Children’s Oncology Group

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

Version 4.0 – October 2013
for Survivors of Childhood,
Adolescent, and Young Adult
Cancers

www.survivorshipguidelines.org
Version 4.0
October 2013

Copyright 2013
© Children’s Oncology GroupAll rights reserved worldwide

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers
Version 4.0 – October 2013www.survivorshipguidelines.org
Copyright 2013 © Children’s Oncology GroupAll rights reserved worldwide

Contents
Content Outline

vi

Section #Page

GenderPotential Late Effect

Abstract

vii

13

15

FemaleGonadal dysfunction (ovarian)

viii

14

17

Acute myeloid leukemia; myelodysplasia

Guidelines Panel of Experts

x

15

18

Pulmonary fibrosis

Guidelines Task Force Membership 2009–2012

xi

16

19

Cataracts

Guidelines Health Link Authors

xvi

17

20

Urinary tract toxicity

Guidelines Health Link Reviewers

xviii

18

21

Bladder malignancy

Guidelines Development Task Force – Initial Versions

xix

19

22

Renal toxicity

Guidelines Reviewers – Initial Versions

xx

20

23

Ototoxicity

xxii

21

25

Peripheral sensory neuropathy;

26

Renal toxicity

Disclaimer and Notice of Proprietary Rights

Introductory Material
Introduction

xxiii

22

Explanation of Scoring

xxviii(n/a)

Instructions for Use

xxix

23

27

Neurocognitive deficits

New to Version 4.0

xxxiv

24

29

Clinical leukoencephalopathy

25

31

No known late effects

Section #Page

Gender[Removed from v4: Dyslipidemia]

26

32

Hepatic dysfunction; veno-occlusive disease (VOD)

Potential Late Effect27

33

Reduced bone mineral density (BMD)

Any Cancer Experience28

35

Renal toxicity: glomerular injury; hypertension

1

2

Adverse psychosocial/QoL effects

29

36

Hepatic dysfunction

2

4

Mental health disorders

30

37

Neurocognitive deficits

3

5

Risky behaviors

31

39

Clinical leukoencephalopathy

4

6

Psychosocial disability due to pain

32

40

Acute myeloid leukemia

5

7

Fatigue

33

41

Male

Cardiac toxicity

68Limitations in healthcare and insurance access

34

43

FemaleCardiac toxicity

Blood/Serum Products

35

45

Pulmonary toxicity

7

9

Chronic hepatitis B

36

47

No known late effects – Dactinomycin

8

10

Chronic hepatitis C

37

48

Reduced bone mineral density (BMD)911

HIV infection38

50

Osteonecrosis (avascular necrosis)

Chemotherapy

39

51

Cataracts

Dental abnormalities

40

52

No known late effects – Asparaginase

41

53

Peripheral sensory or motor neuropathy

10

12

11

13

Male

Gonadal dysfunction (testicular): Reduced fertility

12

14

Male

Gonadal dysfunction (testicular): Testosterone deficiency

COG LTFU Guidelines – Page ii

Version 4.0 – October 2013 – Contents

Contents (cont)Section #Page

Section #

Page

42

54

GenderPotential Late EffectVasospastic attacks (Raynaud’s phenomenon)

70

88

GenderPotential Late EffectOsteoradionecrosis

43

55

Acute myeloid leukemia

71

89

Thyroid nodules

Radiation

72

90

Thyroid cancer

44

58

Secondary benign or malignant neoplasm

73

91

Hypothyroidism

45

59

Dysplastic nevi; skin cancer

74

92

Hyperthyroidism

93

Carotid artery disease46

60

Dermatologic changes

75

47

61

Bone malignancies

76

94

48

62

Brain tumor (benign or malignant)77

95

FemaleBreast cancer

97

FemaleBreast tissue hypoplasia

Subclavian artery disease49

63

Neurocognitive deficits

78

50

65

Clinical leukoencephalopathy

79

98
99

Male

Cardiac toxicity

FemaleCardiac toxicity

Pulmonary toxicity

51

67

Cerebrovascular complications

80

52

68

Craniofacial abnormalities

81

101
103

Functional asplenia

53

69

Chronic sinusitis

82

54

70

Overweight; obesity

83

105

Esophageal stricture[Removed from v4: Metabolic syndrome]

84

106

Impaired glucose metabolism/diabetes mellitus

Growth hormone deficiency

85

107

Dyslipidemia

Precocious puberty

86

108

Hepatic fibrosis; cirrhosis; focal nodular hyperplasia

109

Cholelithiasis

(n/a)
55

72

56

74

Male

57

75

FemalePrecocious puberty

87

58

76

Male

Hyperprolactinemia

88

110

Bowel obstruction

Hyperprolactinemia

89

111

Chronic enterocolitis; fistula, strictures

59

77

Female60

78

Central hypothyroidism

90

112

Colorectal cancer

61

79

Male

Gonadotropin deficiency

91

114

Renal toxicity; renal insufficiency; hypertension

62

80

FemaleGonadotropin deficiency

92

115

Hemorrhagic cystitis

63

81

Central adrenal insufficiency

93

116

Urinary tract toxicity

117

Bladder malignancy

64

82

Cataracts

94

65

83

Ocular toxicity

95

118

FemaleUterine vascular insufficiency

119

FemaleGonadal dysfunction (ovarian)

66

84

Ototoxicity (conductive hearing loss)

96

67

85

Ototoxicity (sensorineural hearing loss)

97

121

FemaleVaginal fibrosis/stenosis

68

86

Xerostomia; salivary gland dysfunction

98

122

Male

Gonadal dysfunction (testicular): Reduced fertility

69

87

Dental abnormalities

COG LTFU Guidelines – Page iii

Version 4.0 – October 2013 – Contents

Contents (cont)Section #Page

GenderPotential Late Effect

99

124

Male

Gonadal dysfunction (testicular): Testosterone deficiency/
insufficiency

Section #

Page

123

153

124

154

GenderPotential Late EffectImpaired cosmesis; poor prosthetic fit; orbital hypoplasia

FemalePelvic floor dysfunction; urinary incontinence; sexual
dysfunction

100

125

Musculoskeletal growth problems

101

126

Scoliosis/kyphosis

125

155

Adhesions; bowel obstruction[Removed from v4: Kyphosis]

126

156

Complications related to limb sparing procedure

127

Radiation-induced fracture

127

158

Male

Hydrocele; renal toxicity

129

TBI-related Potential Late Effects

128

159

FemaleRenal toxicity

Hematopoietic Cell Transplant

129

160

Neurocognitive deficits

Myelodysplasia; acute myeloid leukemia

130

161

Motor and/or sensory deficits

(n/a)
102

103

130

104

131

Male

Solid tumors

131

162

Seizures105

132

FemaleSolid tumors

132

163

Hydrocephalus; shunt malfunction

106

133

Lymphoma

133

164

Overweight/obesity

107

134

Hepatic toxicity

134

165

Diabetes insipidus

108

135

Osteonecrosis (avascular necrosis)

135

166

Neurogenic bladder; urinary incontinence

109

136

Reduced bone mineral density (BMD)

136

167

110

138

Renal toxicity

137

168

Male

Psychosexual dysfunction (male)

111

139

Dermatologic toxicity

138

169

FemalePsychosexual dysfunction (female)

112

140

Xerophthalmia (keratoconjunctivitis sicca)

139

170

113

141

Xerostomia; salivary gland dysfunction; dental caries;
periodontal disease; oral cancer (squamous cell carcinoma)

140

171

FemaleOophoropexy-related complications

141

172

FemalePremature menopause

142

173

FemaleHypogonadism; infertility

143

174

Male

Gonadal dysfunction (testicular): reduced fertility; testosterone
insufficiency

144

175

Male

Gonadal dysfunction (testicular): infertility; testosterone
deficiency

Vaginal fibrosis/stenosis

145

176

Urinary incontinence; urinary tract obstruction

Joint contractures

146

177

Fecal incontinence

Surgery

114

142

Pulmonary toxicity; bronchiolitis obliterans; chronic
bronchitis; bronchiectasis

115

144

Immunologic complications

116

145

Functional asplenia

117

147

Esophageal stricture

118

148

119

149

FemaleNeurogenic bowel; fecal incontinence

Scoliosis/Kyphosis

147

178

Male

Sexual dysfunction (male)

120

150

Amputation-related complications

148

179

FemaleSexual dysfunction (female)

121

151

Thrombosis; vascular insufficiency; infection of retained cuff
or line tract

(n/a)

122

152

Cystectomy-related complications

COG LTFU Guidelines – Page iv[Removed from v4: Hydrocele]

149

180

Asplenia

150

182

Pulmonary dysfunction
Version 4.0 – October 2013 – Contents

Contents (cont)Section #

Page

151

183

GenderPotential Late EffectScoliosis/Kyphosis

152

184

Hypothyroidism
Other Therapeutic Modalities

153

185

Lacrimal duct atrophy

154

186

Hypothyroidism

155

187

Hypothyroidism

156

188

Insufficient information currently available regarding lateeffects of biological agents

157

189

FemaleBreast cancer

158

191

FemaleCervical cancer

159

192

160

194

161

195

Lung cancer

162

196

Oral cancer

Cancer Screening Guidelines

163

197

164

198

165

199

166

200

Colorectal cancer
FemaleMale

Endometrial cancer

Prostate cancer
Skin cancer

Male

COG LTFU Guidelines – Page v

Testicular cancer
General Health Screening (USPSTF link)

Version 4.0 – October 2013 – ContentsCOG Long-Term Follow-Up Guidelines Content Outline
Long-Term Follow-Up Guidelines

Appendix I: Materials for Clinical Application of LTFU Guidelines•

Abstract••

Disclaimer––

Abbreviations•

Contributors––

Chemotherapy Agents––

Panel of Experts––

Radiation Fields Defined––

Task Force Membership––

Health Link Authors and Reviewers––

Summary of Cancer Treatment—Introduction––

Guideline Development Task Force—Initial Versions––

Template for Summary of Cancer Treatment (Abbreviated)––

Reviewers – Initial Versions––

Template for Summary of Cancer Treatment (Comprehensive)––

Key for Completing Summary of Cancer Treatment (Comprehensive Version)••

Introductory Material•

Reference Materials

Summary of Cancer Treatment

Tools for Guideline Application––

Introduction––

Explanation of Scoring––

Patient-Specific Guideline Identification Tool––

Instructions for Use––

Health Link Index by Guideline Section Number––

New to this Version of the COG LTFU Guidelines

Appendix II: Health Links (Patient Education Materials)––

Long-Term Follow-Up Guidelines•

Health Links Index by Title•

Health Links

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 4.0. Monrovia, CA: Children’s
Oncology Group; October 2013; 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 vi

Version 4.0 – October 2013 – Content Outline

Abstract – Version 4.0
The Children’s Oncology Group Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers
Release date:

October 2013

Status:Updated from Version 3.0 incorporating modifications based on recommendations from the Children’s Oncology Group’s Long- Term Follow-Up Guideline
Core Committee and its ten associated multidisciplinary Task Forces.

Overview:

These risk-based, exposure-related clinical practice guidelines provide recommendations for screening and management of late effects in survivorsof 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 theguidelines 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 patients based on therapeutic exposures. The information provided in these guidelines is important 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 isintended to increase awareness of potential late effects and to standardize and enhance follow-up care provided to survivors of pediatric malignancies
throughout their lifespan.

Source:Version 4.0 of the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, and related
Health Links, can be downloaded in their entirety from www.survivorshipguidelines.org.

COG LTFU Guidelines – Page vii

Version 4.0 – October 2013 – Abstract

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 andaccompanying 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 tolate 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 patients (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 theevaluation of childhood cancer survivors. The Children’s Oncology Group recognizes that specific patient care decisions are the prerogative of the patient, family, andhealthcare 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 asof 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 theInformational Content. You agree to the following terms of indemnification: (i) “Indemnified Parties” include authors and contributors to the Informational Content, allofficers, directors, representatives, employees, agents, and members of the Children’s Oncology Group and affiliated organizations; (ii) by using, reviewing, or accessing theInformational 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 theInformational 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 underlaw. You hereby agree to help the Children’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 viii

Version 4.0 – October 2013 – Disclaimer

Contributors

Long-Term Follow-Up Guidelines 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 4.0 of theChildren’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:
Melissa M. Hudson, MD
Co-Chair–COG LTFU Guidelines Core Committee
Member, Department of Oncology
Director, Cancer Survivorship Division
Co-Leader, Cancer Prevention & Control Program
St. Jude Children’s Research Hospital
Memphis, TN
Wendy Landier, PhD, RN, CPNP, CPON®
Co-Chair–COG LTFU Guidelines Core Committee
Clinical Director, Center for Cancer Survivorship
City of Hope Comprehensive Cancer Center
Duarte, CALouis S. Constine, MD, FASTRO
Co-Chair–COG LTFU Guidelines Core Committee
Professor of Radiation Oncology and Pediatrics
Vice Chair, Department of Radiation Oncology
James P. Wilmot Cancer Center
University of Rochester Medical Center
Rochester, NY
Smita Bhatia, MD, MPH
Co-Chair–COG LTFU Guidelines Core Committee
Professor and Chair, Department of Population
Sciences
City of Hope National Medical Center
Associate Director, Population Research
City of Hope Comprehensive Cancer Center
Duarte, CA
Saro Armenian, DO, MPH
Chair, COG Survivorship and Outcomes Committee
Assistant Professor, Department of Population
Sciences
City of Hope Comprehensive Cancer Center
Duarte, CA

COG LTFU Guidelines – Page x

F. Daniel Armstrong, PhD
Professor and Associate Chair, Departmentof Pediatrics
Director, Mailman Center for Child Development
University of Miami School of Medicine
Miami, FL
K. Scott Baker, MD, MS
Professor of Pediatrics
Director, Pediatric Blood and Marrow
Transplant Programand Cancer Survivor Program
Seattle Children’s Hospital
Seattle, WA
Joan Darling, PhD
COG Patient Advocacy Committee Representative
Lincoln, NE
Daniel M. Green, MD
Member, Departments of Oncology andEpidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TN
Nina Kadan-Lottick, MD, MSPH
Associate Professor
Department of Pediatrics
Yale University School of Medicine
New Haven, CT
Matthew J. Krasin, MD
Associate Member
Radiological Sciences
St. Jude Children’s Research Hospital
Memphis, TN

Marcia Leonard, RN, PNP
Coordinator, Late Effects Program
C. S. Mott Children’s Hospital
University of Michigan
Ann Arbor, MI
Anna T. Meadows, MD
Professor of Pediatrics
University of Pennsylvania School of Medicine
Director, Follow-Up Program
The Children’s Hospital of Philadelphia
Philadelphia, PA
Paul Nathan, MD, MSc, FRCPC
Director, Aftercare Program
Hematology/Oncology
The Hospital for Sick Children
Toronto, Ontario, Canada

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

Joseph P. Neglia, MD, MPH
Professor of Pediatrics
Division of Hematology, Oncology,
Blood and Marrow Transplantation
Department Head, Pediatrics
University of Minnesota School of Medicine
Minneapolis, MN
Kirsten Ness, PT, PhD
Associate Member, Departments of Epidemiology
and Cancer Control and Pediatric Medicine
St. Jude Children’s Research Hospital
Memphis, TN
Kevin C. Oeffinger, MD
Director, Living Beyond Cancer Program
Memorial Sloan-Kettering Cancer Center
New York, NY

Version 4.0 – October 2013 – Panel of Experts

Guidelines Task Force Membership 2009–2012
Task Force

Task Force Members

Institution

Expertise

CardiovascularPulmonary

M. Jacob Adams, MD, MPH
Saro Armenian, DO, MPH, Chair
Gregory Aune, MD, PhD
Ming Hui Chen MD, MMSc
Robert Goldsby, MD
Daniel Green, MD
David Hodgson, MD
Hiroto Inaba, MD
Charlene Maxen, RN, CNP, CPON
Kathleen Meeske, PhD, RN
Sadhna Shankar, MD, MPH, Chair
Julia Steinberger, MD
Dennis Stokes, MD, MPH
Rajkumar Venkatramani, MD

University of Rochester
City of Hope
University of Texas Health Science Center, San Antonio
Brigham and Women’s Hospital
UCSF School of Medicine
St. Jude Children’s Research Hospital
Princess Margaret Hospital
St. Jude Children’s Research HospitalChildren’s Hospital Medical Center of Akron
Children’s Hospital Los AngelesChildren’s National Medical Center
University of Minnesota Medical School
Le Bonheur Children’s HospitalChildren’s Hospital Los Angeles

Epidemiology, Patient advocacy
Pediatric oncology
Pediatric oncology
Medical oncology
Pediatric oncology
Pediatric oncology
Radiation oncology
Pediatric oncology
NursingNursing
Pediatric oncology
Pediatric cardiology
Pediatric pulmonology
Pediatric oncology

Endocrine Reproductive

Lillian R. Meacham, MD, ChairChildren’s Healthcare of Atlanta/Emory University

Pediatric endocrinology

Endocrine Reproductive:
Bone mineral density
ObesityInsulin resistance

Jacqueline Casillas, MD
Wassim Chemaitilly, MD
Eric Chow, MD, MPH
Cindy Cochran, RN, MSN
Kristy Gayle Devine, BA
Kimberley Dilley, MD, MPH, Silo Leader
Natia Esiashvili, MD
Dana Hardin, MD
Nobuko Hijiya, MD
Sue Kaste, DO
Caroline Laverdiere, MD
Goli Mostoufi-Moab, MD
Susan Shannon, RN, MSN, CPNP
Rona Sonabend, MD

Mattel Children’s Hospital UCLA
St. Jude Children’s Research Hospital
Seattle Children’s Hospital
University of Texas Southwestern Medical Center
Children’s Oncology GroupAnn & Robert H. Lurie Children’s Hospital of Chicago
Children’s Healthcare of Atlanta/Emory University
Nationwide Children’s Hospital
Ann & Robert H. Lurie Children’s Hospital of Chicago
St. Jude Children’s Research Hospital
Centre Hospitalier Universitaire Sainte-JustineChildren’s Hospital of Philadelphia
Miller Children’s Hospital
Baylor College of Medicine

Pediatric oncology
Pediatric endocrinology
Pediatric oncology
Nursing
Patient advocacy
Pediatrics
Radiation oncology
Pediatric endocrinology
Pediatric oncology
Pediatric radiology
Pediatric oncology
Pediatric endocrinology/oncology
Nursing
Pediatric endocrinology

Endocrine Reproductive:
OvarianJacqueline Casillas, MD
Mary Dwyer, MBBS
Daniel Green, MD
Nobuko Hijiya, MD
Wendy Hobbie, RN, MSN, CRNP
Amy Jacobson, RN, NP-BC
Marcia Leonard, RN, CPNP
Jennifer Levine, MD
Wendy M. Likes, DNSc, ARNP-BC
Monika Metzger, MD, MSc, Silo Leader
Briana Patterson, MD, MSc, Silo Leader

Mattel Children’s Hospital UCLA
Royal Children’s Hospital
St. Jude Children’s Research Hospital
Ann & Robert H. Lurie Children’s Hospital of Chicago
Children’s Hospital of Philadelphia
UCLA-LIVESTRONG Survivorship Center of Excellence
C. S. Mott Children’s Hospital
Columbia University Medical Center
University of Tennessee Health Science Center
St. Jude Children’s Research HospitalChildren’s Healthcare of Atlanta/Emory University

Pediatric oncology
Radiation oncology
Pediatric oncology
Pediatric oncology
Nursing
Family medicine
Nursing
Pediatric oncology
Nursing, Gynecologic oncology
Pediatric oncology
Pediatric endocrinology

COG LTFU Guidelines – Page xi

Version 4.0 – October 2013 – Task Force Membership

Task Force Membership 2009–2012 (cont)
Task Force

Task Force Members

Institution

Expertise

Endocrine Reproductive:
Pituitary
AdrenalThyroid

Nathalie Alos, MD
Christine Chordas, RN, MSN
Laurie Cohen, MD
Adam Esbenshade, MD
Wendy Hobbie, RN, MSN, CRNP
Briana Patterson, MD, MSc
Jill Simmons, MD, Silo Leader
Stacey Urbach, MD
Gregory Charles Wheeler, MBBS FRANZCR

Centre Hospitalier Universitaire Sainte-JustineDana-Farber Cancer InstituteDana-Farber Cancer Institute
Vanderbilt University/Ingram Cancer Center
Children’s Hospital of Philadelphia
Children’s Healthcare of Atlanta/Emory University
Vanderbilt University/Ingram Cancer Center
Hospital for Sick Children
Royal Children’s Hospital

Pediatric endocrinology
Nursing
Pediatric endocrinology
Pediatric oncology
Nursing
Pediatric endocrinology
Pediatric endocrinology
Pediatric endocrinology
Radiation oncology

Endocrine Reproductive:
Testicular

Laurie Cohen, MD
Louis S. Constine, MD
Daniel Green, MD
Nobuko Hijiya, MD
Lisa Kenney, MD, Silo Leader
Eileen Lind, RN, MSN, CPNP
Barbara Lockhart, RN, MSN, CPNP
Monika Metzger, MD, MSc
Margarett Shnorhavorian, MD, MPH

Dana-Farber Cancer Institute
University of Rochester Medical Center
St. Jude Children’s Research Hospital
Ann & Robert H. Lurie Children’s Hospital of Chicago
Dana-Farber Cancer InstituteDana-Farber Cancer Institute
Ann & Robert H. Lurie Children’s Hospital of Chicago
St. Jude Children’s Research Hospital
Seattle Children’s Hospital

Pediatric endocrinology
Radiation oncology
Pediatric oncology
Pediatric oncology
Pediatric oncology, Epidemiology
NursingNursing
Pediatric oncology
Pediatric urology

Gastrointestinal
Hepatic
Oral/Dental

Soraya Beiraghi, DDS
Sharon Castellino, MD, MSH, Chair
Joan Darling, PhD
Andrew Davidoff, MD
Karen Effinger, MD
Cherry Estilo, DMD
Melissa M. Hudson, MD
Sue Kaste, DO
Jennifer Magee, DMD
Kevin McMullen, MD
Cesar Migliorati, DDS, MS, PhD
Andrew Muir, MD, MSH
Man Wai Ng, DDS, MPH
John Petty, MD
Melissa Rayburg Jefferson, MD
Kathy Ruble, PhD, RN, CPNPMarie-Ellen Sarvida, MD
Sheila Shope, RN, FNP

University of Minnesota
Wake Forest University Health Sciences
Children’s Oncology GroupSt. Jude Children’s Research Hospital
Lucile Packard Children’s Hospital Stanford University
Memorial Sloan-Kettering Cancer Center
St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital
Brigham & Women’s Hospital
Riley Hospital for Children
University of Tennessee Health Science Center
Duke University Medical Center
Children’s Hospital Boston
Wake Forest University Health Sciences
Children’s Mercy Hospitals and Clinics
Johns Hopkins University
Loyola University Medical Center
St. Jude Children’s Research Hospital

Pediatric dentistry
Pediatric oncology
Patient advocacy
Surgery
Pediatric oncology
Pediatric dentistry
Pediatric oncology
Pediatric radiology
Pediatric dentistry
Radiation oncology
Pediatric dentistry
Pediatric GI/hepatology
Pediatric dentistry
Surgery
Pediatric oncology
Nursing
Pediatric oncology
Family medicine

COG LTFU Guidelines – Page xii

Version 4.0 – October 2013 – Task Force Membership

Task Force Membership 2009–2012 (cont)
Task Force

Task Force Members

Institution

Expertise

Hematopoietic celltransplantation
ImmuneDermatologic

Smita Bhatia, MD, MPH
Eric Chow, MD, MPH, Chair
Katharina Elliott, MD
Karen Mandel, MD, FRCPC, FAAP
Wendy Pelletier, MSW
Joanna Perkins, MD, MS, Chair
Linda Rivard, RN, BSN, CPON
Tal Schecter-Finkelstein, MD
Ami Shah, MD
Karla Wilson, RN, MSN, FNP-C
Kenneth Wong, MD
Lise Yasui

City of Hope
Seattle Children’s HospitalBronson Methodist HospitalChildren’s Hospital of Eastern Ontario
Alberta Children’s HospitalChildren’s Hospitals and Clinics of Minnesota
Advocate Children’s Hospital-Oak Lawn
Hospital for Sick Children
Mattel Children’s Hospital UCLA
City of HopeChildren’s Hospital of Los AngelesChildren’s Oncology Group

Pediatric oncology
Pediatric oncology
Pediatric oncology
Pediatric oncology
Pediatric oncology, Immunology
Social work
Nursing, Patient advocate
Stem cell transplant
Stem cell transplant
Nursing
Radiation oncology
Patient advocacy

Task Force

Task Force Members

Institution

ExpertiseMusculoskeletal

LaVette Bowles, FNP
Colleen Coulter-O’Berry, PT
Winston Huh, MD, Chair
Joseph Janicki, MD
Sue Kaste, DO
Missy Layfield
Jill Lunsford Lee, RN, MSN, CPNP-AC, CPON
Valerae Lewis, MD
Anita Mahajan, MD
Rajaram Nagarajan, MD, MPH
Kirsten Ness, PT, PhD
Arnold Paulino, MD
Robert Lor Randall, MD
Lynn Tanner, MS, PT
Karen Wasilewski-Masker, MD, Chair

UCLA School of Medicine
Children’s Healthcare of Atlanta/Emory University
M.D. Anderson Cancer Center
Ann & Robert H. Lurie Children’s Hospital of Chicago
St. Jude Children’s Research HospitalChildren’s Oncology Group
University of Minnesota
M.D. Anderson Cancer Center
M.D. Anderson Cancer Center
Cincinnati Children’s Hospital Medical Center
St. Jude Children’s Research Hospital
Baylor College of Medicine
Primary Children’s Medical Center
Children’s Hospitals and Clinics of Minnesota
Children’s Healthcare of Atlanta/Emory University

Family medicine
Physical therapy, Prosthetics
Pediatric oncology
Orthopedic surgery
Pediatric radiology
Patient advocacy
Nursing
Orthopedic oncology
Radiation oncology
Pediatric oncology
Physical therapy, Epidemiology
Radiation oncology
Orthopedic oncology
Physical therapy
Pediatric oncology

COG LTFU Guidelines – Page xiii

Version 4.0 – October 2013 – Task Force Membership

Task Force Membership 2009–2012 (cont)
Task Force

Task Force Members

Institution

Expertise

Neurocognitive
Behavioral
Psychosocial

Christina Baggott, PhD, RN
Matt Bitsko, PhD, Silo Leader
Veronica Bordes-Edgar, PhD
Debra Cohen, MSN, CPNP
Kimberley Dilley, MD, MPH
Robyn Dillon, MSW
Beryl Gantt, MSW
Laura Greve, PsyD
Jeanne Harvey, RN, MSN, PNP
Tracy Howk, MSW
Chad Jacobsen, MD
Nina-Kadan Lottick, MD, ChairJames Klosky, PhD, Chair, Silo Leader
Kevin Krull, PhD, Chair, Silo Leader
Alicia Kunin-Batson, PhD, Silo Leader
Jill Lunsford Lee, RN, MSN, CPNP-AC, CPON
Jennifer Levine, MD
Belinda Mandrell, PhD, RN, Silo Leader
Ann Mertens, PhD
Sunita Patel, PhD
Sheila Judge Santacroce, PhD, APRN, CPNP
Sally Wiard, MSW

UCSF Medical Center-Parnassus
Virginia Commonwealth University
Phoenix Children’s Hospital
Virginia Commonwealth University
Ann & Robert H. Lurie Children’s Hospital of Chicago
Virginia Commonwealth University
Children’s Oncology GroupChildren’s Healthcare of Atlanta/Emory University
Washington University School of Medicine
Children’s Healthcare of Atlanta/Emory University
Carolinas Medical Center/Levine Cancer Institute
Yale University
St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital
University of Minnesota
University of Minnesota
Columbia University Medical Center
St. Jude Children’s Research HospitalChildren’s Healthcare of Atlanta/Emory University
City of Hope
Yale University
University of Texas Health Science Center, San Antonio

Nursing
Pediatric psychology
Neuropsychology
Nursing
Pediatrics
Social work
Patient advocacy
Pediatric psychology
Nursing
Social work
Pediatric oncology
Pediatric oncology
Pediatric psychology
Neuropsychology
Neuropsychology
Nursing
Pediatric oncology
Nursing
Epidemiology
Pediatric psychology
Nursing
Social work

Neurologic

Joann Ater, MD
Jean Belasco, MD
Daniel C. Bowers, MD, Chair
Jeff Buchsbaum, MD, PhD
Linda Butros, MD
Paul Graham Fisher, MD, Chair
Thomas J. Geller, MD
Laura Gilchrist, PT, PhD
Kathy Johnston, RN
Allison King, MD
Peter Manley, MD
E. Brannon Morris, MDJohn Mussman, JD
Sonia Partap, MD
Suzanne Russo, MD
Nicole Ullrich, MD, PhD, Chair
Gregory Wheeler, MD

M.D. Anderson Cancer Center
Children’s Hospital of Philadelphia
University of Texas Southwestern Medical Center
Riley Hospital for Children
University of New Mexico
Lucile Packard Children’s Hospital Stanford University
Cardinal Glennon Children’s Medical Center
Children’s Hospitals and Clinics of Minnesota
Nationwide Children’s Hospital
Washington University School of Medicine
Dana-Farber Cancer Institute
Medical College of Georgia
Children’s Oncology Group
Lucile Packard Children’s Hospital Stanford University
University of South Alabama
Dana-Farber Cancer InstituteRoyal Children’s Hospital, University of Melbourne

Pediatric oncology
Pediatric oncology
Pediatric oncology
Radiation oncology
Pediatric oncology
Pediatric neurology
Pediatric neurology
Physical therapy
Nursing
Pediatric oncology
Neuro-oncology
Pediatric neurology
Patient advocacy
Pediatric neurology
Radiation oncology
Pediatric neuro-oncology
Radiation oncology

COG LTFU Guidelines – Page xiv

Version 4.0 – October 2013 – Task Force Membership

Task Force Membership 2009–2012 (cont)
Task Force

Task Force Members

Institution

Expertise

Sensory
Auditory
OcularJeff Buchsbaum, MD, PhD
Debra L. Friedman, MD
Dan Gombos, MD
Satkiran S. Grewal, MD, Chair
Kristin Knight, MS, CCC-A
Maryrose McInerney, PhD, CCC-A
Thomas Merchant, DO, PhD
Pinki Prasad, MD
Kimberly Whelan, MD, MSPH, Chair
Catherine Woodman, MD

Riley Hospital for Children
Vanderbilt University/Ingram Cancer Center
M.D. Anderson Cancer Center
Baystate Medical Center
Doernbecher Childrens Hospital - OHSU
Hackensack University Medical Center
St. Jude Children’s Research HospitalChildren’s Hospital New OrleansChildren’s Hospital of Alabama
University of Iowa Hospitals and Clinics

Radiation oncology
Pediatric oncology
Ophthalmology
Pediatric oncology
Audiology
Audiology
Radiation oncology
Pediatric oncology
Pediatric oncology
Primary care, Patient advocacy

Subsequent malignant neoplasms Lisa Bashore, PhD, RN, CPNP
Cancer screening
Daniel Bowers, MD
Smita Bhatia, MD, MPH
Louis S. Constine, MD
Debra L. Friedman, MD
Tara Henderson, MD, Chair
Melissa M. Hudson, MD
Wendy Landier, PhD, RN, CPNP
Marilyn Leitch, MD
Martin Mahoney, MD, PhD
Ann Mertens, PhD
Paul Nathan, MD, Chair
Joseph Neglia, MD
Kevin Oeffinger, MD
Robert Smith, MD
Tung Wynn, MD
Lise Yasui
Mark Yeazel, MD
Octavio Zavala

Cook Children’s Medical Center
University of Texas Southwestern Medical Center
City of Hope
University of Rochester Medical Center
Vanderbilt University/Ingram Cancer Center
University of Chicago
St. Jude Children’s Research Hospital
City of Hope
University of Texas Southwestern Medical Center
Roswell Park Cancer InstituteChildren’s Healthcare of Atlanta/Emory University
The Hospital for Sick Children
University of Minnesota
Memorial Sloan-Kettering Cancer Center
American Cancer Society
University of Florida
Children’s Oncology Group
University of Minnesota
Children’s Oncology Group

Nursing
Pediatric oncology
Pediatric oncology
Radiation oncology
Pediatric oncology
Pediatric oncology
Pediatric oncology
Nursing
Surgery
Family medicine
Epidemiology
Pediatric oncology
Pediatric oncology
Family medicine
Medical oncology
Pediatric oncology
Patient advocacy
Family medicine
Patient advocacy

Urinary tract

Vanderbilt University/Ingram Cancer Center
Baylor College of Medicine
St. Jude Children’s Research Hospital
Virginia Commonwealth University
Connecticut Children’s Medical Center
Phoenix Children’s Hospital
Seattle Children’s Hospital
Lucile Packard Children’s Hospital Stanford University
St. Jude Children’s Research Hospital

Pediatric nephrology
Pediatric oncology
Radiation oncology
Nursing
Pediatric oncology
Pediatric urology
Pediatric urology
Pediatric oncology
Nursing

COG LTFU Guidelines – Page xv

Deborah Jones, MD
Kala Kamdar, MD
Matthew Krasin, MD
Anne Mauck, RN, MSN, CPNP
Kerry Moss, MD
Michael Ritchey, MD
Margarett Shnorhavorian, MD, MPH
Sheri Spunt, MD, Chair
Teresa Sweeney, RN, MSN, CPNP

Version 4.0 – October 2013 – Task Force Membership

Long-Term Follow-Up Guidelines 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 :Thomas R. Baker, CP
CFI Prosthetics and Orthotics
Memphis, TN
Julie Blatt, MD
Division of Pediatric Hematology-Oncology
University of North Carolina
Chapel Hill, NC

Debra L. Friedman, MD, MS
Pediatric Hematology-Oncology
Vanderbilt University/Ingram Cancer Center
Nashville, TN
Sharon Frierdich, RN, MS, CPNP
Pediatric Hematology/Oncology
University of Wisconsin Children’s Hospital
Madison, WI

Tori Marchese, PhD, PT
Penn State Hershey Medical Center
Hershey, PA
Anne Mauck, RN, MSN, CPNP
Pediatric Hematology/Oncology
Virginia Commonwealth University Health System
Richmond, VA

Sunita Patel, PhD
Department of Pediatric Hematology/Oncology
City of Hope Comprehensive Cancer Center
Duarte, CA
Michael Ritchey, MD
Pediatric Urology Associates
Phoenix, AZ

Allison Hester, RN, MSN, CPNP
Arkansas Children’s Hospital
Little Rock, AR

Charlene Maxen, RN, CNP, CPON®
Division of Hematology/Oncology
Childrens Hospital Medical Center of Akron
Akron, OH

Kathy Ruble, RN, CPNP, AOCN®
Long Term Follow-Up Program
Johns Hopkins University
Baltimore, MD

Eric J. Chow, MD, MPH
Hematology/Oncology
Seattle Children’s Hospital
Seattle, WA

Melissa M. Hudson, MD
After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, TN

Lillian R. Meacham, MD
Division of Pediatric Endocrinology
Emory University/Children’s Healthcare of Atlanta
Atlanta, GA

Sheila Judge Santacroce, PhD, APRN, CPNP
School of Nursing
Yale University
New Haven, CT

Kimberley Dilley, MD, MPH
Hematology/Oncology/Transplant
Ann & Robert H. Lurie Children’s Hospital
Chicago, IL

Asako Komiya, RN, MSN, PNP
Department of Epidemiology and Outcomes
Research
City of Hope Comprehensive Cancer Center
Duarte, CA

Katherine Myint-Hpu, MSN, MPH, PNP
Leukemia/Lymphoma Clinic
Georgetown University Hospital
Washington, DC

Margery Schaffer, RN, MSN, CPNP
Department of Hematology/Oncology
Children’s Medical Center
Dayton, OH

Rajaram Nagarajan, MD, MPH
University of Minnesota Cancer Center
Pediatric Hematology/Oncology/BMT
Minneapolis, MN

Susan Shannon, RN, MSN, CPNP, CPON®
“STAR” Late Effects Program
Miller Children’s HospitalLong Beach, CA

Kevin Oeffinger MD
Division of Pediatrics
Memorial Sloan-Kettering Cancer Center
New York, NY

Patricia Shearer, MD, MS
University of Maryland Medical Center
Baltimore, MD

Sharon M. Castellino, MD
Department of Pediatrics, Hematology/Oncology
Wake Forest University Health Sciences
Winston-Salem, NC

Debra Eshelman Kent, RN, MSN, CPNP
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH
Fernando A. Ferrer, MD
Department of Surgery
Connecticut Children’s Medical Center
Hartford, CT
Sarah Friebert, MD
Division of Hematology/Oncology
Childrens Hospital Medical Center of Akron
Akron, OH

COG LTFU Guidelines – Page xvi

Deborah Lafond, MS, RNCS, PNP, CPON®
Hematology/Oncology
Children’s National Medical Center
Washington, DC
Wendy Landier, PhD, RN, CPNP, CPON®
Department of Pediatric Hematology/Oncology
City of Hope Comprehensive Cancer Center
Duarte, CA
Marcia Leonard, RN, CPNP
Pediatric Hematology/Oncology andLong-Term Follow-Up Clinic
C.S. Mott Children’s Hospital
Ann Arbor, MI

Arnold Paulino, MD
Division of Radiation Oncology
Methodist Hospital
Houston, TX

Sheila Shope, RN, FNP
After Completion of Therapy Clinic
St. Jude Children’s Hospital
Memphis, TN

Version 4.0 – October 2013 – Health Link Authors

Health Link Authors (cont)
Sheri L. Spunt, MD
Hematology/Oncology
Lucile Packard Children’s Hospital
Stanford University
Palo Alto, CA
Teresa Sweeney, RN, MSN, CPNP
After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, TN
Sally Wiard, MSW, LCSW
University of Texas Health Science Center
San Antonio, TX
Health Link Graphic Artist
Devika Bhatia
Westridge School
Pasadena, CA

COG LTFU Guidelines – Page xvii

Version 4.0 – October 2013 – Health Link Authors

Long-Term Follow-Up Guidelines Health Link Reviewers
The following individuals participated in reviewing 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 :Daniel Armstrong, PhD

Scott Hawkins, LMSW

Rebecca D. Pentz, PhD

Lisa Bashore, PhD, RN, CPNP, CPON®

Melissa M. Hudson, MD

Priscilla Rieves, MS, RN, CPNP

Smita Bhatia, MD, MPH

Winnie Kittiko, RN, MS

Michael L. Ritchey, MD

Julie Blatt, MD

Peggy Kulm, RN, MA

Leslie L. Robison, PhD

Sarah Bottomley, MN, RN, CPNP, CPON®

Wendy Landier, PhD, RN, CPNP, CPON®

Kathleen Ruccione, RN, MPH, FAAN, CPON®

Emmett J. Broxson, Jr., MD

Missy Layfield

E. Clifton Russell, MD

Billie Buchert, RN, BSN

Thanh Le, MD

Susan Shaw, RN, MS, PNP

Jacqueline Casillas, MD

Marcia Leonard, RN, CPNPCharles A. Sklar, MD

Joe Don Cavender, MSN, RN, CPNP

Neyssa Marina, MD

Johanne Soucy, RN, B.SC.N

Vimal Chadha, MD

Gita Massey, MD

Karen Stormer, RN, CNS, CPON®

Louis S. Constine, MD

Lillian R. Meacham, MD

Joetta Deswarte-Wallace, RN, MSN

Joan Darling, PhD

Jill Meredith, RN, BSN, OCN®

Edward Walz, MD

Nancy L. Dunn, MD

Revonda Mosher, RN, MSN, CPNP, CPON®

Fran Wiley, RN, MN

J. Dominic Femino, MD

John R. Mussman

Roberta G. Williams, MD

Debra L. Friedman, MD

Man Wai Ng, DDS

Catherine L. Woodman, MD

Daniel Green, MD

Kevin Oeffinger, MD

Lise Yasui

Elizabeth Hall, CPNP

Josee Pacifico, RN, BSc (N)Octavio Zavala

COG LTFU Guidelines – Page xviii

Version 4.0 – October 2013 – Health Link Reviewers

Long-Term Follow-Up Guidelines
Guideline Development Task Force – Initial Versions
The Children’s Oncology Group Nursing Discipline and Late Effects Committee developed the initial versions (1.0, 1.1, and 1.2) of the Children’s Oncology Group Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers collaboratively through the efforts of the following individuals:
Melissa M. Hudson, MD
Vice-Chair – COG Late Effects Committee
Member, Department of Oncology
Director, After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, Tennessee
Wendy Landier, PhD, RN, MSN, CPNP, CPON®
Chair – COG Nursing Clinical Practice Subcommittee
Clinical Director – Survivorship Clinic
City of Hope Comprehensive Cancer Center
Duarte, California
Debra Eshelman Kent, RN, MSN, CPNP
Late Effects Section Leader – COG Nursing Clinical Practice Subcommittee
Pediatric Nurse Practitioner
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH
Joan Darling, PhD
COG Patient Advocate Committee Representative
Lincoln, Nebraska

COG LTFU Guidelines – Page xix

Allison Hester, RN, MSN, CPNP
Pediatric Nurse Practitioner
Arkansas Children’s Hospital
Memphis, Tennessee
Teresa Sweeney, RN, MSN, CPNP
Pediatric Nurse Practitioner
After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, Tennessee

Special Acknowledgment
With sincere appreciation to
Louis S. “Sandy” Constine, MD
Vice Chair, Department of Radiation Oncology
James P. Wilmont Cancer Center
University of Rochester Medical Centerfor his in-depth expert review and extensive
contributions to all radiation-related sections
in all versions of the COG LTFU Guidelines

Version 4.0 – October 2013 – Task Force – Initial Versions

Long-Term Follow-Up Guidelines Reviewers – Initial Versions
The following individuals participated in the review process during development of the initial versions (1.0, 1.1, and 1.2) of the Children’s Oncology Group Long-Term Follow-Up Guidelines for
Survivors of Childhood, Adolescent, and Young Adult Cancers :Arlina Ahluwalia, MD
Department of General Internal Medicine
Stanford University
Palo Alto, CA

Hope Anne Castoria, BSN, RN, CPON®
Tomorrow Children’s InstituteHackensack University Medical Center
Hackensack, NJ

Debra L. Friedman, MD, MS
Pediatric Hematology-Oncology
Vanderbilt University/Ingram Cancer Center
Nashville, TN

F. Daniel Armstrong, PhD
Department of Pediatrics
University of Miami School of Medicine
Miami, FL

Laurie Cohen, MD
Division of Endocrinology
Dana Farber Cancer InstituteBoston, MA

Lisa Bashore, RN, MS, CPNP
Pediatric Hematology/Oncology
Cook Children’s Medical Center
Fort Worth, TXLouis S. Constine, MD
Department of Radiation Oncology
University of Rochester Medical Center
Rochester, NY

Daniel M. Green, MD
Departments of Oncology
and Epidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TN

Smita Bhatia, MD, MPH
Division of Population Sciences
City of Hope Comprehensive Cancer Center
Duarte, CA

Lola Cremer, PT
Division of Rehabilitation Services
St. Jude Children’s Research Hospital
Memphis, TN

Julie Blatt, MD
Division of Pediatric Hematology-Oncology
University of North Carolina
Chapel Hill, NC

Sarah Donaldson, MD
Radiation Oncology/Radiation Therapy
Stanford University Medical Center
Stanford, CA

Susan Bock, BSN, RN
Department of Pediatric Specialities
Gundersen Lutheran Clinic
LaCrosse, WI

Patty Feist
Patient Advocate
Boulder, CO

Cathy Bourne, RN, BHSc(N)
Pediatric Hematology/Oncology
Cancer Care Manitoba
Winnipeg, Manitoba, Canada
Julianne Byrne, PhD
Department of Hematology-Oncology
Children’s National Medical Center
Washington, DC
COG LTFU Guidelines – Page xx

Paul Fisher, MD
Neurology and Pediatrics
Stanford University Medical Center
Stanford, CA
Carolyn R. Freeman, MB, BS, FRCPC
Department of Radiation Oncology
McGill University Health Centre
Montreal, Quebec, Canada

Mark Greenberg, MB, BCh
Department of Haematology/Oncology
Hospital for Sick Children
Toronto, Ontario, Canada
Wendy Hobbie, MSN, RN, PNP
Division of Oncology
Children’s Hospital of Philadelphia
Philadelphia, PA
Nina Kadan-Lottick, MD, MSPH
Department of Pediatrics
Yale University School of Medicine
New Haven, CT
Nancy Keene
Patient Advocate
Annandale, VA
Lisa B. Kenney, MD, MPH
Perini Quality of Life Clinic
Dana-Farber Cancer InstituteBoston, MA
Winnie Kittiko, RN, MS
COG Patient Advocacy Committee
Douglasville, GA

Margaret Kulm, RN, MA
COG Patient Advocacy Committee
Port Ludlow, WA
Missy Layfield
COG Patient Advocacy Committee
Cedar Falls, IA
Marcia Leonard, RN, CPNP
Department of Pediatric Hematology/Oncology
C.S. Mott Children’s Hospital
Ann Arbor, MI
Mary Leonard, MD, MSCE
Division of Nephrology
Children’s Hospital of Philadelphia
Philadelphia, PA
Louis A. Leone, Esq.
COG Patient Advocacy Committee
Walnut Creek, CA
Neyssa Marina, MD
Pediatric Hematology Oncology
Stanford University Medical Center
Stanford,CA
Leonard Mattano, MD
Pediatric Hematology/Oncology
Kalamazoo Center for Medical Studies
Michigan State University
Kalamazoo, MI
Anne Mauck, RN, MSN, CPNP
Pediatric Hematology/Oncology
Virginia Commonwealth University Health System
Richmond, VA

Version 4.0 – October 2013 – Reviewers – Initial Versions

Reviewers – Initial Versions (cont)Charlene Maxen, RN, CNP, CPON®
Hematology/Oncology
Childrens Hospital Medical Center - Akron
Akron, OH

Mary Nelson, RN, MS, CPNP, CPON®
Childrens Center for Cancer and Blood Diseases
Childrens Hospital Los Angeles
Los Angeles, CA

Kathleen Ruccione, RN, MPH, FAAN, CPON®
Childrens Center for Cancer and Blood Diseases
Childrens Hospital Los Angeles
Los Angeles, CA

Lillian Meacham, MD
Division of Pediatric Endocrinology
Children’s Healthcare of Atlanta
Atlanta, GA

Kevin Oeffinger, MD
Department of Pediatrics
Memorial Sloan-Kettering Cancer Center
New York, NY

Jean Sanders, MD
Pediatric Marrow Transplantation
Children’s Hospital Regional Medical CenterSeattle, WA

Anna T. Meadows, MD
Division of Oncology
Children’s Hospital of Philadelphia
Philadelphia, PA

Roger Packer, MD
Department of Neurology
Children’s National Medical Center
Washington, DC

Cindy Schwartz, MD
Pediatric Hematology/Oncology
Rhode Island Hospital
Providence, RI

Grace Powers Monaco, JD
Childhood Cancer Ombudsman Program
Heathsville, VA

Arnold Paulino, MD
Department of Radiation Oncology
Children’s Healthcare of Atlanta – Emory Clinic
Atlanta, GA

Susan Shaw, RN, MS, PNP
Center for Children’s Cancer and Blood Disorders
State University of New York at Syracuse
Syracuse, NY

Rebecca D. Pentz, PhD
COG Patient Advocacy Committee
Atlanta, GA

Charles A. Sklar, MD
Department of Pediatrics/Endocrinology
Memorial Sloan-Kettering Cancer Center
New York, NY

Raymond Mulhern, PhD
Division of Behavioral Medicine
St. Jude Children’s Research Hospital
Memphis, TNJohn R. Mussman
COG Patient Advocacy Committee
Chicago, IL
Michael Neel, MD
Division of Orthopedics
St. Jude Children’s Research Hospital
Memphis, TN
Joseph P. Neglia, MD, MPH
Department of Pediatrics
Division of Hematology, Oncology,
Blood and Marrow Transplantation
University of Minnesota School of Medicine
Minneapolis, MN

COG LTFU Guidelines – Page xxi

Leslie L. Robison, PhD
Department of Epidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TNDavid Rosenthal, MD
Department of Pediatrics/Cardiology
Lucile Packard Children’s Hospital at Stanford
Palo Alto, CA
Kathy Ruble, RN, MSN, CPNP, AOCN®
Pediatric Oncology
Johns Hopkins Hospital
Baltimore, MD

Fran Wiley, RN, MN
COG Patient Advocacy Committee
Los Angeles, CA
Suzanne L. Wolden, MD
Department of Radiation Oncology
Memorial Sloan-Kettering Cancer Center
New York, NY
Catherine L. Woodman, MD
COG Patient Advocacy Committee
Iowa City, IA
Lise Yasui
COG Patient Advocacy Committee
Philadelphia, PA
Joseph Zins, PhD
COG Patient Advocacy Committee
Cincinnati, OH
Octavio Zavala
COG Patient Advocacy Committee
Los Angeles, CA

Jacquie Toia, RN, ND, CPNP
Hematology/Oncology
Children’s Memorial Medical Center
Chicago, IL
Deborah Waber, PhD
Department of Psychiatry
Boston Children’s Hospital
Boston, MA
Susan L. Weiner, PhD
The Children’s Cause, Inc.
Silver Spring, MD

Version 4.0 – October 2013 – Reviewers – Initial Versions

Introductory
Material

Introduction – Version 4.0
The Children’s Oncology Group Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers
Overview

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, exposure-related clinical practice guidelines for screening and management of late effects resulting from therapeutic
exposures used during treatment for pediatric malignancies. 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 andlate effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of the risk with
the intensity of the screening recommendations). Since therapeutic interventions for a specific pediatric malignancy may vary considerably basedon 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 this regard, 101 (74%) of the screening recommendations outlined for the 156
therapeutic exposures in the COG-LTFU Guidelines comprise assessments derived primarily from the H&P, with 80 (51%) relying solely on the H&P and
31 (20%) relying on the H&P plus a baseline diagnostic study (e.g., lab, imaging), whereas 41 (26%) include periodic laboratory, diagnostic imaging,or other testing, and 4 (3%) recommend no screening (agents with no known late effects). Interventions exceeding minimal screening are provided forconsideration in individuals with positive screening tests. Medical citations supporting the association of each late effect with a specific therapeutic
exposure are included. Patient education materials complementing the guidelines have been organized into Health Links that feature health protective
counseling on 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, and a tool to assist in identifying guideline
applicability for individual patients based on therapeutic exposures.

Goal

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 (a) promotes healthy lifestyles, (b) provides for ongoing
monitoring of health status, (c) facilitates early identification of late effects, and (d) provides timely intervention for late effects.

Target Population

The recommendations for periodic screening evaluations provided in the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivorsof Childhood, Adolescent, and Young Adult Cancers 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 withsigns and symptoms suggesting illness or organ dysfunction.

Focus

These guidelines are intended for use beginning two or more years following the completion of cancer therapy, and provide a framework forongoing late effects monitoring in childhood cancer survivors; however, these guidelines are not intended to provide guidance for follow-up of
the pediatric cancer survivor’s primary disease.

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Introduction (cont)Intended Users

The COG-LTFU Guidelines were developed as a resource for clinicians who provide ongoing healthcare to survivors of pediatric malignancies. The
information within these guidelines is important for clinicians (e.g., physicians, nurse practitioners, physician assistants, nurses) in the fields ofpediatrics, oncology, internal medicine, family practice, and gynecology, as well as subspecialists in many fields (e.g., endocrinology, cardiology,
pulmonology). A basic knowledge of ongoing issues related to the long-term follow-up needs of this patient population is assumed. Healthcare
professionals who do not regularly care for survivors of pediatric malignancies are encouraged to consult with a pediatric oncology long-term followup 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 istargeted to healthcare professionals. Therefore, survivors who choose to review these guidelines are strongly encouraged to do so with the assistanceof a healthcare professional knowledgeable about long-term follow-up care for survivors of childhood, adolescent, and young adult cancers. This isimportant in order to put the recommendations in perspective, avoid over-testing, address potential anxieties, and provide a comprehensive evaluationof the survivor’s health status. The Children’s Oncology Group itself does not provide individualized treatment advice to patients or their families, andstrongly recommends discussing this information with a qualified medical professional.

Developer

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 orother conflicting interests.

Funding SourceThis work was supported by the Children’s Oncology Group Chair’s Grant U10 CA098543 from the National Cancer Institute.

Evidence
Collection

Pertinent information from the published medical literature over the past 20 years (updated as of October 2013) was retrieved and reviewed during
the development and updating of these guidelines. For each therapeutic exposure, a complete search was performed via MEDLINE (National Libraryof Medicine, Bethesda, MD). Keywords included “childhood cancer therapy,” “complications,” and “late effects,” combined with keywords for eachtherapeutic exposure. References from the bibliographies of selected articles were used to broaden the search.

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Introduction (cont)
Methods

In 2002, the leadership of the Children’s Oncology Group Late Effects Committee and Nursing Discipline appointed a 7-member task force, withrepresentation from the Late Effects Committee, Nursing Discipline, and Patient Advocacy Committee. The task force was convened to review andsummarize the medical literature and develop a draft of clinical practice guidelines 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 thenrecruited by the task force to provide an extensive, targeted review of the draft, including focused review of selected guideline sections. Revisions
were made based on 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 from the COG Late Effects Committee.
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 of review; first by the Nursing Clinical Practice Subcommittee to verify accuracy of content and recommendations,and then by members of the Late Effects Committee (to provide expert medical review) and Patient Advocacy Committee (to provide feedback
regarding presentation of content to the lay public).

Grading Criteria

The guidelines were scored by the multidisciplinary panel of experts using a modified version of the National Comprehensive Cancer Network“Categories of Consensus” system. Each score reflects the expert panel’s assessment of the strength of data from the literature linking a specific lateeffect with a therapeutic exposure, coupled with an assessment of the appropriateness of the screening recommendation based on the expert panel’scollective clinical experience. “High-level evidence” (category 1) was defined as evidence derived from high quality case control or cohort studies.
“Lower-level evidence” (category 2A and 2B) was defined as evidence derived from non-analytic studies, case reports, case series and clinicalexperience. Rather than submitting recommendations representing major disagreements, items scored as “Category 3” were either deleted or revisedby the panel of experts to provide at least a “Category 2B” score for all recommendations included in the guidelines.

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.

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Introduction (cont)
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 the adolescent andyoung 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 18 multidisciplinary task forces in March
2004. These task forces are charged with the responsibility for monitoring the medical literature in regard to specific system-related clinical topics
relevant to the guidelines (e.g., cardiovascular, neurocognitive, fertility/reproductive), providing periodic reports to the Late Effects Committee, andrecommending revisions to the guidelines and their associated health education materials and references (including the addition of therapeutic
exposures) as new information becomes available. In 2009, related task forces were merged, reducing the number of task forces to 10. Task force
members are assigned according to their respective areas of expertise and clinical interest and membership is updated every 2 years. A list of thesetask forces and their membership is included in the “Contributors” section of this document, reflecting contributions and recommendations since theprevious release of these guidelines. (Version 3.0 – October 2008).
All revisions proposed by the task forces were evaluated by a panel of experts, and if accepted, assigned a score (see “Scoring Explanation” sectionof this document). 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.

Plan for Updates

The 10 multidisciplinary task forces described above will continue to monitor the literature and report 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, andat least every 5 years. Clinicians are advised to check the Children’s Oncology Group website periodically for the latest updates and revisions to theguidelines, which will be posted at www.survivorshipguidelines.org.

Definitions“Late effects” are defined as therapy-related complications or adverse effects that persist or arise after completion of treatment for a pediatricmalignancy. “Pediatric malignancies” are defined as those malignancies commonly associated with the pediatric population that may arise duringchildhood, adolescence or young adulthood. “Consensus” is defined as general agreement among the panel of experts.

Recommendations Screening and follow-up recommendations are organized by therapeutic exposure and included throughout the guidelines. Pediatric cancer survivors
and Rationale:
represent a relatively small but growing population at high risk for various therapy-related complications. Although several well-conducted studies onlarge populations of childhood cancer survivors have demonstrated associations between specific exposures and late effects, the size of the survivor
population and 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 the late effect. Therefore, scoring of each exposure reflects the expert panel’s assessment of the levelof literature support linking the therapeutic exposure with the late effect coupled with an assessment of the appropriateness of the recommended
screening modality in identifying the potential late effect based on the panel’s collective clinical experience.

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Introduction (cont)
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 health status of survivors. In
addition, ongoing healthcare that promotes healthy lifestyle choices and provides ongoing monitoring of health status is important for all cancer
survivors.
Potential harms of guideline implementation include increased patient anxiety related to enhanced awareness of possible complications, as well as
the potential for false-positive screening evaluations, leading to unnecessary further workup. In addition, costs of long-term follow-up care may beprohibitive for some patients, 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 clinical management 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 specificpatient care decisions are the prerogative of the patient, family, and healthcare provider.

Implementation
Considerations:

Implementation of these guidelines is intended to standardize and enhance follow-up care provided to survivors of pediatric malignancies throughout
the lifespan. Considerations in this regard include the practicality and efficiency of applying these broad guidelines in individual clinical situations.
Studies to address guideline implementation and refinement are a top priority of the COG Long-Term Follow-Up Guideline Core Committee; studies of
feasibility of guideline use have been reported in limited institutions and others are currently underway. Issues being addressed include description of
anticipated barriers to application of the recommendations 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 and depth of these guidelines is important in order to provide clinically-relevant, evidence-based recommendations andsupporting health education materials, clinician time limitations and the effort required to identify the specific recommendations relevant to individual
patients have been identified as barriers to their clinical application. Therefore, the COG Long-Term Follow-Up Guideline Core Committee has partneredwith the Baylor School of Medicine to develop a web-based interface, known as “Passport for Care,” that generates individualized exposure-based
recommendations from these guidelines in a clinician-focused format for ease of patient-specific application of the guidelines in the clinical setting.
The Pasport 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 ).

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Explanation of Scoring for the Long-Term Follow-Up Guidelines
These guidelines represent a statement of consensus from a multidisciplinary panel of experts in the late effects of pediatric cancer treatment. The guidelines outline minimum
recommendations for specific health screening evaluations in order to detect potential late effects arising as a result of therapeutic exposures received during treatment ofchildhood, adolescent, and young adult cancers.
Each score relates to the strength of the association of the identified late effect with the specific therapeutic exposure based on current literature, and is coupled with arecommendation for periodic health screening based on the collective clinical experience of the panel of experts. This is due to the fact that there are no randomized clinical
trials (and none 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 of care”.
Each item was scored based on the level of evidence currently available to support it. Scores 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 and (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 and (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 and (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

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 clinical experience.

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 scored as “Category 3” were either deleted or revised by the panel of experts to provide atleast a “Category 2B” score for all recommendations included in the guidelines.

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Instructions for Use – Version 4.0
The Children’s Oncology Group Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent, and Young Adult Cancers
Guideline Organization
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 cell transplant, andother therapeutic modalities.

Potential Late Effects

Most common late treatment complications associated with specified therapeutic intervention.

Risk Factors

Host factors (e.g., age, sex, race, genetic predisposition), treatment factors (e.g., cumulative dose of therapeutic agent, mode of administration,
combinations of agents), medical conditions (e.g., pre-morbid or co-morbid conditions), and health behaviors (e.g., diet, smoking, alcohol use)that may increase risk of developing the complication.

Highest Risk Factors

Conditions (host factors, treatment factors, medical conditions and/or health behaviors) associated with the highest risk for developing thecomplication.

Periodic Evaluations

Recommended screening evaluations, including health history, physical examination, laboratory evaluation, imaging, and psychosocial
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 clinical experience of the reviewers and panel of experts.

