 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 5.0 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 5.0. Monrovia, CA: Children’s Oncology Group; October
2018; 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 5.0 – October 2018

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 5.0 – October 2018

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 5.0 of the Children’s Oncology Group Long-Term
Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:
Core Committee
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, CPNP
Co-Chair, COG LTFU Guidelines Core Committee
Associate Professor, Pediatrics and Nursing
Member, Institute for Cancer Outcomes andSurvivorshipChildren’s Hospital of Alabama
University of Alabama at Birmingham
Birmingham, AL
Louis S. Constine, MD
Co-Chair, COG LTFU Guidelines Core Committee
Professor, Radiation Oncology and Pediatrics
Vice Chair, Radiation Oncology
Director, Cancer Survivorship Program
University of Rochester Medical Center
Rochester, NY
Smita Bhatia, MD, MPH
Co-Chair, COG LTFU Guidelines Core Committee
Professor and Vice Chair, Pediatrics
Director, Institute for Cancer Outcomes andSurvivorshipChildren’s Hospital of Alabama
University of Alabama at Birmingham
Birmingham, AL

COG LTFU Guidelines – Page xii

Saro H. Armenian, DO, MPH
Associate Professor, Pediatrics and Population
Sciences
Director, Division of Outcomes Research andChildhood Cancer Survivorship Clinic
City of Hope Comprehensive Cancer Center
Duarte, CA
Eric J. Chow, MD, MPH
Associate Professor, Pediatrics
Director, Cancer Survivor Program
University of Washington School of Medicine
Seattle Children’s Hospital
Seattle, WA
Matthew J. Ehrhardt, MD, MS
Assistant Member, Department of Oncology
St. Jude Children’s Research Hospital
Memphis, TN
Paul G. Fisher, MD, MHS
Professor, Pediatrics and Neurology & Neurological
Sciences
Chief, Child Neurology
Director, Program in Human Biology
Lucile Packard Children’s Hospital
Stanford University Medical Center
Stanford, CA
Daniel M. Green, MD
Member, Departments of Oncology andEpidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TN

Nina S. Kadan-Lottick, MD, MSPH
Associate Professor, Pediatrics
Medical Director, HEROS Program
Yale University School of Medicine
New Haven, CT

Kirsten K. Ness, PT, PhD
Member, Department of Epidemiology and Cancer
Control
St. Jude Children’s Research Hospital
Memphis, TN

Kevin R. Krull, 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 andSupportive Care and Survivorship Center
Duke University Medical Center
Durham, NC

Lillian R. Meacham, MD
Professor, Pediatrics
Chair, Cancer Survivorship
Medical Director, Cancer Survivor ProgramChildren’s Healthcare of Atlanta
Emory University
Atlanta, GA
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

Leslie L. Robison, PhD
Chair, Department of Epidemiology and Cancer
Control
Co-Leader, Cancer Control & Survivorship Program
Associate Director, Population Sciences
St. Jude Children’s Research Hospital
Memphis, TNCharles A. Sklar, MD
Professor, Pediatrics
Director, Long-Term Follow-Up Program
Memorial Sloan Kettering Cancer Center
New York, NY
Julia Steinberger, MD, MS
Professor, Pediatrics
Division Director, Pediatric Cardiology
University of Minnesota School of Medicine
Minneapolis, MN

Version 5.0 – October 2018

Contributors
Task Force Membership 2013-2018
Task Force

Task Force Members

COG Institution

Expertise

Auditory

Johnnie K. Bass, AuD, PhD, Co-Chair
Kay W. Chang, MD
Douglas A. Cipkala, MD, Co-Chair
Satkiran S. Grewal, MD, Co-Chair, Mentor
Kristin Knight, MS
Torunn I. Yock, MD

St. Jude Children’s Research Hospital
Lucile Packard Children’s Hospital Stanford University
Saint Vincent Hospital and Health Care Center
Baystate Medical Center
Oregon Health and Science University
Massachusetts General Hospital Cancer Center

Audiology
Otolaryngology
Pediatric Oncology
Hematology-Oncology
Audiology
Radiation Oncology

Cardiovascular

Saro H. Armenian, DO, MPH, Co-Chair, Mentor
Gregory J. Aune, MD, PhD
Anne Blaes, MD
Ming Hui Chen, MD, MMSc
Andrew Dietz, MD, MSCR
Matthew J. Ehrhardt, MD, MS, Co-Chair
Joy M. Fulbright, MD, Co-Chair
Kasey J. Leger, MD
Vickie L. Massey, MD
Shawn Pun, MD
Julia Steinberger, MD, MS
Thomas Walwyn, MBBS

City of Hope Comprehensive Cancer Center
University of Texas Health Science Center at San Antonio
University of Minnesota/Masonic Cancer Center
Dana-Farber/Harvard Cancer Center
Children’s Hospital of Los Angeles
St. Jude Children’s Research HospitalChildren’s Mercy Hospitals and Clinics
Seattle Children’s HospitalChildren’s Mercy Hospitals and Clinics
Memorial Sloan Kettering Cancer Center
University of Minnesota/Masonic Cancer Center
Perth Children’s Hospital

Pediatric Oncology
Pediatric Oncology
Oncology
Cardiology
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Pediatric Radiation Oncology
Cardiology
Pediatric Cardiology
Pediatric Oncology

Endocrine:
Bone Health
ObesityInsulin ResistanceNathalie Alos, MD
Cindy J. Cochran, MSN
Kristy G. Devine, BA
Kimberley Dilley, MD, MPH
Adam J. Esbenshade, MD, MSci
Heather D. Escoto, MD
Natia Esiashvili, MD
Sue C. Kaste, DO
Lillian R. Meacham, MD, Co-Chair, Mentor
Sogol Mostoufi-Moab, MD, MSCE
Pinki K. Prasad, MD, MPH
Susan V. Shannon, RN, MSN, CPNP, CPON®
Jill H. Simmons, MD, Chair
Emily S. Tonorezos, MD, MPH
Lynda M. Vrooman, MD, MSc

Centre Hospitalier Universitaire Sainte-Justine
UT Southwestern/Simmons Cancer Center-Dallas
Children’s Oncology GroupAnn and Robert H. Lurie Children’s Hospital of Chicago
Vanderbilt University/Ingram Cancer Center
Saint Vincent Hospital and Health Care Center
Children’s Healthcare of Atlanta - Egleston
St. Jude Children’s Research HospitalChildren’s Healthcare of Atlanta - Egleston
Children’s Hospital of Philadelphia
Children’s Hospital New Orleans
Miller Children’s and Women’s Hospital Long Beach
Vanderbilt University/Ingram Cancer Center
Memorial Sloan Kettering Cancer Center
Dana-Farber/Harvard Cancer Center

Pediatric Endocrinology
Pediatric Oncology Nursing
Patient Advocate
Pediatrics
Pediatric Oncology
Pediatric Oncology
Radiation Oncology
Pediatric Radiology
Pediatric Endocrinology
Pediatric Oncology and Endocrinology
Pediatric Oncology
Pediatric Oncology Nursing
Pediatric Endocrinology
Internal Medicine
Pediatric Oncology

Endocrine:
OvarianLeslie Appiah, MD
Mary K. Dwyer, MBBS
Sobenna George, MD
Yasmin Gosiengfiao, MD
Daniel M. Green, MD

Nationwide Children’s Hospital
Royal Children’s HospitalChildren’s Healthcare of Atlanta - Egleston
Ann and Robert H. Lurie Children’s Hospital of Chicago
St. Jude Children’s Research Hospital

Pediatric and Adolescent Gynecology
Radiation Oncology
Pediatric Endocrinology
Pediatric Oncology
Pediatric Oncology

COG LTFU Guidelines – Page xiii

Version 5.0 – October 2018

Contributors
Task Force Membership 2013-2018 (cont)
Task Force

Task Force Members

COG Institution

Expertise(cont)
Endocrine:
OvarianJennifer M. Levine, MD
Lillian R. Meacham, MD, Co-Chair, Mentor
Monika Metzger, MD, MS
Briana C. Patterson, MD, MSCR, Chair
Sripriya Raman, MD Co-Chair

Weill Medical College of Cornell University
Children’s Healthcare of Atlanta - Egleston
St. Jude Children’s Research HospitalChildren’s Healthcare of Atlanta - Egleston
Children’s Hospital of Pittsburgh of UPMC

Pediatric Oncology
Pediatric Endocrinology
Pediatric Oncology
Pediatric Endocrinology
Pediatric Endocrinology

Endocrine:
Pituitary
AdrenalThyroid

Wassim Chemaitilly, MD, Chair
Christine Chordas, MSN
Laurie E. Cohen, MD
Lillian R. Meacham, MD, Co-Chair, Mentor
Lilibeth R. Torno, MD
Stacey Urbach, MD
Gregory C. Wheeler, MBBS, FRANZCR
Kevin Yuen, MD

St. Jude Children’s Research HospitalDana-Farber/Harvard Cancer Center
Dana-Farber/Harvard Cancer Center
Children’s Healthcare of Atlanta - Egleston
Children’s Hospital of Orange County
Hospital for Sick Children
Royal Children’s Hospital and Monash Medical Center
Oregon Health and Science University

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

Endocrine:
TesticularZoltan Antal, MD, Co-Chair
Laurie E. Cohen, MD
Louis S. Constine, MD
Daniel M. Green, MD
Lisa B. Kenney, MD, MPH, Chair
Eileen C. Lind, MSN, RN, CPNP
Barbara Lockart, RN, MSN, PNP
Lillian R. Meacham, MD, Co-Chair, Mentor
Leena Nahata, MD
Jonathan C. Routh, MD, MPH

Memorial Sloan Kettering Cancer Center
Dana-Farber/Harvard Cancer Center
University of Rochester
St. Jude Children’s Research HospitalDana-Farber/Harvard Cancer Center
Dana-Farber/Harvard Cancer Center
Ann and Robert H. Lurie Children’s Hospital of Chicago
Children’s Healthcare of Atlanta - Egleston
Nationwide Children’s Hospital
Duke University Medical Center

Pediatric Endocrinology
Pediatric Endocrinology
Radiation Oncology
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Pediatric Endocrinology
Pediatric Endocrinology
Pediatric Urology

Gastrointestinal
Hepatic

Jennifer Burgis, MD Co-Chair
Sharon M. Castellino, MD, MSc, Co-Chair
Cathleen M. Cook, MD
Karen E. Effinger, MD, MS
Kevin McMullen, MD
John K. Petty, MD
Kathy J. Ruble, RN, CRNP, PhD, AOCN®
Sheila Shope, RN, FNP
Julia O’Malley Stepenske, RN, BSN, CPON®

Lucile Packard Children’s Hospital Stanford University
Children’s Healthcare of Atlanta - Egleston
East Carolina University
Children’s Healthcare of Atlanta - Egleston
Riley Hospital for Children
Wake Forest University Health Sciences
Johns Hopkins University/Sidney Kimmel Cancer Center
St. Jude Children’s Research Hospital
Advocate Children’s Hospital-Park Ridge

Pediatric Gastroenterology/ Hepatology
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Radiation Oncology
Pediatric Surgery
Pediatric Oncology
Family Medicine
Pediatric Oncology and Patient Advocate

Hematopoietic Cell Transplantation
ImmuneDermatologic

Muhammad Ali, MD
Lynnette Anderson, RN, MSN, CPNP
Jen Belle, MBA
Eric J. Chow, MD, MPH, Co-Chair, Mentor
Christine N. Duncan, MD
Hesham Eissa, MD

Hospital for Sick ChildrenChildren’s Hospital of WisconsinChildren’s Oncology Group
Seattle Children’s HospitalDana-Farber/Harvard Cancer Center
Children’s Hospital Colorado

Hematopoietic Cell Transplantation
Pediatric Oncology and Survivorship
Patient Advocate
Pediatric Oncology
Hematopoietic Cell Transplantation and Survivorship
Hematopoietic Cell Transplantation and Pediatric Oncology

COG LTFU Guidelines – Page xiv

Version 5.0 – October 2018

Contributors
Task Force Membership 2013-2018 (cont)
Task Force

Task Force Members

COG Institution

Expertise(cont)
Hematopoietic Cell Transplantation
ImmuneDermatologic

Greg Guilcher, MD, Co-Chair
Jennifer T. Huang, MD
Wendy G. Pelletier, MSW, RSW
Joanna L. Perkins, MD, MS
Shanti Ramachandran, MBBS, FRACP, MPaeds
Linda S. Rivard, RN, BSN, CPON®
Tal T. Schecter-Finkelstein, MD
Elizabeth Schnorr, NP
Ami J. Shah, MD
Karla D. Wilson, RN, MSN, FNP, CPON®
Kenneth Wong, MD

Alberta Children’s HospitalDana-Farber/Harvard Cancer Center
Alberta Children’s HospitalChildren’s Hospitals and Clinics of Minnesota - Minneapolis
Perth Children’s Hospital
Advocate Children’s Hospital-Oak Lawn
Hospital for Sick Children
Lucile Packard Children’s Hospital Stanford University
Lucile Packard Children’s Hospital Stanford University
City of Hope Comprehensive Cancer Center
Children’s Hospital of Los Angeles

Hematopoietic Cell Transplantation
Pediatric Dermatology
Hematopoietic Cell Transplantation and Pediatric Oncology
Pediatric Oncology
Hematopoietic Cell Transplantation
Patient Advocate and Survivorship
Hematopoietic Cell Transplantation
Hematopoietic Cell Transplantation and Survivorship
Hematopoietic Cell Transplantation
Family Medicine and Survivorship
Radiation Oncology

Musculoskeletal

LaVette S. Bowles, MN, NPc
Melissa Claar, MA
Colleen Coulter, PT, MS
Winston W. Huh, MD
Sue C. Kaste, DO
Valerae O. Lewis, MD
Jill L. Lee, MSN, CRNP-AC, CPON®
Anita Mahajan, MD
Giselle J. Moore-Higgs, ARNP, PhDc, ACON
Miriam Morrell, DO
Rajaram Nagarajan, MD, MPH
Kirsten K. Ness, PT, PhD
Robert L. Randall, MD, FACS
Karen Wasilewski-Masker, MD, Co-Chair, Mentor
Carmen Wilson, PhD, Co-Chair

Mattel Children’s Hospital UCLA
University of Minnesota/Masonic Cancer Center
Children’s Healthcare of Atlanta - Egleston
MD Anderson Cancer Center
St. Jude Children’s Research Hospital
MD Anderson Cancer Center
University of Minnesota/Masonic Cancer Center
Mayo Clinic
University of Florida Health Science Center - Gainesville
MD Anderson Cancer Center
Cincinnati Children’s Hospital Medical Center
St. Jude Children’s Research HospitalPrimary Children’s HospitalChildren’s Healthcare of Atlanta - Egleston
St. Jude Children’s Research Hospital

Family Medicine and Survivorship
Nursing
Physical Therapy
Pediatric Oncology
Pediatric Radiology
Orthopedic Oncology
Pediatric Oncology, Nursing and Advanced PracticeRadiation Oncology
Clinical Trials, Nursing and Advanced Practice
Pediatric Oncology
Pediatric Oncology
Physical Therapy
Orthopedic Oncology
Pediatric Oncology
Epidemiology

Neurocognitive
Psychosocial

Lyn Balsamo, PhD
Pia Banerjee, PhD
Matthew Bitsko, PhD
Rebecca Foster, PhD, Co-Chair
Matthew Hocking, PhD
Laura Janzen, PhD
Nina S. Kadan-Lottick, MD, MSPH
Lisa Kahalley, PhD
James Klosky, PhD, Co-Chair, Mentor
Kevin R. Krull, PhD, Co-Chair, Mentor
Alicia Kunin-Batson, PhD, Co-Chair
Jennifer M. Levine, MD, MSW

Yale University
St. Jude Children’s Research Hospital
Virginia Commonwealth University/Massey Cancer Center
Washington University School of Medicine
Children’s Hospital of Philadelphia
Hospital for Sick Children
Yale University
Baylor College of Medicine
Children’s Healthcare of Atlanta - Egleston
St. Jude Children’s Research Hospital
University of Minnesota/Masonic Cancer Center
Weill Medical College of Cornell University

Psychology
Neuropsychology
Pediatric Psychology
Pediatric Psychology
Psychology
Neuropsychology
Oncology
Psychology
Pediatric Psychology
Neuropsychology
Neuropsychology
Oncology

COG LTFU Guidelines – Page xv

Version 5.0 – October 2018

Contributors
Task Force Membership 2013-2018 (cont)
Task Force

Task Force Members

COG Institution

Expertise

Neurocognitive
Psychosocial(cont)

Peter E. Manley, MD
Victoria G. Marchese, PhD, PT
April E. Nesin, PhD
Fiona Schulte, PhD, Co-Chair
Lisa A. Schwartz, PhD
Mary Tripp, PhD, MPH
Karin S. Walsh, PsyD

Dana-Farber/Harvard Cancer Center
University of Maryland/Greenebaum Cancer Center
TC Thompson Children’s Hospital
Alberta Children’s HospitalChildren’s Hospital of Philadelphia
MD Anderson Cancer Center
Children’s National Medical Center

Neuro-Oncology
Physical Therapy
Pediatric Psychology
Psychology
Pediatric Psychology
Public Health
Neuropsychology

Neurologic

Daniel C. Bowers, MD, Co-Chair
Jeffrey C. Buchsbaum, MD, PhD, AM
Laura Gilchrist, PT, PhD
Sabine Mueller, MD, PhD
Etan Orgel, MD,
Sonia Partap, MD
Pinki K. Prasad, MD, MPH
Suzanne M. Russo, MD
Zsila S. Sadighi, MD
Nicole Ullrich, MD, PhD, Co-Chair
Elizabeth Wells, MD

UT Southwestern/Simmons Cancer Center-Dallas
National Institutes of Health Clinical Center
Children’s Hospitals and Clinics of Minnesota - Minneapolis
UCSF Medical Center-Mission Bay
Children’s Hospital of Los Angeles
Lucile Packard Children’s Hospital Stanford University
Children’s Hospital New Orleans
Rainbow Babies and Childrens Hospital
St. Jude Children’s Research HospitalDana-Farber/Harvard Cancer Center
Children’s National Medical Center

Neuro-Oncology
Radiation Oncology
Physical Therapy
Neuro-Oncology
Pediatric Oncology
Neurology
Pediatric Oncology
Radiation Oncology
Neurology
Neurology
Neurology

OcularJeffrey C. Buchsbaum, MD, PhD, AM, Co-Chair, Mentor
Douglas A. Cipkala, MD
Tambra R. Dahlheimer, RN, CNP
Debra L. Friedman, MD
Dan S. Gombos, MD
Pinki K. Prasad, MD, MPH, Co-Chair
Kimberly F. Whelan, MD, MSPH
Catherine L. Woodman, MD

National Institutes of Health Clinical Center
Saint Vincent Hospital and Health Care Center
University of Minnesota/Masonic Cancer Center
Vanderbilt University/Ingram Cancer Center
MD Anderson Cancer Center
Children’s Hospital New OrleansChildren’s Hospital of Alabama
University of Iowa/Holden Comprehensive Cancer Center

Radiation Oncology
Pediatric Oncology
Pediatric Oncology Nursing
Pediatric Oncology
Ophthalmology
Pediatric Oncology
Pediatric Oncology
Family Medicine

Oral/Dental

Sharon Castellino, MD, MSc, Co-Chair
Cathleen M. Cook, MD
Karen E. Effinger, MD, MS, Co-Chair
Sue C. Kaste, DO
Kevin McMullen, MD
Cesar Migliorati, DDS, MS, PhD
Kathy J. Ruble, RN, CRNP, PhD, AOCN®
Sheila Shope, RN, FNP
Julia O’Malley Stepenske, RN, BSN, CPON®
Nathaniel Treister, DMD, DMSc

Children’s Healthcare of Atlanta - Egleston
East Carolina University
Children’s Healthcare of Atlanta - Egleston
St. Jude Children’s Research Hospital
Columbus Regional Health
University of Florida Health Science Center - GainesvilleJohns Hopkins University/Sidney Kimmel Cancer Center
St. Jude Children’s Research Hospital
Advocate Children’s Hospital-Park Ridge
Dana-Farber/Harvard Cancer Center

Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Pediatric Radiology
Radiation Oncology
Oral/Dental Medicine
Pediatric Oncology
Family Medicine
Pediatric Oncology and Patient Advocate
Oral/Dental Medicine

PulmonaryJennifer E. Agrusa, MD
Saro H. Armenian, DO, MPH, Co-Chair, Mentor

Baylor College of Medicine
City of Hope Comprehensive Cancer Center

Pediatric Oncology
Pediatric Oncology

COG LTFU Guidelines – Page xvi

Version 5.0 – October 2018

Contributors
Task Force Membership 2013-2018 (cont)
Task Force

Task Force Members

COG Institution

Expertise

Pulmonary(cont)

Aarati Didwania, MD
Andrew Dietz, MD, MSCR, Co-Chair
Mary F. McAleer, MD, PhD
Saumini Srinivasan, MD, MS
Dennis Stokes, MD, MPH
Daniel Weiner, MD

Ann and Robert H. Lurie Children’s Hospital of Chicago
Children’s Hospital of Los Angeles
MD Anderson Cancer Center
St. Jude Children’s Research Hospital
Vanderbilt University/Ingram Cancer Center
Children’s Hospital of Pittsburgh of UPMCInternal Medicine
Pediatric Oncology
Radiation Oncology
Pediatric Pulmonology
Pediatric Pulmonology
Pediatric Pulmonology

