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

Version 2.0 – March 2006

www.survivorshipguidelines.org

Copyright 2006 © Children’s Oncology GroupAll rights reserved worldwide

COG Long-Term Follow-Up Guidelines
Content Outline
Long-Term Follow-Up Guidelines• Abstract• Disclaimer• Contributors- Guideline Development Task Force- Panel of Experts- Reviewers- Task Force Membership- Health Link Authors and Reviewers• Introductory Material- Introduction- Explanation of Scoring- Instructions for Use• Long-Term Follow-Up Guidelines• Index

Appendix I: Materials for Clinical Application of LTFU Guidelines• Reference Materials- Abbreviations- Chemotherapy Agents- Radiation Fields Defined• Summary of Cancer Treatment- Summary of Cancer Treatment - Introduction- Template for Summary of Cancer Treatment (Abbreviated)- Template for Summary of Cancer Treatment (Comprehensive)- Key for Completing Summary of Cancer Treatment(Comprehensive Version)• Tools for Guideline Application- Patient-Specific Guideline Identification Tool
- Health Link Index by Guideline Section Number
Appendix II: Health Links (Patient Education Materials)• Health Links Index by Title• Health Links

Content Outline

Abstract – Version 2.0
The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors ofChildhood, Adolescent, and Young Adult Cancers
Release date: March 2006
Status:Updated from Version 1.2 (incorporating modifications based on recommendations from eighteen multidisciplinary task forces
within the COG Late Effects Committee)

Overview:

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

Source:Version 2.0 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.

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" and accompanying "Health
Links" were developed by the Children’s Oncology Group as a collaborative effort of the Late Effects Committee and Nursing Discipline.
For Informational Purposes Only: The information and contents of each document or series of documents made available by the Children’s Oncology Group relating to late effects of cancer
treatment and care or containing the title "Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers" or the title "Health Link", whether available in print
or electronic format (including any digital format, e-mail transmission, or download from the website), shall be known hereinafter as "Informational Content". All Informational Content is for
informational purposes only. The Informational Content is not intended to substitute for medical advice, medical care, diagnosis or treatment obtained from a physician or healthcare provider.

To cancer 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 haveregarding 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 careor 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 otherreasonable alternative follow-up procedures. The Informational Content is provided as a courtesy, but not intended as a sole source of guidance in the evaluation of childhood cancer
survivors. The Children’s Oncology Group recognizes that specific patient care decisions are the prerogative of the patient, family, and healthcare provider.
No endorsement of any specific tests, products, or procedures is made by Informational Content, the Children’s Oncology Group, or affiliated party or member of the Children’s Oncology Group.
No Claim to Accuracy or Completeness: While the Children's Oncology Group has made every attempt to assure that the Informational Content is accurate and complete as of the date of
publication, no warranty or representation, express or implied, is made as to the accuracy, reliability, completeness, relevance, or timeliness of such Informational Content.
No Liability on Part of Children’s Oncology Group and Related Parties/ Agreement to Indemnify and Hold Harmless the Children’s Oncology Group and Related Parties: No liability is
assumed by the Children's Oncology Group or any affiliated party or member thereof for damage resulting from the use, review, or access of the Informational Content. You agree to thefollowing terms of indemnification: (i) "Indemnified Parties" include authors and contributors to the Informational Content, all officers, directors, representatives, employees, agents, and membersof the Children’s Oncology Group and affiliated organizations; (ii) by using, reviewing, or accessing the Informational Content, you agree, at your own expense, to indemnify, defend and holdharmless 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
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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
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consents and legal documents and limiting dissemination or reproduction of Informational Content.

Disclaimer

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 2.0 – March 2006

Contributors• Guideline Development
Task Force• Panel of Experts• Reviewers• Task Force Membership• Health Link Authors
and Reviewers
Copyright 2006 © Children’s Oncology GroupAll rights reserved worldwide

Guideline Development Task ForceThe 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 theefforts of the following individuals:
Melissa M. Hudson, MD
Vice-Chair – COG Late Effects Committee
Member, Department of Hematology-Oncology
Director, After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, Tennessee
Wendy Landier, RN, MSN, CPNP, CPON®
Chair – COG Nursing Clinical Practice Subcommittee
Clinical Director - Survivorship Clinic
City of Hope Comprehensive Cancer Center
Duarte, California
Debra Eshelman, RN, MSN, CPNP
Late Effects Section Leader– COG Nursing Clinical Practice Subcommittee
Pediatric Nurse Practitioner
After the Cancer Experience (ACE) ProgramChildren’s Medical Center – Dallas
Dallas, Texas
Kathy Forte, RN, MS, CPNP
Co-Chair – COG Nursing Education Subcommittee
Pediatric Nurse Practitioner – Cancer Survivor Program
AFLAC Cancer Center and Blood Disorders Service
Children’s Healthcare of Atlanta
Atlanta, Georgia
Joan Darling, PhD
COG Patient Advocate Committee Representative
Lincoln, Nebraska

Allison Hester, RN, MSN, CPNP
Pediatric Nurse Practitioner
After Completion of Therapy Clinic
St. Jude Children’s Research 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 andextensive contributions to
all radiation-related sections in all versionsof the COG LTFU Guidelines

Guideline Development
Task ForceLong-Term Follow-Up Guidelines
Panel of Experts
The following members of the Children’s Oncology Group Late Effects Committee participated in comprehensive review and scoring of theChildren’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:
Smita Bhatia, MD, MPH
Chair – COG Late Effects Committee
Professor and Chair, Division of Population Sciences
City of Hope Comprehensive Cancer Center
Duarte, CA
Melissa M. Hudson, MD
Vice-Chair – COG Late Effects Committee
Member, Department of Hematology-Oncology
Director, After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, TN
F. Daniel Armstrong, PhD
Professor and Associate Chair, Department of Pediatrics
Director, Mailman Center for Child Development
University of Miami School of Medicine
Miami, FL
Julie Blatt, MD
Professor of Pediatrics
Division of Pediatric Hematology-Oncology
University of North Carolina
Chapel Hill, NC
Louis S. Constine, MD
Professor of Radiation Oncology and Pediatrics
Vice Chair, Department of Radiation Oncology
James P. Wilmot Cancer Center
University of Rochester Medical Center
Rochester, NY

Joan Darling, PhD
COG Patient Advocacy Committee Representative
Lincoln, NE
Paul Graham Fisher, MD, MHS
Associate Professor, Neurology and Pediatrics
The Beirne Family Director of Neuro-Oncology
at Packard Hospital
Stanford University Medical Center
Stanford, CA
Carolyn R. Freeman, MB, BS, FRCPC
Professor and Director
Department of Radiation Oncology
McGill University Health Centre
Montreal, Quebec, Canada
Debra L. Friedman MD, MS
Associate Professor of Pediatrics
Fred Hutchinson Cancer Research CenterSeattle, WA
Daniel M. Green, MD
Department of Pediatrics
Roswell Park Cancer Institute
Buffalo, NY
Professor of Pediatrics
School of Medicine and Biomedical Sciences
University at Buffalo, State University of New York
Buffalo, NY

Panel of Experts
Page 1Long-Term Follow-Up Guidelines
Panel of Experts (cont)Peter D. Inskip, Sc.D.
Senior Investigator
Division of Cancer Epidemiology and Genetics
National Cancer Institute
Bethesda, MD
Nina Kadan-Lottick, MD, MSPH
Associate Research Scientist
Department of Pediatrics
Yale University School of Medicine
New Haven, CT
Wendy Landier, RN, MSN, CPNP, CPON®
Pediatric Nurse Practitioner
Clinical Director, Survivorship Clinic
City of Hope Comprehensive Cancer Center
Duarte, CA
Neyssa Marina, MD
Professor of Pediatrics
Director, Long-Term Survivors Clinic
Department of Pediatrics
Stanford University Medical Center
Stanford, CA
Lillian Meacham, MD
Medical Director, Cancer Survivor Program
Division of Pediatric Endocrinology
Children’s Healthcare of Atlanta
Atlanta, GA

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
Joseph P. Neglia, MD, MPH
Professor of Pediatrics
Division of Hematology, Oncology,
Blood and Marrow Transplantation
University of Minnesota School of Medicine
Minneapolis, MN
Kevin C. Oeffinger, MD
Director, Living Beyond Cancer Program
Memorial Sloan-Kettering Cancer Center
New York, NY
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

Panel of Experts
Page 2

Long-Term Follow-Up Guidelines
Reviewers
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

Cathy Bourne, RN, BHSc(N)
Pediatric Hematology/Oncology
Cancer Care Manitoba
Winnipeg, Manitoba, Canada

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

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

Julianne Byrne, PhD
Department of Hematology-Oncology
Children's National Medical Center
Washington, DC

Patty Feist
Patient Advocate
Boulder, CO

Lisa Bashore, RN, MS, CPNP
Pediatric Hematology/Oncology
Cook Children’s Medical Center
Fort Worth, TX

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

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

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

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

Louis S. Constine, MD
Department of Radiation Oncology
University of Rochester Medical Center
Rochester, NY

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

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

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
Debra L. Friedman MD, MS
Pediatric Hematology-Oncology
Fred Hutchinson Cancer Research CenterSeattle, WA
Daniel M. Green, MD
Department of Pediatrics
Roswell Park Cancer Institute
Buffalo, NY

Reviewers
Page 1Long-Term Follow-Up Guidelines
Reviewers (cont)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, VACharlene Maxen, RN, CNP, CPON®
Hematology/Oncology
Childrens Hospital Medical Center - Akron
Akron, OH
Lillian Meacham, MD
Division of Pediatric Endocrinology
Children’s Healthcare of Atlanta
Atlanta, GA
Anna T. Meadows, MD
Division of Oncology
Children's Hospital of Philadelphia
Philadelphia, PA
Grace Powers Monaco, JD
Childhood Cancer Ombudsman Program
Heathsville, VA
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

Reviewers
Page 2

Long-Term Follow-Up Guidelines
Reviewers (cont)
Joseph P. Neglia, MD, MPH
Department of Pediatrics
Division of Hematology, Oncology,
Blood and Marrow Transplantation
University of Minnesota School of Medicine
Minneapolis, MN
Mary Nelson, RN, MS, CPNP, CPON®
Childrens Center for Cancer and Blood Diseases
Childrens Hospital Los Angeles
Los Angeles, CA
Kevin Oeffinger, MD
Department of Pediatrics
Memorial Sloan-Kettering Cancer Center
New York, NY
Roger Packer, MD
Department of Neurology
Children's National Medical Center
Washington, DC
Arnold Paulino, MD
Department of Radiation Oncology
Children’s Healthcare of Atlanta – Emory Clinic
Atlanta, GA
Rebecca D. Pentz, PhD
COG Patient Advocacy Committee
Atlanta, GA

Leslie L. Robison, PhD
Department of Epidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TN

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

David Rosenthal, MD
Department of Pediatrics/Cardiology
Lucile Packard Children’s Hospital at Stanford
Palo Alto, CACharles A. Sklar, MD
Department of Pediatrics/Endocrinology
Memorial Sloan-Kettering Cancer Center
New York, NY
Jacquie Toia, RN, ND, CPNP
Hematology/Oncology
Children’s Memorial Medical Center
Chicago, IL

Kathy Ruble, RN, MSN, CPNP, AOCN®
Pediatric Oncology
Johns Hopkins Hospital
Baltimore, MD
Kathleen Ruccione, RN, MPH, FAAN, CPON®
Childrens Center for Cancer and Blood Diseases
Childrens Hospital Los Angeles
Los Angeles, CA
Jean Sanders, MD
Pediatric Marrow Transplantation
Children’s Hospital Regional Medical CenterSeattle, WA
Cindy Schwartz, MD
Pediatric Hematology/Oncology
Rhode Island Hospital
Providence, RI

Deborah Waber, PhD
Department of Psychiatry
Boston Children's Hospital
Boston, MA
Susan L. Weiner, PhD
The Children’s Cause, Inc.
Silver Spring, MD
Fran Wiley, RN, MN
COG Patient Advocacy Committee
Los Angeles, CA

Reviewers
Page 3

Long-Term Follow-Up Guidelines
Reviewers (cont)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

Octavio Zavala
COG Patient Advocacy Committee
Los Angeles, CA

Joseph Zins, PhD
COG Patient Advocacy Committee
Cincinnati, OH

Reviewers
Page 4

COG Long Term Follow-Up Guidelines
Task Force Membership
Task Force

Task Force Members

Institution

Expertise

Amputation/Thomas R. Baker, CP

CFI Prosthetics and Orthotics

Prosthetics

Limb Sparing

Laura Feldman, Patient Advocate

Children’s Oncology Group

Patient advocacy

Dominic Femino, MDChildrens Hospital Los Angeles

Orthopedic surgery

Norman Jaffe, MD

M.D. Anderson Cancer Center

Pediatric oncology

Anita Majan, MD

M.D. Anderson Cancer Center

Radiation oncology

Victoria Marchese, PhD, PT*

St. Jude Children’s Research Hospital

Physical therapy

Rajaram Nagarajan, MD, MPH*

University of Minnesota Cancer Center

Pediatric oncology

Teresa Sweeney, RN, MSN, CPNP

St. Jude Children’s Research Hospital

Pediatric oncology nursing

Mark Yeazel, MD

University of Minnesota

Primary care

Cathy Hodge, Patient Advocate

Children’s Oncology Group

Patient advocacy

Wendy Landier, RN, MSN, CPNP*City of Hope National Medical Center

Pediatric oncology nursing

Maryrose McInerney, PhD, CCC-A

Hackensack University Medical Center

Audiology

Thomas Merchant, DO, PhD

St. Jude Children’s Research Hospital

Radiation oncology

Nicole Robbins, AU

St. Jude Children’s Research Hospital

Audiology

Renee F. Reymond, MD

Ochsner Clinic

Primary care

Patricia Shearer, MD, MS*

Ochsner Clinic

Pediatric oncology* Co-Chair
Auditory/Hearing* Co-Chair

Task Force Membership
Page 1

COG Long Term Follow-Up Guidelines
Task Force Membership (cont)
Task Force
Cancer Screening

Cardiovascular

Task Force Members

Institution

ExpertiseLouis S. Constine, MD
Lauren Dome, RN, CPNP
Debra Friedman, MD, MS
Melissa M. Hudson, MD
Marilyn Leitch, MD
Martin Mahoney, MD, PhD, FAAFP
Kathy Meeske, PhD, RN
Ann Mertens, MD
Monika Metzger, MD
Kevin C. Oeffinger, MD*
Robert Smith, MD
Octavio Zavala, Patient Advocate* Chair

University of Rochester Medical Center
St. Jude Children’s Research HospitalFred Hutchinson Cancer Research Center
St. Jude Children’s Research Hospital
University of Texas Southwestern Medical Center
Roswell Park Cancer InstituteChildrens Hospital Los Angeles
University of Minnesota
St. Jude Children’s Research Hospital
Memorial Sloan-Kettering Cancer Center
American Cancer SocietyChildrens Hospital Los Angeles

Radiation oncology
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology
Surgery
Primary care
Pediatric oncology nursing
Epidemiology
Pediatric oncology
Primary care
Medical oncology
Patient advocacy

Ming Hui Chen, MD, MMSc
David Hodgson, MD
Karen Kinahan, MS, RN
Neyssa Marina, MD*
Kathleen Meeske, PhD, RN
Angie Pemberton, Patient Advocate
David Rosenthal,MD*
Sadhna Shankar, MD*
Julia Steinberger, MD, MS*Co-Chair

Brigham and Women’s Hospital
Princess Margaret HospitalNorthwestern University
Stanford University Medical Center
Childrens Hospital Los AngelesChildren’s Oncology Group
Stanford University Medical Center
Vanderbilt Children’s Hospital
University of Minnesota Medical School

Adult cardiology
Radiation oncology
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology nursing
Patient advocacy
Pediatric cardiology
Pediatric oncology
Pediatric cardiology

Task Force Membership
Page 2

COG Long Term Follow-Up Guidelines
Task Force Membership (cont)
Task Force

Task Force Members

Institution

Expertise

Endocrine/Metabolic

Nathalie Alos, MD
Laurie Cohen, MD
Kimberley Dilley, MD, MPH
Eileen Duffey-Lind, RN, MS, PNP
Wendy Hobbie, MSN, RN, CRNP
Patricia Kent, RN, CPNP
Caroline Laverdiere, MD*
Lillian R. Meacham, MD
Daniel Mulrooney, MD*
Charles Sklar, MD
Stacey Urbach, MD
Suzanne Wolden, MD
Octavio Zavala, Patient Advocate*Co-Chair

Ste-Justine HospitalDana-Farber Cancer InstituteChildren’s Memorial HospitalDana-Farber Cancer Institute
The Children’s Hospital of Philadelphia
Massachusetts General Hospital
Ste-Justine HospitalChildren’s Healthcare of Atlanta
University of Minnesota Cancer Center
Memorial Sloan-Kettering Cancer Center
Hospital for Sick Children
Memorial Sloan-Kettering Cancer Center
Childrens Hospital Los Angeles

Pediatric endocrinology
Pediatric endocrinology
Primary care
Pediatric oncology nursing
Pediatric oncology nursing
Pediatric oncology nursing
Pediatric oncology
Pediatric endocrinology
Pediatric oncology
Pediatric endocrinology
Pediatric endocrinology
Radiation oncology
Patient advocacy

Fertility/Reproduction

Sharon Abish, MD
Jacqueline Casillas, MD
Mishel L. Davis, CRA
James Douglas, MD
Fernando A. Ferrer, MD
Senait Fisseha, MD, JD
Daniel Green, MD
Wendy Hobbie, MSN, RN, CRNP
Lisa Kenney, MD
Marcia Leonard, RN, CPNP*
Wendy Likes, DNSc, ARNP-BC
Monika Metzger, MD**Co-Chair

McGill University Health Center
UCLA School of Medicine
Children’s Medical Center of Dallas
Children’s Hospital and Regional Medical Center
Connecticut Children’s Medical Center
University of Michigan
Roswell Park Cancer Institute
The Children’s Hospital of Philadelphia
Dana-Farber Cancer Institute
C. S. Mott Children’s Hospital
University of Tennessee
St. Jude Children’s Research Hospital

Pediatric oncology
Pediatric oncology
Pediatric oncology
Radiation oncology
Urology
Gynecology
Pediatric oncology
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology nursing
Nursing
Pediatric oncology

Task Force Membership
Page 3

COG Long Term Follow-Up Guidelines
Task Force Membership (cont)
Task Force

Task Force Members

Institution

Expertise

Gastrointestinal/Hepatic

Sharon Castellino, MD*
Joan Darling, PhD, Patient Advocate
Andrew Davidoff, MD
Melissa M. Hudson, MD*
Kevin McMullen, MD
Andrew Muir, MD, MSH
Kathy Ruble, RN, CPNP, AOCN
Sheila Shope, RN, FNP*Co-Chair

Wake Forest University Baptist Medical Center
Children’s Oncology GroupSt. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital
Wake Forest University School of Medicine
Duke University School of Medicine
Johns Hopkins Hospital
St. Jude Children’s Research Hospital

Pediatric oncology
Patient advocacy
Pediatric surgery
Pediatric oncology
Radiation oncology
Pediatric GI/hepatology
Pediatric oncology nursing
Primary care

Hematopoietic Cell
Transplant

Scott Baker, MD*
Smita Bhatia, MD, MPH*
Louis S. Constine, MD
Kevin C. Oeffinger, MD
Wendy Pelletier, MSW, RSW
Susan F. Shaw, RN, MS, PNP
Ami Jayant Shah, MD
Lise Yasui, Patient Advocate*Co-Chair

University of Minnesota Cancer Center
City of Hope National Medical Center
University of Rochester Medical Center
Memorial Sloan-Kettering Cancer Center
Alberta Children’s HospitalState University of New York at Syracuse
Childrens Hospital Los AngelesChildren’s Oncology Group

Pediatric oncology
Pediatric oncology
Radiation oncology
Primary care
Social work
Pediatric oncology nursing
Pediatric oncology
Patient advocacy

Immune/Spleen

Jill Ginsberg, MD*
Karen Mandel, MD, FRCPC, FAAP
Anna Meadows, MD*
Joanna Perkins, MD, MS*Co-Chair

The Children’s Hospital of Philadelphia
Children’s Hospital of Eastern Ontario
The Children’s Hospital of Philadelphia
Children’s Hospitals and Clinics of Minnesota

Pediatric oncology
Pediatric oncology
Pediatric oncology
Pediatric oncology

Task Force Membership
Page 4

COG Long Term Follow-Up Guidelines
Task Force Membership (cont)
Task Force

Task Force Members

Institution

ExpertiseMusculoskeletal
DentalDermatologic

La Vette Bowles, RN, FNP
Amy Gilliam, MD
Sue Kaste, DO
Missy Layfield, Patient Advocate
Rex Marco, MD
Man Wai Ng, DDS, MPH
Arnold Paulino, MD*
Susan F. Shaw, RN, MS, PNP
Sheri Spunt, MD
Lynn Tanner, MS, PT*Chair

UCLA School of Medicine
University of California San Francisco
St. Jude Children’s Research HospitalChildren’s Oncology Group
University of Texas Health Sciences at HoustonChildren’s Hospital Boston
Methodist Hospital Houston
State University of New York at Syracuse
St. Jude Children’s Research HospitalChildren’s Hospitals and Clinics of Minnesota

Primary care
Pediatric dermatology
Diagnostic imaging
Patient advocacy
Orthopedic oncology
Pediatric dentistry
Radiation oncology
Pediatric oncology nursing
Pediatric oncology
Physical therapy

Neurocognitive/Behavioral

Danny Armstrong, PhD
Pim Brouwers, PhD
Kimberley Dilley, MD, MPH
Robert Goldsby, MD
Jeanne Harvey, RN, MSN, PNP
Chad Jacobsen, MD
Nina Kadan-Lottick, MD, MSPH
Karen McKinley, PsyD, LCSW
Ida (Ki) Moore, PhD, RN
Paul Nathan, MD, MSc*
Fatih Okcu, MD
Sunita Patel, PhD*
Catherine L. Woodman, MD* Co-Chair

University of Miami School of Medicine
National Institute of Mental HealthChildren’s Memorial Hospital Chicago
UCSF School of Medicine
Washington University Medical Center
Rainbow Babies & Children’s Hospital
Yale University School of Medicine
Children’s Hospital of the King’s Daughters
University of Arizona Health Sciences Center
The Hospital for Sick Children
Texas Children’s Cancer Center
City of Hope National Medical Center
University of Iowa Hospitals and Clinics

Pediatric psychology
Pediatric psychology
Primary care
Pediatric oncology
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology
Social Work
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology
Pediatric psychology
Patient advocacy

Task Force Membership
Page 5

COG Long Term Follow-Up Guidelines
Task Force Membership (cont)
Task Force

Task Force Members

Institution

Expertise

Neurologic(CNS & PNS)Jean Belasco, MD
Jackie Casillas, MD
Paul G. Fisher, MD*
Michael J. Fisher, MD
E. Brannon Morris III, MD
Roger Packer, MD*
Kathy Ruble, RN, CPNP, AOCN
*Co-Chair

The Children’s Hospital of Philadelphia
UCLA School of Medicine
Stanford University Cancer Center
The Children’s Hospital of Philadelphia
St. Jude Children’s Research HospitalChildren’s National Medical Center
Johns Hopkins Hospital

Pediatric oncology
Pediatric oncology
Pediatric neurology
Pediatric neuro-oncology
Pediatric neurology
Pediatric neurology
Pediatric oncology nursing

Ocular/Vision

Louis S. Constine, MD
Debra Friedman, MD, MS*
Sarita Joshi, MD
A. Linn Murphree, MD
Carol L. Shields, MD
Teresa Sweeney, RN, MSN, CPNP
Catherine L. Woodman, MD*ChairUniversity of Rochester Medical CenterFred Hutchinson Cancer Research Center
Women and Childrens HospitalChildrens Hospital Los Angeles
Wills Eye Hospital
St. Jude Children’s Research Hospital
University of Iowa Hospitals and Clinics

Radiation oncology
Pediatric oncology
Pediatric oncology
Pediatric ophthalmology
Pediatric ophthalmology
Pediatric oncology nursing
Patient advocacy

Psychosocial

Debra Eshelman, RN, MSN, CPNPMark Greenberg, MD
Nina Kadan-Lottick, MD, MSPH*
Stuart Kaplan, MD
Ann Mertens, PhD
Sunita Patel, PhD
Sheila Santacroce, PhD, APRN, CPNP
Sally Wiard, MSW
Octavio Zavalo, Patient Advocate
Catherine L. Woodman, MD*ChairChildren’s Medical Center of Dallas
Hospital for Sick Children
Yale University School of Medicine
St. Jude Children’s Research Hospital
University of Minnesota
City of Hope National Medical Center
Yale University School of Nursing
St. Jude Children’s Research HospitalChildrens Hospital Los Angeles
University of Iowa Hospitals and Clinics

Pediatric oncology nursing
Pediatric oncology
Pediatric oncology
Primary care
Epidemiology
Pediatric psychology
Pediatric oncology nursing
Social work
Patient advocacy
Patient advocacy

Task Force Membership
Page 6

COG Long Term Follow-Up Guidelines
Task Force Membership (cont)
Task Force

Task Force Members

Institution

Expertise

PulmonaryJulie Blatt, MD*
Robert Goldsby, MD*
E. Allen Liles, Jr., MD
Charlene Maxen, RN, CNP, CPONDavid E. Morris, MD
Angie Pemberton, Patient Advocate
David L. Robinowitz, MD, MHS, MS
Aimee Sznewajs, RN, MS, PNP
Richard Wardrop, III, MD* Co-Chair

University of North Carolina at Chapel Hill
UCSF School of Medicine
University of North Carolina at Chapel Hill
Children’s Hospital Medical Center of Akron
University of North Carolina at Chapel Hill
Children’s Oncology GroupUCSF Pediatric Pulmonary Medicine
UCSF Children’s Hospital
University of North Carolina at Chapel Hill

Pediatric oncology
Pediatric oncology
Primary care
Pediatric oncology nursing
Radiation oncology
Patient advocacy
Pulmonary
Pediatric oncology nursing
Primary care

Skeletal:
Osteonecrosis
Osteopenia
Osteoporosis

Arlina Ahluwalia, MD
Natia Esiashvili, MD
Sue Kaste, DO
Missy Layfield, Patient Advocate
Victoria Marchese, PhD, PT
Leonard A. Mattano, Jr., MD*
Lillian R. Meacham, MD*
Susan Shannon, RN, MSN, CPNP, CPON
Karen Wasilewski, MD*Co-Chair

Stanford University Medical Center
Emory University
St. Jude Children’s Research HospitalChildren’s Oncology GroupSt. Jude Children’s Research Hospital
Kalamazoo Center for Medical Sciences
Children’s Healthcare of Atlanta
Miller Children’s Hospital/Harbor-UCLA
Children’s Healthcare of Atlanta

Primary care
Radiation oncology
Diagnostic imaging
Patient advocacy
Physical therapy
Pediatric oncology
Pediatric endocrinology
Pediatric oncology nursing
Pediatric oncology

Task Force Membership
Page 7

COG Long Term Follow-Up Guidelines
Task Force Membership (cont)
Task Force

Task Force Members

Institution

Expertise

Subsequent Malignant
Neoplasms

Smita Bhatia, MD, MPH*
Louis S. Constine, MD
Debra Friedman, MD, MS
Wendy Landier, RN, MSN, CPNP
Joseph Neglia, MD, MPH*
Sadhna Shankar, MD
Lise Yasui, Patient Advocate
Mark Yeazel, MD*Co-Chair

City of Hope National Medical Center
University of Rochester Medical CenterFred Hutchinson Cancer Research Center
City of Hope National Medical Center
University of Minnesota Cancer Center
Vanderbilt Children’s HospitalChildren’s Oncology Group
University of Minnesota

Pediatric oncology
Radiation oncology
Pediatric oncology
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology
Patient advocacy
Primary care

Urinary Tract

Joan Darling, PhD, Patient Advocate
Fernando Ferrer, MD
Daniel Green, MD
Deborah Jones, MD
Anne Mauck, RN, MSN, CPNP
Arnold Paulino, MD
Michael Ritchey, MD
Patricia Shearer, MD, MS
Sheri L. Spunt, MD**ChairChildren’s Oncology Group
Connecticut Children’s Medical Center
Roswell Park Cancer Institute
LeBonheur Children’s Medical Center
Virginia Commonwealth University
Methodist Hospital Houston
Pediatric Urology Associates Phoenix
Ochsner Clinic
St. Jude Children’s Research Hospital

Patient advocacy
Pediatric urology
Radiation oncology
Pediatric nephrology
Pediatric oncology nursing
Radiation oncology
Urology
Pediatric oncology
Pediatric oncology

Task Force Membership
Page 8

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

Debra L. Friedman, MD, MS
Pediatric Hematology-Oncology
Fred Hutchinson Cancer Research CenterSeattle, WA

Wendy Landier, RN, MSN, CPNP, CPON®
Department of Pediatric Hematology/Oncology
City of Hope Comprehensive Cancer Center
Duarte, CA

Sharon Frierdich, RN, MS, CPNP
Pediatric Hematology/Oncology
University of Wisconsin Children’s Hospital
Madison, WI

Marcia Leonard, RN, CPNP
Pediatric Hematology/Oncology andLong-Term Follow-Up Clinic
C.S. Mott Children’s Hospital
Ann Arbor, MI

Allison Hester, RN, MSN, CPNP
After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, TN

Debra Eshelman, RN, MSN, CPNP
After the Cancer Experience (ACE) ProgramChildren’s Medical Center – Dallas
Dallas, TX

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

Fernando A. Ferrer, MD
Department of Surgery
Connecticut Children’s Medical Center
Hartford, CT

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

Sarah Friebert, MD
Division of Hematology/Oncology
Childrens Hospital Medical Center of Akron
Akron, OH

Deborah Lafond, MS, RNCS, PNP, CPON®
Hematology/Oncology
Children’s National Medical Center
Washington, DC

Victoria Marchese, PhD, PT
Department of Epidemiology and Cancer Control
St. Jude Children's Research Hospital
Memphis, TN
Anne Mauck, RN, MSN, CPNP
Pediatric Hematology/Oncology
Virginia Commonwealth University Health
SystemRichmond, VACharlene Maxen, RN, CNP, CPON®
Division of Hematology/Oncology
Childrens Hospital Medical Center of Akron
Akron, OH
Health Link Authors
Page 1Long-Term Follow-Up Guidelines
Health Link Authors (cont)
Katherine Myint-Hpu, MSN, MPH, PNP
Leukemia/Lymphoma Clinic
Georgetown University Hospital
Washington, DC

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

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

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

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

Sheri L. Spunt, MD
Hematology/Oncology
St. Jude Children’s Research Hospital
Memphis, TN

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

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

Teresa Sweeney, RN, MSN, CPNP
After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, TN

Arnold Paulino, MD
Division of Radiation Oncology
Methodist Hospital
Houston, TX
Sunita Patel, PhD
Department of Pediatric Hematology/Oncology
City of Hope Comprehensive Cancer Center
Duarte, CA

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

Sally Wiard, MSW, LCSW
After Completion of Therapy Clinic
St. Jude Children’s Research Hospital
Memphis, TN

Patricia Shearer, MD, MS
Pediatric Hematology/Oncology
Ochsner Clinic
New Orleans, LA

Health Link Graphic Artist:
Devika Bhatia
Westridge School
Pasadena, CA

Michael Ritchey, MD
Pediatric Urology Associates
Phoenix, AZ

Health Link Authors
Page 2

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, MS, 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, RN, MSN, 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
Health Link Reviewers

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 2.0 – March 2006

Introductory Material

Copyright 2006 © Children’s Oncology GroupAll rights reserved worldwide

Introduction – Version 2.0
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 andmanagement 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 late effects of pediatric cancer treatment.
The guidelines are both evidence-based (utilizing established associations between therapeutic exposures and lateeffects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching themagnitude of the risk with the intensity of the screening recommendations). Since therapeutic interventions for a
specific pediatric malignancy may vary considerably based on the patient’s age, presenting features, and treatment era,a therapy-based design was chosen to permit modular formatting of the guidelines by therapeutic exposure. Importantly,
the recommended periodic screening underscores the use of a thorough history and physical examination (H&P) as theprimary assessment for cancer-related treatment effects. In this regard, 101 (74%) of the screening recommendations
outlined for the 136 therapeutic exposures in the COG-LTFU Guidelines comprise assessments derived primarily from the
H&P, with 68 (50%) relying solely on the H&P and 33 (24%) relying on the H&P plus a baseline diagnostic study (e.g., lab,
imaging), whereas 31 (23%) include periodic laboratory, diagnostic imaging, or other testing, and 4 (3%) recommend noscreening (agents with no known late effects). Interventions exceeding minimal screening are provided for consideration
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 beenorganized into Health Links that feature health protective counseling on 42 topics, enhancing patient follow-up visits andbroadening application of the guidelines. Additional accompanying materials include detailed instructions, templates forcancer treatment summary forms, and a tool to assist in identifying guideline applicability for individual patients basedon 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 oflate effects, and (d) provides timely intervention for late effects.
Introduction
Page 1

Introduction – Version 2.0 (cont)
TargetPopulation:

The recommendations for periodic screening evaluations provided in the Children’s Oncology Group Long-Term FollowUp Guidelines for Survivors of 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 with signs 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, andprovide a framework for ongoing 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.