Health Counseling/
Further Considerations

Health Links: Health education materials developed specifically to accompany these guidelines. Title(s) of Health Link(s) relevant to eachguideline section are referenced in this column. Health Link documents are included in Appendix II, and are also available on the COG website atwww.survivorshipguidelines.org.
Counseling: Suggested patient counseling regarding measures to prevent/reduce risk or promote early detection of the potential treatmentcomplication.
Resources: Books and websites that may provide the clinician with additional relevant information.
Considerations for Further Testing and Intervention: Recommendations for further diagnostic evaluations beyond minimum screening
for individuals with positive screening tests, recommendations for consultation and/or referral, and recommendations for management of
exacerbating or predisposing conditions.

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System Score

Body system (e.g., auditory, musculoskeletal) most relevant to each guideline section.
Score assigned by expert panel representing the strength of data from the literature linking a specific late effect with a therapeutic exposure
coupled with an assessment of the appropriateness of the screening recommendation based on collective clinical experience.

Cancer Screening
Recommendations

Sections 157–166 contain preventive screening recommendations for common adult-onset cancers, organized by column as follows:
Organ: The organ at risk for developing malignancy.
Population Risk Factors: Risk factors such as age, gender, genetic susceptibility, personal or family history, health-related behaviors or comorbidities generally associated with increased risk for the specified malignancy in general populations.
Highest Risk Factors: Populations considered by the panel of experts or other evaluating bodies (such as the American Cancer Society) as beingat significantly increased risk for the specified malignancy. Risk factors may include therapeutic exposures resulting from cancer treatment, as
well as other factors listed above (e.g., genetic susceptibility).
Periodic Evaluations:Standard Risk: Guidelines provided under the “Standard Risk” category are per the American Cancer Society recommendations for standard-risk
populations and are included here for reference. In addition, clinicians are encouraged to consult recommendations from other organizations,such as the U. S. Preventive Services Task Force (www.ahrq.gov/clinic/serfiles.htm).
Highest Risk: Recommendations for high-risk populations, when applicable, are specified 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

References

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

The following documents are also included to further assist with application of these guidelines:
Explanation of Scoring

Elucidation of the process used by the panel of experts to assign scores to each guideline section.

Patient-Specific
Guideline IdentificationTool

Due to significant overlap of toxicities between therapeutic agents, and in order to avoid an enormously lengthy document, duplicate entries havebeen avoided as much as possible. Therefore, use of the Patient-Specific Guideline Identification Tool is imperative in order to determine
each potential late effect associated with each therapeutic agent within this document (see Appendix I ).

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 been developed 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 expo-

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Version 4.0 – October 2013 – Instructions for UseInstructions for Use (cont)sure-based follow-up recommendations from these guidelines, the following information regarding the survivor’s diagnosis and treatment is required, at minimum :2.

•

Date of diagnosis•

Survivor’s sex•

Survivor’s date of birth•Names of all chemotherapy agents received. For list of chemotherapeutic agents addressed by these guidelines (Sections 10–43), see the “Chemotherapy” portion of
the Patient-Specific Guideline Identification Tool in Appendix I. For list of 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), and age at first anthracycline
dose (if unknown, age at first exposure is presumed to be age at diagnosis).

•

For carboplatin: Whether patient received myeloablative dose (i.e., for hematopoietic cell transplant [HCT] conditioning).

•

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” (all single doses < 1000 mg/m2)•

All radiation field(s) and total radiation dose (in Gy) to each field (for chest radiation, include age at first dose). For list of radiation fields addressed by these guidelines(Sections 44–102), see “Radiation” portion of the Patient-Specific Guideline Identification Tool in Appendix I. For clarification of anatomical areas included in common
radiation fields, see Radiation Fields by Anatomic Region and Radiation Fields Defined in Appendix I. For clarification regarding radiation dose calculations for determining screening recommendations for individual patients, see Determining Applicability of Radiation Sections for Specific Patients Based on Exposure on page 56 ofguidelines and in Appendix 1.

•

Whether or not the survivor underwent a hematopoietic cell transplant (HCT), and if so, whether or not the survivor has a history of chronic graft-versus-host disease(cGVHD).

•

Names of all relevant surgical procedures. For list of surgical procedures addressed by these guidelines (Sections 120–152), see “Surgery” portion of thePatient-Specific Guideline Identification Tool in Appendix I.

•

Names of all other therapeutic modalities. For list of other therapeutic modalities addressed by these guidelines (Sections 153–156), see “Other Therapeutic Modalities” portion of the Patient-Specific Guideline Identification Tool in Appendix I.

Develop a list of guideline sections relevant to the survivor:•

Sections 1–6 (“Any Cancer Experience”) and 157 (“General Health Screening”) are relevant to all survivors.

•

For survivors diagnosed prior to 1993, include relevant sections based on date of diagnosis:•––

If survivor was diagnosed prior to 1972, include Section 7––

If survivor was diagnosed prior to 1993, include Section 8––

If survivor was diagnosed between 1977 and 1985, include Section 9

For survivors who received chemotherapy, include relevant sections:

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•

3.

––

If survivor received any chemotherapy, include Section 10.

––

Review “Chemotherapy” portion of the Patient-Specific Guideline Identification Tool in Appendix I and include Sections 11–43 as applicable based on survivor’s
chemotherapy exposures (Note: Some alkylating agent sections are gender-specific)

For survivors who received radiation therapy, include relevant sections:––

If survivor received any radiation therapy, include Sections 44–47. Exception: If the survivor’s only radiation exposure was TBI, do NOT include Sections 46 or
47.

––

Review “Radiation” portion of the Patient-Specific Guideline Identification Tool in Appendix I and include Sections 48–102 as applicable based on survivor’s
radiation exposures (Note: Some sections are gender-specific and some are relevant only for patients who received the minimum specified dose of radiation to
the indicated field or anatomic area.

•

For survivors who underwent hematopoietic cell transplant (HCT), include Sections 103–110. If the survivor has a history of chronic GVHD (cGVHD), also include
Sections 111–119 (Note: Section 116 is applicable only to survivors with currently active cGVHD; Section 118 is applicable only to females; Copies of the radiation
sections applicable to TBI are reproduced and grouped together for convenience at the end of the HCT section on page 129).

•

For survivors who underwent surgery, review “Surgery” portion of the Patient-Specific Guideline Identification Tool in Appendix I and include Sections 120–152 asapplicable based on survivor’s surgical history. (Note: Some sections are gender-specific).

•

For survivors who received other therapeutic modalities, review “Other Therapeutic Modalities” portion of the Patient-Specific Guideline Identification Tool in Appendix
I and include Sections 153–156 as applicable.

•

Include cancer screening guidelines (Sections 157–166) as applicable based on survivor’s sex and current age. (Note: For survivors whose radiation exposure triggers Section 77, there is no need to include Section 157; for survivors whose radiation exposure triggers Section 90, there is no need to include Section 159).

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 be required in order to generate comprehensive recommendations. Therefore, we strongly advise that a comprehensive treatment summary be prepared foreach 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 these guidelines.
The COG Long-Term Follow-Up Guidelines Core Committee recognizes that the time required to identify patient-specific recommendations from these guidelines is significant,and has been identified as a barrier to clinical use. Therefore, COG has partnered with the Baylor School of Medicine to develop a web-based interface, known as “Passport for

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Version 4.0 – October 2013 – Instructions for UseInstructions for Use (cont)Care,” that generates individualized exposure-based recommendations from these guidelines in a clinician-focused format for ease of patient-specific application in the clinicalsetting. The Pasport 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 Follow-Up 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, pleasecontact:
Co-Chairs, COG Long-Term Follow-Up Guidelines Core Committee:
Melissa M. Hudson, MD
St. Jude Children’s Research Hospital
Memphis, Tennessee(901) 595-3445
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, RN, CPNPCity of Hope National Medical Center
Duarte, California(626) 471-7320
wlandier@coh.org

Smita Bhatia, MD, MPH
City of Hope National Medical Center
Duarte, California(626) 471-7321
sbhatia@coh.org

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New to Version 4.0 of the COG Long-Term Follow-Up Guidelines
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 theapproval of the Expert Panel. The most significant modifications are detailed below.
••

The following NEW sections have been added:––

Impaired glucose metabolism/Diabetes mellitus related to abdominal radiation (Section 84)––

Dyslipidemia related to TBI (Section 85)––

Renal toxicity related to hematopoietic cell transplantation (Section 110)––

Overweight/obesity related to neurosurgery affecting the hypothalamic-pituitary axis (Section 133)––

Diabetes insipidus related to neurosurgery affecting the hypothalamic-pituitary axis (Section 134)––

Scoliosis/kyphosis related to neurosurgery-spine (Section 139)––

Scoliosis/kyphosis related to thoracic surgery (Section 151)

The following existing sections from version 3.0 of the COG LTFU Guidelines have been divided into more than one section in version 4.0:––

Psychosocial disorders; Mental health disorders; Risky behaviors; Psychosocial disability due to pain; Fatigue (Section 1, v3.0), now divided into: Adverse psychosocial/QoL effects (Section 1); Mental health disorders (Section 2); Risky behaviors (Section 3); Psychosocial disability due to pain (Section 4); Fatigue (Section 5);
Limitations in healthcare and insurance access (Section 6)––

Alkylating agents and gonadal dysfunction-testicular (Section 7 [male], v3.0), now divided into: Alkylating agents and reduced fertility (Section 11) and Alkylating
agents and testosterone deficiency/insufficiency; delayed/arrested puberty (Section 12)––

Ototoxicity related to radiation (Section 58, v3.0), now divided into: Tympanosclerosis; ototosclerosis, eustachian tube dysfunction; conductive hearing loss (Section66) and Sensorineural hearing loss; tinnitus (Section 67)––

Orchiectomy and gonadal dysfunction-testicular (Section 125, v3.0), now divided into: Unilateral orchiectomy; Reduced fertility, testosterone insufficiency (Section143) and Bilateral orchiectomy; Infertility; testosterone deficiency (Section 144)––All sections previously divided into “Male” and “Female” sub-sections have been re-categorized as stand-alone male or female sections in version 4.0, as follows:•

Alkylating agents and gonadal dysfunction (Section 7 [male and female], v3.0), now categorized as: Section 11 (male-reduced fertility), Section 12 (male-testosterone deficiency/insufficiency; delayed/arrested puberty) and Section 13 (female-delayed/arrested puberty; premature menopause; infertility)•

Anthracyclines and cardiac toxicity (Section 28 [male and female], v.3.0), now categorized as: Section 33 (male) and Section 34 (female)•

Cranial radiation and precocious puberty (Section 51 [male and female], v3.0), now categorized as: Section 56 (male) and Section 57 (female)•

Cranial radiation and hyperprolactinemia (Section 52 [male and female], v3.0), now categorized as: Section 58 (male) and Section 59 (female)•

Cranial radiation and gonadotropin deficiency (Section 54 [male and female], v3.0), now categorized as: Section 61 (male) and Section 62 (female)•

Chest radiation and cardiac toxicity (Section 71 [male and female], v3.0), now categorized as: Section 80 (male) and Section 81 (female)•

Hematopoietic cell transplant and solid tumors (Section 93 [male and female], v3.0), now categorized as: Section 104 (male) and Section 105 (female)

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•

•

•

•

Nephrectomy (Section 114 [male-hydrocele/renal toxicity and female-renal toxicity], v3.0), now categorized as: Section 127 (male-hyrocele/renal toxicity) andSection 128 (female-renal toxicity)•

Neurosurgery-spinal cord and psychosexual dysfunction (Section 121 [male and female], v3.0), now categorized as: Section 137 (male) and Section 138 (female)•

Pelvic surgery or Cystectomy and sexual dysfunction (Section 128 [male and female], v3.0), now categorized as: Section 147 (male) and Section 148 (female)

The following sections have been removed from version 4.0 of the COG LTFU Guidelines:––

Dyslipidemia related to platinum chemotherapy (Section 17, v3.0)––

Metabolic syndrome related to cranial radiation/TBI (Section 49, v3.0)––

Kyphosis related to musculoskeletal radiation (Section 90, v 3.0): Kyphosis is now merged with Scoliosis in Section 101 of version 4.0 of the COG LTFU Guidelines––

Hydrocele related to Pelvic Surgery or Cystectomy (Section 129 [male], v3.0)

The following modifications have been made to therapeutic exposures:––

Carboplatin at any dose added as a therapeutic exposure for ototoxicity in patients diagnosed at less than 1 year of age (Section 20; score = 1); Info Link added toprovide rationale for this change––

Radiation threshold for screening reduced from ≥ 40 Gy to ≥ 30 Gy for•

Radiation to the neuroendocrine axis and gonadotropin deficiency: Section 61 (male; score = 1) and Section 62 (female; score = 1)•

Radiation to the neuroendocrine axis and central adrenal insufficiency: Section 63 (score = 1)––

Chest (thorax) and whole lung radiation removed as therapeutic exposures related to thyroid dysfunction, thyroid nodules, and thyroid cancer: Sections 71, 72, 73, 74(score = 1 for each section)––

Cranial and nasopharyngeal radiation removed as therapeutic exposures for hyperthyroidism: Section 74––“Autologous” specified as the sole type of hematopoietic cell transplant associated with the potential late effect of therapy-related acute myeloid leukemia/ myelodysplasia (Section 103; score = 1)––

Pulmonary lobectomy, pulmonary metastasectomy, pulmonary wedge resection as therapeutic exposures for pulmonary dysfunction changed to: Thoracic surgery(includes thoracotomy, chest wall surgery, rib resection, pulmonary lobectomy, pulmonary metastasectomy, pulmonary wedge resection): Section 150 (score = 2A)

The following modifications have been made to potential late effects:––“Psychosocial Disorders” re-categorized as “Adverse Psychosocial/QoL Effects” and additional potential late effects added: Dysfunctional marital relationships;
Under-Unemployment; Dependent living (Section 1; score = 2A)––

Additional potential late effect (suicidal ideation) added to: Mental health disorders (Section 2; score = 2A)––

Additional potential late effect (microdontia) added to: Dental abnormalities (Section 10; score = 1)––

Info Link added to explain that ifosfamide-related renal toxicity typically occurs during the acute treatment phase and improves or progresses over time (Section 19)(score = 1)––

Additional potential late effect (hypertension) added to Renal toxicity related to Heavy metals (Section 22; score = 1)––

Additional potential late effects (glomerular injury; hypertension) added to Renal toxicity related to Methotrexate/high-dose IV, IM, PO (Section 28; score = 2A)

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•––Additional potential late effect (deficits in fine motor dexterity) added to Neurocognitive deficits related to: Cytarabine/high-dose IV (Section 23; score = 2A),
Methotrexate/high-dose IV, IT, IO (Section 30; score = 1), and cranial/ear-infratemporal radiation/TBI (Section 49; score =1)––

Additional potential late effect (language deficits) added to: Neurocognitive deficits related to cranial/ear-infratemporal radiation/TBI (Section 49; score = 1)––

Additional potential late effect (cavernomas) added to: Cerebrovascular complications related to cranial radiation (Section 51; score = 1); Info link added to explain
clinical implications of cavernomas––

Additional potential late effect (focal nodular hyperplasia [FNH]) added to: Hepatic fibrosis/cirrhosis related to liver radiation (Section 86; score = 1); Info link added to
explain clinical implications of FNH––

Additional potential late effect (asymptomatic bacteriuria) added to: Cystectomy-related complications (Section 122; score = 1)––

Potential late effect related to neurosurgery-spinal cord changed from “sexual dysfunction” to “psychosexual dysfunction” (Sections 137, 138; score = 2A)

The following modifications have been made to screening recommendations:
––

––

––

––

CBC with differential yearly x 10 years removed as screening for t-AML/MDS and added to Considerations for further testing and intervention (as clinically indicated),in the following sections:•Alkylating agents (Section 14)•

Anthracyclines (Section 32)•

Epipodophyllotoxins (Section 43)•

Autologous hematopoietic cell transplant (Section 103)

Chest x-ray (baseline, repeat as clinically indicated) removed as screening for pulmonary fibrosis from•Busulfan, carmustine [BCNU]), lomustine [CCNU] (Section 15)•

Bleomycin (Section 35)•

Radiation with potential impact to the lungs (Section 79)•

Hematopoietic cell transplant with any history of chronic graft-versus-host disease (Section 114)•

Thoracic surgery (Section 150)

Urinalysis (yearly) removed as screening for hemorrhagic cystitis and added to Considerations for further testing and intervention (for patients with a positive history)
in the following sections:•

Cyclophosphamide, ifosfamide (Section 17)•

Radiation with potential impact to the bladder (Section 92)

Urinalysis (yearly) removed as screening for bladder cancer and added to Considerations for further testing and intervention (for patients with a positive history) in thefollowing sections:•

Cyclophosphamide (Section 18)•

Radiation with potential impact to the bladder (Section 94)

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––

––

––

––

Serum testosterone (males at age 14 and as clinically indicated) modified to indicate that specimen is ideally obtained in the morning for•

Alkylating agents and testosterone deficiency/insufficiency; delayed/arrested puberty (Section 12)•

Radiation to the hypothalamic-pituitary axis and gonadotropin deficiency (Section 61)•

Pelvic/testicular radiation and testosterone deficiency/insufficiency; delayed/ arrested puberty (Section 99)•

Unilateral orchiectomy and testosterone insufficiency (Section 143)

FSH, LH (males at age 14 and as clinically indicated) removed as screening for•

Alkylating agents and testosterone deficiency/insufficiency; delayed/arrested puberty (Section 12)•

Pelvic/testicular radiation and testosterone deficiency/insufficiency; delayed/arrested puberty (Section 99)

FSH (males at age 14 and as clinically indicated) retained/ added as secondary screening for reduced fertility in sexually mature patients if unable to obtain semen
analysis for:•

Alkylating agents and gonadal dysfunction (testicular)—reduced fertility (Section 11)•

Pelvic/testicular radiation and gonadal dysfunction (testicular)—reduced fertility (Section 98)•

Unilateral orchiectomy and gonadal dysfunction (testicular)—reduced fertility (Section 143)

Hemoglobin A1c (every 2 years) added as an option (in place of fasting blood glucose) for•––

Endocrinology evaluation (yearly) replaces previous recommendation for “8:00 a.m. serum cortisol yearly × 15 years” for
•

––

––

•

Recommendation added for clinicians to discuss benefits and risks/harms of screening for patients who received TBI or 10–19 Gy radiation with potential impact
to the breast•

If decision is made to screen patients who received < 20 Gy radiation with potential impact to the breast, screening recommendations are identical to those forpatients who received ≥ 20 Gy and include: Mammogram and breast MRI yearly beginning 8 years after radiation or at age 25, whichever occurs last; Clinicalbreast exam yearly from puberty until age 25, then every 6 months; and Breast self-examination monthly

Examination of external genitalia (yearly) and gynecological consultation when age-appropriate added as screening for
Hematopoietic cell transplant with any history of chronic graft-versus-host disease and vaginal fibrosis/stenosis (Section 118)

Evaluation by neurologist modified to “as clinically indicated” rather than “every six months” for•––Radiation to the hypothalamic-pituitary axis ≥30 Gy and central adrenal insufficiency (Section 63)

Breast cancer screening (Sections 77 and 157):•––

Chest radiation and cardiac toxicity (Sections 80, 81)

Neurosurgery-brain and seizures (Section 131)

Endocrinology consultation (or gynecology-females) for initiation of hormonal replacement therapy modified from “At age 11” to “At age 11 or immediately forpost-pubertal patients” for•Bilateral oophorectomy (Section 142)•

Bilateral orchiectomy (Section 144)

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•––Cervical cancer screening recommendations (Section 158) updated to reflect current American Cancer Society recommendations (i.e., changes to PAP/HPV testing)––

Lung cancer screening recommendations (Section 161) updated to include the following statement for patients at highest risk: “Clinician should discuss the benefits
and risks/harms of spiral CT scanning”

The following modifications have been made to Health Counseling/Further Considerations:––––

Added recommendations for minimum intake of Vitamin D as per the American Academy of Pediatrics to the following sections:•

Methotrexate and reduced bone mineral density (Section 27)•

Corticosteroids and reduced bone mineral density (Section 37)•

Hematopoietic cell transplant and reduced bone mineral density (Section 109)

Added Info Link regarding metabolic syndrome, and recommendations to consider evaluation for other co-morbid conditions, including dyslipidemia, hypertension, or
impaired glucose metabolism for
•

––

•
––

––

•

Splenic radiation and functional asplenia (Section 82)•

Hematopoietic cell transplant with currently active chronic graft-versus-host disease and functional asplenia (Section 116)•

Splenectomy and anatomic asplenia (Section 149)

Added recommendation for consideration of periodic monitoring of serum testosterone levels in males with low normal testosterone, as they age or if they become
symptomatic, for––

Limb sparing procedures (Section 126)

Revised sports/physical activity recommendations for•––

Pelvic/testicular radiation and testosterone deficiency/insufficiency; delayed/ arrested puberty (Section 99)

Updated antibiotic prophylaxis recommendations to indicate lack of current consensus for patients with orthopedic implants for•––

Radiation to the neuroendocrine axis and gonadotropin deficiency (Section 61)

Added recommendations for counseling patients regarding risk of life-threatening infections and indication for medical alert bracelets for•––

Cranial radiation and growth hormone deficiency (Section 55)

Added information regarding induction of spermatogenesis with gonadotropins for•––

Overweight/obesity related to cranial radiation (Section 54)

Updated recommendations regarding monitoring growth and indications for endocrinology referrals for

Nephrectomy and renal toxicity (Sections 127, 128)

Updated to reflect recommendations for sperm retrieval in men with erectile/ejaculatory dysfunction who desire paternity for•

Neurosurgery-spinal cord and erectile dysfunction; ejaculatory dysfunction (Section 137)•

Pelvic surgery/cystectomy and retrograde ejaculation; anejaculation; erectile dysfunction (Section 147)

Added consideration for gynecologic consultation in patients with positive history for•

Neurosurgery-spinal cord and psychosexual dysfunction (Section 138)

COG LTFU Guidelines – Page xxxviii

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––Added importance of monitoring cardiovascular health in hypogonadal females for
•

––

•

Bilateral oophorectomy and hypogonadism/infertility (Section 142)

Added importance of monitoring for surgical complications after prosthesis placement and cautioned that orchiectomy can be associated with psychological distressrelated to altered body image for•

Unilateral orchiectomy (Section 143)•

Bilateral orchiectomy (Section 144)

The following modifications have been made to the Health Links:––

Added new Health Link: “Cardiovascular Risk Factors” (relevant to Sections 19, 22, 28, 33, 34, 54, 80, 81, 84, 85, 91, 110, 128, 133)––

Modified the following Health Links:•

Bone Health: Added recommendations for minimum daily intake of Vitamin D as per the American Academy of Pediatrics•

Central Adrenal Insufficiency: Revised to reflect lower radiation dose for screening (> 30 Gy) and revised screening recommendations (endocrinology evaluation
rather than yearly blood test)•

Dental Health: Removed statement that xerostomia generally occurs only with radiation doses > 40 Gy.

•

Diet and Physical Activity: Updated “My Pyramid” to “My Plate”•

Finding and Paying for Healthcare: Updated with information regarding new insurance options in the United States under the Affordable Care Act•

Hearing Loss: Updated to indicate risk of hearing loss in survivors who received conventional doses of carboplatin prior to one year of age•

Hypopituitarism: Updated to include antidiuretic hormone deficiency and diabetes insipidus related to neurosurgery•

Limb Sparing Procedures: Updated to reflect lack of consensus regarding antibiotic prophylaxis recommendations•

Pulmonary Health: Updated to remove chest x-ray, and to recommend avoidance of inhaled drugs (such as marijuana)•

Scoliosis and Kyphosis: Added information regarding surgical procedures (thoracic and spinal surgeries) that may increase risk of developing scoliosis andkyphosis (from new Sections 139 and 151)•

Reducing the Risk of Second Cancers: Updated with information regarding the role of vaccination in preventing Hepatitis B and HPV-related cancers•

Single Kidney Health: Updated to reflect revised sports/physical activity recommendations for mononephric survivors; removed reference to Single Kidney Health
Link from renal toxicity sections (Sections 19, 22, 28, 91)•

Splenic Precautions: Updated to reflect current vaccine recommendations•

Additional minor modifications made throughout Health Links to reflect current content of version 4.0 of the COG LTFU Guidelines•

Anthracycline isotoxic dose equivalent formula for Daunorubicin has been updated (see Sections 33, 34)•

The Info Link regarding prophylactic antibiotic therapy and immunizations for functionally or anatomically asplenic patients has been updated to indicate that clinicians
should refer to the current edition of the AAP Red Book for recommendations (Sections 82, 116, 149)•

Information regarding the role of the human papillomavirus (HPV) vaccine in prevention of post-transplant malignancies has been added (Sections 104, 105)•

Radiation fields by anatomic area have been updated (see pages 56–57 of guidelines)

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•

The text that introduces the hematopoietic cell transplant sections (103–119) now precedes Section 103, since it is relevant to all hematopoietic cell transplant sections•“Risk Factors” and “Highest Risk Factors” have been updated, based on current literature as reviewed by the Task Forces•

Links for general health screening have been updated (Section 166)•

Updated references have been added and outdated reference removed throughout the guidelines

In addition, the following modifications have been made to Version 4.0 of these guidelines:•

Links to all sections relevant to TBI have been added before the HCT section of the guidelines (see page 129)•

The “Radiation Reference Guide” has been updated to reflect modifications to section numbers and other changes as described above (see Appendix 1)•

The “Patient-Specific Guideline Identification Tool” has been updated to modifications to section numbers and other changes as described above (see Appendix 1)•

French translations of some Health Links have been added

COG LTFU Guidelines – Page xl

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Guidelines

ANY CANCER EXPERIENCE
Sec#
1Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

Any Cancer Experience

Adverse Psychosocial/QoL
Effects
Social withdrawal
Educational problems
Dysfunctional marital
relationships
Under-employment/
Unemployment
Dependent living

Host Factors
Female sex
Family history of depression,anxiety, or mental illness
Younger age at diagnosis
Neurocognitive problems
Physical limitations

Info Link
The Children’s Oncology
Group Long-Term Follow-Up
Guidelines apply to patients
who have been off therapy fora minimum of 2 years.

Social Factors
Lower household income
Lower educational
achievement
Treatment Factors
Hematopoietic Cell Transplant

HighestRisk Factors
Host Factors
CNS tumor
CNS-directed therapy
Hearing loss
Premorbid learning or
emotional difficulties
Social Factors
Failure to graduate from highschoolPeriodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Psychosocial assessment with attentionto:-- Educational and/or vocational
progress-- Social withdrawal
YearlyIntroduction to Long-Term Follow-Up
Emotional Issues
Educational Issues

Resources‘Childhood Cancer Survivors’ by Nancy Keene, Wendy Hobbie& Kathy Ruccione, Childhood Cancer Guides, 2012; ‘Educating
the Child with Cancer’ edited by Nancy Keene, CandlelightersChildhood Cancer Foundation, Bethesda, MD, 2003.
See also: www.cancer.gov (‘Facing Forward’ series forsurvivors)

Considerations for Further Testing and Intervention
Consider psychological consultation in patients with emotionaldifficulties related to cancer experience, including physicaldeformities or chronic disabilities. Consider social work
consultation. Refer as indicated to school liaison in community
or cancer center (psychologist, social worker, school counselor)
to facilitate acquisition of educational resources.

SYSTEM = Psychosocial
SCORE = 2A

SECTION 1 REFERENCES
Arvidson J, Larsson B, Lonnerholm G. A long-term follow-up study of psychosocial functioning after autologous bone marrow transplantation in childhood. Psycho-oncology. Mar-Apr 1999;8(2):123-134.
Barrera M et al. Educational and social late effects of childhood cancer and related clinical, personal and familial characteristics. Cancer. 2005;104:1751-60.
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. Mar 1 2010;116(5):1385-1391.
Brown RT, Madan-Swain A, Walco GA, et al. Cognitive and academic late effects among children previously treated for acute lymphocytic leukemia receiving chemotherapy as CNS prophylaxis. J Pediatr Psychol. Oct
1998;23(5):333-340.
Gurney JG et al. Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors. Pediatrics. 2007;120(5):e1229-36.
Gurney JG, Krull KR, Kadan-Lottick N, et al. Social outcomes in the Childhood Cancer Survivor Study cohort. J Clin Oncol May 10 2009;27(14):2390-2395.
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. Oct 2009;18(10):26262635.
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. Nov 2010;48(11):1015-1025
Kirchhoff AC, Krull KR, Ness KK, et al. Occupational outcomes of adult childhood cancer survivors: A report from the Childhood Cancer Survivor Study. Cancer. Jul 1 2011;117(13):3033-3044.
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. Dec 15 2011;57(7):11971203.
Lancashire ER, Frobisher C, Reulen RC, Winter DL, Glaser A, Hawkins MM. Educational attainment among adult survivors of childhood cancer in Great Britain: a population-based cohort study. J Natl Cancer Inst. Feb 24
2010;102(4):254-270.

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ANY CANCER EXPERIENCESec#Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors(CONT)
HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 1 REFERENCES – continued
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. Feb 15
2003;97(4):1115-1126.
Pastore G, Masso ML, Magnani C, Luzzatto l, Bianchi M, Terracini B. Physical impairment and social life goals among adult long-term survivors of childhood cancer: a population based study from the childhood cancer registry ofPiedmont, Italy. Tumori. Nov-Dec 2001;87(6):372-378.
Stam H et al. The course of life of survivors of childhood cancer. Psycho-oncology. 2005;14:227-38.
Zebrak BJ, Zeltzer LK, Whitton J, et al. Psychological outcomes in long-term survivors of childhood leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma: a report from the Childhood Cancer Survivor Study. Pediatrics
2002;Jul; 110(1 Pt 1):42-52.
Zeltzer LK, Chen, E, Weiss R, et al. Comparison of psychologic outcome in adult survivors of childhood acute lymphoblastic leukemia versus sibling controls: a Cooperative Children’s Cancer Group and National Institutes of
Health study. J Clin Oncol 1997;Feb; 15(2): 547- 556

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ANY CANCER EXPERIENCE
Sec#
2Therapeutic
Agent(s)Any Cancer Experience

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

Risk
Factors
Host Factors
Female sex
Family history of depression,anxiety, or mental illness
Social Factors
Lower household income
Lower educational
achievement
Treatment Factors
Hematopoietic Cell Transplant
Medical Conditions
Chronic pain

(CONT)
HighestRisk Factors
Host Factors
CNS tumor
CNS-directed therapy
Premorbid learning or
emotional difficulties
Perceived poor physicalhealthSocial Factors
Failure to graduate from highschoolPeriodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Psychosocial assessment with attention
to:-- Depression-- Anxiety-- Post-traumatic stress-- Suicidal ideation
YearlyEmotional Issues

Resources‘Childhood Cancer Survivors’ by Nancy Keene, Wendy Hobbie &Kathy Ruccione, Childhood Cancer Guides, 2012

Considerations for Further Testing and Intervention
Consider psychological consultation in patients with emotionaldifficulties related to cancer experience, including physicaldeformities or chronic disabilities. Consider appropriate
psychotropic medications. Consider evaluation of parent for
post-traumatic stress syndrome

SYSTEM = Psychosocial
SCORE = 2A

SECTION 2 REFERENCES
Hobbie Wl, Stuber M, Meeske K, et al. Symptoms of posttraumatic stress in young adult survivors of childhood cancer. J Clin Oncol. Dec 15 2000;18(24):4060-4066
Kazak AE, Derosa BW, Schwartz LA, et al. Psychological outcomes and health beliefs in adolescent and young adult survivors of childhood cancer and controls. J Clin Oncol Apr 20 2010;28(12):2002-2007.
Michel G, Rebholz CE, von der Weid NX, Bergstraesser E, Kuehni CE. Psychological distress in adult survivors of childhood cancer: the Swiss Childhood Cancer Survivor study. J Clin Oncol Apr 1 2010;28(10):1740-1748.
Recklitis CJ, Diller LR, Li X, Najita J, Robison LL, Zeltzer L. Suicide ideation in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol Feb 1 2010;28(4):655-661.
Ross L, Johansen C, Dalton SO, et al. Psychiatric hospitalizations among survivors of cancer in childhood or adolescence. N Engl J Med. Aug 14 2003;349(7):650-657.
Santacroce SJ. Parental uncertainty and posttraumatic stress in serious childhood illness. J Nurs Scholarsh. 2003:35(1):45-51.
Schrag NM et al. Stress-related mental disorders in childhood cancer survivors. Pediatr Blood Cancer. 2008; 50:98-103.
Schultz KA et al. Behavioral and social outcomes in adolescent survivors of childhood cancer. J Clin Oncol 2007;20;25(24):3649-56.
Stuber ML, Meeske KA, Krull KR, et al. Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer. Pediatrics. May 2010;125(5):e1124-1134.
von Essen L, Enskar K, Kreuger A, Larsson B, Sjoden PO. Self-esteem, depression, and anxiety among Swedish children and adolescents on and off cancer treatment. Acta Paediatr. Feb 2000;89(2):229-236.
Zeltzer LK, Recklitis C, Buchbinder D, et al. Psychological status in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Clin Oncol May 10 2009;27(14):2396-2404.

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ANY CANCER EXPERIENCE
Sec#
3

Therapeutic
Agent(s)Any Cancer Experience

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

Risk
Factors
Social Factors
Lower household income(CONT)
HighestRisk Factors
Host Factors
Older age at diagnosis
Social Factors
Lower educational
achievement

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Psychosocial assessment
YearlyEmotional Issues

Resources‘Childhood Cancer Survivors’ by Nancy Keene, Wendy Hobbie &Kathy Ruccione, Childhood Cancer Guides, 2012
See also: www.cancer.gov (‘Facing Forward’ series forsurvivors; smoking cessation information); www.cancer.org(smoking cessation)

SYSTEM = Psychosocial
SCORE = 2A

SECTION 3 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.
Sep 15 2009;115(18 Suppl):4374-4384.
Emmons K, Li FP, Whitton J, et al. Predictors of smoking initiation and cessation among childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. Mar 15 2002:20(6):1608-1616.
and risk factors among childhood cancer survivors compared to siblings and general population peers. Addiction. 2008;103(7):1139-48.
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. May 2010;19(5):11741184.
Kahalley LS, Robinson LA, Tyc VL, et al. Attentional and executive dysfunction as predictors of smoking within the Childhood Cancer Survivor Study cohort. Nicotine Tob Res. Apr 2010;12(4):344-354.
Klosky JL, Tyc VL, Hum A, et al. Establishing the predictive validity of intentions to smoke among preadolescents and adolescents surviving cancer. J Clin Oncol Jan 20 2010;28(3):431-436.
Krull KR, Huang S, Gurney JG, et al. Adolescent behavior and adult health status in childhood cancer survivors. J Cancer Surviv. Sep 2010;4(3):210-217.
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. 2008;103(7):1139-48.
Rabin C. Review of health behaviors and their correlates among young adult cancer survivors. J Behav. Med. Feb 2011;34(1):41-52.
Schultz KA, Chen L, Chen Z, Zeltzer LK, Nicholson HS, Neglia JP. Health and risk behaviors in survivors of childhood acute myeloid leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. Jul 15
2010;55(1):157-164.
Sundberg KK, Lampic C, Arvidson J, Helstrom L, Wettergren L. Sexual function and experience among long-term survivors of childhood cancer. Eur. J. Cancer. Feb 2011;47(3):397-403.
Thompson AL, Gerhardt CA, Miller KS, Vannatta K, Noll RB. Survivors of childhood cancer and comparison peers: the influence of peer factors on later externalizing behavior in emerging adulthood. J Pediatr Psychol. Nov-Dec
2009;34(10):1119-1128.

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ANY CANCER EXPERIENCE
Sec#
4Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

Any Cancer Experience

Psychosocial disability due
to pain

Treatment Factors
Amputation
Radiation to bone/joint
Limb-sparing surgery
Vincristine exposure
Medical Conditions
Osteonecrosis(CONT)
HighestRisk Factors
Host Factors
CNS tumor
Hodgkin lymphoma

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Psychosocial assessment
YearlyChronic Pain after Childhood Cancer

Resources‘Childhood Cancer Survivors’ by Nancy Keene, Wendy Hobbie &Kathy Ruccione, Childhood Cancer Guides, 2012
See also: www.nccn.org (chronic pain)

Considerations for Further Testing and Intervention
Consider psychological consultation in patients with emotionaldifficulties related to cancer experience, including physicaldeformities or chronic disabilities. Consider appropriate
psychotropic medications. Consider referral to pain rehabilitation
clinic.

SYSTEM = Psychosocial
SCORE = 2A

SECTION 4 REFERENCES
Banks S, Kerns R. Explaining high rates of depression in chronic pain: a diathesis-stress framework. Psychol Bull. 1996;119:95-110.
Chapman CR, Gavrin J. Suffering: the contributions of persistent pain. Lancet. Jun 26 1999;353(9171):2233-2237.
Coghill RC, McHaffie JG, Yen YF. Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci U S A. Jul 8 2003;100(14):8538-8542.
Coghill RC, Sang CN, Maisog JM, Iadarola MJ. Pain intensity processing within the human brain: a bilateral, distributed mechanism. J Neurophysiol. Oct 1999;82(4):1934-1943.
Fernandez E, Turk DC. The utility of cognitive coping strategies for altering pain perception: a meta-analysis. Pain. Aug 1989;38(2):123-125.
Holzberg AD, Robinson ME, Geisser ME, Gremillion HA. The effects of depression and chronic pain on psychosocial and physical functioning. Clin J Pain. Jun 1996;12(2):118-125.
Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. NIH Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of Chronic Pain
and Insomnia. JAMA. Jul 24-31 1996;276(4):313-318.
Keefe FJ, Rumble ME, Scipio CD, Giordano LA, Perri LM. Psychological aspects of persistent pain: current state of the science. J Pain. May 2004;5(4):195-211.
Thomas EM, Weiss SM. Nonpharmacological interventions with chronic cancer pain in adults. Cancer Control. Mar-Apr 2000;7(2):157-164.
Zaza C, Reyno L, Moulin DE. The multidimensional pain inventory profiles in patients with chronic cancer-related pain: an examination of generalizability. Pain. Jul 2000;87(1):75-82.

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ANY CANCER EXPERIENCE
Sec#
5Therapeutic
Agent(s)Any Cancer Experience

Potential Late
Effects
Fatigue
Info Link
Risk of sleep disturbanceis increased for patientswith CNS tumors andcraniopharyngiomas.

Risk
Factors
Host Factors
Female sex
Depression
Obesity
Central CNS tumor (e.g.,craniopharyngioma)
Social Factors
Unemployment
Medical Conditions
Sleep disturbance(CONT)
HighestRisk Factors
Host Factors
Pulmonary radiation

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Resources

Psychosocial assessment
Yearly‘Childhood Cancer Survivors’ by Nancy Keene, Wendy Hobbie &Kathy Ruccione, Childhood Cancer Guides, 2012
See also: www.cancer.gov (‘Facing Forward’ series forsurvivors)

Considerations for Further Testing and Intervention
Screen for physical sources of fatigue, such as anemia,
sleep disturbances, nutritional deficiencies, cardiomyopathy,
pulmonary fibrosis, hypothyroidism, or other endocrinopathy.

SYSTEM = Psychosocial
SCORE = 2A

SECTION 5 REFERENCES
Cella D, Davis K, Breitbart W, Curt G. Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol. Jul 15 2001;19(14):3385-3391.
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. Nov 2009;36(6):723-731.
Jacobsen PB. Assessment of fatigue in cancer patients. J Natl Cancer Inst Monogr. 2004(32):93-97.
Knobel H, Havard Loge J, Brit Lund M, Forfang K, Nome O, Kaasa S. Late medical complications and fatigue in Hodgkin’s disease survivors. J Clin Oncol. Jul 1 2001;19(13):3226-3233
Lawrence DP, Kupelnick B, Miller K, Devine D, Lau J. Evidence report on the occurrence, assessment, and treatment of fatigue in cancer patients. J Natl Cancer Inst Monogr. 2004(32):40-50
Mulrooney DA, Ness KK, Neglia JP, et al. Fatigue and sleep disturbance in adult survivors of childhood cancer. Sleep. 2008; 31(2) 271-281.
Rosen G, Brand SR. Sleep in children with cancer: case review of 70 children evaluated in a comprehensive pediatric sleep center. Support Care Cancer. Jul 2011;19(7):985-994.

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Sec#
6Therapeutic
Agent(s)Potential Late
Effects

Any Cancer Experience

Limitations in healthcare
and insurance access

Risk
Factors
Social Factors
Lower household income
Lower educational
achievement
Unemployment(CONT)
HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Psychosocial assessment with attention
to healthcare and insurance accessYearlyFinding and Paying for Healthcare

Considerations for Further Testing and Intervention
Social work consultation

SYSTEM = Psychosocial
SCORE = 2A

SECTION 6 REFERENCES
Langeveld NE, Stam H, Grootenhuis MA, et al: Quality of life in young adult survivors of childhood cancer. Support Care Cancer 2002;Nov; 10(8): 579-600.
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. Jan-Feb 2004;2(1):61-70.
Park ER, Li FP, Liu Y, et al. Health insurance coverage in survivors of childhood cancer: the Childhood Cancer Survivor Study. J Clin Oncol. Dec 20 2005;23(36):9187-9197.

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BLOOD/SERUM PRODUCTS
Sec#
7

Therapeutic
Agent(s)Diagnosed prior to 1972

Potential Late
Effects
Chronic hepatitis B

Info Link• Exposure to blood/serum
products prior to initiationof hepatitis B screening ofblood supply (1972 in the
United States—dates may
differ in other countries)
is associated with risk ofchronic hepatitis B.
• Since the vast majority ofpatients received some typeof blood product duringchildhood cancer treatment,
screening based on dateof diagnosis/treatment isrecommended unless there
is absolute certainty that thepatient 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, andallogeneic marrow, cord
blood, or stem cells.

Risk
Factors

HighestRisk Factors

Host Factors
Living in hyperendemic area

Host Factors
Chronic immunosuppression

Treatment Factors
Blood products before 1972
Health Behaviors
IV drug use
Unprotected sex
Multiple partners
High-risk sexual behavior
Sexually transmitted diseases
Tattoos
Body piercing

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Hepatitis B surface antigen (HBsAg)
Hepatitis B core antibody (anti HBc or
HBcAb)
Once in patients who received treatment forcancer prior to 1972.

Hepatitis

Note: Date may vary for international
patients.

Considerations for Further Testing and Intervention
Gastroenterology or hepatology consultation for patients withchronic hepatitis. Hepatitis A immunization in patients lacking
immunity.

SYSTEM = Immune
SCORE = 1

SECTION 7 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. May 2010;54(5):663-669.
Cheah PL, Looi LM, Lin HP, Yap SF. A case of childhood hepatitis B virus infection related primary hepatocellular carcinoma with short malignant transformation time. Pathology. Jan 1991;23(1):66-68.
Dodd RY. The risk of transfusion-transmitted infection. N Engl J Med. Aug 6 1992;327(6):419-421.
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.
1985;13(4):203-206.
Willers E, Webber L, Delport R, Kruger M. Hepatitis B--a major threat to childhood survivors of leukaemia/lymphoma. J Trop Pediatr. Aug 2001;47(4):220-225.

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BLOOD/SERUM PRODUCTS
Sec#
8Therapeutic
Agent(s)Diagnosed prior to 1993

Potential Late
Effects
Chronic hepatitis C

Info Link• Exposure to blood/serum
products prior to initiationof Hepatitis C screening ofblood supply (1993 in the
United States, considering
more reliable EIA generation
2 released in the UnitedStates in 1992—dates may
differ in other countries)
is associated with risk ofchronic hepatitis C.
• Since the vast majority ofpatients received some typeof blood product duringchildhood cancer treatment,
screening based on dateof diagnosis/treatment isrecommended unless there
is absolute certainty that thepatient 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, andallogeneic marrow, cord
blood, or stem cells.

(cont)

Risk
Factors

HighestRisk Factors

Host Factors
Living in hyperendemic area

Host Factors
Chronic immunosuppression

Treatment Factors
Blood products before 1993

Treatment Factors
Blood products prior to 1986
(when surrogate screeningof blood donors with ALT
was initiated and donors
with self-reported high-risk
behaviors were deferred)

Health Behaviors
IV drug use
Unprotected sex
Multiple partners
High-risk sexual behavior
Sexually transmitted diseases
Tattoos
Body piercing

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Hepatitis C antibody
Once in patients who received treatment forcancer prior to 1993.

Hepatitis

Note: Date may vary for international
patients.

Screen for viral hepatitis in patients with persistently abnormalliver function regardless of transfusion history. Consider HCV
PCR screening in transfused at-risk HCV-antibody negative
patients with abnormal liver function and/ or persistentimmunosuppression (e.g., HCT recipients with chronic GVHD).
Gastroenterology or hepatology consultation for management ofpatients with chronic hepatitis. Hepatitis A and B immunizationin patients lacking immunity.

Hepatitis C PCR (to establish chronic
infection)
Once in patients with positive Hepatitis C
antibody.

Considerations for Further Testing and Intervention

SYSTEM = Immune
SCORE = 1

SECTION 8 REFERENCES
Arico M, Maggiore G, Silini E, et al. Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood. Nov 1 1994;84(9):2919-2922.
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. Apr 1
2004;103(7):2460-2466.
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. May 2010;54(5):663-669.
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. Jul 15 2010;55(1):108-11
Fink FM, Hocker-Schulz S, Mor W, et al. Association of hepatitis C virus infection with chronic liver disease in paediatric cancer patients. Eur J Pediatr. Jun 1993;152(6):490-492.
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. Feb 15 2010;116(4):974-982.
Locasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood. Dec 1 1997;90(11):4628-4633.
Ohata K, Hamasaki K, Toriyama K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer. Jun 15 2003;97(12):3036-3043.
Paul IM, Sanders J, Ruggiero F, Andrews T, Ungar D, Eyster ME. Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood. Jun 1 1999;93(11):3672-3677.
Peffault de Latour R, Levy V, Asselah T, et al. Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood. Mar 1 2004;103(5):1618-1624.
Strasser SI, Sullivan KM, Myerson D, et al. Cirrhosis of the liver in long-term marrow transplant survivors. Blood. May 15 1999;93(10):3259-3266.
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Sec#

Therapeutic
Agent(s)9Diagnosed between 1977
and 1985

Potential Late
Effects
HIV infection

Info Link• Exposure to blood/serum
products prior to initiationof HIV screening of blood
supply (between 1977 and1985 in the United States—
dates may differ in othercountries) is associated withrisk of HIV infection.
• Since the vast majority ofpatients received some typeof blood product duringchildhood cancer treatment,
screening based on dateof diagnosis/treatment isrecommended unless there
is absolute certainty that thepatient 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, andallogeneic marrow, cord
blood, or stem cells.

Risk
Factors
Treatment Factors
Blood products between 1977
and 1985
Medical Conditions
HPV infection
Health Behaviors
IV drug use
Unprotected sex
Multiple partners
High-risk sexual behavior
Sexually transmitted diseases
Tattoos
Body piercing(cont)
HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Counseling

HIV testingOnce in patients who received treatment forcancer between 1977 and 1985.

Standard counseling regarding safe sex, universal precautions
and high-risk behaviors that exacerbate risk

Note: Date may vary for international
patients.

Considerations for Further Testing and Intervention
HIV/infectious diseases specialist consultation for patients withchronic infection.

SYSTEM = Immune
SCORE = 1

SECTION 9 REFERENCES
Busch MP, Kleinman SH, Nemo GJ. Current and emerging infectious risks of blood transfusions. JAMA. Feb 26 2003;289(8):959-962.
Lackritz EM, Satten GA, Aberle-Grasse J, et al. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med. Dec 28 1995;333(26):1721-1725.
Samson S, Busch M, Ward J, et al. Identification of HIV-infected transfusion recipients: the utility of crossreferencing previous donor records with AIDS case reports. Transfusion. Mar-Apr 1990;30(3):214-218.
Stramer SL. Current risks of transfusion-transmitted agents: a review. Arch Pathol Lab. Med. May 2007;131(5):702-707.

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#
10

Therapeutic
Agent(s)Any Chemotherapy

Potential Late
Effects
Dental abnormalities
Tooth/root agenesis
Root thinning/shortening
Enamel dysplasia
Microdontia

ANY CHEMOTHERAPY
Risk
Factors
Host Factors
Any patient who had not
developed permanentdentition at time of cancer
therapy
Treatment Factors
Any radiation treatment
involving the oral cavity orsalivary glands

HighestRisk Factors
Host Factors
Younger age at treatment,
especially < 5 years old

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Dry mouthYearlyDental Health

PHYSICAL
Oral exam
YearlyRegular dental care including fluoride applications. Baseline
panorex prior to dental procedures to evaluate root development.

SCREENING
Dental exam and cleaning
Every 6 months

Considerations for Further Testing and Intervention

SYSTEM = Dental
SCORE = 1

SECTION 10 REFERENCES
Duggal MS, Curzon ME, Bailey CC, Lewis IJ, Prendergast M. Dental parameters in the long-term survivors of childhood cancer compared with siblings. Oral Oncol. Sep 1997;33(5):348-353.
Goho C. Chemoradiation therapy: effect on dental development. Pediatr Dent. Jan-Feb 1993;15(1):6-12.
Hsieh SG, Hibbert S, Shaw P, Ahern V, Arora M. Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy. Cancer. May 15
2011;117(10):2219-2227.
Kaste SC, Hopkins KP, Bowman LC, Santana VM. Dental abnormalities in children treated for neuroblastoma. Med Pediatr Oncol. Jan 1998;30(1):22-27.
Kaste SC, Hopkins KP, Bowman LC. Dental abnormalities in long-term survivors of head and neck rhabdomyosarcoma. Med Pediatr Oncol. Aug 1995;25(2):96-101.
Kaste SC, Hopkins KP, Jones D, Crom D, Greenwald CA, Santana VM. Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia. Jun 1997;11(6):792-796.
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. Dec 15 2009
115(24):5817-5827.
Maguire A, Welbury RR. Long-term effects of antineoplastic chemotherapy and radiotherapy on dental development. Dent Update. Jun 1996;23(5):188-194.
Nasman M, Forsberg CM, Dahllof G. Long-term dental development in children after treatment for malignant disease. Eur J Orthod. Apr 1997;19(2):151-159.
Raney RB, Asmar L, Vassilopoulou-Sellin R, et al. Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma
Studies (IRS)-II and - III. IRS Group of the Children’s Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol. Oct 1999;33(4):362-371.
Sonis AL, Tarbell N, Valachovic RW, Gelber R, Schwenn M, Sallan S. Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities. Cancer. Dec 15
1990;66(12):2645-2652.
Wogelius P, Rosthoj S, Dahllof G, Poulsen S. Oral health-related quality of life among survivors of childhood cancer. Int J Paediatr Dent. Nov 2011;21(6):465-467.

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#
11

(male)

Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa

Potential Late
Effects
Gonadal dysfunction(testicular)
Reduced fertility
Oligospermia
Azoospermia
Infertility

HEAVY METALS
Carboplatin
Cisplatin
NON-CLASSICAL
ALKYLATORS
Dacarbazine (DTIC)
Temozolomide

ALKYLATING AGENTS
Risk
Factors

HighestRisk Factors

Host Factors
Testicular cancer
ObesityEjaculatory dysfunction
Medications
Occupational exposures(pesticides, heavy metals,
solvents)

Treatment Factors
MOPP ≥ 3 cycles
Busulfan ≥ 600 mg/m2
Cyclophosphamide cumulative
dose ≥ 7.5 gm/m2 or as
conditioning for HCT
Ifosfamide ≥ 60 gm/m2
Any alkylators combined with:-- testicular radiation-- pelvic radiation-- TBI

Treatment Factors
Higher cumulative doses ofalkylators or combinationsof alkylators
Combined with radiation to:-- abdomen/pelvis-- testes-- brain, cranium (neuroendocrine axis)-- Genitourinary surgery
Health Behaviors
Tobacco/marijuana use
History of sexually transmitted
diseases
Info Link• Doses that cause gonadal
dysfunction show individual
variation.
• Germ cell function (spermatogenesis) is impaired
at lower doses comparedto Leydig cell (testosterone
production) function.
• Prepubertal status does notprotect from gonadal injury
in males.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyMale Health Issues

PHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchiometer
YearlySCREENING
Semen analysis
At request of sexually mature patient
Periodic evaluation over time isrecommended as resumption of
spermatogenesis can occur up to 10
years post therapy
FSH
In sexually mature patient if unable toobtain semen analysis

Resources
Extensive information regarding infertility for patients andhealthcare professionals is available on the following websites:
American Society for Reproductive Medicine (www.asrm.org );Fertile Hope (www.fertilehope.org )CounselingCounsel regarding the need for contraception, since thereis tremendous individual variability in gonadal toxicity after
exposure to alkylating agents. Recovery of fertility may occur
years after therapy.

Considerations for Further Testing and Intervention
Reproductive endocrinology/urology referral for infertility
evaluation and consultation regarding assisted reproductive
technologies.

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

SECTION 11 REFERENCES
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. Jun 1984;2(6):571-577.
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. Jan 10 2010;28(2):332-339.
Howell SJ, Shalet SM. Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr. 2005(34):12-17.
Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer. Feb 1 2001;91(3):613-621.
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. Sep 20 2012;30(27):3408-3416.
Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol Jun 20 2006;24(18):2917-2931.
Tromp K, Claessens JJ, Knijnenburg SL, et al. Reproductive status in adult male long-term survivors of childhood cancer. Hum Reprod. Jul 2011;26(7):1775-1783.
Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatr Blood Cancer. Feb 2008;50(2):347-351.
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#
12

(male)

Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa

Potential Late
Effects
Gonadal dysfunction(testicular)
Testosterone deficiency/
insufficiency
Delayed/arrested puberty

HEAVY METALS
Carboplatin
Cisplatin
NON-CLASSICAL
ALKYLATORS
Dacarbazine (DTIC)
Temozolomide

ALKYLATING AGENTS (cont)
Risk
Factors
Host Factors
Testicular cancer
Aging
Treatment Factors
Higher cumulative doses ofalkylators or combinationsof alkylators
Combined with radiation to:-- Abdomen/pelvis-- Testes-- Brain, cranium (neuroendocrine axis)
Unilateral orchiectomy
Health Behaviors
Smoking
Info Link• Doses that cause gonadal
dysfunction show individual
variation.
• Germ cell function (spermatogenesis) is impaired
at lower doses comparedto Leydig cell (testosterone
production) function.
• Prepubertal status does notprotect from gonadal injury
in males.

HighestRisk Factors
Treatment Factors
MOPP
Cyclophosphamide cumulative
dose ≥ 20 gm/m2
Conditioning for HCT;
Ifosfamide ≥ 60 gm/m2
Any alkylators combined with-- Testicular radiation-- Pelvic radiation-- Neuroaxis radiation

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyMale Health Issues

PHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchiometer
YearlySCREENING
Testosterone (ideally morning)
Baseline at age 14 AND as clinicallyindicated in patients with delayed orarrested puberty and/or clinical signs andsymptoms of testosterone deficiency

Considerations for Further Testing and Intervention
Bone density evaluation in hypogonadal patients. Refer toendocrinology/urology for delayed puberty, persistently abnormal
hormone levels or hormonal replacement for hypogonadal
patients. Males with low normal testosterone should haveperiodic re-evaluation of testosterone as they age or if they
become symptomatic. Testosterone insufficiency requiringhormone replacement therapy is rare after treatment wth
alkylating agents only.

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

SECTION 12 REFERENCES
Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer. Feb 1 2001;91(3):613-621.
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. Sep 20 2012;30(27):3408-3416.
Ridola V, Fawaz O, Aubier F, et al. Testicular function of survivors of childhood cancer: a comparative study between ifosfamide- and cyclophosphamide-based regimens. Eur J Cancer. Mar 2009;45(5):814-818.
Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatr Blood Cancer. Feb 2008;50(2):347-351.

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#
13

Therapeutic
Agent(s)(female)ALKYLATING AGENTS
Busulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa

Potential Late
Effects
Gonadal dysfunction(ovarian)
Delayed/arrested pubertyPremature menopause
Infertility

HEAVY METALS
Carboplatin
Cisplatin
NON-CLASSICAL
ALKYLATORS
Dacarbazine (DTIC)
Temozolomide

ALKYLATING AGENTS (cont)
Risk
Factors

HighestRisk Factors

Treatment Factors
Higher cumulative doses ofalkylators or combinationsof alkylators
Combined with radiation to:-- Abdomen/pelvis-- Lumbar or sacral spine(from ovarian scatter)-- Brain, cranium (neuroendocrine axis)

Treatment Factors
Any alkylators combined with:-- pelvic radiation-- TBI
Host Factors
Older age at treatment

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Pubertal (onset, tempo), menstrual,
pregnancy history
Sexual function (vaginal dryness, libido)
Medication use
YearlyFemale Health Issues

PHYSICAL
Tanner staging
Yearly until sexually mature

Health Behaviors
Smoking

SCREENING

Info Link• Doses that cause gonadal
dysfunction show individual
variation.
• Females can typicallymaintain gonadal function
at higher cumulative doses
than males.

FSH
LH
Estradiol
Baseline at age 13 AND as clinicallyindicated in patients with delayed orarrested puberty, irregular menses,
primary or secondary amenorrhea, and/or
clinical signs and symptoms of estrogen
deficiency

Resources
Extensive information regarding infertility for patients andhealthcare professionals is available on the following websites:
American Society for Reproductive Medicine (www.asrm.org );Fertile Hope (www.fertilehope.org )CounselingCounsel currently menstruating women at increased risk of earlymenopause to be cautious about delaying childbearing. Counsel
regarding the need for contraception, since there is tremendous
individual variability in gonadal toxicity after exposure toalkylating agents. Recovery of fertility may occur years after
therapy.

Considerations for Further Testing and Intervention
Bone density evaluation in hypogonadal patients. Refer toendocrinology/gynecology for delayed puberty, persistently
abnormal hormone levels or hormonal replacement for
hypogonadal patients. Reproductive endocrinology referral
for infertility evaluation and consultation regarding assisted
reproductive technologies

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

SECTION 13 REFERENCES
Afify Z, Shaw PJ, Clavano-Harding A, Cowell CT. Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. Bone Marrow Transplant. May
2000;25(10):1087-1092.
Bath LE, Wallace WH, Critchley HO. Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. BJOG. Feb 2002;109(2):107-114.
Byrne J, Fears TR, Gail MH, et al. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol. Mar 1992;166(3):788-793.
Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. May 2006;91(5):1723-1728.
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. Jun 1 2009 27(16):2677-2685.
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.
Mar 20 2013;31(9):1239-1247.
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Therapeutic
Agent(s)Potential Late
Effects

ALKYLATING AGENTS (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 13 REFERENCES–CONTINUED
Muller J. Disturbance of pubertal development after cancer treatment. Best Pract Res Clin Endocrinol Metab. Mar 2002;16(1):91-103.
Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. Jul 1999;33(1):2-8.
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. Jul 5 2006;98(13):890-896.

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14

Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Ifosfamide
Lomustine (CCNU)
Mechlorethamine
Melphalan
Procarbazine
Thiotepa

Potential Late
Effects
Acute myeloid leukemia
Myelodysplasia

HEAVY METALS
Carboplatin
Cisplatin
NON-CLASSICAL
ALKYLATORS
Dacarbazine (DTIC)
Temozolomide

ALKYLATING AGENTS (cont)
Risk
Factors
Treatment Factors
Less than 10 years since
exposure to agent
Higher cumulative alkylator
dose or combination ofalkylators
Note: Melphalan andmechlorethamine are morepotent leukemogens thancyclophosphamide
Medical Conditions
Splenectomy (conflicting
evidence)

HighestRisk Factors
Treatment Factors
Autologous HCT

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

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

Reducing the Risk of Second Cancers
CounselingCounsel to promptly report fatigue, pallor, petechiae or bone
pain.