Subsequent Malignant Neoplasms
Cancer Screening

Dana Barnea, MD
Lisa Bashore, PhD, RN, CPNP, CPON®
Louis S. Constine, MD
Danielle N. Friedman, MD, Co-Chair
Debra L. Friedman, MD
Monica M. Gramatges, MD, PhD, Co-Chair
Eleanor Hendershot, MN
Tara O. Henderson, MD, MPH, Co-Chair
Marilyn Leitch, MD
Martin Mahoney, MD, MPH
Ann C. Mertens, PhD, MSPaul C. Nathan, MD, MSc, FRCPC, Co-Chair, Mentor
Kevin C. Oeffinger, MD
Stephanie Smith, MD, MPH
Eugene Suh, MD
Lucie M. Turcotte, MD
Tung T. Wynn, MD
Mark Yeazel, MD, MPH

Memorial Sloan Kettering Cancer Center
Cook Children’s Medical Center
University of Rochester
Memorial Sloan Kettering Cancer Center
Vanderbilt University/Ingram Cancer Center
Baylor College of Medicine/
McMaster Children’s Hospital at Hamilton Health Sciences
University of Chicago Comprehensive Cancer Center
UT Southwestern/Simmons Cancer Center-Dallas
Roswell Park Cancer InstituteChildren’s Healthcare of Atlanta - Egleston
Hospital for Sick Children
Duke University Medical Center
Lucile Packard Children’s Hospital Stanford University
Loyola University Medical Center
University of Minnesota/Masonic Cancer Center
University of Florida Health Science Center - Gainesville
University of Minnesota/Masonic Cancer Center

Internal Medicine
Pediatric Oncology Nursing
Radiation Oncology
Pediatrics
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology Nursing
Pediatric Oncology
Surgery
Family Medicine
Epidemiology
Pediatric Oncology
Family Medicine
Medicine and Pediatrics
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Family Medicine

Urinary Tract

Kala Kamdar, MD
Kathleen Kieran, MD, MS, Co-Chair
Anne Mauck, RN, MSN, CPNP
Kerry M. Moss, MD
Daniel A. Mulrooney, MD, MS, Co-Chair, Mentor
Nameeta P. Richard, MD, Co-Chair
Jonathan C. Routh, MD, MPH
Margarett Shnorhavorian, MD, MPH
Sheri L. Spunt, MD
Teresa Sweeney, RN, MSN, CPNP

Baylor College of Medicine
Seattle Children’s Hospital
Virginia Commonwealth University/Massey Cancer Center
Connecticut Children’s Medical Center
St. Jude Children’s Research Hospital
Randall Children’s Hospital at Legacy EmanuelDuke University Medical CenterSeattle Children’s Hospital
Lucile Packard Children’s Hospital Stanford University
St. Jude Children’s Research Hospital

Pediatric Oncology
Pediatric Urology
Pediatric Oncology Nursing
Pediatric Oncology
Pediatric Oncology
Pediatric Oncology
Pediatric Urology
Pediatric Urology
Pediatric Oncology
Pediatric Oncology Nursing

COG LTFU Guidelines – Page xvii

Version 5.0 – October 2018

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

Contributors
Health Link Authors
The following individuals participated in writing the patient education materials (Health Links) for the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:
Health Link Authors
Thomas R. Baker, CP, Wolfchase Limb and Brace, Jackson, TN
Julie Blatt, MD, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC
Sharon M. Castellino, MD, MSc, Children’s Healthcare of Atlanta - Egleston, Atlanta, GA
Adam J. Esbenshade, MD, MSci, Vanderbilt University/Ingram Cancer Center, Nashville, TN
Fernando A. Ferrer, MD, Children’s Hospital and Medical Center of Omaha, Omaha, NE
Sarah E. Friebert, MD, Childrens Hospital Medical Center of Akron, Akron, OH
Debra L. Friedman, MD, Vanderbilt University/Ingram Cancer Center, Nashville, TN
Sharon A. Frierdich, RN, MS, CPNP, University of Wisconsin Hospital and Clinics, Madison, WI
Allison Hester, RN, MSN, CPNP, Arkansas Children’s Hospital, Little Rock, AR
Melissa M. Hudson, MD, St. Jude Children’s Research Hospital, Memphis, TN
Debra A. Kent, RN, MSN, CPNP, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Asako Komiya, RN, MSN, PNP, City of Hope Comprehensive Cancer Center, Duarte, CA
Deborah Lafond, MS, RNCS, PNP, CPON®, Children’s National Medical Center, Washington, DC
Wendy Landier, PhD, CPNP, Children’s Hospital of Alabama, Birmingham, AL
Marcia S. Leonard, RN, CPNP, C.S. Mott Children’s Hospital, Ann Arbor, MI
Victoria G. Marchese, PhD, PT, University of Maryland/Greenebaum Cancer Center, Baltimore, MD
Anne Mauck, RN, MSN, CPNP, Virginia Commonwealth University/Massey Cancer Center, Richmond, VACharlene Maxen, RN, CNP, CPON®, Childrens Hospital Medical Center of Akron, Akron, OH
COG LTFU Guidelines – Page xviii

Lillian R. Meacham, MD, Children’s Healthcare of Atlanta - Egleston, Atlanta, GA
Katherine Myint-Hpu, MSN, MPH, PNP, National Institutes of Health Clinical Center, Washington, DC
Rajaram Nagarajan, MD, MPH, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Kevin C. Oeffinger, MD, Duke University Medical Center, Durham, NC
Maki Okada, CPNP, FNP-BC, CPON®, Miller Children’s and Women’s Hospital Long Beach, Long Beach, CA
Arnold Paulino, MD, MD Anderson Cancer Center, Houston, TX
Sunita K. Patel, PhD, City of Hope Comprehensive Cancer Center, Duarte, CA
Michael L. Ritchey, MD, Phoenix Childrens Hospital, Phoenix, AZ
Kathy J. Ruble, RN, MSN, CPNP, AOCN®, Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, MD
Sheila J. Santacroce, PhD, APRN, CPNP, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC
Margery Schaffer, RN, MSN, CPNP, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Susan V. Shannon, RN, MSN, CPNP, CPON®, Miller Children’s and Women’s Hospital Long Beach, Long Beach, CA
Patricia Shearer, MD, MS, Emory Healthcare, Johns Creek, GA
Sheila Shope, RN, FNP, St. Jude Children’s Research Hospital, Memphis, TN
Sheri L. Spunt, MD, Lucile Packard Children’s Hospital Stanford University, Palo Alto, CA
Teresa Sweeney, RN, MSN, CPNP, St. Jude Children’s Research Hospital, Memphis, TN
Sally Wiard, MSW, LCSW, Children’s Hospital of San Antonio, San Antonio, TX
Graphic Artist: Devika Bhatia, MD
Version 5.0 – October 2018

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 155 therapeutic
exposures in the COG LTFU Guidelines:•

108 (70%) are derived primarily from the H&P, of which 91 (59%) rely solely on the H&P
and 17 (11%) rely on the H&P plus a baseline diagnostic study (e.g., lab, imaging)•42 (27%) include periodic laboratory, diagnostic imaging, or other testing•

5 (3%) 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 43 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.
COG LTFU Guidelines – Page xix

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
Version 5.0 – October 2018

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 2018) 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

COG LTFU Guidelines – Page xx

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
Version 5.0 – October 2018

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 2 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 5.0 – October 2018).
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

COG LTFU Guidelines – Page xxi

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.
Version 5.0 – October 2018

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 Marc E. Horowitz, MD, (mehorowi@txch.org) or Susan Krause(skrause@txch.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 5.0 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
COG LTFU Guidelines – Page xxii

Version 5.0 – October 2018

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.
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.

COG LTFU Guidelines – Page xxiii

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.

Cancer Screening
Recommendations

Sections 156-164 contain preventive screening recommendations forcommon adult-onset cancers, organized by column as follows:
Organ: The organ at risk for developing malignancy.
Standard Risk Parameters and Screening Guidelines:
Screening guidelines provided under the “Standard Risk” category
are per the American Cancer Society and the U. S. Preventive
Services Task Force recommendations for standard-risk populations
and are included here for reference.
Highest Risk Parameters and Screening Guidelines:
High risk populations were those considered by the panel of experts
or other evaluating bodies (such as the American Cancer Society)as being at significantly increased risk for the specified malignancy.
Recommendations for high-risk populations, when applicable, arespecified and may differ from recommendations for the standard
risk groups due to the significantly increased risk of the specified
malignancy within the high-risk group.
Version 5.0 – October 2018

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:

Demographics

Cancer Treatment: Radiation• Names of all radiation field(s) treated– For list of radiation fields addressed by these guidelines (Sections 43-97), 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)
Cancer Treatment: Hematopoietic Cell Transplant(s)• Name• Sex• Date of birth• Whether or not the survivor underwent a hematopoietic cell transplant (HCT), and if so:– Transplant type (autologous vs allogeneic)– Chronic graft-versus-host disease (cGVHD) status (no history of chronic GVHD, history of chronic
GVHD, currently active chronic GVHD)

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 114–149), see “Surgery”
portion of the Patient-Specific Guideline Identification Tool in Appendix I

Cancer Treatment: Chemotherapy

Cancer Treatment: Other Therapeutic Modalities• Names of all chemotherapy agents received– For a list of chemotherapy agents addressed by these guidelines (Sections 10-42), 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 33 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)• Whether or not the survivor received radioiodine therapy (I-131 thyroid ablation) or systemic MIBG
(in therapeutic doses)

COG LTFU Guidelines – Page xxiv

2.

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

Sections 1 - 6: Applicable to all survivors•

Section 7: Survivors diagnosed before 1972•

Section 8: Survivors diagnosed before 1993•

Section 9: Survivors diagnosed between 1977 and 1985•

Section 10: All survivors who received chemotherapy•

Sections 11-42: For survivors who received chemotherapy, include relevant sections•

Sections 43, 44, 95: All survivors who received radiation

Version 5.0 – October 2018

Instructions for Use (cont)•Sections 45 - 94, 96- 97: For survivors who received radiation, include relevant
sections•

Sections 99 - 104: All survivors who underwent hematopoietic cell transplant
Section 99 is for males only–

Section 100 is for females only•

Section 98: For survivors who underwent autologous hematopoietic cell transplant•

Sections 105 - 113: For survivors who underwent allogeneic hematopoietic celltransplant, include relevant sections•

Sections 114 - 149: For survivors who underwent surgery, include relevant sections•

Sections 150 - 155: For survivors who received other therapeutic modalities, include
relevant sections•

Sections 156 - 164: Applicable to all survivors

•
3.

–

–

Sections 162, 164 are for males only–

Sections 156, 157, 159 are for females only

Section 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.

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
information, please contact Marc E. Horowitz, MD, (mehorowi@txch.org ) or Susan Krause(skrause@txch.org ).
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:
Co-Chairs, COG Long-Term Follow-Up Guidelines Core Committee:
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

COG LTFU Guidelines – Page xxv

Version 5.0 – October 2018

New to Version 5.0
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.

•

References have been updated in all sections•

Some column labels have been changed within the Cancer Screening Guidelines Sections(sections 156-164)

Simplification•

Templates have been added to Appendix I to assist with drafting appeal letters for denied
insurance claims

An overall goal of Version 5.0 of the COG Long-Term Follow-Up Guidelines is to simplify theformat and content of the guidelines in order to focus on clinically-relevant content, reduce theburden of medical record data abstraction necessary to determine tailored recommendations
for survivors, reduce the complexity of guideline application to individual survivors, andbetter align COG’s screening recommendations with those of the International Guideline
Harmonization Group. Version 5.0 therefore features the following modifications:

New Sections/Late Effects
The following new sections/late effects have been added:•

Lung cancer related to chest/axillary radiation and TBI (section 75)•

Psychosexual dysfunction (male) related to pelvic surgery/cystectomy (section 143)•

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

Thyroid nodules related to systemic MIBG in therapeutic doses (section 153)•

Re-definition/simplification of radiation fields•

Thyroid cancer related to systemic MIBG in therapeutic doses (section 154)–

All radiation fields from Version 4.0 are now mapped to body parts•

Melanoma related to HCT (sections 99, 100, 105)–

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

Sections/Late Effects Removed–•

It is no longer necessary to know or record specific radiation doses (with a few
exceptions)Radiation dose cut-offs largely eliminated (with 5 exceptions)–

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 in Version 5.0 are for late effects that require
screening beyond the history and physical examination and for which evidence
indicates that there is a low risk of developing the late effect below the radiationthreshold•

Most InfoLinks have been moved to Additional Information•

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

General Updates••

Some History and Physical Exam elements have been reworded for consistency between
sections
Revisions have been made to Counseling and Potential Considerations in most sections
COG LTFU Guidelines – Page xxvi

The following sections or late effects have been removed from Version 5.0 of the COG LTFU
Guidelines:•

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

Lymphoma related to HCT (section 106 of Version 4.0)•

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

Late Effects Renamed•

Gonadal dysfunction (testicular) renamed as: Testicular hormonal dysfunction (sections
11, 89, 138) and Impaired spermatogenesis (sections 12, 90)•

Gonadal dysfunction (ovarian) renamed as: Ovarian hormone deficiencies (sections 13, 91,
135, 137) and Reduced ovarian follicular pool (sections 14, 92, 136)•

Veno-occlusive disease (VOD) of the liver renamed as: Sinusoidal obstruction syndrome(SOS) (section 26)

Newly Divided Sections
The following sections from Version 4.0 have been divided into more than one section in
Version 5.0:

Version 5.0 – October 2018

New to Version 5.0 (cont)•••

Gonadal dysfunction (ovarian) and premature menopause related to alkylating agents,
radiation and oophorectomy (unilateral) are now separated into: ovarian hormone
deficiencies (sections 13, 91, 135) and reduced ovarian follicular pool (sections 14, 92,
136)
Gonadal dysfunction (testicular) related to orchiectomy (unilateral/partial) are
now separated into: testicular hormonal dysfunction (section 138) and impaired
spermatogenesis (section 139)
Sexual dysfunction (male) related to pelvic surgery/cystectomy are now separated into:
psychosexual dysfunction (section 143) and sexual dysfunction (anatomic), infertility(section 144)•

Functional deficit in academic fluency (section 46)•

Ectopic molar eruption (sections 10, 64)•

Oral cancer (section 43, 107)•

Luteinizing hormone (LH) and follicle stimulating hormone (FSH) deficiency (sections 57,
58)

Screenings moved from Periodic Evaluations to Considerations for Further Testing(now to be considered based on results of History and Physical Examination)•

Ovarian and testicular hormonal function (sections 11, 13, 14, 53, 54, 57, 58, 89, 91, 92,
135, 136, 138)

Newly Combined Sections•

Semen analysis (sections 12, 90, 139)

The following sections from Version 4.0 have been combined into one section in Version 5.0:•

Prolactin level (section 55)•

Cardiac toxicity related to anthracyclines: Male and female sections combined (nowsection 33)•

Urinalysis for assessment of radiation-related urinary tract toxicity (section 87)••

Secondary benign or malignant neoplasms related to radiation: Skin, bone, and soft
tissues combined (now section 43)

Evaluation by subspecialists (gynecologist [section 112], neurologist [sections 124, 125],
physiatrist [sections 124], and neurosurgeon [section 126])•

Cardiac toxicity related to radiation: Male and female sections combined (now section 76)•

Hyperprolactinemia related to head/brain radiation: Male and female sections combined(now section 55)•

Ototoxicity related to radiation: Conductive and sensorineural hearing loss combined (nowsection 62)•

Urinary tract toxicity related to radiation: Hemorrhagic cystitis and urinary tract toxicity
combined (now section 87)

Major Screening Changes
Anthracycline and Radiation-Related Cardiac Toxicity (Sections 33, 76)•

Platinum and Radiation-Related Ototoxicity (Sections 21, 62)•

Late Effects Re-categorized•

Dermatologic toxicity (section 44)•

Hepatic toxicity (section 81)•

Oral toxicity (section 107)

New Potential Late Effects Subcategories Added•

Relationship problems (section 1)•

Sleep problems (section 5)

COG LTFU Guidelines – Page xxvii

Echocardiograms for evaluation of anthracycline and radiation-related cardiac toxicity:
Changes in anthracycline and radiation dose cut-offs; changes in frequency ofrecommended echocardiograms; modification of isotoxic equivalent dose conversion for
daunorubicin
Screening recommendations now based on current age, with recommendations
differing for survivors ≤age 5 years, 6-12 years, and ≥13 years; periodic screening now
recommended for all at-risk survivors; screening for carboplatin no longer based on age;radiation dose cut-off now ≥30 Gy

Nephrectomy (Sections 121, 122)•

Yearly screening for renal toxicity (BP, serum creatinine, eGFR, urine dipstick for protein)
now recommended

Radiation-Related Breast Cancer (Section 72)•

Screening now recommended for radiation to chest, axilla, and TBI without dose threshold
Version 5.0 – October 2018

New to Version 5.0 (cont)
Radiation-Related Colorectal Cancer (Section 85)• Screening now recommended for radiation to abdomen, pelvis, spine (lumbar, sacral,whole), and TBI without dose threshold beginning 5 years after radiation or at age 30,
whichever occurs last.
•Colonoscopy every 5 years is the gold standard for screening in high-risk populations;however, multitarget stool DNA test every 3 years and other options may be consideredbased on informed decision making between patient and provider.

Renal toxicity Related to Chemotherapy, Radiation, and HCT (Sections 20, 23, 86, 104)•

Health Links••

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 5.0 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 alllate effects that are associated with the broader exposure categories in Version 5.0;
for example, survivors with radiation fields that are known to be limited to a specifictargeted area 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.

8AM serum cortisol now recommended annually for patients who received ≥30 Gy head/brain radiation (with guidance added for interpretation/referral)

Additional Screening Change Highlights•

Reduced bone mineral density related to methotrexate, steroids, and HCT: Adjustment forheight age z-score added for survivors younger than 20 years of age (sections 27, 36,
103)•

Cataracts/ocular toxicity related to head/brain radiation and GVHD: Evaluation by
ophthalmologist changed to yearly for all patients; evaluation by optometrist added as an
option; all head/brain radiation fields now included regardless of dose (previously ear/
infratemporal, nasopharyngeal, and Waldeyer’s Ring were excluded and doses <30 Gy
were included for cataract monitoring only) (sections 60, 61, 106)•

Neuropsychological testing is now recommended for all head/brain radiation fields(previously, orbital/eye, nasopharyngeal, and Waldeyer’s Ring were excluded) (section 46)•

Audiologic evaluation is now recommended for all head/brain fields at doses of ≥30 Gy(previously ocular/eye fields were excluded) (section 62)•

Dental precautions regarding osteoradionecrosis of the jaw are now recommended for all
head/brain radiation fields ≥40 Gy (previously, orbital/eye fields were excluded) (section
65)•

Evaluation for febrile illness (PRN T>101° F/38.3° C) is now recommended for all
abdominal radiation ≥40 Gy (previously not recommended for abdominal radiation thatwas limited to the right side, e.g., hepatic) (section 77)•

ALT/AST/Bilirubin (baseline and as clinically indicated) are now recommended for
COG LTFU Guidelines – Page xxviii

The Health Links have been modified to reflect all Version 5.0 Guideline changes.