Intended
Users:The COG-LTFU Guidelines were developed as a resource for clinicians who provide ongoing healthcare to survivors ofpediatric malignancies. The information within these guidelines is important for clinicians (e.g., physicians, nurse
practitioners, physician assistants, nurses) in the fields of pediatrics, oncology, internal medicine, family practice, andgynecology, as well as subspecialists in many fields (e.g., endocrinology, cardiology, pulmonology). A basic knowledgeof ongoing issues related to the long-term follow-up needs of this patient population is assumed. Healthcare
professionals who do not regularly care for survivors of pediatric malignancies are encouraged to consult with apediatric oncology long-term follow-up center if any questions or concerns arise when reviewing or using theseguidelines.
Although the information within the guidelines will certainly prove valuable to the survivors themselves, at this time theonly version available is targeted to healthcare professionals. Therefore, survivors who choose to review theseguidelines are strongly encouraged to do so with the assistance of a healthcare professional knowledgeable about
long-term follow-up care for survivors of childhood, adolescent, and young adult cancers. This is important in order to
put the recommendations in perspective, avoid over-testing, address potential anxieties, and provide a comprehensive
evaluation of the survivor’s health status. The Children’s Oncology Group itself does not provide individualized
treatment advice to patients or their families, and strongly recommends discussing this information with a qualified
medical professional.

Introduction
Page 2

Introduction – Version 2.0 (cont)
Developer:

The COG-LTFU Guidelines were developed as a collaborative effort of the Children’s Oncology Group Nursing Disciplineand Late Effects Committee. All Children’s Oncology Group members have complied with the COG conflict of interest
policy, which requires disclosure of any potential financial or other conflicting interests.

Funding
Source:This work was supported by the Children’s Oncology Group 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 2005) was
retrieved and reviewed during the development and updating of these guidelines. For each therapeutic exposure, acomplete search was performed via MEDLINE (National Library of Medicine, Bethesda, MD). Keywords included"childhood cancer therapy," "complications," and "late effects," combined with keywords for each therapeutic
exposure. References from the bibliographies of selected articles were used to broaden the search.

Methods:

In 2002, the leadership of the Children’s Oncology Group Late Effects Committee and Nursing Discipline appointed a
7-member task force, with representation from the Late Effects Committee, Nursing Discipline, and Patient Advocacy
Committee. The task force was convened to review and summarize the medical literature and develop a draft of clinicalpractice 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 inthe field, including nurses, physicians (pediatric oncologists and other subspecialists), patient advocates, behavioral
specialists, and other healthcare professionals, were then recruited by the task force to provide an extensive, targeted
review of 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 andscoring by a panel of experts in the late effects of pediatric malignancies, comprised of multidisciplinary representatives
from the COG Late Effects Committee.
Introduction
Page 3

Introduction – Version 2.0 (cont)
Methods(cont):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 ofcontent 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 assessmentof the strength of data from the literature linking a specific late effect with a therapeutic exposure, coupled with anassessment of the appropriateness of the screening recommendation based on the expert panel’s collective clinicalexperience. "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, casereports, case series and clinical experience. Rather than submitting recommendations representing major
disagreements, items scored as "Category 3" were either deleted or revised by the panel of experts to provide at least a"Category 2B" score for all recommendations included in the guidelines.

Pre-Release
Review:

The initial version of the guidelines (Version 1.0 – Children’s Oncology Group Late Effects Screening Guidelines) was
released to the Children’s Oncology Group membership in March 2003 for a six-month trial period. This allowed for
initial feedback from the COG membership, resulting in additional review and revision of the guidelines by the Late
Effects Committee prior to public release.

Revisions:

The guidelines were initially released to the public (Version 1.1 – Childhood Cancer Survivor Long-Term Follow-Up
Guidelines) on the Children’s Oncology Group Website in September 2003. Following this release, clarification regarding
the applicability of the guidelines to the adolescent and young adult populations of cancer survivors was requested. In
response, additional minor modifications were made and the title of the guidelines was changed. A revised version(Version 1.2 – Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers) was
released to the public on the Children’s Oncology Group Website in March 2004.

Introduction
Page 4

Introduction – Version 2.0 (cont)
Revisions:(cont)In order to keep the guidelines current and clinically meaningful, the COG Late Effects Committee organized 18 multi
disciplinary task forces in March 2004. These task forces were 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, and recommending
revisions to the guidelines and their associated health education materials and references (including the addition oftherapeutic exposures) as new information became available. Task force members were assigned according to theirrespective areas of expertise and clinical interest. A list of these task forces and their membership is included in the"Contributors" section of this document. The revisions incorporated into the current release of these guidelines(Version 2.0 – March 2006) reflect the contributions and recommendations of these task forces.
All revisions proposed by the task forces were evaluated by a panel of experts, and if accepted, assigned a score (see"Scoring Explanation" section of this document). Proposed revisions that were rejected by the expert panel werereturned with explanation to the relevant task force chair. If desired, task force chairs were given an opportunity torespond by providing additional justification and resubmitting the rejected task force recommendation(s) for further
consideration by the expert panel. A total of 34 sections and 9 Health Links were added to Version 2.0 of theseguidelines.

Plan for Updates:

The 18 task forces described above will continue to monitor the literature and report to the Late Effects committee on abi-annual basis. Periodic revisions to these guidelines are planned as new information becomes available. 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 oftreatment for a pediatric malignancy. "Pediatric malignancies" are defined as those malignancies commonly associatedwith the pediatric population that may arise during childhood, adolescence or young adulthood. "Consensus" is definedas general agreement among the panel of experts.

Introduction
Page 5

Introduction – Version 2.0 (cont)
Recommendations
and Rationale:

Screening and follow-up recommendations are organized by therapeutic exposure and included throughout theguidelines. Pediatric cancer survivors represent a relatively small but growing population at high risk for various
therapy-related complications. Although several well-conducted studies on large populations of childhood cancer
survivors have demonstrated associations between specific exposures and late effects, the size of the survivor
population and the rate of occurrence of late effects does not allow for clinical studies that would assess the impact ofscreening recommendations on the morbidity and mortality associated with the late effect. Therefore, scoring of eachexposure reflects the expert panel’s assessment of the level of literature support linking the therapeutic exposure withthe 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.

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 oflate complications on the health status of survivors. In addition, ongoing healthcare that promotes healthy lifestylechoices 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 be prohibitive 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, andlifestyle. These guidelines are therefore not intended to replace clinical judgment or to exclude other reasonable
alternative follow-up procedures. The Children’s Oncology Group recognizes that specific patient care decisions are theprerogative of the patient, family, and healthcare provider.

Introduction
Page 6

Introduction – Version 2.0 (cont)
Implementation
Considerations:

Implementation of these guidelines is intended to standardize and enhance follow-up care provided to survivors ofpediatric malignancies throughout the lifespan. Considerations in this regard include the practicality and efficiency ofapplying these broad guidelines in individual clinical situations. Studies to address guideline implementation andrefinement are a top priority of the COG Late Effects Committee, and proposals to study feasibility of guideline use inlimited institutions are currently underway. Issues to be addressed include description of anticipated barriers toapplication of the recommendations in the guidelines and development of review criteria for measuring changes in carewhen the guidelines are implemented. Additional concerns surround the lack of current evidence establishing theefficacy of screening for late complications in pediatric cancer survivors. While most clinicians believe that ongoingsurveillance for these late complications is important in order to allow for early detection and intervention forcomplications 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 Late Effects Committee.
While recognizing that the length and depth of these guidelines is important in order to provide clinically-relevant,evidence-based recommendations and supporting 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 theirclinical application. Therefore, the COG Late Effects Committee is currently partnering with the Baylor School of
Medicine in order to develop a web-based interface, known as "Passport for Care," that will generate individualized
exposure-based recommendations from these guidelines in a clinician-focused format for ease of patient-specificapplication of the guidelines in the clinical setting. As additional information regarding implementation of the Passport
for Care web-based interface becomes available, updates will be posted at www.survivorshipguidelines.org.

Introduction
Page 7

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 aresult of therapeutic exposures received during treatment of childhood, adolescent, and young adult cancers.
Each score relates to the strength of the association of the identified late effect with the specific therapeutic exposure based on current
literature, and is coupled with a recommendation for periodic health screening based on the collective clinical experience of the panelof 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 thetherapeutic exposure and (2) the screening recommendation is appropriate based on the collective clinical experienceof panel members.

2A

There is uniform consensus of the panel that: (1) there is lower-level evidence linking the late effect with thetherapeutic exposure and (2) the screening recommendation is appropriate based on the collective clinical experienceof panel members.

2B

There is non-uniform consensus of the panel that: (1) there is lower-level evidence linking the late effect with thetherapeutic exposure and (2) the screening recommendation is appropriate based on the collective clinical experienceof panel members.

3

There is major disagreement that the recommendation is appropriate
Explanation of Scoring
Page 1

Explanation of Scoring for the Long-Term Follow-Up Guidelines (cont)
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 at least a "Category 2B" score for all recommendations included in the guidelines.

Explanation of Scoring
Page 2

Instructions for Use – Version 2.0
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-Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are organizedaccording to therapeutic exposures, arranged by column as follows:
Section Number

Unique identifier for each guideline section corresponding with listing in Index.

Therapeutic Agent

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

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 thecomplication.

Highest Risk Factors

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

Periodic Evaluations

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

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Instructions for Use – Version 2.0 (cont)
Health Counseling/
Further Considerations

Health Links: Health education materials developed specifically to accompany these guidelines. Title(s) of
Health Link(s) relevant to each guideline section are referenced in this column. Health Link documents areincluded in Appendix II, and are also available on the COG website at www.survivorshipguidelines.org.
Counseling: Suggested patient counseling regarding measures to prevent/reduce risk or promote early
detection of the potential treatment complication.
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.

SystemBody system (e.g., auditory, musculoskeletal) most relevant to each guideline section.

Score

Score assigned by expert panel representing 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 collective clinical experience.

Cancer Screening
Recommendations

Sections 137 – 145 contain preventive screening recommendations for common adult-onset cancers,organized by column as follows:
Organ: The organ at risk for developing malignancy.
At Risk Population: Populations generally considered at increased risk for the specified malignancy based onrisk factors such as age, gender, genetic susceptibility, personal or family history, health-related behaviors or
co-morbidities.
Highest Risk: Populations considered by the panel of experts or other evaluating bodies (such as theAmerican Cancer Society) as being at 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).

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Instructions for Use – Version 2.0 (cont)
Cancer Screening
Recommendations(cont)

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 areencouraged to consult recommendations from other organizations, such as the U. S. Preventive Services Task
Force (http://www.ahrq.gov/clinic/serfiles.htm).
Highest Risk: Recommendations for high-risk populations, when applicable, are specified and may differ fromrecommendations 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 the therapeutic 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.

Index

Due to significant overlap of toxicities between therapeutic agents, and in order to avoid an enormously lengthy
document, duplicate entries have been avoided as much as possible. Therefore, use of the Index or PatientSpecific Guideline Identification Tool (see Appendix I) is imperative in order to determine each potential lateeffect associated with each therapeutic agent within this document.

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 isincluded in Appendix I).
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Instructions for Use – Version 2.0 (cont)1. Obtain the survivor’s Summary of Cancer Treatment (see templates and instructions for comprehensive and abbreviated treatment
summaries in Appendix I). Note: In order to generate accurate exposure-based follow-up recommendations from these guidelines, thefollowing information regarding the survivor’s diagnosis and treatment is required, at minimum:• 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, see "Chemotherapy"
portion of Index - Sections 6-37. 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 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, thoracic spine, and upper abdominal radiation, include age atfirst dose). For list of radiation fields addressed by these guidelines, see "Radiation" portion of Index - Sections 38-91. For clarificationof anatomical areas included in common radiation fields, see Radiation Fields Defined in Appendix I.
• Whether or not the survivor underwent a hematopoietic cell transplant (HCT), and if so, whether or not the survivor ever developed
chronic graft-versus-host disease (cGVHD).
• Names of all relevant surgical procedures. For list of surgical procedures addressed by these guidelines, see "Surgery" portion of Index- Sections 107-132.
• Names of all other therapeutic modalities. For list of other therapeutic modalities addressed by these guidelines, see "Other Therapeutic
Modalities" portion of Index - Sections 133-36.
2. Develop a list of guideline sections relevant to the survivor:• Sections 1 and 2 ("Any Cancer Experience") and 146 ("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 3- If survivor was diagnosed prior to 1993, include Section 4- If survivor was diagnosed between 1977 and 1985, include Section 5

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Instructions for Use – Version 2.0 (cont)• For survivors who received chemotherapy, include relevant sections:- If survivor received any chemotherapy, include Section 6.
- Review "Chemotherapy" portion of the Index and include Sections 7-37 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 38 – 39
- Review "Radiation" portion of the Index and include Sections 40-91 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 ofradiation to the indicated field).
- Exception: If the survivor’s only radiation exposure was TBI, do NOT include sections 40 or 41. For convenience, all sections
applicable to TBI are located between pages 102 - 118 of the guidelines.
• For survivors who underwent hematopoietic cell transplant (HCT), include Sections 92-97. If the survivor developed chronic GVHD, also
include sections 98-106• For survivors who underwent surgery, review "Surgery" portion of Index and include Sections 107-132 as applicable 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 Index and include Sections
133-136 as applicable.
• Include cancer screening guidelines (sections 137-145) as applicable based on survivor’s sex and current age.
3. 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.

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Instructions for Use – Version 2.0 (cont)Note: The above procedure is applicable to generation of follow-up guidelines from the current version of this document; however, the COG Late
Effects Committee recognizes that as new evidence becomes available and these guidelines are updated, additional details regarding thechildhood cancer survivor’s therapeutic exposures may be required in order to generate comprehensive recommendations. Therefore, westrongly advise that a comprehensive treatment summary be prepared for each childhood cancer survivor, including a record of all therapeutic
exposures with applicable dates, details of administration, and cumulative doses of all agents, including those not currently addressed by theseguidelines.
The COG Late Effects Committee and Nursing Discipline recognize that the time required to identify patient-specific recommendations fromthese guidelines is significant, and has been identified as a barrier to clinical use. Therefore, the COG Late Effects Committee is currently
partnering with the Baylor School of Medicine in order to develop a web-based interface, known as "Passport for Care," that will generate
individualized exposure-based recommendations from these guidelines in a clinician-focused format for ease of patient-specific application in
the clinical setting. As additional information regarding implementation of the "Passport for Care" web-based interface becomes available,
updates will be posted at www.survivorshipguidelines.org. In the meantime, use of the Patient-Specific Guideline Identification Tool and Index toHealth Links by Guideline Section Number (see Appendix I) should serve to reduce the time required for patient-specific application of theseguidelines.
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, please contact:
Melissa M. Hudson, MD
Vice-Chair – COG Late Effects Committee
St. Jude Children’s Research Hospital
Memphis, Tennessee(901) 495-4781
Melissa.Hudson@stjude.org

Wendy Landier, RN, MSN, CPNP
Chair – COG Nursing Clinical Practice/
Survivorship Subcommittee
City of Hope Comprehensive Cancer Center
Duarte, California(626) 301-8426
wlandier@coh.org

Smita Bhatia, MD, MPH
Chair – COG Late Effects Committee
City of Hope Comprehensive Cancer Center
Duarte, California(626) 301-8426
sbhatia@coh.org

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Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 2.0 – March 2006

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

Copyright 2006 © Children’s Oncology GroupAll rights reserved worldwide

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

1

Any Cancer Experience

Psychosocial Disorders
Social withdrawal
Educational problems

Info Link: The Children's
Oncology Group Long-Term
Follow-Up Guidelines apply topatients who have been off
therapy for a minimum of 2
years.

Risk
Factors
Host Factors
Female sex
Family history of depression,anxiety, or mental illness
Social Factors
Lower household income
Lower educational
achievement

HighestRisk Factors
Host Factors
CNS tumor
CNS-directed therapy
Premorbid learning or
emotional difficulties
Social Factors
Failure to graduate fromhigh school

Treatment Factors
HCT
Mental health disorders
Depression
Anxiety
Post-traumatic stress

Host Factors
Female sex
Family history of depression,anxiety, or mental illness
Social Factors
Lower household income
Lower educational achievement

Host Factors
CNS tumor
CNS-directed therapy
Premorbid learning or
emotional difficulties
Social Factors
Failure to graduate fromhigh school

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

Social Factors
Lower household income

Psychosocial disability
due to pain

Treatment Factors
Amputation
Radiation to bone/joint
Limb-sparing surgery
Vincristine exposure

Host Factors
Older age at diagnosis
Social Factors
Lower educational
achievement

Periodic
Evaluation
HISTORY
Psychosocial assessment, withattention to:- Educational and/or vocational
progress- Depression- Anxiety- Post-traumatic stress- Social withdrawal(Yearly)

Health Counseling
Further Considerations
Health Links
Introduction to Long-Term Follow-Up
Emotional Issues
Educational Issues
Chronic Pain after Childhood Cancer
Resources'Childhood Cancer Survivors' by Nancy Keene, Wendy Hobbie &Kathy Ruccione, Sebastopol, CA: O'Reilly & Associates, 2000
'Educating the Child with Cancer' edited by Nancy Keene,
Candlelighters Childhood Cancer Foundation, Bethesda, MD,
2003.
See also:
www.cancer.gov ('Facing Forward' series for survivors)
www.cancer.org (smoking cessation)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 evaluation of parent for
post-traumatic stress syndrome. 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. Screen for
physical sources of fatigue, such as anemia, sleep
disturbances, nutritional deficiencies, cardiomyopathy,
pulmonary fibrosis, hypothyroidism, or other endocrinopathy.

Host Factors
CNS tumor
Hodgkin lymphoma
SYSTEM = Psychosocial
SCORE = 2A

Medical Conditions
Osteonecrosis
Fatigue

Host Factors
Female sex
Depression
Obesity

Treatment Factors
Pulmonary radiation

Social Factors
Unemployment

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 1 REFERENCES
Psychosocial - General
Arvidson J, Larsson B, Lonnerholm G. A long-term follow-up study of psychosocial functioning after autologous bone marrow transplantation in childhood. Psychooncology. Mar-Apr 1999;8(2):123-134.
Boman K, Bodegard G. Long-term coping in childhood cancer survivors: influence of illness, treatment and demographic background factors. Acta Paediatr. Jan 2000;89(1):105-111.
Felder-Puig R, Peters C, Matthes-Martin S, et al. Psychosocial adjustment of pediatric patients after allogeneic stem cell transplantation. Bone Marrow Transplant. Jul 1999;24(1):75-80.
Zebrack 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. Jul 2002;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. Feb 1997;15(2):547-556.
Social withdrawal/educational problems
Brown RT, Madan-Swain A. Cognitive, neuropsychological, and academic sequelae in children with leukemia. J Learn Disabil. Feb 1993;26(2):74-90.
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.
Deasy-Spinetta P. School issues and the child with cancer. Cancer. May 15 1993;71(10 Suppl):3261-3264.
Lim JW, Zebrack B. Social networks and quality of life for long-term survivors of leukemia and lymphoma. Support Care Cancer. Jul 9 2005.
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.
Mulhern RK, Wasserman AL, Friedman AG, Fairclough D. Social competence and behavioral adjustment of children who are long-term survivors of cancer. Pediatrics. Jan 1989;83(1):18-25.
Pastore G, Mosso 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 of Piedmont, Italy. Tumori. Nov-Dec 2001;87(6):372-378.
Rauck AM, Green DM, Yasui Y, Mertens A, Robison LL. Marriage in the survivors of childhood cancer: a preliminary description from the Childhood Cancer Survivor Study. Med Pediatr Oncol. Jul 1999;33(1):60-63.
Stam H, Grootenhuis MA, Last BF. Social and emotional adjustment in young survivors of childhood cancer. Support Care Cancer. Oct 2001;9(7):489-513.
Mental health disorders
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.
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.
Rourke MT, Stuber ML, Hobbie WL, Kazak AE. Posttraumatic stress disorder: understanding the psychosocial impact of surviving childhood cancer into young adulthood. J Pediatr Oncol Nurs. Jul 1999;16(3):126-135.
Santacroce SJ. Parental uncertainty and posttraumatic stress in serious childhood illness. J Nurs Scholarsh. 2003;35(1):45-51.
Stuber ML, Christakis DA, Houskamp B, Kazak AE. Posttrauma symptoms in childhood leukemia survivors and their parents. Psychosomatics. May-Jun 1996;37(3):254-261.
Stuber ML, Kazak AE, Meeske K, Barakat L. Is posttraumatic stress a viable model for understanding responses to childhood cancer? Child Adolesc Psychiatr Clin N Am. Jan 1998;7(1):169-182.
Stuber ML, Kazak AE, Meeske K, et al. Predictors of posttraumatic stress symptoms in childhood cancer survivors. Pediatrics. Dec 1997;100(6):958-964.
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.

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 1 REFERENCES - continued
Risky behaviors
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.
Hollen PJ, Hobbie WL, Finley SM, Hiebert SM. The relationship of resiliency to decision making and risk behaviors of cancer-surviving adolescents. J Pediatr Oncol Nurs. Sep-Oct 2001;18(5):188-204.
Mulhern RK, Tyc VL, Phipps S, et al. Health-related behaviors of survivors of childhood cancer. Med Pediatr Oncol. Sep 1995;25(3):159-165.
Tyc VL, Hadley W, Allen D, et al. Predictors of smoking intentions and smoking status among nonsmoking and smoking adolescents. Addict Behav. Aug 2004;29(6):1143-1147.
Tyc VL, Hadley W, Crockett G. Prediction of health behaviors in pediatric cancer survivors. Med Pediatr Oncol. Jul 2001;37(1):42-46.
Tyc VL, Lensing S, Klosky J, Rai SN, Robinson L. A comparison of tobacco-related risk factors between adolescents with and without cancer. J Pediatr Psychol. Jun 2005;30(4):359-370.
Psychosocial disability due to pain
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 ofChronic Pain and Insomnia. JAMA. Jul 24-31 1996;276(4):313-318.
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):123-135.
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.
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.
Fatigue
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.
Hinds PS, Hockenberry-Eaton M, Gilger E, et al. Comparing patient, parent, and staff descriptions of fatigue in pediatric oncology patients. Cancer Nurs. Aug 1999;22(4):277-288; quiz 288-279.
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.
Langeveld N, Ubbink M, Smets E. 'I don't have any energy': The experience of fatigue in young adult survivors of childhood cancer. Eur J Oncol Nurs. Mar 2000;4(1):20-28.
Langeveld NE, Grootenhuis MA, Voute PA, de Haan RJ, van den Bos C. No excess fatigue in young adult survivors of childhood cancer. Eur J Cancer. Jan 2003;39(2):204-214.
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.

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

2

Any Cancer Experience

Limitations in healthcare
and insurance access

Risk
Factors
Social Factors
Lower household income
Lower educational
achievement

HighestRisk Factors

Periodic
Evaluation
HISTORY
Psychosocial assessment, withattention to healthcare
insurance and access(Yearly)

Health Counseling
Further Considerations
Health Links
Finding Healthcare
Considerations for Further Testing and Intervention
Social work consultation

SYSTEM = Psychosocial
SCORE = 2A

SECTION 2 REFERENCES
Dolgin MJ, Somer E, Buchvald E, Zaizov R. Quality of life in adult survivors of childhood cancer. Soc Work Health Care. 1999;28(4):31-43.
Hays DM. Adult survivors of childhood cancer. Employment and insurance issues in different age groups. Cancer. May 15 1993;71(10 Suppl):3306-3309.
Langeveld NE, Stam H, Grootenhuis MA, Last BF. Quality of life in young adult survivors of childhood cancer. Support Care Cancer. Nov 2002;10(8):579-600.
Monaco GP, Fiduccia D, Smith G. Legal and societal issues facing survivors of childhood cancer. Pediatr Clin North Am. Aug 1997;44(4):1043-1058.
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.

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BLOOD/SERUM PRODUCTS
Sec#

Therapeutic
Agent(s)3Diagnosed prior to 1972:
Potential exposure toblood/serum products prior toinitiation of Hepatitis B
screening of blood supply(1972 in the United States –dates may differ in othercountries)

Potential
Late Effects
Chronic Hepatitis B

Info Link: Since the vast
majority of patients received
some type of blood productduring childhood cancer
treatment, screening based ondate of diagnosis/treatment isrecommended unless there isabsolute 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
Host Factors
Living in hyperendemic area
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

HighestRisk Factors

Periodic
Evaluation

Host Factors
Chronic immunosuppression

SCREENING
Hepatitis B surface antigen (HBsAg)
Hepatitis B core antibody (anti HBc
or HBcAb)(Once in patients who received
treatment for cancer prior to 1972.
Note: Date may vary for international
patients.)

Health Counseling
Further Considerations
Health Links
Hepatitis
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 3 REFERENCES
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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(cont)BLOOD/SERUM PRODUCTS
Sec#
4

Therapeutic
Agent(s)Potential
Late Effects

Diagnosed prior to 1993:
Chronic Hepatitis C
Potential exposure toblood/serum products prior toinitiation of Hepatitis C screening of blood supply (1993 in the
United States – dates may differ
in other countries)
Info Link: Since the vast
majority of patients received
some type of blood productduring childhood cancer
treatment, screening based ondate of diagnosis/treatment isrecommended unless there isabsolute 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,
and allogeneic marrow, cord
blood, or stem cells.

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Host Factors
Living in hyperendemic area

Host Factors
Chronic immunosuppression

Treatment Factors
Blood products before 1993

SCREENING
Hepatitis C antibody(Once in patients who received
treatment for cancer prior to 1993.
Note: Date may vary for international
patients.)

Treatment Factors
Blood products prior to 1986
(when surrogate screening ofblood donors with ALT was iniHepatitis C PCR (to establish chronic
tiated and donors with selfinfection)
reported high-risk behaviors(Once in patients with positive Hepatitis
were deferred)
C antibody)

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

Health Counseling
Further Considerations
Health Links
Hepatitis
Considerations for Further Testing and Intervention
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.

SYSTEM = Immune
SCORE = 1

SECTION 4 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.
Recommendations for prevention and control of hepatitis C virus (HCV) and HCV-related disease. Atlanta, GA: Centers for Disease Control and Prevention; October 16, 1998 1998. 47 (RR-19).
Cesaro S, Petris MG, Rossetti F, et al. Chronic hepatitis C virus infection after treatment for pediatric malignancy. Blood. Aug 1 1997;90(3):1315-1320.
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.
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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(cont)BLOOD/SERUM PRODUCTS
Sec#

Therapeutic
Agent(s)5Diagnosed between 1977
and 1985:
Potential exposure toblood/serum products prior toinitiation of HIV screening ofblood supply (between 1977
and 1985 in the United States– dates may differ in othercountries)

Potential
Late Effects
HIV infection

Info Link: Since the vast
majority of patients received
some type of blood productduring childhood cancer
treatment, screening based ondate of diagnosis/treatment isrecommended unless there isabsolute 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,
and allogeneic 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

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SCREENING
HIV 1 & 2 antibodies(Once in patients who received
treatment for cancer between 1977
and 1985. Note: Dates may vary forinternational patients.)

CounselingStandard counseling regarding safe sex, universal precautions,and high-risk behaviors that exacerbate risk
Considerations for Further Testing and Intervention
Infectious disease consultation for patients with chronic
infection.

SYSTEM = Immune
SCORE = 1

SECTION 5 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.

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ANY CHEMOTHERAPYCHEMOTHERAPY
Sec#
6

Therapeutic
Agent(s)Any Chemotherapy

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

Risk
Factors
Host Factors
Any patient who had not
developed permanent dentition
at time of cancer therapy
Treatment Factors
Any radiation treatment involving
the oral cavity or salivary glands

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

Periodic
Evaluation
PHYSICAL
Oral exam(Yearly)

SCREENING
Dental exam and cleaning(Every six months)

Health Counseling
Further Considerations
Health Links
Dental Health
Considerations for Further Testing and Intervention
Regular dental care including fluoride applications. Baseline
panorex prior to dental procedures to evaluate root development.

SYSTEM = Dental
SCORE = 1

SECTION 6 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.
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, Bowman LC, Santana VM. Dental abnormalities in children treated for neuroblastoma. Med Pediatr Oncol. Jan 1998;30(1):22-27.
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.
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.

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ALKYLATING AGENTS

CHEMOTHERAPY
Sec#(Male)

7

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

Potential
Late Effects
Gonadal dysfunction(testicular)
Delayed/arrested puberty
Hypogonadism
Oligospermia
Azoospermia
Infertility

HEAVY METALS
Carboplatin
Cisplatin

NON-CLASSICAL ALKYLATORS
Dacarbazine (DTIC)
Temozolomide

Risk
Factors
Treatment Factors
Higher cumulative doses ofalkylators or combinations ofalkylators
Combined with radiation to:- Abdomen/pelvis- Testes- Brain, cranium(neuroendocrine axis)
Health Behaviors
Smoking
Info Link
Doses that cause gonadal
dysfunction show individual
variation. Germ cell function(spermatogenesis) is impaired atlower doses compared to Leydig
cell (testosterone production)function. Prepubertal status does
not protect from gonadal injury inmales.

HighestRisk Factors
Host Factors
Male gender
Treatment Factors
MOPP ≥ 3 cycles
Busulfan ≥ 600 mg/m2
Cyclophosphamide cumulative
dose ≥ 7.5 gm/m2 or as
conditioning for HCT
Any alkylators combined with:- Testicular radiation- Pelvic radiation- TBI

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction(Yearly)
PHYSICAL
Tanner stage
Testicular volume by Prader
orchidometry(Yearly until sexually mature)
SCREENING
FSH
LH
Testosterone(Baseline at age 14 and as clinicallyindicated in patients with delayed
puberty and/or clinical signs andsymptoms of testosterone deficiency)
Semen analysis(As requested by patient and forevaluation of infertility. Periodic
evaluation over time is recommended
as resumption of spermatogenesis canoccur up to 10 years post therapy)

Health Counseling
Further Considerations
Health Links
Male Health Issues
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 there istremendous individual variability in gonadal toxicity after
exposure to alkylating agents. Recovery of fertility may occur
years after therapy.
Considerations for Further Testing and Intervention
Bone density evaluation for osteopenia/osteoporosis in
hypogonadal patients. Refer to endocrinologist for delayed
puberty or persistently abnormal hormone levels. Hormonal
replacement therapy for hypogonadal patients. Reproductive
endocrinology/urology referral for infertility evaluation andconsultation regarding assisted reproductive technologies.

SYSTEM = Male reproductive
SCORE =
Alkylating Agents: 1
Heavy Metals: 2A
Non-Classical Alkylators: 2A

SECTION 7 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.
Gerl A, Muhlbayer D, Hansmann G, Mraz W, Hiddemann W. The impact of chemotherapy on Leydig cell function in long term survivors of germ cell tumors. Cancer. Apr 1 2001;91(7):1297-1303.
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.
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.
Somali M, Mpatakoias V, Avramides A, et al. Function of the hypothalamic-pituitary-gonadal axis in long-term survivors of hematopoietic stem cell transplantation for hematological diseases. Gynecol Endocrinol.
Jul 2005;21(1):18-26.