PHYSICAL

Counseling

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

CBC and bone marrow exam as clinically indicated .

SYSTEM = SMNSCORE =
Alkylating Agents = 1
Heavy Metals = 2A
Non-Classical Alkylators = 2A

SECTION 14 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
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. Jan 1
2007;109(1):46-51.
Cheruku R, Hussain M, Tyrkus M, Edelstein M. Myelodysplastic syndrome after cisplatin therapy. Cancer. Jul 1 1993;72(1):213-218.
Forrest DL, Nevill TJ, Naiman SC, et al. Second malignancy following high-dose therapy and autologous stem cell transplantation: incidence and risk factor analysis. Bone Marrow Transplant. Nov 2003;32(9):915-923.
Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin. Oncol. Aug 2008;35(4):418-429.
Greene MH, Harris EL, Gershenson DM, et al. Melphalan may be a more potent leukemogen than cyclophosphamide. Ann Intern Med. Sep 1986;105(3):360-367.
Hosing C, Munsell M, Yazji S, et al. Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. Ann Oncol. Mar
2002;13(3):450-459.
Howe R, Micallef IN, Inwards DJ, et al. Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma. Bone Marrow Transplant. Aug 2003;32(3):317-324.
Rihani R, Bazzeh F, Faqih N, Sultan I. Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer. Sep 15
2010;116(18):4385-4394.
Schellong G, Riepenhausen M, Creutzig U, et al. Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin’s disease. German-Austrian Pediatric Hodgkin’s Disease Group. J Clin Oncol.
Jun 1997;15(6):2247-2253.
Schneider DT, Hilgenfeld E, Schwabe D, et al. Acute myelogenous leukemia after treatment for malignant germ cell tumors in children. J Clin Oncol. Oct 1999;17(10):3226-3233.

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Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan
Carmustine (BCNU)
Lomustine (CCNU)

Potential Late
Effects
Pulmonary fibrosis

ALKYLATING AGENTS (cont)
Risk
Factors
Treatment Factors
Higher cumulative doses
Combined with bleomycin
Medical Conditions
Atopic history
Health Behaviors
SmokingInhaled illicit drug use

HighestRisk Factors
Treatment Factors
BCNU ≥ 600 mg/m2
Busulfan ≥ 500 mg (transplant
doses)
Combined with:-- Chest radiation-- TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Cough
SOB
DOE
Wheezing
YearlyPulmonary Health

PHYSICALSCREENING

CounselingCounsel regarding tobacco avoidance/smoking cessation. Dueto the potential pulmonary toxicity of this therapy, patients
who desire to SCUBA dive should be advised to obtain medical
clearance from a pulmonologist.

PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patientswith abnormal results or progressive
pulmonary dysfunction.

Considerations for Further Testing and Intervention
In patients with abnormal PFTs, consider repeat evaluation prior
to general anesthesia. Pulmonary consultation for symptomatic
pulmonary dysfunction. Influenza and pneumococcal vaccines.

Pulmonary exam
YearlyResources
Extensive information regarding smoking cessation is available
for patients on the NCI’s website: www.smokefree.gov

SYSTEM = Pulmonary
SCORE = 1

SECTION 15 REFERENCES
Huang TT, Hudson MM, Stokes DC, Krasin MJ, Spunt SL, Ness KK. Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest. Oct 2011;140(4):881-901.
Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol. Oct 1992;19(5):508-520.
Liles A, Blatt J, Morris D, et al. Monitoring pulmonary complications in long-term childhood cancer survivors: guidelines for the primary care physician. Cleve Clin J. Med. Jul 2008;75(7):531-539.
Lohani S, O’Driscoll BR, Woodcock AA. 25-year study of lung fibrosis following carmustine therapy for brain tumor in childhood. Chest. Sep 2004;126(3):1007.
Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. Jul 10 2006;166(13):1359-1367.
O’Driscoll BR, Hasleton PS, Taylor PM, Poulter LW, Gattameneni HR, Woodcock AA. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med. Aug 9 1990;323(6):378-382.
Stolp B, Assistant Medical Director Divers Alert Network, Director Anesthesiology Emergency Airway Services, Durham, N.C. Risks associated with SCUBA diving in childhood cancer survivors. Personal communication to LandierW, Bhatia S Aug 23, 2002.
Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. Feb 12 2007;167(3):221-228.
Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. Mar 2004;25(1):203-216.

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Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan

Potential Late
Effects
Cataracts

ALKYLATING AGENTS (cont)
Risk
Factors
Treatment Factors
Combined with corticosteroids

HighestRisk Factors

Periodic
Evaluation

Treatment Factors
HISTORY
Combined with cranial, orbital, Visual changes (decreased acuity, halos,or eye radiation
diplopia)
TBI
YearlyLonger interval sincetreatment
PHYSICAL
Eye exam (visual acuity, funduscopic
exam for lens opacity)
YearlyHealth Counseling/
Further Considerations
Health Links
Cataracts
Considerations for Further Testing and Intervention
Ophthalmology consultation if problem identified. Refer patientswith visual deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate
acquisition of educational resources.

SYSTEM = Ocular
SCORE = 2B

SECTION 16 REFERENCES
Dahlgren S, Holm G, Svanborg N, Watz R. Clinical and morphological side-effects of busulfan (Myleran) treatment. Acta Med Scand. Jul-Aug 1972;192(1-2):129-135.
Holmstrom G, Borgstrom B, Calissendorff B. Cataract in children after bone marrow transplantation: relation to conditioning regimen. Acta Ophthalmol Scand. Apr 2002;80(2):211-215.
Socie G, Clift RA, Blaise D, et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies.
Blood. Dec 15 2001;98(13):3569-3574.

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Therapeutic
Agent(s)ALKYLATING AGENTS
Cyclophosphamide
Ifosfamide

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

ALKYLATING AGENTS (cont)
Risk
Factors

HighestRisk Factors

Treatment Factors
Higher cumulative doses(decreased incidence with
Mesna)
Combined with pelvic
radiation

Treatment Factors
Cyclophosphamide dose ≥ 3
gm/m2
Pelvic radiation dose ≥30 Gy

Health Behaviors
Alcohol use
Smoking

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyBladder HealthCounselingCounsel to promptly report dysuria or gross hematuria.

Considerations for Further Testing and Intervention
For patients with positive history, obtain urinalysis and consider
urine culture, spot urine calcium/creatinine ratio, and ultrasoundof kidneys and bladder for patients with microscopic hematuria(defined as ≥ 5 RBC/HFP 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 culturenegative macroscopic hematuria.

SYSTEM = Urinary
SCORE = 1

SECTION 17 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. Mar-Apr 1999;21(2):115-122.
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. Apr 1992;10(4):614-623.
Jerkins GR, Noe HN, Hill D. Treatment of complications of cyclophosphamide cystitis. J Urol. May 1988;139(5):923-925.
Lima MV, Ferreira FV, Macedo FY, de Castro Brito GA, Ribeiro RA. Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis. Cancer Chemother Pharmacol. Apr
2007;59(5):643-650.
Stillwell TJ, Benson RC, Jr. Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer. Feb 1 1988;61(3):451-457.
Stillwell TJ, Benson RC, Jr., Burgert EO, Jr. Cyclophosphamide-induced hemorrhagic cystitis in Ewing’s sarcoma. J Clin Oncol. Jan 1988;6(1):76-82.

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Therapeutic
Agent(s)ALKYLATING AGENTS
Cyclophosphamide

Potential Late
Effects
Bladder malignancy

ALKYLATING AGENTS (cont)
Risk
Factors
Treatment Factors
Combined with pelvic
radiation
Health Behaviors
Alcohol use
Smoking

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyBladder HealthCounselingCounsel to promptly report dysuria or gross hematuria.

Considerations for Further Testing and Intervention
For patients with positive history, obtain urinalysis and consider
urine culture, spot urine calcium/creatinine ratio, and ultrasoundof kidneys and bladder for patients with microscopic hematuria(defined as > 5 RBC/HFP 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 culturenegative macroscopic hematuria.

SYSTEM = SMNSCORE = 2A

SECTION 18 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. Oct 5 2010;153(7):461-468.
Kersun LS, Wimmer RS, Hoot AC, Meadows AT. Secondary malignant neoplasms of the bladder after cyclophosphamide treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer. Mar 2004; 42(3):289-291.
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. Apr 21 1988;318(16):1028-1032.
Ritchey M, Ferrer F, Shearer P, Spunt SL. Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Children’s Oncology Group. Pediatr Blood Cancer. Apr 2009 52(4):439-446.
Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst. Apr 5 1995;87(7):524-530.

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Therapeutic
Agent(s)ALKYLATING AGENTS
Ifosfamide

Potential Late
Effects
Renal toxicity
Glomerular injury
Hypertension
Tubular injury (renal
tubular acidosis,
Fanconi’s syndrome,
hypophosphatemic rickets)
Info Link
Ifosfamide-related renal
toxicity typically occurs during
the acute treatment phaseand improves or progresses
over time

ALKYLATING AGENTS (cont)
Risk
Factors

HighestRisk Factors

Host Factors
Younger age at treatment
MononephricHost Factors
Age < 4 years at time oftreatment

Treatment Factors
Higher cumulative dose
Combined with othernephrotoxic agents such as:-- Cisplatin-- Carboplatin-- Aminoglycosides Amphotericin-- ImmunosuppressantsMethotrexate-- Radiation impacting thekidneyTreatment Factors
Ifosfamide dose ≥ 60
grams/m2
Renal radiation dose ≥ 15 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Blood pressure
YearlyKidney Health
Cardiovascular Risk Factors

SCREENING

Considerations for Further Testing and Intervention

BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedElectrolyte supplements for patients with persistent electrolyte
wasting. Nephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency

Urinalysis
YearlySYSTEM = Urinary
SCORE = 1

Medical Conditions
Tumor infiltration of kidney(s)Pre-existing renal impairment
Nephrectomy

SECTION 19 REFERENCES
Arndt C, Morgenstern B, Hawkins D, Wilson D, Liedtke R, Miser J. Renal function following combination chemotherapy with ifosfamide and cisplatin in patients with osteogenic sarcoma. Med Pediatr Oncol. Feb 1999;32(2):93-96.
Burk CD, Restaino I, Kaplan BS, Meadows AT. Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms tumor. J Pediatr. Aug 1990;117(2 Pt 1):331-335.
Fels LM, Bokemeyer C, van Rhee J, Schmoll HJ, Stolte H. Evaluation of late nephrotoxicity in long-term survivors of Hodgkin’s disease. Oncology. Jan-Feb 1996;53(1):73-78.
Ho PT, Zimmerman K, Wexler LH, et al. A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer. Dec 15 1995;76(12):2557-2564.
Langer T, Stohr W, Bielack S, Paulussen M, Treuner J, Beck JD. Late effects surveillance system for sarcoma patients. Pediatr Blood Cancer. Apr 2004;42(4):373-379.
Loebstein R, Atanackovic G, Bishai R, et al. Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children. J Clin Pharmacol. May 1999;39(5):454-461.
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. Nov 1994;16(4):286-295.
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. May 2000;82(10):16361645.
Skinner R, Sharkey IM, Pearson AD, Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol. Jan 1993;11(1):173-190.
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. Apr 2007;48(4):447-452.

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Therapeutic
Agent(s)20

HEAVY METALS
Carboplatin (myeloablative
doses OR any dose if age at
diagnosis < 1 year)
Cisplatin

Potential Late
Effects
Ototoxicity
Sensorineural hearing loss
Tinnitus
VertigoInfo Link• In general, patients who
received carboplatin innonmyeloablative doses
do not appear to be at risk
for clinically significant
ototoxicity.
• Some studies have observed hearing loss among
infants (with retinoblastoma)
exposed to nonmyeloablative doses of carboplatin.

HEAVY METALS
Risk
Factors

HighestRisk Factors

Host Factors
Age < 4 years at treatment

Host Factors
CNS neoplasm

Treatment Factors
Combined with:-- Cranial/ear radiation-- Ototoxic drugs (e.g.,aminoglycosides, loop
diuretics)

Treatment Factors
Cumulative cisplatin dose
≥ 360 mg/m2
High dose cisplatin (i.e., 40
mg/m2 per day × 5 days percourse)Cisplatin administered AFTER
cranial/ear radiation
Carboplatin conditioning for
HCT
Radiation involving ear≥ 30 Gy

Medical Conditions
Chronic otitis
Cerumen impaction
Renal dysfunction

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Hearing difficulties (with/withoutbackground noise)
Tinnitus
VertigoYearlyHearing Loss
Educational Issues

PHYSICAL
Otoscopic exam
YearlySCREENING
Complete audiological evaluation
Baseline at entry into long-term followup.
If hearing loss is detected, test at least
yearly, or as recommended by audiologist.
If clinical suspicion of hearing loss at
any time, test as clinically indicated. If
audiogram is inconclusive or unevaluable,refer to audiologist for consideration ofelectrophysiologic testing e.g., otoacoustic
emissions [OAEs].

Considerations for Further Testing and Intervention
Audiology consultation for amplification in patients with hearing
loss. Speech and language therapy for children with hearing
loss. Otolaryngology consultation in patients with chronic
infection, cerumen impaction, or other anatomical problems
exacerbating or contributing to hearing loss. Refer patients withauditory deficits to school liaison in community or cancer center(psychologist, social worker, school counselor) to facilitate
provision of educational resources. Consider specific needs and/or preferential classroom seating, FM amplification system, andother educational assistance as indicated.

SYSTEM = Auditory
SCORE = 1

Info Link• A “complete audiological evaluation” includes pure tone air and bone conduction,
speech audiometry, and tympanometry forboth ears.
• Frequency-specific auditory brainstem
response (ABR) can be performed if theabove is inconclusive.

SECTION 20 REFERENCES
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. Oct 2004;26(10):649-655.
Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol. 1991;19(4):295-300.
Cushing B, Giller R, Cullen JW, et al. Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ
cell tumors: a pediatric intergroup study–Pediatric Oncology Group 9049 and Children’s Cancer Group 8882. J Clin Oncol. Jul 1 2004;22(13):2691-2700.
Fouladi M, Gururangan S, Moghrabi A, et al. Carboplatin-based primary chemotherapy for infants and young children with CNS tumors. Cancer. Jul 15 2009 115(14):3243-3253.
Gilmer 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. 2005;Dec
1 23(34):8588-8596.
Gurney JG, Tersak JM, Ness KK, Landier W, Matthay KK, Schmidt ML. Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children’s Oncology Group. Pediatrics. Nov
2007;120(5):e1229-1236.
Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al. Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma. Pediatr Blood Cancer. May
2009 52(5):637-643.
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Therapeutic
Agent(s)Potential Late
Effects

HEAVY METALS (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 20 REFERENCES–continued
Knight KR, Kraemer DF, Winter C, Neuwelt EA. 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. Apr 1 2007;25(10):1190-1195.
Kushner BH, Budnick A, Kramer K et al. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006;Jul 15 107(2):417-22.
Laverdiere C, Cheung N-K V, Kushner BH et al. Long-term complications in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer. 2005. Sept 45(3):324-332.
Parsons SK, Neault MW, Lehmann LE, et al. Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant. Oct 1998;22(7):669-674.
Punnett A, Bliss B, Dupuis LL, Abdolell M, Doyle J, Sung L. Ototoxicity following pediatric hematopoietic stem cell transplantation: a prospective cohort study. Pediatr Blood Cancer. Jun 2004;42(7):598-603.
Qaddoumi I, Bass JK, Wu J, et al. Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol. Apr 1 2012;30(10):1034-1041.
Schell MJ, McHaney VA, Green AA, et al. Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation. J Clin Oncol. Jun 1989;7(6):754-760.

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Therapeutic
Agent(s)HEAVY METALS
Carboplatin
Cisplatin

Potential Late
Effects
Peripheral sensory
neuropathy
Paresthesias
Dysesthesias
Info Link• Acute toxicities mostcommonly occur and usually
improve or resolve prior topatients entering long-term
follow-up.
• Neuropathy can persist after
treatment and is typicallynot late in onset.

HEAVY METALS (cont)
Risk
Factors
Treatment Factors
Combined with:-- Vincristine-- Taxanes-- Gemcitabine

HighestRisk Factors
Treatment Factors
Cumulative cisplatin dose
≥ 300 mg/m2

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Numbness
Tingling
Paresthesias
Dysesthesia
Yearly until 2 to 3 years after therapy,
monitor yearly if symptoms persist

Peripheral Neuropathy

PHYSICAL
Neurologic exam
YearlyConsiderations for Further Testing and Intervention
Physical therapy referral for patients with symptomatic
neuropathy. Physical and occupational therapy assessmentof hand function. Consider treatment with agent effective forneuropathic pain (e.g., gabapentin or amitriptyline).

SYSTEM = PNSSCORE = 2A

SECTION 21 REFERENCES
Bosnjak S, Jelic S, Susnjar S, Luki V. Gabapentin for relief of neuropathic pain related to anticancer treatment: a preliminary study. J Chemother. Apr 2002;14(2):214-219.
Cvitkovic E. Cumulative toxicities from cisplatin therapy and current cytoprotective measures. Cancer Treat Rev. Aug 1998;24(4):265-281.
Hilkens PH, ven den Bent MJ. Chemotherapy-induced peripheral neuropathy. J Peripher Nerv Syst. 1997;2:350-361.
Tuxen MK, Hansen SW. Neurotoxicity secondary to antineoplastic drugs. Cancer Treat Rev. Apr 1994;20(2):191-214.
Verstappen CC, Postma TJ, Hoekman K, Heimans JJ. Peripheral neuropathy due to therapy with paclitaxel, gemcitabine, and cisplatin in patients with advanced ovarian cancer. J Neurooncol. Jun 2003;63(2):201-205.

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Therapeutic
Agent(s)HEAVY METALS
Carboplatin
Cisplatin

Potential Late
Effects
Renal toxicity
Glomerular injury
Hypertension
Tubular injury
Renal insufficiency

HEAVY METALS (cont)
Risk
Factors
Host Factors
MononephricTreatment Factors
Combined with othernephrotoxic agents, such as:-- Aminoglycosides-- Amphotericin-- Immunosuppressants-- Methotrexate-- Radiation impacting thekidneyMedical Conditions
Diabetes mellitus
Hypertension
Nephrectomy

HighestRisk Factors
Treatment Factors
Cisplatin dose ≥ 200 mg/m2
Renal radiation dose ≥ 15 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Blood pressure
YearlyKidney Health
Cardiovascular Risk Factors

SCREENING

Counseling

BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedIn patients with salt-wasting tubular dysfunction, educate that
low magnesium levels potentiate coronary atherosclerosis.

Urinalysis
YearlyConsiderations for Further Testing and Intervention
Electrolyte supplements for patients with persistent electrolyte
wasting. Nephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency.

SYSTEM = Urinary
SCORE = 2A

SECTION 22 REFERENCES
Arndt C, Morgenstern B, Hawkins D, Wilson D, Liedtke R, Miser J. Renal function following combination chemotherapy with ifosfamide and cisplatin in patients with osteogenic sarcoma. Med Pediatr Oncol. Feb 1999;32(2):93-96.
Bianchetti MG, Kanaka C, Ridolfi-Luthy A, Hirt A, Wagner HP, Oetliker OH. Persisting renotubular sequelae after cisplatin in children and adolescents. Am J Nephrol. 1991;11(2):127-130.
Ceremuzynski L, Gebalska J, Wolk R, Makowska E. Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. J Intern Med. Jan 2000;247(1):78-86.
Dentino M, Luft FC, Yum MN, Williams SD, Einhorn LH. Long term effect of cis-diamminedichloride platinum (CDDP) on renal function and structure in man. Cancer. Apr 1978;41(4):1274-1281.
Hutchison FN, Perez EA, Gandara DR, Lawrence HJ, Kaysen GA. Renal salt wasting in patients treated with cisplatin. Ann Intern Med. Jan 1988;108(1):21-25.
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. Sep 1998;136(3):480-490.
Marina NM, Poquette CA, Cain AM, Jones D, Pratt CB, Meyer WH. Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas. J Pediatr Hematol Oncol. Mar-Apr
2000 22(2):112-118.
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. Feb 2007;48(2):140-147.
von der Weid NX, Erni BM, Mamie C, Wagner HP, Bianchetti MG. Cisplatin therapy in childhood: renal follow up 3 years or more after treatment. Swiss Pediatric Oncology Group. Nephrol Dial Transplant. Jun 1999;14(6):14411444.

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Therapeutic
Agent(s)23

ANTIMETABOLITES
Cytarabine (high dose IV)
Info Link
High-dose IV is defined as any
single dose ≥ 1000 mg/m2.

ANTIMETABOLITES

Potential Late
Effects

Risk
Factors

HighestRisk Factors

Neurocognitive deficits
Functional deficits in:-- Executive function (planning and 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

Host Factors
Younger age at treatment
CNS leukemia/lymphoma
Relapsed leukemia/lymphoma
treated with CNS-directed
therapy

Host Factors
Age < 3 years old at time oftreatment
Female sex
Premorbid or family historyof learning or attention
problems

Info Link• Neurocognitive deficits
in survivors of leukemia
and lymphoma are more
frequently related to
information processing (e.g.,learning disability).
• Neurocognitive deficits
in brain tumor survivors
treated with higher doses of
cranial radiation are moreglobal (significant decline
in IQ).
• Extent of deficit depends on
age at treatment, intensityof treatment, and time sincetreatment. New deficits may
emerge over time.

Treatment Factors
In combination with:-- Corticosteroids-- TBI-- Cranial radiation-- Methotrexate (IT, IO, highdose IV)-- Longer elapsed time since
therapy
Info Link• Acute toxicity predominates
if cytarabine is administeredsystemically as a single
agent.
• Cytarabine may contributeto late neurotoxicity if
combined with high doseor intrathecal methotrexate
and/or cranial radiation.

Treatment Factors
Radiation dose ≥ 24 Gy
Single fraction TBI (10 Gy).

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Educational and/or vocational progress
YearlyEducational Issues

SCREENING

Formal neuropsychological evaluation to include tests ofprocessing speed, computer-based attention, visual motor
integration, memory, comprehension of verbal instructions,verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orcancer center (psychologist, social worker, school counselor)
to facilitate acquisition of educational resources and/or social
skills training. Consider use of psychotropic medication (e.g.,
stimulants) or evidence-based rehabilitation training. Caution—
lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended. Refer to community
services for vocational rehabilitation or for services fordevelopmentally disabled.

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

Considerations for Further Testing and Intervention

SYSTEM = CNSSCORE = 2A

SECTION 23 REFERENCES
Baker WJ, Royer GL, Jr., Weiss RB. Cytarabine and neurologic toxicity. J Clin Oncol. Apr 1991;9(4):679-693.
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. Apr 2009 52(4):447-454.
Butler RW, Copeland DR, Fairclough DL, et al. A multicenter, randomized clinical trial of a cognitive remediation program for childhood survivors of a pediatric malignancy. J Consult Clin Psychol. Jun 2008;76(3):367-378.
Hwang TL, Yung WK, Estey EH, Fields WS. Central nervous system toxicity with high-dose Ara-C. Neurology. Oct 1985;35(10):1475-1479.
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. Jun 16 2010;102(12):881-893.
Moleski M. Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol. Oct 2000;15(7):603-630.
Nand S, Messmore HL, Jr., Patel R, Fisher SG, Fisher RI. Neurotoxicity associated with systemic high-dose cytosine arabinoside. J Clin Oncol. Apr 1986;4(4):571-575.
Vaughn DJ, Jarvik JG, Hackney D, Peters S, Stadtmauer EA. High-dose cytarabine neurotoxicity: MR findings during the acute phase. AJNR Am J Neuroradiol. Jul-Aug 1993;14(4):1014-1016.
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Therapeutic
Agent(s)Potential Late
Effects

ANTIMETABOLITES (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 23 REFERENCES (continued)
Vera P, Rohrlich P, Stievenart JL, et al. Contribution of single-photon emission computed tomography in the diagnosis and follow-up of CNS toxicity of a cytarabine-containing regimen in pediatric leukemia. J Clin Oncol. Sep
199917(9):2804-2810.

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Therapeutic
Agent(s)24

ANTIMETABOLITES
Cytarabine (high dose IV)
Info Link
High-dose IV is defined as any
single dose ≥ 1000 mg/m2.

Potential Late
Effects
Clinicalleukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures
Info Link• Clinical leukoencephalopathy may present with orwithout imaging abnormalities (e.g., leukoencephalopathy, cerebral lacunes,
cerebral atrophy, dystrophic
calcifications, mineralizing
microangiopathy).
• Transient white matter
anomalies may follow
radiotherapy and highdose chemotherapy for
medulloblastoma/PNET, may
mimic tumor recurrence,and signify risk of persistentneurologic sequelae.
• Neuroimaging changes
do not always correlatewith degree of cognitive
dysfunction.
• Prospective studies areneeded to define the dose/
effect relationship ofneurotoxic agents. Note:
new deficits may emerge
over time.

ANTIMETABOLITES (cont)
Risk
Factors
Host Factors
Younger age at treatment
CNS leukemia/lymphoma
Relapsed leukemia/lymphoma
treated with CNS-directed
therapy
Treatment Factors
Combined with-- Methotrexate (IT, IO, highdose IV)-- Dexamethasone-- Cranial radiation

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 24 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Cognitive, motor and/or sensory deficits
Seizures
Other neurologic symptoms
YearlyBrain CT; Brain MRI with MR angiography as clinically indicatedwith referred study 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.

PHYSICAL
Neurologic exam
YearlySYSTEM = CNSSCORE = 2A

SECTION 24 REFERENCES
Baker WJ, Royer GL, Jr., Weiss RB. Cytarabine and neurologic toxicity. J Clin Oncol. Apr 1991;9(4):679-693.
Butler RW, Copeland DR, Fairclough DL, et al. A multicenter, randomized clinical trial of a cognitive remediation program for childhood survivors of a pediatric malignancy. J Consult Clin Psychol. Jun 2008;76(3):367-378.
Hwang TL, Yung WK, Estey EH, Fields WS. Central nervous system toxicity with high-dose Ara-C. Neurology. Oct 1985;35(10):1475-1479.
Moleski M. Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol. Oct 2000;15(7):603-630.
Nand S, Messmore HL, Jr., Patel R, Fisher SG, Fisher RI. Neurotoxicity associated with systemic high-dose cytosine arabinoside. J Clin Oncol. Apr 1986;4(4):571-575.
Tuxen MK, Hansen SW. Neurotoxicity secondary to antineoplastic drugs. Cancer Treat Rev. Apr 1994;20(2):191-214.
Vaughn DJ, Jarvik JG, Hackney D, Peters S, Stadtmauer EA. High-dose cytarabine neurotoxicity: MR findings during the acute phase. AJNR Am J Neuroradiol. Jul-Aug 1993;14(4):1014-1016.
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Therapeutic
Agent(s)Potential Late
Effects

ANTIMETABOLITES (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 24 REFERENCES (continued)
Vera P, Rohrlich P, Stievenart JL, et al. Contribution of single-photon emission computed tomography in the diagnosis and follow-up of CNS toxicity of a cytarabine-containing regimen in pediatric leukemia. J Clin Oncol. Sep
1999;17(9):2804-2810.

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Therapeutic
Agent(s)25

ANTIMETABOLITES
Cytarabine (low dose IV)
Cytarabine IO
Cytarabine IT
Cytarabine SQInfo Link
Low-dose IV is defined as any
single dose < 1000 mg/m2.

COG LTFU Guidelines – Page 31

Potential Late
Effects
No known late effects

ANTIMETABOLITES (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING
No Known Late Effects

Info Link
Acute toxicities predominate,from which the majority ofpatients recover without
sequelae.

SYSTEM = No Known Late Effects
SCORE = 1

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#
26

Therapeutic
Agent(s)Potential Late
Effects

ANTIMETABOLITES
Mercaptopurine (6MP)
Thioguanine (6TG)

Hepatic dysfunction
Veno-occlusive disease(VOD)

Info Link• Acute hepatotoxicity reported with thioguanine used in
CCG 1952 (regimens B1 and
B2) for ALL maintenancetherapy requires longer
follow-up to determine longterm sequelae.
• See COG Website (CCG 1952
protocol page) for updated
advisories.

Info Link• Acute toxicities predominate
from which the majority ofpatients recover without
sequelae.
• Delayed hepatic dysfunction
may occur after a history ofacute VOD, presenting as
portal hypertension with liver biopsy indicating nodular
regenerative hyperplasia,
fibrosis, or siderosis.

ANTIMETABOLITES (cont)
Risk
Factors
Medical Conditions
Viral hepatitis
Previous VOD
Siderosis

HighestRisk Factors
Medical Conditions
Chronic viral hepatitis

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly
YearlyLiver Health

SCREENING
ALT
AST
Bilirubin
Baseline at entry into long-term follow-up.
Repeat as clinically indicatedConsiderations for Further Testing and Intervention
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 patients lacking
immunity.

SYSTEM = GI/Hepatic
SCORE = 2A

SECTION 26 REFERENCES
Broxson EH, Dole M, Wong R, Laya BF, Stork L. 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. Mar 2005;44(3):226-231.
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. May 2010;54(5):663-669.
De Bruyne R, Portmann B, Samyn M, et al. Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol. Feb 2006;44(2):407-410.
Einhorn M, Davidsohn I. Hepatotoxicity of Mercaptopurine. JAMA. Jun 1 1964;188:802-806.
Mulder RL, van Dalen EC, Van den Hof M, et al. Hepatic late adverse effects after antineoplastic treatment for childhood cancer. The Cochrane database of systematic reviews. 2011(7):CD008205.
Piel B, Vaidya S, Lancaster D, Taj M, Pritchard-Jones K. Chronic hepatotoxicity following 6-thioguanine therapy for childhood acute lymphoblastic leukaemia. Br J Haematol. May 2004;125(3):410-411 author reply 412.
Ravikumara M, Hill FG, Wilson DC, et al. 6-Thioguanine-related chronic hepatotoxicity and variceal haemorrhage in children treated for acute lymphoblastic leukaemia--a dual-centre experience. J Pediatr Gastroenterol Nutr. May
2006;42(5):535-538.
Rawat D, Gillett PM, Devadason D, Wilson DC, McKiernan PJ. Long-term follow-up of children with 6-thioguanine-related chronic hepatoxicity following treatment for acute lymphoblastic leukaemia. J Pediatr Gastroenterol Nutr.
Nov 2011;53(5):478-479

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Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

27

ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO

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

Host Factors
Both genders are at risk
Younger age at diagnosis
Caucasian
Lower weight and BMI

Info Link
High-dose IV is defined as
any single dose ≥ 1000
mg/m2.

Info Link• 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 themean) 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 withtreatment-related hypogonadism, has not been established.
T-scores are not appropriate toassess skeletal health in pediatricpatients who have not achieved
peak adult bone mass.
• Pediatric BMD reference data
sets calculate Z-scores based onage and gender. A Z-score is thenumber of standard deviations themeasurement is above or below
the AGE-MATCHED MEAN BMD.
• The fracture risk in pediatricpatients with low bone density
for chronologic age based on
Z-scores has not been established. There are no defined
standards for referral or treatmentof low BMD in children.

COG LTFU Guidelines – Page 33

Treatment Factors
Corticosteroids
Cyclosporine
Tacrolimus
Cranial radiation
Craniospinal radiation
HCT/TBI
Medical Conditions
Growth hormone
deficiency
Hypogonadism/delayed
puberty
Hyperthyroidism
Health Behaviors
Inadequate intake ofcalcium and vitamin D
Lack of weight bearing
exercise
Smoking
Alcohol use
Carbonated beverages

HighestRisk Factors
Host Factors
Older age at time of treatment
Treatment Factors
Methotrexate cumulative dose
≥ 40 gm/m2
Prolonged corticosteroid therapy(e.g., for chronic GVHD)

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Bone density evaluation (DEXA orquantitative CT)
Baseline at entry into long-term followup, repeat as clinically indicatedBone Health

Info Link• The optimal method of measuring bonehealth in children is controversial. Existing technologies have limitations.
• Dual energy x-ray absorptiometry(DEXA) provides an estimate of totalbone mass at a given site.
• Quantitative CT provides distinct measures of trabecular and cortical bonedimension and density.

Resources
National Osteoporosis Foundation Website: www.nof.org

Considerations for Further Testing and Intervention
Ensure the AAP recommended minimum daily intake of Vitamin
D (400 IU/day) for children, with possible considerations forhigh doses in selected patients (e.g., kidney disease or Vitamin
D deficiency). Many experts recommend higher Vitamin D
intake in adults as well. Also ensure adequate dietary calcium(see table in the “Bone Health” Health Link for age-appropriate
recommendations). Supplements may be necessary if there
are dietary restrictions. Advocate for regular weight-bearing
exercises such as running and jumping. Use caution regarding
calcium supplementation in patients with history of renal
lithiasis. Treatment of exacerbating or predisposing conditions(e.g., hormonal replacement therapy for hypogonadism, growth
hormone deficiency, correction of chronic metabolic acidosisthat could accelerate bone loss). Endocrine consultation forpatients with osteoporosis or history of multiple fractures forpharmacologic interventions (e.g., bisphosphonates, calcitonin,selective estrogen receptor modulators).

SYSTEM = Musculoskeletal
SCORE = 2B

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Agent(s)Potential Late
Effects

ANTIMETABOLITES (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 27 REFERENCES
Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med. Biol. 2008;624:55-71.
Chaiban J, Muwakkit S, Arabi A, et al. Modeling pathways for low bone mass in children with malignancies. J Clin Densitom. Oct-Dec 2009 12(4):441-449.
Grigg AP, Shuttleworth P, Reynolds J, et al. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. Oct 2006;91(10):3835-3843.
International Society for Clinical Densitometry. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom. Spring 2004;7(1):17-26.
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. May 2004;34(5):373-378 quiz 443-374.
Kelly J, Damron T, Grant W, et al. Cross-sectional study of bone mineral density in adult survivors of solid pediatric cancers. J Pediatr Hematol Oncol. May 2005;27(5):248-253.
Sala A, Barr RD. Osteopenia and cancer in children and adolescents: the fragility of success. Cancer. Apr 1 2007;109(7):1420-1431.
van der Sluis IM, van den Heuvel-Eibrink MM. Osteoporosis in children with cancer. Pediatr Blood Cancer. Feb 2008;50(2 Suppl):474-478 discussion 486.
van Leeuwen BL, Kamps WA, Jansen HW, Hoekstra HJ. The effect of chemotherapy on the growing skeleton. Cancer Treat Rev. Oct 2000;26(5):363-376.
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.
Pediatrics. Nov 2008;122(5):1142-1152.
Wasilewski-Masker K, Kaste SC, Hudson MM, Esiashvili N, Mattano LA, Meacham LR. Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics. Mar
2008;121(3):e705-713.

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Therapeutic
Agent(s)28

ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO
Info Link
High-dose IV is defined as any
single dose ≥ 1000 mg/m2.

Potential Late
Effects
Renal toxicity
Glomerular injury
Hypertension
Info Link
Acute toxicities predominate,from which the majority ofpatients recover without
sequelae.

ANTIMETABOLITES (cont)
Risk
Factors
Host Factors
MononephricTreatment Factors
Combined with othernephrotoxic agents such as:-- Cisplatin/carboplatin-- Ifosfamide-- Aminoglycosides-- Amphotericin-- Immunosuppressants-- Radiation impacting thekidneys
Medical Conditions
Diabetes mellitus
Hypertension
Nephrectomy

HighestRisk Factors
Treatment Factors
Treatment before 1970

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Blood pressure
YearlyKidney Health
Cardiovascular Risk Factors

SCREENING

Considerations for Further Testing and Intervention

BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedNephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency.

Urinalysis
YearlySYSTEM = Urinary
SCORE = 2A

SECTION 28 REFERENCES
Abelson HT, Fosburg MT, Beardsley GP, et al. Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. J Clin Oncol. Mar 1983;1(3):208-216.
Christensen ML, Rivera GK, Crom WR, Hancock ML, Evans WE. Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia. J Clin Oncol. May 1988;6(5):797-801.
Gronroos MH, Jahnukainen T, Mottonen M, Perkkio M, Irjala K, Salmi TT. Long-term follow-up of renal function after high-dose methotrexate treatment in children. Pediatr Blood Cancer. Oct 2008;51(4):535-539.
Kreusser W, Herrmann R, Tschope W, Ritz E. Nephrological complications of cancer therapy. Contrib Nephrol. 1982;33:223-238.
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. Oct 2004;77(2):132-139.

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Therapeutic
Agent(s)29

ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO
Info Link
High-dose IV is defined as any
single dose ≥ 1000 mg/m2.

Potential Late
Effects
Hepatic dysfunction
Info Link
Acute toxicities predominate
from which the majority ofpatients recover without
sequelae.

ANTIMETABOLITES (cont)
Risk
Factors

HighestRisk Factors

Treatment Factors
Abdominal radiation

Treatment Factors
Treatment before 1970

Medical Conditions
Viral hepatitis

Medical Conditions
Chronic viral hepatitis

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly
YearlyLiver Health

SCREENING
ALT
AST
Bilirubin
Baseline at entry into long-term follow-up.
Repeat as clinically indicated.

Considerations for Further Testing and Intervention
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 patients lacking
immunity.

SYSTEM = GI/Hepatic
SCORE = 2A

SECTION 29 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. May 2010;54(5):663-669.
Locasciulli A, Mura R, Fraschini D, et al. High-dose methotrexate administration and acute liver damage in children treated for acute lymphoblastic leukemia. A prospective study. Haematologica. Jan-Feb 1992;77(1):49-53.
McIntosh S, Davidson DL, O’Brien RT, Pearson HA. Methotrexate hepatotoxicity in children with leukemia. J Pediatr. Jun 1977;90(6):1019-1021.
Mulder RL, van Dalen EC, Van den Hof M, et al. Hepatic late adverse effects after antineoplastic treatment for childhood cancer. The Cochrane database of systematic reviews. 2011(7):CD008205.
Weber BL, Tanyer G, Poplack DG, et al. Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood. NCI Monogr. 1987(5):207-212.

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Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

30

ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (IO)
Methotrexate (IT)Neurocognitive deficits
Functional deficits in:-- Executive function (planning and 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

Host Factors
Younger age at treatment
CNS leukemia/lymphoma
Relapsed leukemia/lymphoma
treated with CNS-directed
therapy
Female sex

Host Factors
Age < 3 years old at time oftreatment
Premorbid or family historyof learning or attention
problems

Info Link
High-dose IV is defined as any
single dose ≥ 1000 mg/m2.

Info Link• Neurocognitive deficits
in survivors of leukemia
and lymphoma are more
frequently related to
information processing (e.g.,learning disability).
• Neurocognitive deficits
in brain tumor survivors
treated with higher doses of
cranial radiation are moreglobal (significant decline
in IQ).
• Extent of deficit depends on
age at treatment, intensityof treatment, and time sincetreatment.
• New deficits may emerge
over time.

Treatment Factors
In combination with:-- Corticosteroids-- TBI-- Cranial radiation-- Cytarabine (high-dose IV)-- Longer elapsed time since
therapy-- Hyperthyroidism
Health Behaviors
Inadequate intake of calcium
and vitamin D; Lack ofweight bearing exercise;
Smoking; Alcohol use;
Carbonated beverages

Treatment Factors
Radiation dose ≥ 24 Gy
Single fraction TBI (10 Gy)

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Educational and/or vocational progress
YearlyEducational Issues

SCREENING

Formal neuropsychological evaluation to include tests ofprocessing speed, computer-based attention, visual motor
integration, memory, comprehension of verbal instructions,verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orcancer center (psychologist, social worker, school counselor)
to facilitate acquisition of educational resources and/or social
skills training. Consider use of psychotropic medication (e.g.,
stimulants) or evidence-based rehabilitation training. Caution—
lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended. Refer to community
services for vocational rehabilitation or for services fordevelopmentally disabled.

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

Considerations for Further Testing and Intervention

SYSTEM = CNSSCORE = 1

SECTION 30 REFERENCES
Buizer AI, de Sonneville LMJ, van den Heuvel-Eibrink MM, et al. Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. J Intern Neuropsych Soc 11: 554-565, 2005.
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. Apr 2009 52(4):447-454.
Butler RW, Copeland DR, Fairclough DL, et al. A multicenter, randomized clinical trial of a cognitive remediation program for childhood survivors of a pediatric malignancy. J Consult Clin Psychol. Jun 2008;76(3):367-378.
Iuvone L, Mariotti P, Colosimo C, Guzzetta F, Ruggiero A, Riccardi R. Long-term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia. Cancer.
Dec 15 2002;95(12):2562-2570.
Jain N, Brouwers P, Okcu MF, Cirino PT, Krull KR. Sex-specific attention problems in long-term survivors of pediatric acute lymphoblastic leukemia. Cancer. Sep 15 2009 115(18):4238-4245.
Jansen NC, Kingma A, Schuitema A, Bouma A, Veerman AJ, Kamps WA. Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. J Clin Oncol Jun 20 2008;26(18):3025-3030.
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Therapeutic
Agent(s)Potential Late
Effects

ANTIMETABOLITES (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 30 REFERENCES–continued
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.
Aug 27 2009 114(9):1746-1752.
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. Dec 10 2009 27(35):5986-5992.
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. Jul 2008;51(1):99-104.
Riva D, Giorgi C, Nichelli F, et al. Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology. Jul 9 2002;59(1):48-53.

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Therapeutic
Agent(s)31

ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (IO)
Methotrexate (IT)Info Link
High-dose IV is defined as any
single dose ≥ 1000 mg/m2.

Potential Late
Effects
Clinicalleukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures
Info Link• Clinical leukoencephalopathy may present with orwithout imaging abnormalities (e.g., leukoencephalopathy, cerebral lacunes,
cerebral atrophy, dystrophic
calcifications, mineralizing
microangiopathy).
• Transient white matter
anomalies may follow
radiotherapy and highdose chemotherapy for
medulloblastoma/PNET, may
mimic tumor recurrence,and signify risk of persistentneurologic sequelae.
• Neuroimaging changes
do not always correlatewith degree of cognitive
dysfunction. Prospective
studies are needed to define
the dose/effect relationshipof neurotoxic agents.
• New deficits may emerge
over time.

ANTIMETABOLITES (cont)
Risk
Factors
Host Factors
Younger age at treatment
CNS leukemia/lymphoma
Relapsed leukemia/lymphoma
treated with CNS-directed
therapy
Treatment Factors
Combined with:-- Cytarabine (high-dose IV)-- Dexamethasone-- Cranial radiation

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 24 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Cognitive, motor and/or sensory deficits
Seizures
Other neurologic symptoms
YearlyBrain CT; Brain MRI with MR angiography as clinically indicatedwith preferred study based on intracranial lesion to beevaluated:-- 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.

PHYSICAL
Neurological exam
YearlySYSTEM = CNSSCORE = 1

SECTION 31 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. Jun 1997;28(6):387-400.
Lovblad K, Kelkar P, Ozdoba C, Ramelli G, Remonda L, Schroth G. Pure methotrexate encephalopathy presenting with seizures: CT and MRI features. Pediatr Radiol. Feb 1998;28(2):86-91.
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.
Jul 15 1995;32(4):913-918.
Moleski M. Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol. Oct 200015(7):603-630.
Porto L, Kieslich M, Schwabe D, Zanella FE, Lanfermann H. Central nervous system imaging in childhood leukaemia. Eur J Cancer. Sep 2004;40(14):2082-2090.

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32

Therapeutic
Agent(s)ANTHRACYCLINEANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone

Potential Late
Effects
Acute myeloid leukemia

ANTHRACYCLINE ANTIBIOTICS
Risk
Factors
Treatment Factors
Less than 5 years since
exposure to agent

HighestRisk Factors
Treatment Factors
Autologous HCT

Periodic
Evaluation
HISTORY

Health Links

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

Reducing the Risk of Second Cancers

PHYSICAL
Info Link (Mitoxantrone):
Although Mitoxantrone
technically belongs to theanthracenedione class of antitumor antibiotics, it is related
to the anthracycline family.

Health Counseling/
Further Considerations

Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure toagentCounselingCounsel to promptly report fatigue, pallor, petechiae or bone
pain.

Considerations for Further Testing and Intervention
CBC and bone marrow exam as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 32 REFERENCES
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. Jan 1
2007;109(1):46-51.
Felix CA. Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol. May 2001;36(5):525-535.
Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin. Oncol. Aug 2008;35(4):418-429.
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. Mar 15 2003;21(6):1074-1081.
Rihani R, Bazzeh F, Faqih N, Sultan I. Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer. Sep 15
2010;116(18):4385-4394.

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33

(male)

Therapeutic
Agent(s)ANTHRACYCLINEANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone

Info Link (Mitoxantrone)
Although Mitoxantrone
technically belongs to theanthracenedione class of antitumor antibiotics, it is related
to the anthracycline family
and is included here becauseof its cardiotoxic potential.
Info Link (Dose Conversion)• Pediatric studies of anthracycline cardiotoxicity typically describe risks basedon combined cumulative
doses of doxorubicin. Thereis a paucity of literature
to support isotoxic doseconversion.
• To gauge the frequency of
screening, use the following
formulas to convert todoxorubicin isotoxic equivalents prior to calculating
total cumulative anthracycline dose.
Doxorubicin: Multiply total
dose x 1
Daunorubicin: Multiply total
dose x 1
Epirubicin: Multiply total
dose x 0.67
Idarubicin: Multiply total
dose x 5
Mitoxantrone: Multiply total
dose x 4• Clinical judgment should
ultimately be used to determine indicated screening forindividual patients.
COG LTFU Guidelines – Page 41

Potential Late
Effects
Cardiac toxicity
Cardiomyopathy
Arrhythmias
Subclinical left ventricular
dysfunction
Info Link• Dose levels correlating withcardiotoxicity are derived
from adult studies.
• Childhood cancer patients
exhibit clinical and subclinical toxicity at lower levels.
• Certain conditions (suchas isometric exercise andviral infections) have been
anecdotally reported toprecipitate cardiac decompensation.
• Prospective studies areneeded to better define thecontribution of these factors
to cardiac disease risk.

ANTHRACYCLINE ANTIBIOTICS (cont)
Risk
Factors

HighestRisk Factors

Treatment Factors
Combined with radiation
involving the heart
Combined with othercardiotoxic chemotherapy-- Cyclophosphamide conditioning for HCT-- Amsacrine

Host Factors
Black/of African descent
Younger than age 5 years attime of treatment

Medical Conditions
Obesity
Congenital heart disease
Febrile illness
Hypertension
Diabetes mellitus
Health Behaviors
Isometric exercise
Smoking
Drug use (e.g., cocaine, dietpills, ephedra, mahuang)

Treatment Factors
Higher cumulative
anthracycline doses:-- ≥ 550 mg/m2 in patients
18 years or older at time oftreatment-- ≥ 300 mg/m2 in patients
younger than 18 years attime of treatment-- Any dose in infant
Chest radiation ≥ 30 Gy
Longer time elapsed

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

SOB
DOE
Orthopnea
Chest pain
Palpitations
If under 25 yrs: abdominal symptoms(nausea, vomiting)
YearlyHeart Health
Cardiovascular Risk Factors

Info Link• Exertional intolerance is uncommon inpatients younger than 25 years old.
• Abdominal symptoms (nausea, emesis)
may be observed more frequently thanexertional dyspnea or chest pain inyounger patients.

PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlySCREENING

CounselingCounsel patients with prolonged QTc interval about use of
medications that may further prolong the QTc interval (e.g.,
tricyclic anti-depressants, antifungals, macrolide antibiotics,
metronidazole). Counsel regarding maintaining appropriate
weight, blood pressure and heart-healthy diet. Counsel regarding
appropriate exercise. Aerobic exercise is generally safe andshould be encouraged for most patients. Intensive isometricactivities (e.g., heavy weight lifting, wrestling) should generally
be avoided. High repetition weight lifting involving lighter
weights is more likely to be safe. The number of repetitions
should be limited to that which the survivor can perform withease. Patients who choose to engage in strenuous or varsity
team sports should discuss appropriate guidelines and a plan for
ongoing monitoring with a cardiologist.

Considerations for Further Testing and Intervention
Cardiology consultation in patients with subclinical abnormalities
on screening evaluations, left ventricular dysfunction,
dysrhythmia, or prolonged QTc interval. Consider excess riskof intensive isometric exercise program in any high risk patient(defined as needing screening every 1 or 2 years).

SYSTEM = Cardiovascular
SCORE = 1

ECHO (or comparable imaging toevaluate cardiac function)
Baseline at entry into long-term followup, then periodically based on age attreatment, radiation dose, and cumulative
anthracycline dose.
EKG (include evaluation of QTc interval)
Baseline at entry into long-term follow-up,
repeat as clinically indicated.

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Therapeutic
Agent(s)ANTHRACYCLINE ANTIBIOTICS (cont)

Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 33 REFERENCES
Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. Jun 15 2005;4(7):600-606.
Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. Sep 1 20075(25):3991-4008.
Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group. J Clin Oncol. Apr 1 2001;19(7):1926-1934.
Hudson MM, Rai SN, Nunez C, et al. Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol. Aug 20 2007;25(24):3635-3643.
Kremer LC, van Dalen EC, Offringa M, Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review. Ann Oncol. Apr 2002;13(4):503-512.
Kremer LC, van der Pal HJ, Offringa M, van Dalen EC, Voute PA. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. Jun 2002;13(6):819-829.
Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2005;23(12):2629-2636.
Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009 339:b4606.
Shankar SM, Marina N, Hudson MM, et al. Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children’s Oncology Group. Pediatrics. Feb
2008;121(2):e387-39.
Sorensen K, Levitt GA, Bull C, Dorup I, Sullivan ID. Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study. Cancer. Apr 15 2003;97(8):1991-1998.
van Dalen EC, Caron HN, Kremer LC. Prevention of anthracycline-induced cardiotoxicity in children: the evidence. Eur J Cancer. May 2007;43(7):1134-1140.
van Dalen EC, van der Pal HJ, Kok WE, Caron HN, Kremer LC. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer. Dec 2006;42(18):3191-3198.
RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM (or comparable cardiac imaging)Age at Treatment*

Radiation with Potential Impact
to the Heart§Yes<1 year oldNo
Yes

Anthracycline Dose†

Recommended Frequency

Any

Every year

< 200 mg/m2

Every 2 years≥ 200 mg/m

Every year

Any

Every year

2<100 mg/m

Every 5 years≥100 to <300 mg/m2

Every 2 years≥300 mg/m2

Every year

<300 mg/m

Every 2 years

2

1-4 years oldNoYes≥5 years old

2≥300 mg/m2

Every year

<200 mg/m

Every 5 years≥200 to <300 mg/m2

Every 2 years≥300 mg/m2

Every year2No

Any age with decrease in serial function

Every year

Age at time of first cardiotoxic therapy (anthracycline or radiation [see Section 80], whichever was given first)§
See Section 80†
Based on doxorubicin isotoxic equivalent dose [see conversion factors on previous page, “Info Link (Dose Conversion)”]*

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34

(female)Therapeutic
Agent(s)ANTHRACYCLINEANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone

Info Link (Mitoxantrone):
Although Mitoxantrone
technically belongs to theanthracenedione class of antitumor antibiotics, it is related
to the anthracycline family
and is included here becauseof its cardiotoxic potential.
Info Link (Dose Conversion):• Pediatric studies of anthracycline cardiotoxicity typically describe risks basedon combined cumulative
doses of doxorubicin. Thereis a paucity of literature
to support isotoxic doseconversion.
• To gauge the frequency of
screening, use the following
formulas to convert todoxorubicin isotoxic equivalents prior to calculating
total cumulative anthracycline dose.
Doxorubicin: Multiply total
dose x 1
Daunorubicin: Multiply total
dose x 1
Epirubicin: Multiply total
dose x 0.67
Idarubicin: Multiply total
dose x 5
Mitoxantrone: Multiply total
dose x 4• Clinical judgment should
ultimately be used to determine indicated screening forindividual patients.
COG LTFU Guidelines – Page 43

Potential Late
Effects
Cardiac toxicity
Cardiomyopathy
Arrhythmias
Subclinical left ventricular
dysfunction
Info Link• Dose levels correlating withcardiotoxicity are derived
from adult studies.
• Childhood cancer patients
exhibit clinical and subclinical toxicity at lower levels.
• Certain conditions (such as
isometric exercise, pregnancy, and viral infections) havebeen anecdotally reported toprecipitate cardiac decompensation.
• Prospective studies areneeded to better define thecontribution of these factors
to cardiac disease risk.

ANTHRACYCLINE ANTIBIOTICS (cont)
Risk
Factors

HighestRisk Factors

Treatment Factors
Combined with radiation
involving the heart
Combined with othercardiotoxic chemotherapy-- Cyclophosphamide conditioning for HCT-- Amsacrine

Host Factors
Female sex
Black/of African descent
Younger than age 5 years attime of treatment

Medical Conditions
Obesity
Congenital heart disease
Febrile illness
Pregnancy
Hypertension
Diabetes mellitus
Health Behaviors
Isometric exercise
Smoking
Drug use (e.g., cocaine, dietpills, ephedra, mahuang)

Treatment Factors
Higher cumulative
anthracycline doses:-- ≥ 550 mg/m2 in patients
18 years or older at time oftreatment-- ≥ 300 mg/m2 in patients
younger than 18 years attime of treatment-- Any dose in infant-- Chest radiation ≥ 30 Gy
Longer time elapsed

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

SOB
DOE
Orthopnea
Chest pain
Palpitations
If under 25 yrs: abdominal symptoms(nausea, vomiting)
YearlyHeart Health
Cardiovascular Risk Factors

Info Link• Exertional intolerance is uncommon inpatients younger than 25 years old.
• Abdominal symptoms (nausea, emesis)
may be observed more frequently thanexertional dyspnea or chest pain inyounger patients.

PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlySCREENINGECHO (or comparable imaging toevaluate cardiac function))
Baseline at entry into long-term followup, then periodically based on age attreatment, radiation dose, and cumulative
anthracycline dose.

CounselingCounsel patients with prolonged QTc interval about use of
medications that may further prolong the QTc interval (e.g.,
tricyclic anti-depressants, antifungals, macrolide antibiotics,
metronidazole). Counsel regarding maintaining appropriate
weight, blood pressure and heart-healthy diet. Counsel regarding
appropriate exercise. Aerobic exercise is generally safe andshould be encouraged for most patients. Intensive isometricactivities (e.g., heavy weight lifting, wrestling) should generally
be avoided. High repetition weight lifting involving lighter
weights is more likely to be safe. The number of repetitions
should be limited to that which the survivor can perform withease. Patients who choose to engage in strenuous or varsity
team sports should discuss appropriate guidelines and a plan for
ongoing monitoring with a cardiologist.

Considerations for Further Testing and Intervention
Cardiology consultation in patients with subclinical abnormalities
on screening evaluations, left ventricular dysfunction,
dysrhythmia, or prolonged QTc interval. Consider excess riskof intensive isometric exercise program in any high risk patient(defined as needing screening every 1 or 2 years). Additional
cardiology evaluation in patients who received ≥ 300 mg/m2 or< 300 mg/m2 plus chest radiation who are pregnant or planning
pregnancy. Evaluation to include an echocardiogram before andperiodically during pregnancy (especially during third trimester)and monitoring during labor and delivery due to risk of cardiac
failure.

SYSTEM = Cardiovascular
SCORE = 1

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

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Therapeutic
Agent(s)ANTHRACYCLINE ANTIBIOTICS (cont)

Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 34 REFERENCES
Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. Jun 15 2005;44(7):600-606.
Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. Sep 1 2007;25(25):3991-4008.
Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group. J Clin Oncol. Apr 1 2001;19(7):1926-1934.
Hudson MM, Rai SN, Nunez C, et al. Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol. Aug 20 2007;25(24):3635-3643.
Kremer LC, van Dalen EC, Offringa M, Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review. Ann Oncol. Apr 2002;13(4):503-512.
Kremer LC, van der Pal HJ, Offringa M, van Dalen EC, Voute PA. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. Jun 2002;13(6):819-829.
Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2005;23(12):2629-2636.
Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009 339:b4606.
Shankar SM, Marina N, Hudson MM, et al. Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children’s Oncology Group. Pediatrics. Feb
2008;121(2):e387-39.
Sorensen K, Levitt GA, Bull C, Dorup I, Sullivan ID. Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study. Cancer. Apr 15 2003;97(8):1991-1998.
van Dalen EC, Caron HN, Kremer LC. Prevention of anthracycline-induced cardiotoxicity in children: the evidence. Eur J Cancer. May 2007;43(7):1134-1140.
van Dalen EC, van der Pal HJ, Kok WE, Caron HN, Kremer LC. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer. Dec 2006;42(18):3191-3198.
van Dalen EC, van der Pal HJ, van den Bos C, Kok WE, Caron HN, Kremer LC. Clinical heart failure during pregnancy and delivery in a cohort of female childhood cancer survivors treated with anthracyclines. Eur J Cancer. Oct
2006;42(15):2549-2553.
RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM (or comparable cardiac imaging)Age at Treatment*

Radiation with Potential Impact
to the Heart§Yes<1 year oldNo
Yes

Anthracycline Dose†

Recommended Frequency

Any

Every year

< 200 mg/m2

Every 2 years≥ 200 mg/m

Every year

Any

Every year

2<100 mg/m

Every 5 years≥100 to <300 mg/m2

Every 2 years

2

1-4 years oldNo≥300 mg/m

Every year

<300 mg/m2

Every 2 years≥300 mg/m2

Every year

<200 mg/m

Every 5 years≥200 to <300 mg/m2

Every 2 years≥300 mg/m

Every year

2Yes
≥5 years old

2

No

2

Any age with decrease in serial function

Every year

Age at time of first cardiotoxic therapy (anthracycline or radiation [see Section 81], whichever was given first)
See Section 81†
Based on doxorubicin isotoxic equivalent dose [see conversion factors on previous page, “Info Link (Dose Conversion)”]*§

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Therapeutic
Agent(s)35

ANTI-TUMOR ANTIBIOTICS
Bleomycin

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

ANTI-TUMOR ANTIBIOTICS
Risk
Factors
Host Factors
Younger age at treatment
Treatment Factors
Higher cumulative dose
Combined with:-- Busulfan-- Carmustine (BCNU)-- Lomustine (CCNU)
Medical Conditions
Renal dysfunction
High dose oxygen support
such as during generalanesthesia
Health Behaviors
SmokingInhaled illicit drug use

HighestRisk Factors
Treatment Factors
Bleomycin dose≥ 400 U/m2
(injury observed in doses
60–100 U/m2 in children)
Combined with: Chest
radiation
TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Cough
SOB
DOE
Wheezing
YearlyPulmonary HealthBleomycin Alert

PHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patientswith abnormal results or progressive
pulmonary dysfunction.

Resources
Extensive information regarding smoking cessation is available
for patients on the NCI’s website: www.smokefree.gov.

Counseling
Notify healthcare providers of history of bleomycin therapy andrisk of worsening fibrosis with high oxygen exposure such as
during general anesthesia. Administration of high concentrationsof oxygen may result in chronic progressive pulmonary fibrosis.
Counsel regarding tobacco avoidance/smoking cessation. Dueto the potential pulmonary toxicity of this therapy, patients
who desire to SCUBA dive should be advised to obtain medical
clearance from a pulmonologist.

Considerations for Further Testing and Intervention
In patients with abnormal PFTs consider repeat evaluation prior
to general anesthesia. Pulmonary consultation in patients withsymptomatic or progressive pulmonary dysfunction. Influenza
and pneumococcal vaccines.