General Recommendations Regarding Use of the Simplified COG LTFU Guidelines,
Version 5.0

Urinalysis removed

Adrenal Insufficiency Related to Head/Brain Radiation (Section 59)•

radiation doses <30 Gy to the abdomen (previously recommended only for doses ≥30 Gy)(section 81)

Version 5.0 – October 2018

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

Guidelines

Version 5.0
October 2018

ANY CANCER EXPERIENCESec #Therapeutic
Exposure1

Any Cancer Experience

Potential
Late Effects

Periodic Evaluation

Adverse psychosocial/quality HISTORY
of life effects
Psychosocial assessment with attention to:Social withdrawal- Educational and/or vocational progress
Educational problems- Social withdrawal
Relationship problems
YearlyUnder-employment/
Unemployment
Dependent living

Health Counseling/
Further Considerations
HEALTH LINKS
Introduction to Long-Term Follow-Up
Emotional Issues
Educational Issues
RESOURCES‘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
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.
SYSTEM = Psychosocial
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Female sex, younger age at diagnosis, family history of depression, anxiety, or mental illness, lower household income, lower educational achievement, failure to graduate from high school- Cancer/Treatment factors: Bone tumor, CNS tumor, CNS-directed therapy, history of hematopoietic cell transplant- Pre-morbid/Co-morbid medical conditions: Neurocognitive problems, depression, physical limitations, seizures, scarring or disfigurement, vision loss, hearing loss, premorbid learning or emotional difficulties

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
COG LTFU Guidelines – Page 1

Version 5.0 - October 2018

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
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
Gurney JG, Krull KR, Kadan-Lottick N, et al: Social outcomes in the Childhood Cancer Survivor Study cohort. J Clin Oncol 27:2390-5, 2009
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
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
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
Wong KF, Reulen RC, Winter DL, et al: Risk of adverse health and social outcomes up to 50 years after Wilms tumor: the British Childhood Cancer Survivor Study. J Clin Oncol 34:1772-9, 2016

COG LTFU Guidelines – Page 2

Version 5.0 - October 2018

ANY CANCER EXPERIENCE (CONT)Sec #Therapeutic
Exposure2

Any Cancer Experience

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

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORYHEALTH LINKS
Psychosocial assessment with attention to: Emotional Issues- Depression
RESOURCES- Anxiety‘Childhood Cancer Survivors: A Practical Guide to Your Future,’ by Nancy Keene,- Post-traumatic stress
Wendy Hobbie & Kathy Ruccione, Childhood Cancer Guides, 2012
- Suicidal ideation
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Psychological consultation in patients with emotional difficulties related tocancer experience, including physical deformities or chronic disabilities.
Appropriate psychotropic medications.
Evaluation of parent for posttraumatic stress.
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Female sex, family history of depression, anxiety, or mental illness, lower household income, lower educational achievement, especially failure to graduate from high school, 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 hematopoietic cell transplant- Pre-morbid/Co-morbid medical conditions: Chronic pain, scarring or physical disfigurement, permanent hair loss, premorbid learning or emotional difficulties

References
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
Duran B: Posttraumatic growth as experienced by childhood cancer survivors and their families: a narrative synthesis of qualitative and quantitative research. J Pediatr Oncol Nurs 30:179-97, 2013
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
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
Yi J, Zebrack B, Kim MA, et al: Posttraumatic growth outcomes and their correlates among young adult survivors of childhood cancer. J Pediatr Psychol 40:981-91, 2015
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
COG LTFU Guidelines – Page 3

Version 5.0 - October 2018

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

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Psychosocial assessment
YearlyHEALTH LINKS
Emotional Issues
RESOURCES‘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
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Adolescent/young adult at diagnosis or follow-up, male sex, lower household income, lower educational achievement, 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
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
Krull KR, Annett RD, Pan Z, et al: Neurocognitive functioning and health-related behaviours in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer 47:1380-8, 2011
Lown EA, Goldsby R, Mertens AC, et al: Alcohol consumption patterns and risk factors among childhood cancer survivors compared to siblings and general population peers. Addiction 103:1139-48, 2008
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
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
Zhang FF, Saltzman E, Must A, et al: Do childhood cancer survivors meet the diet and physical activity guidelines? A review of guidelines and literature. Int J Child Health Nutr 1:44-58, 2012

COG LTFU Guidelines – Page 4

Version 5.0 - October 2018

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.
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, as appropriate, that may increase risk.
- Patient factors: Female sex- Cancer/Treatment factors: CNS tumor, Hodgkin lymphoma, amputation, limb-sparing surgery, radiation to bone/joint, vincristine exposure- Pre-morbid/Co-morbid medical conditions: History of osteonecrosis

References
Girard P, Auquier P, Barlogis V, et al: Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood. Haematologica 98:1089-97, 2013
Keefe FJ, Rumble ME, Scipio CD, et al: Psychological aspects of persistent pain: current state of the science. J Pain 5:195-211, 2004
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
Thomas EM, Weiss SM: Nonpharmacological interventions with chronic cancer pain in adults. Cancer Control 7:157-64, 2000
Zaza C, Reyno L, Moulin DE: The multidimensional pain inventory profiles in patients with chronic cancer-related pain: an examination of generalizability. Pain 87:75-82, 2000

COG LTFU Guidelines – Page 5

Version 5.0 - October 2018

ANY CANCER EXPERIENCE (CONT)Sec #Therapeutic
Exposure5

Any Cancer Experience

Potential
Late Effects
FatigueSleep problems

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Psychosocial assessment
YearlyRESOURCES‘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 endocrinopathy.
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 and fatigue.
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: CNS tumor (e.g., craniopharyngioma), pulmonary radiation- Pre-morbid/Co-morbid medical conditions: Depression, obesity, history of sleep disturbance

References
Cella D, Davis K, Breitbart W, et al: Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol 19:3385-91, 2001
Gapstur R, Gross CR, Ness K: Factors associated with sleep-wake disturbances in child and adult survivors of pediatric brain tumors: a review. Oncol Nurs Forum 36:723-31, 2009
Jacobsen PB: Assessment of fatigue in cancer patients. J Natl Cancer Inst Monogr:93-7, 2004
Knobel H, Havard Loge J, Lund MB, et al: Late medical complications and fatigue in Hodgkin’s disease survivors. J Clin Oncol 19:3226-33, 2001
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

COG LTFU Guidelines – Page 6

Version 5.0 - October 2018

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.
SYSTEM = Psychosocial
SCORE = 2Aw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Lower household income, lower educational achievement, unemployment- 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), unilateral orchiectomy

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
Langeveld NE, Stam H, Grootenhuis MA, et al: Quality of life in young adult survivors of childhood cancer. Support Care Cancer 10:579-600, 2002
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
Oeffinger KC, Mertens AC, Hudson MM, et al: Health care of young adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Fam Med 2:61-70, 2004
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
Park ER, Li FP, Liu Y, et al: Health insurance coverage in survivors of childhood cancer: the Childhood Cancer Survivor Study. J Clin Oncol 23:9187-97, 2005

COG LTFU Guidelines – Page 7

Version 5.0 - October 2018

BLOOD/SERUM PRODUCTS
Sec #Therapeutic
Exposure

7

Diagnosed prior to 1972

Potential
Late Effects
Chronic hepatitis B

Health Counseling/
Further Considerations

Periodic Evaluation
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 concentrates, and allogeneic marrow, cord blood, or stem cells.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 8

Version 5.0 - October 2018

BLOOD/SERUM PRODUCTS (CONT)Sec #Therapeutic
Exposure

8

Diagnosed prior to 1993

Potential
Late Effects
Chronic hepatitis C

Health Counseling/
Further Considerations

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 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 hepatitis C virus (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, as appropriate, 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
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
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

COG LTFU Guidelines – Page 9

Version 5.0 - October 2018

BLOOD/SERUM PRODUCTS (CONT)Sec #9Therapeutic
Exposure

Potential
Late Effects

Diagnosed between 1977 HIV infection
and 1985

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

Health Counseling/
Further Considerations
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 not receive 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, as appropriate, 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

COG LTFU Guidelines – Page 10

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
10

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 = 1wAdditional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
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
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
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

COG LTFU Guidelines – Page 11

Version 5.0 - October 2018

CHEMOTHERAPYSec #11(male)

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
Potential
Late Effects

Testicular hormonal
dysfunction
Testosterone deficiency/
insufficiency
Delayed/arrested puberty

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
Male Health Issues
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Measurement of early morning testosterone concentration and/or endocrinology
referral for patients with:- no signs of puberty at age 14- failure of pubertal progression- poor growth for age or stage of puberty as evidenced by decline in growthvelocity and change in percentile rankings on growth chart, weight below 3rd
percentile on growth chart- testosterone deficiency/insufficiency to weigh risks and benefits of hormonal
replacement therapy
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.
Testosterone insufficiency requiring hormone replacement therapy is rare after
treatment with alkylating agents only.
SYSTEM = Reproductive (Male)SCOREClassical Alkylating Agents = 1
Heavy Metals = 2A
Non-Classical Alkylators = 2Aw

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, as appropriate, that may increase risk.
- Patient factors: Aging (≥30 years)- 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

COG LTFU Guidelines – Page 12

Version 5.0 - October 2018

CHEMOTHERAPY

ALKYLATING AGENTS (CONT)

Section 11 References (cont)
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
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, 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
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
Practice Committee of American Society for Reproductive Medicine: Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 98:294-301, 2012
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

COG LTFU Guidelines – Page 13

Version 5.0 - October 2018

CHEMOTHERAPYSec #12(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

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Onset and tempo of puberty
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyHEALTH LINKS
Male Health Issues

PHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyCOUNSELING
Need for contraception.
Recovery of fertility may occur years after therapy.

RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org

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 = 2Aw

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, as appropriate, that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents), aging- Cancer/Treatment factors: Testicular cancer, higher cumulative doses of alkylators (especially busulfan ≥600 mg/m2, cyclophosphamide ≥4 gm/m2 or ifosfamide ≥60 gm/m2), combinations of alkylators, 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, chronic GVHD
- Health behaviors: Tobacco/marijuana use
COG LTFU Guidelines – Page 14

Version 5.0 - October 2018

CHEMOTHERAPY

ALKYLATING AGENTS (CONT)

Section 12 References (cont)
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
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, 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
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

COG LTFU Guidelines – Page 15

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #13(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
Female Health Issues
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 at age 13- 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
Classical Alkylating Agents = 1
Heavy Metals = 2B
Non-Classical Alkylators = 2Aw

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, as appropriate, 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
Byrne J, Fears TR, Gail MH, et al: Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 166:788-93, 1992
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
COG LTFU Guidelines – Page 16

Version 5.0 - October 2018

CHEMOTHERAPY

ALKYLATING AGENTS (CONT)

Section 13 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
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

COG LTFU Guidelines – Page 17

Version 5.0 - October 2018

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

Reduced ovarian follicularpool
Infertility

Periodic Evaluation
HISTORY
Menstrual and pregnancy history
Hormonal Therapy
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Female Health Issues
RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Potential for shorter period of fertility (associated with increased risk of earlymenopause) in family planning.
Need for contraception.
Recovery of fertility may occur years after therapy.
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 (anti-Mullerian hormone) to assess for diminished ovarian reserve.
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.
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 = 2Aw

Additional Information
AMH may be low in the presence of normal FSH.
FSH is lowered and AMH may be lowered by concurrent hormonal contraceptive use.
COG LTFU Guidelines – Page 18

Version 5.0 - October 2018

CHEMOTHERAPY

ALKYLATING AGENTS (CONT)

Section 14 Additional Information (cont)
AMH should be interpreted relative to age-specific reference ranges.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

Section 14 References
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
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
Thomas-Teinturier C, Allodji RS, Svetlova E, et al: Ovarian reserve after treatment with alkylating agents during childhood. Hum Reprod 30:1437-46, 2015

COG LTFU Guidelines – Page 19

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
15

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
Myelodysplasia

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after exposure to agent

HEALTH LINKS
Reducing the Risk of Second Cancers

PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure to agent

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.

COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.

SYSTEM = SMN
SCOREClassical Alkylating Agents = 1
Heavy Metals = 2A
Non-Classical Alkylators = 2Aw

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, as appropriate, 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
COG LTFU Guidelines – Page 20

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
16

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

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Pulmonary fibrosis

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 withabnormal results or progressive pulmonary
dysfunction

HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco avoidance/smoking cessation/environmental tobacco smoke.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Influenza and Pneumococcal vaccinations.
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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 21

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
17

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
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 = 2Bw

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

References
Dahlgren S, Holm G, Svanborg N, et al: Clinical and morphological side-effects of busulfan (Myleran) treatment. Acta Med Scand 192:129-35, 1972
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

COG LTFU Guidelines – Page 22

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
18

Therapeutic
ExposureClassical Alkylating
AgentsCyclophosphamide
Ifosfamide

ALKYLATING AGENTS (CONT)
Potential
Late Effects

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

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHEALTH 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, as appropriate, 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
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
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

COG LTFU Guidelines – Page 23

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
19

Therapeutic
ExposureClassical Alkylating
AgentsCyclophosphamide

ALKYLATING AGENTS (CONT)
Potential
Late Effects

Bladder malignancy

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHEALTH 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, as appropriate, 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
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

COG LTFU Guidelines – Page 24

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
20

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

Health Counseling/
Further Considerations

PHYSICAL
Blood pressure
YearlyHEALTH LINKS
Kidney Health
Cardiovascular Risk Factors

SCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicated

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, as appropriate, 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
Burk CD, Restaino I, Kaplan BS, et al: Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms tumor. J Pediatr 117:331-5, 1990
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
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
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
Raney B, Ensign LG, Foreman J, et al: Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor. Am J Pediatr Hematol Oncol 16:286-95, 1994
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
COG LTFU Guidelines – Page 25

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
21

Therapeutic
Exposure
Heavy Metals
Carboplatin (myeloablative
doses)
Cisplatin

HEAVY METALS
Potential
Late Effects

Ototoxicity
Sensorineural hearing loss
Tinnitus
VertigoHealth Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Hearing difficulties (with/withoutbackground noise)
Tinnitus
VertigoYearlyPHYSICAL
Otoscopic exam
YearlySCREENING
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

HEALTH LINKS
Hearing Loss
Educational Issues
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 = 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 (ABR) can be performed if the above is inconclusive.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 26

Version 5.0 - October 2018

CHEMOTHERAPYHEAVY METALS (CONT)

Section 21 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
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
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

COG LTFU Guidelines – Page 27

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
22

Therapeutic
Exposure
Heavy Metals
Carboplatin
Cisplatin

HEAVY METALS (CONT)
Potential
Late Effects

Peripheral sensory
neuropathy
Paresthesias
Dysesthesias

Health Counseling/
Further Considerations

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 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 = 2Aw

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, as appropriate, that may increase risk.
- Cancer/Treatment factors: Cumulative cisplatin dose ≥300 mg/m2, combination with vincristine, taxanes, gemcitabine

References
Hilkens PH, ven den Bent MJ: Chemotherapy-induced peripheral neuropathy. J Peripher Nerv Syst 2:350-61, 1997
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

COG LTFU Guidelines – Page 28

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
23

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

Health Counseling/
Further Considerations

PHYSICAL
Blood pressure
YearlyHEALTH LINKS
Kidney Health
Cardiovascular Risk Factors

SCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicated

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, as appropriate, 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

COG LTFU Guidelines – Page 29

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
24

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

Health Counseling/
Further Considerations

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 LINKS
Educational Issues
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 = 2Aw

Additional Information
High-dose IV is defined as any single dose ≥1000 mg/m2.
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, as appropriate, 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
Buizer AI, de Sonneville LM, Veerman AJ: Effects of chemotherapy on neurocognitive function in children with acute lymphoblastic leukemia: a critical review of the literature. Pediatr Blood Cancer 52:447-54, 2009
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

COG LTFU Guidelines – Page 30

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
25

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

No known late effects
SYSTEM = No Known Late Effects
SCORE = 1w

Additional Information
Low-dose IV is defined as any single dose <1000 mg/m2.
Acute toxicities predominate, from which the majority of patients recover without sequelae.

COG LTFU Guidelines – Page 31

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
26

Therapeutic
Exposure
Antimetabolites
Mercaptopurine (6MP)
Thioguanine (6TG)

ANTIMETABOLITES (CONT)
Potential
Late Effects

Hepatic dysfunction
Sinusoidal obstruction
syndrome (SOS)[previously known as
veno-occlusive disease(VOD)]

Health Counseling/
Further Considerations

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 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 = 2Aw

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 (previously known as VOD), presenting as portal hypertension with liver biopsy indicating nodular regenerative hyperplasia, fibrosis, or siderosis.
Patients treated on CCG-1952, Regimens B1 and B2, received 6-thioguanine (6TG) in place of 6-mercaptopurine (6MP) during maintenance therapy.
- Acute hepatotoxicity (manifesting as SOS, previously known as VOD) 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, as appropriate, that may increase risk.
- Pre-morbid/Co-morbid medical conditions: Viral hepatitis (especially chronic viral hepatitis), previous SOS (previously known as VOD), siderosis

References
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
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

COG LTFU Guidelines – Page 32

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
27

Therapeutic
Exposure

ANTIMETABOLITES (CONT)
Potential
Late Effects

Antimetabolites
Reduced bone mineral
Methotrexate (high dose
density (BMD)IV)
Defined as Z-score >2.0 SD
Methotrexate (low dose IV) below the mean in survivors
Methotrexate IM<20 years old or T-score
Methotrexate PO>1.0 SD below the mean insurvivors ≥20 years old

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Bone density evaluation (DXA)
Adjust for height-age Z-score in survivors<age 20 years*
Baseline at entry into long-term follow-up,
repeat as clinically indicated.
*Pediatric Z-Score Calculator Adjusted for
Height Age: https://zscore.research.chop.
edu/bmdCalculator.php

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 children, with consideration for high doses in selected patients (e.g., kidneydisease or vitamin D deficiency). Many experts recommend higher vitamin D
intake in adults as well.
Ensure adequate dietary calcium (see table in the “Bone Health” Health Link forage-appropriate 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, growth hormone 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 = 2Bw

Additional Information
High-dose IV is defined as any single dose ≥1000 mg/m2.
The World Health Organization definition of osteoporosis in adults is based on comparison of a measured bone mineral density (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.

COG LTFU Guidelines – Page 33

Version 5.0 - October 2018

CHEMOTHERAPYANTIMETABOLITES (CONT)

Section 27 Additional Information (cont)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.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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 chronic GVHD), cyclosporine, tacrolimus, higher cumulative methotrexate dose (especially ≥40 gm/m2), cranial radiation, craniospinal radiation, HCT/TBI- Pre-morbid/Co-morbid medical conditions: Growth hormone deficiency, hypogonadism/delayed puberty, hyperthyroidism- Health behaviors: Intake of calcium and vitamin D, intake of alcohol and carbonated beverages, weight bearing exercise, smoking

Section 27 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: Bone-mineral density deficits from childhood cancer and its therapy. A review of at-risk patient cohorts and available imaging methods. Pediatr Radiol 34:373-8; quiz 443-4, 2004
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
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
van Leeuwen BL, Kamps WA, Jansen HW, et al: The effect of chemotherapy on the growing skeleton. Cancer Treat Rev 26:363-76, 2000
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, et al: Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122:1142-52, 2008
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
Writing Group for the IPDC: Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom 7:17-26, 2004
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

COG LTFU Guidelines – Page 34

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
28

Therapeutic
Exposure

ANTIMETABOLITES (CONT)
Potential
Late Effects

Antimetabolites
No known renal late effects
Methotrexate (high doseIV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO

Periodic Evaluation

Health Counseling/
Further Considerations

No known renal late effects
SYSTEM = No Known Renal Late Effects
SCORE = 2Aw

Additional Information
High-dose IV is defined as any single dose ≥1000 mg/m2.
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

COG LTFU Guidelines – Page 35

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
29

Therapeutic
Exposure

ANTIMETABOLITES (CONT)
Potential
Late Effects

Antimetabolites
Hepatic dysfunction
Methotrexate (high doseIV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO

Health Counseling/
Further Considerations

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 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 = 2Aw

Additional Information
High-dose IV is defined as any single dose ≥1000 mg/m2.
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, as appropriate, 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
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
McIntosh S, Davidson DL, O’Brien RT, et al: Methotrexate hepatotoxicity in children with leukemia. J Pediatr 90:1019-21, 1977

COG LTFU Guidelines – Page 36

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
30

ANTIMETABOLITES (CONT)

Therapeutic
Exposure

Potential
Late Effects

Antimetabolites
Methotrexate (high doseIV)
Methotrexate IO
Methotrexate IT

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

Health Counseling/
Further Considerations

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 LINKS
Educational Issues
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 = 1w

Additional Information
High-dose IV is defined as any single dose ≥1000 mg/m2.
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, as appropriate, 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), radiationdose ≥24 Gy, TBI, especially single fraction TBI (10 Gy), cranial radiation- Pre-morbid/Co-morbid medical conditions: Pre-morbid learning or attention problems

References
Buizer AI, de Sonneville LM, Veerman AJ: Effects of chemotherapy on neurocognitive function in children with acute lymphoblastic leukemia: a critical review of the literature. Pediatr Blood Cancer 52:447-54, 2009
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, 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
Jain N, Brouwers P, Okcu MF, et al: Sex-specific attention problems in long-term survivors of pediatric acute lymphoblastic leukemia. Cancer 115:4238-45, 2009
Jansen NC, Kingma A, Schuitema A, et al: Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. J Clin Oncol 26:3025-30, 2008
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
Kadan-Lottick NS, Brouwers P, Breiger D, et al: Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood
acute lymphoblastic leukemia. J Clin Oncol 27:5986-92, 2009
Peterson CC, Johnson CE, Ramirez LY, et al: A meta-analysis of the neuropsychological sequelae of chemotherapy-only treatment for pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 51:99-104, 2008
Riva D, Giorgi C, Nichelli F, et al: Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 59:48-53, 2002
COG LTFU Guidelines – Page 37

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
31

ANTIMETABOLITES (CONT)

Therapeutic
Exposure

Potential
Late Effects

Antimetabolites
Methotrexate (high doseIV)
Methotrexate IO
Methotrexate IT

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; Brain MRI with MR angiography as clinically indicated with preferredstudy based on intracranial lesion to be evaluated:- Calcifications: CT- White matter: MRI with diffusion-tensor imaging (DTI)- Microvascular injury: Gadolinium-enhanced MRI with diffusion-weighted
imaging (DWI)
Neurology consultation and follow-up as clinically indicated.
SYSTEM = CNSSCORE = 1w

Additional Information
High-dose IV is defined as any single dose ≥1000 mg/m2.
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, as appropriate, 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, cranial radiation, radiation dose ≥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

COG LTFU Guidelines – Page 38

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
32

Therapeutic
Exposure

ANTHRACYCLINE ANTIBIOTICS
Potential
Late Effects

Anthracycline Antibiotics Acute myeloid leukemia
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after exposure to agent

HEALTH LINKS
Reducing the Risk of Second Cancers

PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure to agent

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.

COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.

SYSTEM = SMNSCORE = 1w

Additional Information
Although Mitoxantrone technically belongs to the anthracenedione 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 for AML.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 39

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
33

Therapeutic
Exposure
Anthracycline Antibiotics
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone
Dose Conversion
To gauge the frequencyof screening, use thefollowing formulas toconvert to doxorubicin
isotoxic equivalents
prior to calculating total
cumulative anthracycline
dose. Clinical judgment
should ultimately be used
to determine indicatedscreening for individual
patients.
Doxorubicin: Multiply total
dose x 1
Daunorubicin: Multiply
total dose x 0.5
Epirubicin: Multiply total
dose x 0.67
Idarubicin: Multiply total
dose x 5
Mitoxantrone: Multiply
total dose x 4

ANTHRACYCLINE ANTIBIOTICS (CONT)
Potential
Late Effects

Cardiac toxicity
Cardiomyopathy
Subclinical left ventricular
dysfunction
Congestive heart failure
Arrhythmia

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Shortness of breath
Dyspnea on exertion
Orthopnea
Chest pain
Palpitations
If under 25 yrs: abdominal symptoms(nausea, vomiting)
YearlyPHYSICAL
Blood pressure
Cardiac exam
YearlySCREENINGECHO (or comparable imaging to evaluate
cardiac function)
Recommended Frequency of Echocardiogram
Anthracycline
Dose*
None

< 250 mg/m2≥ 250 mg/m2

Radiation
Dose**

Recommended
Frequency< 15 Gy or none

No screening≥ 15 - < 35 Gy

Every 5 years≥ 35 Gy

Every 2 years< 15 Gy or none

Every 5 years≥ 15 Gy

Every 2 years

Any or none

Every 2 years*Based on doxorubicin isotoxic equivalent dose. See dose conversion
instructions in section 33.
**Based on radiation dose with potential impact to heart (radiation tochest, abdomen, spine [thoracic, whole], TBI). See section 76.