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ALKYLATING AGENTS (cont)CHEMOTHERAPYSec#(Female)7

Therapeutic
Agent(s)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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

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

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

HISTORY
Pubertal (onset, tempo)
Menstrual/pregnancy history
Sexual function (vaginal dryness,
libido)Medication use impacting sexualfunction(Yearly)

Health Behaviors
Smoking
HEAVY METALS
Carboplatin
Cisplatin

NON-CLASSICAL ALKYLATORS
Dacarbazine (DTIC)
Temozolomide

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

PHYSICAL
Tanner stage(Yearly until sexually mature)

SCREENING
FSH
LH
Estradiol(Baseline at age 13 and as clinicallyindicated in patients with delayed
puberty, irregular menses, primary or
secondary amenorrhea, and/or clinicalsigns and symptoms of estrogen
deficiency)

Health Counseling
Further Considerations
Health Links
Female Health Issues
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 ofearly menopause to be cautious about delaying childbearing.
Counsel regarding the need for contraception, since there istremendous individual variability in gonadal toxicity after exposure
to alkylating agents. Recovery of fertility may occur years after
therapy.
Considerations for Further Testing and Intervention
Bone density evaluation for osteopenia/osteoporosis in
hypogonadal patients. 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 2months off hormonal replacement in women with ovarian
failure to assess ovarian recovery.
SYSTEM = Female reproductive
SCORE =
Alkylating Agents: 1
Heavy Metals: 2A
Non-Classical Alkylators: 2A

SECTION 7 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.
KMuller 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.
Teinturier C, Hartmann O, Valteau-Couanet D, Benhamou E, Bougneres PF. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone
Marrow Transplant. Nov 1998;22(10):989-994.

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ALKYLATING AGENTS (cont)CHEMOTHERAPY
Sec#
8Therapeutic
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

Risk
Factors
Treatment Factors
Less than 10 years since
exposure to agent
Higher cumulative alkylator doseor combination of alkylators
Note: Melphalan andmechlorethamine are morepotent leukemogens thancyclophosphamide
Medical Conditions
Splenectomy (conflicting
evidence)

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

HISTORY
Fatigue
Bleeding
Easy bruising(Yearly, up to 10 years after exposure toagent)

Health Links
Reducing the Risk of Second Cancers

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

Considerations for Further Testing and Intervention
Bone marrow exam as clinically indicatedCounselingCounsel to promptly report fatigue, pallor, petechiae, or bonepain.

SYSTEM = SMN
SCREENING
CBC/differential(Yearly, up to 10 years after exposure toagent)SCORE =
Alkylating Agents: 1
Heavy Metals: 2A
Non-Classical Alkylators: 2A

SECTION 8 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, 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.
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.
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.
Meadows AT, Obringer AC, Marrero O, et al. Second malignant neoplasms following childhood Hodgkin's disease: treatment and splenectomy as risk factors. Med Pediatr Oncol. 1989;17(6):477-484.
Miller JS, Arthur DC, Litz CE, Neglia JP, Miller WJ, Weisdorf DJ. Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy. Blood.
Jun 15 1994;83(12):3780-3786.
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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ALKYLATING AGENTS (cont)CHEMOTHERAPYSec#
9Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan
Carmustine (BCNU)
Lomustine (CCNU)

Potential
Late Effects
Pulmonary fibrosis

Risk
Factors
Treatment Factors
Higher cumulative doses
Combined with bleomycin
Medical Conditions
Atopic history
Health Behaviors
Smoking

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

Periodic
Evaluation
HISTORY
Cough
SOB
DOE
Wheezing(Yearly)

PHYSICAL
Pulmonary exam
(Yearly)

SCREENING
Chest x-ray
PFTs (including DLCO and spirometry)(Baseline at entry into long-term followup. Repeat as clinically indicated inpatients with abnormal results orprogressive pulmonary dysfunction.)

Health Counseling
Further Considerations
Health Links
Pulmonary HealthResources
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 diving medicine specialist.
Considerations for Further Testing and Intervention
In patients with abnormal PFTs and/or CXR, consider repeat
evaluation prior to general anesthesia. Pulmonary consultation
for symptomatic pulmonary dysfunction. Influenza andpneumococcal vaccines.

SYSTEM = Pulmonary
SCORE = 1

SECTION 9 REFERENCES
Ginsberg SJ, Comis RL. The pulmonary toxicity of antineoplastic agents. Semin Oncol. Mar 1982;9(1):34-51.
Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol. Oct 1992;19(5):508-520.
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. Personalcommunication to Landier W, Bhatia S Aug 23, 2002.

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ALKYLATING AGENTS (cont)CHEMOTHERAPY
Sec
#
10

Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan

Potential
Late Effects
Cataracts

Risk
Factors

HighestRisk Factors

Treatment Factors
Combined with corticosteroids

Treatment Factors
Combined with cranial, orbital,or eye radiation
TBI
Longer interval sincetreatment

Periodic
Evaluation
HISTORY
Visual difficulties(Yearly)

PHYSICAL
Eye exam (visual acuity, funduscopic
exam for lens opacity)(Yearly)

Health 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 10 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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ALKYLATING AGENTS (cont)CHEMOTHERAPY
Sec
#
11

Therapeutic
Agent(s)ALKYLATING AGENTS
Cyclophosphamide
Ifosfamide

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

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
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream(Yearly)

SCREENING
Urinalysis(Yearly)

Health Counseling
Further Considerations
Health Links
Bladder HealthCounselingCounsel to promptly report dysuria or gross hematuria
Considerations for Further Testing and Intervention
Urine culture, spot urine calcium/creatinine ratio, andultrasound of 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 patientswith culture negative macroscopic hematuria.

SYSTEM = Urinary
SCORE = 1

SECTION 11 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.
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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ALKYLATING AGENTS (cont)CHEMOTHERAPY
Sec
#
12

Therapeutic
Agent(s)ALKYLATING AGENTS
Cyclophosphamide

Potential
Late Effects
Bladder malignancy

Risk
Factors
Treatment Factors
Combined with pelvic radiation
Health Behaviors
Alcohol use
Smoking

HighestRisk Factors

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream(Yearly)

SCREENING
Urinalysis(Yearly)

Health Counseling
Further Considerations
Health Links
Bladder HealthCounselingCounsel to promptly report dysuria or gross hematuria.
Considerations for Further Testing and Intervention
Urine culture, spot urine calcium/creatinine ratio, and ultrasound of 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 patientswith culture negative macroscopic hematuria.

SYSTEM = SMNSCORE = 2A

SECTION 12 REFERENCES
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.
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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ALKYLATING AGENTS (cont)CHEMOTHERAPY
Sec
#
13

Therapeutic
Agent(s)ALKYLATING AGENTS
Ifosfamide

Potential
Late Effects
Renal toxicity
Glomerular toxicity
Tubular toxicity(renal tubular acidosis,
Fanconi's syndrome,
hypophosphatemic rickets)

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Host Factors
Younger age at treatment
MononephricHost Factors
Age < 5 years at time oftreatment

PHYSICAL
Blood pressure(Yearly)

Treatment Factors
Higher cumulative dose
Combined with other nephrotoxic
agents, such as:- Cisplatin- Carboplatin- Aminoglycosides- Amphotericin- Immunosuppressants- Methotrexate- Radiation impacting thekidneyTreatment Factors
Ifosfamide dose ≥60 grams/m2 SCREENING
Renal radiation dose ≥ 15 Gy
BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4(Baseline at entry into long-term followup. If abnormal, repeat as clinicallyindicated.)

Health Counseling
Further Considerations
Health Links
Kidney HealthSee also: Single Kidney Health
Considerations 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 = 1

Urinalysis(Yearly)

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

SECTION 13 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, Sharkey IM, Pearson AD, Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol. Jan 1993;11(1):173-190.
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):1636-1645.
Skinner R. Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol. Sep 2003;41(3):190-197.

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Therapeutic
Agent(s)14

HEAVY METALS
Carboplatin(in myeloablative doses only)
Cisplatin

Potential
Late Effects
Ototoxicity
Sensorineural hearing loss
Tinnitus
VertigoInfo Link: Patients who
received carboplatin in nonmyeloablative doses do notappear to be at risk for clinicallysignificant ototoxicity based on
results of currently available
studies.

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
x 5 days per course)
Cisplatin administered after
cranial/ear radiation
Carboplatin conditioningfor HCT
Radiation involving ear≥ 30 Gy

Medical Conditions
Chronic otitis
Cerumen impaction
Renal dysfunction

Periodic
Evaluation
HISTORY
Hearing difficulties(with/without background noise)
Tinnitus
Vertigo(Yearly)

Health Counseling
Further Considerations
Health Links
Hearing Loss
Educational Issues

Considerations for Further Testing and Intervention
Audiology consultation for amplification in patients with
progressive hearing loss. Speech and language therapy for
PHYSICAL
children with hearing loss. Otolaryngology consultation in
Otoscopic exam
patients with chronic infection, cerumen impaction, or other(Yearly)
anatomical problems exacerbating or contributing to hearing
loss. Refer patients with auditory deficits to school liaison in
SCREENING
community or cancer center (psychologist, social worker,
Complete pure tone audiogram orschool counselor) to facilitate provision of educational
brainstem auditory evoked response resources. Consider specific needs and/or preferential[BAER, ABR]
classroom seating, FM amplification system, and other(Baseline at entry into long-term follow- educational assistance as indicated.
up. If hearing loss is detected, test atleast yearly, or as recommended byaudiologist. For patients who also
SYSTEM = Auditory
received cranial/ear radiation, test yearly after completion of therapy for 5
SCORE = 1
years [for patients <10 years old, continue yearly until age 10], then every 5
years. If clinical suspicion of hearing
loss at any time, test as clinically indicated. If audiogram is inconclusive or
unevaluable, refer to audiologist forconsideration of electrophysiologic testing e.g., otoacoustic emissions [OAEs]. )Info Link:
Complete pure tone audiogram should
include testing of both ears:(1) Air conduction from 250 to 8000 Hz(2) Bone conduction if air conduction
thresholds exceed bone by 15dB at any
frequency(3) Speech discrimination evaluation.
OAEs measure outer hair cell function
only. Because carboplatin selectively
damages inner hair cells, patientstreated with carboplatin should not be
evaluated with OAEs.

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Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 14 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.
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 in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys. Jan 15 2000;46(2):269-279.
Landier W, Merchant T. Adverse effects of cancer treatment on hearing. 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; 2005:109-123.
Macdonald MR, Harrison RV, Wake M, Bliss B, Macdonald RE. Ototoxicity of carboplatin: comparing animal and clinical models at the Hospital for Sick Children. J Otolaryngol. Jun 1994;23(3):151-159.
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.
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.
Shearer PD. Hearing impairment In: Wallace H, Green D, eds. Late Effects of Childhood Cancer. London: Arnold; 2004: 49-54.

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#
15

Therapeutic
Agent(s)HEAVY METALS
Carboplatin
Cisplatin

Potential
Late Effects
Peripheral sensory
neuropathy
Info Link: Neuropathy
presents as persistent effectafter therapy and is typicallynot late in onset

Risk
Factors

HighestRisk Factors

Treatment Factors
Combined with:- Vincristine- Taxanes- Gemcitabine

Treatment Factors
Cumulative cisplatin dose
≥ 300 mg/m2

Periodic
Evaluation
HISTORY
Peripheral neuropathy(Yearly until 2 to 3 years after therapy.
Monitor yearly if symptoms persist.)

PHYSICAL
Neurologic exam
(Yearly until 2 to 3 years after therapy.
Monitor yearly if symptoms persist.)

Health Counseling
Further Considerations
Health Links
Peripheral Neuropathy
Considerations for Further Testing and Intervention
Physical therapy referral for patients with symptomatic
neuropathy. Physical and occupational therapy assessment ofhand function. Consider treatment with agent effective forneuropathic pain (e.g., gabapentin or amitriptyline).

SYSTEM = PNSSCORE = 2A

SECTION 15 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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16

Therapeutic
Agent(s)HEAVY METALS
Carboplatin
Cisplatin

Potential
Late Effects
Renal toxicity
Glomerular injury
Tubular injury
Renal insufficiency

Risk
Factors
Host Factors
MononephricTreatment Factors
Combined with other nephrotoxic
agents such as:- Ifosfamide- 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
PHYSICAL
Blood pressure(Yearly)

SCREENING
BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4(Baseline at entry into long-term
follow-up. If abnormal, repeat asclinically indicated.)

Urinalysis(Yearly)

Health Counseling
Further Considerations
Health Links
Kidney HealthSee also: Single Kidney HealthCounseling
In patients with salt-wasting tubular dysfunction, educate that
low magnesium levels potentiate coronary atherosclerosis
Considerations 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 = 1

SECTION 16 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.
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):1441-1444.

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17

Therapeutic
Agent(s)HEAVY METALS
Carboplatin
Cisplatin

Potential
Late Effects
Dyslipidemia

Risk
Factors
Host Factors
Family history of dyslipidemia
Medical Conditions
Overweight/Obesity

HighestRisk Factors

Periodic
Evaluation
SCREENING
Fasting lipid profile(Baseline at entry into long-term followup, then as per United States
Preventive Task ForceRecommendations: www.ahrq.gov/clinic/prevenix.htm)

Health Counseling
Further Considerations
Health Links
Diet and Physical Activity
Considerations for Further Testing and Intervention
Counsel regarding lipid lowering strategies including diet, exercise, and weight loss in patients with dyslipidemia. Consider
pharmacologic therapy (e.g., statins) in patients with dyslipidemia.

SYSTEM = Cardiovascular
SCORE = 2B

SECTION 17 REFERENCES
Ellis PA, Fitzharris BM, George PM, Robinson BA, Atkinson CH, Colls BM. Fasting plasma lipid measurements following cisplatin chemotherapy in patients with germ cell tumors. J Clin Oncol.
Oct 1992;10(10):1609-1614.
Gietema JA, Meinardi MT, Messerschmidt J, et al. Circulating plasma platinum more than 10 years after cisplatin treatment for testicular cancer. Lancet. Mar 25 2000;355(9209):1075-1076.
Meinardi MT, Gietema JA, van der Graaf WT, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol. Apr 2000;18(8):1725-1732.
Raghavan D, Cox K, Childs A, Grygiel J, Sullivan D. Hypercholesterolemia after chemotherapy for testis cancer. J Clin Oncol. Sep 1992;10(9):1386-1389

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Therapeutic
Agent(s)18

ANTIMETABOLITES
Cytarabine (high dose IV)

Info Link: High-dose IV isdefined as any single dose
≥ 1000 mg/m2.

Potential
Late Effects

Risk
Factors

Neurocognitive deficits
Functional deficits in:- Executive function(planning andorganization)- 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

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

Info Link: Neurocognitive
deficits in survivors ofleukemia and lymphoma are
more frequently related to
information processing (e.g.,learning disability).
Neurocognitive deficits in brain
tumor survivors treated withhigher doses of cranial radiation
are more global (significant
decline in IQ). Extent of deficit
depends on age at treatment,
intensity of treatment, andtime since treatment. New
deficits may emerge overtime.

Treatment Factors
In combination with:- Dexamethasone- TBI- Cranial radiation- Methotrexate(IT, IO, high-dose IV)- Longer elapsed time since
therapy
Info Link
Acute toxicity predominates if
administered systemically as asingle agent. May contribute tolate neurotoxicity if combinedwith high dose or intrathecal
methotrexate and/or cranialradiation.

HighestRisk Factors
Host Factors
Age < 3 years old at timeof treatment
Female sex
Premorbid or family historyof learning or attention
problems
Treatment Factors
Radiation dose ≥ 24 Gy
Single fraction TBI (10 Gy)

Periodic
Evaluation
HISTORY
Educational and/or vocational
progress(Yearly)

SCREENING
Referral for formal
neuropsychological evaluation(Baseline at entry into long-term
follow-up, then periodically as clinicallyindicated for patients with evidence ofimpaired educational or vocational
progress)

Health Counseling
Further Considerations
Health Links
Educational Issues
Considerations for Further Testing and Intervention
Formal neuropsychological evaluation to include tests of processing speed, computer-based attention, visual motor integration, memory, comprehension of verbal instructions, verbal fluency, executive function and planning. Refer patients with neurocognitive deficits to school liaison in community or cancer
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 for developmentallydisabled.

SYSTEM = CNSSCORE = 2A

SECTION 18 REFERENCES
Baker WJ, Royer GL, Jr., Weiss RB. Cytarabine and neurologic toxicity. J Clin Oncol. Apr 1991;9(4):679-693.
Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol. Jan-Feb 2005;30(1):65-78.
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.
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)Potential
Late Effects

19

ANTIMETABOLITES
Cytarabine (high dose IV)

Clinicalleukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures

Info Link: High-dose IV isdefined as any single dose
≥ 1000 mg/m2.

Info Link: Clinicalleukoencephalopathy may
present with or without
imaging abnormalities (e.g.,
leukoencephalopathy, cerebral
lacunes, cerebral atrophy,
dystrophic calcifications,mineralizing microangiopathy).
Transient white matter
anomalies may follow
radiotherapy and high-dose
chemotherapy for
medulloblastoma/PNET, may
mimic tumor recurrence, andsignify risk of persistentneurologic sequelae.
Neuroimaging changes do notalways correlate with degreeof cognitive dysfunction.
Prospective studies are needed
to define the dose/effectrelationship of neurotoxic
agents. Note: 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
Combined with:- Methotrexate(IT, IO, high-dose IV)- Dexamethasone- Cranial radiation

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 24 Gy

Periodic
Evaluation
HISTORY
Cognitive, motor, and/or
sensory deficits
Seizures
Other neurologic symptoms(Yearly)

PHYSICAL
Spasticity
AtaxiaDysarthria
Hemiparesis(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Brain MRI, Brain CT with MR angiography as clinicallyindicated; preferred study based on intracranial lesion to beevaluated:- MRI: White matter- Gadolinium-enhanced MRI: Microvascular injury- CT: Calcifications
Neurology consultation and follow-up as clinically indicated.

SYSTEM = CNSSCORE = 2A

SECTION 19 REFERENCES
Baker WJ, Royer GL, Jr., Weiss RB. Cytarabine and neurologic toxicity. J Clin Oncol. Apr 1991;9(4):679-693.
Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol. Jan-Feb 2005;30(1):65-78.
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.
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)Potential
Late Effects

20

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

No known late effects
Info Link: Acute toxicities
predominate, from which the
majority of patients recover
without sequelae.

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations
SYSTEM = N/ASCORE = 1

Info Link: Low-dose IV isdefined as any single dose
< 1000 mg/m2

SECTION 20 REFERENCES
No known late effects

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21

Therapeutic
Agent(s)ANTIMETABOLITES
Mercaptopurine (6MP)
Thioguanine (6TG)

Info Link: Acute hepatotoxicity
reported with thioguanine usedin CCG 1952 (regimens B1 and
B2) for ALL maintenance therapy requires longer follow-up to
determine long-term sequelae.
See COG Website (CCG 1952
protocol page) for updated
advisories.

Potential
Late Effects

Risk
Factors

Hepatic dysfunction
Veno-occlusive disease(VOD)

Medical Conditions
Viral hepatitis
Previous VOD
Siderosis

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

HighestRisk Factors
Medical Conditions
Chronic viral hepatitis

Periodic
Evaluation
PHYSICAL
Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly(Yearly)

SCREENING
ALT
AST
Bilirubin(Baseline at entry into long-term followup. Repeat as clinically indicated.)

Health Counseling
Further Considerations
Health Links
Liver Health
Considerations for Further Testing and Intervention
Prothrombin time for evaluation of hepatic synthetic function inpatients 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 21 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, 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.
Einhorn M, Davidsohn I. Hepatotoxicity of Mercaptopurine. JAMA. Jun 1 1964;188:802-806.
Lichtman SM, Attivissimo L, Goldman IS, Schuster MW, Buchbinder A. Secondary hemochromatosis as a long-term complication of the treatment of hematologic malignancies. Am J Hematol.
Aug 1999;61(4):262-264.
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.
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.

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22

Therapeutic
Agent(s)ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO

Info Link: High-dose IV isdefined as any single dose
≥ 1000 mg/m2.

Potential
Late Effects
Osteopenia
Osteoporosis
Osteopenia is defined asbone mineral density ≥ 1 and< 2.5 SD below mean
Osteoporosis is defined asbone mineral density ≥ 2.5
SD below mean
Info Link: The World HealthOrganization definition of
osteoporosis in adults is basedon 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 ofstandard deviations the BMD
measurement is above or
below the mean. A T-scoreof ≥ 2.5 standard deviations
BELOW the mean isconsistent with a diagnosis ofosteoporosis. T-scores are notappropriate to assess skeletal
health in pediatric patients
who have not achieved peak
adult bone mass. Instead,
pediatric BMD reference data
sets calculate Z-scores basedon age and gender. A Z-scoreis the number of standard
deviations the measurement isabove or below the AGEMATCHED MEAN BMD. There
are no defined standards forreferral or treatment of low
BMD in children.

COG LTFU Guidelines – Page 26

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Host Factors
Both genders are at risk

Host Factors
Older age at time of treatment

Treatment Factors
Corticosteroids
Cranial radiation
HCT/TBI

Treatment Factors
Methotrexate cumulative dose
≥ 40 gm/m2
Prolonged corticosteroid
therapy (e.g., for chronic
GVHD)

SCREENING
Bone density evaluation (DEXA orquantitative CT)(Baseline at entry into long-term followup. Repeat as clinically indicated.)

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

Info Link: The optimal method of
measuring bone health in children iscontroversial. Existing technologies
have limitations. Dual energy x-ray
absorptiometry (DEXA) provides anestimate of total bone mass at a givensite. Quantitative CT provides distinct
measures of trabecular and corticalbone dimension and density.

Health Counseling
Further Considerations
Health Links
Bone HealthResources
National Osteoporosis Foundation Website: www.nof.org
Considerations for Further Testing and Intervention
Nutritional supplements in cases of osteopenia unresponsive to
behavioral and dietary management: Calcium 1000-1500 mg
daily plus RDA for vitamin D. 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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Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 22 REFERENCES
Holzer G, Krepler P, Koschat MA, Grampp S, Dominkus M, Kotz R. Bone mineral density in long-term survivors of highly malignant osteosarcoma. J Bone Joint Surg Br. Mar 2003;85(2):231-237.
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.
Kaste SC, Jones-Wallace D, Rose SR, et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia.
May 2001;15(5):728-734.
Madsen KL, Adams WC, Van Loan MD. Effects of physical activity, body weight and composition, and muscular strength on bone density in young women. Med Sci Sports Exerc. Jan 1998;30(1):114-120.
Mandel K, Atkinson S, Barr RD, Pencharz P. Skeletal morbidity in childhood acute lymphoblastic leukemia. J Clin Oncol. Apr 1 2004;22(7):1215-1221.
Muller HL, Schneider P, Bueb K, et al. Volumetric bone mineral density in patients with childhood craniopharyngioma. Exp Clin Endocrinol Diabetes. May 2003;111(3):168-173.
Nysom K, Holm K, Michaelsen KF, Hertz H, Muller J, Molgaard C. Bone mass after treatment for acute lymphoblastic leukemia in childhood. J Clin Oncol. Dec 1998;16(12):3752-3760.
Schwartz AM, Leonidas JC. Methotrexate osteopathy. Skeletal Radiol. 1984;11(1):13-16.
van der Sluis IM, van den Heuvel-Eibrink MM, Hahlen K, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic
leukemia in childhood. Med Pediatr Oncol. Oct 2000;35(4):415-420.
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.

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Therapeutic
Agent(s)ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO

Potential
Late Effects
Renal toxicity
Info Link: Acute toxicities
predominate, from which the
majority of patients recover
without sequelae

Info Link: High-dose IV isdefined as any single dose
≥ 1000 mg/m2.

Risk
Factors
Host Factors
MononephricTreatment Factors
Combined with other nephrotoxic
agents such as:- Cisplatin/carboplatin- Ifosfamide- Aminoglycosides- Amphotericin- Immunosuppressants- Radiation impacting thekidneyMedical Conditions
Diabetes mellitus
Hypertension
Nephrectomy

HighestRisk Factors
Treatment Factors
Treatment before 1970

Periodic
Evaluation
PHYSICAL
Blood pressure(Yearly)

Health Counseling
Further Considerations
Health Links
Kidney HealthSee also: Single Kidney Health

Considerations for Further Testing and Intervention
SCREENING
Nephrology consultation for patients with hypertension,
BUN
proteinuria, or progressive renal insufficiency
Creatinine
Na, K, Cl, CO2
Ca, Mg, P04
SYSTEM = Urinary(Baseline at entry into long-term followup. If abnormal, repeat as clinically
SCORE = 2A
indicated.)

Urinalysis(Yearly)

SECTION 23 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.
Kreusser W, Herrmann R, Tschope W, Ritz E. Nephrological complications of cancer therapy. Contrib Nephrol. 1982;33:223-238.

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Therapeutic
Agent(s)ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate (low dose IV)
Methotrexate IM
Methotrexate PO

Potential
Late Effects
Hepatic dysfunction
Info Link: Acute toxicities
predominate from which the
majority of patients recover
without sequelae

Info Link: High-dose IV isdefined as any single dose
≥ 1000 mg/m2.

Risk
Factors

HighestRisk Factors

Treatment Factors
Abdominal radiation

Treatment Factors
Treatment before 1970

Medical Conditions
Viral hepatitis

Medical Conditions
Chronic viral hepatitis

Periodic
Evaluation
PHYSICAL
Scleral icterus
Jaundice
Ascites
Hepatomegaly
Splenomegaly(Yearly)

SCREENING
ALT
AST
Bilirubin(Baseline at entry into long-term followup. Repeat as clinically indicated.)

Health Counseling
Further Considerations
Health Links
Liver Health
Considerations for Further Testing and Intervention
Prothrombin time for evaluation of hepatic synthetic function inpatients 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 24 REFERENCES
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.
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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Therapeutic
Agent(s)ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate IO
Methotrexate IT

Info Link: High-dose IV isdefined as any single dose
≥ 1000 mg/m2.

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
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 timeof treatment
Female sex
Premorbid or family history oflearning or attention problems

Treatment Factors
In combination with:- Dexamethasone- TBI- Cranial radiation- Cytarabine (high-dose IV)- Longer elapsed time since
therapy

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

Info Link: Neurocognitive
deficits in survivors ofleukemia and lymphoma are
more frequently related to
information processing (e.g.,learning disability).
Neurocognitive deficits in brain
tumor survivors treated withhigher doses of cranialradiation are more global(significant decline in IQ).
Extent of deficit depends on
age at treatment, intensity oftreatment, and time sincetreatment. New deficits may
emerge over time.

Periodic
Evaluation
HISTORY
Educational and/or vocational
progress(Yearly)

Health Counseling
Further Considerations
Health Links
Educational Issues

Considerations for Further Testing and Intervention
Formal neuropsychological evaluation to include tests ofprocessing speed, computer-based attention, visual motor
SCREENING
integration, memory, comprehension of verbal instructions,
Referral for formal
verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orneuropsychological evaluation(Baseline at entry into long-term follow- cancer center (psychologist, social worker, school counselor) toup, then periodically as clinically indifacilitate acquisition of educational resources and/or socialcated for patients with evidence ofskills training; Consider use of psychotropic medication (e.g.,
impaired educational or vocational
stimulants) or evidence-based rehabilitation training. Caution lower starting dose and assessment of increased sensitivity
progress)when initiating therapy is recommended. Refer to community
services for vocational rehabilitation or for services fordevelopmentally disabled.

SYSTEM = CNSSCORE = 1

SECTION 25 REFERENCES
Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol. Jan-Feb 2005;30(1):65-78.
Espy KA, Moore IM, Kaufmann PM, Kramer JH, Matthay K, Hutter JJ. Chemotherapeutic CNS prophylaxis and neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study.
J Pediatr Psychol. Jan-Feb 2001;26(1):1-9.
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.
Kingma A, Van Dommelen RI, Mooyaart EL, Wilmink JT, Deelman BG, Kamps WA. No major cognitive impairment in young children with acute lymphoblastic leukemia using chemotherapy only: a prospective
longitudinal study. J Pediatr Hematol Oncol. Feb 2002;24(2):106-114.
Langer T, Martus P, Ottensmeier H, Hertzberg H, Beck JD, Meier W. CNS late-effects after ALL therapy in childhood. Part III: neuropsychological performance in long-term survivors of childhood ALL: impairments ofconcentration, attention, and memory. Med Pediatr Oncol. May 2002;38(5):320-328.
Mennes M, Stiers P, Vandenbussche E, et al. Attention and information processing in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. Pediatr Blood Cancer. May 2005;44(5):478-486.
Moleski M. Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol. Oct 2000;15(7):603-630.
Mulhern RK, Palmer SL. Neurocognitive late effects in pediatric cancer. Curr Probl Cancer. Jul-Aug 2003;27(4):177-197.
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.
Waber DP, Carpentieri SC, Klar N, et al. Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol. May-Jun 2000;22(3):206-213.

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26

Therapeutic
Agent(s)ANTIMETABOLITES
Methotrexate (high dose IV)
Methotrexate IO
Methotrexate IT

Info Link: High-dose IV isdefined as any single dose
≥ 1000 mg/m2.

Potential
Late Effects
Clinicalleukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures
Info Link: Clinicalleukoencephalopathy may
present with or without
imaging abnormalities (e.g.,
leukoencephalopathy, cerebral
lacunes, cerebral atrophy,
dystrophic calcifications,mineralizing microangiopathy).
Transient white matter
anomalies may follow
radiotherapy and high-dose
chemotherapy for
medulloblastoma/PNET, may
mimic tumor recurrence, andsignify risk of persistentneurologic sequelae.
Neuroimaging changes do notalways correlate with degreeof cognitive dysfunction.
Prospective studies areneeded to define thedose/effect relationship ofneurotoxic agents. Note: 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
Combined with:- Cytarabine (high-dose IV)- Dexamethasone- Cranial radiation

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 24 Gy

Periodic
Evaluation
HISTORY
Cognitive, motor, and/or
sensory deficits
Seizures
Other neurologic symptoms(Yearly)

PHYSICAL
Spasticity
AtaxiaDysarthria
Hemiparesis(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Brain MRI, Brain CT with MR angiography as clinically indicated;preferred study based on intracranial lesion to be evaluated:- MRI: White matter- Gadolinium-enhanced MRI: Microvascular injury- CT: Calcifications
Neurology consultation and follow-up as clinically indicated

SYSTEM = CNSSCORE = 1

SECTION 26 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 and neuropsychological 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 2000;15(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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Therapeutic
Agent(s)27

ANTHRACYCLINE ANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone*

Potential
Late Effects
Acute myeloid leukemia*Although Mitoxantrone
technically belongs to theanthracenedione class ofanti-tumor antibiotics, it isrelated to the anthracycline
family.

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

HighestRisk Factors

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

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
CounselingCounsel to promptly report fatigue, pallor, petechiae, or bone
pain
Considerations for Further Testing and Intervention
Bone marrow exam as clinically indicated

SYSTEM = SMNSCORE = 1

SCREENING
CBC/differential(Yearly up to 10 years after exposure toagent)SECTION 27 REFERENCES
Felix CA. Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol. May 2001;36(5):525-535.
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 SocieteFrancaise d'Oncologie Pediatrique. J Clin Oncol. Mar 15 2003;21(6):1074-1081.

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Therapeutic
Agent(s)28

ANTHRACYCLINE ANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone*

Potential
Late Effects
Cardiac toxicity
Cardiomyopathy
Arrhythmias
Subclinical left ventricular
dysfunction (systolic
dysfunction as assessedby ECHO or MUGA)*Although Mitoxantrone
technically belongs to theanthracenedione class ofanti-tumor antibiotics, it isrelated to the anthracycline
family and is included here
because of its cardiotoxic
potential.