SYSTEM = Pulmonary
SCORE =
Interstitial pneumonitis = 1
Pulmonary fibrosis = 1
ARDS = 2B

SECTION 35 REFERENCES
Goldiner PL, Carlon GC, Cvitkovic E, Schweizer O, Howland WS. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J. Jun 24 1978;1(6128):1664-1667.
Haugnes HS, Aass N, Fossa SD, et al. Pulmonary function in long-term survivors of testicular cancer. J Clin Oncol. Jun 10 2009 27(17):2779-2786.
Huang TT, Hudson MM, Stokes DC, Krasin MJ, Spunt SL, Ness KK. Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest. Oct 2011;140(4):881-901.
Liles A, Blatt J, Morris D, et al. Monitoring pulmonary complications in long-term childhood cancer survivors: guidelines for the primary care physician. Cleve Clin J Med. Jul 2008;75(7):531-539.
Marina NM, Greenwald CA, Fairclough DL, et al. Serial pulmonary function studies in children treated for newly diagnosed Hodgkin’s disease with mantle radiotherapy plus cycles of cyclophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Cancer. Apr 1 1995;75(7):1706-1711.
Matei D, Miller AM, Monahan P, et al. Chronic physical effects and health care utilization in long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group study. J Clin Oncol. Sep 1 2009 27(25):4142-4149.
Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med Jul 10 2006;166(13):1359-1367.
Mefferd JM, Donaldson SS, Link MP. Pediatric Hodgkin’s disease: pulmonary, cardiac, and thyroid function following combined modality therapy. Int J Radiat Oncol Biol Phys. Mar 1989;16(3):679-685.
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Therapeutic
Agent(s)Potential Late
Effects

ANTI-TUMOR ANTIBIOTICS (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 35 REFERENCES–continued
Stolp B, Assistant Medical Director Divers Alert Network, Director Anesthesiology Emergency Airway Services, Durham, N.C. Risks associated with SCUBA diving in childhood cancer survivors. Personal communication to LandierW, Bhatia S Aug 23, 2002.
Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. Feb 12 2007167(3):221-228.
Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. Mar 2004;25(1):203-216.

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Therapeutic
Agent(s)36

ANTI-TUMOR ANTIBIOTICS
Dactinomycin

Potential Late
Effects
No known late effects

ANTI-TUMOR ANTIBIOTICS (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation
SCREENING

Health Counseling/
Further Considerations
Health Links

No Known Late Effects
Info Link
Dactinomycin has been
associated with acuteveno-occlusive disease, fromwhich the majority of patients
recover without sequelae.

SYSTEM = No Known Late Effects
SCORE = 1

SECTION 36 REFERENCES
Green DM, Norkool P, Breslow NE, Finklestein JZ, D’Angio GJ. 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. Sep 1990;8(9):1525-1530.

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37

Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

Potential
Late Effects
Reduced bone mineral density(BMD)
Defined as Z-score > 2.0 SD below
the mean in survivors < 20 years
old or T-score >1.0 SD below themean in survivors ≥ 20 years old
Info Link• 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 themean) 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 withtreatment-related hypogonadism, has not been established.
T-scores are not appropriate toassess skeletal health in pediatricpatients who have not achieved
peak adult bone mass.
• Pediatric BMD reference data
sets calculate Z-scores based onage and gender. A Z-score is thenumber of standard deviations themeasurement is above or below
the AGE-MATCHED MEAN BMD.
• The fracture risk in pediatricpatients with low bone density
for chronologic age based on
Z-scores has not been established. There are no defined
standards for referral or treatmentof low BMD in children.

COG LTFU Guidelines – Page 48

CORTICOSTEROIDS
Risk
Factors
Host Factors
Both genders are at risk
Younger age at diagnosis
Caucasian
Lower weight and BMI
Treatment Factors
Corticosteroids
Cyclosporine
Tacrolimus
Cranial radiation
Craniospinal radiation
HCT/TBI
Medical Conditions
Growth hormone deficiency
Hypogonadism/delayed
puberty
Hyperthyroidism
Health Behaviors
Inadequate intake of calcium
and vitamin D
Lack of weight bearing
exercise
Smoking
Alcohol use
Carbonated beverages

HighestRisk Factors
Host Factors
Older age at time of treatment
Treatment Factors
Dexamethasone effectis more potent than
prednisone
Glucocorticoid cumulative
dose ≥ 9 gm/m2 prednisone
equivalent

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Bone density evaluation (DEXA orquantitative CT)
Baseline at entry into long-term follow-up,
repeat as clinically indicatedBone Health

Info Link• The optimal method of measuring bonehealth in children is controversial. Existing
technologies have limitations.
• Dual energy x-ray absorptiometry (DEXA)
provides an estimate of total bone mass
at a given site.
• Quantitative CT provides distinct measures of trabecular and cortical bonedimension and density.

Resources
National Osteoporosis Foundation Website (www.nof.org )Considerations for Further Testing and Intervention
Ensure the AAP recommended minimum daily intake of Vitamin
D (400 IU/day) for children, with possible considerations forhigh doses in selected patients (e.g., kidney disease or Vitamin
D deficiency). Many experts recommend higher Vitamin D
intake in adults as well. Also ensure adequate dietary calcium(see table in the “Bone Health” Health Link for age-appropriate
recommendations). Supplements may be necessary if there
are dietary restrictions. Advocate for regular weight-bearing
exercises such as running and jumping. Use caution regarding
calcium supplementation in patients with history of renal
lithiasis. Treatment of exacerbating or predisposing conditions(e.g., hormonal replacement therapy for hypogonadism, growth
hormone deficiency, correction of chronic metabolic acidosisthat could accelerate bone loss). Endocrine consultation forpatients with osteoporosis or history of multiple fractures forpharmacologic interventions (e.g., bisphosphonates, calcitonin,selective estrogen receptor modulators).

SYSTEM = Musculoskeletal
SCORE = 2B

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Agent(s)Potential Late
Effects

CORTICOSTEROIDS (cont)
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 37 REFERENCES
Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.
Chaiban J, Muwakkit S, Arabi A, et al. Modeling pathways for low bone mass in children with malignancies. J Clin Densitom. Oct-Dec 2009 12(4):441-449.
Grigg AP, Shuttleworth P, Reynolds J, et al. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. Oct 2006;91(10):3835-3843.
International Society for Clinical Densitometry. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom. Spring 2004;7(1):17-26.
Leonard MB. Assessment of bone health in children and adolescents with cancer: promises and pitfalls of current techniques. Med Pediatr Oncol. Sep 2003;41(3):198-207.
Polgreen LE, Petryk A, Dietz AC, et al. Modifiable risk factors associated with bone deficits in childhood cancer survivors. BMC Pediatr. 2012;12:40.
Sala A, Barr RD. Osteopenia and cancer in children and adolescents: the fragility of success. Cancer. Apr 1 2007;109(7):1420-1431.
van der Sluis IM, van den Heuvel-Eibrink MM. Osteoporosis in children with cancer. Pediatr Blood Cancer. Feb 2008;50(2 Suppl):474-478 discussion 486.
van Leeuwen BL, Kamps WA, Jansen HW, Hoekstra HJ. The effect of chemotherapy on the growing skeleton. Cancer Treat Rev. Oct 2000;26(5):363-376.
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.
Pediatrics. Nov 2008;122(5):1142-1152.
Wasilewski-Masker K, Kaste SC, Hudson MM, Esiashvili N, Mattano LA, Meacham LR. Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics. Mar
2008;121(3):e705-713.

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Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

Potential Late
Effects

CORTICOSTEROIDS (cont)
Risk
Factors

HighestRisk Factors

Osteonecrosis (avascularnecrosis)

Host Factors
Host polymorphisms may
confer increased risk

Host Factors
Pubertal/post-pubertal at timeof treatment

Info Link• Osteonecrosis typicallyoccurs during the acutetreatment phase, may progress over time or resolve.
• Multifocal osteonecrosis issignificantly more common(3:1) than unifocal.

Treatment Factors
Combined with high-doseradiation to any bone
Dexamethasone effectis more potent than
prednisone

Treatment Factors
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones

Medical Conditions
Sickle cell disease

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Joint pain
Swelling
Immobility
Limited range of motion
YearlyOsteonecrosis

PHYSICAL
Musculoskeletal exam
YearlyConsiderations for Further Testing and Intervention
MRI as clinically indicated in patients with history suggestiveof osteonecrosis (should be done soon after symptom onset).
Orthopedic consultation in patients with positive imaging and/or symptoms of osteonecrosis. Symptomatic lesions confer
the greatest risk for collapse. Physical therapy evaluation(for non-pharmacologic pain management, range of motion,
strengthening, stretching, functional mobility).

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 38 REFERENCES
Burger B, Beier R, Zimmermann M, Beck JD, Reiter A, Schrappe M. Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)—experiences from trial ALL-BFM 95. Pediatr Blood Cancer. Mar
2005;44(3):220-225.
Elmantaser M, Stewart G, Young D, Duncan R, Gibson B, Ahmed SF. Skeletal morbidity in children receiving chemotherapy for acute lymphoblastic leukaemia. Arch Dis Child. Oct 2010;95(10):805-809.
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. Jun 20 2008;26(18):3038-3045.
Karimova EJ, Rai SN, Howard SC, et al. Femoral head osteonecrosis in pediatric and young adult patients with leukemia or lymphoma. J Clin Oncol. Apr 20 2007;25(12):1525-1531.
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. Feb 2006;186(2):477-482.
Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia?: a 2- to 7-year study. Clin Orthop Relat Res. Sep 2010;468(9):2454-2459.
Kawedia JD, Kaste SC, Pei D, et al. Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood. Feb 24 2011;117(8):2340-2347 quiz 2556.
Mattano LA, Jr., Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol. Sep 15 2000;18(18):3262-3272.
Niinimaki RA, Harila-Saari AH, Jartti AE, et al. High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2007;25(12):1498-1504.
Ojala AE, Paakko E, Lanning FP, Lanning M. Osteonecrosis during the treatment of childhood acute lymphoblastic leukemia: a prospective MRI study. Med Pediatr Oncol. Jan 1999;32(1):11-17.
Relling MV, Yang W, Das S, et al. Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. J Clin Oncol. Oct 1 2004;22(19):3930-3936.
Sedonja I, Jevtic V, Milcinski M. Bone scintigraphy as a prognostic indicator for bone collapse in the early phases of femoral head osteonecrosis. Ann Nucl Med. Jun 2007;21(3):167-173.
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. Nov 1 2011;29(31):4143-4150.

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39

Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

Potential Late
Effects
Cataracts

CORTICOSTEROIDS (cont)
Risk
Factors
Treatment Factors
Combined with:-- TBI-- Busulfan

HighestRisk Factors
Treatment Factors
TBI
Cranial, orbital, or eye
radiation
Longer interval sincetreatment

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Visual changes (decreased acuity, halos,
diplopia)
YearlyCataracts

PHYSICAL
Eye exam (visual acuity, funduscopic
exam for lens opacity)
YearlyConsiderations for Further Testing and Intervention
Ophthalmology consultation if problem identified. Refer patientswith 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

SECTION 39 REFERENCES
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. Jun 15 1995;32(3):661-670.
Hoover DL, Smith LE, Turner SJ, Gelber RD, Sallan SE. Ophthalmic evaluation of survivors of acute lymphoblastic leukemia. Ophthalmology. Feb 1988;95(2):151-155.
Kaye LD, Kalenak JW, Price RL, Cunningham R. Ocular implications of long-term prednisone therapy in children. J Pediatr Ophthalmol Strabismus. May-Jun 1993;30(3):142-144.
Pakisch B, Langmann G, Langmann A, et al. Ocular sequelae of multimodal therapy of hematologic malignancies in children. Med Pediatr Oncol. 1994;23(4):344-349.

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Therapeutic
Agent(s)ENZYMES
Asparaginase

Potential Late
Effects
No known late effects

ENZYMES
Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY
No Known Late Effects

Info Link
Acute toxicities predominate,from which the majority ofpatients recover without
sequelae.

SYSTEM = No Known Late Effects
SCORE = 1

SECTION 40 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 andTreatment of Cancer-Children’s Leukemia Group phase 3 trial. Blood. Apr 15 2002;99(8):2734-2739.
Parsons SK, Skapek SX, Neufeld EJ, et al. Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Blood. Mar 15 1997;89(6):1886-1895.

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41

Therapeutic
Agent(s)PLANT ALKALOIDS
Vinblastine
Vincristine

PLANT ALKALOIDS

Potential Late
Effects

Risk
Factors

HighestRisk Factors

Peripheral sensory or motor
neuropathy
Areflexia
Weakness
Foot drop
Parasthesias

Treatment Factors
Combined with platinum
chemotherapy, gemcitabine
or taxanes

Medical Conditions
Charcot-Marie-Tooth disease

Info Link• Acute toxicities mostcommonly occur and usually
improve or resolve prior topatients entering long-term
follow-up.
• Neuropathy can persist after
treatment and is typicallynot late in onset.

Medical Conditions
Anorexia
Severe weight loss

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

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

Peripheral Neuropathy

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

Considerations for Further Testing and Intervention
Physical therapy referral for patients with symptomatic
neuropathy. Physical therapy and occupational therapy
assessment of hand function. Consider treatment with an
anticonvulsant effective for neuropathic pain (e.g., gabapentin
and amitriptyline).

SYSTEM = PNSSCORE = 2A

SECTION 41 REFERENCES
Chauvenet AR, Shashi V, Selsky C, Morgan E, Kurtzberg J, Bell B. 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. Apr 2003;25(4):316-320.
Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. Apr 1 1996;77x7):1356-1362.
Lehtinen SS, Huuskonen UE, Harila-Saari AH, Tolonen U, Vainionpaa LK, Lanning BM. Motor nervous system impairment persists in long-term survivors of childhood acute lymphoblastic leukemia. Cancer. May 1
2002;94(9):2466-2473.
Trobaugh-Lotrario AD, Smith AA, Odom LF. Vincristine neurotoxicity in the presence of hereditary neuropathy. Med Pediatr Oncol. Jan 2003;40(1):39-43.

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42

Therapeutic
Agent(s)PLANT ALKALOIDS
Vinblastine
Vincristine

Potential Late
Effects
Vasospastic attacks(Raynaud’s phenomenon)

PLANT ALKALOIDS (cont)
Risk
Factors
Health Behaviors
Smoking
Illicit drug use

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Vasospasms of hands, feet, nose, lips,
cheeks, or earlobes related to stressor cold temperatures
YearlyRaynaud’s Phenomenon

PHYSICAL
Physical exam of affected area
As IndicatedCounselingCounsel to wear appropriate protective clothing in cold
environments and to not use tobacco or illicit drugs(vasoconstrictors such as cocaine).

Considerations for Further Testing and Intervention
Consider vasodilating medications (calcium-channel blockers,alpha blockers) for patients with frequent, severe vasospastic
attacks unresponsive to behavioral management.

SYSTEM = PNSSCORE = 2A

SECTION 42 REFERENCES
Bokemeyer C, Berger CC, Kuczyk MA, Schmoll HJ. Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol. Nov 1996;14(11):2923-2932.
Doll DC, Ringenberg QS, Yarbro JW. Vascular toxicity associated with antineoplastic agents. J Clin Oncol. Sep 1986;4(9):1405-1417.
Vogelzang NJ, Bosl GJ, Johnson K, Kennedy BJ. Raynaud’s phenomenon: a common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med. Sep 1981;95(3):288-292.

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Therapeutic
Agent(s)Potential Late
Effects

43

EPIPODOPHYLLOTOXINS
Etoposide (VP16)
Teniposide (VM26)

Acute myeloid leukemia

Info Link
Epipodophyllotoxin
administration schedules
since approximately 1990;
have been modified to reduce
the risk of this complication.

EPIPODOPHYLLOTOXINS
Risk
Factors
Medical Conditions
Splenectomy (conflicting
evidence)

HighestRisk Factors
Treatment Factors
Weekly or twice weekly
administration
Less than 5 years since
exposure to agent
Autologous HCT

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

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

Reducing the Risk of Second Cancers

PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after exposure toagentCounselingCounsel to promptly report fatigue, pallor, petechiae, or bone
pain.

Considerations for Further Testing and Intervention
CBC and bone marrow exam as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 43 REFERENCES
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. Jan 1
2007;109(1):46-51.
Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin Oncol. Aug 2008;35(4):418-429.
Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. Dec 12 1991;325(24):1682-1687.
Pui CH. Epipodophyllotoxin-related acute myeloid leukaemia. Lancet. Dec 7 1991;338(8780):1468.
Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol. Feb 1999;17(2):569-577.
Rihani R, Bazzeh F, Faqih N, Sultan I. Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer. Sep 15
2010;116(18):4385-4394.

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RADIATIONINSTRUCTIONS

Whole lung radiation, if given, should be included in minimum dose calculations for Sections 75–77, 83, 102.

§

GENERAL FACTORS INFLUENCING RADIATION TOXICITY
Include: daily fraction size, cumulative dose, age of patient at irradiation and type of radiation used. Toxicity may not be
manifest until growth is completed or patient ages.

TESTICULAR

If field did not extend below iliac crest.
If field extended below iliac crest.

***

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TOTAL BODY IRRADIATION (TBI)

Total lymphoid irradiation(TLI)

MantleExetended mantle/Subtotal lymphoid irradiation (STLI)

PelvicVaginalProstate
Bladder
Iliac
Inguinal
FemoralMini-Mantle

Hepatic
Renal
Upper quadrant (right) (left)Spleen (partial) (entire)
Paraaortic
Flank/Hemiabdoment*(right) (left)

SPINE

Chest (thorax)
Whole Lung
Medatsitinal

Inverted Y/Whole abdoment/
FlankHemiabdomen** (right) (left)

Use the largest dose of radiation delivered to the spinal field(s) specified in the guideline section.

‡

LumbarTotal dose to each field should include boost dose, if given. If patient received radiation to more than one field relevant toa particular guideline section during a single planned course of radiation treatment (excluding spinal radiation and TBI),
the field that received the largest radiation dose should be used in making the determination as to the applicabilityof the indicated guideline section(s). Exception : If patient received radiation to the same field at different times (e.g.,
at time of diagnosis AND at relapse), these doses should be added together when considering the applicability of theindicated guideline section.

†

Scracl

2. Patient received a combination of radiation to any relevant field(s)† plus relevant spinal radiation‡ and/or TBI, the sumof which is ≥ the specified minimum dose§

EXTREMITIES (Upper) (Lower)OR

Cervical (neck)
Supraclavicular

AXILLA

1. Patient received radiation to any field(s) relevant to the particular guideline section at ≥ the specified minimum dose†

HEAD/BRAIN

Sections with minimum dose specifications are applicable to a patient only if:

NECKThoracic

RADIATION DOSE CALCULATIONS
Some sections of the COG Long-Term Follow-Up Guidelines relevant to radiation exposure include dose specifications.
These specifications indicate the minimum dose of radiation that is believed (based on available evidence and therecommendations of the expert panel) to place patients sufficiently at risk of the referenced late effect to recommend
screening. For guideline sections that have a minimum specified dose, the following considerations apply in determining
the applicability of the section for a patient based on his/her radiation exposure (see Appendix I—“Radiation Reference
Guide”—for examples).

THORAX

To determine specific screening guidelines by section number for an individual patient, use the “Patient-Specific
Guideline Identification Tool” in Appendix I together with the “Radiation Reference Guide.”
Cervical•

CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
Oropharyngeal
Waldeyer’s Ring

ABDOMEN

GENERAL CONSIDERATIONS•
The radiation sections of the COG Long-Term Follow-Up Guidelines (Sections 44–102) are organized by anatomic
region from the head downward. For specifics regarding relevant exposures to each anatomic region and radiation
field, refer to the applicable pages of the “Radiation Reference Guide” in Appendix I and to the figures in thissection.

PELVIS

DETERMINING APPLICABILITY OF RADIATION SECTIONS FOR SPECIFIC PATIENTS BASED ON EXPOSURE

RADIATIONINSTRUCTIONS (cont)GUIDE TO RADIATION SECTION NUMBERS BY ANATOMIC REGIONNOTES• This diagram provides an overview of the organization of the radiation sections of the COG Long-Term Follow-Up Guidelines.

Radiation Section Numbers by Anatomic Region• Radiation sections are arranged by anatomic region beginning with the cranium and proceeding downward.
HEAD/BRAIN• Arrows traversing multiple anatomic areas indicate body systems or organs (i.e., oral cavity, neck/thyroid, heart, esophagus, andbowel) that may be affected by radiation to any of the indicated anatomic regions.
• Additional detailed information, including examples of radiation dose calculations and diagrams of each body region are provided
in the “Radiation Reference Guide” (Appendix I).

NECK• Use the “Patient-Specific Guideline Identification Tool” in Appendix I together with the “Radiation Reference Guide” to determine
specific screening guidelines by section number for individual patients.

Neck/thyroid
71 72 73
74 75 76

Breast
77 78
Lungs
79

Esophagus
83
Heart
80 81

Liver/pancreas
84 85 Spleen
86 87
82
Kidneys
91

Bowel
88
89
Female Reproductive
90
95 96 97

Bladder/Urinary Tract
92 93 94

Male Reproductive
98 99

MUSCULOSKELETAL

THORAXABDOMEN

44
45
46
47

PELVIS

SKIN/ SOFT TISSUES/ BONESAXILLATOTAL BODY IRRADIATION (TBI)

44
45
48
49
50
55
64
69
71
72
73
77§
78
79
80
81
84
85
90§
91
95
96
98

Brain/Cranium/Sensory
48 49 50
51 52 53
54 55 56
57 58 59
60 61 62
Oral Cavity
63 64 65
68 69 70
66 67

Screening may be
indicated for patients
how received TBI
alone—see Info Link
in indicated section(s).

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100
101
102

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44

Therapeutic
Agent(s)All Radiation Fields(Including TBI)ALL FIELDS (INCLUDING TBI)
Potential Late
Effects

Risk
Factors

Secondary benign ormalignant neoplasm
Occurring in or near radiation
field

Host Factors
Cancer predisposing mutation(e.g., p53, RB1, NF1)
Younger age at treatment

Info Link
Patients with bilateral orfamilial retinoblastoma(implying a germline
mutation) are at increased
risk for developing second
malignant neoplasms.

Treatment Factors
High cumulative radiation
dose
Large radiation treatment
volumes
Alkylating agent exposure

HighestRisk Factors
Treatment Factors
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Inspection and palpation of skin and soft
tissues in irradiated field(s)YearlyReducing the Risk of Second Cancers

SCREENING
Other evaluations based on treatment
volumes
See recommendations for specific fields

Considerations for Further Testing and Intervention
Surgical and/or oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

• See “Radiation Reference Guide” in Appendix I for list of all radiation fields
applicable to this section.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 44 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. Mar 2011;41(3):373-379.
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. Aug 1 2011;29(22):3056-3064.
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
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. Dec 1 2003;21(23):4386-4394.
Fletcher O, Easton D, Anderson K, Gilham C, Jay M, Peto J. Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst. Mar 3 2004;96(5):357-363.
Forrest DL, Nevill TJ, Naiman SC, et al. Second malignancy following high-dose therapy and autologous stem cell transplantation: incidence and risk factor analysis. Bone Marrow Transplant. Nov 2003;32(9):915-923.
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. Jul 21 2010;102(14):1083-1095.
Howe R, Micallef IN, Inwards DJ, et al. Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma. Bone Marrow Transplant. Aug 2003;32(3):317-324.
Kolb HJ, Socie G, Duell T, et al. Malignant neoplasms in long-term survivors of bone marrow transplantation. Late Effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European
Late Effect Project Group. Ann Intern Med. Nov 16 1999;131(10):738-744.
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. May 10 2009 27(14):2356-2362.
Menu-Branthomme A, Rubino C, Shamsaldin A, et al. Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood. Int J Cancer. May 20 2004;110(1):87-93.
Rowlings PA, Curtis RE, Passweg JR, et al. Increased incidence of Hodgkin’s disease after allogeneic bone marrow transplantation. J Clin Oncol. Oct 1999;17(10):3122-3127.
Sultan I, Rihani R, Hazin R, Rodriguez-Galindo C. Second malignancies in patients with Ewing Sarcoma Family of Tumors: A population-based study. Acta Oncol. 2010;49(2):237-244.

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Therapeutic
Agent(s)All Radiation Fields(Including TBI)ALL FIELDS (INCLUDING TBI) (cont)
Potential Late
Effects
Dysplastic nevi
Skin cancer
Basal cell carcinoma
Squamous cell carcinoma
Melanoma

Risk
Factors
Host Factors
Gorlin’s syndrome (nevoidbasal cell carcinoma
syndrome)
Health Behaviors
Sun exposure
Tanning booths• See “Radiation Reference Guide” in Appendix I for list of all radiation fields
applicable to this section.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

HighestRisk Factors
Treatment Factors
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Skin lesions
Changing moles (asymmetry, bleeding,increasing size, indistinct borders)YearlySkin Health
Reducing the Risk of Second Cancers

PHYSICAL

Considerations for Further Testing and Intervention
Dermatology consultation for evaluation and monitoring ofatypical nevi. Oncology consultation as clinically indicated.

Dermatologic exam of irradiated fields
YearlySYSTEM = SMNSCORE = 1

SECTION 45 REFERENCES
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
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. May 15
2005;105(10):3802-3811.
Karagas MR, McDonald JA, Greenberg ER, et al. Risk of basal cell and squamous cell skin cancers after ionizing radiation therapy. For The Skin Cancer Prevention Study Group. J Natl Cancer Inst. Dec 18 1996;88(24):18481853.
Perkins JL, Liu Y, Mitby PA, et al. Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. Jun 1 2005;23(16):3733-3741.
Shore RE. Radiation-induced skin cancer in humans. Med Pediatr Oncol. May 2001;36(5):549-554.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J. Clin. Mar-Apr 2013;63(2):88-105.

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Therapeutic
Agent(s)All Radiation Fields(Except TBI)ALL FIELDS (EXCEPT TBI)
Potential Late
Effects
Dermatologic changes
Fibrosis
Telangiectasias
Permanent alopecia
Altered skin pigmentation

Risk
Factors
Host Factors
Younger age at treatment
Treatment Factors
Total radiation dose ≥ 40 Gy
Large dose fractions (e.g., ≥ 2
Gy per fraction)

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 50 Gy
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Dermatologic exam of irradiated fields
YearlySkin Health

SYSTEM = Dermatologic
SCORE = 1

• See “Radiation Reference Guide” in Appendix I for list of all radiation fields
applicable to this section.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 46 REFERENCES
Alsner J, Andreassen CN, Overgaard J. Genetic markers for prediction of normal tissue toxicity after radiotherapy. Semin Radiat Oncol. Apr 2008;18(2):126-135.
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. Jul 10 2012;30(20):2466-2474.
Lawenda BD, Gagne HM, Gierga DP, et al. Permanent alopecia after cranial irradiation: dose-response relationship. Int J Radiat Oncol Biol Phys. Nov 1 2004;60(3):879-887.
Marcus RB, DiCaprio MR, Lindskog DM, McGrath BE, Gamble K, Scarborough M. Musculoskeletal, Integument, Breast. In: Schwartz CL, Hobbie WL, Constine LS, Ruccione KS, eds. Survivors of Childhood and Adolescent Cancer: A
Multidisciplinary Approach, Second Edition. Heidelberg, Germany: Springer-Verlag 2005:262-269.
Rannan-Eliya YF, Rannan-Eliya S, Graham K, Pizer B, McDowell HP. Surgical interventions for the treatment of radiation-induced alopecia in pediatric practice. Pediatr Blood Cancer. Oct 15 2007;49(5):731-736.
Sanli H, Akay BN, Arat M, et al. Vitiligo after hematopoietic cell transplantation: six cases and review of the literature. Dermatology. 2008;216(4):349-354.
Severs GA, Griffin T, Werner-Wasik M. Cicatricial alopecia secondary to radiation therapy: case report and review of the literature. Cutis Feb 2008;81(2):147-153.
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. Feb 2006;91(2):258-261.

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Therapeutic
Agent(s)All Radiation Fields(Except TBI)ALL FIELDS (EXCEPT TBI) (cont)
Potential Late
Effects
Bone malignancies

Risk
Factors
Host Factors
Adolescent at treatment
Cancer-predisposing mutation(e.g., p53, RB1, NF1)
Treatment Factors
Higher radiation dose
Combined with alkylating
agents• See “Radiation Reference Guide” in Appendix I for list of all radiation fields
applicable to this section.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 30 Gy
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Counseling

Bone pain (especially in irradiated field)
YearlyCounsel patient to report symptoms promptly (e.g., bone pain,bone mass, persistent fevers)

PHYSICAL

Considerations for Further Testing and Intervention

Palpation of bones in irradiated field
YearlyX-ray or other diagnostic imaging in patients with clinicalsymptoms. Oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 47 REFERENCES
Hawkins MM, Wilson LM, Burton HS, et al. Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst. Mar 6 1996;88(5):270-278.
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. Sep 1
2012;84(1):224-230.
Lindor NM, McMaster ML, Lindor CJ, Greene MH. Concise handbook of familial cancer susceptibility syndromes–second edition. J Natl Cancer Inst Monogr. 2008;(38):1-93 (http://www.ncbi.nlm.nih.gov/pubmed/18559331).
Newton WA, Jr., Meadows AT, Shimada H, Bunin GR, Vawter GF. Bone sarcomas as second malignant neoplasms following childhood cancer. Cancer. Jan 1 1991;67(1):193-201.
Tucker MA, D’Angio GJ, Boice JD, Jr., et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. Sep 3 1987;317(10):588-593.

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Therapeutic
Agent(s)48

Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
Total Body Irradiation (TBI)

BRAIN/CRANIUM
Potential Late
Effects
Brain tumor (benign ormalignant)

Risk
Factors
Host Factors
Younger age at treatment
Neurofibromatosis
Treatment Factors
Higher radiation dose (Risk ofsubsequent CNS tumor after
cranial radiation increases
in a dose-response
relationship)

HighestRisk Factors
Host Factors
Age < 6 years at time oftreatment
Ataxia telangiectasia

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Headaches
Vomiting
Cognitive, motor or sensory deficits
Seizures and other neurologic symptoms
YearlyBrain MRI as clinically indicated for symptomatic patients.
Consider brain MRI every other year for patients withneurofibromatosis 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 = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 48 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471
Bowers DC, Nathan PC, Constine L, et al. Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol. Jul 2013;14(8):e321-328.
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. Jul 21 2010;102(14):1083-1095.
Lindor NM, McMaster ML, Lindor CJ, Greene MH. Concise handbook of familial cancer susceptibility syndromes–second edition. J Natl Cancer Inst Monogr. 2008;(38):1-93 (http://www.ncbi.nlm.nih.gov/pubmed/18559331).
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. Nov 1 2006;98(21):15281537.
Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst. Jun 3 2009 101(11):806-813.
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. Jun 1 2006;24(16):2570-2575.
Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. Jan 2000;18(2):348-357.
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. Dec 20 2010;28(36):5287-5293.
Vinchon M, Leblond P, Caron S, Delestret I, Baroncini M, Coche B. Radiation-induced tumors in children irradiated for brain tumor: a longitudinal study. Childs Nerv Syst. Mar 2011;27(3):445-453.
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. Dec 1998;16(12):3761-3767.
Witherspoon RP, Fisher LD, Schoch G, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med. Sep 21 1989;321(12):784-789

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Sec#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

49

Cranial
Ear/Infratemporal
Total Body Irradiation (TBI)

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

Host Factors
Younger age at treatment
Primary CNS tumor
CNS leukemia/lymphoma
Relapsed leukemia/lymphoma
treated with CNS-directed
therapy
Head/neck tumors with brain
in radiation field

Host Factors
Age < 3 years at time oftreatment
Female sex
Temporal lobe fieldPremorbid or family historyof learning or attention
problems

Info Link• Neurocognitive deficits
in survivors of leukemia
and lymphoma are more
frequently related to
information processing (e.g.,learning disability).
• Neurocognitive deficits
in brain tumor survivors
treated with higher doses of
cranial radiation are moreglobal (significant decline
in IQ).
• Extent of deficit depends on
age at treatment, intensityof treatment, and time sincetreatment.
• New deficits may emerge
over time.

Treatment Factors
Radiation in combination with:-- Corticosteroids-- Methotrexate (IT, IO, highdose IV)-- Cytarabine (high-dose IV)
Higher radiation dose
Larger radiation field
Greater cortical volumes
Cranial radiation in
combination with TBI
Longer elapsed time since
therapy

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Educational and/or vocational progress
YearlyEducational Issues

SCREENING

Formal neuropsychological evaluation to include tests ofprocessing speed, computer-based attention, visual motor
integration, memory, comprehension of verbal instructions,verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orcancer center (psychologist, social worker, school counselor)
to facilitate acquisition of educational resources and/or social
skills training. Consider use of psychotropic medication (e.g.,
stimulants) or evidence-based rehabilitation training. Caution- lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended. Refer to community
services for vocational rehabilitation or for services fordevelopmentally disabled.

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

Considerations for Further Testing and Intervention

SYSTEM = CNSSCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 49 REFERENCES
Armstrong GT, Jain N, Liu W, et al. Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. Neuro Oncol. Nov 2010;12(11):1173-1186.
Butler RW, Copeland DR, Fairclough DL, et al. A multicenter, randomized clinical trial of a cognitive remediation program for childhood survivors of a pediatric malignancy. J Consult Clin Psychol. Jun 2008;76(3):367-378.
Di Pinto M, Conklin HM, Li C, Xiong X, Merchant TE. Investigating verbal and visual auditory learning after conformal radiation therapy for childhood ependymoma. Int J Radiat Oncol Biol Phys. Jul 15 2010;77(4):1002-1008.
Ellenberg L, Liu Q, Gioia G, et al. Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology. Nov 2009 23(6):705-717.
Kupst MJ, Penati B, Debban B, et al. Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study. Bone Marrow Transplant. Nov 2002;30(9):609-617.
Mabbott DJ, Spiegler BJ, Greenberg ML, Rutka JT, Hyder DJ, Bouffet E. Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol. Apr 1 2005;23(10):2256-2263.
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Therapeutic
Agent(s)BRAIN/CRANIUM (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 49 REFERENCES–continued
Mulhern RK, Palmer SL, Reddick WE, et al. Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss. J Clin Oncol. Jan 15 2001;19(2):472-479.
Palmer SL, Gajjar A, Reddick WE, et al. Predicting intellectual outcome among children treated with 35-40 Gy craniospinal irradiation for medulloblastoma. Neuropsychology. Oct 2003;17(4):548-555.
Phipps S, Dunavant M, Srivastava DK, Bowman L, Mulhern RK. Cognitive and academic functioning in survivors of pediatric bone marrow transplantation. J Clin Oncol. Mar 2000;18(5):1004-1011.
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. Jan 2003;40(1):26-34.
Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol. Aug 1
2001;19(15):3470-3476.
Robinson KE, Kuttesch JF, Champion JE, et al. A quantitative meta-analysis of neurocognitive sequelae in survivors of pediatric brain tumors. Pediatr Blood Cancer. Sep 2010;55(3):525-531.
Simms S, Kazak AE, Gannon T, Goldwein J, Bunin N. Neuropsychological outcome of children undergoing bone marrow transplantation. Bone Marrow Transplant. Jul 1998;22(2):181-184.
Waber DP, Tarbell NJ, Fairclough D, et al. Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol. Oct 1995.
Walter AW, Mulhern RK, Gajjar A, et al. Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children’s Research Hospital. J Clin Oncol. Dec 1999;17(12):3720-3728.

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Therapeutic
Agent(s)50

Cranial
Ear/Infratemporal
Total Body Irradiation (TBI)

BRAIN/CRANIUM (cont)
Potential Late
Effects
Clinicalleukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures
Info Link• Clinical leukoencephalopathy may present with orwithout imaging abnormalities (e.g., leukoencephalopathy, cerebral lacunes,
cerebral atrophy, dystrophic
calcifications, mineralizing
microangiopathy).
• Transient white matter
anomalies may follow
radiotherapy and highdose chemotherapy for
medulloblastoma/PNET, may
mimic tumor recurrence,and signify risk of persistentneurologic sequelae.
• Neuroimaging changes
do not always correlatewith degree of cognitive
dysfunction. Prospective
studies are needed to define
the dose/effect relationshipof neurotoxic agents.
• New deficits may emerge
over time.

Risk
Factors
Host Factors
Younger age at treatment
CNS leukemia/lymphoma
Relapsed leukemia/lymphoma
treated with CNS-directed
therapy
Treatment Factors
In combination with:-- Dexamethasone-- Methotrexate (IT, IO, highdose IV)-- Cytarabine (high-dose IV)-- Higher radiation dose
Larger radiation field
Greater cortical volumes
Longer elapsed time since
therapy

HighestRisk Factors
Host Factors
Radiation dose ≥ 24 Gy
Treatment Factors
Fraction dose ≥ 3 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Cognitive, motor and/or sensory deficits
Seizures
Other neurologic symptoms
YearlyBrain CT; Brain MRI with MR angiography as clinically indicatedwith preferred study based on intracranial lesion to beevaluated:-- 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.

PHYSICAL
Neurologic exam
YearlySYSTEM = CNSSCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 50 REFERENCES
Duffner PK. Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors. Neurologist. Nov 2004;10(6):293-310.
Faraci M, Lanino E, Dini G, et al. Severe neurologic complications after hematopoietic stem cell transplantation in children. Neurology. Dec 24 2002;59(12):1895-1904.
Fouladi M, Chintagumpala M, Laningham FH, et al. White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal
tumor. J Clin Oncol. Nov 15 2004;22(22):4551-4560.
Heckl S, Aschoff A, Kunze S. Radiation-induced cavernous hemangiomas of the brain: a late effect predominantly in children. Cancer. Jun 15 2002;94(12):3285-3291.
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. Jun 1997;28(6):387-400.

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Therapeutic
Agent(s)BRAIN/CRANIUM (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 50 REFERENCES–continued
Kingma A, Mooyaart EL, Kamps WA, Nieuwenhuizen P, Wilmink JT. 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. May 1993;15(2):231-238. 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. Jul 15 1995;32(4):913-918.

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51

Therapeutic
Agent(s)≥ 18 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

BRAIN/CRANIUM (cont)
Potential Late
Effects
Cerebrovascularcomplications
StrokeMoyamoyaOcclusive cerebral
vasculopathy
Cavernomas
Info Link• Moyamoya syndrome isthe complete occlusion of
one or more of the threemajor cerebral vessels withthe development of small,
immature collateral vessels.
• This condition reflects anattempt to revascularize
the ischemic portion of thebrain.
• Cavernomas are a common
late effect of cranialradiation, but the majority ofpatients with cavernomas
are asymptomatic.

Risk
Factors

HighestRisk Factors

Host Factors
Down syndrome

Host Factors
Parasellar tumor

Treatment Factors
Suprasellar radiation

Treatment Factors
Radiation dose ≥ 50 Gy
Circle of Willis in radiation
field

Medical Conditions
Sickle cell disease
Neurofibromatosis

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Hemiparesis
Hemiplegia
Weakness
Aphasia
YearlyBrain MRI with diffusion-weighted imaging with MR angiography
as clinically indicated. Neurology/neurosurgery consultationand follow-up. Physical and occupational therapy as clinicallyindicated. Note: Revascularization procedures are likely helpful
for moyamoya. Aspirin prophylaxis has not yet been shown to bebeneficial for moyamoya or occlusive cerebral vasculopathy.

PHYSICAL
Neurologic exam
Yearly• This section is only applicable to patients who:

SYSTEM = CNSSCORE = 1

1) Received radiation to any of the specified fields at ≥ 18 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 18 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 51 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. Nov 20 2006;24(33):5277-5282.
Burn S, Gunny R, Phipps K, Gaze M, Hayward R. Incidence of cavernoma development in children after radiotherapy for brain tumors. J Neurosurg. May 2007;106(5 Suppl):379-383.
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. Aug 2011;57(2):240-246.
Fung LW, Thompson D, Ganesan V. Revascularisation surgery for paediatric moyamoya: a review of the literature. Childs Nerv Syst. May 2005;21(5):358-364.
Kestle JR, Hoffman HJ, Mock AR. Moyamoya phenomenon after radiation for optic glioma. J Neurosurg. Jul 1993;79(1):32-35.
Merchant TE, Kun LE, Wu S, Xiong X, Sanford RA, Boop FA. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol. Aug 1 2009 27(22):3598-3604.
Morris B, Partap S, Yeom K, Gibbs IC, Fisher PG, King AA. Cerebrovascular disease in childhood cancer survivors: A Children’s Oncology Group Report. Neurology. Dec 1 2009 73(22):1906-1913.
Rudoltz MS, Regine WF, Langston JW, Sanford RA, Kovnar EH, Kun LE. Multiple causes of cerebrovascular events in children with tumors of the parasellar region. J Neurooncol. May 1998;37(3):251-261.
Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology. Mar 20 2007;68(12):932-938.

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52

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring

BRAIN/CRANIUM (cont)
Potential Late
Effects
Craniofacial abnormalities

Risk
Factors
Host Factors
Younger age at treatment
Treatment Factors
Higher radiation dose

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

HighestRisk Factors
Host Factors
Age < 5 years at time oftreatment
Treatment Factors
Radiation dose ≥ 30 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Resources

Psychosocial assessment, with attention
to:
Educational and/or vocational progress
Depression
Anxiety
Post-traumatic stress
Social withdrawal
YearlyFACES—The National Craniofacial Association(www.faces-cranio.org)

PHYSICAL
Craniofacial abnormalities
YearlyConsiderations for Further Testing and Intervention
Reconstructive craniofacial surgical consultation. Consultation
with psychologist in patients with adjustment disorders related
to facial asymmetry/deformity.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 52 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.
Mar 2003;25(3):215-222.
Kaste SC, Chen G, Fontanesi J, Crom DB, Pratt CB. Orbital development in long-term survivors of retinoblastoma. J Clin Oncol. Mar 1997;15(3):1183-1189.
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. Jul 10 2012;30(20):2466-2474.

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53

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring

BRAIN/CRANIUM (cont)
Potential Late
Effects
Chronic sinusitis

Risk
Factors
Treatment Factors
Radiation dose to sinuses≥ 30 Gy
Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)
Medical Conditions
Atopic history
Hypogammaglobulinemia

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Rhinorrhea, postnasal discharge
YearlyCT scan of sinuses as clinically indicated. Otolaryngology
consultation as clinically indicated.

PHYSICAL
SinusesYearlyNasal exam
YearlySYSTEM = Immune
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 53 REFERENCES
Chang CC, Chen MK, Wen YS, Lee HS, Wu HK, Liu MT. Effects of radiotherapy for nasopharyngeal carcinoma on the paranasal sinuses: study based on computed tomography scanning. J Otolaryngol. 2000;Feb 29(1):23-27.
Ellingwood KE, Million RR. Cancer of the nasal cavity and ethmoid/sphenoid sinuses. Cancer. Apr 1979;43(4):1517-1526.
Huang WH, Liu CM, Chao TK, Hung PK. Middle meatus bacteriology of acute rhinosinusitis in patients after irradiation of nasopharynx. Am J Rhinol. May-Jun 2007;21(3):286-288.
Liang KL, Kao TC, Lin JC, et al. Nasal irrigation reduces postirradiation rhinosinusitis in patients with nasopharyngeal carcinoma. Am J Rhinol. May-Jun 2008;

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54

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring

BRAIN/CRANIUM (cont)
Potential Late
Effects
Overweight
Obesity
Info Link
Overweight: Age 2–20 years:
BMI for age ≥ 85th– < 95th
percentile
Age ≥ 21 years:
BMI ≥ 25–29.9
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

Risk
Factors
Host Factors
Younger at treatment
Treatment Factors
Higher cranial radiation dose
Surgery in suprasellar region
Combined with corticosteroids
Prolonged corticosteriod
therapy (e.g., for chronic
GVHD)

HighestRisk Factors
Host Factors
Age < 4 years old at time oftreatment
Female sex
Treatment Factors
Cranial radiation dose ≥ 18 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

HeightWeightBMI
Blood pressure
YearlyDiet and Physical Activity
Cardiovascular Risk Factors

Medical Conditions
Inability to exercise

Medical Conditions
Familial dyslipidemia
Growth hormone deficiency
Hypothyroidism
Hypogonadism• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

CounselingCounsel regarding obesity-related health risks

Considerations for Further Testing and Intervention
Consider evaluation for other co-morbid conditions, including
dyslipidemia, hypertension, or impaired glucose metabolism.
Nutritional counseling.
Info Link• Overweight/obesity may occur in a constellation of conditions
known as the metabolic syndrome.
• Definitions of the metabolic syndrome are evolving, but generally include a combination of central (abdominal) obesity withat least 2 or more of the following:-- hypertension-- atherogenic dyslipidemia (elevated triglycerides, reduced HDLcholesterol), and-- abnormal glucose metabolism (fasting hyperglycemia, hyperinsulinism, insulin resistance, diabetes mellitus type II).

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 54 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. Oct 20 2009 120(16):1640-1645.
Brennan BM, Rahim A, Blum WF, Adams JA, Eden OB, Shalet SM. Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf). Feb
1999;50(2):163-169.
Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med. Jan 14 1993;328(2):87-94.
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. Aug 1 2003;21(15):2953-2960.
de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA. The metabolic syndrome in cancer survivors. Lancet Oncol. Feb 2010;11(2):193-203.
Didi M, Didcock E, Davies HA, Ogilvy-Stuart AL, Wales JK, Shalet SM. High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood. J Pediatr. Jul 1995;127(1):63-67.
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 Oct 1
2008;26(28):4639-4645.
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. Aug 1999;135(2 Pt 1):162-168.
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. Jan 2010;19(1):170-181.
Nathan PC, Jovcevska V, Ness KK, et al. The prevalence of overweight and obesity in pediatric survivors of cancer. J Pediatr. Oct 2006;149(4):518-525.
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Therapeutic
Agent(s)BRAIN/CRANIUM (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 54 REFERENCES–continued
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. Aug 1 2009 27(22):3698-3704.
Oudin C, Simeoni MC, Sirvent N, et al. Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. Blood. Apr 28 2011;117(17):4442-4448.
Razzouk BI, Rose SR, Hongeng S, et al. Obesity in survivors of childhood acute lymphoblastic leukemia and lymphoma. J Clin Oncol. Apr 1 2007;25(10):1183-1189.
Reilly JJ, Ventham JC, Newell J, Aitchison T, Wallace WH, Gibson BE. Risk factors for excess weight gain in children treated for acute lymphoblastic leukaemia. Int J Obes Relat Metab Disord. Nov 2000;24(11):1537-1541.
Sklar CA, Mertens AC, Walter A, et al. Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukemia: role of cranial irradiation. Med Pediatr Oncol. Aug 2000;35(2):91-95.
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). Nov
2008;69(5):819-827.
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. Feb 3 2009 119(4):628-647.
Talvensaari KK, Lanning M, Tapanainen P, Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab. Aug 1996;81(8):3051-3055.
Warner JT, Evans WD, Webb DK, Gregory JW. Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol. Mar 2002;38(3):165-172.
Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. Jun 3 2004;350(23):2362-2374.
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. Dec 15 2009 53(7):1249-1254.

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Therapeutic
Agent(s)Potential Late
Effects

55

Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
Total Body Irradiation (TBI)

Growth hormone deficiency
Info Link
Growth charts available
on-line at www.cdc.gov/
growthcharts/

Risk
Factors
Host Factors
Younger age at treatment
Treatment Factors
Higher radiation doses
Surgery in suprasellar region
Pretransplant radiation
TBI ≥ 10 Gy in single fraction,≥ 12 Gy fractionatedHighestRisk Factors

Periodic
Evaluation

Treatment Factors
Radiation dose ≥ 18 Gy
Pretransplant cranial radiation
TBI given in single fraction

HISTORY

Health Links

Assessment of nutritional status
Every 6 months until growth is completed,then yearly.

Growth Hormone Deficiency
See also: Hypopituitarism

PHYSICAL

www.magicfoundation.org

Tanner staging
Every 6 months until sexually mature
HeightWeightBMI
Every 6 months until growth is completed,then yearly• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

Resources
Considerations for Further Testing and Intervention
For skeletally immature children, refer to endocrinology ifradiation 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 percdentile on
growth chart. Evaluate thyroid function in any poorly growing
child. Consult with endocrinologist regarding risks/benefits ofadult growth hormone replacement therapy. Consider bonedensity testing in patients who are growth hormone deficient.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 55 REFERENCES
Bongers ME, Francken AB, Rouwe C, Kamps WA, Postma A. Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation. Pediatr Blood Cancer. Aug 2005;45(2):139-143.
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. Sep 2004;89(9):4422-4427.
Cohen A, Rovelli A, Bakker B, et al. Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood. Jun 15
1999;93(12):4109-4115.
Costin G. Effects of low-dose cranial radiation on growth hormone secretory dynamics and hypothalamic-pituitary function. Am J Dis Child. Aug 1988;142(8):847-852.
Couto-Silva AC, Trivin C, Esperou H, et al. Final height and gonad function after total body irradiation during childhood. Bone Marrow Transplant. Sep 2006;38(6):427-432.
Didcock E, Davies HA, Didi M, Ogilvy Stuart AL, Wales JK, Shalet SM. Pubertal growth in young adult survivors of childhood leukemia. J Clin Oncol. Oct 1995;13(10):2503-2507.
Frisk P, Arvidson J, Gustafsson J, Lonnerholm G. Pubertal development and final height after autologous bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant. Jan 2004;33(2):205-210.
Giorgiani G, Bozzola M, Locatelli F, et al. Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone.
Blood. Jul 15 1995;86(2):825-831.
Gleeson HK, Darzy K, Shalet SM. Late endocrine, metabolic and skeletal sequelae following treatment of childhood cancer. Best Pract Res Clin Endocrinol Metab. Jun 2002;16(2):335-348.
Gurney JG, Ness KK, Sibley SD, et al. Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer. Sep 15 2006;107(6):1303-1312.
Huma Z, Boulad F, Black P, Heller G, Sklar C. Growth in children after bone marrow transplantation for acute leukemia. Blood. Jul 15 1995;86(2):819-824.
Leung W, Ahn H, Rose SR, et al. A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore). Jul 2007;86(4):215-224.
Merchant TE, Rose SR, Bosley C, Wu S, Xiong X, Lustig RH. Growth hormone secretion after conformal radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol. Dec 20 2011;29(36):4776-4780.
Merchant TE, Williams T, Smith JM, et al. Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function. Int J Radiat Oncol Biol Phys. Sep 1 2002;54(1):45-50.
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. Nov 2009 35(7):616-632.
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Therapeutic
Agent(s)NEUROENDOCRINE AXIS (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 55 REFERENCES–continued
Ogilvy-Stuart AL, Shalet SM. Growth and puberty after growth hormone treatment after irradiation for brain tumours. Arch Dis Child. Aug 1995;73(2):141-146.
Packer RJ, Boyett JM, Janss AJ, et al. Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control. J Clin Oncol. Jan 15 2001;19(2):480-487.
Sanders JE Growth and development after hematopoietic cell transplant in children. Bone Marrow Transplant. Jan 2008;41(2):223-227.
Sanders JE, Guthrie KA, Hoffmeister PA, Woolfrey AE, Carpenter PA, Appelbaum FR. Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood. Feb 1 2005;105(3):1348-1354.
Shalitin S, Gal M, Goshen Y, Cohen I, Yaniv I, Phillip M. Endocrine outcome in long-term survivors of childhood brain tumors. Horm Res Paediatr. 2011;76(2):113-122.
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. Jul 1993;123(1):5964.
Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1113-1121.
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). Nov
2008;69(5):819-827.
Wingard JR, Plotnick LP, Freemer CS, et al. Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation. Blood. Feb 15 1992;79(4):1068-1073.

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56(male)

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects
Precocious puberty

Risk
Factors
Host Factors
Younger age at treatment
Treatment Factors
Radiation doses ≥ 18 Gy• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

HeightWeightTanner staging
Testicular volume by Prader
orchidometry
Yearly until sexually mature

Precocious Puberty

Resources
www.magicfoundation.org

Considerations for Further Testing and Intervention
Obtain FSH, LH, testosterone as clinically indicated in patientswith signs of accelerated pubertal progression and growth.
Obtain x-ray for bone age in rapidly growing children. Endocrine
consultation for accelerated puberty (puberty in boy < 9 years
old).

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 56 REFERENCES
Darzy KH. Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab. Feb 2009 5(2):88-99.
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. Jun 1996;150(6):589-592.
Ogilvy-Stuart AL, Clayton PE, Shalet SM. Cranial irradiation and early puberty. J Clin Endocrinol Metab. Jun 1994;78(6):1282-1286.
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. Jul 20 1989;321(3):143-151.
Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1113-1121.
Sklar CA. Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am. Apr 1997;44(2):489-503.

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Sec#
57

Therapeutic
Agent(s)(female)Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects
Precocious puberty

Risk
Factors
Host Factors
Female sex
Younger age at treatment
Treatment Factors
Radiation doses ≥ 18 Gy

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

HeightWeightTanner staging
Yearly until sexually mature

Precocious Puberty

Resources
www.magicfoundation.org

Considerations for Further Testing and Intervention• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Obtain FSH, LH, estradiol as clinically indicated in patients withsigns of accelerated pubertal progression and growth. Obtain
x-ray for bone age in rapidly growing children. Endocrine
consultation for accelerated puberty (puberty in girl < 8 years
old).

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 57 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. Jun 1 2009 115(11):2562-2570.
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. Apr 2008;50(4):854- 858.
Darzy KH. Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab. Feb 2009 5(2):88-99.
Mills JL, Fears TR, Robison LL, Nicholson HS, Sklar CA, Byrne J. Menarche in a cohort of 188 long-term survivors of acute lymphoblastic leukemia. J Pediatr. Oct 1997;131(4):598-602.
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. Jun 1996;150(6):589-592.
Ogilvy-Stuart AL, Clayton PE, Shalet SM. Cranial irradiation and early puberty. J Clin Endocrinol Metab. Jun 1994;78(6):1282-1286.
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. Jul 20 1989;321(3):143-151.
Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1113-1121.
Sklar CA. Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am. Apr 1997;44(2):489-503.

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58(male)

Therapeutic
Agent(s)≥ 40 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects
Hyperprolactinemia

Risk
Factors
Treatment Factors
Higher radiation dose
Surgery or tumor in
hypothalamic area

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 50 Gy

Periodic
Evaluation
HISTORY

Health Links

Decreased libido
Galactorrhea
YearlyHyperprolactinemia

SCREENING• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 40 Gy

Health Counseling/
Further Considerations

Prolactin level
In patients with galactorrhea or decreased
libido.

• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.

Resources
www.magicfoundation.org

Considerations for Further Testing and Intervention
CT evaluation of sella turcica for pituitary adenoma in patientswith hyperprolactinemia. Endocrine consultation for patientswith hyperprolactinemia or galactorrhea.

SYSTEM = Endocrine/Metabolic
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 58 REFERENCES
Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med. Jan 14 1993;328(2):87-94.
Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1113-1121.

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Sec#
59

Therapeutic
Agent(s)(female)≥ 40 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects
Hyperprolactinemia

Risk
Factors
Treatment Factors
Higher radiation dose
Surgery or tumor in
hypothalamic area

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 50 Gy

Periodic
Evaluation
HISTORY

Health Links

Galactorrhea
Menstrual history
YearlyHyperprolactinemia

SCREENING• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 40 Gy

Health Counseling/
Further Considerations

Prolactin level
In patients with galactorrhea or
amenorrhea.

• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.

Resources
www.magicfoundation.org

Considerations for Further Testing and Intervention
CT evaluation of sella turcica for pituitary adenoma in patientswith hyperprolactinemia. Endocrine consultation for patientswith hyperprolactinemia or galactorrhea.

SYSTEM = Endocrine/Metabolic
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 59 REFERENCES
Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med. Jan 14 1993;328(2):87-94.
Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1113-1121.

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Sec#
60

Therapeutic
Agent(s)≥ 40 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects
Central hypothyroidism

Risk
Factors

HighestRisk Factors

Treatment Factors
Higher radiation dose

Info Link
Central hypothyroidism
includes thyroid-releasing andthyroid-stimulating hormone
deficiency• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening
during periods of rapid growth

Thyroid Problems
See also: Hypopituitarism

PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly, consider more frequent screening
during periods of rapid growthCounselingCounsel at-risk females of childbearing potential to have their
thyroid levels checked prior to attempting pregnancy andperiodically throughout pregnancy.

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 growth

SECTION 60 REFERENCES
Bonato C, Severino RF, Elnecave RH. Reduced thyroid volume and hypothyroidism in survivors of childhood cancer treated with radiotherapy. J Pediatr Endocrinol Metab. Oct 2008;21(10):943-949.
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). Jul 2001;55(1):21-25.
Livesey EA, Brook CG. Thyroid dysfunction after radiotherapy and chemotherapy of brain tumours. Arch Dis Child. Apr 1989;64(4):593-595.
Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, Poulsen HS, Muller J. A population-based study of thyroid function after radiotherapy and chemotherapy for a childhood brain tumor. J Clin Endocrinol Metab. Jan
2003;88(1):136-140.
Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1113-1121.

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61(male)

Therapeutic
Agent(s)≥ 30 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
TBI*

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects

Risk
Factors

Gonadotropin deficiency

Treatment Factors
Higher radiation doseHighestRisk Factors

Info Link
Gonadotropin deficiency
includes LH and FSH
deficiency.

Periodic
Evaluation
HISTORY

Health Links

Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyMale Health Issues
See also: Hypopituitarism

PHYSICAL• This section is only applicable to patients who:
*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

Tanner staging until sexually mature
Testicular volume by Prader orchiometer
YearlySCREENING
Semen analysis
At request of sexually mature patient
FSH
LH
Testosterone (ideally morning)
Baseline at age 14 and as clinicallyindicated in patients with delayed/arrested
puberty and/or clinical signs and symptomsof testosterone deficiency

Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org

Considerations for Further Testing and Intervention
Refer to endocrinologist for delayed puberty or persistently
abnormal hormone levels. Hormonal replacement therapy
for hypogonadal patients. Reproductive endocrinology
referral for infertility evaluation and consultation regarding
assisted reproductive technologies. Spermatogenesis can be
induced with gonadotropins in men with hypogonadotropic
hypogonadism. Consider bone density testing in patients who
are gonadotropin deficient.

SYSTEM = Reproductive (male)
SCORE = 1

SECTION 61 REFERENCES
Darzy KH. Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab. Feb 2009 5(2):88-99.
Gleeson HK, Shalet SM. The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer. Dec 2004;11(4):589-602.
Ogilvy-Stuart AL, Clayton PE, Shalet SM. Cranial irradiation and early puberty. J Clin Endocrinol Metab. Jun 1994;78(6):1282-1286.
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. Jul 20 1989;321(3):143-151.
Schmiegelow M, Lassen S, Poulsen HS, et al. Gonadal status in male survivors following childhood brain tumors. J Clin Endocrinol Metab. Jun 2001;86(6):2446-2452.

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RADIATION
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62

Therapeutic
Agent(s)(female)≥ 30 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
TBI*

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects

Risk
Factors

Gonadotropin deficiency

Treatment Factors
Higher radiation doseHighestRisk Factors

Info Link
Gonadotropin deficiency
includes LH and FSH
deficiency.

Periodic
Evaluation
HISTORY

Health Links

Pubertal (onset, tempo)
Menstrual/pregnancy history
Sexual function (vaginal dryness, libido)
Medication use
YearlyFemale Health Issues
See also: Hypopituitarism

PHYSICAL• This section is only applicable to patients who:
*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

Tanner staging
Yearly until sexually mature

SCREENING
FSH
LH
Estradiol
Baseline at age 13, and as clinicallyindicated in patients with delayed orarrested puberty, irregular menses, primaryor secondary amenorrhea, or clinical signs
and symptoms of estrogen deficiency

Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org

Considerations for Further Testing and Intervention
Refer to endocrinologist for delayed puberty or persistently
abnormal hormone levels. Hormonal replacement therapy for
hypogonadal patients. Reproductive endocrinology referral
for infertility evaluation and consultation regarding assisted
reproductive technologies. Consider bone density testing inpatients who are gonadotropin deficient.