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
Diet and Physical Activity
COUNSELING
Maintain appropriate weight, blood pressure and heart-healthy diet.
Regarding exercise:- Regular exercise is generally safe and should be encouraged for patients who have normal
LV systolic function.
- Survivors with asymptomatic cardiomyopathy should consult cardiology to define limits andprecautions for physical activity.
- Cardiology consultation may be reasonable to define limits and precautions for physicalactivity for high risk survivors (i.e., those requiring an ECHO every 2 years) who plan toparticipate in intensive exercise.
If QTc interval is prolonged: Caution regarding use of medications that may further prolong
the QTc interval (e.g., tricyclic anti-depressants, antifungals, macrolide antibiotics,
metronidazole).

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Cardiac MRI as an adjunct imaging modality when echocardiographic images are suboptimal.
Cardiology consultation in patients with subclinical abnormalities on screening evaluations, left
ventricular dysfunction, dysrhythmia, or prolonged QTc interval.
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- ≥35 Gy chest radiation, or- Anthracycline (any dose) combined with chest radiation (≥15 Gy)
Evaluation should include a baseline echocardiogram (pre- or early-pregnancy). For
those without prior abnormalities and with normal pre- or early-pregnancy baseline
echocardiograms, follow-up echocardiograms 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. Such individuals
should be monitored periodically during pregnancy and during labor and delivery due toincreased risk for cardiac failure.

SYSTEM = Cardiovascular
SCORE = 1w

Additional Information
Although Mitoxantrone technically belongs to the anthracenedione class of anti-tumor antibiotics, it is related to the anthracycline family and is included in this section because of its cardiotoxic potential.
COG LTFU Guidelines – Page 40

Version 5.0 - October 2018

CHEMOTHERAPYANTHRACYCLINE ANTIBIOTICS (CONT)

Section 33 Additional Information (cont)Pediatric studies of anthracycline cardiotoxicity typically describe risks based on combined cumulative doses of doxorubicin. There is a paucity of literature to support isotoxic dose conversion.
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.
Exertional intolerance is an uncommon presentation of left ventricular dysfunction in patients younger than 25 years old.
Abdominal symptoms (nausea, emesis) may be observed more frequently than exertional dyspnea or chest pain in younger patients.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Younger than age 5 years at time of treatment- Cancer/Treatment factors: Combined with radiation involving the heart, higher cumulative anthracycline doses (≥550 mg/m2 in patients 18 years or older at time of treatment, ≥250 mg/m2 in patients younger than 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)

Section 33 References
Abosoudah I, Greenberg ML, Ness KK, et al: Echocardiographic surveillance for asymptomatic late-onset anthracycline cardiomyopathy in childhood cancer survivors. Pediatr Blood Cancer 57:467-72, 2011
Armenian SH, Hudson MM, Mulder RL, et al: Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
Lancet Oncol 16:e123-36, 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
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 MH, Blackington LH, Zhou J, et al: Blood pressure is associated with occult cardiovascular disease in prospectively studied Hodgkin lymphoma survivors after chest radiation. Leuk Lymphoma 55:2477-83, 2014
Chow EJ, Chen Y, Kremer LC, et al: Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol 33:394-402, 2015
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
Hudson MM, Rai SN, Nunez C, et al: Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol 25:3635-43, 2007
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, Yeazel MW, Kawashima T, et al: Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 339:b4606, 2009
Ramjaun A, AlDuhaiby E, Ahmed S, et al: Echocardiographic detection of cardiac dysfunction in childhood cancer survivors: how long is screening required? Pediatr Blood Cancer 62:2197-203, 2015
van 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
Wong FL, Bhatia S, Landier W, et al: Cost-effectiveness of the Children’s Oncology Group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann Intern Med 160:672-83,
2014
Yeh JM, Nohria A, Diller L: Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: a model-based estimation of the clinical and economic effects. Ann Intern Med 160:661-71,
2014

COG LTFU Guidelines – Page 41

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
34

ANTI-TUMOR ANTIBIOTICS

Therapeutic
Exposure

Potential
Late Effects

Anti-Tumor Antibiotics
Bleomycin

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
YearlyHEALTH LINKS
Pulmonary HealthBleomycin Alert

PHYSICAL
Pulmonary exam
YearlyCOUNSELING
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.

SCREENING
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

RESOURCES
www.smokefree.gov

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Influenza and Pneumococcal vaccinations.
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, as appropriate, 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 doses 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

COG LTFU Guidelines – Page 42

Version 5.0 - October 2018

CHEMOTHERAPY

ANTI-TUMOR ANTIBIOTICS (CONT)

Section 34 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

COG LTFU Guidelines – Page 43

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
35

ANTI-TUMOR ANTIBIOTICS (CONT)

Therapeutic
Exposure

Potential
Late Effects

Anti-Tumor Antibiotics
Dactinomycin

No known late effects

Periodic Evaluation

Health Counseling/
Further Considerations

No known late effects
SYSTEM = No Known Late Effects
SCORE = 1w

Additional Information
Dactinomycin has been associated with acute veno-occlusive disease, 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

COG LTFU Guidelines – Page 44

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
36

Therapeutic
Exposure
Corticosteroids
Dexamethasone
Prednisone

CORTICOSTEROIDS
Potential
Late Effects

Reduced bone mineraldensity (BMD)
Defined as Z-score >2.0 SD
below the mean in survivors<20 years old or T-score>1.0 SD below the mean insurvivors ≥20 years old

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Bone density evaluation (DXA)
Adjust for height-age Z-score in survivors<age 20 years*
Baseline at entry into long-term follow-up,
repeat as clinically indicated.
*Pediatric Z-Score Calculator Adjusted for
Height Age: https://zscore.research.chop.
edu/bmdCalculator.php

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 children, with consideration for high doses in selected patients (e.g., kidneydisease or vitamin D deficiency). Many experts recommend higher vitamin D
intake in adults as well.
Ensure adequate dietary calcium (see table in the “Bone Health” Health Link forage-appropriate 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, growth hormone 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 = 2Bw

Additional Information
The World Health Organization definition of osteoporosis in adults is based on comparison of a measured bone mineral density (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 bone density for chronologic age based on Z-scores has not been established.
COG LTFU Guidelines – Page 45

Version 5.0 - October 2018

CHEMOTHERAPYCORTICOSTEROIDS (CONT)

Section 36 Additional Information (cont)
There are no defined standards for referral or treatment of low BMD in children.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Caucasian race, lower weight/BMI. Both genders are at risk.
- Cancer/Treatment factors: Methotrexate, cyclosporine, tacrolimus, higher cumulative corticosteroid dose (especially ≥9 gm/m2), cranial radiation, craniospinal radiation, HCT/TBI. Dexamethasone effect is more potent than
prednisone.
- Pre-morbid/Co-morbid medical conditions: Growth hormone deficiency, hypogonadism/delayed puberty, hyperthyroidism- Health behaviors: Intake of calcium and vitamin D, intake of alcohol and carbonated beverages, weight bearing exercise, smoking

Section 36 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
Polgreen LE, Petryk A, Dietz AC, et al: Modifiable risk factors associated with bone deficits in childhood cancer survivors. BMC Pediatr 12:40, 2012
van Leeuwen BL, Kamps WA, Jansen HW, et al: The effect of chemotherapy on the growing skeleton. Cancer Treat Rev 26:363-76, 2000
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, et al: Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122:1142-52, 2008
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
Writing Group for the IPDC: Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom 7:17-26, 2004
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

COG LTFU Guidelines – Page 46

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
37

Therapeutic
Exposure
Corticosteroids
Dexamethasone
Prednisone

CORTICOSTEROIDS (CONT)
Potential
Late Effects

Osteonecrosis (avascularnecrosis)

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Joint pain
Swelling
Immobility
Limited range of motion
YearlyPHYSICAL
Musculoskeletal exam
YearlyHEALTH 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 = 1w

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 effect is more potent than prednisone.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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 chronic GVHD)- Pre-morbid/Co-morbid medical conditions: Sickle cell disease, chronic GVHD

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
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

COG LTFU Guidelines – Page 47

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
38

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
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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 48

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
39

Therapeutic
Exposure
Enzymes
Asparaginase

ENZYMES
Potential
Late Effects

No known late effects

Periodic Evaluation

Health Counseling/
Further Considerations

No known late effects
SYSTEM = No Known Late Effects
SCORE = 1w

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

COG LTFU Guidelines – Page 49

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
40

Therapeutic
Exposure
Plant Alkaloids
Vinblastine
Vincristine

PLANT ALKALOIDS
Potential
Late Effects

Peripheral sensory or motor
neuropathy
Areflexia
Weakness
Foot drop
Paresthesias
Dysesthesias

Health Counseling/
Further Considerations

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

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).

PHYSICAL
Neurologic exam
Yearly, until 2 to 3 years after therapy, monitor
yearly if symptoms persist

SYSTEM = PNSSCORE = 2Aw

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, as appropriate, 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

COG LTFU Guidelines – Page 50

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
41

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 and other chemicals that cause
vasoconstriction (e.g., pseudoephedrine, stimulants), illicit drugs (e.g., cocaine),and nicotine in tobacco.
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, as appropriate, 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

COG LTFU Guidelines – Page 51

Version 5.0 - October 2018

CHEMOTHERAPY
Sec #
42

EPIPODOPHYLLOTOXINSTherapeutic
Exposure

Potential
Late Effects

Epipodophyllotoxins
Etoposide (VP16)
Teniposide (VM26)

Acute myeloid leukemia

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after exposure to agent

HEALTH LINKS
Reducing the Risk of Second Cancers

PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure to agent

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.

COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.

SYSTEM = SMNSCORE = 1w

Additional Information
Epipodophyllotoxin administration schedules since approximately 1990 have been modified to reduce the risk of this complication.
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, as appropriate, that may increase risk.
- Cancer/Treatment factors: Weekly or twice weekly administration, 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
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
Smith MA, Rubinstein L, Anderson JR, et al: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17:569-77, 1999

COG LTFU Guidelines – Page 52

Version 5.0 - October 2018

RADIATIONINSTRUCTIONS

Determining Applicability of Radiation Sections for Specific Patients Based on Exposure

Guideline Radiation Sections by Field

The radiation sections of the COG Long-Term Follow-Up Guidelines (Sections 43-97) areorganized by anatomic region from the head downward. In this current version of the COG
LTFU Guidelines (V5), the radiation fields have been simplified and categorized by anatomic
region, as follows:

Applicable guideline sections indicated in bold/dark blue; M=Male; F=Female-

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

Radiation Fields Defined, Table: Appendix I, pages 8-9
Radiation Fields Defined, Diagram: Appendix I, page 10

Five sections of these Guidelines (Sections 59, 62, 65, 76, 77) 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 as follows:-

Radiation Dose Calculations: Appendix I, page 11

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

Guideline Radiation Sections by Potential Impact, Table: Appendix I, pages 13-14
Guideline Radiation Sections by Potential Impact, Diagram: Appendix I, page 15
Total Body Irradiation (TBI) Related Potential Late Effects: Appendix I, page 16

Use the “Patient-Specific Guideline Identification Tool” in Appendix 1 (pages 37-44) todetermine specific screening guidelines by section number for individual patients.

COG LTFU Guidelines – Page 53

Version 5.0 - October 2018

RADIATION
Sec #
43

ALL FIELDS

Therapeutic
Exposure

Potential
Late Effects

Any Radiation (Including
TBI)

Secondary benign ormalignant neoplasm
occurring in or nearradiation field
Such as dysplastic nevi, skincancer (basal cell carcinoma,squamous cell carcinoma),bone malignancies, oral
cancerPeriodic Evaluation

Health Counseling/
Further Considerations

HISTORYHEALTH LINKS
Skin lesions
Reducing the Risk of Second Cancers
Changing moles (asymmetry, bleeding,
Skin Healthincreasing size, indistinct borders)
COUNSELING
Bone pain (especially in irradiated field)
Persistent thickening or lump of soft tissue Promptly seek medical attention for symptoms (e.g., bone pain, bone mass,
persistent fevers).
or boneYearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
See relevant guideline sections to determine screening for specific radiation
PHYSICAL
fields.
Skin self exam
Dermatology consultation for evaluation and monitoring of atypical nevi.
Monthly
X-ray or other diagnostic imaging in patients as clinically indicated.
Inspection and palpation of skin and soft
Surgical and/or oncology consultation as clinically indicated.
tissues in irradiated field(s)Dermatologic exam of irradiated fields
SYSTEM = SMN
Palpation of bones in irradiated field
YearlySCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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 germline mutation), Gorlin syndrome (nevoid basal cell carcinoma syndrome)- Health behaviors: Sun exposure, tanning booths

References
Araki Y, Matsuyama Y, Kobayashi Y, et al: Secondary neoplasms after retinoblastoma treatment: retrospective cohort study of 754 patients in Japan. Jpn J Clin Oncol 41:373-9, 2011
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, 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
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
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
Meadows AT, Friedman DL, Neglia JP, et al: Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol 27:2356-62, 2009
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
COG LTFU Guidelines – Page 54

Version 5.0 - October 2018

RADIATION

ALL FIELDS (CONT)

Section 43 References (cont)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
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
Watt TC, Inskip PD, Stratton K, et al: Radiation-related risk of basal cell carcinoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 104:1240-50, 2012

COG LTFU Guidelines – Page 55

Version 5.0 - October 2018

RADIATION
Sec #
44

ALL FIELDS (CONT)

Therapeutic
Exposure
Any Radiation (Including
TBI)

Potential
Late Effects
Dermatologic toxicity
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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Younger age at treatment- Cancer/Treatment factors: Total radiation dose ≥40 Gy, especially dose ≥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 andbones

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

COG LTFU Guidelines – Page 56

Version 5.0 - October 2018

POTENTIAL IMPACT TO
BRAIN/CRANIUM

RADIATION
Sec #45

Therapeutic
Exposure
Head/Brain
TBI

Potential
Late Effects
Brain tumor (benign ormalignant)Periodic Evaluation

Health Counseling/
Further Considerations

HISTORY
Headaches
Vomiting
Cognitive, motor or sensory deficits
Seizures and other neurologic symptoms
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.

PHYSICAL
Neurologic exam
YearlySYSTEM = SMNSCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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-response relationship)- Pre-morbid/Co-morbid medical conditions: Neurofibromatosis, ataxia telangiectasia

References
Bowers DC, Nathan PC, Constine L, et al: Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol 14:e321-8, 2013Friedman 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
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

COG LTFU Guidelines – Page 57

Version 5.0 - October 2018

POTENTIAL IMPACT TO
BRAIN/CRANIUM (CONT)RADIATION
Sec #46

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

Health Counseling/
Further Considerations

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 LINKS
Educational Issues
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 = 1w

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, as appropriate, 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, higher radiationdose, larger radiation field, greater cortical volumes, cranial radiation in combination with TBI, 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

References
Armstrong GT, Reddick WE, Petersen RC, et al: Evaluation of memory impairment in aging adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiotherapy. J Natl Cancer Inst 105:899-907, 2013
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
Clanton NR, Klosky JL, Li C, et al: Fatigue, vitality, sleep, and neurocognitive functioning in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 117:2559-68, 2011
Holland AA, Hughes CW, Stavinoha PL: School competence and fluent academic performance: informing assessment of educational outcomes in survivors of pediatric medulloblastoma. Appl Neuropsychol Child 4:249-56, 2015
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
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, Zhang N, Santucci A, et al: Long-term decline in intelligence among adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation. Blood 122:550-3, 2013
COG LTFU Guidelines – Page 58

Version 5.0 - October 2018

POTENTIAL IMPACT TO
BRAIN/CRANIUM (CONT)RADIATION
Sec #47

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; Brain MRI with MR angiography as clinically indicated with preferredstudy based on intracranial lesion to be evaluated:- Calcifications: CT- White matter: MRI with diffusion-tensor imaging (DTI)- Microvascular injury: Gadolinium-enhanced MRI with diffusion-weighted
imaging (DWI)
Neurology consultation and follow-up as clinically indicated.
SYSTEM = CNSSCORE = 1w

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, as appropriate, 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 dose ≥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
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

COG LTFU Guidelines – Page 59

Version 5.0 - October 2018

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

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 diffusion-weighted imaging with MR angiography as clinicallyindicated.
Neurology/neurosurgery consultation and follow-up.
Physical and occupational therapy as clinically indicated.
Revascularization procedures as indicated for moyamoya.
SYSTEM = CNSSCORE = 1w

Additional Information
Moyamoya syndrome is the complete occlusion of one or more of the three major cerebral vessels with the development of small, immature collateral vessels. This condition 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, as appropriate, that may increase risk.
- Cancer/Treatment factors: Parasellar tumor, radiation dose ≥18 Gy, especially radiation dose ≥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
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

COG LTFU Guidelines – Page 60

Version 5.0 - October 2018

POTENTIAL IMPACT TO
BRAIN/CRANIUM (CONT)RADIATION
Sec #49

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
PHYSICALSCORE = 1
Craniofacial abnormalities
Yearlyw

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

References
Estilo CL, Huryn JM, Kraus DH, et al: Effects of therapy on dentofacial development in long-term survivors of head and neck rhabdomyosarcoma: the Memorial Sloan-Kettering Cancer Center experience. J Pediatr Hematol Oncol
25:215-22, 2003
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
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

COG LTFU Guidelines – Page 61

Version 5.0 - October 2018

POTENTIAL IMPACT TO
BRAIN/CRANIUM (CONT)RADIATION
Sec #50

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Chronic sinusitis

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Rhinorrhea, postnasal discharge
History of URIs
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CT scan of sinuses as clinically indicated.
Otolaryngology consultation as clinically indicated.

PHYSICAL
Nasal and sinus exam
YearlySYSTEM = Immune
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
Ellingwood KE, Million RR: Cancer of the nasal cavity and ethmoid/sphenoid sinuses. Cancer 43:1517-26, 1979
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
Liang KL, Kao TC, Lin JC, et al: Nasal irrigation reduces postirradiation rhinosinusitis in patients with nasopharyngeal carcinoma. Am J Rhinol 22:258-62, 2008

COG LTFU Guidelines – Page 62

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NEUROENDOCRINE AXISRADIATION
Sec #51

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Overweight
Obesity

Periodic Evaluation
PHYSICAL
HeightWeight
BMI
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Diet 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 dietician for 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 the metabolic syndrome.
Definitions of the metabolic syndrome generally include a combination of central (abdominal) obesity with at least 2 or more of the following: hypertension, atherogenic dyslipidemia (elevated triglycerides, reduced HDL cholesterol),and abnormal glucose metabolism (fasting hyperglycemia, hyperinsulinism, insulin resistance, diabetes mellitus type II).
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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 chronic GVHD)- Pre-morbid/Co-morbid medical conditions: Growth hormone 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
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
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
COG LTFU Guidelines – Page 63

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)

Section 51 References (cont)
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
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

COG LTFU Guidelines – Page 64

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #52

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
www.magicfoundation.org
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
For skeletally immature children, refer to endocrinology if radiation dose ≥30
Gy. For those treated with <30 Gy, obtain x-ray for bone age in poorly growing
children.
Endocrine consultation for: Poor growth for age or stage of puberty as evidenced
by decline in growth velocity and change in percentile rankings on growth
chart, weight below 3rd percentile on growth chart.
Evaluate thyroid function in any poorly growing child.
Consult with endocrinologist regarding risks/benefits of adult growth hormone
replacement therapy.
Consider bone density testing in patients who are growth hormone deficient.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

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

References
Bongers ME, Francken AB, Rouwe C, et al: Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation. Pediatr Blood Cancer 45:139-43, 2005
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
Couto-Silva AC, Trivin C, Esperou H, et al: Final height and gonad function after total body irradiation during childhood. Bone Marrow Transplant 38:427-32, 2006
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
Gurney JG, Ness KK, Sibley SD, et al: Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 107:1303-12, 2006
COG LTFU Guidelines – Page 65

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)

Section 52 References (cont)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
Mulder RL, Kremer LC, van Santen HM, et al: Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: a systematic review. Cancer Treat Rev 35:616-32, 2009
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
Sanders JE: Growth and development after hematopoietic cell transplant in children. Bone Marrow Transplant 41:223-7, 2008
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 C, Mertens A, Walter A, et al: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 123:59-64, 1993

COG LTFU Guidelines – Page 66

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #53

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Precocious puberty(male)

Health Counseling/
Further Considerations

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

HEALTH LINKS
Precocious Puberty
RESOURCES
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.
Endocrine consultation for accelerated puberty (puberty in boy <9 years old).
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
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: Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am 44:489-503, 1997
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995

COG LTFU Guidelines – Page 67

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATIONSec #54

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Precocious puberty(female)Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
HeightWeightTanner staging
Yearly until sexually mature

HEALTH LINKS
Precocious Puberty
RESOURCES
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.
Endocrine consultation for accelerated puberty (puberty in girl <8 years old).
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
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
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
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
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: Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am 44:489-503, 1997
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995

COG LTFU Guidelines – Page 68

Version 5.0 - October 2018

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

Therapeutic
Exposure
Head/Brain

Potential
Late Effects
Hyperprolactinemia

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Decreased libido
Galactorrhea
If female: Menstrual history
YearlyHEALTH LINKS
Hyperprolactinemia
RESOURCES
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, as appropriate, 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

COG LTFU Guidelines – Page 69

Version 5.0 - October 2018

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

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

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 and endocrinology care is readily available, refer toendocrinologist for ongoing management, given risk of multiple 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

SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growthw

Additional Information
Central hypothyroidism includes thyroid-releasing and thyroid-stimulating hormone deficiency.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
Bonato C, Severino RF, Elnecave RH: Reduced thyroid volume and hypothyroidism in survivors of childhood cancer treated with radiotherapy. J Pediatr Endocrinol Metab 21:943-9, 2008
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
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
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
Livesey EA, Brook CG: Thyroid dysfunction after radiotherapy and chemotherapy of brain tumours. Arch Dis Child 64:593-5, 1989
Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al: A population-based study of thyroid function after radiotherapy and chemotherapy for a childhood brain tumor. J Clin Endocrinol Metab 88:136-40, 2003
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995
COG LTFU Guidelines – Page 70

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #57(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
Male Health Issues
Hypopituitarism
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 and endocrinology care is readily available, refer toendocrinologist for ongoing management, given risk of multiple hormone
deficiencies. If endocrinology care is not readily available, screen as indicated,
and refer to endocrinologist for delayed puberty or persistently abnormal
hormone levels.
Hormonal replacement therapy for hypogonadal patients.
Refer to reproductive endocrinology as clinically indicated for infertility
evaluation and consultation regarding assisted reproductive technologies.
Bone density 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, as appropriate, 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
COG LTFU Guidelines – Page 71

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)

Section 57 References (cont)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

COG LTFU Guidelines – Page 72

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #58(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
Female Health Issues
Hypopituitarism
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 and endocrinology care is readily available, refer toendocrinologist for ongoing management, given risk of multiple hormone
deficiencies. If endocrinology care is not readily available, screen as indicated,
and refer to endocrinologist for delayed puberty or persistently abnormal
hormone levels.
Hormonal replacement therapy for hypogonadal patients.
Refer to reproductive endocrinology as clinically indicated for infertility
evaluation and consultation regarding assisted reproductive technologies.
Bone density 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, as appropriate, 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
COG LTFU Guidelines – Page 73

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)

Section 58 References (cont)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
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

COG LTFU Guidelines – Page 74

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NEUROENDOCRINE AXIS (CONT)RADIATION
Sec #59

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

Health Counseling/
Further Considerations

Periodic Evaluation
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
www.magicfoundation.org
COUNSELING
Need for corticosteroid replacement therapy and stress dosing.
Medical Alert bracelet.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
If dose ≥30 Gy and endocrinology care is readily available, refer toendocrinologist for ongoing management, given risk of multiple hormone
deficiencies. If endocrinology care is not readily available, screen as indicated,
and refer to endocrinologist if results are abnormal.
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, as appropriate, 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
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
Rose SR, Danish RK, Kearney NS, et al: ACTH deficiency in childhood cancer survivors. Pediatr Blood Cancer 45:808-13, 2005
Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al: Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor. J Clin Endocrinol Metab 88:314954, 2003
Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113-21, 1995
COG LTFU Guidelines – Page 75

Version 5.0 - October 2018

POTENTIAL IMPACT TO
EYE

RADIATION
Sec #60

Therapeutic
Exposure
Head/Brain
TBI

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
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 = 1w

Additional Information
Radiation-related ocular complications other than cataracts are generally associated only with orbital/eye radiation or higher dose cranial radiation.
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, as appropriate, 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
Ainsbury EA, Bouffler SD, Dorr W, et al: Radiation cataractogenesis: a review of recent studies. Radiat Res 172:1-9, 2009
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

COG LTFU Guidelines – Page 76

Version 5.0 - October 2018

POTENTIAL IMPACT TO
EYE (CONT)RADIATION
Sec #61

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

Health Counseling/
Further Considerations

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
YearlyHEALTH 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

SCREENING
Evaluation by ophthalmologist or
optometrist
Yearlyw

Additional Information
Radiation-related ocular complications other than cataracts are generally associated only with orbital/eye radiation or higher dose cranial radiation.
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.
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, as appropriate, 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: Chronic GVHD [xerophthalmia only]

References
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
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

COG LTFU Guidelines – Page 77

Version 5.0 - October 2018

POTENTIAL IMPACT TO
EARRADIATION
Sec #62

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
VertigoHealth Counseling/
Further Considerations

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

HEALTH LINKS
Hearing Loss
Educational Issues
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 = 1w

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 (ABR) can be performed if the above is inconclusive.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
COG LTFU Guidelines – Page 78

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
EAR (CONT)

Section 62 References (cont)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
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
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

COG LTFU Guidelines – Page 79

Version 5.0 - October 2018

POTENTIAL IMPACT TO
ORAL CAVITY

RADIATION
Sec #63

Therapeutic
Exposure

Potential
Late Effects

Head/Brain
Neck
Spine (cervical, whole)
TBI

Xerostomia
Salivary gland dysfunction

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 = Dental
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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: Chronic GVHD

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

COG LTFU Guidelines – Page 80

Version 5.0 - October 2018

POTENTIAL IMPACT TO
ORAL CAVITY (CONT)RADIATION
Sec #64

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

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.
Consultation with orthodontist experienced in management of irradiatedchildhood cancer survivors.
SYSTEM = Dental
SCORE
Ectopic Molar Eruption = 2A
All Else = 1wAdditional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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 dose ≥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
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

COG LTFU Guidelines – Page 81

Version 5.0 - October 2018

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

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 the
jaw

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
If dose ≥40 Gy:
Impaired or delayed healing following
dental work
Persistent jaw pain or swelling
TrismusYearlyHEALTH 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.

PHYSICAL
If dose ≥40 Gy:
Impaired wound healing
Jaw swelling
TrismusAs clinically indicated

SYSTEM = Dental
SCORE = 1w

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

COG LTFU Guidelines – Page 82

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NECK/THYROIDRADIATION
Sec #66

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

Potential
Late Effects
Thyroid nodules

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, as appropriate, 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
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

COG LTFU Guidelines – Page 83

Version 5.0 - October 2018

POTENTIAL IMPACT TO
NECK/THYROID (CONT)RADIATION
Sec #67

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, as appropriate, 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, 2007de 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
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

COG LTFU Guidelines – Page 84

Version 5.0 - October 2018

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

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

Potential
Late Effects
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

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.

PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening
during periods of rapid growth

SYSTEM = Endocrine/Metabolic
SCORE = 1

SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growthw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
Cheuk DK, Billups CA, Martin MG, et al: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117:197-206, 2011
Chin D, Sklar C, Donahue B, et al: Thyroid dysfunction as a late effect in survivors of pediatric medulloblastoma/primitive neuroectodermal tumors: a comparison of hyperfractionated versus conventional radiotherapy. Cancer 80:798804, 1997
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
COG LTFU Guidelines – Page 85

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
NECK/THYROID (CONT)

Section 68 References (cont)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
Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR: Thyroid function after treatment of brain tumors in children. J Pediatr 119:733-7, 1991
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 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
Sklar CA, Kim TH, Ramsay NK: Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med 73:688-94, 1982
Vogelius IR, Bentzen SM, Maraldo MV, et al: Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis. Cancer 117:5250-60, 2011

COG LTFU Guidelines – Page 86

Version 5.0 - October 2018

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

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

Potential
Late Effects
Hyperthyroidism

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Heat intolerance
Tachycardia
Palpitations
Weight loss
Emotional lability
Muscular weakness
Hyperphagia
YearlyHEALTH LINKS
Thyroid Problems
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Endocrine consultation for medical management.
SYSTEM = Endocrine/Metabolic
SCORE = 1

PHYSICAL
Eyes
Skin
Thyroid
Cardiac
Neurologic
YearlySCREENING
TSHFree T4
Yearlyw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
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

COG LTFU Guidelines – Page 87

Version 5.0 - October 2018

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

Therapeutic
Exposure

Potential
Late Effects

Head/Brain
Neck
Spine (cervical, whole)

Carotid artery disease

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Memory impairment
YearlyHEALTH LINKS
Cardiovascular Risk Factors
Diet and Physical Activity

PHYSICALPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Blood pressure
Optimize cardiovascular risk factors, including blood pressure, lipid profile, andDiminished carotid pulses
blood glucose.
Carotid bruits
Doppler ultrasound of carotid vessels as clinically indicated. Refer to cardiology
Abnormal neurologic exam (compromise of if abnormal.
blood flow to brain)
MRI with diffusion-weighted imaging with MR angiography and cardiovascularYearlysurgery consultation as clinically indicated.
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, as appropriate, 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
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
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

COG LTFU Guidelines – Page 88

Version 5.0 - October 2018

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

Therapeutic
Exposure
Neck
Chest
Spine (thoracic, whole)

Potential
Late Effects
Subclavian artery disease

Health Counseling/
Further Considerations

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 LINKS
Cardiovascular Risk Factors
Diet and Physical Activity
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Optimize cardiovascular risk factors, including blood pressure, lipid profile, andblood glucose.
Doppler ultrasound of carotid vessels as clinically indicated. Refer to cardiology
if abnormal.
MRI with diffusion-weighted imaging with MR angiography and cardiovascularsurgery consultation as clinically indicated.
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, as appropriate, 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

COG LTFU Guidelines – Page 89

Version 5.0 - October 2018

POTENTIAL IMPACT TO
BREAST

RADIATION
Sec #72(female)Therapeutic
Exposure
Chest
AxillaTBI

Potential
Late Effects
Breast cancer

Health Counseling/
Further Considerations

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

HEALTH LINKS
Breast Cancer
COUNSELING
Teach breast self-exam and counsel to perform monthly beginning at puberty.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery and/or oncology consultation as clinically indicated.
SYSTEM = SMNSCORE = 1w

Additional Information
Mammography is currently 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 gene mutation 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, as appropriate, 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
De Bruin ML, Sparidans J, van’t Veer MB, et al: Breast cancer risk in female survivors of Hodgkin’s lymphoma: lower risk after smaller radiation volumes. J Clin Oncol 27:4239-46, 2009Friedman 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
Inskip PD, Robison LL, Stovall M, et al: Radiation dose and breast cancer risk in the Childhood Cancer Survivor Study. J Clin Oncol 27:3901-7, 2009
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
Mulder RL, Kremer LC, Hudson MM, et al: Recommendations for breast cancer surveillance for female survivors of childhood, adolescent, and young adult cancer given chest radiation: a report from the International Late Effects ofChildhood Cancer Guideline Harmonization Group. Lancet Oncol 14:e621-9, 2013
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
Swerdlow AJ, Cooke R, Bates A, et al: Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin’s lymphoma in England and Wales: a National Cohort Study. J Clin Oncol 30:2745-52, 2012
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
COG LTFU Guidelines – Page 90

Version 5.0 - October 2018

POTENTIAL IMPACT TO
BREAST (CONT)RADIATION
Sec #73(female)Therapeutic
Exposure
Chest
AxillaTBI

Potential
Late Effects
Breast tissue hypoplasia

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Clinical breast exam
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgical consultation for breast reconstruction after completion of growth.
SYSTEM = Reproductive (Female)
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
Macklis RM, Oltikar A, Sallan SE: Wilms’ tumor patients with pulmonary metastases. Int J Radiat Oncol Biol Phys 21:1187-93, 1991

COG LTFU Guidelines – Page 91

Version 5.0 - October 2018

POTENTIAL IMPACT TOLUNGSRADIATION
Sec #74

Therapeutic
Exposure
Chest
AxillaTBI

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

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 withabnormal results or progressive pulmonary
dysfunction

HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco avoidance/smoking cessation/environmental tobacco smoke.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Influenza and Pneumococcal vaccinations.
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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Younger age at irradiation- Cancer/Treatment factors: Radiation dose >10 Gy, especially radiation dose ≥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
COG LTFU Guidelines – Page 92

Version 5.0 - October 2018

POTENTIAL IMPACT TO
LUNGS (CONT)RADIATION
Sec #75

Therapeutic
Exposure
Chest
AxillaTBI

Potential
Late Effects
Lung cancer

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Cough
Wheezing
Shortness of breath
Dyspnea on exertion
YearlyHEALTH LINKS
Reducing the Risk of Second Cancers
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Imaging and surgery and/or oncology consultation as clinically indicated.

PHYSICAL
Pulmonary Exam
YearlySYSTEM = SMNSCORE = 1

SCREENING
Spiral CT Scan
Discuss the benefits and risks/harms of spiral
CT scanning for patients at highest risk (i.e.,smokers)w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
Bhatia S, Yasui Y, Robison LL, et al: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group. J Clin Oncol 21:4386-94, 2003
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

COG LTFU Guidelines – Page 93

Version 5.0 - October 2018

POTENTIAL IMPACT TO
HEARTRADIATION
Sec #76

Therapeutic
Exposure

Potential
Late Effects

Chest
AbdomenSpine (thoracic, whole)
TBI(TBI is included for
cumulative dose
calculation purposes
only; this section is notapplicable to patients
who received TBI alone.)

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

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
YearlyRecommended Frequency of Echocardiogram
Anthracycline
Dose*
None

< 250 mg/m2≥ 250 mg/m2

HEALTH LINKS
Heart Health
Cardiovascular Risk Factors
Diet and Physical Activity
Dental Health

COUNSELING
Maintain appropriate weight, blood pressure and heart-healthy diet.
Regarding exercise:- Regular exercise is generally safe and should be encouraged for patients who have normal LV
systolic function.
- Survivors with asymptomatic cardiomyopathy should consult cardiology to define limits andprecautions for physical activity.
- Cardiology consultation may be reasonable to define limits and precautions for physical activity for high risk survivors (i.e., those requiring an ECHO every 2 years) who plan to participate
in intensive exercise.
If QTc interval is prolonged: Caution regarding use of medications that may further prolong the
QTc interval (e.g., tricyclic anti-depressants, antifungals, macrolide antibiotics, metronidazole).

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTIONSCREENINGECHO (or comparable imaging to evaluate
cardiac anatomy and function)

Radiation
Dose**

Recommended
Frequency< 15 Gy or none

No screening≥ 15 - < 35 Gy

Every 5 years≥ 35 Gy

Every 2 years< 15 Gy or none

Every 5 years≥ 15 Gy

Every 2 years

Any or none

Every 2 years*Based on doxorubicin isotoxic equivalent dose. See dose conversion
instructions in section 33.
**Based on radiation dose with potential impact to heart (radiation tochest, abdomen, spine [thoracic, whole], TBI). See section 76.

If dose ≥15 Gy:
EKG (include evaluation of QTc interval)
Baseline at entry into long-term follow-up,
repeat as clinically indicated

COG LTFU Guidelines – Page 94

Health Counseling/
Further Considerations

Periodic Evaluation

Optimize cardiovascular risk factors, including blood pressure, lipid profile, and blood glucose.
Cardiac MRI as an adjunct imaging modality when echocardiographic images are suboptimal.
Cardiology consultation in patients with subclinical abnormalities on screening evaluations, left
ventricular dysfunction, dysrhythmia, or prolonged QTc interval.
Cardiology consultation (5 to 10 years after radiation) may be reasonable to evaluate risk forcoronary artery disease in survivors who received ≥35 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- ≥35 Gy chest radiation, or- Anthracycline (any dose) combined with chest radiation (≥15 Gy)
Evaluation should include a baseline echocardiogram (pre- or early-pregnancy). For those
without prior abnormalities and with normal pre- or early-pregnancy baseline echocardiograms,
follow-up echocardiograms may be obtained at the provider’s discretion. Those with a history ofsystolic dysfunction or with pre- or early-pregnancy systolic dysfunction are at highest risk for
pregnancy-associated cardiomyopathy. Such individuals should be monitored periodically during
pregnancy and during labor and delivery due to increased risk for cardiac failure.

SYSTEM = Cardiovascular
SCORE = 1

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
HEART (CONT)

Section 76 Additional Information
Exertional intolerance is an uncommon presentation of left ventricular dysfunction in patients younger than 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, as appropriate, that may increase risk.
- Patient factors: Younger age at irradiation, especially age <5 years, family history of dyslipidemia, coronary artery disease- 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 ≥35 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)

Section 76 References
Adams MJ, Lipsitz SR, Colan SD, et al: Cardiovascular status in long-term survivors of Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol 22:3139-48, 2004
Armenian SH, Wong FL: Screening for anthracycline-related cardiac dysfunction in childhood cancer survivors: can less be more? Pediatr Blood Cancer 62:2067-8, 2015
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
Chen MH, Blackington LH, Zhou J, et al: Blood pressure is associated with occult cardiovascular disease in prospectively studied Hodgkin lymphoma survivors after chest radiation. Leuk Lymphoma 55:2477-83, 2014
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
Haddy N, Diallo S, El-Fayech C, et al: Cardiac diseases following childhood cancer treatment: cohort study. Circulation 133:31-8, 2016
Heidenreich PA, Schnittger I, Strauss HW, et al: Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol 25:43-9, 2007
Hines MR, Mulrooney DA, Hudson MM, et al: Pregnancy-associated cardiomyopathy in survivors of childhood cancer. J Cancer Surviv 10:113-21, 2016
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
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, Yeazel MW, Kawashima T, et al: Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 339:b4606, 2009
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

COG LTFU Guidelines – Page 95

Version 5.0 - October 2018

POTENTIAL IMPACT TO
SPLEENRADIATION
Sec #77

Therapeutic
Exposure

Potential
Late Effects

Periodic Evaluation

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

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

PHYSICAL
If 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 associated with malaria and tick-borne diseases if living in or visiting
endemic areas.
Obtain medical alert bracelet/card noting functional asplenia.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Administer a long-acting, broad-spectrum parenteral antibiotic (e.g., ceftriaxone)
in patients with T ≥101°F (38.3°C) or other signs of serious illness andcontinue close medical monitoring while awaiting blood culture results.
Hospitalize and broaden antimicrobial coverage (e.g., addition of vancomycin)
under certain circumstances, such as the presence of marked leukocytosis,
neutropenia, or significant change from baseline CBC, toxic clinicalappearance, fever ≥104°F (40°C), meningitis, pneumonia, or other serious
focus of infection, signs of septic shock, or previous history of serious infection.
Immunize with Pneumococcal, Meningococcal (including serotype B), Influenza
and HIB vaccines according to current ACIP recommendations.
Discuss with dental provider potential need for antibiotic prophylaxis based onplanned procedure.
For further details regarding antibiotic prophylaxis and immunizations, seecurrent edition of AAP Red Book.
SYSTEM = Immune
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: Higher radiation dose, larger volume of spleen in treatment field

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
COG LTFU Guidelines – Page 96

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
SPLEEN (CONT)

Section 77 References (cont)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
Cohn AC, MacNeil JR, Clark TA, et al: Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 62:1-28, 2013
Coleman CN, McDougall IR, Dailey MO, et al: Functional hyposplenia after splenic irradiation for Hodgkin’s disease. Ann Intern Med 96:44-7, 1982
Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Brady MT, Jackson MA, et al (eds): Red Book: 2018 Report of the Committee on Infectious Diseases(ed 31). Itasca, IL, American Academy of Pediatrics, 2018, pp 67-112
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
Weiner MA, Landmann RG, DeParedes L, et al: Vesiculated erythrocytes as a determination of splenic reticuloendothelial function in pediatric patients with Hodgkin’s disease. J Pediatr Hematol Oncol 17:338-41, 1995

COG LTFU Guidelines – Page 97

Version 5.0 - October 2018

POTENTIAL IMPACT TO
GI/HEPATIC SYSTEMRADIATION
Sec #78

Therapeutic
Exposure

Potential
Late Effects

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

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

COG LTFU Guidelines – Page 98

Version 5.0 - October 2018

POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #79

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
Diet 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 dietician for blood sugar management.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information
Impaired glucose metabolism may occur in a constellation of conditions known as the metabolic syndrome.
Definitions of the metabolic syndrome generally include a combination of central (abdominal) obesity with at least 2 or more of the following: hypertension, atherogenic dyslipidemia (elevated triglycerides reduced HDL cholesterol),abnormal glucose metabolism (fasting hyperglycemia, hyperinsulinism, insulin resistance, diabetes mellitus type II).
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, as appropriate, that may increase risk.
- Patient factors: Family history of diabetes mellitus- Cancer/Treatment factors: Prolonged corticosteroid therapy (e.g., for chronic GVHD)- 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, 2012
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
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

COG LTFU Guidelines – Page 99

Version 5.0 - October 2018

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

Therapeutic
Exposure
Abdomen
TBI

Potential
Late Effects
Dyslipidemia

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Fasting lipid profile
Every 2 years

HEALTH LINKS
Diet 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 dietician.
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, as appropriate, that may increase risk.
- Patient factors: Family history of dyslipidemia- Cancer/Treatment factors: Prolonged corticosteroid therapy (e.g., for chronic GVHD)

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

COG LTFU Guidelines – Page 100

Version 5.0 - October 2018

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

Therapeutic
Exposure
AbdomenPotential
Late Effects
Hepatic toxicity
Hepatic fibrosis
Cirrhosis
Focal nodular hyperplasia

Health Counseling/
Further Considerations

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 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 = 1w

Additional Information
Focal nodular hyperplasia (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, as appropriate, 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 (previously known as VOD)
- 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
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

COG LTFU Guidelines – Page 101

Version 5.0 - October 2018

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

Therapeutic
Exposure
AbdomenPotential
Late Effects
Cholelithiasis

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Colicky abdominal pain related to fatty
food intake
Excessive flatulence
YearlyHEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gallbladder ultrasound in patients with chronic abdominal pain.

PHYSICALRUQ or epigastric tenderness
Positive Murphy’s sign
As clinically indicated

SYSTEM = GI/Hepatic
SCORE = 2Bw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
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

COG LTFU Guidelines – Page 102

Version 5.0 - October 2018

POTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)RADIATION
Sec #83

Therapeutic
Exposure
AbdomenPelvisSpine (lumbar, sacral,whole)

Potential
Late Effects
Bowel obstruction

Periodic Evaluation
HISTORY
Abdominal pain
Distention
Vomiting
Constipation
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
KUB as clinically indicated for suspected obstruction.
Surgical consultation in patients unresponsive to medical management.