Info Link: Dose levels
correlating with cardiotoxicity
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
Info Link: Use the following
infections) have beenformulas to convert toanecdotally reported to precipdoxorubicin/daunorubicinitate cardiac decompensation.
isotoxic equivalents prior to
Prospective studies arecalculating total cumulativeneeded to define risk factors.
Note: Pediatric studies ofanthracycline dose.
anthracycline cardiotoxicity
Epirubicin:
Multiply total dose x 0.67
typically describe risks based
Idarubicin:
on combined cumulative
Multiply total dose x 5
doses of daunomycin and
Mitoxantrone:
doxorubicin, assuming an
Multiply total dose x 3.5
equivalent relative
Note: There is a paucity of liter- cardiotoxicity per mg dose.
ature to support isotoxic dose
Idarubicin and mitoxantrone
conversion; however, the above are more cardiotoxic thanconversion factors may be used doxorubicin or daunorubicin on
for convenience in order toa mg per mg dose basis. In
gauge screening frequency.
limited studies, epirubicin has
Clinical judgment should ultisimilar dose equivalency tomately be used to determine
daunomycin and doxorubicin.
indicated screening for individual patients.

Risk
Factors
Treatment Factors
Combined with radiation involving
the heart
Combined with other cardiotoxic
chemotherapy:- Cyclophosphamide
conditioning for HCT- Amsacrine
Medical Conditions
Obesity
Congenital heart disease
Febrile illness
Pregnancy
Health Behaviors
Isometric exercise
Smoking
Drug use (e.g., cocaine, diet pills,
ephedra, mahuang)

HighestRisk Factors
Host Factors
Female sex
Black/of African descent
Younger than age 5 years
at time of treatment
Treatment Factors
Higher cumulative
anthracycline doses:- Patients 18 years or older
at time of treatment:≥ 550 mg/m2- Patients younger than 18
years at time of treatment:≥ 300 mg/m2- Any dose in infant
Chest radiation ≥ 30 Gy
Longer time elapsed sincetreatment

Periodic
Evaluation
HISTORY
SOB
DOE
Orthopnea
Chest pain
Palpitations
If under 25 years:
Abdominal symptoms(nausea, vomiting)(Yearly)
Info Link: Exertional intolerance isuncommon in young patients (< 25years). Abdominal symptoms (nausea,
emesis) may be observed more frequently than exertional dyspnea or
chest pain in young patients.
PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema(Yearly)

SCREENINGECHO or MUGA for evaluation ofsystolic function(Baseline at entry to long-term followup, then periodically, based on age attreatment, history of chest radiationand cumulative anthracycline
dose - see table on next page.)

Health Counseling
Further Considerations
Health Links
Heart HealthCounselingCounsel 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 and should be encouraged for most patients. Intensive
isometric activities (e.g., heavy weight lifting, wrestling) should
generally be avoided. Limited high repetition weight lifting (i.e.,
lifting a lighter weight with ease no more than 15 to 20 times
in a row) is much less stressful to the heart and is more likely
to be safe. Patients who choose to engage in strenuous orvarsity team sports should discuss appropriate guidelines and aplan 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 risk ofisometric exercise program in any high risk patient (defined as
needing screening every 1 or 2 years). Females only:
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 and periodically during pregnancy (especially during
third trimester) and monitoring during labor and delivery due torisk of cardiac failure.

SYSTEM = Cardiovascular
SCORE = 1

EKG (include evaluation of QTc
interval)(Baseline at entry into long-term followup. Repeat as clinically indicated.)

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Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

28

RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM OR MUGA SCAN
Age at Treatment*<1 year old

Chest Radiation

Anthracycline Dose†

Yes

Any
<200 mg/m2≥200 mg/m2

Every year
Every 2 years
Every year

Any<100 mg/m2≥100 to <300 mg/m2≥300 mg/m2

Every year
Every 5 years
Every 2 years
Every year

<300 mg/m2≥300 mg/m2<200 mg/m2≥200 to <300 mg/m2≥300 mg/m2

Every 2 years
Every year
Every 5 years
Every 2 years
Every yearNoYes

1-4 years oldNoYes≥5 years oldNo

Any age with decrease in serial function

Recommended Frequency

Every year

*Age at time of first cardiotoxic therapy (anthracycline or chest irradiation, whichever was given first)†Based on equivalent mg of doxorubicin/daunorubicin

SECTION 28 REFERENCES
Ali MK, Ewer MS, Gibbs HR, Swafford J, Graff KL. Late doxorubicin-associated cardiotoxicity in children. The possible role of intercurrent viral infection. Cancer. Jul 1 1994;74(1):182-188.
Green DM, Hyland A, Chung CS, Zevon MA, Hall BC. Cancer and cardiac mortality among 15-year survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol. Oct 1999;17(10):3207-3215.
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.
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.
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.
Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol. Jan 1 2001;19(1):191-196.
Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Lipshultz SE. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience.
J Clin Oncol. Apr 1997;15(4):1544-1552.
Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med. Jun 29 1995;332(26):1738-1743.
Nysom K, Holm K, Lipsitz SR, et al. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol. Feb 1998;16(2):545-550.
Sorensen K, Levitt G, Bull C, Chessells J, Sullivan I. Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity. J Clin Oncol. Jan 1997;15(1):61-68.

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Therapeutic
Agent(s)ANTI-TUMOR ANTIBIOTICS
Bleomycin

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

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 suchas during general anesthesia
Health Behaviors
Smoking

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
HISTORY
Cough
SOB
DOE
Wheezing(Yearly)

Health Counseling
Further Considerations
Health Links
Pulmonary HealthBleomycin Alert
Resources
Extensive information regarding smoking cessation is available
for patients on the NCI's website: www.smokefree.gov

Counseling
SCUBA diving should be avoided (potential exacerbation of
pulmonary fibrosis as a result of increased oxygen
concentrations associated with underwater pressures). Notify
healthcare providers of history of bleomycin therapy and riskof worsening fibrosis with high oxygen exposure such as during
SCREENING
general anesthesia. Administration of high concentrations of
Chest x-ray
oxygen may result in chronic progressive pulmonary fibrosis.
PFTs (including DLCO and spirometry) Counsel regarding tobacco avoidance/smoking cessation.
(Baseline at entry into long-term followConsiderations for Further Testing and Intervention
up. Repeat as clinically indicated in
In patients with abnormal PFTs and/or CXR, consider repeat
patients with abnormal results orevaluation prior to general anesthesia. Pulmonary consultation
progressive pulmonary dysfunction.)in patients with symptomatic or progressive pulmonary
dysfunction. Influenza and pneumococcal vaccines.
PHYSICAL
Pulmonary exam
(Yearly)

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

SECTION 29 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.
Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol. Oct 1992;19(5):508-520.
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.
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.
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. Personalcommunication to Landier W, Bhatia S Aug 23, 2002.

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Therapeutic
Agent(s)ANTI-TUMOR ANTIBIOTICS
Dactinomycin

Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

No known late effects
Info Link: Dactinomycin has
been associated with acuteveno-occlusive disease, fromwhich the majority of patients
recover without sequelae

SYSTEM = N/ASCORE = 1

SECTION 30 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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Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

Potential
Late Effects
Osteopenia
Osteoporosis
Osteopenia is defined as bonemineral density ≥ 1 and < 2.5
SD below mean
Osteoporosis is defined asbone mineral density ≥ 2.5 SD
below mean
Info Link: The World HealthOrganization definition of
osteoporosis in adults is basedon comparison of a measured
bone mineral density (BMD) of
young adults at peak bone age
and defined as a T-score. A Tscore is the number ofstandard deviations the BMD
measurement is above or
below the mean. A T-score of≥ 2.5 standard deviations
BELOW the mean is consistent
with a diagnosis ofosteoporosis. T-scores are notappropriate to assess skeletal
health in pediatric patients
who have not achieved peak
adult bone mass. Instead,
pediatric BMD reference data
sets calculate Z-scores basedon age and gender. A Z-scoreis the number of standard
deviations the measurement isabove or below the AGEMATCHED MEAN BMD. There
are no defined standards forreferral or treatment of low
BMD in children.

COG LTFU Guidelines – Page 37

Risk
Factors
Host Factors
Both genders are at risk
Treatment Factors
Methotrexate
Cranial 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

HighestRisk Factors

Periodic
Evaluation

SCREENING
Bone density evaluation (DEXA orquantitative CT)(Baseline at entry into long-term followTreatment Factors
Glucocorticoid cumulative dose up. Repeat as clinically indicated.)≥ 9 gm/m2 prednisone
equivalent
Dexamethasone effect is more Info Link: The optimal method of
potent than prednisone
measuring bone health in children iscontroversial. Existing technologies
have limitations. Dual energy x-ray
absorptiometry (DEXA) provides anestimate of total bone mass at a givensite. Quantitative CT provides distinct
measures of trabecular and corticalbone dimension and density.
Host Factors
Older age at time of treatment

Health Counseling
Further Considerations
Health Links
Bone HealthResources
National Osteoporosis Foundation Website: www.nof.org
Considerations for Further Testing and Intervention
Nutritional supplements in cases of osteopenia unresponsive to
behavioral and dietary management: Calcium 1000-1500 mg
daily plus RDA for vitamin D. 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 = 1

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CORTICOSTEROIDS (cont)CHEMOTHERAPY
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 31 REFERENCES
Aisenberg J, Hsieh K, Kalaitzoglou G, et al. Bone mineral density in young adult survivors of childhood cancer. J Pediatr Hematol Oncol. May-Jun 1998;20(3):241-245.
Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition. Int J Cancer Suppl. 1998;11:35-39.
Kaste SC, Chesney RW, Hudson MM, Lustig RH, Rose SR, Carbone LD. Bone mineral status during and after therapy of childhood cancer: an increasing population with multiple risk factors for impaired bone health.
J Bone Miner Res. Dec 1999;14(12):2010-2014.
Kaste SC, Jones-Wallace D, Rose SR, et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia.
May 2001;15(5):728-734.
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.
Mandel K, Atkinson S, Barr RD, Pencharz P. Skeletal morbidity in childhood acute lymphoblastic leukemia. J Clin Oncol. Apr 1 2004;22(7):1215-1221.
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.
Nysom K, Holm K, Michaelsen KF, Hertz H, Muller J, Molgaard C. Bone mass after treatment for acute lymphoblastic leukemia in childhood. J Clin Oncol. Dec 1998;16(12):3752-3760.
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.

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CORTICOSTEROIDS (cont)CHEMOTHERAPY
Sec
#
32

Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

Potential
Late Effects
Osteonecrosis(Avascular Necrosis)
Info Link: Osteonecrosis typically occurs during the acutetreatment phase, may
progress over time or resolve.
Multifocal osteonecrosis issignificantly more common(3:1) than unifocal.

Risk
Factors
Host Factors
Both genders are at risk
Host polymorphisms may confer
increased risk
Treatment Factors
Combined with high-doseradiation to any bone
Dexamethasone effect is morepotent than prednisone

HighestRisk Factors

Periodic
Evaluation

Host Factors
Age ≥ 10 years at timeof treatment

HISTORY
Joint pain
Swelling
Immobility
Limited range of motion(Yearly)

Treatment Factors
Orthovoltage radiation(commonly used before 1970)
due to delivery of greater doseto skin and bones

PHYSICAL
Musculoskeletal exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Osteonecrosis
Considerations 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. Physical therapy evaluation(for non-pharmacologic pain management, range of motion,
strengthening, stretching, functional mobility).

Medical Conditions
Sickle cell disease
SYSTEM = Musculoskeletal
SCORE = 1

SECTION 32 REFERENCES
Arico M, Boccalatte MF, Silvestri D, et al. Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica. Jul 2003;88(7):747-753.
Beltran J, Herman LJ, Burk JM, et al. Femoral head avascular necrosis: MR imaging with clinical-pathologic and radionuclide correlation. Radiology. Jan 1988;166(1 Pt 1):215-220.
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.
Koo KH, Ahn IO, Kim R, et al. Bone marrow edema and associated pain in early stage osteonecrosis of the femoral head: prospective study with serial MR images. Radiology. Dec 1999;213(3):715-722.
Korholz D, Bruder M, Engelbrecht V, Ruther W, Gobel U. Aseptic osteonecrosis in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol. Jul-Aug 1998;15(4):307-315.
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.
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.
Ribeiro RC, Fletcher BD, Kennedy W, et al. Magnetic resonance imaging detection of avascular necrosis of the bone in children receiving intensive prednisone therapy for acute lymphoblastic leukemia
or non-Hodgkin lymphoma. Leukemia. Jun 2001;15(6):891-897.
Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB. Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol. Jun 15 2001;19(12):3066-3072.

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Sec
#
33

Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

Potential
Late Effects
Cataracts

Risk
Factors
Treatment Factors
Combined with:- TBI- Busulfan

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

Periodic
Evaluation
HISTORY
Visual difficulties(Yearly)

PHYSICAL
Eye exam (visual acuity, funduscopic
exam for lens opacity)(Yearly)

Health 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) tofacilitate acquisition of educational resources.

SYSTEM = Ocular
SCORE = 1

SECTION 33 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):344-349.2001;19(12):3066-3072.

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ENZYMESCHEMOTHERAPY
Sec
#
34

Therapeutic
Agent(s)ENZYMES
Asparaginase

Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

No known late effects
Info Link: Acute toxicities
predominate, from which the
majority of patients recover
without sequelae

SYSTEM = N/ASCORE = 1

SECTION 34 REFERENCES
Duval M, Suciu S, Ferster A, et al. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for
Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 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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PLANT ALKALOIDSCHEMOTHERAPY
Sec
#
35

Therapeutic
Agent(s)PLANT ALKALOIDS
Vinblastine
Vincristine

Potential
Late Effects
Peripheral sensory or
motor neuropathy
Areflexia
Weakness
Foot drop
Paresthesias
Info Link: Acute toxicities
most commonly occur andusually resolve prior topatients entering long-term
follow-up. Neuropathy canpersist after treatment and istypically not late in onset.

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Treatment Factors
Combined with platinum
chemotherapy, gemcitabine or
taxanes

Medical Conditions
Charcot-Marie-Tooth disease

HISTORY
Peripheral neuropathy(Yearly, until 2 to 3 years after therapy.
Monitor yearly if symptoms persist.)

Medical Conditions
Anorexia
Severe weight loss

PHYSICAL
Neurologic exam
(Yearly, until 2 to 3 years after therapy;
continue to monitor yearly if symptoms
persist)Health Counseling
Further Considerations
Health Links
Peripheral Neuropathy
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 35 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;77(7):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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PLANT ALKALOIDS (cont)CHEMOTHERAPY
Sec
#
36

Therapeutic
Agent(s)PLANT ALKALOIDS
Vinblastine
Vincristine

Potential
Late Effects
Vasospastic attacks(Raynaud's phenomenon)

Risk
Factors
Health Behaviors
Smoking
Illicit drug use

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

HISTORY
Vasospasms of hands, feet, nose,
lips, cheeks, or earlobes related tostress or cold temperatures(Yearly)

Health Links
Raynaud's Phenomenon

PHYSICAL
Physical exam of affected area
(As Indicated)

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.

CounselingCounsel to wear appropriate protective clothing in cold environments and not to use tobacco or illicit drugs

SYSTEM = Cardiovascular
SCORE = 2A

SECTION 36 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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EPIPODOPHYLLOTOXINSCHEMOTHERAPY
Sec#

Therapeutic
Agent(s)Potential
Late Effects

37

EPIPODOPHYLLOTOXINS
Etoposide (VP16)
Teniposide (VM26)

Acute myeloid leukemia

Info Link: Administration
schedules since approximately
1990 have been modified toreduce the risk of thiscomplication.

Risk
Factors
Medical Conditions
Splenectomy (conflicting
evidence)

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

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

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
CounselingCounsel to promptly report fatigue, pallor, petechiae, or bone
pain
Considerations for Further Testing and Intervention
Bone marrow exam as clinically indicated

SYSTEM = SMNSCORE = 1

SCREENING
CBC/differential(Yearly, up to 10 years after exposure toagent)SECTION 37 REFERENCES
Pui CH. Epipodophyllotoxin-related acute myeloid leukaemia. Lancet. Dec 7 1991;338(8780):1468.
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.
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.

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ALL FIELDS (INCLUDING TBI)RADIATION
Sec#
38

Therapeutic
Agent(s)All Radiation Fields(Including TBI)
Info Link: General factors
influencing radiation toxicity
include daily fraction size,
cumulative dose, age of patient
at irradiation and type ofradiation used. Toxicity may not
be manifest until growth iscompleted or patient ages.

Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Secondary benign ormalignant neoplasm
Occurring in or near radiation
field

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

Treatment Factors
Orthovoltage radiation(commonly used before 1970)
due to delivery of greater doseto skin and bones

PHYSICAL
Inspection and palpation of skin andsoft tissues in irradiated field(s)(Yearly)

Info Link: Patients withbilateral or familial
retinoblastoma (implying agermline mutation) are atincreased risk for developing
second malignant neoplasms

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

SCREENING
Other evaluations based on treatment volumes(See recommendations for specificfields)Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
There is currently a deficiency in the literature regardingwhether or not TBI is a risk factor for the development of breast
cancer. Monitoring for breast cancer in females who received
TBI should be determined on an individual basis.
Surgical and/or oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 38 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, 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.
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.
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.
Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst. Apr 18 2001;93(8):618-629.
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.

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ALL FIELDS (INCLUDING TBI) (cont)

RADIATION
Sec#
39

Therapeutic
Agent(s)All Radiation Fields(Including TBI)

Potential
Late Effects
Dysplastic nevi
Skin cancer
Basal cell carcinoma
Squamous cell carcinoma
Melanoma

Risk
Factors

HighestRisk Factors

Host Factors
Gorlin's syndrome (nevoid basal
cell carcinoma syndrome)

Treatment Factors
Orthovoltage radiation(commonly used before 1970)
due to delivery of greater doseto skin and bones

Periodic
Evaluation
HISTORY
Skin lesions
Changing moles (asymmetry,
bleeding, increasing size,
indistinct borders)(Yearly)

PHYSICAL
Dermatologic exam of irradiatedfields(Yearly)

Health Counseling
Further Considerations
Health Links
Skin Health
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
Dermatology consultation for evaluation and monitoring ofatypical nevi. Oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 39 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.
Cancer Prevention and Early Detection Facts and Figures: American Cancer Society; 2005.
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):1848-1853.
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.

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ALL FIELDS (EXCEPT TBI)RADIATION
Sec#
40

Therapeutic
Agent(s)All Radiation Fields(Except TBI)

Potential
Late Effects
Dermatologic changes
Fibrosis
Telangiectasias
Permanent hair loss
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 before 1970)
due to delivery of greater doseto skin and bones

Periodic
Evaluation
PHYSICAL
Dermatologic exam of irradiatedfields(Yearly)

Health Counseling
Further Considerations
Health Links
Skin Health

SYSTEM = Dermatologic
SCORE = 1

SECTION 40 REFERENCES
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 andAdolescent Cancer: A Multidisciplinary Approach, Second Edition. Heidelberg, Germany: Springer-Verlag; 2005:262-269.

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ALL FIELDS (EXCEPT TBI) (cont)

RADIATION
Sec#
41

Therapeutic
Agent(s)All Radiation Fields(Except TBI)

Potential
Late Effects
Bone malignancies

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

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

Treatment Factors
Radiation dose ≥ 30 Gy
Orthovoltage radiation(commonly used before 1970)
due to delivery of greater doseto skin and bones

HISTORY
Bone pain (especially in irradiatedfield)(Yearly)CounselingCounsel patient to report symptoms promptly (e.g., bone pain,bone mass, persistent fevers)

Treatment Factors
Higher radiation dose
Combined with alkylating agents

PHYSICAL
Palpation of bones in irradiated field(Yearly)

Considerations for Further Testing and Intervention
X-ray or other diagnostic imaging in patients with clinicalsymptoms. Oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 41 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.
Lindor NM, Greene MH. The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst. Jul 15 1998;90(14):1039-1071.
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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POTENTIAL IMPACT TO

RADIATION
Sec#
42

Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
TBI

BRAIN/CRANIUM
Potential
Late Effects
Brain tumor(benign or malignant)

Risk
Factors
Host Factors
Younger age at treatment
Neurofibromatosis
Treatment Factors
Higher radiation doseHighestRisk Factors
Host Factors
Age < 6 years at timeof treatment
Ataxia telangiectasia

Periodic
Evaluation
HISTORY
Headaches
Vomiting
Cognitive, motor or sensory deficits
Seizures and other neurologic
symptoms(Yearly)

PHYSICAL
Neurologic exam
(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Brain 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.

SYSTEM = SMNSCORE = 1

SECTION 42 REFERENCES
Lindor NM, Greene MH. The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst. Jul 15 1998;90(14):1039-1071.
Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst. Apr 18 2001;93(8):618-629.
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.

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RADIATION
Sec#
43

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
TBI

BRAIN/CRANIUM (cont)
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
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
Supratentorial tumor
Premorbid or family history oflearning or attention problems

Treatment Factors
Radiation in combination with:- Dexamethasone- TBI- Methotrexate
Info Link: Neurocognitive(IT, IO, high-dose IV)
deficits in survivors of- Cytarabine (high-dose IV)
leukemia and lymphoma are
Higher radiation dosemore frequently related toLarger radiation field
information processing (e.g.,
Greater cortical volumes
learning disability).
Cranial radiation in
Neurocognitive deficits in brain
combination with TBI
tumor survivors treated withLonger elapsed time since therapy
higher doses of cranialradiation are more global(significant decline in IQ).
Extent of deficit depends on
age at treatment, intensity oftreatment, and time sincetreatment. Note: New deficits
may emerge over time.

Periodic
Evaluation
HISTORY
Educational and/or vocational
progress(Yearly)

SCREENING
Referral for formal neuropsychologicalevaluation(Baseline at entry into long-term followup, then periodically as clinically indicated for patients with evidence ofimpaired educational or vocational
progress)

Health Counseling
Further Considerations
Health Links
Educational Issues
Considerations for Further Testing and Intervention
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 patients withneurocognitive deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) tofacilitate 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.

SYSTEM = CNSSCORE = 1

SECTION 43 REFERENCES
Butler RW, Hill JM, Steinherz PG, Meyers PA, Finlay JL. Neuropsychologic effects of cranial irradiation, intrathecal methotrexate, and systemic methotrexate in childhood cancer. J Clin Oncol. Dec 1994;12(12):2621-2629.
Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol. Jan-Feb 2005;30(1):65-78.
Keene N, Hobbie W, Ruccione K, eds. Childhood Cancer Survivors: A Practical Guide to Your Future. Sebastopol, CA: O'Reilly; 2002.
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.
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.
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;13(10):2490-2496.
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)Cranial

BRAIN/CRANIUM (cont)
Potential
Late Effects
Clinicalleukoencephalopathy
Spasticity
AtaxiaDysarthria
Dysphagia
Hemiparesis
Seizures
Info Link: Clinicalleukoencephalopathy may
present with or without
imaging abnormalities (e.g.,
leukoencephalopathy, cerebral
lacunes, cerebral atrophy,
dystrophic calcifications,mineralizing microangiopathy).
Transient white matter
anomalies may follow
radiotherapy and high-dose
chemotherapy for
medulloblastoma/PNET, may
mimic tumor recurrence, andsignify risk of persistentneurologic sequelae.
Neuroimaging changes do notalways correlate with degree of
cognitive dysfunction.
Prospective studies are needed
to define the dose/effectrelationship of neurotoxic
agents. Note: 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, high-dose 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
HISTORY
Cognitive, motor, and/or
sensory deficits
Seizures
Other neurologic symptoms(Yearly)

PHYSICAL
Spasticity
AtaxiaDysarthria
Hemiparesis(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Brain MRI, Brain CT with MR angiography as clinically indicated;preferred study based on intracranial lesion to be evaluated:- MRI: White matter- Gadolinium-enhanced MRI: Microvascular injury- CT: Calcifications
Neurology consultation and follow-up as clinically indicated

SYSTEM = CNSSCORE = 1

SECTION 44 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 and neuropsychological performance. The German Late Effects Working Group. Med Pediatr Oncol. Jun 1997;28(6):387-400.
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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Therapeutic
Agent(s)≥ 40 Gy to:
CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

BRAIN/CRANIUM (cont)
Potential
Late Effects
Cerebrovascularcomplications
StrokeMoyamoyaOcclusive cerebral
vasculopathy
Info Link: Moyamoya syndrome is the complete
occlusion of one or more of
the three major cerebral
vessels with the developmentof small, immature collateral
vessels, which reflect anattempt to revascularize theischemic portion of the brain.

Risk
Factors
Host Factors
Down syndrome
Treatment Factors
Suprasellar radiation
Medical Conditions
Sickle cell disease
Neurofibromatosis

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 55 Gy

Periodic
Evaluation
HISTORY
Hemiparesis
Hemiplegia
Weakness
Aphasia(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Brain MRI with diffusion-weighted imaging with MRangiography as clinically indicated. Neurology/neurosurgery
consultation and follow-up. Physical and occupational therapy
as clinically indicated. Note: Revascularization procedures arelikely helpful for moyamoya. Aspirin prophylaxis has not yet
been shown to be beneficial for moyamoya or occlusive
cerebral vasculopathy.

PHYSICAL
Neurologic exam
(Yearly)
SYSTEM = CNSSCORE = 1

SECTION 45 REFERENCES
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.
Grenier Y, Tomita T, Marymont MH, Byrd S, Burrowes DM. Late postirradiation occlusive vasculopathy in childhood medulloblastoma. Report of two cases. J Neurosurg. Sep 1998;89(3):460-464.
Kestle JR, Hoffman HJ, Mock AR. Moyamoya phenomenon after radiation for optic glioma. J Neurosurg. Jul 1993;79(1):32-35.
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

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Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

BRAIN/CRANIUM (cont)
Potential
Late Effects
Craniofacial abnormalities

Risk
Factors
Host Factors
Younger age at treatment
Treatment Factors
Higher radiation doseHighestRisk Factors
Host Factors
Age < 5 years at timeof treatment
Treatment Factors
Radiation dose ≥ 30 Gy

Periodic
Evaluation
HISTORY
Psychosocial assessment, withattention to:
Educational and/or vocational
progress
Depression
Anxiety
Post-traumatic stress
Social withdrawal(Yearly)
PHYSICAL
Craniofacial abnormalities(Yearly)

Health Counseling
Further Considerations
Resources
FACES - The National Craniofacial Associationwww.faces-cranio.org
Considerations 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 46 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.

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Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

BRAIN/CRANIUM (cont)
Potential
Late Effects
Chronic sinusitis

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Treatment Factors
Radiation dose to sinuses≥ 30 Gy
Radiomimetic chemotherapy(e.g., doxorubicin, dactinomycin)

HISTORY
Rhinorrhea
Postnasal discharge(Yearly)

Medical Conditions
Atopic history
Hypogammaglobulinemia

PHYSICAL
Nasal exam
Sinuses(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
CT scan of sinuses as clinically indicated. Otolaryngology
consultation as clinically indicated

SYSTEM = Immune
SCORE = 1

SECTION 47 REFERENCES
Ellingwood KE, Million RR. Cancer of the nasal cavity and ethmoid/sphenoid sinuses. Cancer. Apr 1979;43(4):1517-1526.

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Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

BRAIN/CRANIUM (cont)
Potential
Late Effects
OverweightAge 2-20 years:
BMI for age ≥ 85th < 95th percentile
Age ≥ 21 years:
BMI ≥ 25 - 29.9
ObesityAge 2-20 years:
BMI for age≥ 95th percentile
Age ≥ 21 years:
BMI ≥ 30
Info Link:
BMI=wt(kg)/ht(M2)
BMI calculator available
on-line at:
http://nhlbisupport.com/bmi/
Growth charts for patients< 21 years of age available
on-line at:www.cdc.gov/growthcharts

Risk
Factors

HighestRisk Factors

Host Factors
Younger at treatment

Host Factors
Age < 4 years old at timeof treatment
Female sex

Treatment Factors
Higher cranial radiation dose
Combined with corticosteroids
Medical Conditions
Familial dyslipidemia
Growth hormone deficiency
Hypothyroidism

Treatment Factors
Hypothalamic radiation dose
≥ 20 Gy
Medical Conditions
Inability to exercise

Periodic
Evaluation
PHYSICAL
HeightWeightBMI
Blood pressure(Yearly)

SCREENING
Fasting blood glucose
Fasting serum insulin
Fasting lipid profile(Every 2 years in overweight or obese
patients. Every 5 years in patients ofnormal weight. More frequently if
indicated based on patient evaluation.)

Health Counseling
Further Considerations
Health Links
Diet and Physical Activity
CounselingCounsel regarding obesity-related health risks
Considerations for Further Testing and Intervention
Consider evaluation for other co-morbid conditions including
dyslipidemia, hypertension, glucose intolerance, diabetes
mellitus, hyperinsulinism, and insulin resistance. Nutritionalcounseling. Endocrine consultation for patients withdyslipidemia or hyperglycemia.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 48 REFERENCES
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.
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.
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.
Oeffinger KC, Mertens AC, Sklar CA, et al. Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol. Apr 1 2003;21(7):1359-1365.
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.
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.

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Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
TBI

BRAIN/CRANIUM (cont)
Potential
Late Effects
Metabolic syndrome
Info Link: The metabolic
syndrome is a clustering ofcardiovascular risk factors that
may further increase risk for
cardiovascular disease.
Definitions of metabolic
syndrome are evolving, but
generally include a
combination of obesity withinsulin resistance,
dyslipidemia, and elevatedblood pressure. Note: Patients
who received TBI may develop
features of metabolic
syndrome without associatedobesity.

Risk
Factors
Treatment Factors
Surgery in suprasellar region
Prolonged corticosteroid therapy(e.g., for chronic GVHD)
Medical Conditions
Growth hormone deficiency
Hypogonadism

HighestRisk Factors
Host Factors
Obesity
Treatment Factors
Cranial radiation dose ≥ 18 Gy

Periodic
Evaluation
PHYSICAL
HeightWeightBMI
Blood pressure(Yearly)

SCREENING
Fasting blood glucose
Fasting serum insulin
Fasting lipid profile(Every 5 years. More frequently if
indicated based on patient evaluation.)

Health Counseling
Further Considerations
Health Links
Diet and Physical Activity
CounselingCounsel regarding obesity-related health risks
Considerations for Further Testing and Intervention
Consider endocrine consult if insulin resistance/metabolic syndrome is suspected. Nutritional counseling. Cardiology consultation as clinically indicated.

SYSTEM = Endocrine/Metabolic
SCORE = 2A

SECTION 49 REFERENCES
Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. Dec 4 2002;288(21):2709-2716.
Link K, Moell C, Garwicz S, et al. Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood. J Clin Endocrinol Metab. Oct 2004;89(10):5003-5012.
Mohn A, Di Marzio A, Capanna R, Fioritoni G, Chiarelli F. Persistence of impaired pancreatic beta-cell function in children treated for acute lymphoblastic leukaemia. Lancet. Jan 10 2004;363(9403):127-128.
Moschovi M, Trimis G, Apostolakou F, Papassotiriou I, Tzortzatou-Stathopoulou F. Serum lipid alterations in acute lymphoblastic leukemia of childhood. J Pediatr Hematol Oncol. May 2004;26(5):289-293.
Nuver J, Smit AJ, Postma A, Sleijfer DT, Gietema JA. The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures. Cancer Treat Rev. Aug 2002;28(4):195-214.
Oeffinger KC, Buchanan GR, Eshelman DA, et al. Cardiovascular risk factors in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. Oct 2001;23(7):424-430.
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.
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.