SYSTEM = Reproductive (female)
SCORE = 1

SECTION 62 REFERENCES
Darzy KH. Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab. Feb 2009 5(2):88-99.
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. Apr 2008;50(4):854-858.
Gleeson HK, Shalet SM. The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer. Dec 2004;11(4):589-602.
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. Jun 1 2009 27(16):2677-2685.
Mills JL, Fears TR, Robison LL, Nicholson HS, Sklar CA, Byrne J. Menarche in a cohort of 188 long-term survivors of acute lymphoblastic leukemia. J Pediatr. Oct. 1997;131(4):598-602.
Ogilvy-Stuart AL, Clayton PE, Shalet SM. Cranial irradiation and early puberty. J Clin Endocrinol Metab. Jun 1994;78(6):1282-1286.
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. Jul 20 1989;321(3):143-151.
Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys. Apr 1 2009 73(5):1304-1312.

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63

Therapeutic
Agent(s)≥ 30 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Orbital/Eye
Waldeyer’s Ring
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

NEUROENDOCRINE AXIS (cont)
Potential Late
Effects
Central adrenal
insufficiency

Risk
Factors
Treatment Factors
Higher radiation dose
Surgery or tumor in the
suprasellar region

HighestRisk Factors
Treatment Factors
Prior development of anotherhypothalamic-pituitaryendocrinopathy• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Failure to thrive
Anorexia
Dehydration
Hypoglycemia
Lethargy
Unexplained hypotension
YearlyCentral Adrenal Insufficiency
See also: Hypopituitarism

SCREENING
Refer for yearly endocrinology evaluation
if dose to hypothalamic-pituitary axis
≥30 GyResources
www.magicfoundation.org

CounselingCounsel regarding corticosteroid replacement therapy and stressdosing. Counsel regarding Medical Alert bracelet.

SYSTEM = Endocrine/Metabolic
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 63 REFERENCES
Darzy KH. Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab. Feb 2009 5(2):88-99.
Gleeson HK, Shalet SM. The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer. Dec 2004;11(4):589-602.
Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. Nov 2008;93(11):4245-4253.
Oberfield SE, Nirenberg A, Allen JC, et al. Hypothalamic-pituitary-adrenal function following cranial irradiation. Horm Res. 1997;47(1):9-16.
Patterson BC, Truxillo L, Wasilewski-Masker K, Mertens AC, Meacham LR. Adrenal function testing in pediatric cancer survivors. Pediatr Blood Cancer. Dec 15 2009 53(7):1302-1307.
Rose SR, Danish RK, Kearney NS, et al. ACTH deficiency in childhood cancer survivors. Pediatr Blood Cancer. Nov 2005;45(6):808-813.
Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, Lange M, Poulsen HS, Muller J. Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor. J
Clin Endocrinol Metab. Jul 2003;88(7):3149-3154.
Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1113-1121.

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Therapeutic
Agent(s)64

CranialOrbital/Eye
Total Body Irradiation (TBI)
Info Link• Radiation-related ocularcomplications other thancataracts are generally
associated only with orbital/
eye radiation or higher dose
cranial radiation.
• Patients with a historyof an ocular tumor (e.g.,
retinoblastoma) are athigher risk for late-onset
ocular complications andshould receive ongoing
follow-up by an ophthalmologist at least annually, andmore frequently if clinicallyindicated.

EYE
Potential Late
Effects
Cataracts

Risk
Factors

HighestRisk Factors

Treatment Factors
Radiation dose ≥ 10 Gy
TBI ≥ 2 Gy in single fraction or≥ 5 Gy fractionatedRadiation combined with:-- Corticosteroids-- Busulfan-- Longer interval sincetreatment

Treatment Factors
Radiation dose ≥ 15 Gy
Fraction dose ≥ 2 Gy
TBI ≥ 5 Gy in single fraction or≥ 10 Gy fractionatedCranial/orbital/eye radiation
combined with TBI

Periodic
Evaluation
HISTORY

Health Links

Visual changes (decreased acuity, halos,
diplopia)
YearlyCataracts

PHYSICAL
Eye exam (visual acuity, funduscopic
exam for lens opacity)
YearlySCREENING• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

Evaluation by ophthalmologist
Yearly for patients with ocular tumors[regardless of radiation dose] and for
those who received TBI or ≥ 30 Gy cranial/
orbital/eye radiation
Every 3 years for patients without oculartumors who received < 30 Gy

Considerations for Further Testing and Intervention
Ongoing ophthalmology follow-up for identified problems. Refer
patients with visual deficits to school liaison in community orcancer center (psychologist, social worker, school counselor) tofacilitate acquisition of educational resources

SYSTEM = Ocular
SCORE = 1

SECTION 64 REFERENCES
Abramson DH, Servodidio CA. Ocular complications due to cancer treatment. In: Schwartz CL, Hobbie WL, Constine LS, Ruccione KS, eds. Survivors of Childhood Cancer: Assessment and Management. St. Louis: Mosby
1994:111-131.
Ainsbury EA, Bouffler SD, Dorr W, et al. Radiation cataractogenesis: a review of recent studies. Radiat Res. Jul 2009 172(1):1-9.
Fahnehjelm KT, Tornquist AL, Olsson M, Winiarski J. Visual outcome and cataract development after allogeneic stem-cell transplantation in children. Acta Ophthalmol Scand. Nov 2007;85(7):724-733.
Ferry C, Gemayel G, Rocha V, et al. Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies. Bone Marrow Transplant. Aug 2007;40(3):219-224.
Gurney JG, Ness KK, Rosenthal J, Forman SJ, Bhatia S, Baker KS. 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. Mar 15 2006;106(6):1402-1408.
Holmstrom G, Borgstrom B, Calissendorff B. Cataract in children after bone marrow transplantation: relation to conditioning regimen. Acta Ophthalmol Scand. Apr 2002;80(2):211-215.
Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. May 1 2003;101(9):3373-3385.
van Kempen-Harteveld ML, Belkacemi Y, Kal HB, Labopin M, Frassoni F. 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. Apr 1 2002;52(5):1367-1374.
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. Apr 1 2002;52(5):1375-1380.
Zierhut D, Lohr F, Schraube P, et al. Cataract incidence after total-body irradiation. Int J Radiat Oncol Biol Phys. Jan 1 2000;46(1):131-135.

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65

Therapeutic
Agent(s)≥ 30 Gy to:
CranialOrbital/Eye
TBI**TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.
Info Link• Radiation-related ocularcomplications other thancataracts are generally
associated only with orbital/
eye radiation or higher dose
cranial radiation.
• Patients with a historyof an ocular tumor (e.g.,
retinoblastoma) are athigher risk for late-onset
ocular complications andshould receive ongoing
follow-up by an ophthalmologist at least annually, andmore frequently if clinicallyindicated.

EYE (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

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

Treatment Factors
Higher radiation doseHigher daily fraction doseRadiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin) [problems
related to tearing]

Host Factors
Chronic GVHD (xerophthalmia
only)Treatment Factors
Total dose ≥ 50 Gy
Fraction dose ≥ 2 Gy

Info Link
Reduced visual acuity may
be associated with cataracts,
retinal damage, and optic
nerve damage.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Visual changes (decreased acuity, halos,
diplopia)
Dry eye
Persistent eye irritation
Excessive tearing
Light sensitivity
Poor night vision
Painful eye
YearlyEye Health

PHYSICAL
Visual acuity
Funduscopic exam
YearlySCREENING

Resources
FACES–The National Craniofacial Association website:www.faces-cranio.org/

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

Evaluation by ophthalmologist
Yearly• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 65 REFERENCES
Abramson DH, Servodidio CA. Ocular complications due to cancer treatment. In: Schwartz CL, Hobbie WL, Constine LS, Ruccione KS, eds. Survivors of Childhood Cancer: Assessment and Management. St. Louis: Mosby
1994:111-131.
Jeganathan VS, Wirth A, MacManus MP. Ocular risks from orbital and periorbital radiation therapy: a critical review. Int J Radiat Oncol. Biol. Phys. Mar 1 2011;79(3):650-659.
Mayo C, Martel MK, Marks LB, Flickinger J, Nam J, Kirkpatrick J. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol. Biol. Phys. Mar 1 2010;76(3 Suppl):S28-35.
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. Jan 2001;19(1):197-204.
Parsons JT, Bova FJ, Mendenhall WM, Million RR, Fitzgerald CR. Response of the normal eye to high dose radiotherapy. Oncology (Williston Park). Jun 1996;10(6):837-847 discussion 847-838, 851-832.
Shields CL, Shields JA, Cater J, Othmane I, Singh AD, Micaily B. Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology. Nov 2001;108(11):2116-2121.
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. Jan 2010;54(1):103-109.
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. Nov 2002;29(11):1428-1432.
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RADIATION
Sec#
66

Therapeutic
Agent(s)≥ 30 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Waldeyer’s Ring
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

EAR
Potential Late
Effects
Ototoxicity
Tympanosclerosis
Otosclerosis
Eustachian tube dysfunction
Conductive hearing loss

Risk
Factors
Host Factors
Younger age at treatment

HighestRisk Factors
Treatment Factors
Dose ≥ 50 Gy

Treatment Factors
Higher radiation dose
Medical Conditions
Chronic otitis
Chronic cerumen impaction

Periodic
Evaluation
HISTORY

Health Links

Hearing difficulties (with/withoutbackground noise)
Tinnitus
VertigoYearlyHearing Loss
Educational Issues

PHYSICAL
Otoscopic exam
Yearly• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

SCREENING
Complete audiological evaluation
Yearly after completion of therapy for
5 years [for patients < 10 years old,
continue yearly until age 10], then every
5 years
If hearing loss is detected, test at least
yearly or as recommended by audiologist
If clinical suspicion of hearing loss at any
time, test as clinically indicated
If audiogram is inconclusive or unevaluable,refer to audiologist for consideration ofelectrophysiologic testing e.g., otoacoustic
emissions [OAEs]

Considerations for Further Testing and Intervention
Audiology consultation for patients with hearing loss.
Otolaryngology consultation for patients with chronic infection,
cerumen impaction, or other anatomical problems exacerbatingor contributing to hearing loss. Speech and language therapy forchildren with hearing loss. Refer patients with auditory deficits
to school liaison in community or cancer center (psychologist,social worker, school counselor) to facilitate provision of
educational resources. Consider specialized evaluation for
specific needs and/or preferential classroom seating, FM
amplification system, and other educational assistance as
indicated.

SYSTEM = Auditory
SCORE = 1

Info Link• A “complete audiological evaluation” includes pure tone air and bone conduction,
speech audiometry, and tympanometry forboth ears.
• Frequency-specific auditory brainstem
response (ABR) can be performed if theabove is inconclusive.

SECTION 66 REFERENCES
Freilich RJ, Kraus DH, Budnick AS, Bayer LA, Finlay JL. Hearing loss in children with brain tumors treated with cisplatin and carboplatin-based high-dose chemotherapy with autologous bone marrow rescue. Med Pediatr Oncol.
Feb 1996;26(2):95-100.
Hua C, Bass JK, Khan R et al. Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose. Int J Biol Phys. 2008;Nov 1 72(3):892-899.
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. Mar 1 2002;52(3):599-605.
Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma inchildhood: results of the German prospective randomized trial HIT ‘91. Int J Radiat Oncol Biol Phys. Jan 15 2000;46(2):269-279.
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. Mar 15 2004;58(4):1194-1207.
Paulino AC, Simon JH, Zhen W, Wen BC. Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phy. Dec 12000;48(5):1489-1495.
Schell MJ, McHaney VA, Green AA, et al. Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation. J Clin Oncol. Jun 19897(6):754-760.
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RADIATION
Sec#
67

Therapeutic
Agent(s)≥ 30 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal
Waldeyer’s Ring
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

EAR (cont)
Potential Late
Effects
Ototoxicity
Sensorineural hearing loss
Tinnitus

Risk
Factors
Host Factors
Younger age at treatment
CNS tumor
Treatment Factors
Higher radiation dose
Conventional (non-conformal)
radiation
Medical Conditions
CSF shunting

HighestRisk Factors
Treatment Factors
Radiation administered prior
to platinum chemotherapy
Combined with other ototoxic
agents such as:-- Cisplatin-- Carboplatin in
myeloablative doses-- Aminoglycosides

Periodic
Evaluation
HISTORY

Health Links

Hearing difficulties (with/withoutbackground noise)
Tinnitus
VertigoYearlyHearing Loss
Educational Issues

PHYSICAL
Otoscopic exam
YearlySCREENING• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

Complete audiological evaluation
Yearly after completion of therapy for 5
years [for patients <10 years old, continue
yearly until age 10], then every 5 years
If hearing loss is detected, test at least
yearly or as recommended by audiologist
If clinical suspicion of hearing loss at any
time, test as clinically indicated
If audiogram is inconclusive or unevaluable,refer to audiologist for consideration ofelectrophysiologic testing e.g., otoacoustic
emissions [OAEs]

Considerations for Further Testing and Intervention
Audiology consultation for patients with hearing loss.
Otolaryngology consultation for patients with chronic infection,
cerumen impaction, or other anatomical problems exacerbatingor contributing to hearing loss. Speech and language therapy forchildren with hearing loss. Refer patients with auditory deficits
to school liaison in community or cancer center (psychologist,social worker, school counselor) to facilitate provision of
educational resources. Consider specialized evaluation for
specific needs and/or preferential classroom seating, FM
amplification system, and other educational assistance as
indicated.

SYSTEM = Auditory
SCORE = 1

Info Link• A “complete audiological evaluation” includes pure tone air and bone conduction,
speech audiometry, and tympanometry forboth ears.
• Frequency-specific auditory brainstem
response (ABR) can be performed if theabove is inconclusive.

SECTION 67 REFERENCES
Freilich RJ, Kraus DH, Budnick AS, Bayer LA, Finlay JL. Hearing loss in children with brain tumors treated with cisplatin and carboplatin-based high-dose chemotherapy with autologous bone marrow rescue. Med Pediatr Oncol.
Feb 1996;26(2):95-100.
Hua C, Bass JK, Khan R et al. Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose. Int J Biol Phys. 2008;Nov 1 72(3):892-899.
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. Mar 1 2002;52(3):599-605.
Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma inchildhood: results of the German prospective randomized trial HIT ‘91. Int J Radiat Oncol Biol Phys. Jan 15 2000;46(2):269-279.
Merchant et al. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer. 2008;51: 110-117.
Paulino AC, Simon JH, Zhen W, Wen BC. Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phy. Dec 12000;48(5):1489-1495.
Schell MJ, McHaney VA, Green AA, et al. Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation. J Clin Oncol. Jun 19897(6):754-760.
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RADIATION

ORAL CAVITYSec#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

68

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
MantleMini-Mantle
Total Lymphoid Irradiation(TLI)

Xerostomia
Salivary gland dysfunction

Treatment Factors
Head and neck radiation
involving the parotid gland
Higher radiation doses
Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)

Treatment Factors
Salivary gland dose ≥ 30 Gy
Medical Conditions
Chronic GVHD

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Xerostomia
YearlyDental Health

PHYSICAL

Supportive care with saliva substitutes, moistening agents, andsialogogues (pilocarpine)
Regular dental care including fluoride applications

Oral exam
YearlyConsiderations for Further Testing and Intervention

SCREENING
Dental exam and cleaning
Every 6 months

SYSTEM = Dental
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 68 REFERENCES
Antin JH. Clinical practice. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med. Jul 4 2002;347(1):36-42.
Chao KS, Deasy JO, Markman J, et al. A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results. Int J Radiat
Oncol Biol Phys. Mar 15 2001;49(4):907-916.
Deasy JO, Moiseenko V, Marks L, Chao KS, Nam J, Eisbruch A. Radiotherapy dose-volume effects on salivary gland function. Int J Radiat Oncol Biol Phys. Mar 1 2010;76(3 Suppl):S58-63.
Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. May 15 1991;21(1):109-122.
Guchelaar HJ, Vermes A, Meerwaldt JH. Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment. Support Care Cancer. Jul 1997;5(4):281-288.
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. Aug
2010;18(8):1039-1060.
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. Dec 15 2009 115(24):5817-5827.

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Sec#

Therapeutic
Agent(s)69

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
MantleMini-Mantle
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

ORAL CAVITY (cont)
Potential Late
Effects
Dental abnormalities
Tooth/root agenesis
Microdontia
Root thinning/shortening
Enamel dysplasia
Periodontal disease
Dental caries
Malocclusion
Temporomandibular joint
dysfunction

Risk
Factors
Host Factors
Younger age at treatment
Gorlin’s syndrome (nevoidbasal cell carcinoma
syndrome)
Treatment Factors
Higher radiation doseHighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

Host Factors
Age < 5 years at time oftreatment

PHYSICAL

Health Links

Oral exam
YearlyDental Health

Treatment Factors
Dose ≥ 10 Gy

SCREENING

Regular dental care including fluoride applications. Consultation
with orthodontist experienced in management of irradiatedchildhood cancer survivors. Baseline panorex prior to dental
procedures to evaluate root development.

Dental exam and cleaning
Every 6 months

Considerations for Further Testing and Intervention

SYSTEM = Dental
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 69 REFERENCES
Dahllof G, Bagesund M, Remberger M, Ringden O. Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol. Sep 1997;33(5):327-331.
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. Sep 1997;20(6):479-483.
Dahllof G, Jonsson A, Ulmner M, Huggare J. Orthodontic treatment in long-term survivors after pediatric bone marrow transplantation. Am J Orthod Dentofacial Orthop. Nov 2001;120(5):459-465.
Goho C. Chemoradiation therapy: effect on dental development. Pediatr Dent. Jan-Feb 1993;15(1):6-12.
Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol. Nov 1 2007;25(31):4873-4879.
Kaste SC, Hopkins KP, Bowman LC. Dental abnormalities in long-term survivors of head and neck rhabdomyosarcoma. Med Pediatr Oncol. Aug 1995;25(2):96-101.
Kaste SC, Hopkins KP, Jones D, Crom D, Greenwald CA, Santana VM. Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia. Jun 1997;11(6):792-796.
Maguire A, Welbury RR. Long-term effects of antineoplastic chemotherapy and radiotherapy on dental development. Dent Update. Jun 1996;23(5):188-194.
Raney RB, Asmar L, Vassilopoulou-Sellin R, et al. Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma
Studies (IRS)-II and - III. IRS Group of the Children’s Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol. Oct 1999;33(4):362-371.
Sonis AL, Tarbell N, Valachovic RW, Gelber R, Schwenn M, Sallan S. Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities. Cancer. Dec 15
1990;66(12):2645-2652.

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Sec#

Therapeutic
Agent(s)70≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
MantleMini-Mantle
Total Lymphoid Irradiation
(TLI)
TBI*

ORAL CAVITY (cont)
Potential Late
Effects
Osteoradionecrosis

Risk
Factors
Treatment Factors
Radiation dose to bone
≥ 45 Gy

HighestRisk Factors
Treatment Factors
Dose ≥ 50 Gy• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Impaired or delayed healing following
dental work
Persistent jaw pain or swelling
TrismusAs clinically indicatedOsteoradionecrosis

PHYSICAL
Impaired wound healing
Jaw swelling
TrismusAs clinically indicatedConsiderations for Further Testing and Intervention
Imaging studies (x-ray, CT scan and/or MRI) may assist in
making diagnosis. Surgical biopsy may be needed to confirm
diagnosis. Consider hyperbaric oxygen treatments.

SYSTEM = Dental
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

SECTION 70 REFERENCES
Ashamalla HL, Ames JW, Uri A, Winkler P. Hyperbaric oxygen in the management of osteoradionecrosis. Med Pediatr Oncol. Jul 1996;27(1):48-53.
Duggal MS, Curzon ME, Bailey CC, Lewis IJ, Prendergast M. Dental parameters in the long-term survivors of childhood cancer compared with siblings. Oral Oncol. Sep 1997;33(5):348-353.
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.
Mar 2003;25(3):215-222.
Nasman M, Forsberg CM, Dahllof G. Long-term dental development in children after treatment for malignant disease. Eur J Orthod. Apr 1997;19(2):151-159.
Paulino AC, Simon JH, Zhen W, Wen BC. Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. Dec 1 2000;48(5):1489-1495.

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RADIATION
Sec#

Therapeutic
Agent(s)71

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
MantleMediastinal
Mini-Mantle
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

NECK/THYROID
Potential Late
Effects
Thyroid nodules

Risk
Factors
Host Factors
Younger age at treatment
Female sex

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 25 Gy

Treatment Factors
Higher radiation dose
Thyroid gland directly inradiation field
TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Thyroid exam
YearlyThyroid Problems

Considerations for Further Testing and Intervention
Ultrasound and FNA for evaluation of palpable nodule(s).
Endocrine and/or surgical consultation for diagnostic biopsy or
thyroidectomy.

SYSTEM = SMN• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SCORE = 1

SECTION 71 REFERENCES
Black P, Straaten A, Gutjahr P. Secondary thyroid carcinoma after treatment for childhood cancer. Med Pediatr Oncol. Aug 1998;31(2):91-95.
Constine LS, Donaldson SS, McDougall IR, Cox RS, Link MP, Kaplan HS. Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer. Feb 15 1984;53(4):878-883.
DeGroot LJ. Effects of irradiation on the thyroid gland. Endocrinol Metab Clin North Am. Sep 1993;22(3):607-615.
Faraci M, Barra S, Cohen A, et al. Very late nonfatal consequences of fractionated TBI in children undergoing bone marrow transplant. Int J Radiat Oncol Biol Phys. Dec 1 2005;63(5):1568-1575.
Metzger ML, Howard SC, Hudson MM, et al. Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma. Pediatr Blood Cancer. Mar 2006;46(3):314-319.
Schneider AB, Shore-Freedman E, Weinstein RA. Radiation-induced thyroid and other head and neck tumors: occurrence of multiple tumors and analysis of risk factors. J Clin Endocrinol Metab. Jul 1986;63(1):107-112.
Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet. Jun 28 2005;365(9476):2014-2023.
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. Sep 2000;85(9):3227-3232.

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RADIATION
Sec#

Therapeutic
Agent(s)72

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
MantleMediastinal
Mini-Mantle
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

NECK/THYROID (cont)
Potential Late
Effects
Thyroid cancer

Risk
Factors

HighestRisk Factors

Host Factors
Younger age at treatment
Female sex
Treatment Factors> 5 years after irradiation
Thyroid gland directly inradiation field
TBI
Risk increased up to 30 Gy
with a downturn of risk after
30 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Thyroid exam
YearlyThyroid Problems

Considerations for Further Testing and Intervention
Ultrasound and FNA for evaluation of palpable nodule(s). Surgicalconsultation for resection. Nuclear medicine consultation
for ablation of residual disease. Endocrine consultation for
postoperative medical management.

SYSTEM = SMNSCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 72 REFERENCES
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
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. Dec
2010;174(6):741-752.
Brignardello E, Corrias A, Isolato G, et al. Ultrasound screening for thyroid carcinoma in childhood cancer survivors: a case series. J Clin Endocrinol Metab. Dec 2008;93(12):4840-4843.
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. Jun 10 2007;25(17):2449-2454.
Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med. Mar 27 1997;336(13):897-904.
DeGroot LJ. Effects of irradiation on the thyroid gland. Endocrinol Metab Clin North Am. Sep 1993;22(3):607-615.
Hancock SL, McDougall IR, Constine LS. Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1165-1170.
Hegedus L. Thyroid ultrasonography as a screening tool for thyroid disease. Thyroid. Nov 2004;14(11):879-880.
Inskip PD. Thyroid cancer after radiotherapy for childhood cancer. Med Pediatr Oncol. May 2001;36(5):568-573.
Jereczek-Fossa BA, Alterio D, Jassem J, Gibelli B, Tradati N, Orecchia R. Radiotherapy-induced thyroid disorders. Cancer Treat Rev. Jun 2004;30(4):369-384.
Martinek A, Dvorackova J, Honka M, Horacek J, Klvana P. Importance of guided fine needle aspiration cytology (FNAC) for the diagnostics of thyroid nodules—own experience. Biomed Pap Med Fac Univ Palacky Olomouc Czech
Repub. Jul 2004;148(1):45-50.
Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst. Jun 3 2009 101(11):806-813.
Robison LL. Treatment-associated subsequent neoplasms among long-term survivors of childhood cancer: the experience of the Childhood Cancer Survivor Study. Pediatr Radiol. Feb 2009 39 Suppl 1:S32-37.
Schneider AB, Fogelfeld L. Radiation-induced endocrine tumors. Cancer Treat Res. 1997;89:141-161.
Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet. Jun 28 2005;365(9476):2014-2023.
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. Sep 2000;85(9):3227-3232.
Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. Jan 2000;18(2):348-357.
Taylor AJ, Croft AP, Palace AM, et al. Risk of thyroid cancer in survivors of childhood cancer: results from the British Childhood Cancer Survivor Study. Int J Cancer. Nov 15 2009 125(10):2400-2405.

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RADIATION
Sec#

Therapeutic
Agent(s)73

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
MantleMediastinal
Mini~Mantle
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

NECK/THYROID (cont)
Potential Late
Effects
Hypothyroidism

Risk
Factors
Host Factors
Female sex

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 20 Gy

Treatment Factors
Radiation dose ≥ 10 Gy
Thyroid gland directly inradiation field
TBI

Periodic
Evaluation
HISTORY

Health Links

Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearlyConsider more frequent screening during
periods of rapid growth

Thyroid Problems

PHYSICAL• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

HeightWeightHair and skin
Thyroid exam
YearlyConsider more frequent screening during
periods of rapid growthCounselingCounsel at-risk females of childbearing potential to have their
thyroid levels checked prior to attempting pregnancy andperiodically throughout pregnancy.

Considerations for Further Testing and Intervention
Endocrine consultation for medical management.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SCREENING
TSHFree T4
YearlyConsider more frequent screening during
periods of rapid growth

SECTION 73 REFERENCES
Cheuk DK, Billups CA, Martin MG, et al. Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer. Jan 1 2011;117(1):197-206.
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.
Aug 15 1997;80(4):798-804.
Constine LS, Donaldson SS, McDougall IR, Cox RS, Link MP, Kaplan HS. Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer. Feb 15 1984;53(4):878-883.
DeGroot LJ. Effects of irradiation on the thyroid gland. Endocrinol Metab Clin North Am. Sep 1993;22(3):607-615.
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. May 1990;5(5):335-340.
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. Jul 15 2011;57(1):166-168.
Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR. Thyroid function after treatment of brain tumors in children. J Pediatr. Nov 1991;119(5):733-737.
Sanders JE. Endocrine complications of high-dose therapy with stem cell transplantation. Pediatr Transplant. Jun 2004;8 Suppl 5:39-50.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.
Sklar C, Kim TH, Ramsay NK. Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med. Nov 1982;73(5):688-694
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. Sep 2000;85(9):3227-3232.
Vogelius IR, Bentzen SM, Maraldo MV, Petersen PM, Specht L. Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis. Cancer. Dec 1 2011;117(23):5250-5260.

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RADIATION
Sec#

Therapeutic
Agent(s)74≥ 40 Gy to:
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
MantleMediastinal
Mini-Mantle
Total Lymphoid Irradiation
(TLI)
TBI*

NECK/THYROID (cont)
Potential Late
Effects
Hyperthyroidism

Risk
Factors

HighestRisk Factors

Treatment Factors
Higher radiation dose

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Heat intolerance
Tachycardia
Palpitations
Weight loss
Emotional lability
Muscular weakness
Hyperphagia
YearlyThyroid Problems

PHYSICAL

Considerations for Further Testing and Intervention
Endocrine consultation for medical management.

SYSTEM = Endocrine/Metabolic
SCORE = 1

Eyes
Skin
Thyroid
Cardiac
Neurologic
YearlySCREENING
TSHFree T4
YearlySECTION 74 REFERENCES
Constine LS, Donaldson SS, McDougall IR, Cox RS, Link MP, Kaplan HS. Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer. Feb 15 1984;53(4):878-883.
DeGroot LJ. Effects of irradiation on the thyroid gland. Endocrinol Metab Clin North Am. Sep 1993;22(3):607-615.
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. May 1990;5(5):335-340.
Perz JB, Marin D, Szydlo RM, et al. Incidence of hyperthyroidism after unrelated donor allogeneic stem cell transplantation. Leuk Res. Oct 2007;31(10):1433-1436.
Sanders JE. Endocrine complications of high-dose therapy with stem cell transplantation. Pediatr Transplant. Jun 2004;8 Suppl 5:39-50.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.
Sklar C, Kim TH, Ramsay NK. Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med. Nov 1982;73(5):688-694
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. Sep 2000;85(9):3227-3232.

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RADIATION
Sec#

Therapeutic
Agent(s)75≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Chest (thorax)
Extended Mantle
MantleMediastinal
Mini~Mantle
Whole lung
Total Lymphoid Irradiation
(TLI)
TBI*

NECK/THYROID (cont)
Potential Late
Effects
Carotid artery disease

Risk
Factors

HighestRisk Factors

Medical Conditions
Hypertension
Diabetes mellitus
Hypercholesterolemia

Periodic
Evaluation
HISTORY

Considerations for Further Testing and Intervention

Memory impairment
YearlyDoppler ultrasound of carotid vessels as clinically indicated.
MRI with diffusion-weighted imaging with MR angiography
and cardiovascular surgery consultation as clinically indicated.
Consider color Doppler 10 years after completion of radiation
therapy to the neck as a baseline refer to cardiologist if
abnormal.

PHYSICAL• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 40 Gy

Health Counseling/
Further Considerations

Diminished carotid pulses
Carotid bruits
Abnormal neurologic exam (compromiseof blood flow to brain)
YearlySYSTEM = Cardiovascular
SCORE = 2A

• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

SECTION 75 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. Sep 20 2005;23(27):6508-6515.
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. Jul 1 2009 101(13):928-937.
Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA. Dec 3 2003;290(21):2831-2837.
Meeske KA, Siegel SE, Gilsanz V, et al. Premature carotid artery disease in pediatric cancer survivors treated with neck irradiation. Pediatr Blood Cancer. Oct 2009 53(4):615-621.
Morris B, Partap S, Yeom K, Gibbs IC, Fisher PG, King AA. Cerebrovascular disease in childhood cancer survivors: A Children’s Oncology Group Report. Neurology. Dec 1 2009 73(22):1906-1913.
Qureshi AI, Alexandrov AV, Tegeler CH, Hobson RW, 2nd, Dennis Baker J, Hopkins LN. Guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary practiceguidelines committee of the American Society of Neuroimaging cosponsored by the Society of Vascular and Interventional Neurology. J Neuroimaging. Jan 2007;17(1):19-47.

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NECK/THYROID (cont)

Sec#

Therapeutic
Agent(s)Potential Late
Effects76≥ 40 Gy to:
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Chest (thorax)
Extended Mantle
MantleMediastinal
Mini-Mantle
Whole lung
Total Lymphoid Irradiation
(TLI)
TBI*

Subclavian artery disease

Risk
Factors

HighestRisk Factors• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Considerations for Further Testing and Intervention

Diminished brachial and radial pulses
Pallor of upper extremities
Coolness of skin
Unequal blood pressure
YearlyDoppler ultrasound of subclavian vessels as clinically indicated.
MRI with diffusion-weighted imaging with MR angiography
and cardiovascular surgery consultation as clinically indicated.
Consider color Doppler 10 years after completion of radiation
therapy to the neck as a baseline refer to cardiologist if
abnormal.

SYSTEM = Cardiovascular
SCORE = 2A

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

SECTION 76 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. Sep 20 2005;23(27):6508-6515.
Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA. Dec 3 2003;290(21):2831-2837.

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RADIATION
Sec#

Therapeutic
Agent(s)77≥ 10 Gy to:
Subtotal Lymphoid Irradiation(STLI)
AxillaChest (thorax)
Extended Mantle
MantleMediastinal
Mini~Mantle
Whole lung
Total Body Irradiation (TBI)*
Total Lymphoid Irradiation(TLI)(female)Info Link• *Important: The risk of breast
cancer in patients who received 10–19 Gy of radiation
with potential impact to thebreast or those who received
TBI alone is of a lower magnitude compared to those who
received ≥ 20 Gy of radiation
with potential impact to thebreast (e.g.,thorax, axilla).
• Monitoring of patients who
received 10-19 Gy of radiation
with potential impact to thebreast, or those who received
TBI without additional radiation,should be determined on
an individual basis.
• After the clinician discusses the benefits and risks/
harms of screening with thepatient, if a decision is madeto screen, then follow therecommendations for patients
who received ≥ 20 Gy.

BREAST
Potential Late
Effects
Breast cancer

Risk
Factors
Host Factors
Family history of breast
cancerHighestRisk Factors
Host Factors
BRACA1, BRACA2, ATMmutation

Treatment Factors
Higher radiation doseLonger time since radiation( > 5 years)
Decreased risk in women
treated with alkylating
agents• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 10 Gy
OR2) Received a combination of radiation to any of the specified fields, thesum of which is ≥ 10 Gy
OR3) Received TBI alone• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Breast exam
Yearly, beginning at puberty until age 25,
then every 6 months

Breast Cancer

SCREENING≥ 20 Gy
Mammogram
Yearly, beginning 8 years after radiation orat age 25, whichever occurs last.
Breast MRI
Yearly, as an adjunct to mammography
beginning 8 years after radiation or at age
25, whichever occurs last.
10 –19 Gy or TBI alone
Clinician to discuss benefits and risks/
harms of screening with patient. If
decision is made to screen, then follow
screening recommendations for ≥ 20 Gy.

Counseling
Teach breast self-exam and counsel to perform monthly
beginning at puberty.

Considerations for Further Testing and Intervention
Surgical consultation for diagnostic procedure in patients withbreast mass or suspicious radiographic finding. Decisions
regarding the use of HRT should be based on current literatureand should take into consideration the risk/benefit ratio forindividual patients.

SYSTEM = SMNSCORE = 1

Info Link• Mammography is currently limited in its
ability to evaluate the premenopausal
breast.
• MRI is now recommended as an adjunctto mammography in women treatedwith chest radiation for childhood cancer
similar to screening of other populations
at high risk for breast cancer (e.g.,premenopausal known or likely carriers ofgene mutation of known penetrance).
• The upper age limit at which both modalities should be used for breast cancer
surveillance has not been established.

SECTION 77 REFERENCES
Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med. Mar 21 1996;334(12):745-751.
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. Dec 1 2003;21(23):4386-4394.
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. Sep 10 2009 27(26):4239-4246.
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Therapeutic
Agent(s)BREAST (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 77 REFERENCES—continued
Friedman DL, Rovo A, Leisenring W, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party. Blood. Jan 15
2008;111(2):939-944.
Guibout C, Adjadj E, Rubino C, et al. Malignant breast tumors after radiotherapy for a first cancer during childhood. J Clin Oncol. Jan 1 2005;23(1):197-204.
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. Apr 6 2010;152(7):444-455
W144-454.
Inskip PD, Robison LL, Stovall M, et al. Radiation dose and breast cancer risk in the childhood cancer survivor study. J Clin Oncol. Aug 20 2009 27(24):3901-3907.
Kaste SC, Hudson MM, Jones DJ, et al. Breast masses in women treated for childhood cancer: incidence and screening guidelines. Cancer. Feb 15 1998;82(4):784-792.
Kenney LB, Yasui Y, Inskip PD, et al. Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med. Oct 19 2004;141(8):590-597.
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
of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. Dec 2013;14(13):e621-629.
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. Mar-Apr 2007;57(2):75-89.
Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. Jul 23 2003;290(4):465-475.
van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst. Jul 2 2003;95(13):971-980.
Wolden SL, Hancock SL, Carlson RW, Goffinet DR, Jeffrey SS, Hoppe RT. Management of breast cancer after Hodgkin’s disease. J Clin Oncol. Feb 2000;18(4):765-772.

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Therapeutic
Agent(s)78

Subtotal Lymphoid
Irradiation (STLI)
AxillaChest (thorax)
Extended Mantle
MantleMediastinal
Mini~Mantle
Whole lung
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)(female)BREAST (cont)
Potential Late
Effects
Breast tissue hypoplasia

Risk
Factors

HighestRisk Factors

Host Factors
Treatment Factors
Prepubertal at time of breast≥ 20 Gy to prepubertal
irradiation Treatment Factors
breast bud may ablate
development
Treatment Factors
Radiation dose ≥ 10 Gy to
prepubertal breast bud
may cause failure ofdevelopment (hypoplasia)

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Considerations for Further Testing and Intervention

Breast exam
YearlySurgical consultation for breast reconstruction after completionof growth.

SYSTEM = Reproductive (female)
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 78 REFERENCES
Furst CJ, Lundell M, Ahlback SO, Holm LE. Breast hypoplasia following irradiation of the female breast in infancy and early childhood. Acta Oncol. 1989;28(4):519-523.
Macklis RM, Oltikar A, Sallan SE. Wilms’ tumor patients with pulmonary metastases. Int J Radiat Oncol Biol Phys. Oct 1991;21(5):1187-1193.

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Therapeutic
Agent(s)79

Subtotal Lymphoid
Irradiation (STLI)
AxillaChest (thorax)
Extended Mantle
MantleMediastinal
Mini~Mantle
Whole lung
Total Body Irradiation (TBI)
Total Lymphoid Irradiation
(TLI)

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

Risk
Factors
Host Factors
Younger age at irradiation
Treatment Factors
Radiation dose > 10 Gy
Radiation combined with:-- Bleomycin-- Busulfan-- Carmustine (BCNU)-- Lomustine (CCNU)-- Radiomimetic chemotherapy (e.g., doxorubicin,
dactinomycin)
Chest radiation combinedwith TBI
Medical Conditions
Atopic history
Health Behaviors
SmokingInhaled illicit drug use• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 15 Gy
TBI ≥ 6 Gy in single fraction or≥ 12 Gy fractionated

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Cough
SOB
DOE
Wheezing
YearlyPulmonary Health

PHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patientswith abnormal results or progressive
pulmonary dysfunction

Resources
Extensive information regarding smoking cessation is available
for patients on the NCI’s website: www.smokefree.gov

CounselingCounsel regarding tobacco avoidance/smoking cessation. Dueto the potential pulmonary toxicity of this therapy, patients
who desire to SCUBA dive should be advised to obtain medical
clearance from a pulmonologist.

Considerations for Further Testing and Intervention
In patients with abnormal PFTs, consider repeat evaluation
prior to general anesthesia. Pulmonary consultation for patientswith symptomatic pulmonary dysfunction. Influenza andPneumococcal vaccinations.

SYSTEM = Pulmonary
SCORE = 1

SECTION 79 REFERENCES
Hoffmeister PA, Madtes DK, Storer BE, Sanders JE. Pulmonary function in long-term survivors of pediatric hematopoietic cell transplantation. Pediatr Blood Cancer. Oct 15 2006;47(5):594-606.
Huang TT, Hudson MM, Stokes DC, Krasin MJ, Spunt SL, Ness KK. Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest. Oct 2011;140(4):881-901.
Lund MB, Kongerud J, Nome O, et al. Lung function impairment in long-term survivors of Hodgkin’s disease. Ann Oncol. May 1995;6(5):495-501.
Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. Jul 10 2006;166(13):1359-1367.
Mertens AC, Yasui Y, Liu Y, et al. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer. Dec 1 2002;95(11):2431-2441.
Nysom K, Holm K, Hertz H, Hesse B. Risk factors for reduced pulmonary function after malignant lymphoma in childhood. Med Pediatr Oncol. Apr 1998;30(4):240-248.
Nysom K, Holm K, Olsen JH, Hertz H, Hesse B. Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood. Br J Cancer. Jul 1998;78(1):21-27.
Stolp B, Assistant Medical Director Divers Alert Network, Director Anesthesiology Emergency Airway Services, Durham, N.C. Risks associated with SCUBA diving in childhood cancer survivors. Personal communication to LandierW, Bhatia S Aug 23, 2002.
Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. Feb 12 2007;167(3):221-228.
Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. Mar 2004;25(1):203-216.

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Sec
#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

80

Chest (thorax)
Extended Mantle
MantleMediastinal
Whole lungHepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

Cardiac toxicity
Congestive heart failure
Cardiomyopathy
Pericarditis
Pericardial fibrosis
Valvular disease
Myocardial infarction
Arrhythmia
Atherosclerotic heart disease

Host Factors
Younger age at irradiation
Family history of dyslipidemia
Coronary artery disease

Host Factors
Black/of African descent
Younger than age 5 years attreatment

Treatment Factors
Radiation dose ≥ 20 Gy to
chest
TBI
Combined with radiomimetic
chemotherapy (e.g.,doxorubicin, dactinomycin)
Combined with othercardiotoxic chemotherapy:-- Anthracyclines-- Cyclophosphamide conditioning for HCT-- Amsacrine

Treatment Factors
Anteriorly-weighted radiation
fieldsLack of subcarinal shielding
Doses ≥ 30 Gy in patients
who have received
anthracyclines
Doses ≥ 40 Gy in patients
who have not received
anthracyclines
Longer time since treatment(male)

Medical Conditions
Hypertension
Obesity
Dyslipidemia
Diabetes mellitus
Congenital heart disease
Febrile illness

RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM
Age atTreatment*

Radiation
Dose

Anthracycline
Dose†

Recommended
Frequency< 5 years old

Any

None

Every 2 years

Any

Every year

< 30 Gy‡

None

Every 5 years≥ 30 Gy

None

Every 2 years< 300 mg/m2

Every 2 years≥ 300 mg/m2

Every year

Any age with decrease in serial function

Every year

≥5 years old‡

Any

Age at time of first cardiotoxic therapy (anthracycline orradiation with potential to impacte heart, whichever was
given first)†
Based on doxorubicin isotoxic equivalent dose [seeconversion factors in Section 33 “Info Link (DoseConversion)”]‡If patient received radiation to more than one specified
field, see dose calculation rules on page 56.
*

COG LTFU Guidelines – Page 99

Health Behaviors
Smoking
Isometric exercise
Drug use (e.g., cocaine, dietpills, ephedra)• See “Patient-Specific Guideline Identification
Tool” in Appendix I to determine specificscreening guidelines by section number forindividual patients.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

SOB
DOE
Orthopnea
Chest pain
Palpitations
If under 25 yrs: abdominal symptoms(nausea, vomiting)
YearlyHeart Health
Cardiovascular Risk Factors
Diet and Physical Activity
Dental Health

Info Link• Exertional intolerance is uncommon inpatients younger than 25 years old.
• Abdominal symptoms (nausea, emesis)
may be observed more frequently thanexertional dyspnea or chest pain inyounger patients.

PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlySCREENING
Fasting blood glucose OR HbA1c andlipid profile
Every 2 years
If abnormal, refer for ongoing management
EKG (include evaluation of QTc interval)
Baseline at entry into long-term follow-up,
repeat as clinically indicated
ECHO (or comparable imaging toevaluate cardiac anatomy andfunction)
Baseline at entry into long-term followup, then periodically based on age attreatment, radiation dose, and cumulative
anthracycline dose.

CounselingCounsel patients with prolonged QTc interval about use of
medications that may further prolong the QTc interval (e.g.,
tricyclic anti-depressants, antifungals, macrolide antibiotics,
metronidazole). Counsel regarding maintaining appropriate
weight, blood pressure and heart-healthy diet. Counsel
regarding endocarditis prophylaxis if at highest risk. Note: The
AHA now limits their recommendation regarding endocarditis
prophylaxis only to patients whose cardiac conditions areassociated 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 needfor endocarditis prophylaxis with their cardiologist. See Wilson etal. (2007) for specifics. Counsel regarding appropriate exercise.
Aerobic exercise is generally safe and should be encouraged formost patients. Intensive isometric activities (e.g., heavy weightlifting, wrestling) should generally be avoided. High repetition
weight lifting involving lighter weights is more likely to be safe.
The number of repetitions should be limited to that which thesurvivor can perform with ease. Patients who choose to engage
in strenuous or varsity team sports should discuss appropriate
guidelines and a plan for ongoing monitoring with a cardiologist.

Considerations for Further Testing and Intervention
Cardiology consultation for patients with subclinicalabnormalities on screening evaluations or with left ventricular
dysfunction, dysrhythmia or prolonged QTc interval. Consider
cardiology consultation (5 to 10 years after radiation) to evaluate
risk for coronary artery disease in patients who received≥ 40 Gy chest radiation alone or ≥ 30 Gy chest radiation plus
anthracycline. Consider excess risk of intensive isometric
exercise program in any high risk patient defined as needing
screening every 1 or 2 years.

SYSTEM = Cardiovascular
SCORE = 1

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Therapeutic
Agent(s)HEART (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 80 REFERENCES
Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE. Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol. Jan 2003;45(1):55-75.
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. Aug 1 2004;22(15):3139-3148.
Glanzmann C, Kaufmann P, Jenni R, Hess OM, Huguenin P. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother Oncol. Jan 1998;46(1):51-62.
Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group. J Clin Oncol. Apr 2001;19(7):1926-1934.
Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol. Jul 1993;11(7):1208-1215.
Heidenreich PA, Schnittger I, Strauss HW, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol. Jan 1 2007;25(1):43-49.
Hertenstein B, Stefanic M, Schmeiser T, et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol. May 1994;12(5):998-1004.
Hogarty AN, Leahey A, Zhao H, et al. Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr. Mar 2000;136(3):311-317.
Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA. Dec 3 2003;290(21):2831-2837.
Jakacki RI, Goldwein JW, Larsen RL, Barber G, Silber JH. Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol. Jun 1993;11(6):1033-1038.
Lonnerholm G, Arvidson J, Andersson LG, Carlson K, Jonzon A, Sunnegardh J. Myocardial function after autologous bone marrow transplantation in children: a prospective long-term study. Acta Pediatr. Feb 1999;88(2):186-192.
Pihkala J, Saarinen UM, Lundstrom U, et al. Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplant. Feb 1994;13(2):149-155.
Qureshi AI, Alexandrov AV, Tegeler CH, Hobson RW, 2nd, Dennis Baker J, Hopkins LN. Guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary practiceguidelines committee of the American Society of Neuroimaging cosponsored by the Society of Vascular and Interventional Neurology. J Neuroimaging. Jan 2007;17(1):19-47.
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. Feb 7 2007;99(3):206-214.
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. Oct 9 2007;116(15):1736-1754.

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HEART (cont)

Sec#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

81

Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Chest (thorax)
Extended Mantle
MantleMediastinal
Whole lung
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

Cardiac toxicity
Congestive heart failure
Cardiomyopathy
Pericarditis
Pericardial fibrosis
Valvular disease
Myocardial infarction
Arrhythmia
Atherosclerotic heart disease

Host Factors
Younger age at irradiation
Family history ofdyslipidemia
Coronary artery disease

Host Factors
Female sex
Black/of African descent
Younger than age 5 years
at treatment

Treatment Factors
Radiation dose ≥ 20 Gy to
chest
TBI
Combined withradiomimetic
chemotherapy(e.g., doxorubicin,
dactinomycin)
Combined withother cardiotoxic
chemotherapy:-- Anthracyclines-- Cyclophosphamide
conditioning for HCT-- Amsacrine

Treatment Factors
Anteriorly-weighted
radiation fields
Lack of subcarinal
shielding
Doses ≥ 30 Gy in patients
who have received
anthracyclines
Doses ≥ 40 Gy in patients
who have not received
anthracyclines
Longer time sincetreatment(female)RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM
Age atTreatment*

RadiationDose< 5 years oldAny≥5 years old

Anthracycline
Dose†

Recommended
Frequency

None

Every 2 years

Any

Every year

< 30 Gy‡

None

Every 5 years≥ 30 Gy

None

Every 2 years‡

Any< 300 mg/m2

Every 2 years≥ 300 mg/m

Every year

Any age with decrease in serial function

2

Medical Conditions
Hypertension
Obesity
Dyslipidemia
Diabetes mellitus
Congenital heart disease
Febrile illness
Pregnancy
Premature ovarian failure(untreated)
Health Behaviors
Smoking
Isometric exercise
Drug use (e.g., cocaine,
diet pills, ephedra)

Every year

Age at time of first cardiotoxic therapy (anthracycline orradiation with potential to impacte heart, whichever was
given first)†
Based on doxorubicin isotoxic equivalent dose [seeconversion factors in Section 34 “Info Link (DoseConversion)”]‡If patient received radiation to more than one specified
field, see dose calculation rules on page 56.
*

COG LTFU Guidelines – Page 101• See “Patient-Specific Guideline Identification
Tool” in Appendix I to determine specificscreening guidelines by section number forindividual patients.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

SOB
DOE
Orthopnea
Chest pain
Palpitations
If under 25 yrs: abdominal
symptoms (nausea, vomiting)
YearlyHeart Health
Cardiovascular Risk Factors
Diet and Physical Activity
Dental Health

Info Link• Exertional intolerance is uncommon
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.

PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlySCREENING
Fasting blood glucose OR HbA1c
and lipid profile
Every 2 years
If abnormal, refer for ongoing
management
EKG (include evaluation of QTc
interval)
Baseline at entry into long-term
follow-up, repeat as clinicallyindicated
ECHO (or comparable imaging toevaluate cardiac anatomy andfunction)
Baseline at entry into long-term
follow-up, then periodically basedon age at treatment, radiation dose,and cumulative anthracycline dose.

CounselingCounsel patients with prolonged QTc interval about use of medications
that may further prolong the QTc interval (e.g., tricyclic anti-depressants,
antifungals, macrolide antibiotics, metronidazole). Counsel regarding
maintaining appropriate weight, blood pressure, and heart-healthy diet.
Counsel regarding endocarditis prophylaxis if at highest risk.
Note: The AHA now limits their recommendation regarding endocarditis
prophylaxis only to patients whose cardiac conditions are associated withthe highest risk of adverse outcome, which includes, but is not limited to thefollowing 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 withheart valve disorders should discuss the need for endocarditis prophylaxis
with their cardiologist. See Wilson et al. (2007) for specifics. Counsel
regarding appropriate exercise. Aerobic exercise is generally safe andshould be encouraged for most patients. Intensive isometric activities (e.g.,heavy weight lifting, wrestling) should generally be avoided. High repetition
weight lifting involving lighter weights is more likely to be safe. The numberof repetitions should be limited to that which the survivor can perform withease. Patients who choose to engage in strenuous or varsity team sports
should discuss appropriate guidelines and a plan for ongoing monitoringwith a cardiologist.

Considerations for Further Testing and Intervention
Cardiology consultation for patients with subclinical abnormalities onscreening evaluations or with left ventricular dysfunction, dysrhythmia
or prolonged QTc interval. Additional cardiology evaluation for patients
who are pregnant or planning pregnancy who: (1) received ≥ 30 Gy chest
radiation, or (2) received chest radiation in combination with cardiotoxic
chemotherapy (anthracyclines or high-dose cyclophosphamide).Evaluation
to include echocardiogram before and periodically during pregnancy(especially during third trimester) and monitoring during labor and delivery
due to risk of cardiac failure. Consider cardiology consultation (5 to 10
years after radiation) to evaluate risk for coronary artery disease in patients
who received ≥ 40 Gy chest radiation alone or ≥ 30 Gy chest radiation plus
anthracycline. Consider excess risk of intensive isometric exercise programin any high-risk patient defined as needing screening every 1 or 2 years.
SYSTEM = Cardiovascular
SCORE = 1

Version 4.0 – October 2013

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RADIATION
Sec#

Therapeutic
Agent(s)HEART (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 81 REFERENCES
Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE. Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol. Jan 2003;45(1):55-75.
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. Aug 1 2004;22(15):3139-3148.
Glanzmann C, Kaufmann P, Jenni R, Hess OM, Huguenin P. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother Oncol. Jan 1998;46(1):51-62.
Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group. J Clin Oncol. Apr 2001;19(7):1926-1934.
Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol. Jul 1993;11(7):1208-1215.
Heidenreich PA, Schnittger I, Strauss HW, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol. Jan 1 2007;25(1):43-49.
Hertenstein B, Stefanic M, Schmeiser T, et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol. May 1994;12(5):998-1004.
Hogarty AN, Leahey A, Zhao H, et al. Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr. Mar 2000;136(3):311-317.
Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA. Dec 3 2003;290(21):2831-2837.
Jakacki RI, Goldwein JW, Larsen RL, Barber G, Silber JH. Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol. Jun 1993;11(6):1033-1038.
Lonnerholm G, Arvidson J, Andersson LG, Carlson K, Jonzon A, Sunnegardh J. Myocardial function after autologous bone marrow transplantation in children: a prospective long-term study. Acta Pediatr. Feb 1999;88(2):186-192.
Pihkala J, Saarinen UM, Lundstrom U, et al. Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplant. Feb 1994;13(2):149-155.
Qureshi AI, Alexandrov AV, Tegeler CH, Hobson RW, 2nd, Dennis Baker J, Hopkins LN. Guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary practiceguidelines committee of the American Society of Neuroimaging cosponsored by the Society of Vascular and Interventional Neurology. J Neuroimaging. Jan 2007;17(1):19-47.
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. Feb 7 2007;99(3):206-214.
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. Oct 9 2007;116(15):1736-1754.

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SPLEENSec#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors82≥ 40 Gy to:Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Spleen (entire)
Whole abdomen
Subtotal Lymphoid
Irradiation (STLI)
Total Lymphoid Irradiation
(TLI)
TBI*

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

Treatment Factors
Higher radiation dose to entire
spleen*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.
Info Link• Not all paraaortic and inverted Y treatment fields include
the spleen.
• Survivors are at risk forfunctional asplenia only if
the spleen was included in
the radiation field.

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Physical exam at time of febrile illness
to evaluate degree of illness andpotential source of infection
When febrile T ≥ 101ºF

Splenic Precautions

SCREENING
Blood culture
When febrile T ≥ 101°F

Counseling
Medical alert bracelet/card noting functional asplenia
Counsel regarding risk of life-threatening infections withencapsulated organisms. Also counsel regarding risk associatedwith malaria and tick-borne diseases if living in or visiting
endemic areas.

Considerations for Further Testing and Intervention• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

In patients with T ≥ 101° (38.3° C) or other signs of serious
illness, administer a long-acting, broad-spectrum parenteralantibiotic (e.g., ceftriaxone), and continue close medical
monitoring while awaiting blood culture results. Hospitalization
and broadening of antimicrobial coverage (e.g., addition of
vancomycin) may be necessary under certain circumstances,such as the presence of marked leukocytosis, neutropenia, or
significant change from baseline CBC toxic clinical appearance
fever ≥ 104°F meningitis, pneumonia, or other serious focus
of infection signs of septic shock or previous history of serious
infection. Immunize with Pneumococcal, Meningococcal, andHIB vaccines according to current ACIP recommendations.
Discuss with dental provider potential need for antibiotic
prophylaxis based on planned procedure.
Info Link
See current edition of AAP Red Book for current
recommendations regarding antibiotic prophylaxis andimmunizations
SYSTEM = Immune
SCORE = 1

SECTION 82 REFERENCES
American Academy of Pediatrics. Red Book: 2012;Report of the Committee on Infectious Diseases. Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics 2012
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. Oct 12 2012;61(40):816-819.
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. Jun 28 2013;62(25):521-524.
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. Nov
2003;71(5):319-326.
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Sec#

Therapeutic
Agent(s)SPLEEN (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 82 REFERENCES–continued
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. Mar 22 2013;62(RR-2):1-28.
Coleman CN, McDougall IR, Dailey MO, Ager P, Bush S, Kaplan HS. Functional hyposplenia after splenic irradiation for Hodgkin’s disease. Ann Intern Med. Jan 1982;96(1):44-47
Mourtzoukou EG, Pappas G, Peppas G, Falagas ME. Vaccination of asplenic or hyposplenic adults. Br J Surg. Mar 2008;95(3):273-280.
Price VE, Blanchette VS, Ford-Jones EL. The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am. Sep 2007;21(3):697-710, viii-ix.
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. Jul 20
2007;25(29):5278-5282.
Spelman D, Buttery J, Daley A, et al. Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J. May 2008;38(5):349-356.
Weiner MA, Landmann RG, DeParedes L, Leventhal BG. Vesiculated erythrocytes as a determination of splenic reticuloendothelial function in pediatric patients with Hodgkin’s disease. J Pediatr Hematol Oncol. Nov
1995;17(4):338-341.

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Sec#

Therapeutic
Agent(s)83≥ 30 Gy to:
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Cervical (neck)
SupraclavicularSpine (cervical)
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Chest (thorax)
Extended Mantle
MantleMediastinal
Mini~Mantle
Whole lung
Total Lymphoid Irradiation
(TLI)
TBI*

GI/HEPATIC SYSTEM
Potential Late
Effects
Esophageal stricture

Risk
Factors
Treatment Factors
Higher radiation doseRadiomimetic chemotherapy(e.g., doxorubicin,
actinomycin)

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 40 Gy
Medical Conditions
Gut GVHD

Medical Conditions
Gastroesophageal reflux
History of Candida esophagitis

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Dysphagia
HeartburnYearlyGastrointestinal Health

Considerations for Further Testing and Intervention
Surgical and/or gastroenterology consultation for symptomaticpatients.

SYSTEM = GI/Hepatic
SCORE = 1
• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

SECTION 83 REFERENCES
Lal DR, Foroutan HR, Su WT, Wolden SL, Boulad F, La Quaglia MP. The management of treatment-related esophageal complications in children and adolescents with cancer. J Pediatr Surg. Mar 2006;41(3):495-499.
Mahboubi S, Silber JH. Radiation-induced esophageal strictures in children with cancer. Eur Radiol. 1997;7(1):119-122.
Rodriguez ML, Martin MM, Padellano LC, Palomo AM, Puebla YI. Gastrointestinal toxicity associated to radiation therapy. Clin Transl Oncol. Aug 2010;12(8):554-561.

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Sec#

Therapeutic
Agent(s)84[Abdominal radiation]
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
Total Lymphoid Irradiation(TLI)
Total Body Irradiation (TBI)

GI/HEPATIC SYSTEM (cont)
Potential Late
Effects

Risk
Factors

Impaired Glucose
Metabolism/Diabetes
Mellitus

Host Factors
Family history of diabetes
mellitus

Info Link• Impaired glucose metabolism may occur in aconstellation of conditions
known as the metabolic
syndrome.
• Definitions of the metabolic
syndrome are evolving but
generally include a combination of central (abdominal)
obesity with at least 2 ormore 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 ofmetabolic syndrome without
associated obesity

Treatment Factors
Prolonged corticosteriod
therapy (e.g., for chronic
GVHD)

HighestRisk Factors
Medical Conditions
Obesity (not necessary in HCT
survivors who received TBI)

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Fasting blood glucose OR HbA1c
Every 2 years. More frequently if indicatedbased on patient evaluation

Diet and Physical Activity
Cardiovascular Risk Factors

CounselingCounsel regarding obesity-related health risks and nutrition.

Considerations for Further Testing and Intervention
Consider endocrine consultation if impaired glucose metabolism
is suspected. Consider evaluation for other co-morbid
conditions, including overweight/obesity, hypertension, anddyslipidemia.

SYSTEM = Endocrine/Metabolic
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 84 REFERENCES
American Diabetes Association Diagnosis and classification of diabetes mellitus. Diabetes Care. Jan 2010;33 Suppl 1:S62-69.
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. Feb 15
2007;109(4):1765-1772.
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. Dec 2010;16(12):1674-1681.
Daniels SR, Greer FR, Committee on N. Lipid screening and cardiovascular health in childhood. Pediatrics. Jul 2008;122(1):198-208.
de 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. 2012;Oct 13(10):1002-10.
Hoffmeister PA, Storer BE, Sanders JE. Diabetes mellitus in long-term survivors of pediatric hematopoietic cell transplantation. J Pediatr Hematol Oncol. Feb 2004;26(2):81-90.
Lorini R, Cortona L, Scaramuzza A, et al. Hyperinsulinemia in children and adolescents after bone marrow transplantation. Bone Marrow Transplant. Jun 1995;15(6):873-877.
Meacham LR, Sklar CA, Li S, et al. Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the Childhood Cancer Survivor Study. Arch Intern Med. 2009 Aug 10
169(15):1381-8.
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. Jan 2010;19(1):170-181.
Shalitin S, Phillip M, Stein J, Goshen Y, Carmi D, Yaniv I. Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant. Jun
2006, 37(12):1109-1117.
Taskinen M, Saarinen-Pihkala UM, Hovi L, Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet. Sep 16 2000;356(9234):993-997.
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Sec#

Therapeutic
Agent(s)85

Total Body Irradiation (TBI)

GI/HEPATIC SYSTEM (cont)
Potential Late
Effects
Dyslipidemia

Note: For all guideline
sections relevant to patients
who received TBI please see
page 129.