PHYSICAL
Tenderness
Abdominal guarding
Distension
YearlySYSTEM = GI/Hepatic
SCORE = 1w

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, as appropriate, that may increase risk.
- Cancer/Treatment factors: Abdominal surgery, radiation dose ≥20 Gy (particularly radiation dose ≥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

COG LTFU Guidelines – Page 103

Version 5.0 - October 2018

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

Therapeutic
Exposure
AbdomenPelvisSpine (lumbar, sacral,whole)

Potential
Late Effects
Chronic enterocolitis
FistulaStrictures

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
NauseaVomiting
Abdominal pain
Diarrhea
YearlyHEALTH 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, as appropriate, 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
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

COG LTFU Guidelines – Page 104

Version 5.0 - October 2018

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

Therapeutic
Exposure
AbdomenPelvisSpine (lumbar, sacral,whole)
TBI

Potential
Late Effects
Colorectal cancer

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Regular screening selected from theoptions below based on informed
decision-making between patient andproviderBeginning 5 years after radiation or at age 30
years (whichever occurs last)
Radiation-Related Colorectal Cancer
Screening Options
Test

HEALTH LINKS
Colorectal Cancer
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gastroenterology, surgery and/or oncology consultation as clinically indicated.
SYSTEM = SMNSCORE = 2A

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 and benefits of the available options, and to select an option that is acceptable to the survivor and thus 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, and Syngal et al. 2015).
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 105

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
GI/HEPATIC SYSTEM (CONT)

Section 85 References
Bhatia S, Yasui Y, Robison LL, et al: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group. J Clin Oncol 21:4386-94, 2003
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
Giardiello FM, Allen JI, Axilbund JE, et al: Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 109:1159-79,
2014
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
Kahi CJ, Boland CR, Dominitz JA, et al: Colonoscopy Surveillance After Colorectal Cancer Resection: Recommendations of the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 150:758-768 e11, 2016
Lieberman DA, Rex DK, Winawer SJ, et al: Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 143:844-857, 2012
Metayer C, Lynch CF, Clarke EA, et al: Second cancers among long-term survivors of Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol 18:2435-43, 2000
Nottage K, McFarlane J, Krasin MJ, et al: Secondary colorectal carcinoma after childhood cancer. J Clin Oncol 30:2552-8, 2012
Syngal S, Brand RE, Church JM, et al: ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 110:223-62; quiz 263, 2015
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
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
Wolf AMD, Fontham ETH, Church TR, et al: Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin, 2018
Wong KF, Reulen RC, Winter DL, et al: Risk of adverse health and social outcomes up to 50 years after Wilms tumor: the British Childhood Cancer Survivor Study. J Clin Oncol 34:1772-9, 2016

COG LTFU Guidelines – Page 106

Version 5.0 - October 2018

POTENTIAL IMPACT TO
URINARY TRACTRADIATION
Sec #86

Therapeutic
Exposure
Abdomen
TBI

Potential
Late Effects
Renal toxicity
Glomerular injury
Renal insufficiency
Hypertension

Periodic Evaluation

Health Counseling/
Further Considerations

PHYSICAL
Blood pressure
YearlyHEALTH LINKS
Kidney Health
Cardiovascular Risk Factors

SCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicated

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
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, as appropriate, 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 radiation 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
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
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

COG LTFU Guidelines – Page 107

Version 5.0 - October 2018

POTENTIAL IMPACT TO
URINARY TRACT (CONT)RADIATIONSec #87

Therapeutic
Exposure
PelvisSpine (sacral, whole)

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

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHEALTH 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 iliac crest.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
COG LTFU Guidelines – Page 108

Version 5.0 - October 2018

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

Therapeutic
Exposure
PelvisSpine (sacral, whole)

Potential
Late Effects
Bladder malignancy

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHEALTH 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, as appropriate, 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

COG LTFU Guidelines – Page 109

Version 5.0 - October 2018

POTENTIAL IMPACT TO
MALE REPRODUCTIVE SYSTEMRADIATION
Sec #89

Therapeutic
Exposure
Testes(male)

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

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
Male Health Issues
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Measurement of early morning testosterone concentration and/or endocrinology
referral for patients with:- no signs of puberty at age 14- failure of pubertal progression- poor growth for age or stage of puberty as evidenced by decline in growthvelocity and change in percentile rankings on growth chart, weight below 3rd
percentile on growth chart- testosterone deficiency/insufficiency to weigh risks and benefits of hormonal
replacement therapy
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.
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, as appropriate, that may increase risk.
- Patient factors: Aging (≥30 years)- 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
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, 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
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
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
Rowley MJ, Leach DR, Warner GA, et al: Effect of graded doses of ionizing radiation on the human testis. Radiat Res 59:665-78, 1974
Sarafoglou K, Boulad F, Gillio A, et al: Gonadal function after bone marrow transplantation for acute leukemia during childhood. J Pediatr 130:210-6, 1997
Sklar CA: Reproductive physiology and treatment-related loss of sex hormone production. Medical Pediatr Oncol 33:2-8, 1999
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
COG LTFU Guidelines – Page 110

Version 5.0 - October 2018

POTENTIAL IMPACT TO
MALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #90(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
YearlyHEALTH LINKS
Male Health Issues

PHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyCOUNSELING
Need for contraception.
Recovery of fertility may occur years after therapy.

RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org

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.
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, as appropriate, that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents), aging- 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 testicular dose ≥20 Gy), combination with alkylating agents, genitourinary surgery- Pre-morbid/Co-morbid medical conditions: Obesity, ejaculatory dysfunction, history of sexually transmitted infections, chronic GVHD
- 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
Ash P: The influence of radiation on fertility in man. Br J Radiol 53:271-8, 1980
Centola GM, Keller JW, Henzler M, et al: Effect of low-dose testicular irradiation on sperm count and fertility in patients with testicular seminoma. J Androl 15:608-13, 1994
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
Eskenazi B, Wyrobek AJ, Sloter E, et al: The association of age and semen quality in healthy men. Hum Reprod 18:447-454, 2003
COG LTFU Guidelines – Page 111

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
MALE REPRODUCTIVE SYSTEM (CONT)

Section 90 References (cont)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, 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
Kinsella TJ, Trivette G, Rowland J, et al: Long-term follow-up of testicular function following radiation therapy for early-stage Hodgkin’s disease. J Clin Oncol 7:718-24, 1989
Nudell DM, Monoski MM, Lipshultz LI: Common medications and drugs: how they affect male fertility. Urol Clin N Am 29:965-+, 2002
Pedrick TJ, Hoppe RT: Recovery of spermatogenesis following pelvic irradiation for Hodgkin’s disease. Int J Radiat Oncol Biol Phys 12:117-21, 1986
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
Rowley MJ, Leach DR, Warner GA, et al: Effect of graded doses of ionizing radiation on the human testis. Radiat Res 59:665-78, 1974
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

COG LTFU Guidelines – Page 112

Version 5.0 - October 2018

POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEMRADIATION
Sec #91(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
Female Health Issues
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 at age 13- 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 iliac crest.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Patient factors: Older age at irradiation- Cancer/Treatment factors: Radiation dose ≥5 Gy if pubertal (especially dose ≥10 Gy), radiation dose ≥10 Gy if prepubertal (especially dose ≥15 Gy), combination with alkylating agent chemotherapy, longer time since treatment, combination with cyclophosphamide conditioning for HCT- Health behaviors: Smoking

References
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
Livesey EA, Brook CG: Gonadal dysfunction after treatment of intracranial tumours. Arch Dis Child 63:495-500, 1988
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
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

COG LTFU Guidelines – Page 113

Version 5.0 - October 2018

POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #92(female)Therapeutic
Exposure
PelvisSpine (sacral, whole)
TBI

Potential
Late Effects
Reduced ovarian follicularpool
Infertility

Periodic Evaluation
HISTORY
Menstrual and pregnancy history
Hormonal Therapy
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyHealth Counseling/
Further Considerations
HEALTH LINKS
Female Health Issues
RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Potential for shorter period of fertility (associated with increased risk of earlymenopause) in family planning.
Need for contraception.
Recovery of fertility may occur years after therapy.
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 (anti-Mullerian hormone) to assess for diminished ovarian reserve.
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 = 1w

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

COG LTFU Guidelines – Page 114

Version 5.0 - October 2018

RADIATIONPOTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)

Section 92 References
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
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

COG LTFU Guidelines – Page 115

Version 5.0 - October 2018

POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #93(female)Therapeutic
Exposure
PelvisSpine (sacral, whole)
TBI

Potential
Late Effects

Health Counseling/
Further Considerations

Periodic Evaluation

Uterine vascular insufficiency HISTORY
Resulting in adverse pregnancy Pregnancy
outcomes such as:Childbirth history- spontaneous abortion
Yearly- neonatal death- low-birth weight infant- fetal malposition- premature labor

HEALTH LINKS
Female Health Issues
RESOURCES
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, as appropriate, that may increase risk.
- Patient factors: Wilms tumor and associated Müllerian anomalies, 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
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
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

COG LTFU Guidelines – Page 116

Version 5.0 - October 2018

POTENTIAL IMPACT TO
FEMALE REPRODUCTIVE SYSTEM (CONT)RADIATION
Sec #94

Therapeutic
Exposure
PelvisPotential
Late Effects
Vaginal fibrosis/stenosis(female)Periodic Evaluation
HISTORY
Psychosocial assessment
Dyspareunia
Post-coital bleeding
Difficulty with tampon insertion
Vaginal dryness
Vulvar pain/tenderness
Vulvovaginal burning or pruritus
Dysuria
YearlyHealth 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 = 2A

PHYSICAL
Exam of external genitalia
Yearlyw

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, as appropriate, 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: Chronic GVHD

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

COG LTFU Guidelines – Page 117

Version 5.0 - October 2018

POTENTIAL IMPACT TO
MUSCULOSKELETAL SYSTEMRADIATION
Sec #95

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
Limb lengths
Yearly for patients who had extremity 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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 118

Version 5.0 - October 2018

POTENTIAL IMPACT TO
MUSCULOSKELETAL SYSTEM (CONT)RADIATION
Sec #96

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, as appropriate, 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
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
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
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

COG LTFU Guidelines – Page 119

Version 5.0 - October 2018

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

Therapeutic
Exposure
Any Radiation (Not
Including TBI)

Potential
Late Effects
Radiation-induced fracture

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Pain, swelling, deformity of bone
As clinically indicated

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, as appropriate, 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
Paulino AC: Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 60:265-74, 2004

COG LTFU Guidelines – Page 120

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT

INSTRUCTIONS

Hematopoietic Cell Transplant Introductory Information
•

•
•
•

•

Complications after hematopoietic cell transplantation have multifactorial etiologies,
including prior therapy for primary 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.

Sex

Potential Late Effect

43

Both

Secondary benign or malignant neoplasm occurring in or nearradiation field

44

Both

Dermatologic toxicity

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

45

Both

Brain tumor (benign or malignant)

46

Both

Neurocognitive deficits

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

47

Both

Clinical leukoencephalopathy

52

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 theAmerican 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.

57

Male

Gonadotropin deficiency

58

FemaleGonadotropin deficiency

60

Both

Cataracts

63

Both

Xerostomia; Salivary gland dysfunction

64

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.

66

Both

Thyroid nodules

67

Both

Thyroid cancer

68

Both

Hypothyroidism

72

FemaleBreast cancer

73

FemaleBreast tissue hypoplasia

74

Both

Pulmonary toxicity

75

Both

Lung cancer

79

Both

Impaired glucose metabolism/diabetes mellitus

80

Both

Dyslipidemia

85

Both

Colorectal cancer

86

Both

Renal toxicity

90

Male

Impaired spermatogenesis

91

FemaleOvarian hormone deficiencies

92

FemaleReduced ovarian follicular pool

93

FemaleUterine vascular insufficiency

95

Both

Musculoskeletal growth problems

Total Body Irradiation (TBI) Related Potential Late Effects•

Total Body Irradiation (TBI) Related Potential Late Effects
SectionNumberThe complete list of potential late effects and associated Guideline section numbers areincluded on the accompanying table for clinician convenience when evaluating patients
who received TBI. For details regarding each potential late effect and indicated screening,please refer to the relevant section within the Guidelines.

COG LTFU Guidelines – Page 121

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
98

Therapeutic
Exposure

Potential
Late Effects

Autologous
Hematopoietic Cell
Transplant (HCT)Acute myeloid leukemia
Myelodysplasia

Periodic Evaluation

Health Counseling/
Further Considerations

HISTORY
Fatigue
Bleeding
Easy bruising
Yearly, up to 10 years after transplant

HEALTH LINKS
Reducing the Risk of Second Cancers

PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after transplant

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
CBC and bone marrow exam as clinically indicated.

COUNSELING
Promptly seek medical attention for fatigue, pallor, petechiae or bone pain.

SYSTEM = SMNSCORE = 1w

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, as appropriate, 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

COG LTFU Guidelines – Page 122

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)Sec #99(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 Second 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, as appropriate, 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, anti-thymocyte globulin (ATG)- Pre-morbid/Co-morbid medical conditions: Hepatitis C infection, chronic GVHD, 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

COG LTFU Guidelines – Page 123

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
100
(female)Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

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

Periodic Evaluation
PHYSICAL
Skin self exam
Monthly

Health Counseling/
Further Considerations
HEALTH LINKS
Reducing the Risk of Second Cancers

Dermatologic exam
Abdominal exam
YearlyCOUNSELING
Importance of sun protection measures.
Safer sexual practices to reduce HPV transmission.
Importance of HPV vaccination.

Pelvic exam
Every 3–5 years beginning at age 21(see “Screening” below for specificrecommendations)

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Dermatology, gynecology and/or oncology consultation as clinically indicated.
HPV vaccination per current recommendations.

SCREENING
Cervical PAP smear
Cervical cancer screening should begin at age
21 y.
Women ages 21 to 29: PAP test every 3 years.
Women ages 30 to 65: HPV and PAP test every
5 years (optimal), or PAP test alone every 3
years (alternative).
Women over age 65: No testing for cervicalcancer if normal cervical cancer screening
results in past 10 years.

SYSTEM = SMNSCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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, anti-thymocyte globulin (ATG)- Pre-morbid/Co-morbid medical conditions: Hepatitis C infection, human papillomavirus (HPV) infection, chronic GVHD, 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
COG LTFU Guidelines – Page 124

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Section 100 References (cont)
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

COG LTFU Guidelines – Page 125

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
101

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Hepatic toxicity
Chronic hepatitis
Cirrhosis
Iron overload
Cholelithiasis
Focal nodular hyperplasia

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 indicatedHealth Counseling/
Further Considerations
HEALTH LINKS
Liver Health
Gastrointestinal 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.
PCR testing for hepatitis C virus (HCV) in immunosuppressed patients who are
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
Focal nodular hyperplasia (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, as appropriate, that may increase risk.
- Cancer/Treatment factors: History of multiple transfusions, radiation to the liver, antimetabolite therapy- Pre-morbid/Co-morbid medical conditions: Chronic GVHD, viral hepatitis, history of SOS (previously known as VOD), 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
COG LTFU Guidelines – Page 126

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Section 101 References (cont)
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

COG LTFU Guidelines – Page 127

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
102

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Osteonecrosis (avascularnecrosis)

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Joint pain
Swelling
Immobility
Limited range of motion
YearlyPHYSICAL
Musculoskeletal exam
YearlyHEALTH 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 = 1w

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, as appropriate, 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 chronic GVHD), TBI, high-dose radiation to any
bone, allogeneic HCT >autologous HCT- Pre-morbid/Co-morbid medical conditions: Sickle cell disease, chronic GVHD

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
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
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
Schulte CM, Beelen DW: Low pretransplant bone-mineral density and rapid bone loss do not increase risk for avascular osteonecrosis after allogeneic hematopoietic stem cell transplantation. Transplantation 79:1748-55, 2005
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

COG LTFU Guidelines – Page 128

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
103

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Reduced bone mineraldensity (BMD)
Defined as Z-score >2.0 SD
below the mean in survivors<20 years old or T-score>1.0 SD below the mean insurvivors ≥20 years old

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Bone density evaluation (DXA)
Adjust for height-age Z-score in survivors<age 20 years*
Baseline at entry into long-term follow-up,
repeat as clinically indicated.
*Pediatric Z-Score Calculator Adjusted for
Height Age: https://zscore.research.chop.
edu/bmdCalculator.php

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 children, with consideration for high doses in selected patients (e.g., kidneydisease or vitamin D deficiency). Many experts recommend higher vitamin D
intake in adults as well.
Ensure adequate dietary calcium (see table in the “Bone Health” Health Link forage-appropriate 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, growth hormone 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 = 2Bw

Additional Information
The World Health Organization definition of osteoporosis in adults is based on comparison of a measured bone mineral density (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 bone density for chronologic age based on Z-scores has not been established.
COG LTFU Guidelines – Page 129

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Section 103 Additional Information (cont)
There are no defined standards for referral or treatment of low BMD in children.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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 chronic GVHD), methotrexate, cyclosporine, tacrolimus, cranial radiation, craniospinal radiation, HCT/TBI- Pre-morbid/Co-morbid medical conditions: Growth hormone deficiency, hypogonadism/delayed puberty, hyperthyroidism- Health behaviors: Intake of calcium and vitamin D, intake of alcohol and carbonated beverages, weight bearing exercise, smoking

Section 103 References
Bhatia S, Ramsay NK, Weisdorf D, et al: Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant 22:87-90, 1998
Bischoff-Ferrari HA: Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol 624:55-71, 2008
Chemaitilly W, Sklar CA: Endocrine complications of hematopoietic stem cell transplantation. Endocrinol Metab Clin North Am 36:983-98; ix, 2007
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
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
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
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, et al: Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122:1142-52, 2008
Writing Group for the IPDC: Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom 7:17-26, 2004
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

COG LTFU Guidelines – Page 130

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT (CONT)
Sec #
104

Therapeutic
Exposure
Hematopoietic Cell
Transplant (HCT)

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

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Blood pressure
YearlyHEALTH LINKS
Kidney Health
Cardiovascular Risk Factors

SCREENING
BUN
Creatinine
Na, K, Cl, CO2, Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicated

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, as appropriate, 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 chronic GVHD

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

COG LTFU Guidelines – Page 131

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
105

Therapeutic
Exposure

Potential
Late Effects

HCT with any history of
Chronic GVHD

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

WITH CHRONIC GVHD
Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Skin self exam
Monthly
Hair (alopecia)
Nails (hypoplasia)
Skin (vitiligo, sclerodermatous changes)
YearlyHEALTH LINKS
Skin Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery, dermatology, and/or oncology consultation as clinically indicated.
SYSTEM = Dermatologic
SCORE = 1w

Additional Information
Dermatologic toxicity is more common in presence of active chronic GVHD; effects may persist after chronic GVHD 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

COG LTFU Guidelines – Page 132

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
106

Therapeutic
Exposure
HCT with any history of
Chronic GVHD

Potential
Late Effects

WITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations

Periodic Evaluation

Xerophthalmia
HISTORY(keratoconjunctivitis sicca) Dry eyes (burning, itching, foreign bodysensation, inflammation)
YearlyHEALTH LINKS
Eye Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Supportive care with artificial tears.