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Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
TBI

NEUROENDOCRINE AXIS
Potential
Late Effects
Growth hormone deficiency
Info Link: Growth charts
available on-line atwww.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
TBI ≥ 12 Gy fractionatedHighestRisk Factors
Treatment Factors
Radiation dose ≥ 18 Gy
Pretransplant cranial radiation
TBI given in single fraction

Periodic
Evaluation
HISTORY
Assessment of nutritional status(Every six months until growth iscompleted, then yearly)

Health Counseling
Further Considerations
Health Links
Growth Hormone Deficiency
See also: Hypopituitarism
Resources
www.magicfoundation.org

PHYSICAL
HeightWeightBMI(Every six months until growth iscompleted, then yearly)

Considerations for Further Testing and Intervention
Obtain x-ray for bone age in poorly growing children. Endocrine
consultation for: Height below 3rd percentile on growth chart;
Drop ≥ 2 percentile rankings on growth chart; Growth velocity< 4-5 cm/year during childhood; Lack of pubertal growth spurt.
Evaluate thyroid function in any poorly growing child. Consult
with endocrinologist regarding risks/benefits of adult growthTanner staging(Every six months until sexually mature) hormone replacement therapy. Consider bone density testing inpatients who are growth hormone deficient.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 50 REFERENCES
Brownstein CM, Mertens AC, Mitby PA, et al. Factors that affect final height and change in height standard deviation scores in survivors of childhood cancer treated with growth hormone: a report from the childhood
cancer survivor study. J Clin Endocrinol Metab. Sep 2004;89(9):4422-4427.
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.
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.
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.
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.
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.
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):59-64.
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)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

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
PHYSICAL
HeightWeightTanner stage
Testicular volume by Prader
orchidometry (males only)(Yearly until sexually mature)

SCREENING
FSH
LH
Testosterone (males only)
Estradiol (females only)(As clinically indicated in patients withsigns of accelerated pubertal
progression and growth)

Health Counseling
Further Considerations
Health Links
Precocious Puberty
Resources
www.magicfoundation.org
Considerations for Further Testing and Intervention
Obtain x-ray for bone age in rapidly growing children.
Endocrine consultation for accelerated puberty (puberty ingirl < 8 years old or boy < 9 years old).

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 51 REFERENCES
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. Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am. Apr 1997;44(2):489-503.
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)≥ 40 Gy to:
CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects
Hyperprolactinemia

Risk
Factors

HighestRisk Factors

Treatment Factors
Higher radiation dose
Surgery or tumor in
hypothalamic area

Treatment Factors
Radiation dose ≥ 50 Gy

Periodic
Evaluation
HISTORY
Galactorrhea
Decreased libido (males)
Menstrual history (females)(Yearly)

SCREENING
Prolactin level(Males with galactorrhea or decreased
libido; Females with galactorrhea or
amenorrhea)

Health Counseling
Further Considerations
Health Links
Hyperprolactinemia
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 (or amenorrhea infemales).

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 52 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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Therapeutic
Agent(s)≥ 40 Gy to:
CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects

Risk
Factors

Central hypothyroidism

Treatment Factors
Higher radiation dose

Info Link: Central hypothyroidism includes thyroidreleasing and thyroid-stimulating hormone deficiency

HighestRisk Factors

Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed mood(Yearly; Consider more frequent
screening during periods of rapid
growth)PHYSICAL
HeightWeightHair
Skin
Thyroid exam
(Yearly; Consider more frequent
screening during periods of rapid
growth)Health Counseling
Further Considerations
Health Links
Thyroid Problems
See also: Hypopituitarism
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
Consider TSH surge testing. 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 53 REFERENCES
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.
Rose SR, Lustig RH, Pitukcheewanont P, et al. Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. J Clin Endocrinol Metab. Dec 1999;84(12):4472-4479.
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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Therapeutic
Agent(s)≥ 40 Gy to:
CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects

Risk
Factors

Gonadotropin deficiency

Treatment Factors
Higher radiation dose

Info Link: Gonadotropin
deficiency includes LH andFSH deficiency.

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

MALES:

MALES:HISTORY
Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction(Yearly)

Health Links
Male Health Issues
See also: Hypopituitarism

PHYSICAL
Tanner stage
Testicular volume by Prader
orchdiometry(Yearly until sexually mature)
SCREENING
FSH
LH
Testosterone(Baseline at age 14 and as clinicallyindicated in patients with delayed
puberty and/or clinical signs andsymptoms of 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. Consider bone density testing inpatients who are gonadotropin deficient.

SYSTEM = Male reproductive

Semen analysis(As requested by patient and forevaluation of infertility)
FEMALES:FEMALES:HISTORY
Pubertal (onset, tempo)
Menstrual/pregnancy history
Sexual function (vaginal dryness,
libido)Medication use impacting sexualfunction(Yearly)

Health Links
Female Health Issues
See also: Hypopituitarism

PHYSICAL
Tanner stage(Yearly until sexually mature)

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 in patients
who are gonadotropin deficient.

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

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SCORE = 1

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

SYSTEM = Female reproductive
SCORE = 1

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Therapeutic
Agent(s)NEUROENDOCRINE AXIS (cont)
Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 54 REFERENCES
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.
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.
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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Therapeutic
Agent(s)≥ 40 Gy to:
CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal

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

Periodic
Evaluation
HISTORY
Failure to thrive
Anorexia
Dehydration
Hypoglycemia
Lethargy
Unexplained hypotension(Yearly)

SCREENING
8:00 a.m. serum cortisol(Yearly for at least 15 years after
treatment and as clinically indicated)

Health Counseling
Further Considerations
Health Links
Central Adrenal Insufficiency
See also: Hypopituitarism
Resources
www.magicfoundation.org
CounselingCounsel regarding corticosteroid replacement therapy andstress dosing. Counsel regarding Medical Alert bracelet.
Considerations for Further Testing and Intervention
Endocrine consultation for further evaluation and replacement
steroids

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 55 REFERENCES
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.
Oberfield SE, Nirenberg A, Allen JC, et al. Hypothalamic-pituitary-adrenal function following cranial irradiation. Horm Res. 1997;47(1):9-16.
Rose SR, Danish RK, Kearney NS, et al. ACTH deficiency in childhood cancer survivors. Pediatr Blood Cancer. Feb 7 2005.
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)CranialOrbital/Eye
TBI

EYE
Potential
Late Effects
Cataracts

Info Link: Radiation-related
ocular complications other thancataracts are generally
associated only with orbital/eye
radiation or higher dose cranialradiation. However, patientswith a history of an oculartumor (e.g., retinoblastoma) are
at higher risk for late-onset
ocular complications and should
receive ongoing follow-up by anophthalmologist at least
annually, and more frequently ifclinically indicated.

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

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

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

HISTORY
Visual changes (decreased acuity,
halos, diplopia)(Yearly)

PHYSICAL
Visual acuity
Funduscopic exam to evaluate forlens opacity(Yearly)

Health Counseling
Further Considerations
Health Links
Cataracts
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
SCREENING
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 ocular tumors
who received <30 Gy.)

SCORE = 1

SECTION 56 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.
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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Therapeutic
Agent(s)≥ 30 Gy to:
CranialOrbital/Eye
Info Link: Radiation-related
ocular complications other thancataracts are generally associated only with orbital/eye radiation or higher dose cranial radiation. However, patients with ahistory of an ocular tumor (e.g.,
retinoblastoma) are at higher
risk for late-onset ocular complications and should receive
ongoing follow-up by an ophthalmologist at least annually,
and more frequently if clinicallyindicated.

EYE (cont)
Potential
Late Effects

Risk
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]

Info Link: Reduced visualacuity may be associated withcataracts, retinal damage, andoptic nerve damage.

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

Periodic
Evaluation
HISTORY
Visual changes (decreased acuity,
halos, diplopia)
Dry eye
Persistent eye irritation
Excessive tearing
Light sensitivity
Poor night vision
Painful eye(Yearly)

PHYSICAL
Visual acuity
Funduscopic exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Eye HealthResources
FACES - The National Craniofacial Association website:www.faces-cranio.org
Considerations for Further Testing and Intervention
Consider every six month ophthalmology evaluation for patientswith corneal damage (usually associated with xerophthalmia)
or complex ocular problems. 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
SCREENING
Evaluation by ophthalmologist(Yearly)

SCORE = 1

SECTION 57 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.
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 1 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.
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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Therapeutic
Agent(s)≥ 30 Gy to:
Cranial
Ear/Infratemporal
Nasopharyngeal

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

Sensorineural hearing loss
Tinnitus

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

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

Periodic
Evaluation
HISTORY
Hearing difficulties(with/without background noise)
Tinnitus
Vertigo(Yearly)
PHYSICAL
Otoscopic exam
(Yearly)
SCREENING
Complete pure tone audiogram orbrainstem auditory evoked response[BAER, ABR]
(Yearly after completion of therapy for 5
years [for patients <10 years old,
continue yearly until age 10], thenevery 5 years. If hearing loss is
detected, test at least yearly or asrecommended by audiologist. If clinicalsuspicion of hearing loss at any time,
test as clinically indicated. If audiogramis inconclusive or unevaluable, refer toaudiologist for consideration ofelectrophysiologic testing e.g.,
otoacoustic emissions [OAEs].)

Health Counseling
Further Considerations
Health Links
Hearing Loss
Educational Issues
Considerations for Further Testing and Intervention
Audiology consultation for patients with progressive hearing
loss. Otolaryngology consultation for patients with chronic
infection, cerumen impaction, or other anatomical problems
exacerbating or contributing to hearing loss. Speech andlanguage therapy for children with hearing loss. Refer patientswith auditory deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) tofacilitate provision of educational resources. Consider
specialized evaluation for specific needs and/or preferential
classroom seating, FM amplification system, and othereducational assistance as indicated.

SYSTEM = Auditory
SCORE = 1

Info Link:
Complete pure tone audiogram should
include testing of both ears:(1) Air conduction from 250 to 8000 Hz(2) Bone conduction if air conduction
thresholds exceed bone by 15dB at any
frequency(3) Speech discrimination evaluation.
OAEs measure outer hair cell function
only. Because carboplatin selectively
damages inner hair cells, patientstreated with carboplatin should not be
evaluated with OAEs.

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Therapeutic
Agent(s)EAR (cont)
Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 58 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.
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.
Johannesen TB, Rasmussen K, Winther FO, Halvorsen U, Lote K. Late radiation effects on hearing, vestibular function, and taste in brain tumor patients. Int J Radiat Oncol Biol Phys. May 1 2002;53(1):86-90.
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 in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys. Jan 15 2000;46(2):269-279.
Landier W, Merchant T. Adverse effects of cancer treatment on hearing. 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; 2005:109-123.
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.
Ondrey FG, Greig JR, Herscher L. Radiation dose to otologic structures during head and neck cancer radiation therapy. Laryngoscope. Feb 2000;110(2 Pt 1):217-221.
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.
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.
Shearer PD. Hearing impairment In: Wallace H, Green D, eds. Late Effects of Childhood Cancer. London: Arnold; 2004: 49-54.

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Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle

ORAL CAVITY
Potential
Late Effects

Risk
Factors

HighestRisk Factors

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

Periodic
Evaluation
HISTORY
Xerostomia(Yearly)

Medical Conditions
Chronic GVHDPHYSICAL
Oral exam(Yearly)

SCREENING
Dental exam and cleaning(Every six months)

Health Counseling
Further Considerations
Health Links
Dental Health
Considerations for Further Testing and Intervention
Supportive care with saliva substitutes, moistening agents, andsialogogues (pilocarpine); Regular dental care including fluoride
applications

SYSTEM = Dental
SCORE = 1

SECTION 59 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.
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

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Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

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 (nevoid basal
cell carcinoma syndrome)
Treatment Factors
Higher radiation doseHighestRisk Factors
Host Factors
Age < 5 years at time oftreatment
Treatment Factors
Dose ≥ 10 Gy

Periodic
Evaluation
PHYSICAL
Oral exam(Yearly)

SCREENING
Dental exam and cleaning(Every six months)

Health Counseling
Further Considerations
Health Links
Dental Health
Considerations for Further Testing and Intervention
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.

SYSTEM = Dental
SCORE = 1

SECTION 60 REFERENCES
Goho C. Chemoradiation therapy: effect on dental development. Pediatr Dent. Jan-Feb 1993;15(1):6-12.
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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Therapeutic
Agent(s)≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle

ORAL CAVITY (cont)
Potential
Late Effects
Osteoradionecrosis

Risk
Factors
Treatment Factors
Radiation dose to bone ≥ 45 Gy

HighestRisk Factors
Treatment Factors
Radiation dose to bone
≥ 50 Gy

Periodic
Evaluation
HISTORY
Impaired or delayed healing
following dental work
Persistent jaw pain or swelling
Trismus(As clinically indicated)

PHYSICAL
Impaired wound healing
Jaw swelling
Trismus(As clinically indicated)

Health Counseling
Further Considerations
Health Links
Osteoradionecrosis
Considerations 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

SECTION 61 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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Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

NECK/THYROID
Potential
Late Effects
Thyroid nodules

Risk
Factors
Host Factors
Younger age at treatment
Female sex
Treatment Factors
Higher radiation dose
Thyroid gland directly inradiation field
TBI

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 25 Gy

Periodic
Evaluation
PHYSICAL
Thyroid exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Thyroid 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 = SMNSCORE = 1

SECTION 62 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.
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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Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

NECK/THYROID (cont)
Potential
Late Effects
Thyroid cancer

Risk
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

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Thyroid exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Thyroid Problems
Considerations for Further Testing and Intervention
Ultrasound and FNA for evaluation of palpable nodule(s).
Surgical consultation for resection. Nuclear medicine
consultation for ablation of residual disease. Endocrine
consultation for postoperative medical management.

SYSTEM = SMNSCORE = 1

SECTION 63 REFERENCES
De Groot 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.
Ron E, Saftlas AF. Head and neck radiation carcinogenesis: epidemiologic evidence. Otolaryngol Head Neck Surg. Nov 1996;115(5):403-408.
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.

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64

Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

NECK/THYROID (cont)
Potential
Late Effects
Hypothyroidism

Risk
Factors
Host Factors
Female sex
Treatment Factors
Radiation dose ≥ 10 Gy
Thyroid gland directly inradiation field
TBI

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 20 Gy

Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed mood(Yearly; Consider more frequent
screening during periods of rapid
growth)PHYSICAL
HeightWeightHair
Skin
Thyroid exam
(Yearly; Consider more frequent
screening during periods of rapid
growth)Health Counseling
Further Considerations
Health Links
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.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SCREENING
TSHFree T4(Yearly; Consider more frequent
screening during periods of rapid
growth)SECTION 64 REFERENCES
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.
Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR. Thyroid function after treatment of brain tumors in children. J Pediatr. Nov 1991;119(5):733-737.
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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65

Therapeutic
Agent(s)≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle

NECK/THYROID (cont)
Potential
Late Effects
Hyperthyroidism

Risk
Factors
Treatment Factors
Higher radiation doseHighestRisk Factors

Periodic
Evaluation
HISTORY
Heat intolerance
Tachycardia
Palpitations
Weight loss
Emotional lability
Muscular weakness
Hyperphagia(Yearly)

Health Counseling
Further Considerations
Health Links
Thyroid Problems
Considerations for Further Testing and Intervention
Endocrine consultation for medical management.

SYSTEM = Endocrine/Metabolic
SCORE = 1

PHYSICAL
Eyes
Skin
Thyroid
Cardiac
Neurologic(Yearly)

SCREENING
TSHFree T4(Yearly)

SECTION 65 REFERENCES
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.
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, 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.
Sklar CA, Kim TH, Ramsay NK. Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med. Nov 1982;73(5):688-694.

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Therapeutic
Agent(s)≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle

NECK/THYROID (cont)
Potential
Late Effects
Carotid artery disease

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
HISTORY
Memory impairment(Yearly)

PHYSICAL
Diminished carotid pulses
Carotid bruits
Abnormal neurologic exam
(compromise of blood flow to brain)(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Doppler ultrasound of carotid vessels as clinically indicated.
MRI with diffusion-weighted imaging with MR angiography andcardiovascular 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

SECTION 66 REFERENCES
Grenier Y, Tomita T, Marymont MH, Byrd S, Burrowes DM. Late postirradiation occlusive vasculopathy in childhood medulloblastoma. Report of two cases. J Neurosurg. Sep 1998;89(3):460-464.
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.
Larsen RL, Barber G, Heise CT, August CS. Exercise assessment of cardiac function in children and young adults before and after bone marrow transplantation. Pediatrics. Apr 1992;89(4 Pt 2):722-729.
Liesner RJ, Leiper AD, Hann IM, Chessells JM. Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood. J Clin Oncol. May 1994;12(5):916-924.
Rovelli A, Pezzini C, Silvestri D, Tana F, Galli MA, Uderzo C. Cardiac and respiratory function after bone marrow transplantation in children with leukaemia. Bone Marrow Transplant. Oct 1995;16(4):571-576

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Therapeutic
Agent(s)≥ 40 Gy to:
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle

NECK/THYROID (cont)
Potential
Late Effects
Subclavian artery disease

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Diminished brachial andradial pulses
Pallor of upper extremities
Coolness of skin
Unequal blood pressure(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Doppler ultrasound of subclavian vessels as clinically indicated.
MRI with diffusion-weighted imaging with MR angiography andcardiovascular 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

SECTION 67 REFERENCES
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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Therapeutic
Agent(s)≥ 20 Gy to:
MantleMini-Mantle
Mediastinal
Chest (thorax)
AxillaBREAST
Potential
Late Effects
Breast cancer

Risk
Factors
Host Factors
Family history of breast cancer
Treatment Factors
Higher radiation doseLonger time since radiation(≥ 5 years)
Info Link
There is currently a deficiency inthe literature regarding whether
or not TBI is a risk factor for thedevelopment of breast cancer.
Monitoring of patients who
received TBI should bedetermined on an individual
basis.

HighestRisk Factors
Host Factors
Female gender

Periodic
Evaluation
PHYSICAL
Breast exam
(Yearly beginning at puberty until age
25, then every six months)

SCREENING
Mammogram(Beginning 8 years after radiation or atage 25, whichever occurs last)

Info Link: Mammography is currently
limited in its ability to evaluate thepremenopausal breast. The role of MRI
is evolving for screening of otherpopulations at high risk for breast
cancer (e.g., premenopausal known orlikely carriers of gene mutation of
known penetrance).

Health Counseling
Further Considerations
Health Links
Breast Cancer
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

SECTION 68 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.
Goss PE, Sierra S. Current perspectives on radiation-induced breast cancer. J Clin Oncol. Jan 1998;16(1):338-347.
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.
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.
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.
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)MantleMini-Mantle
Mediastinal
Chest (thorax)
Whole lung
AxillaTBI

BREAST (cont)
Potential
Late Effects
Breast tissue hypoplasia

Risk
Factors
Host Factors
Prepubertal at time ofbreast irradiation

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Breast exam
(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Surgical consultation for breast reconstruction after completionof growth.

Treatment Factors
Higher radiation dose
SYSTEM = Female reproductive
SCORE = 1

SECTION 69 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.
Johnston KA, Vowels MR, Carroll S. Failure to lactate: an unexpected late effect of cranial radiation. Med Pediatr Oncol 2001;37(3):169.
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)MantleMediastinal
Chest (thorax)
Whole lung
TBI

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
Chest radiation combinedwith TBI
Radiation combined with:- Bleomycin- Busulfan- Carmustine (BCNU)- Lomustine (CCNU)- Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)

Medical Conditions
Atopic history
Health Behaviors
Smoking

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 15 Gy
TBI ≥ 6 Gy in single fraction
TBI ≥ 12 Gy fractionated

Periodic
Evaluation
HISTORY
Cough
SOB
DOE
Wheezing(Yearly)

PHYSICAL
Pulmonary exam
(Yearly)

SCREENING
Chest x-ray
PFTs (including DLCO andspirometry)(Baseline at entry into long-term followup. Repeat as clinically indicated inpatients with abnormal results orprogressive pulmonary dysfunction.)

Health Counseling
Further Considerations
Health Links
Pulmonary HealthResources
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 diving medicine specialist.
Considerations for Further Testing and Intervention
In patients with abnormal PFTs and/or CXR, consider repeat
evaluation prior to general anesthesia. Pulmonary consultation
for patients with symptomatic pulmonary dysfunction. Influenza
and Pneumococcal vaccinations.

SYSTEM = Pulmonary
SCORE = 1

SECTION 70 REFERENCES
Hinkle AS, Proukou C, Chen Y. Pulmonary effects of antineoplastic therapy. 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; 2005:161-180.
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.
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. Personalcommunication to Landier W, Bhatia S Aug 23, 2002.

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#
71

HEART

Therapeutic
Agent(s)MantleMediastinal
Chest (thorax)
AxillaSpine (thoracic)
Whole abdomen
All upper abdominal fields

Potential
Late Effects

Risk
Factors

HighestRisk Factors

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

RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM
Age atTreatment*

Radiation Dose

< 5 years old≥ 5 years old

Anthracycline
Dose†

Recommended
Frequency

Any

None
Any

Every 2 years
Every year

<30 Gy≥30 GyNone
None

Every 5 years
Every 2 years

Any< 300 mg/m2≥ 300 mg/m2

Every 2 years
Every year

Any age with serial decrease in function

Every year

*Age at time of first cardiotoxic therapy (anthracycline or chest
irradiation, whichever was given first)†Based on equivalent mg of doxorubicin/daunorubicin

COG LTFU Guidelines – Page 80

Periodic
Evaluation

HISTORY
SOB
DOE
Orthopnea
Chest pain
Palpitations
Treatment Factors
If under 25 years: Abdominal
Radiation dose ≥ 20 Gy to chest Treatment Factors
TBI
Anteriorly-weighted radiation ‘ symptoms (nausea, vomiting)(Yearly)
Combined with radiomimetic
fieldschemotherapy
Lack of subcarinal shielding(e.g., doxorubicin, dactinomycin) Doses ≥ 30 Gy in patients who Info Link: Exertional intolerance is
Combined with other cardiotoxic
have received anthracyclines uncommon in young patients (< 25chemotherapy
years). Abdominal symptoms (nausea,
Doses ≥ 40 Gy in patients- Anthracyclines
emesis) may be observed more
who have not received
frequently than exertional dyspnea or- Cyclophosphamide
anthracyclines
conditioning for HCT
chest pain in young patients.
Longer time since treatment- Amsacrine
PHYSICAL
Cardiac murmur
Medical Conditions
S3, S4Hypertension
Increased P2 soundObesity
Pericardial rub
Dyslipidemia
Rales
Diabetes mellitus
Wheezes
Congenital heart disease
Jugular venous distension
Febrile illness
Peripheral edema
Pregnancy(Yearly)
Premature ovarian failure(untreated)
SCREENING
Fasting glucose and lipid profile(Every 3 to 5 years. If abnormal, refer
Health Behaviors
for ongoing management.)
Smoking
Isometric exercise
EKG (include evaluation of QTc
Drug use (e.g., cocaine,interval)diet pills, ephedra)(Baseline at entry into long-term followup. Repeat as clinically indicated.)

Health Counseling
Further Considerations
Health Links
Heart Health
Diet and Physical Activity
Resources
A downloadable wallet card is available from the AHA website
for patients requiring endocarditis prophylaxis: www.americanheart.org/downloadable/heart/1023826501754walletcard.pdf
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 valvular abnormalities
present. Counsel regarding appropriate exercise. Aerobic
exercise is generally safe and should be encouraged for mostpatients. Intensive isometric activities (e.g., heavy weight lifting,wrestling) should generally be avoided. Limited highrepetition weight lifting (i.e., lifting a lighter weight with easeno more than 15 to 20 times in a row) is much less stressful tothe heart and is more likely to be safe. Patients who choose toengage in strenuous or varsity team sports should discussappropriate guidelines and a plan for ongoing monitoring with acardiologist.

Considerations for Further Testing and Intervention
Cardiology consultation for patients with subclinical abnormalities
on screening 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 laborand delivery due to risk of cardiac failure. Consider
cardiology consultation (5 to 10 years after radiation) toevaluate 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 isometric
ECHO
exercise program in any high-risk patient defined as needing(Baseline at entry into long-term followscreening every 1 or 2 years.
up, then periodically based on age attreatment, radiation dose, andSYSTEM = Cardiovascular
cumulative anthracycline dose see table at left.)
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 71 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.
Eames GM, Crosson J, Steinberger J, et al. Cardiovascular function in children following bone marrow transplant: a cross-sectional study. Bone Marrow Transplant. Jan 1997;19(1):61-66.
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 1 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.
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 Paediatr.
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.

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Therapeutic
Agent(s)≥ 40 Gy to:
Spleen (entire)
Whole abdomen
Left Upper quadrant
Inverted Y

SPLEEN
Potential
Late Effects

Risk
Factors

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

Treatment Factors
Higher radiation dose to entire
spleenHighestRisk Factors

Periodic
Evaluation
PHYSICAL
Physical exam at time of febrileillness to evaluate degree of illness
and potential source of infection(When febrile T ≥ 101ºF)

SCREENING
Blood culture(When febrile T ≥ 101°F)

Health Counseling
Further Considerations
Health Links
Splenic Precautions
Counseling
Medical alert bracelet/card noting functional asplenia; Counsel
to avoid malaria and tick bites if living in or visiting endemicareas
Considerations for Further Testing and Intervention
In patients with T ≥ 101°F (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. Pneumovax booster in patients ≥10 years old at≥ 5 years after previous dose
(AAP-CIDP Recommendations, 2003).

SYSTEM = Immune
SCORE = 1

SECTION 72 REFERENCES
Immunization in special clinical circumstances: asplenic children. In: Pickering LK, ed. Red Book 2003: Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2003.
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.
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.

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73

Therapeutic
Agent(s)≥ 30 Gy to:
Cervical (neck)
Spine (cervical, thoracic)
Supraclavicular
MantleMini-Mantle
Mediastinal
Chest (thorax)
Whole abdomen
All upper abdominal fields

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
Gastroesophageal reflux

Periodic
Evaluation
HISTORY
Dysphagia
Heartburn(Yearly)

Health Counseling
Further Considerations
Health Links
Gastrointestinal Health
Considerations for Further Testing and Intervention
Surgical and/or gastroenterology consultation for symptomaticpatients.

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 73 REFERENCES
Mahboubi S, Silber JH. Radiation-induced esophageal strictures in children with cancer. Eur Radiol. 1997;7(1):119-122.

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74

Therapeutic
Agent(s)≥ 30 Gy to:
Whole abdomen
All upper abdominal fields

GI/HEPATIC SYSTEM (cont)
Potential
Late Effects
Hepatic fibrosis
Cirrhosis

Risk
Factors
Treatment Factors
Higher radiation dose
Medical Conditions
Chronic hepatitis
History of VOD
Health Behaviors
Alcohol use

HighestRisk Factors
Treatment Factors
Dose ≥ 40 Gy to at least
1/3 of liver volume
Dose 20-30 Gy to entire liver

Periodic
Evaluation
PHYSICAL
Jaundice
Spider angiomas
Palmar erythema
Xanthomata
Hepatomegaly
Splenomegaly(Yearly)

SCREENING
ALT
AST
Bilirubin(Baseline at entry into long-term followup. Repeat as clinically indicated.)

Health Counseling
Further Considerations
Health Links
Liver Health
Considerations for Further Testing and Intervention
Prothrombin time for evaluation of hepatic synthetic function inpatients 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

SECTION 74 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.
Jirtle RL, Anscher MS, Alati T. Radiation sensitivity of the liver. Advances Rad Biol. 1990;14:269-311.

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Therapeutic
Agent(s)≥ 30 Gy to:
Whole abdomen
All upper abdominal fields

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
HISTORY
Colicky abdominal pain related tofatty food intake
Excessive flatulence(Yearly and PRN)

PHYSICALRUQ or epigastric tenderness
Positive Murphy's sign(Yearly and PRN)

Health Counseling
Further Considerations
Health Links
Gastrointestinal Health
Considerations for Further Testing and Intervention
Consider gallbladder ultrasound in patients with chronic
abdominal pain

SYSTEM = GI/Hepatic
SCORE = 2B

SECTION 75 REFERENCES
Mahmoud H, Schell M, Pui CH. Cholelithiasis after treatment for childhood cancer. Cancer. Mar 1 1991;67(5):1439-1442.

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76

Therapeutic
Agent(s)≥ 30 Gy to:
Whole abdomen
All upper abdominal fields
PelvicSpine (thoracic, lumbar,
sacral)GI/HEPATIC SYSTEM (cont)
Potential
Late Effects
Bowel obstruction

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Treatment Factors
Higher radiation dose to bowel
Abdominal surgery

Treatment Factors
Radiation dose ≥ 45 Gy(Obstruction may occur inpeople who received lower
doses of abdominal radiation
during childhood)

HISTORY
Abdominal pain
EmesisDistention
Vomiting
Constipation(With clinical symptoms of obstruction)

Info Link
Bowel obstruction is rarely seen
in individuals treated withabdominal radiation who have
not had abdominal surgery

PHYSICAL
Tenderness
Abdominal guarding
Distension(With clinical symptoms of obstruction)

Health Counseling
Further Considerations
Health Links
Gastrointestinal Health
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

SECTION 76 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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77

Therapeutic
Agent(s)≥ 30 Gy to:
Whole abdomen
All upper abdominal fields
PelvicSpine (thoracic, lumbar,
sacral)GI/HEPATIC SYSTEM (cont)
Potential
Late Effects
Chronic enterocolitis
FistulaStrictures

Risk
Factors
Treatment Factors
Higher radiation dose to bowel
Abdominal surgery

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 45 Gy

Periodic
Evaluation
HISTORY
NauseaVomiting
Abdominal pain
Diarrhea(Yearly)

Health Counseling
Further Considerations
Health Links
Gastrointestinal 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

SECTION 77 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.

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Therapeutic
Agent(s)≥ 30 Gy to:
Whole abdomen
All upper abdominal fields
PelvicSpine (thoracic, lumbar,
sacral)GI/HEPATIC SYSTEM (cont)
Potential
Late Effects
Colorectal cancer
Info Link: Reports ofcolorectal cancer in cohorts oflong-term survivors suggestthat radiation likely increases
risk, but the median age of
onset is not as wellestablished as that ofsecondary breast cancer
following chest radiation. The
expert panel agreed that early
onset of screening is likely
beneficial, and that a prudent
course would be to initiate
screening for colorectal cancer
for those at highest risk
(abdominal, pelvic, and/or
spinal radiation ≥ 30 Gy) atage 35, or 10 years post
radiation, whichever occurs
last. Surveillance should bedone via colonoscopy as perrecommendations for
populations at highest risk,
with information from the firstcolonoscopy informing thefrequency of follow-up testing.

Risk
Factors
Host Factors
Current age ≥ 50 years
Treatment Factors
Higher radiation dose to bowel
Higher daily dose fraction
Combined with chemotherapy(especially alkylators)
Medical Conditions
Obesity
Health Behaviors
High fat/low fiber diet

HighestRisk Factors

Periodic
Evaluation

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

SCREENING
Colonoscopy(Every 5 years [minimum] beginning at
10 years after radiation or at age 35
years [whichever occurs last]; more
frequently if indicated based oncolonoscopy results; 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 thefirst colonoscopy will inform frequencyof follow-up testing)

Health Counseling
Further Considerations
Health Links
Colorectal Cancer
Considerations for Further Testing and Intervention
Surgical and/or oncology consultation as needed.

SYSTEM = SMNSCORE = 2A

SECTION 78 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.
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.
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

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79

Therapeutic
Agent(s)Whole abdomen
All upper abdominal fields
TBI

URINARY TRACT
Potential
Late Effects
Renal toxicity
Renal insufficiency
Hypertension

Info Link: Includes all upper
abdominal fields except
Paraaortic

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 other nephrotoxic
agents such as:- Cisplatin- Carboplatin- Ifosfamide- Aminoglycosides- Amphotericin- ImmunosuppressantsHighestRisk Factors
Treatment Factors
Radiation dose ≥ 15 Gy
TBI ≥ 6 Gy in single fraction
TBI ≥ 12 Gy fractionated

Periodic
Evaluation
PHYSICAL
Blood pressure(Yearly)

Health Counseling
Further Considerations
Health Links
Kidney HealthSee also: Single Kidney Health

Considerations for Further Testing and Intervention
SCREENING
Nephrology consultation for patients with hypertension,
BUN
proteinuria, or progressive renal insufficiency
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4(Baseline at entry into long-term followSYSTEM = Urinary
up. If abnormal, repeat as clinicallyindicated.)
SCORE = 1

Urinalysis(Yearly)

Medical Conditions
Diabetes mellitus
Hypertension
Nephrectomy

SECTION 79 REFERENCES
Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys. Mar 30 1995;31(5):1249-1256.
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.
Keane WF, Crosson JT, Staley NA, Anderson WR, Shapiro FL. Radiation-induced renal disease. A clinicopathologic study. Am J Med. Jan 1976;60(1):127-137.
Kumar M, Kedar A, Neiberger RE. Kidney function in long-term pediatric survivors of acute lymphoblastic leukemia following allogeneic bone marrow transplantation. Pediatr Hematol Oncol.
Jul-Aug 1996;13(4):375-379.
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.