Risk
Factors
Host Factors
Family history of dyslipidemia
Treatment Factors
Prolonged corticosteriod
therapy (e.g., for chronic
GVHD)

HighestRisk Factors
Medical Conditions

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Fasting lipid profile
Every 2 years and as clinically indicatedDiet and Physical Activity
Cardiovascular Risk Factors

CounselingCounsel regarding nutrition.

Considerations for Further Testing and Intervention• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Consider evaluation for other co-morbid conditions including
hypertension, impaired glucose metabolism, and overweight/
obesity.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 85 REFERENCES
Baker KS, Chow E, Steinberger J. Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation. Bone Marrow Transplant. May 2012;47(5):619-625.
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. Feb 15
2007;109(4):1765-1772.
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. Dec 2010;16(12):1674-1681.
Daniels SR, Greer FR, Committee on N. Lipid screening and cardiovascular health in childhood. Pediatrics. Jul 2008122(1):198-208.
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. Jan 2010;19(1):170-181.
Shalitin S, Phillip M, Stein J, Goshen Y, Carmi D, Yaniv I. Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant. Jun
2006;37(12):1109-1117.
Taskinen M, Saarinen-Pihkala UM, Hovi L, Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet. Sep 16 2000;356(9234):993-997.

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GI/HEPATIC SYSTEM (cont)

Sec#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors86≥ 30 Gy to:
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
Total Lymphoid Irradiation
(TLI)
TBI*

Hepatic fibrosis
Cirrhosis
Focal nodular hyperplasia

Treatment Factors
Higher radiation dose

Info Link• Focal nodular hyperplasia(FNH) is a benign changethat represents a scar in
the liver.
• FNH is usually an asymptomatic finding noted on
MRI or ultrasound of theliver.
• Continued observation or
biopsy may be indicateddepending on individual
patient factors and imaging
features.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

Medical Conditions
Chronic hepatitis
History of VOD

HighestRisk Factors
Treatment Factors
Dose ≥ 40 Gy to at least 1/3
of liver volume
Dose 20-30 Gy to entire liver

Health Behaviors
Alcohol use

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Jaundice
Spider angiomas
Palmar erythema
Xanthomata
Hepatomegaly
Splenomegaly
YearlyLiver Health

SCREENING
ALT
AST
Bilirubin
Baseline at entry into long-term follow-up,
repeat as clinically indicatedConsiderations for Further Testing and Intervention
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 immunizations in patients lacking
immunity.

SYSTEM = GI/Hepatic
SCORE = 1

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 86 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. May 2010;54(5):663-669.
Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. May 15 1991;21(1):109-122.
Jirtle RL, Anscher MS, Alati T. Radiation sensitivity of the liver. Advances Rad Biol. 1990;14:269-311.
Mulder RL, van Dalen EC, Van den Hof M, et al. Hepatic late adverse effects after antineoplastic treatment for childhood cancer. The Cochrane database of systematic reviews. 2011(7):CD008205.
Pan CC, Kavanagh BD, Dawson LA, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys. Mar 1 2010;76(3 Suppl):S94-100.

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Sec#

Therapeutic
Agent(s)87≥ 30 Gy to:
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
Total Lymphoid Irradiation
(TLI)
TBI*

GI/HEPATIC SYSTEM (cont)
Potential Late
Effects
Cholelithiasis

Risk
Factors

HighestRisk Factors

Host Factors
Ileal conduit
ObesityPregnancy
Family history of cholelithiasis
Treatment Factors
Abdominal surgery
Abdominal radiation
TPN

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Colicky abdominal pain related to fatty
food intake
Excessive flatulence
Yearly and as clinically indicatedGastrointestinal Health

PHYSICALRUQ or epigastric tenderness
Positive Murphy’s signYearly and as clinically indicatedConsiderations for Further Testing and Intervention
Consider gallbladder ultrasound in patients with chronic
abdominal pain

SYSTEM = GI/Hepatic
SCORE = 2B

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 87 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. May 2010;54(5):663-669.
Mahmoud H, Schell M, Pui CH. Cholelithiasis after treatment for childhood cancer. Cancer. Mar 1 1991;67(5):1439-1442.
Mulder RL, van Dalen EC, Van den Hof M, et al. Hepatic late adverse effects after antineoplastic treatment for childhood cancer. The Cochrane database of systematic reviews. 2011(7):CD008205.

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POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)88≥ 30 Gy to:
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
BladderFemoralIliac
Inguinal
PelvicProstate
VaginalSpine (lumbar)
Spine (sacral)
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
Total Lymphoid Irradiation
(TLI)
TBI*

GI/HEPATIC SYSTEM (cont)
Potential Late
Effects
Bowel obstruction

Risk
Factors
Treatment Factors
Higher radiation dose tobowel
Abdominal surgery
Info Link
Bowel obstruction is rarely
seen in individuals treatedwith abdominal radiation
who have not had abdominal
surgery

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 45 Gy(Obstruction may occur
in people who received
lower doses of abdominal
radiation during childhood)

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Abdominal pain
Distention
Vomiting
Constipation
With clinical symptoms of obstruction

Gastrointestinal Health

PHYSICAL
Tenderness
Abdominal guarding
Distension
With clinical symptoms of obstruction

Considerations for Further Testing and Intervention
Obtain KUB in patients with clinical symptoms of obstruction.
Surgical consultation in patients unresponsive to medical
management.

SYSTEM = GI/Hepatic
SCORE = 1

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

SECTION 88 REFERENCES
Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. May 15 1991;21(1):109-122.

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Sec#

Therapeutic
Agent(s)89≥ 30 Gy to:
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
BladderFemoralIliac
Inguinal
PelvicProstate
VaginalSpine (lumbar)
Spine (sacral)
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
Total Lymphoid Irradiation
(TLI)
TBI*

GI/HEPATIC SYSTEM (cont)
Potential Late
Effects
Chronic enterocolitis
FistulaStrictures

Risk
Factors
Treatment Factors
Higher radiation dose tobowel
Abdominal surgery

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 45 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

NauseaVomiting
Abdominal pain
Diarrhea
YearlyGastrointestinal Health

Considerations for Further Testing and Intervention
Serum protein and albumin yearly in patients with chronic
diarrhea or fistula. Surgical and/or gastroenterology consultation
for symptomatic patients.

SYSTEM = GI/Hepatic
SCORE = 1
• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

SECTION 89 REFERENCES
Donaldson SS, Jundt S, Ricour C, Sarrazin D, Lemerle J, Schweisguth O. Radiation enteritis in children. A retrospective review clinicopathologic correlation and dietary management. Cancer. Apr 1975;35(4):1167-1178.
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. Apr 1992;10(4):614-623.
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. Apr 1 1993;71(7):2387-2394.
Rodriguez ML, Martin MM, Padellano LC, Palomo AM, Puebla YI. Gastrointestinal toxicity associated to radiation therapy. Clin Transl Oncol. Aug 2010;12(8):554-561.

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Sec#
90

Therapeutic
Agent(s)≥ 30 Gy to:
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
BladderFemoralIliac
Inguinal
PelvicProstate
VaginalSpine (lumbar)
Spine (sacral)
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid Irradiation(STLI)
Extended Mantle
Total Body Irradiation (TBI)*
Total Lymphoid Irradiation (TLI)

GI/HEPATIC SYSTEM (cont)
Potential Late
Effects
Colorectal cancer
Info Link• Reports of colorectal cancer
in cohorts of long-term
survivors suggest thatradiation likely increases
risk but the median age of
onset is not as well established as that of secondary
breast cancer following
chest radiation.
• The expert panel agreed
that early onset of screening is likely beneficial andthat a prudent course
would be to initiate
screening for colorectal
cancer for those at highest
risk (abdominal pelvic and/or spinal radiation ≥ 30 Gy)
at age 35 or 10 years post
radiation whichever occurs
last.
• Surveillance should bedone via colonoscopy as
per recommendations for
populations at highest risk
with information from thefirst colonoscopy informing
the frequency of follow-up
testing.

Risk
Factors

HighestRisk Factors

Host Factors
Current age ≥ 50 years
Treatment Factors
Higher radiation dose tobowel
Higher daily dose fraction
Combined with chemotherapy(especially alkylators)

Host Factors
Personal history of ulcerative
colitis, gastrointestinal
malignancy, adenomatous
polyps, or hepatoblastoma
Familial polyposis
Family history of colorectal
cancer or polyps in first
degree relative

Medical Conditions
Obesity
Health Behaviors
High fat/low fiber diet

Periodic
Evaluation
SCREENING

Health Counseling/
Further Considerations
Health Links

Colonoscopy
Colorectal Cancer
Every 5 years [minimum]
beginning at 10 years after
Considerations for Further Testing and Intervention
radiation or at age 35 years
Surgical and/or oncology consultation as needed.
[whichever occurs last]More frequently if indicated basedon colonoscopy results
SYSTEM = SMN
Per the ACS, begin screening
earlier for the following highSCORE = 2A
risk groups—HNPCC: at puberty
FAP: at age 21 years
IBD: 8 years after diagnosis of IBD
Information from the firstcolonoscopy will inform
frequency of follow-up testing• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Info Link• *Reports of colorectal cancer in cohorts of long-term survivors suggestthat radiation likely increases risk
however the risk related to TBI alone
has not been established.
• Monitoring of patients who received
TBI without additional radiation
potentially impacting the colon/
rectum should be determined on an
individual basis. (See Info Link innext column.)

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Therapeutic
Agent(s)GI/HEPATIC SYSTEM (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 90 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. Dec 1 2003;21(23):4386-4394.
Henderson TO, Oeffinger KC, Whitton J, et al. Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med. Jun 5 2012;156(11):757-766, W-260.
Hodgson DC, Koh ES, Tran TH, et al. Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin lymphoma. Cancer. Dec 1 2007;110(11):2576-2586.
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. Jun 2000;18(12):2435-2443.
Nottage K, McFarlane J, Krasin MJ, et al. Secondary colorectal carcinoma after childhood cancer. J Clin Oncol. Jul 10 2012;30(20):2552-2558.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin Mar-Apr 2013;63(2):88-105.
Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malignancy after Hodgkin’s disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol. Feb 2000;18(3):498-509.
Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. Sep 21 2005;97(18):1354-1365.
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. Mar 1 2012;82(3):e383-390
U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. Nov 4 2008;149(9):627-637.

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Sec#

Therapeutic
Agent(s)91

Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Subtotal Lymphoid
Irradiation (STLI)
Extended Mantle
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

URINARY TRACT
Potential Late
Effects
Renal toxicity
Renal insufficiency
Hypertension• See “Patient-Specific Guideline Identification Tool” inAppendix I to determine specific screening guidelines
by section number for individual patients.

Risk
Factors
Host Factors
Bilateral Wilms tumor
MononephricTreatment Factors
Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)
Radiation dose ≥ 10 Gy
TBI combined with radiation
to the kidney
Combined with othernephrotoxic agents, such as:-- Cisplatin-- Carboplatin-- Ifosfamide-- Aminoglycosides-- Amphotericin-- ImmunosuppressantsHighestRisk Factors
Treatment Factors
Radiation dose ≥ 15 Gy
TBI ≥ 6 Gy in single fraction or≥ 12 Gy fractionated

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Blood pressure
YearlyKidney Health
Cardiovascular Risk Factors

SCREENING

Considerations for Further Testing and Intervention

BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedNephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency

Urinalysis
YearlySYSTEM = Urinary
SCORE = 1

Medical Conditions
Diabetes mellitus
Hypertension
Nephrectomy

SECTION 91 REFERENCES
Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1249-1256.
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. Jan 2006;12(1):75-83.
Fels LM, Bokemeyer C, van Rhee J, Schmoll HJ, Stolte H. Evaluation of late nephrotoxicity in long-term survivors of Hodgkin’s disease. Oncology. Jan-Feb 1996;53(1):73-78.
Frisk P, Bratteby LE, Carlson K, Lonnerholm G. Renal function after autologous bone marrow transplantation in children: a long-term prospective study. Bone Marrow Transplant. Jan 2002;29(2):129-136.
Gronroos MH, Bolme P, Winiarski J, Berg UB. Long-term renal function following bone marrow transplantation. Bone Marrow Transplant. Jun 2007;39(11):717-723.
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. Dec 1997;20(12):10691074.
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. Feb 1996
14(2):579-585.
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. Feb 1996;26(2):75-80.
Tarbell NJ, Guinan EC, Niemeyer C, Mauch P, Sallan SE, Weinstein HJ. Late onset of renal dysfunction in survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys. Jul 1988;15(1):99-104.

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Therapeutic
Agent(s)92≥ 30 Gy to:Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
Bladder
Iliac
Inguinal
PelvicProstate
VaginalSpine (sacral)
Spine (whole)
Total Lymphoid Irradiation
(TLI)
TBI*
*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

URINARY TRACT (cont)
Potential Late
Effects
Hemorrhagic cystitis

Risk
Factors

HighestRisk Factors

Treatment Factors
Higher radiation dose( ≥ 30 Gy to entire bladder,≥ 60 Gy to portion of
bladder)

Treatment Factors
Combined withcyclophosphamide and/or
ifosfamide• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyBladder HealthCounselingCounsel to promptly report dysuria or gross hematuria

Considerations for Further Testing and Intervention
For patients with positive history, obtain urinalysis and consider
urine culture, spot urine calcium/creatinine ratio, and ultrasoundof kidneys and bladder for patients with microscopic hematuria(defined as > 5 RBC/HFP 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.

SYSTEM = Urinary
SCORE = 2A

Info Link
The bladder is includedin the left and right flank/
hemiabdomen treatment
fields only if the fields
extended below iliac crest.

SECTION 92 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. Mar-Apr 1999;21(2):115-122.
Marks LB, Carroll PR, Dugan TC, Anscher MS. The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1257-1280.
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. Mar 1988;71(3 Pt 2):435-437.
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. Apr 1 1993;71(7):2387-2394.
Stillwell TJ, Benson RC, Jr. Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer. Feb 1 1988;61(3):451-457.
Stillwell TJ, Benson RC, Jr., Burgert EO, Jr. Cyclophosphamide-induced hemorrhagic cystitis in Ewing’s sarcoma. J Clin Oncol. Jan 1988;6(1):76-82.
Yeung CK, Ward HC, Ransley PG, Duffy PG, Pritchard J. Bladder and kidney function after cure of pelvic rhabdomyosarcoma in childhood. Br J Cancer. Nov 1994;70(5):1000-1003.

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Sec#

Therapeutic
Agent(s)93≥ 30 Gy to:Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
Bladder
Iliac
Inguinal
PelvicProstate
VaginalSpine (sacral)
Spine (whole)
Total Lymphoid Irradiation
(TLI)
TBI*

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

URINARY TRACT (cont)
Potential Late
Effects
Urinary tract toxicity
Bladder fibrosis
Dysfunctional voiding
Vesicoureteral reflux
Hydronephrosis

Risk
Factors

HighestRisk Factors

Treatment Factors
Higher cumulative radiationdose ( ≥ 45 Gy)
Radiation to entire bladder
Combined with:-- Cyclophosphamide-- Ifosfamide-- Vincristine

Periodic
Evaluation
HISTORY

Health Links

Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyBladder Health

SCREENING• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 30 Gy

Health Counseling/
Further Considerations

Urinalysis
YearlyConsiderations for Further Testing and Intervention
Urologic consultation for patients with incontinence ordysfunctional voiding.

SYSTEM = Urinary
SCORE = 1

• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Info Link
The bladder is includedin the left and right flank/
hemiabdomen treatment
fields only if the fields
extended below iliac crest.

SECTION 93 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. Mar-Apr 1999;21(2):115-122.
Marks LB, Carroll PR, Dugan TC, Anscher MS. The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1257-1280.
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. Mar 1988;71(3 Pt 2):435-437.
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. Apr 1 1993;71(7):2387-2394.
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. Dec 2005;174(6):2343-2346.
Yeung CK, Ward HC, Ransley PG, Duffy PG, Pritchard J. Bladder and kidney function after cure of pelvic rhabdomyosarcoma in childhood. Br J Cancer. Nov 1994;70(5):1000-1003.

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Therapeutic
Agent(s)94

Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
Bladder
Iliac
Inguinal
PelvicProstate
VaginalSpine (sacral)
Spine (whole)
Total Lymphoid Irradiation(TLI)

URINARY TRACT (cont)
Potential Late
Effects
Bladder malignancy

Risk
Factors

HighestRisk Factors

Treatment Factors
Radiation to pelvis
Combined with:-- Cyclophosphamide-- Ifosfamide
Health Behaviors
Alcohol use
Smoking• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Info Link
The bladder is includedin the left and right flank/
hemiabdomen treatment
fields only if the fields
extended below iliac crest.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyBladder HealthCounselingCounsel to promptly report dysuria or gross hematuria

Considerations for Further Testing and Intervention
For patients with positive history, obtain urinalysis and consider
urine culture, spot urine calcium/creatinine ratio, and ultrasoundof kidneys and bladder for patients with microscopic hematuria(defined as > 5 RBC/HFP 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.

SYSTEM = SMNSCORE = 2A

SECTION 94 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. Oct 5 2010;153(7):461-468.
Kersun LS, Wimmer RS, Hoot AC, Meadows AT. Secondary malignant neoplasms of the bladder after cyclophosphamide treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer. Mar 2004;42(3):289-291.
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. Apr 211988;318(16):1028-1032.
Ritchey M, Ferrer F, Shearer P, Spunt SL. Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Children’s Oncology Group. Pediatr Blood Cancer. Apr 2009 52(4):439-446.
Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst. Apr 5 1995;87(7):524-530.
Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. Sep 21 2005;97(18):1354-1365.

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Agent(s)Potential Late
Effects

Risk
Factors

95

Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
Bladder
PelvicVaginalSpine (lumbar)
Spine (sacral)
Spine (whole)
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)

Uterine vascularinsufficiency
Resulting in adverse
pregnancy outcomes, suchas spontaneous abortion,
neonatal death, lowbirth weight infant, fetal
malposition, and prematurelabor

Host Factors
Females with Wilms tumor
and associated Mülleriananomalies(female)Info Link
10% of girls with Wilms
tumor have congenital uterine
anomalies.

Info Link
The uterus is included in
the left and right flank/
hemiabdomen fields only if
the fields extended below
iliac crest.

Treatment Factors
Higher radiation dose to pelvis

HighestRisk Factors
Host Factors
Prepubertal at treatment
Treatment Factors
Radiation dose ≥ 30 Gy
TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Pregnancy
Yearly and as clinically indicatedFemale Health Issues

Childbirth history
Yearly and as clinically indicatedResources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org

Considerations for Further Testing and Intervention• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Consider 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 = 2B

SECTION 95 REFERENCES
Byrne J, Nicholson HS. Excess risk for Mullerian duct anomalies in girls with Wilms tumor. Med Pediatr Oncol. Apr 2002;38(4):258-259.
Critchley HO, Wallace WH. Impact of cancer treatment on uterine function. J Natl Cancer Inst Monogr. 2005(34):64-68.
Critchley HO. Factors of importance for implantation and problems after treatment for childhood cancer. Med Pediatr Oncol. Jul 1999;33(1):9-14.
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. Jun 10 2010;28(17):2824-2830.
Gulati SC, Van Poznak C. Pregnancy after bone marrow transplantation. J Clin Oncol. May 1998;16(5):1978-1985.
Madanat-Harjuoja LM, Malila N, Lahteenmaki PM, Boice JD, Jr., Gissler M, Dyba T. Preterm delivery among female survivors of childhood, adolescent and young adulthood cancer. Int J Cancer. Oct 1 2010;127(7):1669-1679.
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.
Mar 20 2013;31(9):1239-1247.
Sanders JE, Hawley J, Levy W, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood. Apr 1 1996;87(7):3045-3052.
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. Oct 18 2006;98(20):1453-1461.
Signorello LB, Mulvihill JJ, Green DM, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet. Aug 21 2010;376(9741):624-630.
Waring AB, Wallace WH. Subfertility following treatment for childhood cancer. Hosp Med. Aug 2000;61(8):550-557.
Winther JF, Boice JD, Jr., Svendsen AL, Frederiksen K, Stovall M, Olsen JH. Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors. J Clin Oncol. Sep 10 2008;26(26):4340-4346.

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Therapeutic
Agent(s)96

Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
Bladder
PelvicVaginalSpine (lumbar)
Spine (sacral)
Spine (whole)
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)(female)Info Link
The ovaries are includedin the left and right flank/
hemiabdomen treatment
fields only if the fields
extended below iliac crest.

FEMALE REPRODUCTIVE SYSTEM (cont)
Potential Late
Effects
Gonadal dysfunction(ovarian)
Delayed/arrested pubertyPremature menopause
Infertility

Risk
Factors
Host Factors
Older age at irradiation
Treatment Factors
Radiation dose ≥ 5 Gy
if pubertal, ≥ 10 Gy if
prepubertal
Combined with alkylating
agent chemotherapy
Longer time since treatment

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 10 Gy
if pubertal, ≥ 15 Gy if
prepubertal
Combined withcyclophosphamide
conditioning for HCT

Periodic
Evaluation
HISTORY

Health Links

Pubertal (onset, tempo), menstrual,
pregnancy history
Sexual function (vaginal dryness, libido)
Medication use
YearlyFemale Health Issues

PHYSICAL
Tanner staging
Yearly until sexually mature

SCREENING• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling/
Further Considerations

FSH
LH
Estradiol
Baseline at age 13 AND as clinicallyindicated in patients with delayed orarrested puberty, irregular menses,
primary or secondary amenorrhea, and/or
clinical signs and symptoms of estrogen
deficiency

Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org

CounselingCounsel regarding the need for contraception, since thereis tremendous individual variability in gonadal toxicity after
exposure to radiation. Recovery of fertility may occur years after
therapy. Counsel regarding risks and benefits of HRT.

Considerations for Further Testing and Intervention
Bone density evaluation in hypogonadal patients. Refer toendocrinology/gynecology for delayed puberty, persistently
abnormal hormone levels or hormonal replacement for
hypogonadal patients. Reproductive endocrinology referral
for infertility evaluation and consultation regarding assisted
reproductive technologies.

SYSTEM = Reproductive (Female)
SCORE = 1

SECTION 96 REFERENCES
Bath LE, Wallace WH, Critchley HO. Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. BJOG. Feb 2002; 109(2):107-114.
Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. May 2006;91(5):1723-1728.
Couto-Silva AC, Trivin C, Thibaud E, Esperou H, Michon J, Brauner R. Factors affecting gonadal function after bone marrow transplantation during childhood. Bone Marrow Transplant. Jul 2001;28(1):67-75.
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. Jun 1 2009 27(16):2677-2685.
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. May 10 2009 27(14):2374-2381.
Grigg AP, McLachlan R, Zaja J, Szer J. Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant. Nov 2000;26(10):1089-1095.
Hamre MR, Robison LL, Nesbit ME, et al. Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group. J Clin Oncol. Nov
1987;5(11):1759-1765.
Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am. Dec 1998;27(4):927-943.
Livesey EA, Brook CG. Gonadal dysfunction after treatment of intracranial tumours. Arch Dis Child. May 1988;63(5):495-500.
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.
Mar 20 2013;31(9):1239-1247.
Papadakis V, Vlachopapadopoulou E, Van Syckle K, et al. Gonadal function in young patients successfully treated for Hodgkin disease. Med Pediatr Oncol. May 1999;32(5):366-372.
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. Mar 15 2000;46(5):1239-1246.
Sanders JE. Endocrine problems in children after bone marrow transplant for hematologic malignancies. The Long-term Follow-up Team. Bone Marrow Transplant. 1991;8 Suppl 1:2-4.
Sarafoglou K, Boulad F, Gillio A, Sklar C. Gonadal function after bone marrow transplantation for acute leukemia during childhood. J Pediatr. Feb 1997;130(2):210-216.
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Therapeutic
Agent(s)FEMALE REPRODUCTIVE SYSTEM (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 96 REFERENCES–CONTINUED
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.
Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. Jul 1999;33(1):2-8.
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. Jul 5 2006;98(13):890-896.
Stillman RJ, Schinfeld JS, Schiff I, et al. Ovarian failure in long-term survivors of childhood malignancy. Am J Obstet Gynecol. Jan 1981;139(1):62-66.
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. Mar 1 2010;76(3):867-873.
Thibaud E, Rodriguez-Macias K, Trivin C, Esperou H, Michon J, Brauner R. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant. Feb 1998;21(3):287-290.
Waring AB, Wallace WH. Subfertility following treatment for childhood cancer. Hosp Med. Aug 2000;61(8):550-557.

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Therapeutic
Agent(s)97

Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
Bladder
Iliac
PelvicVaginal
Total Lymphoid Irradiation(TLI)(female)Info Link
The vagina is included in
the left and right flank/
hemiabdomen treatment
fields only if the fields
extended below iliac crest.

FEMALE REPRODUCTIVE SYSTEM (cont)
Potential Late
Effects
Vaginal fibrosis/stenosis

Risk
Factors
Host Factors
Vaginal tumor or pelvic tumor
adjacent to vagina
Treatment Factors
Radiation dose ≥ 50 Gy in
postpubertal female
Radiation dose ≥ 25 Gy in
prepubertal female

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 55 Gy in
postpubertal female
Radiation dose ≥ 35 Gy in
prepubertal female

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Psychosocial assessment
Dyspareunia
Vulvar pain
Post-coital bleeding
Difficulty with tampon insertion
YearlyGynecologic consultation for management. Psychologicalconsultation in patients with emotional difficulties.

SYSTEM = Reproductive (Female)
SCORE = 2A

Medical Conditions
Chronic GVHD
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 97 REFERENCES
Brand AH, Bull CA, Cakir B. Vaginal stenosis in patients treated with radiotherapy for carcinoma of the cervix. Int J Gynecol Cancer. Jan-Feb 2006;16(1):288-293.
Flamant F, Gerbaulet A, Nihoul-Fekete C, Valteau-Couanet D, Chassagne D, Lemerle J. Long-term sequelae of conservative treatment by surgery, brachytherapy, and chemotherapy for vulval and vaginal rhabdomyosarcoma inchildren. J Clin Oncol. Nov 1990;8(11):1847-1853.
Gaillard P, Krasin MJ, Laningham FH, et al. Hematometrocolpos in an adolescent female treated for pelvic Ewing sarcoma. Pediatr Blood Cancer. Jan 2008;50(1):157-160.
Magne N, Oberlin O, Martelli H, Gerbaulet A, Chassagne D, Haie-Meder C. Vulval and vaginal rhabdomyosarcoma in children: update and reappraisal of Institut Gustave Roussy brachytherapy experience. Int J Radiat Oncol Biol
Phys. Nov 1 2008;72(3):878-883.
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.
Mar 20 2013;31(9):1239-1247.
Spunt SL, Sweeney TA, Hudson MM, Billups CA, Krasin MJ, Hester AL. Late effects of pelvic rhabdomyosarcoma and its treatment in female survivors. J Clin Oncol. Oct 1 2005;23(28):7143-7151.

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Therapeutic
Agent(s)98

Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
BladderFemoralIliac
Inguinal
PelvicProstate
Testicular
Total Body Irradiation (TBI)
Total Lymphoid Irradiation(TLI)(male)

MALE REPRODUCTIVE SYSTEM
Potential Late
Effects
Gonadal dysfunction(testicular)
Reduced fertility
Oligospermia
Azoospermia
Infertility

Info Link
The testes are includedin the left and right flank/
hemiabdomen only if the
fields extended below iliac
crest.

• See “Patient-Specific Guideline Identification Tool” inAppendix I to determine specific screening guidelines
by section number for individual patients.

Risk
Factors

HighestRisk Factors

Host Factors
Testicular cancer
ObesityEjaculatory dysfunction
Medications
Occupational exposures(pesticides, heavy metals,
solvents)

Treatment Factors
Radiation dose to testes≥ 6 Gy—azoospermia likely
permanent

Treatment Factors
Radiation dose to testes:-- 1 to 3 Gy—azoospermia
may be reversible-- 3 to 6 Gy—azoospermia
possibly reversible (butunlikely)-- 8 to 10 Gy—azoospermia
likely permanent
Fractionated small doses
greater risk than single
large doses
Combined with alkylating
agentsGenitourinary surgery

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyMale Health Issues

PHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchiometer
YearlySCREENING
Semen analysis
At request of sexually mature patient
Periodic evaluation over time isrecommended as resumption of
spermatogenesis can occur up to 10
years post therapy
FSH
In sexually mature patient if unable toobtain semen analysis

Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org

CounselingCounsel regarding the need for contraception, since thereis tremendous individual variability in gonadal toxicity after
exposure to radiation. Recovery of fertility may occur years after
therapy.

Considerations for Further Testing and Intervention
Reproductive endocrinology consultation for infertile couples
interested in assisted reproductive technologies.
SYSTEM = Reproductive (Male)SCORE = 1

Medical Conditions
Chronic GVHD
Health Behaviors
Tobacco/marijuana use
History of sexually transmitted
diseases

SECTION 98 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. Oct 2002;30(7):447-451.
Bordallo MA, Guimaraes MM, Pessoa CH, et al. Decreased serum inhibin B/FSH ratio as a marker of Sertoli cell function in male survivors after chemotherapy in childhood and adolescence. J Pediatr Endocrinol Metab. Jun
2004;17(6):879-887.
Couto-Silva AC, Trivin C, Thibaud E, Esperou H, Michon J, Brauner R. Factors affecting gonadal function after bone marrow transplantation during childhood. Bone Marrow Transplant. Jul 2001;28(1):67-75.
Goldman S, Johnson FL. Effects of chemotherapy and irradiation on the gonads. Endocrinol Metab Clin North Am. Sep 1993;22(3):617-629.
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. Jan 10 2010;28(2):332-339.
Grigg AP, McLachlan R, Zaja J, Szer J. Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant. Nov 2000;26(10):1089-1095.
Howell SJ, Shalet SM. Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr. 2005(34):12-17.
Jacob A, Barker H, Goodman A, Holmes J. Recovery of spermatogenesis following bone marrow transplantation. Bone Marrow Transplant. Aug 1998;22(3):277-279.
Jahnukainen K, Ehmcke J, Hou M, Schlatt S. Testicular function and fertility preservation in male cancer patients. Best Pract Res Clin Endocrinol Metab. Apr 2011;25(2):287-302.
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. Sep 20 2012;30(27):3408-3416.
Kinsella TJ. Effects of radiation therapy and chemotherapy on testicular function. Prog Clin Biol Res. 1989;302:157-171 discussion 172-157.
Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. Jun 20 2006;24(18):2917-2931.
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Therapeutic
Agent(s)MALE REPRODUCTIVE SYSTEM (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 98 REFERENCES–CONTINUED
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. Aug 1 2006;108(3):1100-1105.
Rowley MJ, Leach DR, Warner GA, Heller CG. Effect of graded doses of ionizing radiation on the human testis. Radiat Res. Sep 1974;59(3):665-678.
Sanders JE. Endocrine problems in children after bone marrow transplant for hematologic malignancies. The Long-term Follow-up Team. Bone Marrow Transplant. 1991;8 Suppl 1:2-4.
Sarafoglou K, Boulad F, Gillio A, Sklar C. Gonadal function after bone marrow transplantation for acute leukemia during childhood. J Pediatr. Feb 1997;130(2):210-216.
Simon B, Lee SJ, Partridge AH, Runowicz CD. Preserving fertility after cancer. CA Cancer J Clin. Jul-Aug 2005;55(4):211-228 quiz 263-214.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.
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. Dec
1990;8(12):1981-1987.
Wallace WH, Thomson AB. Preservation of fertility in children treated for cancer. Arch Dis Child. Jun 2003;88(6):493-496.
Waring AB, Wallace WH. Subfertility following treatment for childhood cancer. Hosp Med. Aug 2000;61(8):550-557.

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MALE REPRODUCTIVE SYSTEM (cont)

Sec#

Therapeutic
Agent(s)Potential Late
Effects99≥ 20 Gy to:Inverted Y
Left Flank/Hemiabdomen
Right Flank/Hemiabdomen
Whole abdomen
BladderFemoralIliac
Inguinal
PelvicProstate
Testicular
Total Lymphoid Irradiation
(TLI)
TBI*

Gonadal dysfunction(testicular): Testosterone
deficiency/insufficiency
Delayed/arrested puberty(male)*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

Risk
Factors
Host Factors
Testicular cancer
Aging
Treatment Factors
Testicular irradiation
combined with head/brain
irradiation
Combined with unilateralorchiectomy

HighestRisk Factors
Treatment Factors
Combined with alkylating
agentsCombined withcyclophosphamide
conditioning for HCT• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 20 Gy
OR2) Received a combination of radiation to any of the specified fields and
TBI, the sum of which is ≥ 20 Gy• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyMale Health Issues

PHYSICAL
Tanner staging until sexually mature
Testicular volume by Prader orchiometer
YearlySCREENING
Testosterone (ideally morning)
Baseline at age 14 AND as clinicallyindicated in patients with delayed orarrested puberty and/or clinical signs andsymptoms of testosterone deficiency

Considerations for Further Testing and Intervention
Bone density evaluation in hypogonadal patients. Refer toendocrinology/urology for delayed puberty, persistently abnormal
hormone levels or hormonal replacement for hypogonadal
patients. Males with low normal testosterone should haveperiodic repeat measurements of testosterone as they age or ifthey become symptomatic.

SYSTEM = Reproductive (Male)SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Info Link
The testes are includedin the left and right flank/
hemiabdomen only if the
fields extended below iliac
crest.

SECTION 99 REFERENCES
Goldman S, Johnson FL. Effects of chemotherapy and irradiation on the gonads. Endocrinol Metab Clin North Am. Sep 1993;22(3):617-629.
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. Sep 2007;92(9):3476-3482.
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. Sep 20 2012;30(27):3408-3416.
Kinsella TJ. Effects of radiation therapy and chemotherapy on testicular function. Prog Clin Biol Res. 1989;302:157-171 discussion 172-157.
Rowley MJ, Leach DR, Warner GA, Heller CG. Effect of graded doses of ionizing radiation on the human testis. Radiat Res. Sep 1974;59(3):665-678.
Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. Jul 1999;33(1):2-8.
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. Dec
1990;8(12):1981-1987.

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Sec
#
100

Therapeutic
Agent(s)All Radiation Fields(including TBI)MUSCULOSKELETAL SYSTEM
Potential Late
Effects
Musculoskeletal growth
problems
Hypoplasia
Fibrosis
Reduced or uneven growth
Shortened trunk height (trunkradiation)
Limb length discrepancy(extremity radiation)

Risk
Factors

HighestRisk Factors

Host Factors
Younger age at treatment

Host Factors
Prepubertal at treatment

Treatment Factors
Higher cumulative radiation
dose
Larger radiation treatment
field
Higher radiation dose per
fraction

Treatment Factors
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones
Epiphysis in treatment field
Dose ≥ 20 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Counseling

Limb lengths
Yearly for patients who had extremity
radiationCounsel regarding increased risk of fractures in weight-bearing
irradiated bones

HeightWeightYearlySitting height
Yearly for patients who had trunk radiation

Considerations for Further Testing and Intervention
Orthopedic consultation for any deficit noted in growing child.
Consider plastic surgery consult for reconstruction.

SYSTEM = Musculoskeletal
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 100 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. Apr 2007;150(4):370-375, 375 e371.
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. Jan 2013;60(1):110115.
Donaldson SS. Pediatric patients: tolerance levels and effects of treatment. In: Vaeth JM, Meyer JL, eds. Front Radiat Ther Oncol. 1989;23:390-407.
Fletcher BD. Effects of pediatric cancer therapy on the musculoskeletal system. Pediatr Radiol. Aug 1997;27(8):623-636.
Hogeboom CJ, Grosser SC, Guthrie KA, Thomas PR, D’Angio GJ, Breslow NE. Stature loss following treatment for Wilms tumor. Med Pediatr Oncol. Feb 2001;36(2):295-304.
Katzman H, Waugh T, Berdon W. Skeletal changes following irradiation of childhood tumors. J Bone Joint Surg Am. Jul 1969;51(5):825-842.
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. Nov 2010;186(11):614-620.
Merchant TE, Nguyen L, Nguyen D, Wu S, Hudson MM, Kaste SC. Differential attenuation of clavicle growth after asymmetric mantle radiotherapy. Int J Radiat Oncol Biol Phys. Jun 1 2004;59(2):556-561.
Noorda EM, Somers R, van Leeuwen FE, Vulsma T, Behrendt H. Adult height and age at menarche in childhood cancer survivors. Eur J Cancer. Mar 2001;37(5):605-612.
Probert JC, Parker BR, Kaplan HS. Growth retardation in children after megavoltage irradiation of the spine. Cancer. Sep 1973;32(3):634-639.
Probert JC, Parker BR. The effects of radiation therapy on bone growth. Radiology. Jan 1975;114(1):155-162.
Rohde RS, Puhaindran ME, Morris CD, et al. Complications of radiation therapy to the hand after soft tissue sarcoma surgery. J Hand Surg Am. Nov 2010;35(11):1858-1863.

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Sec#

Therapeutic
Agent(s)101

Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
Chest (thorax)
Extended Mantle
MantleMediastinal
Whole lung
Total Lymphoid Irradiation(TLI)

MUSCULOSKELETAL SYSTEM (cont)
Potential Late
Effects
Scoliosis/Kyphosis

Risk
Factors
Host Factors
Younger age at irradiation
Paraspinal malignancies
Neurofibromatosis
Treatment Factors
Hemithoracic or abdominal
radiation
Hemithoracic, abdominal or
spinal surgery
Radiation of only a portion of(rather than whole) vertebral
body
Info Link
With contemporary treatment
approaches, scoliosis is
infrequently seen as aconsequence of radiation
unless the patient has also
undergone surgery to thehemithorax, abdomen or
spine.

HighestRisk Factors
Treatment Factors
Radiation doses ≥ 20 Gy(lower doses for infants)
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Spine exam for scoliosis and kyphosis
Yearly until growth completed, may needmore frequent assessment during puberty
or if curve detected

Scoliosis and Kyphosis

Considerations for Further Testing and Intervention
Spine films in patients with clinically apparent curve. Orthopedic
consultation as indicated based on radiographic exam.

SYSTEM = Musculoskeletal
SCORE = 1

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 101 REFERENCES
de Jonge T, Slullitel H, Dubousset J, Miladi L, Wicart P, Illes T. Late-onset spinal deformities in children treated by laminectomy and radiation therapy for malignant tumours. Eur Spine J. Oct 2005;14(8):765-771.
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. Aug 19 2009 101(16):1131-1140.
Marcus RB, DiCaprio MR, Lindskog DM, McGrath BE, Gamble K, Scarborough M. Musculoskeletal, Integument, Breast. In: Schwartz CL, Hobbie WL, Constine LS, Ruccione KS, eds. Survivors of Childhood and Adolescent Cancer: A
Multidisciplinary Approach, Second Edition. Heidelberg, Germany: Springer-Verlag 2005:262-269.
Paulino AC, Mayr NA, Simon JH, Buatti JM. Locoregional control in infants with neuroblastoma: role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys. Mar 15 2002;52(4):1025-1031.
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. Mar 15 2000;46(5):1239-1246.
Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys. Mar 1 2012;82(3):1142-1148.

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MUSCULOSKELETAL SYSTEM (cont)

Sec#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors102≥ 40 Gy to:
Hepatic
Inverted Y
Left Flank/Hemiabdomen
Left upper quadrant
Paraaortic
Renal
Right Flank/Hemiabdomen
Right Upper quadrant
Spleen (entire)
Spleen (partial)
Whole abdomen
Lower extremity
Upper extremity
Cervical (neck)
Supraclavicular
BladderFemoralIliac
Inguinal
PelvicProstate
VaginalSpine (cervical)
Spine (lumbar)
Spine (sacral)
Spine (thoracic)
Spine (whole)
Subtotal Lymphoid
Irradiation (STLI)
AxillaChest (thorax)
Extended Mantle
MantleMediastinal
Mini~Mantle
Whole lung
Total Lymphoid Irradiation
(TLI)
TBI*

Radiation-induced fracture

Treatment Factors
History of surgery to cortex
of boneHighestRisk Factors
Treatment Factors
Radiation dose ≥ 50 Gy tobone• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus
relevant spinal radiation and/or TBI, the sum of which is ≥ 40 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Considerations for Further Testing and Intervention

Pain, swelling, deformity of bone
As indicatedRadiograph of affected bone as clinically indicated. Orthopedic
evaluation as clinically indicated.

SYSTEM = Musculoskeletal
SCORE = 1

• See dose calculation rules on page 56 for patients who received: (a) radiation
to more than one of the specified fields, or (b) more than one planned courseof treatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI is included for dose
calculation purposes only;
this section is not applicableto patients who received
TBI alone.

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RADIATIONSec#Therapeutic
Agent(s)MUSCULOSKELETAL SYSTEM (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 102 REFERENCES
Blaes AH, Lindgren B, Mulrooney DA, Willson L, Cho LC. Pathologic femur fractures after limb-sparing treatment of soft-tissue sarcomas. J Cancer Surviv. Dec 2010;4(4):399-404.
Cannon CP, Lin PP, Lewis VO, Yasko AW. Management of radiation-associated fractures. J Am Acad Orthop Surg. Sep 2008;16(9):541-549.
Paulino AC. Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys. Sep 1 2004;60(1):265-274.
Wagner LM, Neel MD, Pappo AS, et al. Fractures in pediatric Ewing sarcoma. J Pediatr Hematol Oncol. Dec 2001;23(9):568-571.

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HEMATOPOIETIC CELL TRANSPLANTINTRODUCTION

HEMATOPOIETIC CELL TRANSPLANT INTRODUCTORY INFORMATION/TBI-RELATED POTENTIAL LATE EFFECTS
Info Link: Hematopoietic Cell Transplant Introductory
Information
•

•

•

•

COG LTFU Guidelines – Page 129

Complications after hematopoietic cell transplantation have multifactorial etiology: 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,complication of transplant process (immunosuppression and GVHD), complications in the post-transplant
period, underlying disease, host genetic factors,
lifestyle behaviors.
This section includes late treatment complications
that may be observed in hematopoietic cell transplant recipients not covered elsewhere in theseguidelines.
Refer to other sections of these guidelines for specific details related to late complications of radiationand of specific chemotherapeutic agents.
For HCT follow-up recommendations from theEuropean Group for Blood and Marrow Transplantation, Center for International Blood and Marrow
Transplant Research, and the American Society for
Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT), see: Majhail NS, Rizzo JD, Lee SJ, et al.
Recommended screening and preventive practices for long-term survivors after hematopoietic
cell transplantation. Bone Marrow Transplant. Mar
2012;47(3):337-341.

TBI-Related Potential Late Effects
The complete list of potential late effects and associated Guideline section numbers
are included here for clinician convenience when evaluating patients who received
TBI. For details regarding each potential late effect and indicated screening, pleaserefer to the relevant section within these Guidelines.
Section #GenderPotential Late Effect

44

Both

Secondary benign or malignant neoplasms

45

Both

Dysplastic nevi/skin cancer

48

Both

Brain tumor (benign or malignant)

49

Both

Neurocognitive deficits

50

Both

Clinical leukoencephalopathy

55

Both

Growth hormone deficiency

64

Both

Cataracts

69

Both

Dental abnormalities

71

Both

Thyroid nodules

72

Both

Thyroid cancer

73

Both

Hypothyroidism

77*

FemaleBreast cancer

78

FemaleBreast tissue hypoplasia

79

Both

Pulmonary toxicity

80

Male

Cardiac toxicity

81

FemaleCardiac toxicity

84

Both

Impaired glucose metabolism/diabetes mellitus

85

Both

Dyslipidemia

90*

Both

Colorectal cancer

91

Both

Renal toxicity

95

FemaleUterine vascular insufficiency

96

FemaleGonadal dysfunction (ovarian)

98

Male

Gonadal dysfunction (testicular)

100

Both

Musculoskeletal growth problems*Screening may be indicated for patients who received TBI alone – see Info Link in this section

Version 4.0 – October 2013

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)103Autologous Hematopoietic
Cell Transplant (HCT)

Potential Late
Effects
Myelodysplasia
Acute myeloid leukemia

Risk
Factors
Treatment Factors
Radiation therapy
Stem cell mobilization withetoposide
Alkylating agent
chemotherapy
Epipodophyllotoxins
Anthracyclines
Autologous transplant

HighestRisk Factors
Host Factors
Older age
Treatment Factors
Autologous transplant for
non-Hodgkin and Hodgkin
lymphoma
Peripheral blood stem cells

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

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

Reducing the Risk of Second Cancers

PHYSICAL
Dermatologic exam (pallor, petechiae,
purpura)Yearly, up to 10 years after transplantCounselingCounsel to promptly report fatigue, pallor, petechiae or bone
pain.

Considerations for Further Testing and Intervention
CBC and bone marrow exam as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 103 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
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. Jan 1
2007;109(1):46-51.
Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood. May 1 1996;87(9):3633-3639.
Del Canizo M, Amigo M, Hernandez JM, et al. Incidence and characterization of secondary myelodysplastic syndromes following autologous transplantation. Haematologica. Apr 2000;85(4):403-409.
Forrest DL, Nevill TJ, Naiman SC, et al. Second malignancy following high-dose therapy and autologous stem cell transplantation: incidence and risk factor analysis. Bone Marrow Transplant. Nov 2003;32(9):915-923.
Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin. Oncol. Aug 2008;35(4):418-429.
Hosing C, Munsell M, Yazji S, et al. Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. Ann Oncol. Mar
2002;13(3):450-459.
Howe R, Micallef IN, Inwards DJ, et al. Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma. Bone Marrow Transplant. Aug 2003;32(3):317-324.
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. Aug 1 2006;24(22):36043610.
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. Mar 1 2000;95(5):1588-1593.
Rihani R, Bazzeh F, Faqih N, Sultan I. Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer. Sep 15
2010;116(18):4385-4394.

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(male)

Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential Late
Effects
Solid tumors

Risk
Factors
Host Factors
Younger age at transplant
Fanconi’s anemia
Treatment Factors
Radiation therapy
Medical Conditions
Hepatitis C infection
Chronic GVHD
Human Papillomavirus (HPV)
infection(cont)

HighestRisk Factors
Treatment Factors
TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Evaluation for benign or malignant
neoplasms
YearlyReducing the Risk of Second Cancers

Counseling
Avoid excessive sun exposure and tanning booths. Counsel
regarding safer sexual practices.

Considerations for Further Testing and Intervention
Oncology consultation as clinically indicated. HPV vaccination
per current recommendations.

SYSTEM = SMNSCORE = 1

SECTION 104 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood. May 1 1996;87(9):3633-3639.
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. Jun 10 2007;25(17):2449-2454.
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. May 15
2005;105(10):3802-3811.
Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med. Mar 27 1997;336(13):897-904.
Gallagher G, Forrest DL. Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer. Jan 1 2007;109(1):84-92.
Klosky JL, Gamble HL, Spunt SL, Randolph ME, Green DM, Hudson MM. Human papillomavirus vaccination in survivors of childhood cancer. Cancer. Dec 15 2009 115(24):5627-5636.
Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. Mar 1 2006;24(7):1119-1126.
Majhail NS, Brazauskas R, Rizzo JD, et al. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood. Jan 6 2011
117(1):316-322.
Rizzo JD, Curtis RE, Socie G, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. Jan 29 2009 113(5):1175-1183.
Schwartz JL, Kopecky KJ, Mathes RW, Leisenring WM, Friedman DL, Deeg HJ. Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation. Radiat Res. Feb 2009 171(2):155-163.
Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. Jan 2000;18(2):348-357.

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Therapeutic
Agent(s)(female)Hematopoietic Cell
Transplant (HCT)

Potential Late
Effects
Solid tumors

Risk
Factors
Host Factors
Younger age at transplant
Fanconi’s anemia
Treatment Factors
Radiation therapy
Medical Conditions
Hepatitis C infection
Chronic GVHD
Human Papillomavirus (HPV)
infection(cont)

HighestRisk Factors
Treatment Factors
TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Evaluation for benign or malignant
neoplasms
YearlyReducing the Risk of Second Cancers

Counseling
Avoid excessive sun exposure and tanning booths. Counsel
regarding safer sexual practices.

Considerations for Further Testing and Intervention
Females with cGVHD appear to be at increased risk for cervicalcancer and should, at minimum, have pelvic exams and PAP
testing according to ACS recommendations (see Section158) with more aggressive monitoring as clinically indicated.
Oncology consultation as clinically indicated. HPV vaccination
per current recommendations.

SYSTEM = SMNSCORE = 1

SECTION 105 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood. May 1 1996;87(9):3633-3639.
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. Jun 10 2007;25(17):2449-2454.
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. May 15
2005;105(10):3802-3811.
Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med. Mar 27 1997;336(13):897-904.
Friedman DL, Rovo A, Leisenring W, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party. Blood. Jan 15 2008
111(2):939-944.
Gallagher G, Forrest DL. Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer. Jan 1 2007;109(1):84-92.
Klosky JL, Gamble HL, Spunt SL, Randolph ME, Green DM, Hudson MM. Human papillomavirus vaccination in survivors of childhood cancer. Cancer. Dec 15 2009 115(24):5627-5636.
Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. Mar 1 2006;24(7):1119-1126.
Majhail NS, Brazauskas R, Rizzo JD, et al. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood. Jan 6 2011;117(1):316-322.
Rizzo JD, Curtis RE, Socie G, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. Jan 29 2009 113(5):1175-1183.
Schwartz JL, Kopecky KJ, Mathes RW, Leisenring WM, Friedman DL, Deeg HJ. Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation. Radiat Res. Feb 2009 171(2):155-163.
Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. Jan 2000;18(2):348-357.

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Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential Late
Effects
Lymphoma

Risk
Factors
Medical Conditions
Chronic GVHD

(cont)

HighestRisk Factors
Host Factors
Diagnosis of primary immune
deficiency
Treatment Factors
HLA mismatch
Unrelated donor transplantT-cell depletion
ATG

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Considerations for Further Testing and Intervention

Lymphadenopathy
YearlyOncology consultation as clinically indicated.

Splenomegaly
YearlySYSTEM = SMNSCORE = 1

SECTION 106 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood. May 1 1996;87(9):3633-3639.
Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood. Oct 1 1999;94(7):2208-2216.
Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. May 14 2009 113(20):4992-5001.
Rowlings PA, Curtis RE, Passweg JR, et al. Increased incidence of Hodgkin’s disease after allogeneic bone marrow transplantation. J Clin Oncol. Oct 1999;17(10):3122-3127.
Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. Jan 2000;18(2):348-357.
Witherspoon RP, Fisher LD, Schoch G, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med. Sep 21 1989;321(12):784-789.

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Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential Late
Effects
Hepatic toxicity
Chronic hepatitis
Cirrhosis
Iron overload

Risk
Factors

HighestRisk Factors

Treatment Factors
History of multiple
transfusions
Radiation to the liver
Antimetabolite therapy

Medical Conditions
Chronic hepatitis C withsiderosis and steatosis

Medical Conditions
Chronic GVHD
Viral hepatitis
History of VOD
Health Behaviors
Alcohol use(cont)
Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

ALT
AST
Bilirubin
Ferritin
Baseline at entry into long-term follow-up,
repeat as clinically indicatedLiver Health
Gastrointestinal Health

Considerations for Further Testing and Intervention
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.
Note: PCR testing for HCV may be required in
immunosuppressed patients who are negative for antibody.
Gastroenterology/hepatology consultation in patients withpersistent liver dysfunction or known hepatitis. Hepatitis A and
B immunizations in patients lacking immunity. Consider liverbiopsy in patients with persistent elevation of ferritin (basedon clinical context and magnitude of elevation). Consider
phlebotomy or chelation therapy for treatment of iron overload.

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 107 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. May 2010;54(5):663-669.
McDonald GB. Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology. Apr 2010;51(4):1450-1460.
McKay PJ, Murphy JA, Cameron S, et al. Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. Bone Marrow Transplant. Jan 1996;17(1):63-66.
Mulder RL, van Dalen EC, Van den Hof M, et al. Hepatic late adverse effects after antineoplastic treatment for childhood cancer. The Cochrane Database of Systematic Reviews. 2011(7):CD008205.
Ohata K, Hamasaki K, Toriyama K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer. Jun 15 2003;97(12):3036-3043.
Paul IM, Sanders J, Ruggiero F, Andrews T, Ungar D, Eyster ME. Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood. Jun 1 1999;93(11):3672-3677.
Peffault de Latour R, Levy V, Asselah T, et al. Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood. Mar 1 2004;103(5):1618-1624.
Strasser SI, Myerson D, Spurgeon CL, et al. Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology. Jun 1999;29(6):1893-1899.
Strasser SI, Sullivan KM, Myerson D, et al. Cirrhosis of the liver in long-term marrow transplant survivors. Blood. May 15 1999;93(10):3259-3266.

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Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential Late
Effects

Risk
Factors

HighestRisk Factors

Osteonecrosis (Avascular
Necrosis)

Treatment Factors
Corticosteroids(dexamethasone effectis more potent than
prednisone)
Other immunosuppressants
TBI
High-dose radiation to any
bone
Allogeneic HCT > autologous

Host Factors
Pubertal or post-pubertal attime of transplant

Info Link• Osteonecrosis typicallyoccurs during the acutetreatment phase, and may
progress over time orresolve.
• Multifocal osteonecrosis issignificantly more common(3:1) than unifocal.

(cont)

Treatment Factors
Prolonged
immunosuppressive therapy(e.g., for chronic GVHD)
Medical Conditions
Chronic GVHD

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Joint pain
Swelling
Immobility
Limited range of motion
YearlyOsteonecrosis

PHYSICAL
Musculoskeletal exam
YearlyConsiderations for Further Testing and Intervention
MRI as clinically indicated in patients with history suggestiveof osteonecrosis (should be done soon after symptom onset).
Orthopedic consultation in patients with positive imaging and/or symptoms of osteonecrosis. Symptomatic lesions confer
the greatest risk for collapse. Physical therapy evaluation(for non-pharmacologic pain management, range of motion,
strengthening, stretching, functional mobility).

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 108 REFERENCES
Campbell S, Sun CL, Kurian S, et al. Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation. Cancer. Sep 15 2009 115(18):4127-4135.
Faraci M, Calevo MG, Lanino E, et al. Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica. Aug 2006;91(8):1096-1099.
Fink JC, Leisenring WM, Sullivan KM, Sherrard DJ, Weiss NS. Avascular necrosis following bone marrow transplantation: a case-control study. Bone. Jan 1998;22(1):67-71.
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. Jun 20 2008
26(18):3038-3045.
Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia?: a 2- to 7-year study. Clin Orthop Relat Res. Sep 2010;468(9):2454-2459.
Kaste SC, Shidler TJ, Tong X, et al. Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant. Feb 2004;33(4):435-441.
Leung W, Ahn H, Rose SR, et al. A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore). Jul 2007;86(4):215-224.
Mattano LA, Jr., Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol. Sep 15 2000;18(18):3262-3272.
Schulte CM, Beelen DW. Avascular osteonecrosis after allogeneic hematopoietic stem-cell transplantation: diagnosis and gender matter. Transplantation. Oct 15 2004;78(7):1055-1063.
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. Jun 27
2005;79(12):1748-1755.
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. Oct 28
2010;116(17):3129-3139 quiz 3377.
Tauchmanova L, De Rosa G, Serio B, et al. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and a review. Cancer. May 15 2003;97(10):2453-2461.

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Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Reduced bone mineral density(BMD)
Defined as Z-score > 2.0 SD below
the mean in survivors < 20 years old
or T-score > 1.0 SD below the meanin survivors ≥ 20 years old
Info Link• The World Health Organization
definition of osteoporosis in adults isbased on comparison of a measured
bone mineral density (BMD) of
young adults at peak bone age anddefined 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 thecontext of postmenopausal women.
In this population, T-scores have awell-validated correlation with fracture risk that increases with age.
• The fracture risk associated with
T-scores in younger populations,
including cancer survivors withtreatment-related hypogonadism,
has not been established. T-scores
are not appropriate to assess
skeletal health in pediatric patients
who have not achieved peak adultbone mass.
• Pediatric BMD reference data
sets calculate Z-scores based onage and gender. A Z-score is thenumber of standard deviations themeasurement is above or below theAGE-MATCHED MEAN BMD.
• The fracture risk in pediatricpatients with low bone density forchronologic age based on Z-scores
has not been established. There are
no defined standards for referral ortreatment of low BMD in children.

COG LTFU Guidelines – Page 136

Risk
Factors
Host Factors
Both genders are at risk
Younger age at diagnosis
Caucasian
Lower weight and BMI
Treatment Factors
Corticosteroids
Cyclosporine
Tacrolimus
Cranial radiation
Craniospinal radiation
HCT/TBI
Medical Conditions
Growth hormone deficiency
Hypogonadism/delayed
puberty
Hyperthyroidism
Health Behaviors
Inadequate intake of calcium
and vitamin D
Lack of weight bearing
exercise
Smoking
Alcohol use
Carbonated beverages(cont)

HighestRisk Factors
Host Factors
Older age at time of treatment
Treatment Factors
Prolonged corticosteroid
therapy (e.g., for chronic
GVHD)

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Bone density evaluation (DEXA orquantitative CT)
Baseline at entry into long-term
follow-up, repeat as clinicallyindicated

Bone Health

Info Link• The optimal method of measuringbone health in children is controversial. Existing technologies have
limitations.
• Dual energy x-ray absorptiometry(DEXA) provides an estimate of
total bone mass at a given site.
• Quantitative CT provides distinct
measures of trabecular and cortical bone dimension and density.

Ensure the AAP recommended minimum daily intake of Vitamin D(400 IU/day) for children, with possible considerations for high doses
in selected patients (e.g., kidney disease or Vitamin D deficiency).
Many experts recommend higher Vitamin D intake in adults aswell. Also ensure adequate dietary calcium (see table in the“Bone Health” Health Link for age-appropriate recommendations).
Supplements may be necessary if there are dietary restrictions.
Advocate for regular weight-bearing exercises such as runningand jumping. Use caution regarding calcium supplementation inpatients with history of renal lithiasis. Treatment of exacerbatingor 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).

Resources
National Osteoporosis Foundation website: www.nof.org

Considerations for Further Testing and Intervention

SYSTEM = Musculoskeletal
SCORE = 2B

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Agent(s)Potential Late
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Risk
Factors

HighestRisk Factors(cont)
Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 109 REFERENCES
Bhatia S, Ramsay NK, Weisdorf D, Griffiths H, Robison LL. Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant. Jul 1998;22(1):87-90.
Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med. Biol. 2008;624:55-71.
Chemaitilly W, Sklar CA. Endocrine complications of hematopoietic stem cell transplantation. Endocrinol Metab Clin. North Am. Dec 2007;36(4):983-998 ix.
Ebeling PR. Approach to the patient with transplantation-related bone loss. J Clin Endocrinol Metab. May 2009 94(5):1483-1490.
Grigg AP, Shuttleworth P, Reynolds J, et al. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. Oct 2006;91(10):3835-3843.
International Society for Clinical Densitometry. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom. Spring 2004;7(1):17-26.
Kaste SC, Shidler TJ, Tong X, et al. Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant. Feb 2004;33(4):435-441.
Klopfenstein KJ, Clayton J, Rosselet R, Kerlin B, Termuhlen A, Gross T. Prevalence of abnormal bone density of pediatric patients prior to blood or marrow transplant. Pediatr Blood Cancer. Oct 2009 53(4):675-677.
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. Aug 11 2011;118(6):14811489.
Polgreen LE, Petryk A, Dietz AC, et al. Modifiable risk factors associated with bone deficits in childhood cancer survivors. BMC Pediatr. 2012;12:40.
Ruble K. Skeletal complications after bone marrow transplant in childhood. J Pediatr Oncol Nurs. Mar-Apr 2008;25(2):79-85.
Sala A, Barr RD. Osteopenia and cancer in children and adolescents: the fragility of success. Cancer. Apr 1 2007;109(7):1420-1431.
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. Dec 15 2010;55(7):13621369.
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.
Pediatrics. Nov 2008;122(5):1142-1152.