PHYSICAL
Eye exam
YearlySYSTEM = Ocular
SCORE = 1

SCREENING
Evaluation by ophthalmologist or
optometrist
Yearlyw

Additional Information
Xerophthalmia is more common in presence of active chronic GVHD; effects may persist after chronic GVHD resolves.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 133

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
107

Therapeutic
Exposure
HCT with any history of
Chronic GVHD

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

WITH CHRONIC GVHD (CONT)
Health Counseling/
Further Considerations

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

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 screening for intraoral
malignancy.
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 chronic GVHD; effects may persist after chronic GVHD resolves.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: Use of azathioprine for chronic GVHD 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 chronic GVHD, Fanconi anemia, dyskeratosis congenita, human papillomavirus (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
COG LTFU Guidelines – Page 134

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT

WITH CHRONIC GVHD (CONT)

Section 107 References (cont)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

COG LTFU Guidelines – Page 135

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
108

Therapeutic
Exposure
HCT with any history of
Chronic GVHD

Potential
Late Effects
Pulmonary toxicity
Bronchiolitis obliterans
Chronic bronchitis
Bronchiectasis

WITH CHRONIC GVHD (CONT)
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 withabnormal results or progressive pulmonary
dysfunction

HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco avoidance/smoking cessation/environmental tobacco smoke.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Influenza and Pneumococcal vaccinations.
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 = 1w

Additional Information
Pulmonary late effects are more common in presence of active chronic GVHD; effects may persist after chronic GVHD resolves.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: Prolonged immunosuppression related to chronic GVHD, 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
COG LTFU Guidelines – Page 136

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
109

Therapeutic
Exposure

Potential
Late Effects

HCT with any history of
Chronic GVHD

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 (previously pneumocystis carinii) pneumonia
prophylaxis and consider anti-viral and anti-fungal prophylaxis in patients withactive chronic GVHD 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.
SYSTEM = Immune
SCORE = 1w

Additional Information
Immunologic complications related to chronic GVHD 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, as appropriate, that may increase risk.
- Pre-morbid/Co-morbid medical conditions: Active chronic GVHD, prolonged immunosuppression related to chronic GVHD 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
Cohn AC, MacNeil JR, Clark TA, et al: Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 62:1-28, 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
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
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

COG LTFU Guidelines – Page 137

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
110

Therapeutic
Exposure

Potential
Late Effects

Periodic Evaluation

HCT with CURRENTLY
ACTIVE Chronic GVHD

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

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 indicatedfor patients with active chronic GVHDSCREENING
Blood culture
When febrile T ≥101°F (38.3°C) as indicatedfor patients with active chronic GVHD

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
endemic areas.
Obtain medical alert bracelet/card noting functional asplenia.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Antibiotic prophylaxis for encapsulated organisms and bacteremia/endocarditis
prophylaxis for duration of immunosuppressive therapy for chronic GVHD (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)
in patients with T ≥101°F (38.3°C) or other signs of serious illness andcontinue close medical monitoring while awaiting blood culture results.
Hospitalize and broaden antimicrobial coverage (e.g., addition of vancomycin)
under certain circumstances, such as the presence of marked leukocytosis,
neutropenia, or significant change from baseline CBC, toxic clinicalappearance, fever ≥104°F (40°C), meningitis, pneumonia, or other serious
focus of infection, signs of septic shock, or previous history of serious infection.
Immunize with Pneumococcal, Meningococcal (including serotype B), Influenza
and HIB vaccines according to current ACIP recommendations.
For further details regarding antibiotic prophylaxis and immunizations, seecurrent edition of AAP Red Book.
SYSTEM = Immune
SCORE = 1w

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

COG LTFU Guidelines – Page 138

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT

WITH CHRONIC GVHD (CONT)

Section 110 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
Cohn AC, MacNeil JR, Clark TA, et al: Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 62:1-28, 2013
Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Brady MT, Jackson MA, et al (eds): Red Book: 2018 Report of the Committee on Infectious Diseases(ed 31). Itasca, IL, American Academy of Pediatrics, 2018, pp 67-112
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
Mourtzoukou EG, Pappas G, Peppas G, et al: Vaccination of asplenic or hyposplenic adults. Br J Surg 95:273-80, 2008
Picardi M, Selleri C, Rotoli B: Spleen sizing by ultrasound scan and risk of pneumococcal infection in patients with chronic GVHD: preliminary observations. Bone Marrow Transplant 24:173-7, 1999
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

COG LTFU Guidelines – Page 139

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
111

Therapeutic
Exposure
HCT with any history of
Chronic GVHD

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 chronic GVHD is generally not reversible over time.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 140

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
112
(female)Therapeutic
Exposure
HCT with any history of
Chronic GVHD

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
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

PHYSICAL
Exam of genitalia for lichen planus-likefeatures, erosions, fissures, ulcers
Yearlyw

Additional Information
Vulvovaginal chronic GVHD 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 chronic GVHD is made.
Vaginal fibrosis/stenosis related to chronic GVHD is generally not reversible over time.
Physical examination should be done with each assessment for chronic GVHD to detect vulvar lesions before vaginal stenosis develops.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
COG LTFU Guidelines – Page 141

Version 5.0 - October 2018

HEMATOPOIETIC CELL TRANSPLANT
Sec #
113

Therapeutic
Exposure
HCT with any history of
Chronic GVHD

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 = 1w

Additional Information
Joint contractures related to chronic GVHD 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

COG LTFU Guidelines – Page 142

Version 5.0 - October 2018

SURGERYSec #114

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

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Phantom pain
Functional and activity limitations
YearlyPHYSICAL
Residual limb integrity
YearlySCREENING
Prosthetic evaluation
Every 6 months until skeletally mature, thenyearlyHEALTH 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 weight gain or gait training with a new prosthesis, and for nonpharmacological pain management.
Occupational therapy consultation as needed to assist with activities of dailyliving.
Psychological/social work consultation 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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
COG LTFU Guidelines – Page 143

Version 5.0 - October 2018

SURGERYAMPUTATION (CONT)

Section 114 References (cont)Eiser C, Grimer RJ: Quality of life in survivors of a primary bone tumour: a systematic review. Sarcoma 3:183-90, 1999
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
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

COG LTFU Guidelines – Page 144

Version 5.0 - October 2018

SURGERYCENTRAL VENOUS CATHETERSec #Therapeutic
Exposure

Potential
Late Effects

115

Central venous catheter

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

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

PHYSICAL
Venous stasis
Swelling
Tenderness at previous catheter site
Yearlyw

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

COG LTFU Guidelines – Page 145

Version 5.0 - October 2018

SURGERYSec #116

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 = 1wAdditional 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

COG LTFU Guidelines – Page 146

Version 5.0 - October 2018

SURGERYSec #117

ENUCLEATION

Therapeutic
Exposure
Enucleation

Potential
Late Effects
Impaired cosmesis
Poor prosthetic fit
Orbital hypoplasia

Health Counseling/
Further Considerations

Periodic Evaluation
SCREENING
Evaluation by ocularist
YearlyEvaluation by ophthalmologist
YearlyHEALTH 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, as appropriate, 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

COG LTFU Guidelines – Page 147

Version 5.0 - October 2018

SURGERYSec #118

HYSTERECTOMY

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

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Psychosocial assessment
Urinary leakage
Abdominal pain
Dyspareunia
YearlyHEALTH LINKS
Female Health Issues
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 135-136 (unilateral oophorectomy) or section 137 (bilateral oophorectomy).
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 148

Version 5.0 - October 2018

SURGERYSec #119

LAPAROTOMY

Therapeutic
Exposure
Laparotomy

Potential
Late Effects
Adhesions
Bowel obstruction

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Abdominal pain
Distention
Vomiting
Constipation
YearlyHEALTH LINKS
Gastrointestinal Health
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
KUB as clinically indicated for suspected obstruction.
Surgical consultation for patients unresponsive to medical management.

PHYSICAL
Tenderness
Abdominal guarding
Distension
YearlySYSTEM = GI/Hepatic
SCORE = 1w

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

References
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

COG LTFU Guidelines – Page 149

Version 5.0 - October 2018

SURGERY

LIMB SPARING PROCEDURE

Sec #Therapeutic
Exposure

Potential
Late Effects

120

Limb sparing procedure

Complications 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)

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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
Henderson ER, Pepper AM, Marulanda G, et al: Outcome of lower-limb preservation with an expandable endoprosthesis after bone tumor resection in children. J Bone Joint Surg Am 94:537-47, 2012
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
Shehadeh A, Noveau J, Malawer M, et al: Late complications and survival of endoprosthetic reconstruction after resection of bone tumors. Clin Orthop Relat Res 468:2885-95, 2010
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
Tunn PU, Schmidt-Peter P, Pomraenke D, et al: Osteosarcoma in children: long-term functional analysis. Clin Orthop Relat Res:212-7, 2004
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
COG LTFU Guidelines – Page 150

Version 5.0 - October 2018

SURGERYSec #121

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*
Yearly*eGFR Calculator available at: https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratoryevaluation/glomerular-filtration-ratecalculators

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 = 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.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: Bilateral Wilms tumor, combination with 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
COG LTFU Guidelines – Page 151

Version 5.0 - October 2018

SURGERYNEPHRECTOMY (CONT)

Section 121 References (cont)Finklestein JZ, Norkool P, Green DM, et al: Diastolic hypertension in Wilms’ tumor survivors: a late effect of treatment? A report from the National Wilms’ Tumor Study Group. Am J Clin Oncol 16:201-5, 1993
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
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
Mitus A, Tefft M, Fellers FX: Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics 44:912-21, 1969
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

COG LTFU Guidelines – Page 152

Version 5.0 - October 2018

SURGERYSec #122

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*
Yearly*eGFR Calculator available at: https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratoryevaluation/glomerular-filtration-ratecalculators

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 = 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.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: Bilateral Wilms tumor, combination with 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
Finklestein JZ, Norkool P, Green DM, et al: Diastolic hypertension in Wilms’ tumor survivors: a late effect of treatment? A report from the National Wilms’ Tumor Study Group. Am J Clin Oncol 16:201-5, 1993
Grinsell MM, Showalter S, Gordon KA, et al: Single kidney and sports participation: perception versus reality. Pediatrics 118:1019-27, 2006
COG LTFU Guidelines – Page 153

Version 5.0 - October 2018

SURGERYNEPHRECTOMY (CONT)

Section 122 References (cont)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
Mitus A, Tefft M, Fellers FX: Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics 44:912-21, 1969
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

COG LTFU Guidelines – Page 154

Version 5.0 - October 2018

SURGERYSec #Therapeutic
Exposure

123

Neurosurgery-Brain

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

Health Counseling/
Further Considerations

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 LINKS
Educational Issues
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 = 1w

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, as appropriate, 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 towhole brain, radiation dose ≥40 Gy to local fields, TBI, cranial radiation- Pre-morbid/Co-morbid medical conditions: Pre-morbid learning or attention problems, hydrocephalus/history of shunt placement, seizures, posterior fossa syndrome, CNS infection

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

COG LTFU Guidelines – Page 155

Version 5.0 - October 2018

SURGERYSec #Therapeutic
Exposure

124

Neurosurgery-Brain

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.
Consultations with nutrition, endocrine, and psychiatry (for obsessivecompulsive behaviors) in patients with hypothalamic-pituitary axis tumors.
Ophthalmology evaluation as clinically indicated.
SYSTEM = CNSSCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 156

Version 5.0 - October 2018

SURGERYSec #Therapeutic
Exposure

125

Neurosurgery-Brain

NEUROSURGERY—BRAIN (CONT)
Potential
Late Effects
Seizures

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
SeizuresYearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluation by neurologist as clinically indicated.

PHYSICAL
Neurologic exam
YearlySYSTEM = CNSSCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 157

Version 5.0 - October 2018

SURGERYSec #Therapeutic
Exposure

126

Neurosurgery-Brain

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

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Headaches
Nausea/Vomiting
AtaxiaIrritability
Drowsiness
YearlyPHYSICAL
Neurologic exam
YearlyCOUNSELING
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.
Antibiotic prophylaxis prior to dental work is not indicated for survivors with V-Pshunts.

SCREENING
Abdominal x-ray
After pubertal growth spurt for patients withshunts to assure distal shunt tubing inperitoneum

SYSTEM = CNSSCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 158

Version 5.0 - October 2018

SURGERYSec #127

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
Diet and Physical Activity
Cardiovascular Risk Factors
COUNSELING
Obesity-related health risks.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Evaluate for central endocrinopathies, including growth hormone 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 dietician 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, as appropriate, 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

COG LTFU Guidelines – Page 159

Version 5.0 - October 2018

SURGERYSec #128

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 growth hormone
deficiency, central hypothyroidism, central adrenal insufficiency, precocious
puberty, and gonadotropin deficiency
Refer to endocrine to manage hormonal dysfunction.
SYSTEM = Endocrine/Metabolic
SCORE = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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
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

COG LTFU Guidelines – Page 160

Version 5.0 - October 2018

SURGERYSec #129

NEUROSURGERY—SPINAL CORD

Therapeutic
Exposure
Neurosurgery-Spinal
cord

Potential
Late Effects
Neurogenic bladder
Urinary incontinence

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHEALTH 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, as appropriate, 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

COG LTFU Guidelines – Page 161

Version 5.0 - October 2018

SURGERYSec #130

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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 162

Version 5.0 - October 2018

SURGERYSec #131(male)NEUROSURGERY—SPINAL CORD (CONT)

Therapeutic
Exposure
Neurosurgery-Spinal
cord

Potential
Late Effects
Psychosexual dysfunction
Erectile dysfunction
Ejaculatory dysfunction

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyHEALTH LINKS
Male Health Issues
RESOURCES
www.urologychannel.com
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, as appropriate, 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

COG LTFU Guidelines – Page 163

Version 5.0 - October 2018

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

Therapeutic
Exposure
Neurosurgery-Spinal
cord

Potential
Late Effects
Psychosexual dysfunction

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Altered or diminished sensation, loss of
sensation
Dyspareunia
Medication use
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation in patients with positive history.
SYSTEM = Reproductive (Female)
SCORE = 2Aw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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, chronic GVHD, injury above the level of the sacrum

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
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

COG LTFU Guidelines – Page 164

Version 5.0 - October 2018

SURGERYSec #133

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, as appropriate, 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

COG LTFU Guidelines – Page 165

Version 5.0 - October 2018

SURGERYSec #134

OOPHOROPEXY

Therapeutic
Exposure
Oophoropexy(female)Potential
Late Effects
Oophoropexy-related
complications
Inability to conceive despite
normal ovarian function
Dyspareunia
Symptomatic ovarian cysts
Bowel obstruction
Pelvic adhesions

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Inability to conceive
Dyspareunia
Abdominal pain
Pelvic pain
YearlyPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation for patients with positive history.
SYSTEM = Reproductive (Female)
SCORE = 2Aw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 166

Version 5.0 - October 2018

SURGERYSec #135(female)OOPHORECTOMY (UNILATERAL)

Therapeutic
Exposure
Oophorectomy
unilateral

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

Health Counseling/
Further Considerations

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 LINKS
Female Health Issues
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 at age 13- 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, as appropriate, that may increase risk.
- Cancer/Treatment factors: Combination with pelvic radiation, TBI, or alkylating agents- Health behaviors: Smoking

References
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

COG LTFU Guidelines – Page 167

Version 5.0 - October 2018

SURGERYSec #136(female)OOPHORECTOMY (UNILATERAL) (CONT)

Therapeutic
Exposure
Oophorectomy
unilateral

Potential
Late Effects
Reduced ovarian follicularpool
Infertility

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Menstrual and pregnancy history
Hormonal therapy
YearlyPHYSICAL
Tanner staging until sexually mature
YearlyHEALTH LINKS
Female Health Issues
RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
COUNSELING
Potential for shorter period of fertility (associated with increased risk of earlymenopause) in family planning.
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 (anti-Mullerian hormone) to assess for diminished ovarian reserve.
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.
FSH is lowered and AMH may be lowered by concurrent hormonal contraceptive use.
AMH should be interpreted relative to age-specific reference ranges.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: Combination with pelvic radiation, TBI, or alkylating agents- Health behaviors: Smoking

References
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
COG LTFU Guidelines – Page 168

Version 5.0 - October 2018

SURGERYSec #137(female)Therapeutic
Exposure
Oophorectomy
bilateral

OOPHORECTOMY (BILATERAL)
Potential
Late Effects

Periodic Evaluation

Health Counseling/
Further Considerations

Ovarian hormone deficiencies SCREENINGHEALTH LINKS
Absence of puberty
Endocrinologic or gynecologic consultation Female Health Issues
Loss of ovarian follicular poolfor initiation of hormonal replacement
RESOURCES
Infertility
therapy
American Society for Reproductive Medicine: www.asrm.org
At age 11 or immediately for post-pubertal
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org
patients
COUNSELING
Benefits of hormone replacement therapy in promoting pubertal progression,bone and cardiovascular health.
Counsel women regarding pregnancy potential with donor eggs (if uterus is
intact).
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Reproductive endocrinology referral regarding assisted reproductive
technologies.
Bone density 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

COG LTFU Guidelines – Page 169

Version 5.0 - October 2018

SURGERYSec #138(male)ORCHIECTOMY (UNILATERAL, PARTIAL)

Therapeutic
Exposure
Orchiectomy
unilateralpartialPotential
Late Effects
Testicular hormonal
dysfunction
Testosterone deficiency/
insufficiency
Delayed/arrested puberty

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
Male Health Issues
COUNSELING
Wear athletic supporter with protective cup during athletic activities.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Measurement of early morning testosterone concentration and/or endocrinology
referral for patients with:- no signs of puberty at age 14- failure of pubertal progression- poor growth for age or stage of puberty as evidenced by decline in growthvelocity and change in percentile rankings on growth chart, weight below 3rd
percentile on growth chart- testosterone deficiency/insufficiency to weigh risks and benefits of hormonal
replacement therapy
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, as appropriate, that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents), aging- 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

COG LTFU Guidelines – Page 170

Version 5.0 - October 2018

SURGERYORCHIECTOMY (UNILATERAL, PARTIAL) (CONT)

Section 138 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

COG LTFU Guidelines – Page 171

Version 5.0 - October 2018

SURGERYSec #139(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
YearlyHEALTH LINKS
Male Health Issues

PHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchidometer
YearlyCOUNSELING
Wear athletic supporter with protective cup during athletic activities.
Need for contraception.

RESOURCES
American Society for Reproductive Medicine: www.asrm.org
Alliance for Fertility Preservation: www.allianceforfertilitypreservation.org

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.
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, as appropriate, that may increase risk.
- Patient factors: Medications (anabolic steroids, testosterone), occupational exposures (pesticides, heavy metals, solvents), aging- 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
COG LTFU Guidelines – Page 172

Version 5.0 - October 2018

SURGERYORCHIECTOMY (UNILATERAL, PARTIAL) (CONT)

Section 139 References (cont)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
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
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

COG LTFU Guidelines – Page 173

Version 5.0 - October 2018

SURGERYSec #140(male)

Therapeutic
Exposure
Orchiectomy
bilateral

ORCHIECTOMY (BILATERAL)
Potential
Late Effects
Testosterone deficiency
Absence of puberty
Azoospermia
Infertility

Health Counseling/
Further Considerations

Periodic Evaluation
PHYSICAL
Exam of testicular prostheses
YearlyHEALTH LINKS
Male Health Issues

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTIONSCREENING
Surgical placement of testicular prostheses and ongoing monitoring for surgical
Endocrinologic consultation for initiation of complications after prostheses placement.
hormonal replacement therapy
Psychology referral (because orchiectomy can be associated with psychologicalAt age 11 or immediately for post-pubertal
distress related to altered body image).
patients
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

COG LTFU Guidelines – Page 174

Version 5.0 - October 2018

SURGERYSec #141

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 116.
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 175

Version 5.0 - October 2018

SURGERYSec #142

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 = 1w

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, 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

COG LTFU Guidelines – Page 176

Version 5.0 - October 2018

SURGERYSec #143(male)PELVIC SURGERY (CONT)

Therapeutic
Exposure
Pelvic surgery
Cystectomy

Potential
Late Effects
Psychosexual dysfunction
Erectile dysfunction

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyHEALTH LINKS
Male Health Issues
RESOURCES
www.urologychannel.com
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, as appropriate, 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

COG LTFU Guidelines – Page 177

Version 5.0 - October 2018

SURGERYSec #144(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
Male Health Issues
with first void after intercourse suggests
RESOURCES
retrograde ejaculation)www.urologychannel.com
YearlyCOUNSELING
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, as appropriate, 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

COG LTFU Guidelines – Page 178

Version 5.0 - October 2018

SURGERYSec #145(female)PELVIC SURGERY (CONT)

Therapeutic
Exposure
Pelvic surgery
Cystectomy

Potential
Late Effects
Sexual dysfunction

Health Counseling/
Further Considerations

Periodic Evaluation
HISTORY
Altered or diminished sensation, loss of
sensation
Dyspareunia
Medication use
YearlyHEALTH LINKS
Female Health Issues
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecologic consultation for patients with positive history.
SYSTEM = Reproductive (Female)
SCORE = 2Aw

Additional Information
Consider patient and cancer/treatment factors, pre-morbid/co-morbid health conditions, and health behaviors, as appropriate, that may increase risk.
- Cancer/Treatment factors: Tumor adjacent to spine, radiation to bladder, pelvis or spine- Pre-morbid/Co-morbid medical conditions: Chronic GVHD, 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
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

COG LTFU Guidelines – Page 179

Version 5.0 - October 2018

SURGERYSec #146

Therapeutic
Exposure
Splenectomy

SPLENECTOMY
Potential
Late Effects
Asplenia
At risk for life-threatening
infection with encapsulatedorganisms (e.g., Haemophilus
influenzae, Streptococcus
pneumoniae, meningococcus)

Health Counseling/
Further Considerations

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 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
endemic areas.
Obtain medical alert bracelet/card noting asplenia.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Administer a long-acting, broad-spectrum parenteral antibiotic (e.g., ceftriaxone)
in patients with T ≥101°F (38.3°C) or other signs of serious illness andcontinue close medical monitoring while awaiting blood culture results.
Hospitalize and broaden antimicrobial coverage (e.g., addition of vancomycin)
under certain circumstances, such as the presence of marked leukocytosis,
neutropenia, or significant change from baseline CBC, toxic clinicalappearance, fever ≥104°F (40°C), meningitis, pneumonia, or other serious
focus of infection, signs of septic shock, or previous history of serious infection.
Immunize with Pneumococcal, Meningococcal (including serotype B), Influenza
and HIB vaccines according to current ACIP recommendations.
Discuss with dental provider potential need for antibiotic prophylaxis based onplanned procedure.
For further details regarding antibiotic prophylaxis and immunizations, seecurrent edition of AAP Red Book.
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 the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 62:521-4, 2013
Cohn AC, MacNeil JR, Clark TA, et al: Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 62:1-28, 2013
COG LTFU Guidelines – Page 180

Version 5.0 - October 2018

SURGERYSPLENECTOMY (CONT)

Section 146 References (cont)Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Brady MT, Jackson MA, et al (eds): Red Book: 2018 Report of the Committee on Infectious Diseases(ed 31). Itasca, IL, American Academy of Pediatrics, 2018, pp 67-112
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
Kaiser CW: Complications from staging laparotomy for Hodgkin disease. J Surg Oncol 16:319-25, 1981
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

COG LTFU Guidelines – Page 181

Version 5.0 - October 2018

SURGERY
Sec #147

THORACIC SURGERY

Therapeutic
ExposureThoracic surgery

Potential
Late Effects
Pulmonary dysfunction

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 withabnormal results or progressive pulmonary
dysfunction

HEALTH LINKS
Pulmonary HealthRESOURCES
www.smokefree.gov
COUNSELING
Tobacco avoidance/smoking cessation/environmental tobacco smoke.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Repeat PFTs prior to general anesthesia.
Influenza and Pneumococcal vaccinations.
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 = 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, as appropriate, 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

COG LTFU Guidelines – Page 182

Version 5.0 - October 2018

SURGERY
Sec #148

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, as appropriate, 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
DeRosa GP: Progressive scoliosis following chest wall resection in children. Spine 10:618-22, 1985
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
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

COG LTFU Guidelines – Page 183

Version 5.0 - October 2018

SURGERYSec #149

THYROIDECTOMY

Therapeutic
Exposure
Thyroidectomy

Potential
Late Effects
Hypothyroidism

Periodic Evaluation

Health Counseling/
Further Considerations

SCREENING
HEALTH LINKS
Endocrinologic consultation for initiation of Thyroid Problems
thyroid hormone replacement
COUNSELING
Immediately
For 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

COG LTFU Guidelines – Page 184

Version 5.0 - October 2018

OTHER THERAPEUTIC MODELS
Sec #
150

Therapeutic
ExposureRadioiodine therapy (I131 thyroid ablation)

Potential
Late Effects
Lacrimal duct atrophy

SYSTEMIC RADIATION
Periodic Evaluation

HISTORY
Excessive tearing
YearlyHealth Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Ophthalmology consultation as clinically indicated.
SYSTEM = Ocular
SCORE = 2Aw

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

COG LTFU Guidelines – Page 185

Version 5.0 - October 2018

OTHER THERAPEUTIC MODELS
Sec #
151

Therapeutic
ExposureRadioiodine therapy (I131 thyroid ablation)

Potential
Late Effects
Hypothyroidism

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

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 = 2A

SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growthw

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

COG LTFU Guidelines – Page 186

Version 5.0 - October 2018

OTHER THERAPEUTIC MODELS
Sec #
152

Therapeutic
Exposure
Systemic MIBG (intherapeutic doses)

Potential
Late Effects
Hypothyroidism

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

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

SCREENING
TSHFree T4
Yearly, consider more frequent screening
during periods of rapid growthw

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
COG LTFU Guidelines – Page 187

Version 5.0 - October 2018

OTHER THERAPEUTIC MODELS
Sec #
153

Therapeutic
Exposure
Systemic MIBG (intherapeutic doses)

Potential
Late Effects
Thyroid nodules

SYSTEMIC RADIATION (CONT)
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 = 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

COG LTFU Guidelines – Page 188

Version 5.0 - October 2018

OTHER THERAPEUTIC MODELS
Sec #
154

Therapeutic
Exposure
Systemic MIBG (intherapeutic doses)

Potential
Late Effects
Thyroid cancer

SYSTEMIC RADIATION (CONT)
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 = 2Aw

References
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

COG LTFU Guidelines – Page 189

Version 5.0 - October 2018

OTHER THERAPEUTIC MODELS
Sec #
155

Therapeutic
Exposure
Bioimmunotherapy(e.g., G-CSF, IL-2,
erythropoietin)

COG LTFU Guidelines – Page 190

Potential
Late Effects
Insufficient information
currently available
regarding late effects ofbiological agents

BIOIMMUNOTHERAPY
Periodic Evaluation

Health Counseling/
Further Considerations

No known late effects
SYSTEM = No Known Late Effects
SCORE = N/A

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

156

Breast(female)Standard Risk Parametersand Screening Guidelines
STANDARD RISK PARAMETERS≥ Age 40PHYSICAL
Clinical breast exam is NOT recommended
for women of any age at standard risk

Highest Risk Parametersand Screening Guidelines

BREAST CANCER
Health Counseling/
Further Considerations

HIGHEST RISK PARAMETERS
History of radiation (TBI, chest, axilla), seesection 72

COUNSELING
For standard risk patients, general guidance regarding routine screening
beginning at age 40 per current ACS guidelines.