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80

Therapeutic
Agent(s)≥ 30 Gy to:
Whole abdomen
PelvicSpine (sacral)

URINARY TRACT (cont)
Potential
Late Effects
Hemorrhagic cystitis

Risk
Factors
Treatment Factors
Higher radiation dose (≥ 30 Gy toentire bladder; ≥ 60 Gy to portionof bladder)HighestRisk Factors
Treatment Factors
Combined withcyclophosphamide and/or
ifosfamide

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream(Yearly)

SCREENING
Urinalysis(Yearly)

Health Counseling
Further Considerations
Health Links
Bladder HealthCounselingCounsel to promptly report dysuria or gross hematuria
Considerations for Further Testing and Intervention
Urine culture, spot urine calcium/creatinine ratio, andultrasound of kidneys and bladder for patients withmicroscopic 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

SECTION 80 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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81

Therapeutic
Agent(s)≥ 30 Gy to:
Whole abdomen
PelvicSpine (sacral)

URINARY TRACT (cont)
Potential
Late Effects
Urinary tract toxicity
Bladder fibrosis
Dysfunctional voiding
Vesicoureteral reflux
Hydronephrosis

Risk
Factors
Treatment Factors
Higher cumulative radiation dose(≥ 45 Gy)
Radiation to entire bladder
Combined with:- Cyclophosphamide- Ifosfamide- Vincristine

HighestRisk Factors

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream(Yearly)

Health Counseling
Further Considerations
Health Links
Bladder Health
Considerations for Further Testing and Intervention
Urologic consultation for patients with incontinence ordysfunctional voiding.

SYSTEM = Urinary
SCREENING
Urinalysis(Yearly)

SCORE = 1

SECTION 81 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.
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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82

Therapeutic
Agent(s)Whole abdomen
PelvicSpine (sacral)

URINARY TRACT (cont)
Potential
Late Effects
Bladder malignancy

Info Link: Applies to sacral
spine at doses ≥ 30 Gy only.

Risk
Factors
Treatment Factors
Radiation to pelvis
Combined with:- Cyclophosphamide- Ifosfamide
Health Behaviors
Alcohol use
Smoking

HighestRisk Factors

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream(Yearly)

SCREENING
Urinalysis(Yearly)

Health Counseling
Further Considerations
Health Links
Bladder HealthCounselingCounsel to promptly report dysuria or gross hematuria
Considerations for Further Testing and Intervention
Urine culture, spot urine calcium/creatinine ratio, andultrasound of 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 82 REFERENCES
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.
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)83

Whole abdomen
PelvicSpine (lumbar, sacral)
TBI(Female)Sec#

Info Link: Applies to all pelvic
fields except iliac/inguinal.
Applies to lumbar and sacral
spine at doses ≥ 25 Gy.

FEMALE REPRODUCTIVE SYSTEM
Potential
Late Effects

Risk
Factors

Uterine vascularinsufficiency(resulting in adverse
pregnancy outcomes, such as
spontaneous abortion,
neonatal death, low-birthweight infant, fetal
malposition, and prematurelabor)

Host Factors
Females with Wilms tumor andassociated müllerian anomalies

Info Link: 10% of girls withWilms tumor have congenitaluterine anomalies.

Treatment Factors
Higher radiation dose to pelvis

HighestRisk Factors
Host Factors
Prepubertal at treatment
Treatment Factors
Radiation dose ≥ 30 Gy
TBI

Periodic
Evaluation
HISTORY
PregnancyChildbirth history(Yearly and as clinically indicated)

Health Counseling
Further Considerations
Health Links
Female Health Issues
Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org
Considerations for Further Testing and Intervention
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 = Female reproductive
SCORE = 2B

SECTION 83 REFERENCES
Blatt J. Pregnancy outcome in long-term survivors of childhood cancer. Med Pediatr Oncol. Jul 1999;33(1):29-33.
Byrne J. Infertility and premature menopause in childhood cancer survivors. Med Pediatr Oncol. Jul 1999;33(1):24-28.
Byrne J, Mulvihill JJ, Connelly RR, et al. Reproductive problems and birth defects in survivors of Wilms' tumor and their relatives. Med Pediatr Oncol. 1988;16(4):233-240.
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. Factors of importance for implantation and problems after treatment for childhood cancer. Med Pediatr Oncol. Jul 1999;33(1):9-14.
Green DM, Peabody EM, Nan B, Peterson S, Kalapurakal JA, Breslow NE. Pregnancy outcome after treatment for Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol.
May 15 2002;20(10):2506-2513.
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)Potential
Late Effects

84

Whole abdomen
PelvicSpine (lumbar, sacral)
TBI

Gonadal dysfunction(ovarian)
Delayed/arrested pubertyPremature menopause
Infertility(Female)Sec#

Info Link: Applies to lumbar
and sacral spine at doses ≥ 25
Gy only.

Risk
Factors
Host Factors
Older age at irradiation
Treatment Factors
Prepubertal female:
Radiation dose ≥10 Gy
Pubertal female:
Radiation dose ≥ 5 Gy
Combined with alkylating agent
chemotherapy
Longer time since treatment

HighestRisk Factors
Treatment Factors
Prepubertal female:
Radiation dose ≥15 Gy
Pubertal female:
Radiation dose ≥10 Gy
Combined with cyclophosphamide conditioning for HCT

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Menstrual/pregnancy history
Sexual function (vaginal dryness,
libido)Medication use impacting sexualfunction(Yearly)
PHYSICAL
Tanner stage(Yearly until sexually mature)
SCREENING
FSH
LH
Estradiol(Baseline at age 13, and as clinicallyindicated in patients with delayed
puberty, irregular menses or primary or
secondary amenorrhea, clinical signs
and symptoms of estrogen deficiency)

Health Counseling
Further Considerations
Health Links
Female Health Issues
Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org
CounselingCounsel regarding the need for contraception, since there istremendous 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
Refer to endocrinologist for delayed/arrested puberty or
persistently abnormal hormone levels. Gynecology or
endocrinology consultation for HRT. Consider evaluation for
conditions exacerbated by hypogonadism (e.g.,
osteopenia/osteoporosis). Reproductive endocrinology
consultation for infertile couples interested in assisted
reproductive technologies.

SYSTEM = Female reproductive
SCORE = 1

SECTION 84 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.
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.
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.
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.
Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. Jul 1999;33(1):2-8.
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.
Waring AB, Wallace WH. Subfertility following treatment for childhood cancer. Hosp Med. Aug 2000;61(8):550-557

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PelvicPotential
Late Effects
Vaginal fibrosis/stenosis(Female)85

Therapeutic
Agent(s)FEMALE REPRODUCTIVE SYSTEM (cont)
Risk
Factors
Host Factors
Vaginal tumor or pelvic tumor
adjacent to vagina
Treatment Factors
Prepubertal female:
Radiation dose ≥ 25 Gy
Postpubertal female:
Radiation dose ≥ 50 Gy

HighestRisk Factors
Treatment Factors
Prepubertal female:
Radiation dose ≥ 35 Gy
Postpubertal female:
Radiation dose ≥ 55 Gy

Periodic
Evaluation
HISTORY
Psychosocial assessment
Dyspareunia
Vulvar pain
Post-coital bleeding
Difficulty with tampon insertion(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Gynecologic consultation for management. Psychologicalconsultation in patients with emotional difficulties.

SYSTEM = Female reproductive
SCORE = 2A

Medical Conditions
Chronic GVHDSECTION 85 REFERENCES
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 rhab
domyosarcoma in children. J Clin Oncol. Nov 1990;8(11):1847-1853.
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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Sec#(Male)

86

Therapeutic
Agent(s)PelvicTesticular
TBI

MALE REPRODUCTIVE SYSTEM
Potential
Late Effects
Gonadal dysfunction(testicular):Germ cell failure
Oligospermia
Azoospermia
Infertility

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Treatment Factors
Radiation dose to testes:- 1 to 3 Gy: Azoospermia may
be reversible- 3 to 6 Gy: Azoospermia
possibly reversible (butunlikely)

Treatment Factors
Radiation dose to testes≥ 6 Gy: Azoospermia likely
permanent

SCREENING
Semen analysis(As requested by patient and forevaluation of infertility. Periodic
evaluation over time is recommended
as resumption of spermatogenesis canoccur up to 10 years post therapy.)

Health Counseling
Further Considerations
Health Links
Male Health Issues
Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org
CounselingCounsel regarding the need for contraception, since there istremendous 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. Testing forInhibin B can be considered in conjunction with FSH as anindicator of germ cell function.

SYSTEM = Male reproductive
SCORE = 1

SECTION 86 REFERENCES
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.
Goldman S, Johnson FL. Effects of chemotherapy and irradiation on the gonads. Endocrinol Metab Clin North Am. Sep 1993;22(3):617-629.
Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am. Dec 1998;27(4):927-943.
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.
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.
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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87

Therapeutic
Agent(s)≥ 20 Gy to:
PelvicTesticular

MALE REPRODUCTIVE SYSTEM (cont)
Potential
Late Effects
Gonadal dysfunction(testicular):
Leydig cell dysfunction
Delayed/arrested puberty
Hypogonadism

Risk
Factors
Treatment Factors
Testicular irradiation combinedwith head/brain irradiation

HighestRisk Factors
Treatment Factors
Combined with:- Alkylating agents- Cyclophosphamide
conditioning for HCT

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction(Yearly)

PHYSICAL
Tanner stage
Testicular volume by Prader
orchdiometry(Yearly until sexually mature)

Health Counseling
Further Considerations
Health Links
Male Health Issues
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. Urology or endocrinology
consultation for HRT. Consider evaluation for conditions
exacerbated by hypogonadism (e.g., osteopenia/osteoporosis).

SYSTEM = Male reproductive
SCREENING
FSH, LH, testosterone(Baseline at age 14, and as clinicallyindicated in patients with delayed
puberty or clinical signs and symptomsof testosterone deficiency)

SCORE = 1

SECTION 87 REFERENCES
Goldman S, Johnson FL. Effects of chemotherapy and irradiation on the gonads. Endocrinol Metab Clin North Am. Sep 1993;22(3):617-629.
Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am. Dec 1998;27(4):927-943.
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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Therapeutic
Agent(s)All neck fields
All chest fields
Whole abdomen
All upper abdominal fields
All extremity fields
PelvicAll spinal fields
Info Link: Applies to spine atdoses ≥ 12 Gy only.

MUSCULOSKELETAL SYSTEM
Potential
Late Effects
Musculoskeletal growth
problems
Hypoplasia
Fibrosis
Reduced or uneven growth
Shortened trunk height(trunk radiation)
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
Epiphysis in treatment field
Dose ≥ 20 Gy
Orthovoltage radiation (commonly used before 1970) due
to delivery of greater dose toskin and bones

Periodic
Evaluation
PHYSICAL
HeightWeight(Yearly)
Sitting height(Yearly for patients who had trunkradiation)
Limb lengths(Yearly for patients who had extremity
radiation)

Health Counseling
Further Considerations
CounselingCounsel regarding increased risk of fractures in weight-bearing
irradiated bones
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

SECTION 88 REFERENCES
Donaldson SS. Pediatric patients: tolerance levels and effects of treatment. In: Vaeth JM, Meyer JL, eds. Frontiers of Radiation Therapy and Oncology. Vol 23. New York, NY: Karger; 1989:390-407.
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.
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. The effects of radiation therapy on bone growth. Radiology. Jan 1975;114(1):155-162.
Probert JC, Parker BR, Kaplan HS. Growth retardation in children after megavoltage irradiation of the spine. Cancer. Sep 1973;32(3):634-639.

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Therapeutic
Agent(s)MantleMini-Mantle
Mediastinal
Whole lung
Chest (thorax)
Whole abdomen
All upper abdominal fields
PelvicSpine (lumbar, sacral,
thoracic)

MUSCULOSKELETAL SYSTEM (cont)
Potential
Late Effects
Scoliosis

Info Link: Applies to spine atdoses ≥ 12 Gy only.

Risk
Factors
Host Factors
Younger age at irradiation
Paraspinal malignancies
Treatment Factors
Hemithoracic or abdominal
radiation
Hemithoracic, abdominal or
spinal surgery
Radiation of only a portion of(rather than whole) vertebral
body

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
PHYSICAL
Spine exam for scoliosis(Yearly until growth completed. May
need more frequent assessment duringpuberty.)

Health Counseling
Further Considerations
Health Links
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

Info Link
With contemporary treatment
approaches, scoliosis is
infrequently seen as aconsequence of radiation unlessthe patient has also undergone
surgery to the hemithorax,
abdomen or spine

SECTION 89 REFERENCES
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 andAdolescent 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.

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Therapeutic
Agent(s)MantleMini-Mantle
Mediastinal
Whole lung
Chest (thorax)
Whole abdomen
All upper abdominal fields
Spine (thoracic)

MUSCULOSKELETAL SYSTEM (cont)
Potential
Late Effects
Kyphosis

Risk
Factors
Host Factors
Younger age at irradiation
Paraspinal malignancies
Neurofibromatosis

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
PHYSICAL
Spine exam for kyphosis(Yearly until growth completed. May
need more frequent assessment duringpuberty.)

Health Counseling
Further Considerations
Health Links
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
Info Link: Applies to thoracic
spine at doses ≥ 30 Gy only.

SCORE = 1

SECTION 90 REFERENCES
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.

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Therapeutic
Agent(s)≥ 40 Gy to:
All neck fields
All chest fields
Whole abdomen
All upper abdominal fields
PelvicAll spinal fields
All extremity fields

MUSCULOSKELETAL SYSTEM (cont)
Potential
Late Effects
Radiation-induced fracture

Risk
Factors
Treatment Factors
History of surgery to cortex
of boneHighestRisk Factors
Treatment Factors
Radiation dose ≥ 50 Gy
to bonePeriodic
Evaluation
PHYSICAL
Pain, swelling, deformity of bone
(As Indicated)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Radiograph of affected bone as clinically indicated. Orthopedic
evaluation as clinically indicated.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 91 REFERENCES
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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RADIATION
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#
38
TBI

Therapeutic
Agent(s)All Radiation Fields(Including TBI)
Info Link: General factors
influencing radiation toxicity
include daily fraction size,
cumulative dose, age of patient
at irradiation and type ofradiation used. Toxicity may not
be manifest until growth iscompleted or patient ages.

Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Secondary benign ormalignant neoplasm
Occurring in or near radiation
field

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

Treatment Factors
Orthovoltage radiation(commonly used before 1970)
due to delivery of greater doseto skin and bones

PHYSICAL
Inspection and palpation of skin andsoft tissues in irradiated field(s)(Yearly)

Info Link: Patients withbilateral or familial
retinoblastoma (implying agermline mutation) are atincreased risk for developing
second malignant neoplasms

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

SCREENING
Other evaluations based on treatment volumes(See recommendations for specificfields)Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
There is currently a deficiency in the literature regardingwhether or not TBI is a risk factor for the development of breast
cancer. Monitoring for breast cancer in females who received
TBI should be determined on an individual basis.
Surgical and/or oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 38 TBI 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, 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.
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.
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.
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.
Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst. Apr 18 2001;93(8):618-629.
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.

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Sec
#
39
TBI

Therapeutic
Agent(s)All Radiation Fields(Including TBI)

Potential
Late Effects
Dysplastic nevi
Skin cancer
Basal cell carcinoma
Squamous cell carcinoma
Melanoma

Risk
Factors

HighestRisk Factors

Host Factors
Gorlin's syndrome (nevoid basal
cell carcinoma syndrome)

Treatment Factors
Orthovoltage radiation(commonly used before 1970)
due to delivery of greater doseto skin and bones

Periodic
Evaluation
HISTORY
Skin lesions
Changing moles (asymmetry,
bleeding, increasing size,
borders)(Yearly)

PHYSICAL
Dermatologic exam of irradiatedfields(Yearly)

Health Counseling
Further Considerations
Health Links
Skin Health
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
Dermatology consultation for evaluation and monitoring ofatypical nevi. Oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 39 TBI 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.
Cancer Prevention and Early Detection Facts and Figures: American Cancer Society; 2005.
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):1848-1853.
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

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Sec
#
42
TBI

Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
TBI

Potential
Late Effects
Brain tumor(benign or malignant)

Risk
Factors
Host Factors
Younger age at treatment
Neurofibromatosis
Treatment Factors
Higher radiation doseHighestRisk Factors
Host Factors
Age < 6 years at timeof treatment
Ataxia telangiectasia

Periodic
Evaluation
HISTORY
Headaches
Vomiting
Cognitive, motor or sensory deficits
Seizures and other neurologic
symptoms(Yearly)

PHYSICAL
Neurologic exam
(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Brain 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.

SYSTEM = SMNSCORE = 1

SECTION 42 TBI 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.
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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43
TBI

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
TBI

Potential
Late Effects

Risk
Factors

Neurocognitive deficits
Functional deficits in:- Executive function(planning and organization)- Sustained attention- Memory (particularly visual,sequencing, temporal
memory)- Processing speed- Visual-motor integration

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 inradiation field

Learning deficits in math andreading (particularly reading
comprehension)
Diminished IQ
Behavioral change

Treatment Factors
Radiation in combination with:- Dexamethasone- TBI- Methotrexate(IT, IO, high-dose 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

Info Link: Neurocognitive
deficits in survivors ofleukemia and lymphoma are
more frequently related to
information processing (e.g.,learning disability).
Neurocognitive deficits in brain
tumor survivors treated withhigher doses of cranialradiation are more global(significant decline in IQ).
Extent of deficit depends on
age at treatment, intensity oftreatment, and time sincetreatment. Note: New deficits
may emerge over time.

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

Periodic
Evaluation
HISTORY
Educational and/or vocational
progress(Yearly)

Health Counseling
Further Considerations
Health Links
Educational Issues

Considerations for Further Testing and Intervention
Formal neuropsychological evaluation to include tests ofprocessing speed, computer-based attention, visual motor
SCREENING
integration, memory, comprehension of verbal instructions,
Referral for formal
verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orneuropsychological evaluation(Baseline at entry into long-term follow- cancer center (psychologist, social worker, school counselor) toup, then periodically as clinicallyfacilitate acquisition of educational resources and/or social
indicated for patients with evidence ofskills training. Consider use of psychotropic medication (e.g.,
impaired educational or vocational
stimulants) or evidence-based rehabilitation training. Caution lower starting dose and assessment of increased sensitivity
progress)when initiating therapy is recommended. Refer to community
services for vocational rehabilitation or for services fordevelopmentally disabled.

SYSTEM = CNSSCORE = 1

SECTION 43 TBI REFERENCES
Chou RH, Wong GB, Kramer JH, et al. Toxicities of total-body irradiation for pediatric bone marrow transplantation. Int J Radiat Oncol Biol Phys. Mar 1 1996;34(4):843-851.
Felder-Puig R, Peters C, Matthes-Martin S, et al. Psychosocial adjustment of pediatric patients after allogeneic stem cell transplantation. Bone Marrow Transplant. Jul 1999;24(1):75-80.
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.
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.
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.

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Sec
#
49
TBI

Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
TBI

Potential
Late Effects
Metabolic syndrome
Info Link: The metabolic
syndrome is a clustering ofcardiovascular risk factors that
may further increase risk for
cardiovascular disease.
Definitions of metabolic
syndrome are evolving, but
generally include a
combination of obesity withinsulin resistance,
dyslipidemia, and elevatedblood pressure. Note: Patients
who received TBI may develop
features of metabolic
syndrome without associatedobesity

Risk
Factors
Treatment Factors
Surgery in suprasellar region
Prolonged corticosteroid therapy(e.g., for chronic GVHD)
Medical Conditions
Growth hormone deficiency
Hypogonadism

HighestRisk Factors
Host Factors
Obesity
Treatment Factors
Cranial radiation dose ≥ 18 Gy

Periodic
Evaluation
PHYSICAL
HeightWeightBMI
Blood pressure(Yearly)

SCREENING
Fasting blood glucose
Fasting serum insulin
Fasting lipid profile(Every 5 years. More frequently if
indicated based on patient evaluation.)

Health Counseling
Further Considerations
Health Links
Diet and Physical Activity
CounselingCounsel regarding obesity-related health risks
Considerations for Further Testing and Intervention
Consider endocrine consult if insulin resistance/metabolic
syndrome is suspected. Nutritional counseling. Cardiology
consultation as clinically indicated.

SYSTEM = Endocrine/Metabolic
SCORE = 2A

SECTION 49 TBI REFERENCES
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.
Smedmyr B, Wibell L, Simonsson B, Oberg G. Impaired glucose tolerance after autologous bone marrow transplantation. Bone Marrow Transplant. Aug 1990;6(2):89-92.
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.
Traggiai C, Stanhope R, Nussey S, Leiper AD. Diabetes mellitus after bone marrow transplantation during childhood. Med Pediatr Oncol. Feb 2003;40(2):128-129.

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Sec
#
50
TBI

Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
TBI

Potential
Late Effects
Growth hormone deficiency
Info Link: Growth charts
available on-line atwww.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
TBI ≥ 12 Gy fractionatedHighestRisk Factors
Treatment Factors
Radiation dose ≥ 18 Gy
Pretransplant cranial radiation
TBI given in single fraction

Periodic
Evaluation
HISTORY
Assessment of nutritional status(Every six months until growth iscompleted, then yearly)

Health Counseling
Further Considerations
Health Links
Growth Hormone Deficiency
See also: Hypopituitarism
Resources
www.magicfoundation.org

PHYSICAL
HeightWeightBMI(Every six months until growth iscompleted, then yearly)

Considerations for Further Testing and Intervention
Obtain x-ray for bone age in poorly growing children. Endocrine
consultation for: Height below 3rd percentile on growth chart;
Drop ≥ 2 percentile rankings on growth chart; Growth velocity< 4-5 cm/year during childhood; Lack of pubertal growth spurt.
Evaluate thyroid function in any poorly growing child. Consult
with endocrinologist regarding risks/benefits of adult growthTanner staging(Every six months until sexually mature) hormone replacement therapy. Consider bone density testing inpatients who are growth hormone deficient.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SECTION 50 TBI REFERENCES
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.
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.
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.
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.
Sanders JE, Pritchard S, Mahoney P, et al. Growth and development following marrow transplantation for leukemia. Blood. Nov 1986;68(5):1129-1135.
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
TBI

Therapeutic
Agent(s)CranialOrbital/Eye
TBI

Potential
Late Effects
Cataracts

Info Link: Radiation-related
ocular complications other thancataracts are generally
associated only with orbital/eye
radiation or higher dose cranialradiation. However, patientswith a history of an oculartumor (e.g., retinoblastoma) are
at higher risk for late-onset
ocular complications and should
receive ongoing follow-up by anophthalmologist at least
annually, and more frequently ifclinically indicated.

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

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

HISTORY
Visual changes (decreased acuity,
halos, diplopia)(Yearly)

PHYSICAL
Visual acuity
Funduscopic exam to evaluate forlens opacity(Yearly)

Health Counseling
Further Considerations
Health Links
Cataracts
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
SCREENING
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 ocular tumors
who received < 30 Gy.)

SCORE = 1

SECTION 56 TBI REFERENCES
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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TBI (cont)

RADIATION
Sec
#
60
TBI

Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

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 (nevoid basal
cell carcinoma syndrome)
Treatment Factors
Higher radiation doseHighestRisk Factors
Host Factors
Age < 5 years at timeof treatment
Treatment Factors
Dose ≥ 10 Gy

Periodic
Evaluation
PHYSICAL
Oral exam(Yearly)

SCREENING
Dental exam and cleaning(Every six months)

Health Counseling
Further Considerations
Health Links
Dental Health
Considerations for Further Testing and Intervention
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.

SYSTEM = Dental
SCORE = 1

SECTION 60 TBI 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.

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TBI (cont)

RADIATION
Sec
#
62
TBI

Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

Potential
Late Effects
Thyroid nodules

Risk
Factors
Host Factors
Younger age at treatment
Female sex
Treatment Factors
Higher radiation dose
Thyroid gland directly inradiation field
TBI

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 25 Gy

Periodic
Evaluation
PHYSICAL
Thyroid exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Thyroid 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 = SMNSCORE = 1

SECTION 62 TBI REFERENCES
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.

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TBI (cont)

RADIATION
Sec
#
63
TBI

Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

Potential
Late Effects
Thyroid cancer

Risk
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

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Thyroid exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Thyroid Problems
Considerations for Further Testing and Intervention
Ultrasound and FNA for evaluation of palpable nodule(s).
Surgical consultation for resection. Nuclear medicine
consultation for ablation of residual disease. Endocrine
consultation for postoperative medical management.

SYSTEM = SMNSCORE = 1

SECTION 63 TBI 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, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med. Mar 27 1997;336(13):897-904.
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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TBI (cont)

RADIATION
Sec
#
64
TBI

Therapeutic
Agent(s)CranialNasopharyngeal
Oropharyngeal
Spine (cervical)
Cervical (neck)
Supraclavicular
MantleMini-Mantle
TBI

Potential
Late Effects
Hypothyroidism

Risk
Factors
Host Factors
Female sex
Treatment Factors
Radiation dose ≥ 10 Gy
Thyroid gland directly inradiation field
TBI

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 20 Gy

Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed mood(Yearly; Consider more frequent
screening during periods of rapid
growth)PHYSICAL
HeightWeightHair
Skin
Thyroid exam
(Yearly; Consider more frequent
screening during periods of rapid
growth)Health Counseling
Further Considerations
Health Links
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.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SCREENING
TSHFree T4(Yearly; Consider more frequent
screening during periods of rapid
growth)SECTION 64 TBI REFERENCES
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.
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 CA, Kim TH, Ramsay NK. Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med. Nov 1982;73(5):688-694.

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TBI (cont)

RADIATION
Sec#(Female)69
TBI

Therapeutic
Agent(s)MantleMini-Mantle
Mediastinal
Chest (thorax)
Whole lung
AxillaTBI

Potential
Late Effects
Breast tissue hypoplasia

Risk
Factors
Host Factors
Prepubertal at time of breast
irradiation

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Breast exam
(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Surgical consultation for breast reconstruction after completionof growth.

Treatment Factors
Higher radiation dose

SYSTEM = Female reproductive
SCORE = 1

SECTION 69 TBI 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.

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TBI (cont)

RADIATION
Sec
#
70
TBI

Therapeutic
Agent(s)MantleMediastinal
Chest (thorax)
Whole lung
TBI

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
Chest radiation combinedwith TBI
Radiation combined with:- Bleomycin- Busulfan- Carmustine (BCNU)- Lomustine (CCNU)- Radiomimetic chemotherapy(e.g., doxorubicin,
dactinomycin)

Medical Conditions
Atopic history
Health Behaviors
Smoking

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 15 Gy
TBI ≥ 6 Gy in single fraction
TBI ≥ 12 Gy fractionated

Periodic
Evaluation
HISTORY
Cough
SOB
DOE
Wheezing(Yearly)

PHYSICAL
Pulmonary exam
(Yearly)

SCREENING
Chest x-ray
PFTs (including DLCO andspirometry)(Baseline at entry into long-term followup. Repeat as clinically indicated inpatients with abnormal results orprogressive pulmonary dysfunction.)

Health Counseling
Further Considerations
Health Links
Pulmonary HealthResources
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 diving medicine specialist.
Considerations for Further Testing and Intervention
In patients with abnormal PFTs and/or CXR, consider repeat
evaluation prior to general anesthesia. Pulmonary consultation
for patients with symptomatic pulmonary dysfunction. Influenza
and Pneumococcal vaccinations.

SYSTEM = Pulmonary
SCORE = 1

SECTION 70 TBI REFERENCES
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.
Frankovich J, Donaldson SS, Lee Y, Wong RM, Amylon M, Verneris MR. High-dose therapy and autologous hematopoietic cell transplantation in children with primary refractory and relapsed Hodgkin's disease:
atopy predicts idiopathic diffuse lung injury syndromes. Biol Blood Marrow Transplant. 2001;7(1):49-57.
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.
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.
Kader HA, Khanna S, Hutchinson RM, Aukett RJ, Archer J. Pulmonary complications of bone marrow transplantation: the impact of variations in total body irradiation parameters. Clin Oncol (R Coll Radiol).
1994;6(2):96-101.
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.
Nysom K, Holm K, Hesse B, et al. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. Arch Dis Child. May 1996;74(5):432-436.
Palmas A, Tefferi A, Myers JL, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol. Mar 1998;100(4):680-687.
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. Personalcommunication to Landier W, Bhatia S Aug 23, 2002.

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TBI (cont)

RADIATION
Sec
#
79
TBI

Therapeutic
Agent(s)Whole abdomen
All upper abdominal fields
TBI

Potential
Late Effects
Renal toxicity
Renal insufficiency
Hypertension

Info Link: Includes all upper
abdominal fields except
Paraaortic

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 other nephrotoxic
agents such as:- Cisplatin- Carboplatin- Ifosfamide- Aminoglycosides- Amphotericin- ImmunosuppressantsHighestRisk Factors
Treatment Factors
Radiation dose ≥ 15 Gy
TBI ≥ 6 Gy in single fraction
TBI ≥ 12 Gy fractionated

Periodic
Evaluation
PHYSICAL
Blood pressure(Yearly)

Health Counseling
Further Considerations
Health Links
Kidney HealthSee also: Single Kidney Health

Considerations for Further Testing and Intervention
SCREENING
Nephrology consultation for patients with hypertension,
BUN
proteinuria, or progressive renal insufficiency
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
SYSTEM = Urinary(Baseline at entry into long-term followup. If abnormal, repeat as clinically
SCORE = 1
indicated.)

Urinalysis(Yearly)

Medical Conditions
Diabetes mellitus
Hypertension
Nephrectomy

SECTION 79 TBI REFERENCES
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):1069-1074.
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.
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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TBI (cont)

RADIATION
Therapeutic
Agent(s)83
TBI

Whole abdomen
PelvicSpine (lumbar, sacral)
TBI(Female)Sec#

Info Link: Applies to all pelvic
fields except iliac/inguinal.
Applies to lumbar and sacral
spine at doses ≥ 25 Gy.

Potential
Late Effects

Risk
Factors

Uterine vascularinsufficiency(resulting in adverse pregnancy
outcomes, such as
spontaneous abortion,
neonatal death, low-birthweight infant, fetal
malposition, and prematurelabor)

Host Factors
Females with Wilms tumor andassociated müllerian anomalies

Info Link: 10% of girls withWilms tumor have congenitaluterine anomalies.

Treatment Factors
Higher radiation dose to pelvis

HighestRisk Factors
Host Factors
Prepubertal at treatment
Treatment Factors
Radiation dose ≥ 30 Gy
TBI

Periodic
Evaluation
HISTORY
PregnancyChildbirth history(Yearly and as clinically indicated)

Health Counseling
Further Considerations
Health Links
Female Health Issues
Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org
Considerations for Further Testing and Intervention
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 = Female reproductive
SCORE = 2B

SECTION 83 TBI REFERENCES
Gulati SC, Van Poznak C. Pregnancy after bone marrow transplantation. J Clin Oncol. May 1998;16(5):1978-1985.
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.

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TBI (cont)

RADIATION
Therapeutic
Agent(s)Potential
Late Effects

84
TBI

Whole abdomen
PelvicSpine (lumbar, sacral)
TBI

Gonadal dysfunction(ovarian)
Delayed/arrested pubertyPremature menopause
Infertility(Female)Sec#

Info Link: Applies to lumbar
and sacral spine at doses≥ 25 Gy only.