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Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential Late
Effects
Renal toxicity
Glomerular injury
Tubular injury
Hypertension

Risk
Factors
Treatment Factors
Chronic cyclosporine use(cont)

HighestRisk Factors
Host Factors
Older age at transplant
Treatment Factors
TBI
Medical Conditions
Acute kidney injury within 6months of HCTHistory of cGVHD

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Blood pressure
YearlyKidney Health
Cardiovascular Risk Factors

SCREENING

Considerations for Further Testing and Intervention

BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term follow-up,
repeat as clinically indicatedNephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency

Urinalysis
YearlySYSTEM = Renal
SCORE = 1

SECTION 110 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. Oct 2009 15(10):1251-1257.
Al-Hazzouri A, Cao Q, Burns LJ, Weisdorf DJ, Majhail NS. Similar risks for chronic kidney disease in long-term survivors of myeloablative and reduced-intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow
Transplant. Jun 2008;14(6):658-663.
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. Jan 2010;25(1):278-282.
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. Oct 1 2008;113(7):1580-1587.
Ellis MJ, Parikh CR, Inrig JK, Kanbay M, Patel UD. Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant. Nov 2008;8(11):2378-2390.
Esiashvili N, Chiang KY, Hasselle MD, Bryant C, Riffenburgh RH, Paulino AC. Renal toxicity in children undergoing total body irradiation for bone marrow transplant. Radiother Oncol. Feb 2009 90(2):242-246.
Gerstein J, Meyer A, Sykora KW, Fruhauf J, Karstens JH, Bremer M. Long-term renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT). Strahlenther Onkol. Nov
2009 185(11):751-755.
Hoffmeister PA, Hingorani SR, Storer BE, Baker KS, Sanders JE. Hypertension in long-term survivors of pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant. Apr 2010;16(4):515-524.
Majhail NS, Challa TR, Mulrooney DA, Baker KS, Burns LJ. Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. Sep 2009 15(9):11001107.
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. Nov 2011;17(11):1573-1584.

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Therapeutic
Agent(s)Potential Late
Effects111

HCT with any history of
Chronic GVHD

Dermatologic toxicity
Permanent alopecia
Nail dysplasia
Vitiligo
Scleroderma
Squamous cell carcinoma of
the skin

Risk
Factors

WITH CHRONIC GVHD

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Hair (alopecia)
Nails (hypoplasia)
Skin (vitiligo, scleroderma)YearlySkin Health

SYSTEM = Dermatologic
SCORE = 1

Info Link
Dermatologic toxicity is morecommon in presence of active
cGVHD; effects may persist
after cGVHD resolves.

SECTION 111 REFERENCES
Antin JH. Clinical practice. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med. Jul 4 2002;347(1):36-42.
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. May 15
2005;105(10):3802-3811.
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. Jul 10 2012;30(20):2466-2474.
Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. Mar 1 2006;24(7):1119-1126.
Sanli H, Akay BN, Arat M, et al. Vitiligo after hematopoietic cell transplantation: six cases and review of the literature. Dermatology. 2008;216(4):349-354.
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. Feb 2006;91(2):258-261.

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Therapeutic
Agent(s)112

HCT with any history of
Chronic GVHD

Potential Late
Effects
Xerophthalmia(keratoconjunctivitis
sicca)
Info Link
Xerophthalmia is morecommon in presence of active
cGVHD; effects may persist
after cGVHD resolves.

WITH CHRONIC GVHD (cont)

Risk
Factors

HighestRisk Factors

Treatment Factors
Cranial radiation
Eye radiation
Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)

Treatment Factors
Radiation dose to eye ≥ 30 Gy
Radiation fraction ≥ 2 Gy

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Dry eyes (burning, itching, foreign bodysensation, inflammation)
YearlyEye Health

PHYSICAL
Eye exam
YearlyConsiderations for Further Testing and Intervention
Supportive care with artificial tears. Schirmer’s testing as
clinically indicated. Ongoing ophthalmology follow-up for
identified problems. Consider every six month ophthalmology
evaluation for patients with corneal damage.

SYSTEM = Ocular
SCORE = 1

SECTION 112 REFERENCES
Ng JS, Lam DS, Li CK, et al. Ocular complications of pediatric bone marrow transplantation. Ophthalmology. Jan 1999;106(1):160-164.
Riemens A, te Boome L, Imhof S, Kuball J, Rothova A. Current insights into ocular graft-versus-host disease. Curr Opin Ophthalmol. Nov 2010;21(6):485-494.
Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. May 1 2003;101(9):3373-3385.
Suh DW, Ruttum MS, Stuckenschneider BJ, Mieler WF, Kivlin JD. Ocular findings after bone marrow transplantation in a pediatric population. Ophthalmology. Aug 1999;106(8):1564-1570.
Tichelli A, Duell T, Weiss M, et al. Late-onset keratoconjunctivitis sicca syndrome after bone marrow transplantation: incidence and risk factors. European Group or Blood and Marrow Transplantation (EBMT) Working Party on
Late Effects. Bone Marrow Transplant. Jun 1996;17(6):1105-1111.
Townley JR, Dana R, Jacobs DS. Keratoconjunctivitis sicca manifestations in ocular graft versus host disease: pathogenesis, presentation, prevention, and treatment. Semin Ophthalmol. Jul-Sep 2011;26(4-5):251-260.
Westeneng AC, Hettinga Y, Lokhorst H, Verdonck L, van Dorp S, Rothova A. Ocular graft-versus-host disease after allogeneic stem cell transplantation. Cornea. Jul 2010;29(7):758-763.

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Sec#

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Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

113

HCT with any history of
Chronic GVHD

Xerostomia
Salivary gland dysfunction
Dental caries
Periodontal disease
Oral cancer (squamous cell
carcinoma)

Treatment Factors
Head and neck radiation
involving the parotid gland
Higher radiation doses
Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)

Treatment Factors
Salivary gland radiation dose≥ 30 Gy
Use of azathioprine for cGVHD
management

Info Link
Oral-dental late effects are
more common in presenceof active cGVHD; effects may
persist after cGVHD resolves.

Medical Conditions
High grade of cGVHD
Fanconi anemia

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Xerostomia
YearlyDental Health

PHYSICAL

Supportive care with saliva substitutes, moistening agents, andsialogogues (pilocarpine). Regular dental care including fluoride
applications and regular screening for intraoral malignancy.

Oral exam
YearlyConsiderations for Further Testing and Intervention

SCREENING
Dental exam and cleaning
Every 6 months

SYSTEM = Dental
SCORE = 1

SECTION 113 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
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. May 15
2005;105(10):3802-3811.
Dahllof G, Bagesund M, Remberger M, Ringden O. Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol. Sep 1997;33(5):327-331.
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. Sep 1997;20(6):479-483.
Dahllof G, Jonsson A, Ulmner M, Huggare J. Orthodontic treatment in long-term survivors after pediatric bone marrow transplantation. Am J Orthod Dentofacial Orthop. Nov 2001;120(5):459-465.
Demarosi F, Lodi G, Carrassi A, Soligo D, Sardella A. Oral malignancies following HSCT: graft versus host disease and other risk factors. Oral Oncol. Oct 2005;41(9):865-877.
Dignan FL, Scarisbrick JJ, Cornish J, et al. Organ-specific management and supportive care in chronic graft-versus-host disease. Br J Haematol. Jul 2012;158(1):62-78.
American Academy of Pediatric Dentistry, Guideline on Dental Management of Pediatric Patients Receiving Chemotherapy, Hematopoietic Cell Transplantation, and/or Radiation. Pediatr Dent. 2013;35(5):185-193.
Guchelaar HJ, Vermes A, Meerwaldt JH. Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment. Support Care Cancer. Jul 1997;5(4):281-288.
Imanguli MM, Atkinson JC, Mitchell SA, et al. Salivary gland involvement in chronic graft-versus-host disease: prevalence, clinical significance, and recommendations for evaluation. Biol Blood Marrow Transplant. Oct
2010;16(10):1362-1369.
Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. Mar 1 2006;24(7):1119-1126.
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. Dec 15 2008;113(12):3315-3322.
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. Apr 201115(2):127-139.
Treister NS, Woo SB, O’Holleran EW, Lehmann LE, Parsons SK, Guinan EC. Oral chronic graft-versus-host disease in pediatric patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. Sep
2005;11(9):721-731.
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. Sep 2009 17(9):1169-1175.

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Therapeutic
Agent(s)114

HCT with any history of
Chronic GVHD

Potential Late
Effects
Pulmonary toxicity
Bronchiolitis obliterans
Chronic bronchitis
Bronchiectasis
Info Link
Pulmonary late effects are
more common in presenceof active cGVHD; effects may
persist after cGVHD resolves.

Risk
Factors
Treatment Factors
Chest radiation
TBI
Pulmonary toxic
chemotherapy:-- Busulfan-- Bleomycin-- Carmustine (BCNU)-- Lomustine (CCNU)
Health Behaviors
SmokingInhaled illicit drug use

WITH CHRONIC GVHD (cont)HighestRisk Factors
Medical Conditions
Prolonged
immunosuppression related
to cGVHD and its treatment

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Cough
SOB
DOE
Wheezing
YearlyPulmonary Health

PHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patientswith abnormal results or progressive
pulmonary dysfunction

Resources
Extensive information regarding smoking cessation is available
for patients on the NCI’s website: www.smokefree.gov

CounselingCounsel regarding tobacco avoidance/smoking cessation.
Patients who desire to SCUBA dive should be advised to obtain
medical clearance from a pulmonologist.

Considerations for Further Testing and Intervention
In patients with abnormal PFTs, consider repeat evaluation
prior to general anesthesia. Pulmonary consultation for patientswith symptomatic pulmonary dysfunction. Influenza andPneumococcal vaccinations.

SYSTEM = Pulmonary
SCORE = 1

SECTION 114 REFERENCES
Cerveri I, Fulgoni P, Giorgiani G, et al. Lung function abnormalities after bone marrow transplantation in children: has the trend recently changed? Chest. Dec 2001;120(6):1900-1906.
Fanfulla F, Locatelli F, Zoia MC, et al. Pulmonary complications and respiratory function changes after bone marrow transplantation in children. Eur Respir J. Oct 1997;10(10):2301-2306.
Ferry C, Gemayel G, Rocha V, et al. Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies. Bone Marrow Transplant. Aug 200740(3):219-224.
Gore EM, Lawton CA, Ash RC, Lipchik RJ. Pulmonary function changes in long-term survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys. Aug 1 1996;36(1):67-75.
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. Jun 2010;11(2):115-122.
Griese M, Rampf U, Hofmann D, Fuhrer M, Reinhardt D, Bender-Gotze C. Pulmonary complications after bone marrow transplantation in children: twenty-four years of experience in a single pediatric center. Pediatr Pulmonol. Nov
2000;30(5):393-401.
Hoffmeister PA, Madtes DK, Storer BE, Sanders JE. Pulmonary function in long-term survivors of pediatric hematopoietic cell transplantation. Pediatr Blood Cancer. Oct 15 2006;47(5):594-606.
Huang TT, Hudson MM, Stokes DC, Krasin MJ, Spunt SL, Ness KK. Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest. Oct 2011;140(4):881-901.
Inaba H, Yang J, Pan J, et al. Pulmonary dysfunction in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Cancer. Apr 15 2010116(8):2020-2030.
Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. Jul 10 2006;166(13):1359-1367.
Nenadov Beck M, Meresse V, Hartmann O, Gaultier C. Long-term pulmonary sequelae after autologous bone marrow transplantation in children without total body irradiation. Bone Marrow Transplant. Dec 1995;16(6):771-775.
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. Sep 2009 44(5):303-308.
Stolp B, Assistant Medical Director Divers Alert Network, Director Anesthesiology Emergency Airway Services, Durham, N.C. Risks associated with SCUBA diving in childhood cancer survivors. Personal communication to LandierW, Bhatia S Aug 23, 2002.
Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. Feb 12 2007;167(3):221-228.
Uderzo C, Pillon M, Corti P, et al. Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem
cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties. Bone Marrow Transplant. Jun 2007;39(11):667-675.
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Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

WITH CHRONIC GVHD (cont)
Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 114 REFERENCES–continued
Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. Mar 2004;25(1):203-216.
Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allo geneic
hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. Jul 2007;13(7):749-759.

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Agent(s)115

HCT with any history of
Chronic GVHD

Potential Late
Effects
Immunologic complications
Secretory IgA deficiency
Hypogammaglobulinemia
Decreased B cells
T cell dysfunction
Chronic infections (e.g.,
conjunctivitis, sinusitis, andbronchitis associated withchronic GVHD)
Info Link
Immunologic complications
related to cGVHD may persist
or resolve over time.

Risk
Factors

WITH CHRONIC GVHD (cont)HighestRisk Factors
Host Factors
Active cGVHD
Medical Conditions
Prolonged
immunosuppression related
to cGVHD and its treatment

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Chronic conjunctivitis
Chronic sinusitis
Chronic bronchitis
Recurrent or unusual infections
SepsisYearlyConsider PCP and anti-fungal prophylaxis in patients withactive cGVHD for duration of immunosuppressive therapy.
Immunology or infectious diseases consultation for assistancewith management of infections. Immunologic abnormalities may
persist for up to 20 years post transplant.

PHYSICAL
Pulmonary exam
YearlySYSTEM = Immune
SCORE = 1

Eye exam
YearlyNasal exam
YearlySECTION 115 REFERENCES
American Academy of Pediatric Dentistry, Guideline on Dental Management of Pediatric Patients Receiving Chemotherapy, Hematopoietic Cell Transplantation, and/or Radiation. Pediatr Dent. 2013;35(5):185-193.
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. Nov
2003;71(5):319-326.
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 theAdvisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. Oct 12 2012;61(40):816-819.
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. Jun 28 2013;62(25):521-524.
Clave E, Rocha V, Talvensaari K, et al. Prognostic value of pretransplantation host thymic function in HLA-identical sibling hematopoietic stem cell transplantation. Blood. Mar 15 2005;105(6):2608-2613.
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. Mar 22 2013;62(RR-2):1-28.
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. May 2002;117(2):444-450.
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. Dec 2001;115(3):630-641.
Nordoy T, Kolstad A, Endresen P, et al. Persistent changes in the immune system 4-10 years after ABMT. Bone Marrow Transplant. Oct 1999;24(8):873-878.
Perez-Simon JA, Encinas C, Silva F, et al. Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the National Institutes Health scale plus the type of onset can
predict survival rates and the duration of immunosuppressive therapy. Biol Blood Marrow Transplant. Oct 2008;14(10):1163-1171.
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. Nov 2007;13(11):1304-1312.
Storek J, Dawson MA, Storer B, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood. Jun 1 2001;97(11):3380-3389.
Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol. Feb 1997;54(2):131-138.

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Agent(s)Potential Late
Effects

Risk
Factors

116

HCT with currently active
chronic GVHD

Functional asplenia
At risk for life-threatening
infection with encapsulatedorganisms (e.g.,
Haemophilus influenzae,
Streptococcus pneumoniae,
meningococcus )Treatment Factors
Splenic radiation
Ongoing immunosuppression

WITH CHRONIC GVHD (cont)HighestRisk Factors
Host Factors
Hypogammaglobulinemia

Periodic
Evaluation
PHYSICAL

Health Links

Physical exam at time of febrile illness
to evaluate degree of illness andpotential source of infection
When febrile T ≥ 101ºF as indicated forpatients with active chronic GVHD

Splenic Precautions

SCREENING
Info Link
This section applies only topatients who have active
cGVHD.

Health Counseling/
Further Considerations

Blood culture
When febrile T ≥ 101ºF as indicated forpatients with active chronic GVHD

Counseling
Advise obtaining medical alert bracelet/card noting functional
asplenia. Counsel regarding risk of life-threatening infections
with encapsulated organisms. Also counsel regarding risk
associated with malaria and tick-borne diseases if living in orvisiting endemic areas

Considerations for Further Testing and Intervention
Consider 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). In patientswith T ≥ 101° (38.3° C) or other signs of serious illness,
administer a long-acting, broad-spectrum parenteral antibiotic(e.g., ceftriaxone), and continue close medical monitoring while
awaiting blood culture results. Hospitalization and broadeningof antimicrobial coverage (e.g., addition of vancomycin) may benecessary under certain circumstances, such as the presenceof marked leukocytosis, neutropenia, or significant change
from baseline CBC, toxic clinical appearance; fever ≥ 104°F;
meningitis, pneumonia, or other serious focus of infection;
signs of septic shock; or previous history of serious infection.
Immunize with Pneumococcal, Meningococcal, and HIB vaccines
according to current ACIP recommendations.
Info Link
See current edition of AAP Red Book for current
recommendations regarding antibiotic prophylaxis andimmunizations

SYSTEM = Immune
SCORE = 1

SECTION 116 REFERENCES
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
American Academy of Pediatric Dentistry, Guideline on Dental Management of Pediatric Patients Receiving Chemotherapy, Hematopoietic Cell Transplantation, and/or Radiation. Pediatr Dent. 2013;35(5):185-193.

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Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

WITH CHRONIC GVHD (cont)
Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 116 REFERENCES–continued
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. Nov
2003;71(5):319-326.
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 theAdvisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. Oct 12 2012;61(40):816-819.
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. Jun 28 2013;62(25):521-524.
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. Mar 22 2013;62(RR-2):1-28.
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. May 2002;117(2):444-450.
Mourtzoukou EG, Pappas G, Peppas G, Falagas ME. Vaccination of asplenic or hyposplenic adults. Br J Surg. Mar 2008;95(3):273-280.
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. Jul 1999;24(2):173-177.
Price VE, Blanchette VS, Ford-Jones EL. The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am. Sep 2007;21(3):697-710, viii-ix.
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. Jul 20
2007;25(29):5278-5282.
Spelman D, Buttery J, Daley A, et al. Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J. May 2008;38(5):349-356.

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Agent(s)117

HCT with any history ofchronic GVHD

Potential Late
Effects
Esophageal stricture
Info Link
Esophageal stricture related
to cGVHD is generally notreversible over time.

Risk
Factors
Treatment Factors
Radiation involving theesophagus
Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)
Medical Conditions
Gastroesophageal reflux
History of Candida esophagitis

WITH CHRONIC GVHD (cont)HighestRisk Factors
Treatment Factors
Radiation dose ≥ 40 Gy
Medical Conditions
Gut GVHD

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Dysphagia
HeartburnYearlyGastrointestinal Health

Considerations for Further Testing and Intervention
Surgery and/or gastroenterology consultation for symptomaticpatients.

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 117 REFERENCES
Lal DR, Foroutan HR, Su WT, Wolden SL, Boulad F, La Quaglia MP. The management of treatment-related esophageal complications in children and adolescents with cancer. J Pediatr Surg. Mar 2006;41(3):495-499.
Memoli D, Spitzer TR, Cottler-Fox M, Cahill R, Benjamin S, Deeg HJ. Acute esophageal stricture after bone marrow transplantation. Bone Marrow Transplant. Sep 1988;3(5):513-516.
Stemmelin GR, Pest P, Peters RA, Ceresetto JM, Shanley CM, Bullorsky EO. Severe esophageal stricture after autologous bone marrow transplant. Bone Marrow Transplant. Jun 1995;15(6):1001-1002.
Williams M. Gastrointestinal manifestations of graft-versus-host disease: diagnosis and management. AACN Clin Issues. Nov 1999;10(4):500-506.

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Effects

118

HCT with any history ofchronic GVHD

Vaginal fibrosis/stenosis(female)Info Link
Vaginal fibrosis/stenosis
related to cGVHD is generally
not reversible over time.

Risk
Factors
Treatment Factors
Pelvic radiation

WITH CHRONIC GVHD (cont)HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Psychosocial assessment
Dyspareunia
Vulvar pain
Post-coital bleeding
Difficulty with tampon insertion
YearlyPsychological consultation in patients with emotional difficulties.

SYSTEM = Reproductive (female)
SCORE = 1

PHYSICAL
Examine genitalia for lichen planus-likefeatures as well as erosions, fissures,and ulcers
YearlySCREENING
Gynecologic consultation when age
appropriate

SECTION 118 REFERENCES
Costantini S, Di Capua E, Bosi S, Chiodi S, Spinelli S. The management of severe vaginal obstruction from genital chronic graft-versus-host disease: diagnosis, surgical technique and follow-up. Minerva Ginecol. Feb
2006;58(1):11-16.
Couriel DR. Ancillary and supportive care in chronic graft-versus-host disease. Best Pract. Res. Clin. Haematol. Jun 2008;21(2):291-307.
DeLord C, Treleaven J, Shepherd J, Saso R, Powles RL. Vaginal stenosis following allogeneic bone marrow transplantation for acute myeloid leukaemia. Bone Marrow Transplant. Mar 1999;23(5):523-525.
Filipovich AH. Diagnosis and manifestations of chronic graft-versus-host disease. Best Pract Res Clin Haematol. Jun 2008;21(2):251-257.
Hayes EC, Rock JA. Treatment of vaginal agglutination associated with chronic graft-versus-host disease. Fertil Steril. Nov 2002;78(5):1125-1126.
Hirsch P, Leclerc M, Rybojad M, et al. Female genital chronic graft-versus-host disease: importance of early diagnosis to avoid severe complications. Transplantation. Jun 27 2012;93(12):1265-1269.
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.
Mar 20 2013;31(9):1239-1247.
Shanis D, Merideth M, Pulanic TK, Savani BN, Battiwalla M, Stratton P. Female long-term survivors after allogeneic hematopoietic stem cell transplantation: evaluation and management. Semin Hematol. Jan 2012;49(1):83-93.
Spinelli S, Chiodi S, Costantini S, et al. Female genital tract graft-versus-host disease following allogeneic bone marrow transplantation. Haematologica. Oct 2003;88(10):1163-1168.
Spiryda LB, Laufer MR, Soiffer RJ, Antin JA. Graft-versus-host disease of the vulva and/or vagina: diagnosis and treatment. Biol Blood Marrow Transplant. Dec 2003;9(12):760-765.
Stratton P, Turner ML, Childs R, et al. Vulvovaginal chronic graft-versus-host disease with allogeneic hematopoietic stem cell transplantation. Obstet Gynecol. Nov 2007;110(5):1041-1049.
Tauchmanova L, Selleri C, Di Carlo C, et al. Estrogen-progestogen induced hematocolpometra following allogeneic stem cell transplant. Gynecol Oncol. Apr 2004;93(1):112-115.
Zantomio D, Grigg AP. Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management. Bone Marrow Transplant. 2006 Oct;38(8):567-72.

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Therapeutic
Agent(s)119

HCT with any history ofchronic GVHD

Potential Late
Effects
Joint contractures
Info Link
Joint contractures related
to cGVHD are generally notreversible over time.

Risk
Factors

HighestRisk Factors

WITH CHRONIC GVHD (cont)
Periodic
Evaluation
Musculoskeletal exam
YearlyHealth Counseling/
Further Considerations
Considerations for Further Testing and Intervention
Consultation with physical therapy, rehabilitation medicine/
physiatrist.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 119 REFERENCES
Antin JH. Clinical practice. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med. Jul 4 2002;347(1):36-42.
Beredjiklian PK, Drummond DS, Dormans JP, Davidson RS, Brock GT, August C. Orthopaedic manifestations of chronic graft-versus-host disease. J Pediatr Orthop. Sep-Oct 1998;18(5):572-575.
Carpenter PA. Late effects of chronic graft-versus-host disease. Best Pract Res Clin Haematol. Jun 2008;21(2):309-331.
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. Jul 15 2002;100(2):415-419.

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Therapeutic
Agent(s)Amputation

AMPUTATION
Potential Late
Effects

Risk
Factors

Amputation-related
complications
Impaired cosmesis
Functional and activity
limitations
Residual limb integrity
problems
Phantom pain
Neuropathic pain
Musculoskeletal pain
Increased energy expenditure
Impaired quality of life andfunctional status
Psychological maladjustment

Host Factors
Skeletally immature/growing
childrenTreatment Factors
Site of amputation:
Hemipelvectomy> Trans-femur amputation> Trans-tibia amputation
Medical Conditions
Obesity
Diabetes
Poor residual limb healing

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Phantom pain
Functional and activity limitations
YearlyAmputation

PHYSICAL
Residual limb integrity
YearlySCREENING
Prosthetic evaluation
Every 6 months until skeletally mature,then yearlyCounselingCounsel regarding skin checks, signs of poor prosthetic fit,
residual limb and prosthetic hygiene, physical fitness andimportance of maintaining a healthy weight and lifestyle.

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 non-pharmacological pain management.
Occupational therapy consultation as needed to assist withactivities of daily living. Psychological/social work consultation
to assist with emotional difficulties related to body image,marriage, pregnancy, parenting, employment, insurance anddepression. Vocational counseling/training to identify vocations
that will not produce/exacerbate functional limitations.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 120 REFERENCES
Aulivola B, Hile CN, Hamdan AD, et al. Major lower extremity amputation: outcome of a modern series. Arch Surg. Apr 2004;139(4):395-399; discussion 399.
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. Mar 1
2011;103(3):276-282.
Eiser C. Quality of life implications as a consequence of surgery: limb salvage, primary and secondary amputation. Sarcoma. 2001;5(4):189-195.
Eiser C. Quality of life in survivors of a primary bone tumor: a systematic review. Sarcoma. 1999;4:183-190.
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. Jan 2012;91(1):24-32.
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. May 15
2003;97(10):2554-2564.
Nagarajan R, Mogil R, Neglia JP, Robison LL, Ness KK. 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.
Mar 2009;3(1):59-65.
Renard AJ, Veth RP, Schreuder HW, van Loon CJ, Koops HS, van Horn JR. Function and complications after ablative and limb-salvage therapy in lower extremity sarcoma of bone. J Surg Oncol. Apr 2000;73(4):198-205.
Rougraff BT, Simon MA, Kneisl JS, Greenberg DB, Mankin HJ. Limb salvage compared with amputation for osteosarcoma of the distal end of the femur. A long-term oncological, functional, and quality-of-life study. J Bone Joint
Surg Am. May 1994;76(5):649-656.

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Therapeutic
Agent(s)121Central venous catheter

CENTRAL VENOUS CATHETER
Potential Late
Effects
Thrombosis
Vascular insufficiency
Infection of retained cuff orline tract

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY
Tenderness or swelling at previous
catheter site
YearlyPHYSICALSYSTEM = Cardiovascular
SCORE = 1

Venous stasis
Swelling
Tenderness at previous catheter site
Yearly and as clinically indicated

SECTION 121 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. Apr 2008;6(4):589-594.
Revel-Vilk S, Menahem M, Stoffer C, Weintraub M. Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors is associated with a history of obstruction. Pediatr Blood Cancer. Jul 15
2010;55(1):153-156.
Wilimas JA, Hudson M, Rao B, Luo X, Lott L, Kaste SC. Late vascular occlusion of central lines in pediatric malignancies. Pediatrics. Feb 1998;101(2):E7.

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122

Therapeutic
Agent(s)Cystectomy
Info Link
All potential late effects
for pelvic surgery apply to
Cystectomy (see also Sections
145–148).

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 entercystoplasty only)
Info Link
Reservoir calculi are stones in
the neobladder (a reservoir for
urine usually constructed ofileum/colon)

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
SCREENING
Vitamin B12 level
Yearly starting 5 years after cystectomy(patients with ileal enterocystoplasty only)
Urology evaluation
YearlyHealth Counseling/
Further Considerations
Health Links
Cystectomy
Kidney Health

SYSTEM = Urinary
SCORE =
Asymptomatic bacteriuria: 1
Chronic urinary tract infection: 1
Renal dysfunction: 1
Vesicoureteral reflux: 1
Hydronephrosis: 1
Spontaneous neobladderperforation: 1
Reservoir calculi: 2A
Vitamin B12/folate/carotene deficiency: 2B

SECTION 122 REFERENCES
DeFoor W, Tackett L, Minevich E, Wacksman J, Sheldon C. Risk factors for spontaneous bladder perforation after augmentation cystoplasty. Urology. Oct 2003;62(4):737-741.
Hautmann RE, de Petriconi R, Gottfried HW, Kleinschmidt K, Mattes R, Paiss T. The ileal neobladder: complications and functional results in 363 patients after 11 years of followup. J Urol. Feb 1999;161(2):422-427; discussion
427-428.
Hensle TW, Bingham J, Lam J, Shabsigh A. Preventing reservoir calculi after augmentation cystoplasty and continent urinary diversion: the influence of an irrigation protocol. BJU Int. Mar 2004;93(4):585-587.
Jahnson S, Pedersen J. Cystectomy and urinary diversion during twenty years--complications and metabolic implications. Eur Urol. 1993;24(3):343-349.
Kaefer M, Tobin MS, Hendren WH, et al. Continent urinary diversion: the Children’s Hospital experience. J Urol. Apr 1997;157(4):1394-1399.
Kalloo NB, Jeffs RD, Gearhart JP. Long-term nutritional consequences of bowel segment use for lower urinary tract reconstruction in pediatric patients. Urology. Dec 1997;50(6):967-971.
Metcalfe PD, Casale AJ, Kaefer MA, et al. Spontaneous bladder perforations: a report of 500 augmentations in children and analysis of risk. J Urol. Apr 2006;175(4):1466-1470; discussion 1470-1461.
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. Apr 1 1993;71(7):2387-2394.
Rosenbaum DH, Cain MP, Kaefer M, et al. Ileal enterocystoplasty and B12 deficiency in pediatric patients. J Urol. Apr 2008;179(4):1544-1547; discussion 1547-1548.
Sim HG, Lau WK, Cheng CW. A twelve-year review of radical cystectomies in Singapore General Hospital. Ann Acad Med Singapore. Sep 2002;31(5):645-650.

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123

Therapeutic
Agent(s)Enucleation

ENUCLEATION
Potential Late
Effects
Impaired cosmesis
Poor prosthetic fit
Orbital hypoplasia

Risk
Factors
Host Factors
Younger age at enucleation
Treatment Factors
Combined with radiation

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Evaluation by ocularist
YearlyEye Health

Evaluation by ophthalmologist
YearlyConsiderations for Further Testing and Intervention
Psychological consultation in patients with emotional difficulties
related to cosmetic and visual impairment. Vocational
rehabilitation referral as indicated.

SYSTEM = Ocular
SCORE = 1

SECTION 123 REFERENCES
Kaste SC, Chen G, Fontanesi J, Crom DB, Pratt CB. Orbital development in long-term survivors of retinoblastoma. J Clin Oncol. Mar 1997;15(3):1183-1189.

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124

Therapeutic
Agent(s)(female)Hysterectomy
Info Link
For patients who also
underwent oophorectomy, seealso: Section 141 (unilateraloophorectomy) or Section 142(bilateral oophorectomy)

HYSTERECTOMY
Potential Late
Effects
Pelvic floor dysfunction
Urinary incontinence
Sexual dysfunction

Risk
Factors
Treatment Factors
Pelvic radiation

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Urinary leakage
Abdominal pain
Dyspareunia
Psychosocial assessment
YearlyFemale Health Issues

CounselingCounsel patients with ovaries regarding potential for biologic
parenthood using gestational surrogate.

Considerations for Further Testing and Intervention
Reproductive endocrinology consultation for patients wishing topursue pregnancy via gestational surrogate.

SYSTEM = Reproductive (female)
SCORE = 2A

SECTION 124 REFERENCES
Abdel-Fattah M, Barrington J, Yousef M, Mostafa A. Effect of total abdominal hysterectomy on pelvic floor function. Obstet Gynecol Surv. Apr 2004;59(4):299-304.
Benedetti-Panici P, Zullo MA, Plotti F, Manci N, Muzii L, Angioli R. Long-term bladder function in patients with locally advanced cervical carcinoma treated with neoadjuvant chemotherapy and type 3-4 radical hysterectomy.
Cancer. May 15 2004;100(10):2110-2117.
Brown JS, Sawaya G, Thom DH, Grady D. Hysterectomy and urinary incontinence: a systematic review. Lancet. Aug 12 2000;356(9229):535-539.
Butler-Manuel SA, Summerville K, Ford A, et al. Self-assessment of morbidity following radical hysterectomy for cervical cancer. J Obstet Gynaecol. Mar 1999;19(2):180-183.
Dragisic KG, Milad MP. Sexual functioning and patient expectations of sexual functioning after hysterectomy. Am J Obstet Gynecol. May 2004;190(5):1416-1418.
Duru C, Jha S, Lashen H. Urodynamic outcomes after hysterectomy for benign conditions: a systematic review and meta-analysis. Obstet Gynecol Surv. Jan 2012;67(1):45-54.
El-Toukhy TA, Hefni M, Davies A, Mahadevan S. The effect of different types of hysterectomy on urinary and sexual functions: a prospective study. J Obstet Gynaecol. Jun 2004;24(4):420-425.
Gustafsson C, Ekstrom A, Brismar S, Altman D. Urinary incontinence after hysterectomy—three-year observational study. Urology. Oct 2006;68(4):769-774.
Jensen PT, Groenvold M, Klee MC, Thranov I, Petersen MA, Machin D. Early-stage cervical carcinoma, radical hysterectomy, and sexual function. A longitudinal study. Cancer. Jan 1 2004;100(1):97-106.
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.
Mar 20 2013;31(9):1239-1247.
Miller JJ, Botros SM, Beaumont JL, et al. Impact of hysterectomy on stress urinary incontinence: an identical twin study. Am J Obstet Gynecol. May 2008;198(5):565 e561-564.
Skjeldestad FE, Hagen B. Long-term consequences of gynecological cancer treatment on urinary incontinence: a population-based cross-sectional study. Acta Obstet Gynecol Scand. 2008;87(4):469-475.

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125

Therapeutic
Agent(s)Laparotomy

LAPAROTOMY
Potential Late
Effects
Adhesions
Bowel obstruction

Risk
Factors
Treatment Factors
Combined with radiation

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Abdominal pain
Distention
Vomiting
Constipation
With clinical symptoms of obstruction

Gastrointestinal Health

Considerations for Further Testing and Intervention
KUB as clinically indicated for suspected obstruction. Surgicalconsultation for patients unresponsive to medical management.

PHYSICAL
Tenderness
Abdominal guarding
Distension
With clinical symptoms of obstruction

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 125 REFERENCES
Jockovich M, Mendenhall NP, Sombeck MD, Talbert JL, Copeland EM, 3rd, Bland KI. Long-term complications of laparotomy in Hodgkin’s disease. Ann Surg. Jun 1994;219(6):615-621; discussion 621-614.
Kaiser CW. Complications from staging laparotomy for Hodgkin disease. J Surg Oncol. 1981;16(4):319-325.
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. Mar 15 2000;46(5):1239-1246.
Ritchey ML, Green DM, Thomas PR, et al. Surgical complications after primary nephrectomy for Wilms’ tumor: report from the National Wilms’ Tumor Study Group. J Am Coll Surg. Jan 2001;192(1)63-68; quiz 146.

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Therapeutic
Agent(s)126

Limb sparing procedure

LIMB SPARING PROCEDURE
Potential Late
Effects
Complications related tolimb sparing procedure
Functional and activity
limitations
Contractures
Chronic infection
Chronic pain
Limb length discrepancy
Musculoskeletal pain
Increased energy expenditure
Fibrosis
Prosthetic malfunction(loosening, non-union,
fracture) requiring revision,
replacement or amputation
Prosthetic revision required
due to growth
Impaired quality of life
Complications withpregnancy/delivery (infemale patients with internal
hemipelvectomy)

Risk
Factors
Host Factors
Younger age at surgery
Rapid growth spurt
Skeletally immature
Treatment Factors
Tibial endoprosthesis
Use of biologic material(allograft or autograft) forreconstruction
Medical Conditions
Endoprosthetic infection
Obesity
Health Behaviors
High level of physical activity(associated with higher riskloosening)
Low level of physical activity(associated with higher riskof contractures or functional
limitations)

HighestRisk Factors
Treatment Factors
Radiation to extremity
Medical Conditions
Poor healing; Infection ofreconstruction

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Functional and activity limitations
Yearly and as clinically indicated

Limb Sparing Procedures

PHYSICAL

Counsel regarding need for antibiotic prophylaxis prior to dental
and invasive procedures if applicable.

Residual limb integrity
Yearly and as clinically indicated

SCREENING
Radiograph of affected limb
YearlyEvaluation by orthopedic surgeon(ideally by an orthopedic oncologist)
Every 6 months until skeletally mature,then yearlyCounselingConsiderations for Further Testing and Intervention
There is not consensus at the present time regarding antibiotic
prophylaxis for patients with orthopedic implants undergoing
dental procedures; guidelines are currently under developmentby the American Dental Association (ADA) and American
Academy of Orthopedic Surgery (AAOS). Counsel patients todiscuss the potential need for antibiotic prophylaxis prior todental and invasive procedures with their treating dentist/
orthopedic surgeon. Physical therapy consultation as needed
per changes in functional status (such as post-lengthening,
revisions, life changes such as pregnancy), and for nonpharmacological pain management. Consider psychologicalconsultation as needed to assist with emotional difficulties
related to body image, marriage, pregnancy, parenting,
employment, insurance and depression. Vocational counseling/training to identify vocations that will not produce/exacerbate
functional limitations.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 126 REFERENCES
American Dental Association and American Academy of Orthopedic Surgeons. Prevention of orthopaedic implant infection in patients undergoing dental procedures. Rosemont, IL: American Academy of Orthopaedic Surgeons,2012. www.ada.org/sections/professionalResources/pdfs/PUDP_guideline.pdf
Carty CP, Dickinson IC, Watts MC, Crawford RW, Steadman P. Impairment and disability following limb salvage procedures for bone sarcoma. Knee. Oct 2009;16(5):405-408.
Chihara IG, Osada H, Iitsuka Y, Masuda K, Sekiya S. Pregnancy after limb-sparing hemipelvectomy for Ewing’s sarcoma. A case report and review of the literature. Gynecol Obstet Invest. 2003;56(4):218-220.
Davidge KM, Wunder J, Tomlinson G, Wong R, Lipa J, Davis AM. Function and health status outcomes following soft tissue reconstruction for limb preservation in extremity soft tissue sarcoma. Ann Surg Oncol. Apr
2010;17(4):1052-1062.
Davis AM, Sennik S, Griffin AM, et al. Predictors of functional outcomes following limb salvage surgery for lower-extremity soft tissue sarcoma. J Surg Oncol. Apr 2000;73(4):206-211.
Eiser C. Quality of life implications as a consequence of surgery: limb salvage, primary and secondary amputation. Sarcoma. 2001;5(4):189-195.
Henderson ER, Groundland JS, Pala E, et al. Failure mode classification for tumor endoprostheses: retrospective review of five institutions and a literature review. J. Bone Joint Surg Am. Mar 2 2011;93(5):418-429.
Henderson ER, Pepper AM, Marulanda G, Binitie OT, Cheong D, Letson GD. Outcome of lower-limb preservation with an expandable endoprosthesis after bone tumor resection in children. J Bone Joint Surg Am. Mar 21
2012;94(6):537-547.
Jeys LM, Grimer RJ, Carter SR, Tillman RM. Risk of amputation following limb salvage surgery with endoprosthetic replacement, in a consecutive series of 1261 patients. Int Orthop. 2003;27(3):160-163.
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Therapeutic
Agent(s)LIMB SPARING PROCEDURE (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 126 REFERENCES
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. May 15
2003;97(10):2554-2564.
Nagarajan R, Neglia JP, Clohisy DR, Robison LL. Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications? J Clin Oncol. Nov 15 2002;20(22):4493-4501.
Nagarajan R, Mogil R, Neglia JP, Robison LL, Ness KK. 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.
Mar 2009;3(1):59-65.
Renard AJ, Veth RP, Schreuder HW, van Loon CJ, Koops HS, van Horn JR. Function and complications after ablative and limb-salvage therapy in lower extremity sarcoma of bone. J Surg Oncol. Apr 2000;73(4):198-205.
Shehadeh A, Noveau J, Malawer M, Henshaw R. Late complications and survival of endoprosthetic reconstruction after resection of bone tumors. Clin Orthop Relat. Res. Nov 2010;468(11):2885-2895.
Song WS, Kong CB, Jeon DG, et al. The impact of amount of bone resection on uncemented prosthesis failure in patients with a distal femoral tumor. J Surg Oncol. Aug 1 2011;104(2):192-197.
Tunn PU, Schmidt-Peter P, Pomraenke D, Hohenberger P. Osteosarcoma in children: long-term functional analysis. Clin Orthop Relat Res. Apr 2004(421):212-217.
Wright EH, Gwilym S, Gibbons CL, Critchley P, Giele HP. Functional and oncological outcomes after limb-salvage surgery for primary sarcomas of the upper limb. J Plast Reconstr Aesthet Surg. 2008;61(4):382-387.
Veenstra KM, Sprangers MA, van der Eyken JW, Taminiau AH. Quality of life in survivors with a Van Ness-Borggreve rotationplasty after bone tumour resection. J Surg Oncol. Apr 2000;73(4):192-197.
Yonemoto T, Tatezaki S, Ishii T, Hagiwara Y. Marriage and fertility in long-term survivors of high grade osteosarcoma. Am J Clin Oncol. Oct 2003;26(5):513-516.

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127(male)

Therapeutic
Agent(s)Nephrectomy

NEPHRECTOMY
Potential Late
Effects

Risk
Factors

Hydrocele
Renal toxicity
Proteinuria
Hyperfiltration
Renal insufficiency

Host Factors
Denys-Drash syndrome
WAGR syndrome
Hypospadias
Cryptorchidism
Bilateral Wilms tumor

Info Link• Surgery-induced renal
atrophy (vanishing kidney) isa rare complication reported
in survivors who haveundergone retroperitoneal
tumor resections.
• Once this diagnosis is established, annual screening
should include evaluations
recommended for children
treated with nephrectomy.

Treatment Factors
Combined with othernephrotoxic therapy suchas:-- Cisplatin-- Carboplatin-- Ifosfamide-- Aminoglycosides-- Amphotericin-- Immunosuppressants-- Methotrexate-- Radiation impacting thekidneysHighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Blood pressure
YearlySingle Kidney HealthSee also: Kidney Health
Cardiovascular Risk Factors

Testicular exam to evaluate forhydrocele
YearlySCREENING
BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term follow-up.
Repeat as clinically indicatedUrinalysis
YearlyCounselingCounsel mononephric survivors regarding sports and activity
safety, stressing the importance of physical fitness, and properuse of seatbelts (i.e., wearing lapbelts around hips, not waist).
Consideration should be given to survivor health status, current
kidney health (position, size, function), and acceptability ofunlikely risk of renal injury to the survivor and/or family. Counsel
to use NSAIDS with caution. Documentation of this discussion isrecommended.

Considerations for Further Testing and Intervention
Nephrology consultation for patients with hypertension,
proteinuria or progressive renal insufficiency.

SYSTEM = Urinary
SCORE = 1

SECTION 127 REFERENCES
Bailey S, Roberts A, Brock C, et al. Nephrotoxicity in survivors of Wilms’ tumours in the North of England. Br J Cancer. Nov 4 2002;87(10):1092-1098.
Breslow NE, Collins AJ, Ritchey ML, Grigoriev YA, Peterson SM, Green DM. 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. Nov 2005;174(5):1972-1975.
Cozzi F, Schiavetti A, Morini F, et al. Renal function adaptation in children with unilateral renal tumors treated with nephron sparing surgery or nephrectomy. J Urol. Oct 2005;174(4 Pt 1):1404-1408.
Diokno E, Rowe D. Medical and orthopedic conditions and sports participation. Pediatr Clin North Amer. 2010; 57:839-47.
Finklestein JZ, Norkool P, Green DM, Breslow N, D’Angio GJ. Diastolic hypertension in Wilms’ tumor survivors: a late effect of treatment? A report from the National Wilms’ Tumor Study Group. Am J Clin Oncol. Jun
1993;16(3):201-205.
Ginsberg JP, Hobbie WL, Ogle SK, Canning DA, Meadows AT. Prevalence of and risk factors for hydrocele in survivors of Wilms tumor. Pediatr Blood Cancer. Apr 2004;42(4):361-363.
Grinsell MM, Showalter S, Gordon KA et al. Single kidney and sports participation: perception versus reality. Pediatrics 2006; 118:1019-1027.
Johnson B, Christensen C, Dirusso S et al. A need for reevaluation of sports participation recommendations for children with a solitary kidney. J Urol. 2005; 174:686-689.
McAleer IM, Kaplan GW, LoSasso BE. Renal and testis injuries in team sports. J Urol. 2002: 168:1805-1807.
Mitus A, Tefft M, Fellers FX. Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics. Dec 1969;44(6):912-921.
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. Mar 15 2000;46(5):1239-1246.
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. Feb 1996;26(2):75-80.
Sharp DS, Ross JH, Kay R. Attitudes of pediatric urologists regarding sports participation by children with a solitary kidney. J Urol. Oct 2002;168(4 Pt 2):1811-1814; discussion 1815.
Srinivas M, Agarwala S, Padhy AK, et al. Somatic growth and renal function after unilateral nephrectomy for Wilms’ tumor. Pediatr Surg Int. Dec 1998;14(3):185-188.
Wan J, Corvino TF, Greenfield SP et al. Kidney and testicle injuries in team and individual sports: data from the national pediatric trauma registry. J Urol. 2003; 170:1528-1533.

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128

Therapeutic
Agent(s)(female)Nephrectomy

NEPHRECTOMY (cont)
Potential Late
Effects

Risk
Factors

Renal toxicity
Proteinuria
Hyperfiltration
Renal insufficiency

Host Factors
Denys-Drash syndrome
WAGR syndrome
Bilateral Wilms tumor

Info Link• Surgery-induced renal
atrophy (vanishing kidney) isa rare complication reported
in survivors who haveundergone retroperitoneal
tumor resections.
• Once this diagnosis is established, annual screening
should include evaluations
recommended for children
treated with nephrectomy.

Treatment Factors
Combined with othernephrotoxic therapy suchas:Cisplatin
Carboplatin
Ifosfamide
Aminoglycosides
Amphotericin
ImmunosuppressantsMethotrexate
Radiation impacting thekidneysHighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Blood pressure
YearlySingle Kidney HealthSee also: 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 indicatedUrinalysis
YearlyCounselingCounsel mononephric survivors regarding sports and activity
safety, stressing the importance of physical fitness, and properuse of seatbelts (i.e., wearing lapbelts around hips, not waist).
Consideration should be given to survivor health status, current
kidney health (position, size, function), and acceptability ofunlikely risk of renal injury to the survivor and/or family. Counsel
to use NSAIDS with caution. Documentation of this discussion isrecommended.

Considerations for Further Testing and Intervention
Nephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency.

SYSTEM = Urinary
SCORE = 1

SECTION 128 REFERENCES
Bailey S, Roberts A, Brock C, et al. Nephrotoxicity in survivors of Wilms’ tumours in the North of England. Br J Cancer. Nov 4 2002;87(10):1092-1098.
Breslow NE, Collins AJ, Ritchey ML, Grigoriev YA, Peterson SM, Green DM. End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data
Cozzi F, Schiavetti A, Morini F, et al. Renal function adaptation in children with unilateral renal tumors treated with nephron sparing surgery or nephrectomy. J Urol. Oct 2005;174(4 Pt 1):1404-1408.
Diokno E, Rowe D. Medical and orthopedic conditions and sports participation. Pediatr Clin North Amer. 2010; 57:839-47.
Finklestein JZ, Norkool P, Green DM, Breslow N, D’Angio GJ. Diastolic hypertension in Wilms’ tumor survivors: a late effect of treatment? A report from the National Wilms’ Tumor Study Group. Am J Clin Oncol. Jun
1993;16(3):201-205.
Grinsell MM, Showalter S, Gordon KA et al. Single kidney and sports participation: perception versus reality. Pediatrics 2006; 118:1019-1027.
Johnson B, Christensen C, Dirusso S et al. A need for reevaluation of sports participation recommendations for children with a solitary kidney. J Urol. 2005; 174:686-689.
McAleer IM, Kaplan GW, LoSasso BE. Renal and testis injuries in team sports. J Urol. 2002: 168:1805-1807.
Mitus A, Tefft M, Fellers FX. Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics. Dec 1969;44(6):912-921.
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. Mar 15 2000;46(5):1239-1246.
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. Feb 1996;26(2):75-80.
Sharp DS, Ross JH, Kay R. Attitudes of pediatric urologists regarding sports participation by children with a solitary kidney. J Urol. Oct 2002;168(4 Pt 2):1811-1814; discussion 1815.
Srinivas M, Agarwala S, Padhy AK, et al. Somatic growth and renal function after unilateral nephrectomy for Wilms’ tumor. Pediatr Surg Int. Dec 1998;14(3):185-188.
Wan J, Corvino TF, Greenfield SP et al. Kidney and testicle injuries in team and individual sports: data from the national pediatric trauma registry. J Urol. 2003; 170:1528-1533.

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Therapeutic
Agent(s)Neurosurgery–Brain

NEUROSURGERY—BRAIN
Potential Late
Effects
Neurocognitive deficits
Functional deficits in:-- Executive function (planning and 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
Info Link• Neurocognitive deficits varywith extent of surgery andpostoperative complications.
• In general, mild delays
occur in most areas ofneuropsychological function
compared to healthy
children.
• Extent of deficit depends on
age at treatment, intensityof treatment, and time sincetreatment.
• New deficits may emerge
over time.
• Neurosensory deficits (i.e.,
vision, hearing) due totumor or its therapy may
complicate neurocognitive
outcomes.

Risk
Factors
Host Factors
Younger age at treatment
Primary CNS tumor
Treatment Factors
In combination with:-- TBI-- Cranial radiation;
Methotrexate (IT, IO, highdose IV)-- Cytarabine (high-dose IV)
Longer elapsed time since
therapy
Extent and location ofresection
Medical Conditions
Hydrocephalus/history ofshunt placement

HighestRisk Factors
Host Factors
Age < 3 years at time oftreatment
Predisposing family historyof learning or attention
problems
Treatment Factors
Radiation dose ≥ 24 Gy towhole brain
Radiation dose ≥ 40 Gy tolocal fields
Medical Conditions
Posterior fossa syndrome
CNS infection

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Educational and/or vocational progress
YearlyEducational Issues

SCREENING

Formal neuropsychological evaluation to include tests ofprocessing speed, computer-based attention, visual motor
integration, memory, comprehension of verbal instructions,verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orcancer center (psychologist, social worker, school counselor)
to facilitate acquisition of educational resources and/or social
skills training. Consider use of psychotropic medication (e.g.,
stimulants) or evidence-based rehabilitation training. Caution—
lower starting dose and assessment of increased sensitivity
when initiating therapy is recommended. Refer to community
services for vocational rehabilitation or for services fordevelopmentally disabled.

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

Considerations for Further Testing and Intervention

SYSTEM = CNSSCORE = 1

SECTION 129 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. Jul 20 2009;27(21):3526-3532.
Butler RW, Copeland DR, Fairclough DL, et al. A multicenter, randomized clinical trial of a cognitive remediation program for childhood survivors of a pediatric malignancy. J Consult Clin Psychol. Jun 2008;76(3):367-378.
Carpentieri SC, Waber DP, Pomeroy SL, et al. Neuropsychological functioning after surgery in children treated for brain tumor. Neurosurgery. Jun 2003;52(6):1348-1356; discussion 1356-1347.
Catsman-Berrevoets CE, Aarsen FK. The spectrum of neurobehavioural deficits in the Posterior Fossa Syndrome in children after cerebellar tumour surgery. Cortex. Jul-Aug 2010;46(7):933-946.
Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol. Jul 2004;5(7):399-408.
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. Jan 2003;40(1):26-34.

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Therapeutic
Agent(s)Neurosurgery–Brain

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

Risk
Factors
Host Factors
Primary CNS tumor
Medical Conditions
Hydrocephalus

HighestRisk Factors
Host Factors
Optic pathway tumor;
Hypothalamic tumor;
Suprasellar tumor (eyeproblems)

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Considerations for Further Testing and Intervention

Evaluation by neurologist
Yearly, until 2 to 3 years after surgery or
stable; Continue to monitor if symptoms
persistSpeech, physical, and occupational therapy in patients withpersistent deficits. Consider consultations with nutrition,
endocrine, and psychiatry (for obsessive-compulsive
behaviors) in patients with hypothalamic-pituitary axis tumors.
Ophthalmology evaluation as clinically indicated.

Evaluation by physiatrist/rehabilitation
medicine specialist
Yearly, or more frequently as clinicallyindicated in patients with motor
dysfunction

SYSTEM = CNSSCORE = 1

SECTION 130 REFERENCES
Cassidy L, Stirling R, May K, Picton S, Doran R. Ophthalmic complications of childhood medulloblastoma. Med Pediatr Oncol. Jan 2000;34(1):43-47.
Doxey D, Bruce D, Sklar F, Swift D, Shapiro K. Posterior fossa syndrome: identifiable risk factors and irreversible complications. Pediatr Neurosurg. Sep 1999;31(3):131-136.
Elliott RE, Hsieh K, Hochm T, Belitskaya-Levy I, Wisoff J, Wisoff JH. Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children. J Neurosurg Pediatr. Jan 2010;5(1):30-48.
Jane JA, Jr., Prevedello DM, Alden TD, Laws ER, Jr. The transsphenoidal resection of pediatric craniopharyngiomas: a case series. J Neurosurg Pediatr. Jan 2010;5(1):49-60.
Morris EB, Laningham FH, Sandlund JT, Khan RB. Posterior reversible encephalopathy syndrome in children with cancer. Pediatr Blood Cancer. Nov 29 2005.
Mulhern RK, Palmer SL. Neurocognitive late effects in pediatric cancer. Curr Probl Cancer. Jul-Aug 2003;27(4):177-197.
Sonderkaer S, Schmiegelow M, Carstensen H, Nielsen LB, Muller J, Schmiegelow K. Long-term neurological outcome of childhood brain tumors treated by surgery only. J Clin Oncol. Apr 1 2003;21(7):1347-1351

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Therapeutic
Agent(s)Neurosurgery–Brain

NEUROSURGERY—BRAIN (cont)
Potential Late
Effects
Seizures

Risk
Factors
Host Factors
Primary CNS tumor
Treatment Factors
Methotrexate (IV, IT, IO)

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING
Evaluation by neurologist
As clinically indicated

SYSTEM = CNSSCORE = 1

SECTION 131 REFERENCES
Khan RB, Hunt DL, Boop FA, et al. Seizures in children with primary brain tumors: incidence and long-term outcome. Epilepsy Res. May 2005;64(3):85-91.
Khan RB, Marshman KC, Mulhern RK. Atonic seizures in survivors of childhood cancer. J Child Neurol. Jun 2003;18(6):397-400.
Morris EB, Laningham FH, Sandlund JT, Khan RB. Posterior reversible encephalopathy syndrome in children with cancer. Pediatr Blood Cancer. Nov 29 2005.
Mulhern RK, Palmer SL. Neurocognitive late effects in pediatric cancer. Curr Probl Cancer. Jul-Aug 2003;27(4):177-197.
Sonderkaer S, Schmiegelow M, Carstensen H, Nielsen LB, Muller J, Schmiegelow K. Long-term neurological outcome of childhood brain tumors treated by surgery only. J Clin Oncol. Apr 1 2003;21(7):1347-1351.

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Therapeutic
Agent(s)Neurosurgery–Brain

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

Risk
Factors
Host Factors
Primary CNS tumor

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Counseling

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

Education patient/family regarding potential symptoms of shunt
malfunction.

Evaluation by neurologist
Yearly for patients with shunts

Per the American Academy of Pediatric Dentistry endocarditis
prophylaxis guidelines, antibiotics are not indicated prior todental work for patients with V-P shunts (indicated for V-A and
V-V shunts only).

Considerations for Further Testing and Intervention

SYSTEM = CNSSCORE = 1

SECTION 132 REFERENCES
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.
Dias MS, Albright AL. Management of hydrocephalus complicating childhood posterior fossa tumors. Pediatr Neurosci. 1989;15(6):283-289; discussion 290.

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Agent(s)133

Neurosurgery–Brain(applies only to neurosurgery
with potential to affect the
Hypothalamic-Pituitary Axis)

NEUROSURGERY—BRAIN (cont)
Potential Late
Effects
Overweight/obesity
Info Link
Overweight-- Age 2– 20 years: BMI
for age ≥ 85th – < 95th
percentile-- Age ≥ 21 years: BMI ≥25– 29.9;
Obesity-- Age 2– 20 years: BMI forage ≥ 95th percentile-- Age ≥ 21 years: BMI ≥ 30
BMI = wt(kg)/ht(M2)
BMI calculator available online 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

Risk
Factors
Treatment Factors
Surgery in suprasellar region

HighestRisk Factors
Host Factors
Extension of tumor intohypothalamus
Pre-treatment obesity
Craniopharyngioma

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

HeightWeight
BMI
YearlyDiet and Physical Activity
Cardiovascular Risk Factors

Counseling
Nutritional counseling. Counsel regarding obesity-related healthrisks

Considerations for Further Testing and Intervention
Consider evaluation for central endocrinopathies, including
growth hormone deficiency, central hypothyroidism, central
adrenal insufficiency, precocious puberty, and gonadotropin
deficiency. Refer to endocrine to manage hormonal dysfunction.
Consider evaluation for other co-morbid conditions, including
dyslipidemia, hypertension, and impaired glucose metabolism/
diabetes mellitus.

SYSTEM = Endocrine/Metabolic
SCORE = 2A

SECTION 133 REFERENCES
De Vile CJ, Grant DB, Kendall BE, et al. Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted? J Neurosurg. Jul 1996;85(1):73-81.
Elliott RE, Hsieh K, Hochm T, Belitskaya-Levy I, Wisoff J, Wisoff JH. Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children. J Neurosurg Pediatr. Jan 2010;5(1):30-48.
Elliott RE, Wisoff JH. Surgical management of giant pediatric craniopharyngiomas. J Neurosurg Pediatr. Nov 2010;6(5):403-416.
Jane JA, Jr., Prevedello DM, Alden TD, Laws ER, Jr. The transsphenoidal resection of pediatric craniopharyngiomas: a case series. J Neurosurg Pediatr. Jan 2010;5(1):49-60
Lustig RH, Post SR, Srivannaboon K, et al. Risk factors for the development of obesity in children surviving brain tumors. J Clin Endocrinol Metab. Feb 2003;88(2):611-616.
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. Jul 2004;89(7):3298-3305.
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. Jul
2005;21(7):539-545.
Puget S, Garnett M, Wray A, et al. Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg. Jan 2007;106(1 Suppl):3-12.
Sainte-Rose C, Puget S, Wray A, et al. Craniopharyngioma: the pendulum of surgical management. Childs Nerv Syst. Aug 2005;21(8-9):691-695.