Personal history of BRCA1, BRCA2, ATM or
p53 mutation
In absence of personal genetic testing,known BRCA mutation in first degree
relative

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery and/or oncology consultation as clinically indicated.

SCREENING
Mammogram
Women ages 40 to 44: May initiate yearly
PHYSICAL
screening based on shared decision-making For patients with history of radiation (TBI,
between patient and provider
chest, axilla), see section 72
Women ages 45 to 54: Yearly screening
SCREENING
Women ages 55 and older: May transition
For patients with history of radiation (TBI,
to biennial screening or continue yearlychest, axilla), see section 72
screening (based on shared decision-making
between patient and provider). Women
For patients at high risk due to personal or
should continue screening mammography
family history of hereditary syndromes
as long as overall health is good and life
expectancy is ≥10 years
predisposing to breast cancer, seecurrent ACS high risk screening
recommendations (Smith et al. 2018)

Additional Information
Mammography is currently limited in its ability to evaluate the premenopausal breast.
Standard population risk factors include family history of breast cancer in first degree relative, early onset of menstruation, late onset of menopause (age 55 or older), older than 30 at birth of first child, never pregnant, obesity, previous breast biopsy with atypical hyperplasia, and hormone replacement therapy.

References
Kriege M, Brekelmans CT, Boetes C, et al: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351:427-37, 2004
National Comprehensive Cancer Network: Breast cancer screening and diagnosis guidelines version 1.2015. Plymouth Meeting, PA, National Comprehensive Cancer Network, 2015
Oeffinger KC, Fontham ET, Etzioni R, et al: Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA 314:1599-614, 2015
Saslow D, Boetes C, Burke W, et al: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57:75-89, 2007
Siu AL, U. S. Preventive Services Task Force: Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 164:279-96, 2016
Smith RA, Andrews KS, Brooks D, et al: Cancer screening in the United States, 2018: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin, 2018
COG LTFU Guidelines – Page 191

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

157

Cervical(female)Standard Risk Parametersand Screening Guidelines

Highest Risk Parametersand Screening Guidelines

STANDARD RISK PARAMETERS≥ Age 21HIGHEST RISK PARAMETERS
History of HCT, see section 100

PHYSICAL
Pelvic exam
Every 3–5 years beginning at age 21(see “Screening” below for specificrecommendations)

Personal history of cervical dysplasia
Prenatal DES exposure
HPV infection
Immunosuppression
Chronic steroid use
HIV positive
History of Hodgkin lymphoma
Chronic GVHDCERVICAL CANCER
Health Counseling/
Further Considerations
COUNSELING
Safer sexual practices to reduce HPV transmission.
Importance of HPV vaccination.
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Gynecology and/or oncology consultation as clinically indicated.
HPV vaccination per current recommendations.

SCREENING
Cervical PAP smear
Cervical cancer screening should begin at age
21 y.
SCREENING
Women ages 21 to 29: PAP test every 3 years. Same as standard risk
Women ages 30 to 65: HPV and PAP test every
5 years (optimal), or PAP test alone every 3
years (alternative).
Women over age 65: No testing for cervicalcancer if normal cervical cancer screening
results in past 10 years.

Additional Information
Human papillomavirus virus (HPV) is the leading cause of cervical cancer in women.
HPV vaccination protects against 90% of cervical cancers and reduces the incidence of genital warts.
The Centers for Disease Control Advisory Committee on Immunization Practices (CDC/ACIP) and American Cancer Society (ACS) both recommend routine HPV immunization of girls when they are 11–12 years old.
- Females as young as 9 years can receive HPV vaccination at the discretion of their health care provider.
- HPV vaccination is also recommended (CDC/ACIP) for females 13–26 years to catch up on missed vaccines or to complete the series.
- For optimal protection, the vaccine should be administered before the onset of sexual activity.
- Females who are sexually active may still benefit from vaccination through protection against strains to which they have not been exposed.
HPV vaccination does not change recommendations for cervical cancer PAP screening, since the vaccine does not protect against all cancer-causing types of HPV. See Petrosky E et al. (2015) and Centers for Disease Control andPrevention (2010), for further information.
Standard population risk factors include early age at first intercourse, multiple lifetime sex partners, smoking, sexually transmitted infections.

References
Joura EA, Giuliano AR, Iversen OE, et al: A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 372:711-23, 2015
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
COG LTFU Guidelines – Page 192

Version 5.0 - October 2018

CANCER SCREENING GUIDELINESCERVICAL CANCER (CONT)

Section 157 References (cont)
Petrosky E, Bocchini JA, Jr., Hariri S, et al: Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep
64:300-4, 2015
Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of
cervical cancer. Am J Clin Pathol 137:516-42, 2012
Smith RA, Andrews KS, Brooks D, et al: Cancer screening in the United States, 2018: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin, 2018

COG LTFU Guidelines – Page 193

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

158

Colorectal

Standard Risk Parametersand Screening Guidelines
STANDARD RISK PARAMETERS≥ Age 45
SCREENING
Regular screening with either stoolbased testing or structural examination
based on patient preference and test
availability, selected from the options
below
Beginning at age 45
Colorectal Cancer Screening Options
Type

Test

Stool-Based
Tests

Fecal
immunochemical test*

YearlyHigh-sensitivity,
guaiac-based fecal
occult blood test*

YearlyMultitarget stool
DNA test*

Every 3 years

Colonoscopy

Every 10 years

CT colonography*

Every 5 years

Flexible
sigmoidoscopy*

Every 5 years

Structural
Examinations

Frequency*All positive results on non-colonoscopy screening tests should
be followed up with timely colonoscopy.

Highest Risk Parametersand Screening Guidelines

COLORECTAL CANCER
Health Counseling/
Further Considerations

HIGHEST RISK PARAMETERSPOTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
History of radiation (TBI, abdominal, pelvic, Gastroenterology, surgery and/or oncology consultation as clinically indicated.
spinal [lumbar, sacral, whole]), seesection 85
Familial adenomatous polyposis (FAP)
Hereditary Nonpolyposis Colon Cancer(HNPCC)
Lynch syndrome
Inflammatory bowel disease (IBD)
Personal history of ulcerative colitis,
gastrointestinal malignancy,
adenomatous polyps or hepatoblastoma
Family history of colorectal cancer or
polyps in first degree relative
SCREENING
For patients with history of radiation (TBI,
abdominal, pelvic, spinal [lumbar, sacral,whole]), see section 85
For patients at high risk due to personal orfamily 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,
and Syngal et al. 2015)

Additional Information
Standard population risk factors include high fat/low fiber diet and obesity.

References
Bacchus CM, Dunfield L, Gorber SC, et al: Recommendations on screening for colorectal cancer in primary care. CMAJ 188:340-8, 2016

COG LTFU Guidelines – Page 194

Version 5.0 - October 2018

CANCER SCREENING GUIDELINESCOLORECTAL CANCER (CONT)

Section 158 References (cont)
Giardiello FM, Allen JI, Axilbund JE, et al: Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 109:1159-79,
2014
Kahi CJ, Boland CR, Dominitz JA, et al: Colonoscopy surveillance after colorectal cancer resection: recommendations of the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 150:758-768 e11, 2016
Levin B, Lieberman DA, McFarland B, et al: Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Forceon Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 58:130-60, 2008
Lieberman DA, Rex DK, Winawer SJ, et al: Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 143:844-857, 2012
Provenzale D, Gray RN: Colorectal cancer screening and treatment: review of outcomes research. J Natl Cancer Inst Monogr 33:45-55, 2004
Qaseem A, Denberg TD, Hopkins RH, Jr., et al: Screening for colorectal cancer: a guidance statement from the American College of Physicians. Ann Intern Med 156:378-86, 2012
Smith RA, Andrews KS, Brooks D, et al: Cancer screening in the United States, 2018: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin, 2018
Syngal S, Brand RE, Church JM, et al: ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 110:223-62; quiz 263, 2015
Wilt TJ, Harris RP, Qaseem A, et al: Screening for cancer: advice for high-value care from the American College of Physicians. Ann Intern Med 162:718-25, 2015
Wolf AMD, Fontham ETH, Church TR, et al: Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin, 2018

COG LTFU Guidelines – Page 195

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

159

Endometrial(female)Standard Risk Parametersand Screening Guidelines

Highest Risk Parametersand Screening Guidelines

SCREENING
No screening for standard risk patientsHIGHEST RISK PARAMETERS
History of/at risk for hereditary
nonpolyposis colon cancer (HNPCC)ENDOMETRIAL CANCER
Health Counseling/
Further Considerations
COUNSELING
Risks and symptoms of endometrial cancer.
Promptly seek medical attention for unexpected vaginal bleeding or spotting.

SCREENING
Endometrial biopsy
Yearly, beginning at age 35, based on shareddecision-making between patient andproviderAdditional Information
Women at highest risk should be informed that the screening recommendation for endometrial biopsy beginning at age 35 is based on expert opinion.
In the absence of definitive scientific evidence, the potential benefits and risks/harms of testing for early endometrial cancer detection should be discussed.
Standard population risk factors include obesity, older age, unopposed estrogen therapy, tamoxifen, diabetes, hypertension, high fat diet, early menopause, late menopause, nulliparity, infertility, and failure to ovulate.

References
Smith RA, Andrews KS, Brooks D, et al: Cancer screening in the United States, 2018: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin, 2018

COG LTFU Guidelines – Page 196

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

160

Lung

Standard Risk Parametersand Screening Guidelines
SCREENING
No screening for standard risk patients

LUNG CANCER

Highest Risk Parametersand Screening Guidelines

Health Counseling/
Further Considerations

HIGHEST RISK PARAMETERS
History of radiation (TBI, chest, axilla), seesection 75

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Imaging and surgery and/or oncology consultation as clinically indicated.

History of heavy smoking (30 pack years
or more), AND smoke now or have quit
within the past 15 years, AND current
age 55-80
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

Additional Information
A pack year is smoking an average of one pack of cigarettes per day for one year. For example, a person could have a 30 pack-year history by smoking one pack a day for 30 years or two packs a day for 15 years.
Standard population risk factors include smoking, workplace exposures to asbestos, arsenic, radiation, and second hand smoke (in non-smokers).

References
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
Smith RA, Andrews KS, Brooks D, et al: Cancer screening in the United States, 2018: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin, 2018

COG LTFU Guidelines – Page 197

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

161

Oral

Standard Risk Parametersand Screening Guidelines

Highest Risk Parametersand Screening Guidelines

ORAL CANCER
Health Counseling/
Further Considerations

STANDARD RISK PARAMETERS
Tobacco use (smoking cigars, cigarettes,
or pipes, dipping, chewing)
Alcohol abuse
Excessive sun exposure (increases risk ofcancer of lower lip)
Human Papillomavirus (HPV) infection

HIGHEST RISK PARAMETERSCOUNSELING
History of radiation (TBI, head/brain, neck), Importance of HPV vaccination.
see section 43
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Acute/chronic GVHD, see section 107
Head and neck/otolaryngology consultation as indicated.
HPV vaccination per current recommendations.
Fanconi anemia
Dyskeratosis congenita

PHYSICAL
Oral exam
YearlySCREENING
Same as standard risk

Additional Information
HPV vaccination is associated with reduction in vaccine-type oral HPV prevalence among young adults in the United States.
Although HPV vaccine is not currently licensed for prevention of oral cancers (efficacy studies not yet available), it is recommended for the prevention of anogenital cancers in males and females 9-26 years of age.
Survivors should be encouraged to receive the HPV vaccine, due to their increased risk (compared with age- and sex-matched general population) for development of HPV-related cancers.

References
Alter BP, Giri N, Savage SA, et al: Cancer in dyskeratosis congenita. Blood 113:6549-57, 2009
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
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
Scheckenbach K, Wagenmann M, Freund M, et al: Squamous cell carcinomas of the head and neck in Fanconi anemia: risk, prevention, therapy, and the need for guidelines. Klin Padiatr 224:132-8, 2012

COG LTFU Guidelines – Page 198

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

162

Prostate(male)PROSTATE CANCER

Standard Risk Parametersand Screening Guidelines

Highest Risk Parametersand Screening Guidelines

Health Counseling/
Further Considerations

STANDARD RISK PARAMETERS
Older age, with steadily increasing risk
after age 40 years

HIGHEST RISK PARAMETERS
African-American race
Family history of prostate cancer in first
degree relative

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Urology and/or oncology consultation as clinically indicated.

SCREENING
Clinicians should be prepared to discuss
prostate cancer screening with patients.

SCREENING
Same as standard risk

Additional Information
The U.S. Preventive Services Task Force (USPSTF) found good evidence that PSA screening can detect early-stage prostate cancer, but mixed and inconclusive evidence that early detection improves health outcomes.
Screening is associated with important harms, including frequent false-positive results and unnecessary anxiety, biopsies, and potential complications of treatment of some cancers that may never have affected a patient’s health.
The USPSTF concludes that evidence is insufficient to determine whether the benefits outweigh the harms for a screened population; ACS concurs with this conclusion.

References
Andriole GL, Crawford ED, Grubb RL, 3rd, et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360:1310-9, 2009
Carroll PR, Parsons JK, Andriole G, et al: NCCN guidelines insights: Prostate cancer early detection, Version 2.2016. J Natl Compr Canc Netw 14:509-19, 2016
Carter HB, Albertsen PC, Barry MJ, et al: Early detection of prostate cancer: AUA Guideline. J Urol 190:419-26, 2013
Ilic D, Neuberger MM, Djulbegovic M, et al: Screening for prostate cancer. Cochrane Database Syst Rev:CD004720, 2013
Lin K, Croswell JM, Koenig H, et al: Prostate-specific antigen-based screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force, Evidence Syntheses. Rockville, MD, Agency for Healthcare Research
and Quality, 2011
Schroder FH, Hugosson J, Roobol MJ, et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360:1320-8, 2009
Smith RA, Andrews KS, Brooks D, et al: Cancer screening in the United States, 2018: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin, 2018

COG LTFU Guidelines – Page 199

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

163

Skin

Standard Risk Parametersand Screening Guidelines

Highest Risk Parametersand Screening Guidelines

SCREENING
No screening for standard risk patientsHIGHEST RISK PARAMETERS
History of any radiation, see section 43
History of HCT, see section 99 (male) or
section 100 (female)
Chronic GVHD, see section 105

SKIN CANCER
Health Counseling/
Further Considerations
POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Surgery, dermatology, and/or oncology consultation as clinically indicated.

Personal history of melanoma or skincancerDysplastic nevi
Family history of melanoma or skin cancer
History of severe sunburn at young age
Light skin and age 65 and older
Atypical moles or ≥50 moles
PHYSICAL
Skin self exam
Monthly
Dermatologic exam
Yearly in the context of physical examinations
performed for other purposes

Additional Information
The U.S. Preventive Services Task Force (USPSTF) concludes that the evidence is insufficient to recommend for or against routine screening for skin cancer using a total-body skin examination for the early detection of cutaneous
melanoma, basal cell cancer, or squamous cell skin cancer.
There are no randomized trials or case-control studies that directly examine whether screening by clinicians is associated with improved clinical outcomes such as reduced morbidity or mortality from skin cancer; no studies were
found that evaluated whether screening improves the outcomes of these cancers.
The American Cancer Society recommends skin examination as part of a cancer-related checkup, which should occur on the occasion of the patient’s periodic health examination.
Self-examination of skin is recommended once a month for patients at highest risk.
Standard population factors include light skin color and chronic exposure to sun.

References
Smith RA, Brooks D, Cokkinides V, et al: Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening andlung cancer screening. CA Cancer J Clin 63:88-105, 2013
U. S. Preventive Services Task Force: Screening for skin cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 150:188-93, 2009

COG LTFU Guidelines – Page 200

Version 5.0 - October 2018

CANCER SCREENING GUIDELINES
Sec #

Organ

164

Testicular(male)TESTICULAR CANCER

Standard Risk Parametersand Screening Guidelines

Highest Risk Parametersand Screening Guidelines

Health Counseling/
Further Considerations

SCREENING
No screening for standard risk patientsHIGHEST RISK PARAMETERS
History of cryptorchidism
History of testicular cancer or carcinoma
in-situ in contralateral testis
History of gonadal dysgenesis
Klinefelter’s syndrome
Family history of testicular cancer

POTENTIAL CONSIDERATIONS FOR FURTHER TESTING AND INTERVENTION
Self examination techniques or increased awareness about the signs andsymptoms of testicular cancer can be discussed based on the patient’s
interests.

SCREENING
No screening for high risk patients

Additional Information
For standard and high risk populations, the USPSTF recommends against routine screening for testicular cancer in asymptomatic adolescent and adult males, due to lack of evidence that screening with clinical examination or testicular self-examination is effective in reducing mortality from testicular cancer.
Even in the absence of screening, the current treatment interventions provide very favorable health outcomes.
Given the low prevalence of testicular cancer, limited accuracy of screening tests, and no evidence for the incremental benefits of screening, the USPSTF concluded that the harms of screening exceed any potential benefits.
ACS also no longer recommends clinical testicular cancer screening or testicular self-examination.
Standard population risk factors include young males.

References
Smith RA, Brooks D, Cokkinides V, et al: Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening andlung cancer screening. CA Cancer J Clin 63:88-105, 2013
U. S. Preventive Services Task Force: Screening for testicular cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 154:483-6, 2011

COG LTFU Guidelines – Page 201

Version 5.0 - October 2018

GENERAL HEALTH SCREENINGSec #Screening

165

SCREENING
Refer to United Stated Preventive Services Task
Force recommendations at www.ahrq.gov/clinic
YearlyHealth Counseling/
Further Considerations
COUNSELING
Importance of general health maintenance based on age and gender, including all recommended immunizations.
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 forlipid disorders, sexually transmitted infections, and diabetes mellitus. Others require counseling regarding the prevention ofcardiovascular disease, osteoporosis, and other disorders. See www.ahrq.gov/clinic/uspstfix.htm for specific recommendations.
Assess immunization status on all patients and screen for HPV vaccination in males and females. Reimmunize as indicated. See
www.cdc.gov/vaccines/ for current immunization schedules. For all HCT patients, reimmunization per current recommendations(Ljungman et al, 2009: www.nature.com/bmt/journal/v44/n8/full/bmt2009263a.html).

References
Agency for Healthcare Research and Quality: Clinical Guidelines and Recommendations: U.S. Preventive Services Task Force. www.ahrq.gov/clinic/uspstfi
Committee on Infectious Disease, American Academy of Pediatrics: Immunization in special clinical circumstances, in Kimberlin DW, Brady MT, Jackson MA, et al (eds): Red Book: 2018 Report of the Committee on Infectious Diseases(ed 31). Itasca, IL, American Academy of Pediatrics, 2018, pp 67-112

COG LTFU Guidelines – Page 202

Version 5.0 - October 2018