Risk
Factors
Host Factors
Older age at irradiation
Treatment Factors
Prepubertal female:
Radiation dose ≥10 Gy
Pubertal female:
Radiation dose ≥ 5 Gy
Combined with alkylating agent
chemotherapy
Longer time since treatment

HighestRisk Factors
Treatment Factors
Prepubertal female:
Radiation dose ≥15 Gy
Pubertal female:
Radiation dose ≥10 Gy
Combined withcyclophosphamide
conditioning for HCT

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Menstrual/pregnancy history
Sexual function (vaginal dryness,
libido)Medication use impacting sexualfunction(Yearly)
PHYSICAL
Tanner stage(Yearly until sexually mature)
SCREENING
FSH
LH
Estradiol(Baseline at age 13, and as clinicallyindicated in patients with delayed
puberty, irregular menses or primary or
secondary amenorrhea, clinical signs
and symptoms of estrogen deficiency)

Health Counseling
Further Considerations
Health Links
Female Health Issues
Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org
CounselingCounsel regarding the need for contraception, since there istremendous 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
Refer to endocrinologist for delayed/arrested puberty or
persistently abnormal hormone levels. Gynecology or
endocrinology consultation for HRT. Consider evaluation for
conditions exacerbated by hypogonadism (e.g.,
osteopenia/osteoporosis). Reproductive endocrinology
consultation for infertile couples interested in assisted
reproductive technologies.

SYSTEM = Female reproductive
SCORE = 1

SECTION 84 TBI REFERENCES
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.
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.
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.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.
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.

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TBI (cont)

RADIATION
Sec#(Male)

86
TBI

Therapeutic
Agent(s)PelvicTesticular
TBI

Potential
Late Effects
Gonadal dysfunction(testicular):Germ cell failure
Oligospermia
Azoospermia
Infertility

Risk
Factors
Treatment Factors
Radiation dose to testes:- 1 to 3 Gy: Azoospermia may
be reversible- 3 to 6 Gy: Azoospermia
possibly reversible (butunlikely)HighestRisk Factors
Treatment Factors
Radiation dose to testes≥ 6 Gy: Azoospermia likely
permanent

Periodic
Evaluation
SCREENING
Semen analysis(As requested by patient and forevaluation of infertility. Periodic
evaluation over time is recommended
as resumption of spermatogenesis canoccur up to 10 years post therapy.)

Health Counseling
Further Considerations
Health Links
Male Health Issues
Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org
CounselingCounsel regarding the need for contraception, since there istremendous 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. Testing forInhibin B can be considered in conjunction with FSH as anindicator of germ cell function.

SYSTEM = Male reproductive
SCORE = 1

SECTION 86 TBI 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.
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.
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.
Jacob A, Barker H, Goodman A, Holmes J. Recovery of spermatogenesis following bone marrow transplantation. Bone Marrow Transplant. Aug 1998;22(3):277-279.
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.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.

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HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)92

Hematopoietic Cell Transplant(HCT)

Potential
Late Effects
Acute myeloid leukemia
Myelodysplasia

Info Link: Complications after
hematopoietic celltransplantation havemultifactorial etiology: priortherapy for primary malignancy;
intensity of transplantconditioning; stem cell product(e.g., marrow, cord blood,
peripheral stem cells); donor(e.g., autologous, allogeneic,
unrelated); quality of donor torecipient match; complication oftransplant process(immunosuppression and
GVHD); complications in the
post-transplant period;
underlying disease; host genetic
factors; lifestyle behaviors. Thissection includes late treatmentcomplications that may beobserved in hematopoietic celltransplant recipients not covered elsewhere in theseguidelines. Refer to othersections of these guidelines for
specific details related to latecomplications of radiation andof specific chemotherapeutic
agents.

COG LTFU Guidelines – Page 119

Risk
Factors
Treatment Factors
Radiation therapy
Stem cell mobilization
with etoposide
Alkylating agent chemotherapy
Epipodophyllotoxins
Anthracyclines
Autologous transplant

HighestRisk Factors
Host Factors
Older age
Treatment Factors
Autologous transplant for
non-Hodgkin's and Hodgkin's
lymphoma

Periodic
Evaluation

Health Counseling
Further Considerations

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

Health Links
Reducing the Risk of Second Cancers

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

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

CounselingCounsel to promptly report fatigue, pallor, petechiae, or bonepain.

SYSTEM = SMN
SCREENING
CBC/differential(Yearly up to 10 years after transplant)

SCORE = 1

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HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors(cont)
Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 92 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.
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.
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.
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 Transplantationand the European Late Effect Project Group. Ann Intern Med. Nov 16 1999;131(10):738-744.
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.
Miller JS, Arthur DC, Litz CE, Neglia JP, Miller WJ, Weisdorf DJ. Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy.
Blood. Jun 15 1994;83(12):3780-3786.
Stone RM, Neuberg D, Soiffer R, et al. Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol.
Dec 1994;12(12):2535-2542

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HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)93

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 papilloma virus infection(females)HighestRisk Factors
Treatment Factors
TBI(cont)
Periodic
Evaluation
PHYSICAL
Evaluation for benign or malignant
neoplasms(Yearly)

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
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 Section 138)with more aggressive monitoring as clinically indicated.
Oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 93 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.
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.
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.
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 Transplantationand the European Late Effect Project Group. Ann Intern Med. Nov 16 1999;131(10):738-744.
Lishner M, Patterson B, Kandel R, et al. Cutaneous and mucosal neoplasms in bone marrow transplant recipients. Cancer. Feb 1 1990;65(3):473-476.
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)94

Hematopoietic Cell Transplant(HCT)

Potential
Late Effects
Lymphoma

Risk
Factors

HighestRisk Factors

Medical Conditions
Chronic GVHD

Medical Conditions
Chronic hepatitis C withsiderosis and steatosis(cont)
Periodic
Evaluation
PHYSICAL
Lymphadenopathy
Splenomegaly(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Oncology consultation as clinically indicated.

SYSTEM = SMNSCORE = 1

SECTION 94 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.
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.
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)95

Hematopoietic Cell Transplant(HCT)

Potential
Late Effects
Hepatic toxicity
Chronic hepatitis
Cirrhosis
Iron overload

Risk
Factors
Treatment Factors
History of multiple transfusions
Radiation to the liver
Antimetabolite therapy
Medical Conditions
Chronic GVHD
Viral hepatitis
History of VOD
Health Behaviors
Alcohol use

HighestRisk Factors
Medical Conditions
Chronic hepatitis C withsiderosis and steatosis(cont)
Periodic
Evaluation
SCREENING
ALT
AST
Bilirubin
Ferritin(Baseline at entry into long-term followup. Repeat as clinically indicated.)

Health Counseling
Further Considerations
Health Links
Liver Health
Gastrointestinal Health
Considerations for Further Testing and Intervention
Prothrombin time for evaluation of hepatic synthetic function inpatients 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 consultationin patients with persistent liver dysfunction or known hepatitis.
Hepatitis A and B immunizations in patients lacking immunity.
Consider liver biopsy in patients with persistent elevation of
ferritin (based on clinical context and magnitude of elevation).
Consider phlebotomy or chelation therapy for treatment of ironoverload. Consider erythropoietin in patients with iron overload
and low hemoglobin.

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 95 REFERENCES
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.
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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96

Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Osteonecrosis(Avascular Necrosis)
Info Link: Osteonecrosis
typically occurs during theacute treatment phase, may
progress over time or resolve.
Multifocal osteonecrosis issignificantly more common(3:1) than unifocal.

Risk
Factors
Host Factors
Age ≥ 10 years at time oftransplant
Treatment Factors
Corticosteroids (dexamethasone
effect is more potent than
prednisone)
TBI
High-dose radiation to any bone
Allogeneic HCT > autologous(cont)

HighestRisk Factors

Periodic
Evaluation

Treatment Factors
Prolonged corticosteroid
therapy (e.g., for chronic
GVHD)

HISTORY
Joint pain
Swelling
Immobility
Limited range of motion(Yearly)

Medical Conditions
Chronic GVHDPHYSICAL
Musculoskeletal exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Osteonecrosis
Considerations for Further Testing and Intervention
MRI as clinically indicated in patients with history suggestive ofosteonecrosis (should be done soon after symptom onset).
Orthopedic consultation in patients with positive imaging
and/or symptoms of osteonecrosis. Physical therapy evaluation(for non-pharmacologic pain management, range of motion,
strengthening, stretching, functional mobility).

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 96 REFERENCES
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.
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.
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.
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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97

Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects
Osteopenia
Osteoporosis
Osteopenia is defined as bonemineral density ≥ 1 and < 2.5
SD below mean
Osteoporosis is defined asbone mineral density ≥ 2.5 SD
below mean
Info Link: The World HealthOrganization definition of
osteoporosis in adults is basedon 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 ofstandard deviations the BMD
measurement is above or
below the YOUNG-NORMAL
MEAN BMD. A T-score of ≥ 2.5
standard deviations BELOW
the mean is consistent with adiagnosis of osteoporosis.
T-scores are not appropriate toassess skeletal health inpediatric patients who havenot achieved peak adult bonemass. Instead, pediatric BMD
reference data sets calculate
Z-scores based on age andgender. A Z-score is thenumber of standard deviations
the measurement is above or
below the AGE-MATCHED
MEAN BMD. There are notdefined standards for referralor treatment of low BMD inchildren.

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Risk
Factors(cont)

HighestRisk Factors

Periodic
Evaluation

Host Factors
Both genders are at risk

Host Factors
Older age at time of treatment

Treatment Factors
Methotrexate
Corticosteroids
Cranial radiation

Treatment Factors
Prolonged corticosteroid
therapy (e.g., for chronic
GVHD)

SCREENING
Bone density evaluation (DEXA orquantitative CT)(Baseline at entry into long-term followup. Repeat as clinically indicated. )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

Info Link: The optimal method of
measuring bone health in children iscontroversial. Existing technologies
have limitations. Dual energy x-ray
absorptiometry (DEXA) provides anestimate of total bone mass at a givensite. Quantitative CT provides distinct
measures of trabecular and corticalbone dimension and density.

Health Counseling
Further Considerations
Health Links
Bone HealthResources
National Osteoporosis Foundation website: www.nof.org
Considerations for Further Testing and Intervention
Nutritional supplements in cases of osteopenia unresponsive to
behavioral and dietary management: Calcium 1000-1500 mg
daily plus RDA for vitamin D. 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 acidosis that
could accelerate bone loss). Endocrine consultation for patientswith osteoporosis or history of multiple fractures forpharmacologic interventions (e.g., bisphosphonates, calcitonin,selective estrogen receptor modulators).

SYSTEM = Musculoskeletal
SCORE = 1

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Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors(cont)
Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 97 REFERENCES
Baker KS, Gurney JG, Ness KK, et al. Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study. Blood.
Sep 15 2004;104(6):1898-1906.
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.
Kaste SC, Chesney RW, Hudson MM, Lustig RH, Rose SR, Carbone LD. Bone mineral status during and after therapy of childhood cancer: an increasing population with multiple risk factors for impaired bone health.
J Bone Miner Res. Dec 1999;14(12):2010-2014.
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.
Nysom K, Holm K, Michaelsen KF, et al. Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant. Jan 2000;25(2):191-196.
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. May 2004;62(5):527-534.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.
Stern JM, Chesnut CH, 3rd, Bruemmer B, et al. Bone density loss during treatment of chronic GVHD. Bone Marrow Transplant. Mar 1996;17(3):395-400.

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Therapeutic
Agent(s)Potential
Late Effects

98

HCT with Chronic GVHD

Dermatologic toxicity
Permanent alopecia
Nail dysplasia
Vitiligo
Scleroderma

Risk
Factors

WITH CHRONIC GVHD

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Hair (alopecia)
Nail (hypoplasia)
Skin (vitiligo, scleroderma)(Yearly)

Health Counseling
Further Considerations
Health Links
Skin Health

SYSTEM = Dermatologic
Info Link:
More common with active
cGVHD; effects may persist
after cGVHD resolves.

SCORE = 1

SECTION 98 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.

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Therapeutic
Agent(s)99

HCT with Chronic GVHD

Potential
Late Effects
Xerophthalmia(keratoconjunctivitis sicca)
Info Link:
More common with active
cGVHD; effects may persist
after cGVHD resolves.

Risk
Factors

WITH CHRONIC GVHD (cont)HighestRisk Factors

Treatment Factors
Treatment Factors
Cranial radiation
Radiation dose to eye ≥ 30 Gy
Eye radiation
Radiation fraction ≥ 2 Gy
Radiomimetic chemotherapy(e.g., doxorubicin, dactinomycin)

Periodic
Evaluation
HISTORY
Dry eyes (burning, itching, foreign
body sensation, inflammation)(Yearly)

PHYSICAL
Eye exam(Yearly)

Health Counseling
Further Considerations
Health Links
Eye Health
Considerations 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 99 REFERENCES
Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. May 1 2003;101(9):3373-3385.
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.
Ng JS, Lam DS, Li CK, et al. Ocular complications of pediatric bone marrow transplantation. Ophthalmology. Jan 1999;106(1):160-164.
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.

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Therapeutic
Agent(s)100 HCT with Chronic GVHD

Potential
Late Effects
Xerostomia
Salivary gland dysfunction
Dental caries
Periodontal disease
Oral cancer
Info Link:
More common with active
cGVHD; effects may persist
after cGVHD resolves.

Risk
Factors

WITH CHRONIC GVHD (cont)HighestRisk Factors

Treatment Factors
Treatment Factors
Head and neck radiation
Salivary gland radiation dose
involving the parotid gland≥ 30 Gy
Higher radiation doses
Radiomimetic chemotherapy(e.g., doxorubicin, dactinomycin)

Periodic
Evaluation
HISTORY
Xerostomia(Yearly)

PHYSICAL
Oral exam(Yearly)

SCREENING
Dental exam and cleaning(Every six months)

Health Counseling
Further Considerations
Health Links
Dental Health
Considerations for Further Testing and Intervention
Supportive care with saliva substitutes, moistening agents, andsialogogues (pilocarpine). Regular dental care including fluoride
applications and regular screening for intraoral malignancy.

SYSTEM = Dental
SCORE = 1

SECTION 100 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.
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.
Guchelaar HJ, Vermes A, Meerwaldt JH. Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment. Support Care Cancer. Jul 1997;5(4):281-288.
Makkonen TA, Edelman L, Forsten L. Salivary flow and caries prevention in patients receiving radiotherapy. Proc Finn Dent Soc. 1986;82(2):93-100.
Maxymiw WG, Wood RE. The role of dentistry in patients undergoing bone marrow transplantation. Br Dent J. Oct 7 1989;167(7):229-234.

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Therapeutic
Agent(s)Potential
Late Effects

101 HCT with Chronic GVHD

Pulmonary toxicity
Bronchiolitis obliterans
Chronic bronchitis
Bronchiectasis
Info Link:
More common with active
cGVHD; effects may persist
after cGVHD resolves.

WITH CHRONIC GVHD (cont)

Risk
Factors

HighestRisk Factors

Treatment Factors
Chest radiation
TBI
Pulmonary toxic chemotherapy:- Bleomycin- Busulfan- Carmustine (BCNU)- Lomustine (CCNU)

Medical Conditions
Prolonged immunosuppression
related to cGVHD and its
treatment

Periodic
Evaluation
HISTORY
Cough
SOB
DOE
Wheezing(Yearly)

PHYSICAL
Pulmonary exam
(Yearly)

SCREENING
Chest x-ray
PFTs (including DLCO andspirometry)(Baseline at entry into long-term followup. Repeat as clinically indicated inpatients with abnormal results orprogressive pulmonary dysfunction.)

Health Counseling
Further Considerations
Health Links
Pulmonary HealthResources
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 diving medicine specialist.
Considerations for Further Testing and Intervention
In patients with abnormal PFTs and/or CXR, consider repeat
evaluation prior to general anesthesia. Pulmonary consultation
for patients with symptomatic pulmonary dysfunction. Influenza
and Pneumococcal vaccinations.

SYSTEM = Pulmonary
SCORE = 1

SECTION 101 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.
Cerveri I, Zoia MC, Fulgoni P, et al. Late pulmonary sequelae after childhood bone marrow transplantation. Thorax. Feb 1999;54(2):131-135.
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.
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.
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.
Kader HA, Khanna S, Hutchinson RM, Aukett RJ, Archer J. Pulmonary complications of bone marrow transplantation: the impact of variations in total body irradiation parameters. Clin Oncol (R Coll Radiol).
1994;6(2):96-101.
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.
Nysom K, Holm K, Hesse B, et al. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. Arch Dis Child. May 1996;74(5):432-436.
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. Personalcommunication to Landier W, Bhatia S Aug 23, 2002

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Therapeutic
Agent(s)102 HCT with Chronic GVHD

Potential
Late Effects
Immunologic complications
Secretory IgA deficiency
Hypogammaglobulinemia
Chronic infections (e.g.,
conjunctivitis, sinusitis, andbronchitis associated withchronic GVHD)
Info Link:
Related to cGVHD; effects may
persist or resolve over time.

Risk
Factors

HighestRisk Factors
Host Factors
Low CD4 T-cell count

WITH CHRONIC GVHD (cont)
Periodic
Evaluation

HISTORY
Chronic conjunctivitis
Chronic sinusitis
Chronic bronchitis
Medical Conditions
Prolonged immunosuppression (Yearly)
related to cGVHD and its
treatment
PHYSICAL
Eye exam
Nasal exam
Pulmonary exam
(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Consider PCP and anti-fungal prophylaxis in patients withactive cGVHD for duration of immunosuppressive therapy.
Immunology or infectious diseases consultation for assistancewith management of chronic infections

SYSTEM = Immune
SCORE = 1

SECTION 102 REFERENCES
Castagnola E, Fioredda F. Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes.
Eur J Haematol. Nov 2003;71(5):319-326.
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.
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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Therapeutic
Agent(s)103 HCT with Chronic GVHD

Potential
Late Effects

Risk
Factors

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

Treatment Factors
Splenic radiation
Ongoing immunosuppression

Info Link:
This section applies only topatients who have active
cGVHD

HighestRisk Factors
Host Factors
Hypogammaglobulinemia

WITH CHRONIC GVHD (cont)
Periodic
Evaluation
PHYSICAL
Physical exam at time of febrileillness to evaluate degree of illness
and potential source of infection(When febrile T ≥ 101ºF)

SCREENING
Blood culture(When febrile T ≥ 101ºF)

Health Counseling
Further Considerations
Health Links
Splenic precautions
Considerations for Further Testing and Intervention
Consider antibiotic prophylaxis for encapsulated organisms andbacteremia/endocarditis prophylaxis for duration of
immunosuppressive therapy for chronic GVHD (see Dajani AS et
al. Circulation 1997 for endocarditis prophylaxis dosing
recommendations per the AHA). In patients with T ≥ 101°F(38.3° C) or other signs of serious illness, administer along-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
be necessary under certain circumstances, such as thepresence 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. Pneumovax booster in patients ≥10 years old at≥ 5 years after previous dose (AAP-CIDP Recommendations,
2003).

SYSTEM = Immune
SCORE = 1

SECTION 103 REFERENCES
Castagnola E, Fioredda F. Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes.
Eur J Haematol. Nov 2003;71(5):319-326.
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.
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. -138.

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Therapeutic
Agent(s)104 HCT with Chronic GVHD

Potential
Late Effects
Esophageal stricture
Info Link:
Related to cGVHD; generally
not reversible over time.

Risk
Factors

WITH CHRONIC GVHD (cont)HighestRisk Factors

Treatment Factors
Treatment Factors
Radiation involving the
Radiation dose ≥ 40 Gy
esophagus
Radiomimetic chemotherapy(e.g., doxorubicin, dactinomycin)

Periodic
Evaluation
HISTORY
Dysphagia
Heartburn(Yearly)

Health Counseling
Further Considerations
Health Links
Gastrointestinal Health
Considerations for Further Testing and Intervention
Surgery and/or gastroenterology consultation for symptomaticpatients.

Medical Conditions
Gastroesophageal reflux
SYSTEM = GI/Hepatic
SCORE = 1

SECTION 104 REFERENCES
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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Therapeutic
Agent(s)(Female)105 HCT with Chronic GVHD

Potential
Late Effects
Vaginal fibrosis/stenosis
Info Link:
Related to cGVHD; generally
not reversible over time.

Risk
Factors
Treatment Factors
Pelvic radiation

HighestRisk Factors

WITH CHRONIC GVHD (cont)
Periodic
Evaluation
HISTORY
Psychosocial assessment
Dyspareunia
Vulvar pain
Post-coital bleeding
Difficulty with tampon insertion(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Gynecologic consultation for management. Psychologicalconsultation in patients with emotional difficulties.

SYSTEM = Female reproductive
SCORE = 1

SECTION 105 REFERENCES
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.
Hayes EC, Rock JA. Treatment of vaginal agglutination associated with chronic graft-versus-host disease. Fertil Steril. Nov 2002;78(5):1125-1126.
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.

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HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)106 HCT with Chronic GVHD

Potential
Late Effects
Joint contractures
Info Link:
Related to cGVHD; generally
not reversible over time.

Risk
Factors

HighestRisk Factors

WITH CHRONIC GVHD (cont)
Periodic
Evaluation
PHYSICAL
Musculoskeletal exam
(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Consultation with physical therapy, rehabilitation
medicine/physiatrist.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 106 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.
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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AMPUTATIONSURGERY
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Therapeutic
Agent(s)107 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
HISTORY
Phantom pain
Functional and activity limitations(Yearly)

PHYSICAL
Residual limb integrity(Yearly)

SCREENING
Prosthetic evaluation(Every six months until skeletally
mature, then yearly thereafter)

Health Counseling
Further Considerations
Health Links
AmputationCounselingCounsel 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 physicalstatus 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 107 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.
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.
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.
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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CENTRAL VENOUS CATHETERSURGERY
Sec#

Therapeutic
Agent(s)108 Central venous catheter

Potential
Late Effects
Thrombosis
Vascular insufficiency
Infection of retained cuff
or line tract

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
HISTORY
Tenderness or swelling at previous
catheter site(Yearly and as clinically indicated)

Health Counseling
Further Considerations
SYSTEM = Cardiovascular
SCORE = 1

PHYSICAL
Venous stasis
Swelling
Tenderness at previous catheter site(Yearly and as clinically indicated)

SECTION 108 REFERENCES
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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CYSTECTOMY

SURGERY
Sec#

Therapeutic
Agent(s)109 Cystectomy
Info Link: All potential lateeffects for pelvic surgery apply
to Cystectomy (see also
sections 126-129).

Potential
Late Effects
Cystectomy-related
complications
Chronic urinary tract infection
Renal dysfunction
Vesicoureteral reflux
Hydronephrosis
Reservoir calculi
Spontaneous neobladderperforation
Vitamin B12/folate/carotene
deficiency
Info Link: Reservoir calculi
are stones in the neobladder(a reservoir for urine usuallyconstructed of ileum/colon)

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
SCREENING
Urology evaluation(Yearly)

Health Counseling
Further Considerations
Health Links
Cystectomy
Kidney Health

SYSTEM = Urinary
SCORE =
Chronic urinary tract infection: 1
Renal dysfunction: 1
Vesicoureteral reflux: 1
Hydronephrosis: 1
Spontaneous neobladder perforation: 1
Reservoir calculi: 2A
Vitamin B12/folate/carotene deficiency: 2B

SECTION 109 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.
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.
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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ENUCLEATIONSURGERY
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Therapeutic
Agent(s)110 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
SCREENING
Evaluation by ocularist
Evaluation by ophthalmologist(Yearly)

Health Counseling
Further Considerations
Health Links
Eye Health
Considerations for Further Testing and Intervention
Psychological consultation in patients with emotionaldifficulties related to cosmetic and visual impairment.
Vocational rehabilitation referral as indicated.

SYSTEM = Ocular
SCORE = 1

SECTION 110 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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HYSTERECTOMY

SURGERY
Sec#

Therapeutic
Agent(s)Potential
Late Effects(Female)111 Hysterectomy

Pelvic floor dysfunction
Urinary incontinence
Info Link: For patients who also Sexual dysfunction
underwent oophorectomy, seealso: Section 123 (unilateraloophorectomy) or Section 124(bilateral oophorectomy)

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
HISTORY
Psychosocial assessment
Abdominal pain
Urinary leakage
Dyspareunia(Yearly)

Health Counseling
Further Considerations
Health Links
Female 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 = Female reproductive
SCORE = 2A

SECTION 111 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.
Brown JS, Sawaya G, Thom DH, Grady D. Hysterectomy and urinary incontinence: a systematic review. Lancet. Aug 12 2000;356(9229):535-539.
Dragisic KG, Milad MP. Sexual functioning and patient expectations of sexual functioning after hysterectomy. Am J Obstet Gynecol. May 2004;190(5):1416-1418.

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LAPAROTOMYSURGERY
Sec#

Therapeutic
Agent(s)112 Laparotomy

Potential
Late Effects
Adhesions
Bowel obstruction

Risk
Factors
Treatment Factors
Combined with radiation

HighestRisk Factors

Periodic
Evaluation
HISTORY
Abdominal pain
EmesisDistention
Vomiting
Constipation(With clinical symptoms of obstruction)

PHYSICAL
Tenderness
Abdominal guarding
Distension(With clinical symptoms of obstruction)

Health Counseling
Further Considerations
Health Links
Gastrointestinal Health
Considerations for Further Testing and Intervention
KUB as clinically indicated for suspected obstruction. Surgicalconsultation for patients unresponsive to medical management.

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 112 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. Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol. Feb 1996;26(2):75-80.

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LIMB SPARING PROCEDURE

SURGERY
Sec#

Therapeutic
Agent(s)113 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
Treatment Factors
Tibial endoprosthesis
Medical Conditions
Endoprosthetic infection
Obesity
Health Behaviors
High level of physical activity(associated with higher riskloosening)
Low level of physical activity(associated with higher risk ofcontractures or functional
limitations)

HighestRisk Factors
Treatment Factors
Radiation to extremity
Medical Conditions
Poor healing
Infection of reconstruction

Periodic
Evaluation
HISTORY
Functional and activity limitations(Yearly and as clinically indicated)

PHYSICAL
Residual limb integrity(Yearly and as clinically indicated)

SCREENING
Radiograph(Yearly)
Evaluation by orthopedic surgeon(Every six months until skeletally
mature, then yearly)

Health Counseling
Further Considerations
Health Links
Limb Sparing ProceduresCounselingCounsel regarding need for antibiotic prophylaxis prior to dental
and invasive procedures.
Considerations for Further Testing and Intervention
Antibiotic prophylaxis prior to dental and invasive procedures.
Physical therapy consultation As needed per changes infunctional status (such as post-lengthening, revisions, lifechanges such as pregnancy), and for non-pharmacological pain
management. Consider psychological consultation as needed toassist 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 113 REFERENCES
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.
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.
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.
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, 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.
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.
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.
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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NEPHRECTOMY

SURGERY
Sec#

Therapeutic
Agent(s)114 Nephrectomy

Potential
Late Effects
Renal toxicity
Proteinuria
Hyperfiltration
Renal insufficiency
Hydrocele(males only)

Risk
Factors
Treatment Factors
Combined with other nephrotoxic
therapy, such as:- Cisplatin- Carboplatin- Ifosfamide- Aminoglycosides- Amphotericin- Immunosuppressants- Methotrexate- Radiation impacting thekidneysHighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

PHYSICAL
Blood pressure(Yearly)

Health Links
Single Kidney HealthSee also: Kidney Health

Testicular exam to evaluate forhydrocele(Yearly for males)

Counseling
Discuss contact sports, bicycle safety (e.g., avoiding handlebar
injuries), and proper use of seatbelts (i.e., wearing lapbelts
around hips, not waist). Counsel to use NSAIDS with caution.

SCREENING
BUN
Considerations for Further Testing and Intervention
Creatinine
Nephrology consultation for patients with hypertension,
Na, K, Cl, CO2proteinuria, or progressive renal insufficiency
Ca, Mg, PO4(Baseline at entry into long-term followup. If abnormal, repeat as clinically
SYSTEM = Urinary
indicated.)
Urinalysis(Yearly)

SCORE = 1

SECTION 114 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.
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.
Gerstenbluth RE, Spirnak JP, Elder JS. Sports participation and high grade renal injuries in children. J Urol. Dec 2002;168(6):2575-2578.
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.
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.
Mpofu C, Mann JR. Urinary protein/creatinine index in follow up of patients with Wilms' tumour after nephrectomy. Arch Dis Child. Dec 1992;67(12):1462-1466.
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.

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NEUROSURGERY - BRAIN

SURGERY
Sec#

Therapeutic
Agent(s)115 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 vary with extent ofsurgery and postoperativecomplications. In general, mild
delays occur in most areas ofneuropsychological function
compared to healthy children.
Extent of deficit depends on
age at treatment, intensity oftreatment, and time sincetreatment. New deficits may
emerge over time.
Neurosensory deficits (i.e.,
vision, hearing) due to tumor
or its therapy may complicate
neurocognitive outcomes.

Risk
Factors
Host Factors
Younger age at treatment
Primary CNS tumor
Treatment Factors
Extent and location of resection
Longer elapsed time since
therapy
In combination with:- TBI- Cranial radiation- Methotrexate(IT, IO, high-dose IV)- Cytarabine (high-dose IV)

HighestRisk Factors
Host Factors
Age < 3 years at time oftreatment
Supratentorial tumor
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
HISTORY
Educational and/or vocational
progress(Yearly)

Health Counseling
Further Considerations
Health Links
Educational Issues

Considerations for Further Testing and Intervention
Formal neuropsychological evaluation to include tests ofprocessing speed, computer-based attention, visual motor
SCREENING
integration, memory, comprehension of verbal instructions,
Referral for formal
verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orneuropsychological evaluation(Baseline at entry into long-term follow- cancer center (psychologist, social worker, school counselor) to
up. Periodically as clinically indicatedfacilitate acquisition of educational resources and/or social
for patients with evidence of impaired
skills training. Consider use of psychotropic medication (e.g.,
educational or vocational progress.)
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.

SYSTEM = CNSSCORE = 1

SECTION 115 REFERENCES
Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol. Jan-Feb 2005;30(1):65-78.
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.
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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NEUROSURGERY - BRAIN (cont)

SURGERY
Sec#

Therapeutic
Agent(s)116 Neurosurgery - Brain

Potential
Late Effects
Motor and/or sensory deficits
Paralysis
Movement disorders
AtaxiaEye problems(ocular nerve palsy, gazeparesis, 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(eye problems)Periodic
Evaluation

Health Counseling
Further Considerations

SCREENING
Evaluation by neurologist(Yearly, until 2 to 3 years after surgery
or stable; continue to monitor if
symptoms persist)

Considerations for Further Testing and Intervention
Speech, 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 116 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.
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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NEUROSURGERY - BRAIN (cont)

SURGERY
Sec#

Therapeutic
Agent(s)117 Neurosurgery - Brain

Potential
Late Effects
Seizures

Risk
Factors
Host Factors
Primary CNS tumor
Treatment Factors
Methotrexate (IV, IT, IO)

HighestRisk Factors

Periodic
Evaluation
SCREENING
Evaluation by neurologist(Every six months for patients withseizure disorder)

Health Counseling
Further Considerations
SYSTEM = CNSSCORE = 1

SECTION 117 REFERENCES
Khan RB, Marshman KC, Mulhern RK. Atonic seizures in survivors of childhood cancer. J Child Neurol. Jun 2003;18(6):397-400.
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.
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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NEUROSURGERY - SPINAL CORD

SURGERY
Sec#

Therapeutic
Agent(s)118 Neurosurgery - Brain

Potential
Late Effects
Hydrocephalus
Shunt malfunction

Risk
Factors
Host Factors
Primary CNS tumor

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SCREENING
Abdominal x-ray(After pubertal growth spurt for patientswith shunts to assure distal shunt tubing in peritoneum)Counseling
Education patient/family regarding potential symptoms of shunt
malfunction.

SYSTEM = CNS
Evaluation by neurosurgeon(Yearly for patients with shunts)

SCORE = 1

SECTION 118 REFERENCES
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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NEUROSURGERY - SPINAL CORD

SURGERY
Sec#

Therapeutic
Agent(s)119 Neurosurgery - Spinal cord

Potential
Late Effects
Neurogenic bladder
Urinary incontinence

Risk
Factors

HighestRisk Factors

Host Factors
Tumor adjacent to or compressing 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
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream(Yearly)

Health Counseling
Further Considerations
Health Links
Neurogenic 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 119 REFERENCES
Fowler C. Neurology of Bowel, Bladder, and Sexual Dysfunction Vol 23: Elsevier; 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 occurrring during the neonatal period. Pediatr Surg Int. 1996;10(5-6):366-370.