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Agent(s)134

Neurosurgery–Brain(applies only to neurosurgery
with potential to affect the
Hypothalamic-Pituitary Axis)

NEUROSURGERY—BRAIN (cont)
Potential Late
Effects
Diabetes insipidus

Risk
Factors
Treatment Factors
Surgery in suprasellar region
Reoperation for recurrent
tumor

HighestRisk Factors
Host Factors
Extension of tumor intohypothalamus
Craniopharyngioma

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Assessment of excessive thirst/polyuria
YearlyHypopituitarism

SCREENING

Consider 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.

Na, K, Cl, CO2
Serum Osmolality
Urine Osmolality
As clinically indicated if history consistent
with excessive thirst and/or polyuria

Considerations for Further Testing and Intervention

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 134 REFERENCES
Elliott RE, Hsieh K, Hochm T, Belitskaya-Levy I, Wisoff J, Wisoff JH. Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children. J Neurosurg Pediatr. Jan 2010;5(1):30-48.
Elliott RE, Wisoff JH. Surgical management of giant pediatric craniopharyngiomas. J Neurosurg Pediatr. Nov 2010;6(5):403-416.
Jane JA, Jr., Prevedello DM, Alden TD, Laws ER, Jr. The transsphenoidal resection of pediatric craniopharyngiomas: a case series. J Neurosurg Pediatr. Jan 2010;5(1):49-60
Puget S, Garnett M, Wray A, et al. Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg. Jan 2007;106(1 Suppl):3-12.
Sainte-Rose C, Puget S, Wray A, et al. Craniopharyngioma: the pendulum of surgical management. Childs Nerv Syst. Aug 2005;21(8-9):691-695.
Vinchon M, Baroncini M, Leblond P, Delestret I. Morbidity and tumor-related mortality among adult survivors of pediatric brain tumors: a review. Childs Nerv Syst. May 2011;27(5):697-704.

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Agent(s)135

Neurosurgery–Spinal cord

NEUROSURGERY—SPINAL CORD
Potential Late
Effects
Neurogenic bladder
Urinary incontinence

Risk
Factors

HighestRisk Factors

Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina

Host Factors
Injury above the level of thesacrumTreatment Factors
Radiation dose ≥ 45 Gy tolumbar and/or sacral spine
and/or cauda equina

Treatment Factors
Radiation dose ≥ 50 Gy tolumbar and/or sacral spine
and/or cauda equina

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyNeurogenic BladderCounselingCounsel regarding adequate fluid intake, regular voiding,seeking medical attention for symptoms of voiding dysfunction
or urinary tract infection and compliance with recommended
bladder catheterization regimen.

Considerations for Further Testing and Intervention
Urologic consultation for patients with dysfunctional voiding or
recurrent urinary tract infections.

SYSTEM = CNSSCORE = 1

SECTION 135 REFERENCES
Fowler C, ed. Neurology of Bladder, Bowel, and Sexual Dysfunction. Vol 23. 2nd ed. Burlington, MA: Butterworth-Heinemann; 1999.
Hoover M, Bowman LC, Crawford SE, et al. Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol. May 1999;32(5):353-359.
McGirt MJ, Chaichana KL, Atiba A, Attenello F, Yao KC, Jallo GI. Resection of intramedullary spinal cord tumors in children: assessment of long-term motor and sensory deficits. J Neurosurg Pediatrics. Jan 2008;1(1):63-67.
Moore SW, Kaschula ROC, Albertyn R, Rode H, Millar AJW, Karabus C. The outcome of solid tumors occurring during the neonatal period. Pediatr Surg Int. 1995;10(5-6):366-370.
Poretti A, Zehnder D, Boltshauser E, Grotzer MA. Long-term complications and quality of life in children with intraspinal tumors. Pediatr Blood Cancer. Apr 2008;50(4):844-848.

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Agent(s)136

Neurosurgery–Spinal cord

NEUROSURGERY—SPINAL CORD (cont)
Potential Late
Effects
Neurogenic bowel
Fecal incontinence

Risk
Factors

HighestRisk Factors

Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina

Host Factors
Injury above the level of thesacrumTreatment Factors
Radiation dose ≥ 50 Gy to
bladder, pelvis, or spine

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Counseling

Chronic constipation
Fecal soiling
YearlyCounsel regarding benefits of adherence to bowel regimen,
including adequate hydration, fiber, laxatives/enemas asclinically indicated.

PHYSICAL

Considerations for Further Testing and Intervention

Rectal exam
As clinically indicated

GI consultation to establish bowel regimen for patients withchronic impaction or fecal soiling.

SYSTEM = CNSSCORE = 1

SECTION 136 REFERENCES
Fowler C, ed. Neurology of Bladder, Bowel, and Sexual Dysfunction. Vol 23. 2nd ed. Burlington, MA: Butterworth-Heinemann; 1999.
Hoover M, Bowman LC, Crawford SE, et al. Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol. May 1999;32(5):353-359.
Moore SW, Kaschula ROC, Albertyn R, Rode H, Millar AJW, Karabus C. The outcome of solid tumors occurring during the neonatal period. Pediatr Surg Int. 1995;10(5-6):366-370.

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Sec#

Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

137

Neurosurgery–Spinal cord

Psychosexual dysfunction
Erectile dysfunction
Ejaculatory dysfunction

Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina

Host Factors
Injury above the level of thesacrum(male)

Treatment Factors
Radiation to bladder, pelvis,
or spine
Medical Conditions
Hypogonadism

Treatment Factors
Radiation dose ≥ 55 Gy topenile bulb in adult and ≥ 45
Gy in prepubertal child

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Sexual function (erections, nocturnal
emissions, libido)
YearlyMale Health Issues

Medication use
YearlyMen with erectile/ejaculatory dysfunction desiring paternity canconsider assisted reproductive technology for sperm retrieval
Resources. www.urologychannel.com

CounselingConsiderations for Further Testing and Intervention
Urologic consultation in patients with positive history.

SYSTEM = CNSSCORE = 2A

SECTION 137 REFERENCES
Brackett NL, Ibrahim E, Iremashvili V, Aballa TC, Lynne CM. Treatment for ejaculatory dysfunction in men with spinal cord injury: an 18-year single center experience. J Urol. Jun 2010;183(6):2304-2308.
Fowler C, ed. Neurology of Bladder, Bowel, and Sexual Dysfunction. Vol 23. 2nd ed. Burlington, MA: Butterworth-Heinemann; 1999.
Hoover M, Bowman LC, Crawford SE, et al. Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol. May 1999;32(5):353-359.
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. Sep 20 2012;30(27):3408-3416.
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. Sep 2004;39(9):13281332.
Moore SW, Kaschula ROC, Albertyn R, Rode H, Millar AJW, Karabus C. The outcome of solid tumors occurring during the neonatal period. Pediatr Surg Int. 1995;10(5-6):366-370.

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Therapeutic
Agent(s)Potential Late
Effects

Risk
Factors

HighestRisk Factors

138

Neurosurgery–Spinal cord

Psychosexual dysfunction

Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina

Host Factors
Injury above the level of thesacrum(female)Treatment Factors
Radiation to bladder, pelvis,
or spine

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Altered or diminished sensation, loss of
sensation )Dyspareunia
Medication use
YearlyGynecologic consultation in patients with positive history.

SYSTEM = CNSSCORE = 2A

Medical Conditions
Hypogonadism
Vaginal fibrosis/stenosis
Chronic GVHDSECTION 138 REFERENCES
Fowler C, ed. Neurology of Bladder, Bowel, and Sexual Dysfunction. Vol 23. 2nd ed. Burlington, MA: Butterworth-Heinemann; 1999.
Hoover M, Bowman LC, Crawford SE, et al. Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol. May 1999;32(5):353-359.
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.
Mar 20 2013;31(9):1239-1247.
Moore SW, Kaschula ROC, Albertyn R, Rode H, Millar AJW, Karabus C. The outcome of solid tumors occurring during the neonatal period. Pediatr Surg Int. 1995;10(5-6):366-370.
Piotrowski K, Snell L. Health needs of women with disabilities across the lifespan. J Obstet Gynecol Neonatal Nurs. Jan-Feb 2007;36(1):79-87.

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Therapeutic
Agent(s)139

Neurosurgery–Spinal cord
Laminectomy
Laminoplasty

NEUROSURGERY—SPINAL CORD (cont)
Potential Late
Effects
Scoliosis/Kyphosis

Risk
Factors
Host Factors
Preoperative deformity
Young age (deformity can stilldevelop even if skeletally
mature at time of surgery)
Treatment Factors
Radiation to the spine
Increasing number of laminae
removedFacetectomy
Laminectomy (versus
laminotomy)
Laminectomy without fusion

HighestRisk Factors
Treatment Factors> 3 laminae removed;
Increasing number ofresections
Surgery of thoracolumbar
junction

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Spine exam for scoliosis and kyphosis
Yearly until growth completed, may needmore frequent assessment during puberty
or if curve detected

Scoliosis and Kyphosis

Considerations for Further Testing and Intervention
Spine films in patients with clinically apparent curve. Orthopedic
consultation as indicated based on radiographic exam.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 139 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. Jul-Aug 2011;31(5):475-479.
de Jonge T, Slullitel H, Dubousset J, Miladi L, Wicart P, Illes T. Late-onset spinal deformities in children treated by laminectomy and radiation therapy for malignant tumours. Eur Spine J. Oct 2005;14(8):765-771.
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. Aug 19 2009;101(16):1131-1140.
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. Jan
2008;1(1):57-62.
Papagelopoulos PJ, Peterson HA, Ebersold MJ, Emmanuel PR, Choudhury SN, Quast LM. Spinal column deformity and instability after lumbar or thoracolumbar laminectomy for intraspinal tumors in children and young adults.
Spine (Phila Pa 1976 ). Feb 15 1997;22(4):442-451.
Paulino AC, Fowler BZ. Risk factors for scoliosis in children with neuroblastoma. Int J Radiat Oncol Biol Phys. Mar 1 2005;61(3):865-869.
Yao KC, McGirt MJ, Chaichana KL, Constantini S, Jallo GI. Risk factors for progressive spinal deformity following resection of intramedullary spinal cord tumors in children: an analysis of 161 consecutive cases. J Neurosurg. Dec
2007;107(6 Suppl):463-468.

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140

Therapeutic
Agent(s)(female)Oophoropexy
Info Link
Also see Section 96 if
shielding from radiation wasincomplete.

OOPHOROPEXY
Potential Late
Effects
Oophoropexy-related
complications
Inability to conceive despite
normal ovarian function
Dyspareunia
Symptomatic ovarian cysts
Bowel obstruction
Pelvic adhesions

Risk
Factors
Treatment Factors
Ovarian radiationTubo-ovarian dislocation,
especially with lateralovarian transposition

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Inability to conceive despite normal
ovarian function
Dyspareunia
Abdominal pain
Pelvic pain
YearlyGynecologic consultation for patients with positive history and/or physical findings.

SYSTEM = Reproductive (female)
SCORE = 2A

SECTION 140 REFERENCES
Chambers SK, Chambers JT, Kier R, Peschel RE. Sequelae of lateral ovarian transposition in irradiated cervical cancer patients. Int J Radiat Oncol Biol Phys. Jun 1991;20(6):1305-1308.
Damewood MD, Hesla HS, Lowen M, Schultz MJ. Induction of ovulation and pregnancy following lateral oophoropexy for Hodgkin’s disease. Int J Gynaecol Obstet. Dec 1990;33(4):369-371.
Hadar H, Loven D, Herskovitz P, Bairey O, Yagoda A, Levavi H. An evaluation of lateral and medial transposition of the ovaries out of radiation fields. Cancer. Jul 15 1994;74(2):774-779.
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.
Mar 20 2013;31(9):1239-1247.
Thibaud E, Ramirez M, Brauner R, et al. Preservation of ovarian function by ovarian transposition performed before pelvic irradiation during childhood. J Pediatr. Dec 1992;121(6):880-884.
Terenziani M, Piva L, Meazza C, Gandola L, Cefalo G, Merola M. Oophoropexy: a relevant role in preservation of ovarian function after pelvic irradiation. Fertil Steril. Mar 2009;91(3):935 e915-936.

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Therapeutic
Agent(s)(female)Oophorectomy(unilateral)

OOOPHORECTOMY (UNILATERAL)
Potential Late
EffectsPremature menopause
Info Link
Evidence for prematuremenopause following
unilateral oophorectomy
is limited and has been
extrapolated from the adultliterature.

Risk
Factors
Health Behaviors
Smoking

HighestRisk Factors
Treatment Factors-- Combined with:-- Pelvic radiation-- Alkylating agents-- TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

FSH
LH
Estradiol
Baseline at age 13 AND as clinicallyindicated in patients with delayed orarrested puberty, irregular menses,
primary or secondary amenorrhea, and/or
clinical signs and symptoms of estrogen
deficiency

Female Health Issues

Resources
American Society for Reproductive Medicine (www.asrm.org)
Fertile Hope (www.fertilehope.org)

CounselingCounsel currently menstruating women to be cautious about
delaying childbearing. Counsel regarding need for contraception.

Considerations for Further Testing and Intervention
Refer to reproductive endocrinology for counseling regarding
oocyte cryopreservation in patients wishing to preserve options
for future fertility.

SYSTEM = Reproductive (female)
SCORE = 2A

SECTION 141 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. Mar-Apr 1999;21(2):115-122.
Lass A. The fertility potential of women with a single ovary. Hum Reprod Update. Sep-Oct 1999;5(5):546-550.
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.
Mar 20 2013;31(9):1239-1247.
Schover LR. Sexuality and fertility after cancer. Hematology (Am Soc Hematol Educ Program). 2005:523-527.
Tangir J, Zelterman D, Ma W, Schwartz PE. Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol. Feb 2003;101(2):251-257.

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142

Therapeutic
Agent(s)(female)Oophorectomy(bilateral)

OOOPHORECTOMY (BILATERAL)
Potential Late
Effects
Hypogonadism
Infertility

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Health Links

Gynecologic or endocrinologic
consultation for initiation of hormonal
replacement therapy
At age 11 or immediately for post-pubertal
patients

Female Health Issues

Resources
American Society for Reproductive Medicine (www.asrm.org)
Fertile Hope (www.fertilehope.org)

CounselingCounsel regarding benefits of HRT in promoting pubertal
progression, bone and cardiovascular health. Counsel womenregarding pregnancy potential with donor eggs (if uterus is
intact).

Considerations for Further Testing and Intervention
Bone density evaluation in hypogonadal patients. Reproductive
endocrinology referral regarding assisted reproductive
technologies. Monitor cardiovascular health.

SYSTEM = Reproductive (female)
SCORE = 1

SECTION 142 REFERENCES
Archer DF. Premature menopause increases cardiovascular risk. Climacteric. 2009;12 Suppl 1:26-31.
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. Mar-Apr 1999;21(2):115-122.
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. Mar 20 2013;31(9):1239-1247.
Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. Jan-Feb 2009;16(1):15-23.
Sayakhot P, Vincent A, Deeks A, Teede H. Potential adverse impact of ovariectomy on physical and psychological function of younger women with breast cancer. Menopause. Jul 2011;18(7):786-793.
Schover LR. Sexuality and fertility after cancer. Hematology (Am Soc Hematol Educ Program). 2005:523-527.
Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. Sep 7 2000;343(10):682-688.
Tangir J, Zetterman D, Ma W, Schwartz PE. Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol. Feb 2003;101(2):251-257.

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143(male)

Therapeutic
Agent(s)Orchiectomy
unilateral

ORCHIECTOMY (UNILATERAL)
Potential Late
Effects
Gonadal dysfunction(testicular)
Reduced fertility
Testosterone insufficiency

Risk
Factors
Host Factors
Testicular cancer
ObesityEjaculatory dysfunction
Medications
Occupational exposures(pesticides, heavy metals,
solvents)
Treatment Factors
Unilateral orchiectomy
combined with pelvic or
testicular radiation and/or
alkylating agents
Health Behaviors
Tobacco/marijuana use
History of sexually transmitted
diseasesHighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use
YearlyMale Health Issues

PHYSICAL
Tanner staging
Until sexually mature
Testicular volume by Prader
orchiometer; Testicular examination(including prosthesis)
YearlySCREENING
Screening for reduced fertility: Semen
analysis
As requested by sexually mature patient

CounselingCounsel to wear athletic supporter with protective cup during
athletic activities.

Considerations for Further Testing and Intervention
Consider surgical placement of testicular prosthesis andongoing monitoring for surgical complications after prosthesis
placement. Orchiectomy can be associated with psychologicaldistress related to altered body image.

SYSTEM = Reproductive (male)
SCORE = 1

FSH
In sexually mature patient if unable toobtain semen analysis
Screening for testosterone insufficiency:
Testosterone (ideally morning)
As clinically indicated in patients withdelayed or arrested puberty and/or clinicalsigns and symptoms of testosterone
deficiency

SECTION 143 REFERENCES
Bandak M, Aksglaede L, Juul A, Rorth M, Daugaard G. The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer. Eur J Cancer. Nov 2011;47(17):2585-2591.
Eberhard J, Stahl O, Cwikiel M, et al. Risk factors for post-treatment hypogonadism in testicular cancer patients. Eur J Endocrinol. Apr 2008;158(4):561-570
Herr HW, Bar-Chama N, O’Sullivan M, Sogani PC. Paternity in men with stage I testis tumors on surveillance. J Clin Oncol. Feb 1998;16(2):733-734.
Huddart RA, Norman A, Moynihan C, et al. Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer. Jul 25 2005;93(2):200-207.
Jacobsen KD, Fossa SD, Bjoro TP, Aass N, Heilo A, Stenwig AE. Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Eur Urol. Sep 2002;42(3):229-238; discussion 237-228.
Lee PA, Coughlin MT. The single testis: paternity after presentation as unilateral cryptorchidism. J Urol. Oct 2002;168(4 Pt 2):1680-1682; discussion 1682-1683.

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144(male)

Therapeutic
Agent(s)Orchiectomy
bilateral

ORCHIECTOMY (BILATERAL)
Potential Late
Effects
Gonadal dysfunction(testicular)
Infertility
Testosterone Deficiency

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Examination of testicular prostheses
YearlyMale Health Issues

SCREENING

Consider surgical placement of testicular prostheses andongoing monitoring for surgical complications after prostheses
placement. Orchiectomy can be associated with psychologicaldistress related to altered body image.

Refer to endocrinology at age 11 forinitiation of hormonal replacement therapy
to induce puberty (or immediately for postpubertal patients)

Considerations for Further Testing and Intervention

SYSTEM = Reproductive (male)
SCORE = 1

SECTION 144 REFERENCES
Huddart RA, Norman A, Moynihan C, et al. Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer. Jul 25 2005;93(2):200-207.
Jacobsen KD, Fossa SD, Bjoro TP, Aass N, Heilo A, Stenwig AE. Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Eur Urol. Sep 2002;42(3):229-238; discussion 237-228.
Rossen P, Pedersen AF, Zachariae R, von der Maase H. Sexuality and body image in long-term survivors of testicular cancer. Eur J Cancer. Mar 2012;48(4):571-578.
Yossepowitch O, Aviv D, Wainchwaig L, Baniel J. Testicular prostheses for testis cancer survivors: patient perspectives and predictors of long-term satisfaction. J Urol. Dec 2011;186(6):2249-2252

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145

Therapeutic
Agent(s)Pelvic surgery
Cystectomy

PELVIC SURGERY
Potential Late
Effects
Urinary incontinence
Urinary tract obstruction

Info Link
For patients with cystectomy:
See also Section 122

Risk
Factors
Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina
Treatment Factors
Retroperitoneal nodedissection
Extensive pelvic dissection(e.g., bilateral ureteral reimplantation, retroperitoneal
tumor resection)
Radiation to the bladder,pelvis, and/or lumbar-sacral
spine

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Counseling

Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyCounsel regarding adequate fluid intake, regular voiding,seeking medical attention for symptoms of voiding dysfunction
or urinary tract infection and compliance with recommended
bladder catheterization regimen.

Considerations for Further Testing and Intervention
Urologic consultation for patients with dysfunctional voiding or
recurrent urinary tract infections.

SYSTEM = Urinary
SCORE = 1

SECTION 145 REFERENCES
Derikx JP, 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. Jun 2007;42(6):1122-1126.
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. Mar-Apr 1999;21(2):115-122.
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. Apr 1992;10(4):614-623.
Koyle MA, Hatch DA, Furness PD, 3rd, Lovell MA, Odom LF, Kurzrock EA. Long-term urological complications in survivors younger than 15 months of advanced stage abdominal neuroblastoma. J Urol. Oct 2001;166(4):14551458.
Ozkan KU, Bauer SB, Khoshbin S, Borer JG. Neurogenic bladder dysfunction after sacrococcygeal teratoma resection. J Urol. Jan 2006;175(1):292-296; discussion 296.
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. Nov 2006;176(5):2190-2194; discussion 2194-2195.

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146

Therapeutic
Agent(s)Pelvic surgery
Cystectomy

PELVIC SURGERY (cont)
Potential Late
Effects
Fecal incontinence

Risk
Factors
Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina
Treatment Factors
Radiation to the bladder,pelvis, or spine

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Counseling

Chronic constipation
Fecal soiling
YearlyCounsel regarding benefits of adherence to bowel regimen,
including adequate hydration, fiber, laxatives/enemas asclinically indicated.

PHYSICAL

Considerations for Further Testing and Intervention

Rectal exam
As clinically indicated

GI consultation to establish bowel regimen for patients withchronic impaction or fecal soiling.

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 146 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. Mar-Apr 1999;21(2):115-122.
Hoover M, Bowman LC, Crawford SE, et al. Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol. May 1999;32(5):353-359.
Moore SW, Kaschula ROC, Albertyn R, Rode H, Millar AJW, Karabus C. The outcome of solid tumors occurring during the neonatal period. Pediatr Surg Int. 1995;10(5-6):366-370.
Mosiello G, Gatti C, De Gennaro M, et al. Neurovesical dysfunction in children after treating pelvic neoplasms. BJU Int. Aug 2003;92(3):289-292.
Rao S, Azmy A, Carachi R. Neonatal tumours: a single-centre experience. Pediatr Surg Int. Sep 2002;18(5-6):306-309.

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147(male)

Therapeutic
Agent(s)Pelvic surgery
Cystectomy

PELVIC SURGERY (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Sexual dysfunction (male)
Retrograde ejaculation
Anejaculation
Erectile dysfunction

Treatment Factors
Retroperitoneal nodedissection
Retroperitoneal tumor
resection
Cystectomy
Radical prostatectomy
Tumor adjacent to spine;
Radiation to bladder, pelvis,
or spine

Host Factors
Extensive presacral tumor
resection or dissection;
Radiation dose ≥ 55 Gy topenile bulb in adult and ≥ 45
Gy in prepubertal child

Medical Conditions
Hypogonadism

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Sexual function (erections, nocturnal
emissions, libido)
Medication use
Quality of ejaculate (frothy white urine
with first void after intercourse
suggests retrograde ejaculation)
YearlyMale Health Issues

Resources
www.urologychannel.com

Counseling
Men with erectile/ejaculatory dysfunction desiring paternity canconsider assisted reproductive technology for sperm retrieval.

Considerations for Further Testing and Intervention
Urologic consultation in patients with positive history and/or
physical exam findings.

SYSTEM = Reproductive (male)
SCORE = 2A

SECTION 147 REFERENCES
Brydoy M, Fossa SD, Klepp O, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst. Nov 2 2005;97(21):1580-1588.
Fossa SD. Long-term sequelae after cancer therapy--survivorship after treatment for testicular cancer. Acta Oncol. 2004;43(2):134-141.
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. Mar-Apr 1999;21(2):115-122.
Hartmann JT, Albrecht C, Schmoll HJ, Kuczyk MA, Kollmannsberger C, Bokemeyer C. Long-term effects on sexual function and fertility after treatment of testicular cancer. Br J Cancer. May 1999;80(5-6):801-807.
Jacobsen KD, Ous S, Waehre H, et al. Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection. Br J Cancer. Apr 1999;80(1-2):249-255.
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. Dec 2010;6(6):605-608
Zippe C, Nandipati K, Agarwal A, Raina R. Sexual dysfunction after pelvic surgery. Int J Impot Res. 2006 Jan-Feb;18(1):1-18. Review.

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Therapeutic
Agent(s)(female)Pelvic surgery
Cystectomy

PELVIC SURGERY (cont)
Potential Late
Effects
Sexual dysfunction (female)

Risk
Factors
Host Factors
Chronic GVHD
Hypogonadism
Tumor adjacent to spine
Medical Conditions
Radiation to bladder, pelvis,
or spine

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY
Altered or diminished sensation, loss of
sensation
Dyspareunia
Medication use
YearlySYSTEM = Reproductive (female)
SCORE = 2A

SECTION 148 REFERENCES
Aerts L, Enzlin P, Verhaeghe J, Vergote I, Amant F. Sexual and psychological functioning in women after pelvic surgery for gynaecological cancer. Eur J Gynaecol Oncol. 2009;30(6):652-656.
Burton KA, Wallace WH, Critchley HO. Female reproductive potential post-treatment for childhood cancer. Hosp Med. Sep 2002;63(9):522-527.
El-Toukhy TA, Hefni M, Davies A, Mahadevan S. The effect of different types of hysterectomy on urinary and sexual functions: a prospective study. J Obstet Gynaecol. Jun 2004;24(4):420-425.
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.
Mar 20 2013;31(9):1239-1247.
Schover LR. Sexuality and fertility after cancer. Hematology (Am Soc Hematol Educ Program). 2005:523-527.
Spunt SL, Sweeney TA, Hudson MM, Billups CA, Krasin MJ, Hester AL. Late effects of pelvic rhabdomyosarcoma and its treatment in female survivors. J Clin Oncol. Oct 1 2005;23(28):7143-7151

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149

Therapeutic
Agent(s)Splenectomy

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Physical exam at time of febrile illness
to evaluate degree of illness andpotential source of infection
When febrile T ≥ 101ºF

Splenic Precautions

SCREENING
Blood culture
When febrile T ≥ 101ºF

Counseling
Advise obtaining medical alert bracelet/card noting asplenia.
Counsel regarding risk of life-threatening infections withencapsulated organisms. Also counsel regarding risk associatedwith malaria and tick-borne diseases if living in or visiting
endemic areas.

Considerations for Further Testing and Intervention
In patients with T ≥ 101° (38.3° C) or other signs of serious
illness, administer a long-acting, broad-spectrum parenteralantibiotic (e.g., ceftriaxone), and continue close medical
monitoring while awaiting blood culture results. Hospitalization
and broadening of antimicrobial coverage (e.g., addition of
vancomycin) may be necessary under certain circumstances,such as the presence of marked leukocytosis, neutropenia, or
significant change from baseline CBC; toxic clinical appearance;
fever ≥ 104°F; meningitis, pneumonia, or other serious focus of
infection; signs of septic shock; or previous history of serious
infection. Immunize with Pneumococcal, Meningococcal, andHIB vaccines according to current ACIP recommendations.
Discuss with dental provider potential need for antibiotic
prophylaxis based on planned procedure.
Info Link
See current edition of AAP Red Book for recommendations
regarding antibiotic prophylaxis and immunizations

SYSTEM = Immune
SCORE = 2A

SECTION 149 REFERENCES
American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012
American Academy of Pediatric Dentistry, Guideline on Dental Management of Pediatric Patients Receiving Chemotherapy, Hematopoietic Cell Transplantation, and/or Radiation. Pediatr Dent. 2013;35(5):185-193.
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. Nov
2003;71(5):319-326.
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 theAdvisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. Oct 12 2012;61(40):816-819.
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. Jun 28 2013;62(25):521-524.
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Therapeutic
Agent(s)SPLENECTOMY (cont)
Potential Late
Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 149 REFERENCES
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. Mar 22 2013;62(RR-2):1-28.
Jockovich M, Mendenhall NP, Sombeck MD, Talbert JL, Copeland EM, 3rd, Bland KI. Long-term complications of laparotomy in Hodgkin’s disease. Ann Surg. Jun 1994;219(6):615-621; discussion 621-614.
Kaiser CW. Complications from staging laparotomy for Hodgkin disease. J Surg Oncol. 1981;16(4):319-325.
Mourtzoukou EG, Pappas G, Peppas G, Falagas ME. Vaccination of asplenic or hyposplenic adults. Br J Surg. Mar 2008;95(3):273-280.
Newland A, Provan D, Myint S. Preventing severe infection after splenectomy. BMJ. Aug 20 2005;331(7514):417-418.
Omlin AG, Muhlemann K, Fey MF, Pabst T. Pneumococcal vaccination in splenectomised cancer patients. Eur J Cancer. Aug 2005;41(12):1731-1734.
Price VE, Blanchette VS, Ford-Jones EL. The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North Am. Sep 2007;21(3):697-710, viii-ix.
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. Jul 20
2007;25(29):5278-5282.
Spelman D, Buttery J, Daley A, et al. Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J. May 2008;38(5):349-356.
Taylor MD, Genuit T, Napolitano LM. Overwhelming postsplenectomy sepsis and trauma: time to consider revaccination? J Trauma. Dec 2005;59(6):1482-1485.

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Therapeutic
Agent(s)150Thoracic surgery (includes
thoracotomy, chestwall surgery, rib
resection, pulmonary
lobectomy, pulmonary
metastasectomy,
pulmonary wedge
resection)

THORACIC SURGERY
Potential Late
Effects
Pulmonary dysfunction

Risk
Factors
Treatment Factors
Combined with pulmonary
toxic therapy:-- Bleomycin-- Busulfan-- Carmustine (BCNU)-- Lomustine (CCNU)
Medical Conditions
Atopic history
Health Behaviors
SmokingInhaled illicit drug use

HighestRisk Factors
Treatment Factors
Combined with:-- Chest radiation-- TBI

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Cough
SOB
DOE
Wheezing
YearlyPulmonary Health

PHYSICAL
Pulmonary exam
YearlySCREENING
PFTs (including DLCO and spirometry)
Baseline at entry into long-term follow-up,
repeat as clinically indicated in patientswith abnormal results or progressive
pulmonary dysfunction

Resources
Extensive information regarding smoking cessation is available
for patients on the NCI’s website: www.smokefree.gov

CounselingCounsel regarding tobacco avoidance/smoking cessation.
Patients who desire to SCUBA dive should be advised to obtain
medical clearance from a pulmonologist.

Considerations for Further Testing and Intervention
In patients with abnormal PFTs, consider repeat evaluation
prior to general anesthesia. Pulmonary consultation for patientswith symptomatic pulmonary dysfunction; Influenza andpneumococcal vaccinations .

SYSTEM = Pulmonary
SCORE = 2A

SECTION 150 REFERENCES
Berend N, Woolcock AJ, Marlin GE. Effects of lobectomy on lung function. Thorax. Feb 1980;35(2):145-150.
Bolliger CT, Jordan P, Soler M, et al. Pulmonary function and exercise capacity after lung resection. Eur Respir J. Mar 1996;9(3):415-421.
Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. Jul 10 2006;166(13):1359-1367.
Pelletier C, Lapointe L, LeBlanc P. Effects of lung resection on pulmonary function and exercise capacity. Thorax. Jul 1990;45(7):497-502.
Stolp B, Assistant Medical Director Divers Alert Network, Director Anesthesiology Emergency Airway Services, Durham, N.C. Risks associated with SCUBA diving in childhood cancer survivors. Personal communication to LandierW, Bhatia S. Aug 23, 2002.”
Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. Feb 12 2007;167(3):221-228.
Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. Mar 2004;25(1):203-216.

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Therapeutic
Agent(s)151Thoracic surgery (includes
thoracotomy, chestwall surgery, rib
resection, pulmonary
lobectomy, pulmonary
metastasectomy,
pulmonary wedge
resection)

THORACIC SURGERY (cont)
Potential Late
Effects
Scoliosis/Kyphosis

Risk
Factors
Host Factors
Young age (deformity can stilldevelop even if skeletally
mature at time of surgery)
Preoperative deformity
Treatment Factors
Radiation to the spine

HighestRisk Factors
Treatment Factors
Greater number of ribs
resected

Periodic
Evaluation

Health Counseling/
Further Considerations

PHYSICAL

Health Links

Spine exam for scoliosis and kyphosis
Yearly until growth completed, may needmore frequent assessment during puberty
or if curve detected

Scoliosis and Kyphosis

Considerations for Further Testing and Intervention
Spine films in patients with clinically apparent curve. Orthopedic
consultation as indicated based on radiographic exam

SYSTEM = Musculoskeletal
SCORE = 2A

SECTION 151 REFERENCES
DeRosa GP. Progressive scoliosis following chest wall resection in children. Spine (Phila Pa 1976 ). Sep 1985;10(7):618-622.
Deschamps C, Tirnaksiz BM, Darbandi R, et al. Early and long-term results of prosthetic chest wall reconstruction. J Thorac Cardiovasc Surg. Mar 1999;117(3):588-591; discussion 591-582.
Dingemann C, Linderkamp C, Weidemann J, Bataineh ZA, Ure B, Nustede R. Thoracic wall reconstruction for primary malignancies in children: short- and long-term results. Eur J Pediatr Surg. Feb 2012;22(1):34-39.
Kawakami N, Winter RB, Lonstein JE, Denis F. Scoliosis secondary to rib resection. J Spinal Disord. Dec 1994;7(6):522-527.
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. Aug 19 2009;101(16):1131-1140.
Soyer T, Karnak I, Ciftci AO, Senocak ME, Tanyel FC, Buyukpamukcu N. The results of surgical treatment of chest wall tumors in childhood. Pediatr Surg. Int. Feb 2006;22(2):135-139.

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152

Therapeutic
Agent(s)Thyroidectomy

THYROIDECTOMY
Potential Late
Effects
Hypothyroidism

Info Link• Total thyroidectomy isuncommon, but if done isassociated with the risk ofhypoparathyroidism. This
complication generally occurs in the early postoperative period and may persist.
• Patients with a history of
total thyroidectomy should
be monitored for signs andsymptoms of hypoparathyroidism (e.g., paresthesias,
muscle cramping, alteredmental status, hyperreflexia,
tetany, hypocalcemia, andhyperphosphatemia).

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearlyThyroid Problems

PHYSICAL
HeightWeightHair and skin
Thyroid exam
Yearly, consider more frequent screening
during periods of rapid growthCounselingCounsel at-risk females of childbearing potential to have their
thyroid levels checked prior to attempting pregnancy andperiodically throughout pregnancy.

Considerations for Further Testing and Intervention
Endocrine consultation for medical management.

SYSTEM = Endocrine/Metabolic
SCORE = 1

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

SECTION 152 REFERENCES
Diesen DL, Skinner MA. Pediatric thyroid cancer. Semin Pediatr Surg. Feb 2012;21(1):44-50.
La Quaglia MP, Telander RL. Differentiated and medullary thyroid cancer in childhood and adolescence. Semin Pediatr Surg. Feb 1997;6(1):42-49.
Lallier M, St-Vil D, Giroux M, et al. Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg. Jun 1998;33(6):846-848.

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OTHER THERAPEUTIC MODALITIESSec#Therapeutic
Agent(s)153

Radioiodine therapy(I-131 thyroid ablation)

Potential Late
Effects
Lacrimal duct atrophy

Risk
Factors

SYSTEMIC RADIATION

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Considerations for Further Testing and Intervention

Excessive tearing
YearlyOphthalmology consultation as clinically indicated.

SYSTEM = Ocular
SCORE = 2A

SECTION 153 REFERENCES
Burns JA, Morgenstern KE, Cahill KV, Foster JA, Jhiang SM, Kloos RT. Nasolacrimal obstruction secondary to I(131) therapy. Ophthal Plast Reconstr Surg. Mar 2004;20(2):126-129.
Morgenstern KE, Vadysirisack DD, Zhang Z, 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 Reconstr Surg. Sep 2005;21(5):337-344.
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. Nov 2002;29(11):1428-1432.

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OTHER THERAPEUTIC MODALITIESSec#Therapeutic
Agent(s)154Radioiodine therapy(I-131 thyroid ablation)

Potential Late
Effects
Hypothyroidism

Risk
Factors

SYSTEMIC RADIATION (cont)HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening
during periods of rapid growth

Thyroid Problems

CounselingCounsel at-risk females of childbearing potential to have their
thyroid levels checked prior to attempting pregnancy andperiodically throughout pregnancy.

Considerations for Further Testing and Intervention
Endocrine consultation for medical management.

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

SYSTEM = Endocrine/Metabolic
SCORE = 2A

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

SECTION 154 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. Jan 23 1975;292(4):167-171.
Safa AM, Skillern PG. Treatment of hyperthyroidism with a large initial dose of sodium iodide I 131. Arch Intern Med. May 1975;135(5):673-675.

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#
155

Therapeutic
Agent(s)Systemic MIBG
(in therapeutic doses)

Potential Late
Effects
Hypothyroidism

Info Link
MIBG used for diagnostic
purposes (i.e., MIBG scanning)
does NOT put patients at riskfor hypothyroidism.

Risk
Factors

SYSTEMIC RADIATION (cont)HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

HISTORY

Health Links

Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly, consider more frequent screening
during periods of rapid growth

Thyroid Problems

CounselingCounsel at-risk females of childbearing potential to have their
thyroid levels checked prior to attempting pregnancy andperiodically throughout pregnancy.

Considerations for Further Testing and Intervention
Endocrine consultation for medical management.

PHYSICAL
HeightWeightHair and 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 growth

SECTION 155 REFERENCES
Bhandari S, Cheung NK, Kushner BH, et al. Hypothyroidism after 131I-monoclonal antibody treatment of neuroblastoma. Pediatr Blood Cancer. Jul 15 2010;55(1):76-80.
Brans B, Monsieurs M, Laureys G, Kaufman JM, Thierens H, Dierckx RA. Thyroidal uptake and radiation dose after repetitive I-131-MIBG treatments: influence of potassium iodide for thyroid blocking. Med Pediatr Oncol. Jan
2002;38(1):41-46.
Picco P, Garaventa A, Claudiani F, Gattorno M, De Bernardi B, Borrone C. Primary hypothyroidism as a consequence of 131-I-metaiodobenzylguanidine treatment for children with neuroblastoma. Cancer. Nov 1 1995;76(9):16621664.
van Santen HM, de Kraker J, van Eck BL, de Vijlder JJ, Vulsma T. High incidence of thyroid dysfunction despite prophylaxis with potassium iodide during (131)I-metaiodobenzylguanidine treatment in children with neuroblastoma.
Cancer. Apr 1 2002;94(7):2081-2089.
van Santen HM, de Kraker J, van Eck BL, de Vijlder JJ, Vulsma T. Improved radiation protection of the thyroid gland with thyroxine, methimazole, and potassium iodide during diagnostic and therapeutic use of radiolabeled metaiodobenzylguanidine in children with neuroblastoma. Cancer. Jul 15 2003;98(2):389-396.

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156

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

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

Risk
Factors

HighestRisk Factors

BIOIMMUNOTHERAPY
Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING
No Known Late Effects
SYSTEM = No Known Late Effects
SCORE = N/A

SECTION 156 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. Jan 23 1975;292(4):167-171.
Safa AM, Skillern PG. Treatment of hyperthyroidism with a large initial dose of sodium iodide I 131. Arch Intern Med. May 1975;135(5):673-675.

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CANCER SCREENING GUIDELINES

BREAST CANCER

Sec#

Periodic
Evaluation

157

Organ

(female)BreastPopulation Risk
Factors

HighestRisk Factors

Over age 40
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 firstchild
Never pregnant
ObesityPrevious breast biopsy withatypical hyperplasia
Hormone replacement therapy

Chest radiation with potential impact
to the breast (see Section 77),
including ≥ 20 Gy to the following
fields:-- Chest (thorax)-- Whole lung-- Mediastinal-- Axilla-- Mini-Mantle-- Mantle-- Extended Mantle-- TLI-- STLI-- TBI*BRACA1, BRACA2, ATM mutation
Info Link• *Important : The risk of breast
cancer in patients who received
10–19 Gy of radiation withpotential impact to the breast or
those who received TBI alone isof a lower magnitude comparedto those who received ≥20 Gy ofradiation with potential impact tothe breast (e.g.,thorax, axilla).
• Monitoring of patients who
received 10–19 Gy of radiation
with potential impact to thebreast or those who received
TBI without additional radiation
should be determined on an
individual basis.
• After the clinician discusses
the benefits and risks/harms ofscreening with the patient, if adecision is made to screen, thenfollow the recommendations forpatients who received ≥ 20 Gy.

PATIENTS AT STANDARD RISK (ACS Recommendation)

PHYSICAL

Clinical breast exam
Every 3 years between ages 20–39, then yearly beginning at age 40

SCREENING
Mammogram
Yearly, beginning at age 40
PATIENTS AT HIGHEST RISK(≥ 20 Gy radiation with potential impact to the breast)

Health Counseling/
Further Considerations
Health Links
Breast Cancer (for patients at highest risk only)Counseling
For patients at highest risk, counsel to perform breast selfexamination monthly, beginning at puberty. For standard risk patients,
provide general guidance regarding routine screening beginning at age
40 per current ACS guidelines.

Considerations for Further Testing and Interventions
Surgery and/or oncology consultation as clinically indicated

PHYSICAL
Breast self exam
Monthly, beginning at puberty
Clinical breast exam
Yearly, beginning at puberty until age 25, then every 6 months

SCREENING
Mammogram
Yearly, beginning 8 years after radiation or at age 25, whicheveroccurs last.
Breast MRI
Yearly, as an adjunct to mammography beginning 8 years afterradiation or at age 25, whichever occurs last.
Info Link• Mammography is currently limited in its ability to evaluate thepremenopausal breast.
• MRI is now recommended as an adjunct to mammography inwomen treated with chest radiation for childhood cancer similar toscreening 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 both modalities should be used forbreast cancer surveillance has not been established.

SECTION 157 REFERENCES
Breast Cancer Screening and Diagnosis Guidelines. National Comprehensive Cancer Network Clinical Practice Guidelines v.1.2008. April 15, 2008. Available at: www.nccn.org. Accessed October 24, 2008.
Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA. Mar 26 1997;277(12):997-1003.
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. Sep 10 2009;27(26):4239-4246.
Diller L, Medeiros Nancarrow C, Shaffer K, et al. Breast cancer screening in women previously treated for Hodgkin’s disease: a prospective cohort study. J Clin Oncol. Apr 15 2002;20(8):2085-2091.
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Organ

Population Risk
Factors

HighestRisk Factors

BREAST CANCER (cont)
Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 157 REFERENCES (continued)
Friedman DL, Rovo A, Leisenring W, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party. Blood. Jan 15
2008;111(2):939-944.
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. Apr 6 2010;152(7):444455; W144-454.
Inskip PD, Robison LL, Stovall M, et al. Radiation dose and breast cancer risk in the Childhood Cancer Survivor Study. J Clin Oncol. Aug 20 2009;27(24):3901-3907.
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. Jul 29 2004;351(5):427-437.
Liberman L. Breast cancer screening with MRI--what are the data for patients at high risk? N Engl J Med. Jul 29 2004;351(5):497-500.
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
of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. Dec 2013;14(13):e621-629.
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. Mar-Apr 2007;57(2):75-89.
Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol. Mar 1 2002;20(5):1260-1268.
Shaw de Paredes E, Marsteller LP, Eden BV. Breast cancers in women 35 years of age and younger: mammographic findings. Radiology. Oct 1990;177(1):117-119.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.
Tardivon AA, Garnier ML, Beaudre A, Girinsky T. Breast carcinoma in women previously treated for Hodgkin’s disease: clinical and mammographic findings. Eur Radiol. 1999;9(8):1666-1671.
Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. Jul 23 2003;290(4):465-475.
Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA. Sep 15 2004;292(11):1317-1325.

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158

Organ

(female)CervicalPopulation Risk
Factors
Early age at first intercourse
Multiple lifetime sex partners
Smoking
Sexually transmitted diseases

HighestRisk Factors
Personal history of cervical
dysplasia
Prenatal DES exposure
HPV infection
Immunosuppression
Chronic steroid use
HIV positive
Chronic GVHDCERVICAL CANCER
Periodic
Evaluation

PATIENTS AT STANDARD RISK (ACS Recommendation)

Health Counseling/
Further Considerations
Health Links

PHYSICAL

Reducing the Risk of Second Cancers

Pelvic exam
Every 3–5 years beginning at age 21 (see “Screening” below for
specific recommendations)CounselingCounsel regarding risk/benefits of HPV vaccination.

SCREENING
Cervical PAP smear• Cervical cancer screening should begin at age 21 y.
• For women aged 21–29 y, screening should be done every 3 y withconventional or liquid-based Pap tests.
• For women aged 30–65 y, screening should be done every 5 y withboth the HPV test and the Pap test (preferred), or every 3 y with the
Pap test alone (acceptable).
• Women aged > 65 y who have had > 3 consecutive negative Pap
tests or > 2 consecutive negative HPV and Pap tests within the last
10 y, with the most recent test occurring within the last 5 y, andwomen who have had a total hysterectomy should stop cervicalcancer screening.
• Women at any age should not be screened annually by any screening method.

Info Link• Human papillomavirus virus (HPV) is the leading cause of cervicalcancer in women. HPV vaccination protects against 70% of cervicalcancers and the quadrivalent form the vaccine reduces the incidenceof 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 the receive HPV vaccination at thediscretion of their health care provider. HPV vaccination is also recommended for females 13–26 (CDC/ACIP) years to catch up 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 cervicalcancer PAP screening since the vaccine does not protect against
all cancer-causing types of HPV. See Markowitz LE et al. (2007)
and Centers for Disease Control and Prevention (2010), for further
information.

Considerations for Further Testing and Interventions
Gynecology and/or oncology consultation as clinically indicated.

SECTION 158 REFERENCES
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
Centers for Disease Control and Prevention. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. May 28 2010;59(20):626-629.
Cervical Cancer. National Comprehensive Cancer Network Clinical Practice Guideline V3.2013. Available at: www.nccn.org. Accessed December 9, 2013.
Klosky JL, Gamble HL, Spunt SL, Randolph ME, Green DM, Hudson MM. Human papillomavirus vaccination in survivors of childhood cancer. Cancer. Dec 15 2009;115(24):5627-5636.
Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007 Mar 23;56(RR-2):1-24.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.

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#
159

Organ
Colorectal

Population
Risk Factors

HighestRisk Factors

High fat/low fiber dietAge ≥ 50 years
Obesity

Radiation with potential impact tothe colon/rectum (see Section 90),
including ≥ 30 Gy to the following
fields:-- Spine (thoracic, lumbar, sacral,whole)-- Extended Mantle-- Hepatic-- Renal-- Upper quadrant (right, left)-- Spleen (partial, entire)-- Paraaortic-- Flank/Hemiabdomen (right, left)-- Whole abdomen-- Inverted Y-- Pelvic-- Vaginal-- Prostate-- Bladder-- Iliac-- Inguinal-- Femoral-- TLI-- STLI-- TBI*
Personal history of ulcerative colitis,
gastrointestinal malignancy,
adenomatous polyps or
hepatoblastoma
Familial polyposis
Family history of colorectal cancer
or polyps in first degree relative
Info Link• *Important: Reports of colorectal
cancer in cohorts of long-term
survivors suggest that radiation
likely increases risk; however, therisk related to TBI alone has notbeen established.
• Monitoring of patients who
received TBI without additionalradiation potentially impacting
the colon/rectum should be determined on an individual basis.
(See Info Link in next column).

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COLORECTAL CANCER
Periodic
Evaluation

PATIENTS AT STANDARD RISK (ACS Recommendation)

Health Counseling/
Further Considerations
Health Links

SCREENING

Colorectal Cancer

Option 1
Fecal occult blood (minimum of 3 cards)
Yearly, beginning at age 50
AND/OR
Flexible sigmoidoscopy
Every 5 years, beginning at age 50

Gastroenterology, surgery and/or oncology consultation as clinicallyindicated.

Considerations for Further Testing and Interventions

Note: The combination of yearly fecal occult blood testing and every 5 year
flexible sigmoidoscopy is preferable to either test done alone.
Option 2
Double contrast barium enema
Every 5 years, beginning at age 50
Option 3
Colonoscopy
Every 10 years, beginning at age 50
PATIENTS AT HIGHEST RISKSCREENING

Colonoscopy
Every 5 years (minimum); more frequently if indicated based on colonoscopy
results. Begin monitoring 10 years after radiation or at age 35, whicheveroccurs last. Monitor more frequently if clinically indicated. Per the ACS, begin
screening earlier for the following high-risk groups: HNPCC (at puberty), FAP(at age 21 years), IBD (8 years after diagnosis of IBD). Information from the firstcolonoscopy will inform frequency of follow-up testing.
Info Link• Reports of gastrointestinal malignancies in cohorts of long-term survivors suggest that radiation likely increases risk, but the median age of onset is not aswell established as that of secondary breast cancer following chest radiation.
• The expert panel agreed that early onset of screening likely was beneficial, andthat a prudent course would be to initiate screening for colorectal cancer for
those at highest risk (abdominal, pelvic, and/or spinal radiation ≥ 30 Gy) at age
35, or 10 years post radiation, whichever occurs last.
• Surveillance should be done via colonoscopy as per recommendations for populations at highest risk, with information from the first colonoscopy informing
the frequency of follow-up testing.
• While the American Cancer Society recently added computed tomographic
colonography (CTC) (AKA “Virtual Colonoscopy”) as an acceptable option forcolorectal cancer screening of average-risk adults, the National Comprehensive Cancer Network and United States Preventive Services Task Forceconcluded that data was too premature to warrant its use in screening.
• Colonoscopy remains the preferred screening modality for survivors at highest
risk of colorectal cancer.

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Organ

Population Risk
Factors

HighestRisk Factors

COLORECTAL CANCER (cont)
Periodic
Evaluation

Health Counseling/
Further Considerations

SECTION 159 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. Dec 1 2003;21(23):4386-4394.
Colorectal Screening. National Comprehensive Cancer Network Clinical Practice Guidelines v.2.2008. June 17, 2008. Available at: www.nccn.org. Accessed October 24, 2008.
Henderson TO, Oeffinger KC, Whitton J, et al. Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med. Jun 5 2012;156(11):757-766, W-260.
Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, Dash C, Giardiello FM, Glick S, Levin TR, Pickhardt P, Rex DK, Thorson A, Winawer SJ; for the American Cancer Society Colorectal Cancer Advisory Group,
the US Multi-Society Task Force, and the American College of Radiology Colon Cancer Committee. Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guidelinefrom the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin, 2008 May-June;58(3):130-160.
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. Jun 2000;18(12):2435-2443.
Nottage K, McFarlane J, Krasin MJ, et al. Secondary colorectal carcinoma after childhood cancer. J Clin Oncol. Jul 10 2012;30(20):2552-2558.
Provenzale D, Gray RN. Colorectal cancer screening and treatment: review of outcomes research. J Natl Cancer Inst Monogr. 2004(33):45-55.
Screening for Colorectal Cancer. Oct 2008; File Inventory, Recommendation Statement Publication No. 08-05124-EF-3. Available at: www.ahrq.gov/clinic/uspstf08/colocancer/colors.htm. Accessed Oct 24, 2008.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.
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. Mar 1 2012;82(3):e383-390.
U. S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. Nov 4 2008;149(9):627-637.
van Leeuwen FE, Klokman WJ, Veer MB, et al. Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol. Feb 2000;18(3):487-497.

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Organ

(female)Endometrial

Population Risk
Factors

HighestRisk Factors

Obesity
Older age
Unopposed estrogen therapy
Tamoxifen
Diabetes
Hypertension
High fat diet
Early menopause
Late menopause
Nulliparity
Infertility
Failure to ovulate

History of/at risk for hereditary
nonpolyposis colon cancer (HNPCC)ENDOMETRIAL CANCER
Periodic
Evaluation

PATIENTS AT STANDARD RISK (ACS Recommendation)

SCREENING

Health Counseling/
Further Considerations
Health Links
Reducing the Risk of Second Cancers

Endometrial biopsy
Yearly, beginning at age 35 for patients at highest risk
Info Link• 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.

SECTION 160 REFERENCES
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.

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Organ
Lung

Population Risk
Factors
Chest radiation with potential
impact to the lung
Smoking
Workplace exposures toasbestos, arsenic, radiation
Second hand smoke (in nonsmokers)

HighestRisk Factors

LUNG CANCER
Periodic
Evaluation

Chest radiation with potential impact PATIENTS AT HIGHEST RISK
to the lung combined with smoking
HISTORY
Cough
Wheezing
SOB
DOE
Yearly, and as clinically indicatedHealth Counseling/
Further Considerations
Health Links
Reducing the Risk of Second Cancers

Considerations for Further Testing and Intervention
Imaging and surgery and/or oncology consultation as clinicallyindicated.

PHYSICAL
Pulmonary Exam
Yearly, and as clinically indicated

SCREENING
Clinicians should discuss the benefits and risks/harms of spiral CT
scanning for patients at highest risk

SECTION 161 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. Dec 1 2003;21(23):4386-4394.
Black WC. Computed tomography screening for lung cancer: review of screening principles and update on current status. Cancer. Dec 1 2007;110(11):2370-2384.
Ibrahim EM, Kazkaz GA, Abouelkhair KM, et al. Increased risk of second lung cancer in Hodgkin’s lymphoma survivors: a meta-analysis. Lung. Feb 2013;191(1):117-134.
Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. Jul 10 2006;166(13):1359-1367.
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. Jun 2000;18(12):2435-2443.
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. May 23 2013;368(21):1980-1991.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.
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. Nov 1 2011;29(31):4096-4104.
Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch. Intern. Med. Feb 12 2007;167(3):221-228.
Van’t Westeinde SC, van Klaveren RJ. Screening and early detection of lung cancer. Cancer J. Jan-Feb 2011;17(1):3-10.
Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. Mar 2004;25(1):203-216.

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Organ
Oral

Population Risk
Factors
Tobacco use (smoking cigars,
cigarettes, or pipes; dipping,chewing)
Alcohol abuse
Excessive sun exposure(increases risk of cancer oflower lip)
HCT (allogeneic > autologous)
Human Papillomavirus (HPV)
infection

HighestRisk Factors
Head/brain radiation
Neck radiation
TBI
Acute/chronic GVHD

ORAL CANCER
Periodic
Evaluation

PATIENTS AT STANDARD RISK (ACS Recommendation)

PHYSICAL

Oral cavity exam
YearlyHealth Counseling/
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Dental Health

Considerations for Further Testing and Intervention
Head and neck/otolaryngology consultation as indicated.

SECTION 162 REFERENCES
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. Apr 1 2003;21(7):1352-1358.
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. Dec 1 2003;21(23):4386-4394.
Jemal A, Simard EP, Dorell C, et al. Annual Report to the Nation on the Status of Cancer, 1975-2009, featuring the burden and trends in human papillomavirus(HPV)-associated cancers and HPV vaccination coverage levels. J NatlCancer Inst. Feb 6 2013;105(3):175-201.
Joseph BK. Oral cancer: prevention and detection. Med Princ Pract. 2002;11 Suppl 1:32-35.
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. Jun 2000;18(12):2435-2443.

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(male)

Organ
Prostate

PROSTATE CANCER

Population Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Older age, with steadily
increasing risk after age 40
years.

African-American race
Family history of prostate cancer infirst degree relative

ALL PATIENTSClinicians should be prepared to discuss prostate cancer testing withpatients

Health Counseling/
Further Considerations
Health Links
Reducing the Risk of Second Cancers

Considerations for Further Testing and Intervention
Info Link• The 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 haveaffected 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.

Urology and/or oncology consultation as clinically indicated.

SECTION 163 REFERENCES
Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. Mar 26 2009;360(13):1310-1319.
Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ. 2010;341:c4543.
Prostate Cancer Early Detection National Comprehensive Cancer Network Clinical Practice Guideline V.1.2014. Availalbe at: www.nccn.org. Accessed December 9, 2013
Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. Mar 26 2009;360(13):1320-1328.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.
Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. Mar-Apr 2010;60(2):70-98.

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Organ
Skin

Population Risk
Factors

HighestRisk Factors

Light skin color
Chronic exposure to sun
Atypical moles or ≥ 50 moles

Any history of radiation
Personal history of melanoma or
skin cancer
Dysplastic nevi
Family history of melanoma or skincancerHistory of severe sunburn at youngage

SKIN CANCER
Periodic
Evaluation

PATIENTS AT STANDARD RISKInfo Link• The U.S. Preventive Services Task Force (USPSTF) concludes that theevidence 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 squamouscell 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 skincancer. No studies were found that evaluated whether screening
improves the outcomes of these cancers.
• The American Cancer Society recommends skin examination as partof a cancer-related checkup, which should occur on the occasion of
the patient’s periodic health examination. Self-examination of skin isrecommended once a month.

Health Counseling/
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Skin Health

Considerations for Further Testing and Intervention
Surgery, dermatology, and/or oncology consultation as clinicallyindicated.

PATIENTS AT HIGHEST RISKPHYSICAL

Skin self exam
Monthly
Dermatologic exam with attention to skin lesions and pigmented
nevi in radiation field
YearlySECTION 164 REFERENCES
Armstrong GT, Liu W, Leisenring W, et al. Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. Aug 1 2011;29(22):3056-3064.
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. Jul 21 2010;102(14):1083-1095.
Perkins JL, Liu Y, Mitby PA, et al. Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study. J Clin Oncol. Jun 1 2005;23(16):3733-3741.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.
U. S. Preventive Services Task Force. Screening for skin cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. Feb 3 2009;150(3):188-193.

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(male)

Organ
Testicular

Population Risk
Factors
Young males

TESTICULAR CANCER

HighestRisk Factors

Periodic
Evaluation

History of cryptorchidism
History of testicular cancer or
carcinoma in-situ in contralateral
testisHistory of gonadal dysgenesis
Klinefelter’s syndrome
Family history of testicular cancer

Info Link• For standard and high risk populations, the USPSTF recommends
against routine screening for testicular cancer in asymptomaticadolescent and adult males.
• In 2004, the USPSTF found no new evidence that screening withclinical examination or testicular self-examination is effective in
reducing mortality from testicular cancer. Even in the absence ofscreening, the current treatment interventions provide very favorable
health outcomes.
• Given the low prevalence of testicular cancer, limited accuracyof screening tests, and no evidence for the incremental benefitsof screening, the USPSTF concluded that the harms of screening
exceed any potential benefits.
• ACS also no longer recommends clinical testicular cancer screeningor testicular self-examination.

Health Counseling/
Further Considerations

SECTION 165 REFERENCES
Screening for Testicular Cancer, AHRQ Pub. No. 05-0553-A, February 2004. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD, www.uspreventiveservicestaskforce.org/3rduspstf/
testicular/testiculrs.pdf, accessed December 10, 2013.
Smith RA, Brooks D, Cokkinides V, Saslow D, Brawley OW. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervicalcancer screening and lung cancer screening. CA Cancer J Clin. Mar-Apr 2013;63(2):88-105.

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Organ

Population Risk
Factors

General Health
Screening

ANY CANCER EXPERIENCE

HighestRisk Factors

Periodic
Evaluation

Health Counseling/
Further Considerations

SCREENING

Considerations for Further Testing and Intervention

Refer to United States Preventive Services Task Forcerecommendations at www.ahrq.gov/clinic/uspstfix.htm
YearlyChildhood cancer survivors should receive general health maintenance
per standard recommendations for age. Recommended preventive
services per the USPSTF include screening for hypertension, obesity,
depression, tobacco use, and alcohol misuse. In addition, certain
subpopulations require screening for lipid disorders, sexuallytransmitted diseases, and diabetes mellitus. Others require counselingregarding the prevention of cardiovascular disease, osteoporosis, andother disorders. See www.ahrq.gov/clinic/uspstfix.htm for specificrecommendations.
Assess immunization status on all patients; 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 ).

SECTION 166 REFERENCES
Ljungman P, Cordonnier C, Einsele H, et al. Vaccination of hematopoietic cell transplant recipients. Bone Marrow Transplant. Oct 2009;44(8):521-526.
Agency for Healthcare Research and Quality. Clinical Guidelines and Recommendations: U.S. Preventive Services Task Force. Available at http://www.ahrq.gov/clinic/uspstfix.htm.

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