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NEUROSURGERY - SPINAL CORD (cont)

SURGERY
Sec#

Therapeutic
Agent(s)120 Neurosurgery - Spinal cord

Potential
Late Effects
Neurogenic bowel
Fecal incontinence

Risk
Factors
Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina
Treatment Factors
Radiation dose ≥ 50 Gy to
bladder, pelvis, or spine

HighestRisk Factors
Host Factors
Injury above the level of thesacrumPeriodic
Evaluation
HISTORY
Chronic constipation
Fecal soiling(Yearly)

PHYSICAL
Rectal exam
(As clinically indicated)

Health Counseling
Further Considerations
CounselingCounsel regarding benefits of adherence to bowel regimen,
including adequate hydration, fiber, laxatives/enemas asclinically indicated.
Considerations for Further Testing and Intervention
GI consultation to establish bowel regimen for patients withchronic impaction or fecal soiling.

SYSTEM = CNSSCORE = 1

SECTION 120 REFERENCES
Fowler C. Neurology of Bowel, Bladder, and Sexual Dysfunction Vol 23: Elsevier; 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 occurrring during the neonatal period. Pediatr Surg Int. 1996;10(5-6):366-370.

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NEUROSURGERY - SPINAL CORD (cont)

SURGERY
Sec#

Therapeutic
Agent(s)(Male)

121 Neurosurgery - Spinal cord

Potential
Late Effects
Sexual dysfunction (Male)
Erectile dysfunction

Risk
Factors
Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina
Treatment Factors
Radiation to bladder, pelvis, or
spine

HighestRisk Factors

Periodic
Evaluation

Host Factors
Injury above the level of thesacrumHISTORY
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction(Yearly)

Treatment Factors
Radiation dose ≥ 55 Gy topenile bulb in adult
Radiation dose ≥ 45 Gy in
prepubertal child

Health Counseling
Further Considerations
Health Links
Male Health Issues
Resources
www.urologychannel.com
Considerations for Further Testing and Intervention
Urologic consultation in patients with positive history.

Medical Conditions
Hypogonadism
SYSTEM = CNSSCORE = 2A

Sexual dysfunction (Female)(Female)121 Neurosurgery - Spinal cord

Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina
Treatment Factors
Radiation to bladder, pelvis, or
spine

Host Factors
Injury above the level of thesacrumHISTORY
Dyspareunia
Altered or diminished sensation,
loss of sensation
Medication use impacting sexualfunction(Yearly)

SYSTEM = CNSSCORE = 2A

Medical Conditions
Hypogonadism
Vaginal fibrosis/stenosis
Chronic GVHDSECTION 121 REFERENCES
Fowler C. Neurology of Bowel, Bladder, and Sexual Dysfunction Vol 23: Elsevier; 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 occurrring during the neonatal period. Pediatr Surg Int. 1996;10(5-6):366-370.

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OOPHOROPEXYSURGERY
Sec#

Therapeutic
Agent(s)(Female)122 Oophoropexy
Info Link:
If shielding from radiation wasincomplete: See also Section 84(ovarian dysfunction related toradiation)

Potential
Late Effects

Risk
Factors

Oophoropexy-related
complications
Inability to conceive despite
normal ovarian function
Dyspareunia
Symptomatic ovarian cysts
Bowel obstruction
Pelvic adhesions

Treatment Factors
Ovarian radiationTubo-ovarian dislocation,
especially with lateral ovariantransposition

HighestRisk Factors

Periodic
Evaluation
HISTORY
Abdominal pain
Pelvic pain
Dyspareunia
Inability to conceive despite normal
ovarian function(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Gynecologic consultation for patients with positive history
and/or physical findings.

SYSTEM = Female reproductive
SCORE = 2A

SECTION 122 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.
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.

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OOPHORECTOMY (UNILATERAL)

SURGERY
Sec#

Therapeutic
Agent(s)(Female)123 Oophorectomy (unilateral)

Potential
Late Effects
Premature menopause
Info Link: Evidence forpremature menopause
following unilateraloophorectomy is limited andhas been extrapolated fromthe adult literature.

Risk
Factors
Health Behaviors
Smoking

HighestRisk Factors
Treatment Factors
Combined with:- Pelvic radiation- Alkylating agents- TBI

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Menstrual/pregnancy history
Sexual function (vaginal dryness,
libido)Medication use impacting sexualfunction(Yearly)
PHYSICAL
Tanner stage(Yearly until sexually mature)

SCREENING
FSH
LH
Estradiol(Baseline at age 13 and as clinicallyindicated in patients with delayed
puberty, irregular menses, primary or
secondary amenorrhea, and/or clinicalsigns and symptoms of estrogen
deficiency)

Health Counseling
Further Considerations
Health Links
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 forcontraception.
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 = Female reproductive
SCORE = 2A

SECTION 123 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.
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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OOPHORECTOMY (BILATERAL)

SURGERY
Sec#

Therapeutic
Agent(s)(Female)124 Oophorectomy (bilateral)

Potential
Late Effects
Hypogonadism
Infertility

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
SCREENING
Gynecologic or endocrinologic
consultation for initiation of
hormonal replacement therapy(At age 11)

Health Counseling
Further Considerations
Health Links
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 for osteopenia/osteoporosis in
hypogonadal patients. Reproductive endocrinology referral
regarding assisted reproductive technologies.

SYSTEM = Female reproductive
SCORE = 1

SECTION 124 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.
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, 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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ORCHIECTOMY

SURGERY
Sec#

Therapeutic
Agent(s)(Male)

125 Orchiectomy

Potential
Late Effects
Hypogonadism
Infertility

Risk
Factors
Treatment Factors
Unilateral orchiectomy combinedwith pelvic or testicular radiation
and/or alkylating agentsHighestRisk Factors
Treatment Factors
Bilateral orchiectomy

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction(Yearly)

PHYSICAL
Tanner stage
Testicular volume by Prader
orchdiometry(Yearly until sexually mature)

Health Counseling
Further Considerations
Health Links
Male Health Issues
Counseling
For patients with single testis - counsel to wear athletic
supporter with protective cup during athletic activities.
Considerations for Further Testing and Intervention
Refer to endocrinologist for bilateral orchiectomy, delayed
puberty, or persistently abnormal hormone levels. Consider
surgical placement of testicular prosthesis.

SYSTEM = Male reproductive
SCREENING
Semen analysis(As requested by patient for evaluationof infertility)

SCORE = 1

FSH, LH, testosterone(For patient with bilateral orchiectomy,refer to endocrinology at about age 11.
For patients with unilateral orchiectomy, obtain as clinically indicated fordelayed puberty or signs and symptomsof testosterone deficiency.)

SECTION 125 REFERENCES
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.
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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PELVIC SURGERY

SURGERY
Sec#

Therapeutic
Agent(s)126 Pelvic surgery
Info Link:
For patients with cystectomy:
See also Section 109

Potential
Late Effects
Urinary incontinence
Urinary tract obstruction
Info Link: Urinary tract
obstruction related toretroperitoneal fibrosis

Risk
Factors
Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina
Treatment Factors
Retroperitoneal node dissection
Extensive pelvic dissection (e.g.,bilateral ureteral re-implantation,
retroperitoneal tumor resection):
Radiation to the bladder, pelvis,
and/or lumbar-sacral spine

HighestRisk Factors

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream(Yearly)

Health Counseling
Further Considerations
CounselingCounsel regarding adequate fluid intake, regular voiding,seeking medical attention for symptoms of voiding dysfunction
or urinary tract infection, 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 126 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.
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):1455-1458.

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PELVIC SURGERY (cont)

SURGERY
Sec#

Therapeutic
Agent(s)127 Pelvic surgery

Potential
Late Effects
Fecal incontinence

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina

HISTORY
Chronic constipation, fecal soiling(Yearly)CounselingCounsel regarding benefits of adherence to bowel regimen,
including adequate hydration, fiber, laxatives/enemas asclinically indicated.

Treatment Factors
Radiation to the bladder, pelvis,
or spine

PHYSICAL
Rectal exam
(As clinically indicated)

Considerations for Further Testing and Intervention
GI consultation to establish bowel regimen for patients withchronic impaction or fecal soiling.

SYSTEM = GI/Hepatic
SCORE = 1

SECTION 127 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 occurrring during the neonatal period. Pediatr Surg Int. 1996;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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PELVIC SURGERY (cont)

SURGERY
Sec#

Therapeutic
Agent(s)(Male)

128 Pelvic surgery

Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Sexual dysfunction (Male)
Retrograde ejaculation
Anejaculation
Erectile dysfunction

Treatment Factors
Retroperitoneal node dissection
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

HISTORY
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction
Quality of ejaculate (frothy whiteurine with first void after
intercourse suggests retrograde
ejaculation)(Yearly)

Medical Conditions
Hypogonadism

Health Counseling
Further Considerations
Health Links
Male Health Issues
Resources
www.urologychannel.com
Considerations for Further Testing and Intervention
Urologic consultation in patients with positive history and/or
physical exam findings.

SYSTEM = Male reproductive
SCORE = 2A

Sexual dysfunction (Female)(Female)128 Pelvic surgery

Host Factors
Chronic GVHD
Hypogonadism
Tumor adjacent to spine
Medical Conditions
Radiation to bladder, pelvis, or
spine

HISTORY
Dyspareunia
Altered or diminished sensation,
loss of sensation
Medication use impacting sexualfunction(Yearly)

SYSTEM = Female reproductive
SCORE = 2A

(Male)(Female)SECTION 128 REFERENCES
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.
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.
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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PELVIC SURGERY (cont)

SURGERY
Sec#

Therapeutic
Agent(s)Hydrocele(Male)

129 Pelvic surgery

Potential
Late Effects

Risk
Factors
Treatment Factors
Retroperitoneal node dissection

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Testicular exam to evaluate forhydrocele(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Urologic consultation for patients with hydrocele.

SYSTEM = Urinary
SCORE = 1

SECTION 129 REFERENCES
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.

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PULMONARY

SURGERY
Sec#

Therapeutic
Agent(s)130 Pulmonary lobectomy
Pulmonary metastasectomy
Pulmonary wedge resection

Potential
Late Effects
Pulmonary dysfunction

Risk
Factors
Treatment Factors
Combined with pulmonary toxic
therapy- Bleomycin- Busulfan- Carmustine (BCNU)- Lomustine (CCNU)
Medical Conditions
Atopic history

HighestRisk Factors
Treatment Factors
Combined with:- Chest radiation- TBI

Periodic
Evaluation
HISTORY
Cough
SOB
DOE
Wheezing(Yearly)

PHYSICAL
Pulmonary exam
(Yearly)

Health Behaviors
Smoking
SCREENING
Chest x-ray
PFTs (including DLCO andspirometry)(Baseline at entry into long-term followup. Repeat as clinically indicated inpatients with abnormal results orprogressive pulmonary dysfunction.)

Health Counseling
Further Considerations
Health Links
Pulmonary HealthResources
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 diving medicine specialist.
Considerations for Further Testing and Intervention
In patients with abnormal PFTs and/or CXR, consider repeat
evaluation prior to general anesthesia. Pulmonary consultation
for patients with symptomatic pulmonary dysfunction; Influenza
and pneumococcal vaccinations

SYSTEM = Pulmonary
SCORE = 2A

SECTION 130 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.
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. Personalcommunication to Landier W, Bhatia S Aug 23, 2002.

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SPLENECTOMY

SURGERY
Sec#

Therapeutic
Agent(s)131 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
Physical exam at time of febrile illness to evaluate degree of illness
and potential source of infection(When febrile T ≥ 101ºF)

Health Links
Splenic Precautions

SCREENING
Blood culture(When febrile T ≥ 101ºF)

Considerations for Further Testing and Intervention
In patients with T ≥101°F (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 ofserious infection. Immunize with Pneumococcal,
Meningococcal, and HIB vaccines. Pneumovax booster inpatients ≥10 years old at ≥ 5 years after previous dose
(AAP-CIDP Recommendations, 2003).

Counseling
Medical alert bracelet/card noting asplenia. Counsel to avoid
malaria and tick bites if living in or visiting endemic areas

SYSTEM = Immune
SCORE = 1

SECTION 131 REFERENCES
Immunization in special clinical circumstances: asplenic children. In: Pickering LK, ed. Red Book 2003: Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2003.
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.
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.

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THYROIDECTOMY

SURGERY
Sec#

Therapeutic
Agent(s)132 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 ahistory of total thyroidectomy
should be monitored for signs
and symptoms of hypoparathyroidism (e.g., parasthesias,
muscle cramping, alteredmental status, hyperreflexia,
tetany, hypocalcemia, andhyperphosphatemia)

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed mood(Yearly; Consider more frequent
screening during periods of rapid
growth)Health Counseling
Further Considerations
Health Links
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
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 132 REFERENCES
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.
Telander RL, Moir CR. Medullary thyroid carcinoma in children. Semin Pediatr Surg. Aug 1994;3(3):188-193.

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OTHER THERAPEUTIC MODALITIESSec#Therapeutic
Agent(s)Potential
Late Effects

133 Radioiodine therapy(I-131 thyroid ablation)

Lacrimal duct atrophy

Risk
Factors

HighestRisk Factors

SYSTEMIC RADIATION
Periodic
Evaluation
HISTORY
Excessive tearing(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Ophthalmology consultation as clinically indicated.

SYSTEM = Ocular
SCORE = 2A

SECTION 133 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 inI(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)134 Radioiodine therapy(I-131 thyroid ablation)

Potential
Late Effects
Hypothyroidism

Risk
Factors

HighestRisk Factors

SYSTEMIC RADIATION (cont)
Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed mood(Yearly; Consider more frequent
screening during periods of rapid
growth)PHYSICAL
HeightWeightHair
Skin
Thyroid exam
(Yearly; Consider more frequent
screening during periods of rapid
growth)Health Counseling
Further Considerations
Health Links
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.

SYSTEM = Endocrine/Metabolic
SCORE = 2A

SCREENING
TSHFree T4(Yearly; Consider more frequent
screening during periods of rapid
growth)SECTION 134 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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OTHER THERAPEUTIC MODALITIESSec#Therapeutic
Agent(s)135 Systemic MIBG
(in therapeutic doses)

Potential
Late Effects
Hypothyroidism

Info Link: MIBG used for
diagnostic purposes (i.e., MIBG
scanning) does NOT put patientsat risk for hypothyroidism.

Risk
Factors

HighestRisk Factors

SYSTEMIC RADIATION (cont)
Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed mood(Yearly; Consider more frequent
screening during periods of rapid
growth)PHYSICAL
HeightWeightHair
Skin
Thyroid exam
(Yearly; Consider more frequent
screening during periods of rapid
growth)Health Counseling
Further Considerations
Health Links
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.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SCREENING
TSHFree T4(Yearly; Consider more frequent
screening during periods of rapid
growth)SECTION 135 REFERENCES
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):1662-1664.
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-meta-iodobenzylguanidine 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 ofradiolabeled metaiodobenzylguanidine in children with neuroblastoma. Cancer. Jul 15 2003;98(2):389-396.

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OTHER THERAPEUTIC MODALITIESSec#Therapeutic
Agent(s)Potential
Late Effects

136 Bioimmunotherapy
Insufficient information(e.g., G-CSF, IL-2, erythropoietin) currently available regarding
late effects of biologicalagents

Risk
Factors

HighestRisk Factors

BIOIMMUNOTHERAPY
Periodic
Evaluation

Health Counseling
Further Considerations
SYSTEM = N/ASCORE = N/A

SECTION 136 REFERENCES
No information currently available regarding late effects.

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#

Organ

(Female)137 Breast

BREAST CANCER

At Risk
Population

HighestRisk Factors

Periodic
Evaluation

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 offirst child
Never pregnant
ObesityPrevious breast biopsy withatypical hyperplasia
Hormone replacement therapy

Chest radiation with potential
impact to the breast (see Section
68), including ≥ 20 Gy to thefollowing fields:- Mantle- Mini-Mantle- Mediastinal- Chest (thorax)- Axilla

PATIENTS AT STANDARD RISK (ACS Recommendation)

BRACA1, BRACA2, ATM mutation

PHYSICAL
Breast self exam
(Monthly, beginning at puberty)
Clinical breast exam
(Yearly, beginning at puberty until age 25, then every six months)

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

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 Intervention
Surgery and/or oncology consultation as clinically indicated.

SCREENING
Mammogram(Yearly, beginning 8 years after radiation or at age 25, whichever occurs
last)
Info Link:
There is currently a deficiency in the literature regarding whether or not
TBI is a risk factor for the development of breast cancer. Monitoring ofpatients who received TBI should be determined on an individual basis.
Mammography is currently limited in its ability to evaluate
premenopausal breasts. The role of MRI is evolving for screening of otherpopulations at high risk for breast cancer (e.g., premenopausal known orlikely carriers of gene mutation of known penetrance).

SECTION 137 REFERENCES
Breast Cancer Screening and Diagnosis Guidelines. National Comprehensive Cancer Network Clinical Practice Guidelines. July 13, 2004. Available at: www.nccn.org. Accessed January 5, 2006, 2005.
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.
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.
Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer, 2005. CA Cancer J Clin. Jan-Feb 2005;55(1):31-44; quiz 55-36.
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.
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.
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.
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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Sec
#

Organ

(Female)138 Cervical

At Risk
Population
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)
PHYSICAL
Pelvic exam(Every 1 to 2 years)

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
Gynecology and/or oncology consultation as clinically indicated.

SCREENING
Cervical PAP smear(Yearly for regular PAP test. Every 2 years for liquid-based PAP test. Afterage 30, if patient has had 3 consecutive normal annual PAP tests, may
screen every 2-3 years [with conventional or liquid-based cervicalcytology] or every 3 years [with HPV DNA test plus cervical cytology]).
Info Link:
Begin screening (in patients with a cervix) 3 years after first vaginal
intercourse, or at age 21, whichever occurs first.

SECTION 138 REFERENCES
Screening for Cervical Cancer. File Inventory, Systematic Evidence Review #25:http://www.ahrq.gov. Accessed July 11, 2005, 2005.
Cervical Screening. October 1, 2004; v 1.2005:www.nccn.org. Accessed July 11, 2005, 2005.
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
Smith RA, Cokkinides V, von Eschenbach AC, et al. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin. Jan-Feb 2002;52(1):8-22.

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Sec
#

Organ

139 Colorectal

At Risk
Population
High fat/low fiber dietAge ≥ 50 years
Obesity

COLORECTAL CANCER

HighestRisk Factors
Radiation with potential impact tothe colon/rectum (see Section
78), including ≥ 30 Gy to thefollowing fields:- Whole abdomen- All upper abdominal fields- Pelvic- Spine (thoracic, lumbar,
sacral)Personal history of ulcerative
colitis, gastrointestinal
malignancy, adenomatous
polyps or hepatoblastoma
Familial polyposis
Family history of colorectal
cancer or polyps in first degree
relative

Periodic
Evaluation
PATIENTS AT STANDARD RISK (ACS Recommendation)
SCREENING
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)
Note: The combination of yearly fecal occult blood testing and every 5
year flexible sigmoidoscopy is preferable to either test done alone.

Health Counseling
Further Considerations
Health Links
Colorectal Cancer
Considerations for Further Testing and Intervention
Gastroenterology, surgery and/or oncology consultation asclinically indicated.

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 oncolonoscopy results. Begin monitoring 10 years after radiation or at age
35, whichever occurs 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 first colonoscopy will inform frequency offollow 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 as well established as that of secondary breast cancer
following chest radiation. The expert panel agreed that early onset ofscreening likely was beneficial, and that a prudent course would be toinitiate 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 offollow-up testing.

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Sec
#

Organ

At Risk
Population

HighestRisk Factors

COLORECTAL CANCER (CONT)Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 139 REFERENCES
Screening for Colorectal Cancer in Adults. July 2002; File Inventory, Systematic Evidence Review Number 7AHRQ Publication No. 02-S003:http://www.ahrq.gov/clinic/prev/colscinv.htm.
Accessed July 11, 2005, 2005.
Colorectal Screening. March 24, 2005; v 1.2005:http://www.nccn.org. Accessed July 11, 2005, 2005.
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.
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.
Provenzale D, Gray RN. Colorectal cancer screening and treatment: review of outcomes research. J Natl Cancer Inst Monogr. 2004(33):45-55.
Smith RA, Cokkinides V, von Eschenbach AC, et al. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin. Jan-Feb 2002;52(1):8-22.
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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Sec
#

Organ

(Female)140 Endometrial

At Risk
Population

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 HIGHEST RISK (ACS Recommendation)
SCREENING
Endometrial biopsy(Yearly, beginning at age 35 for patients at highest risk)

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers

Info Link:
Women at highest risk should be informed that screening
recommendation of endometrial biopsy beginning at age 35 is based on
expert opinion in the absence of definitive scientific evidence and thepotential benefits, risks, and limitations of testing for early endometrial
cancer detection should be discussed.

SECTION 140 REFERENCES
Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer, 2005. CA Cancer J Clin. Jan-Feb 2005;55(1):31-44..

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#

Organ

141 Lung

At Risk
Population

HighestRisk Factors

Smoking
Workplace exposures toasbestos, arsenic, radiation
Second hand smoke(in non-smokers)

Chest radiation with potential
impact to the lung

LUNG CANCER
Periodic
Evaluation

PATIENTS AT HIGHEST RISKHISTORY
Cough
Wheezing
SOB
DOE(Yearly, and as clinically indicated)

Health 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)

SECTION 141 REFERENCES
Bauer T. Lung cancer screening. Hematol Oncol Clin North Am. Apr 2005;19(2):209-217.
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.
Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet. Jul 10 1999;354(9173):99-105.
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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#

Organ

142 OralAt Risk
Population
Tobacco use (smoking cigars,
cigarettes, or pipes; dipping,chewing)
Alcohol abuse
Excessive sun exposure(increases risk of cancer oflower lip)
HCT (allogeneic > autologous)

ORAL CANCER

HighestRisk Factors
Head/brain radiation
Neck radiation
TBI
Acute/chronic GVHD

Periodic
Evaluation
PATIENTS AT HIGHEST RISKPHYSICAL
Oral cavity exam
(Yearly)

Health Counseling
Further Considerations
Health Links
Reducing Risk of Second Cancers
Dental Health
Considerations for Further Testing and Intervention
Head and neck/otolaryngology consultation as indicated.

SECTION 142 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.
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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Organ

(Male)

143 Prostate

At Risk
Population
Older age, with steadily
increasing risk after age
40 years.

HighestRisk Factors
African-American race
Family history of prostate cancer
in first degree relative

PROSTATE CANCER
Periodic
Evaluation

ALL PATIENTSClinicians should be prepared to discuss prostate cancer testingwith patients
Info Link:
The USPSTF found good evidence that PSA screening can detect
early-stage prostate cancer but mixed and inconclusive evidence thatearly detection improves health outcomes. Screening is associated with
important harms, including frequent false-positive results andunnecessary anxiety, biopsies, and potential complications of treatmentof some cancers that may never have affected a patient's health. The
USPSTF concludes that evidence is insufficient to determine whether the
benefits outweigh the harms for a screened population. ACS concurs
with this conclusion.

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
Urology and/or oncology consultation as clinically indicated.

SECTION 143 REFERENCES
Prostate Cancer Early Detection. March 24, 2005; v 1.2005:http://www.nccn.org. Accessed July 11, 2005, 2005.
Screening for Prostate Cancer. December 2002; File Inventory, Systematic Evidence Review Number 16:http://www.ahrq.gov/clinic/prev/prostinv.htm. Accessed July 11, 2005, 2005.
Harris R, Lohr KN. Screening for prostate cancer: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. Dec 3 2002;137(11):917-929.
Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer, 2005. CA Cancer J Clin. Jan-Feb 2005;55(1):31-44.

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#

Organ

144 Skin

At Risk
Population

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 skin cancer
History of severe sunburnat young age

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 squamous cellskin cancer. There are no randomized trials or case-control studies that
directly examine whether screening by clinicians is associated withimproved clinical outcomes such as reduced morbidity or mortality fromskin cancer. No studies were found that evaluated whether screening
improves the outcomes of these cancers. The American Cancer Society
recommends skin examination as part of a cancer-related checkup,
which should occur on the occasion of the patient’s periodic healthexamination. Self-examination of skin is recommended 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(Yearly)

SECTION 144 REFERENCES
Screening for Skin Cancer. File Inventory, Systematic Evidence Review Number 2:http://www.ahrq.gov/clinic/serfiles.htm. Accessed July 11, 2005, 2005.
Ferrini R. Screening for skin cancer. Am Fam Physician. Apr 1 2002;65(7):1401-1402.
Ferrini RL, Perlman M, Hill L. American College of Preventive Medicine practice policy statement: skin protection from ultraviolet light exposure. The American College of Preventive Medicine.
Am J Prev Med. Jan 1998;14(1):83-86.
Ferrini RL, Perlman M, Hill L. American College of Preventive Medicine policy statement: screening for skin cancer. Am J Prev Med. Jan 1998;14(1):80-82.
Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst. Apr 18 2001;93(8):618-629.
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.
Wolden SL, Lamborn KR, Cleary SF, Tate DJ, Donaldson SS. Second cancers following pediatric Hodgkin's disease. J Clin Oncol. Feb 1998;16(2):536-544.

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Organ

Young males(Male)

145 Testicular

At Risk
Population

TESTICULAR CANCER

HighestRisk Factors

Periodic
Evaluation

History of cryptorchidism
History of testicular cancer
or carcinoma in-situ incontralateral testis
History of gonadal dysgenesis
Klinefelter's syndrome
Family history of testicularcancerInfo 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 newevidence that screening with clinical examination or testicular
self-examination is effective in reducing mortality from testicular cancer.
Even in the absence of screening, the current treatment interventions
provide very favorable health outcomes. Given the low prevalence oftesticular cancer, limited accuracy of screening tests, and no evidence
for the incremental benefits of screening, the USPSTF concluded that theharms of screening exceed any potential benefits. ACS also no longer
recommends clinical testicular cancer screening or testicular
self-examination.

Health Counseling
Further Considerations

SECTION 145 REFERENCES
Screening for Testicular Cancer PDQ. www.nci.nih.gov. Accessed 01/26/2003.
Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer, 2005. CA Cancer J Clin. Jan-Feb 2005;55(1):31-44.

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ANY CANCER EXPERIENCE

GENERAL HEALTH SCREENING
Sec#

Therapeutic
Agent(s)Potential
Late Effects

146 General Health Screening

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
SCREENING
Refer to United States Preventive
Services Task Forcerecommendations at
www.ahrq.gov/clinic/uspstfix.htm(Yearly)

Health Counseling
Further Considerations
Considerations for Further Testing and Intervention
Childhood cancer survivors should receive general healthmaintenance 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, sexually transmitted diseases, anddiabetes mellitus. Others require counseling regarding theprevention of cardiovascular disease, osteoporosis, and otherdisorders. See www.ahrq.gov/clinic/uspstfix.htm for specificrecommendations.
Assess immunization status on all patients; reimmunize as
indicated. See http://www.cdc.gov/nip/default.htm#schedules
for current immunization schedules.
For all HCT patients, reimmunization per CDC Guidelines(http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm see table 4) or EBMT Guidelines(http://www.nature.com/bmt/journal/v23/n7/pdf/1701641a.pdf).

SECTION 146 REFERENCES
Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society ofAmerica, and the American Society of Blood and Marrow Transplantation. MMWR 2000; 49:1-128 (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm)
Ljungman P. Immunization of transplant recipients. Bone Marrow Transplant. 1999 Apr;23(7):635-6.
United States Preventive Services Task Force recommendations at http://www.ahrq.gov/clinic/uspstfix.htm

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Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 2.0 – March 2006

Index

Copyright 2006 © Children’s Oncology GroupAll rights reserved worldwide

IndexTherapeutic Exposure

SectionAny Cancer Experience

Therapeutic Exposure

SectionAlkylating Agents (continued)

Psychosocial disorders

1

Mental health disorders

1

Male: Gonadal dysfunction (testicular)

7M

Risky behaviors

1

Female: Gonadal dysfunction (ovarian)

7F

Psychosocial disability due to pain

1

Acute myeloid leukemia/myelodysplasia

8

Fatigue

1

Urinary tract toxicity

11

Limitations in healthcare and insurance access2

Bladder malignancy

12

Cyclophosphamide

Ifosfamide
Blood/Serum Products

Male: Gonadal dysfunction (testicular)

7M

Chronic Hepatitis B

3

Female: Gonadal dysfunction (ovarian)

7F

Chronic Hepatitis C

4Acute myeloid leukemia/myelodysplasia

8

HIV infection

5

Urinary tract toxicity

11

Renal toxicity

13

CHEMOTHERAPY

Lomustine (CCNU)
Male: Gonadal dysfunction (testicular)

7M

Any Chemotherapy

Female: Gonadal dysfunction (ovarian)

7F

Dental abnormalities

6

Alkylating AgentsAcute myeloid leukemia/myelodysplasia

8

Pulmonary fibrosis

9

Mechlorethamine
Male: Gonadal dysfunction (testicular)

7M

Male: Gonadal dysfunction (testicular)

7M

Female: Gonadal dysfunction (ovarian)

7F

Female: Gonadal dysfunction (ovarian)

7F

Acute myeloid leukemia/myelodysplasia

8

Acute myeloid leukemia/myelodysplasia

8MelphalanPulmonary fibrosis

9

Male: Gonadal dysfunction (testicular)

7M

Cataracts

10Female: Gonadal dysfunction (ovarian)

7F

Acute myeloid leukemia/myelodysplasia

8

Busulfan

Carmustine (BCNU)
Male: Gonadal dysfunction (testicular)

7M

Female: Gonadal dysfunction (ovarian)

7F

Male: Gonadal dysfunction (testicular)

7M

Acute myeloid leukemia/myelodysplasia

8

Female: Gonadal dysfunction (ovarian)

7F

Pulmonary fibrosis

9

Acute myeloid leukemia/myelodysplasia

8

Chlorambucil

Procarbazine

Thiotepa

Male: Gonadal dysfunction (testicular)

7M

Male: Gonadal dysfunction (testicular)

7M

Female: Gonadal dysfunction (ovarian)

7F

Female: Gonadal dysfunction (ovarian)

7F

Acute myeloid leukemia/myelodysplasia

8

Acute myeloid leukemia/myelodysplasia8

M = Males only; F = Females only

Index
Page 1

Index (cont)
Therapeutic Exposure

SectionNon-Classical Alkylators

Therapeutic Exposure

SectionAntimetabolites (continued)

Dacarbazine (DTIC)

Mercaptopurine (6-MP)

Male: Gonadal dysfunction (testicular)

7M

Hepatic dysfunction, veno-occlusive disease (VOD)

Female: Gonadal dysfunction (ovarian)

7F

Methotrexate (PO, IM, low and high dose IV)

Acute myeloid leukemia/myelodysplasia

8

Osteopenia, osteoporosis

22

Renal toxicity

23
24

Temozolomide

21

Male: Gonadal dysfunction (testicular)

7M

Hepatic dysfunction

Female: Gonadal dysfunction (ovarian)

7F

Methotrexate (high dose IV, IT, IO)

Acute myeloid leukemia/myelodysplasia

8

Neurocognitive deficits

25

Clinical leukoencephalopathy

26

Heavy Metals

Thioguanine (6-TG)

Carboplatin

Hepatic dysfunction, veno-occlusive disease (VOD)

21

Male: Gonadal dysfunction (testicular)

7M

Female: Gonadal dysfunction (ovarian)

7F

Anthracycline Antibiotics

Acute myeloid leukemia/myelodysplasia

8

Daunorubicin

Ototoxicity (myeloablative doses only)

14

Acute myeloid leukemia

27

Peripheral sensory neuropathy

15

Cardiac toxicity

28

Renal toxicity

16

Doxorubicin

Dyslipidemia

17

Acute myeloid leukemia

27

Cardiac toxicity

28

Cisplatin
Male: Gonadal dysfunction (testicular)

7M

Epirubicin

Female: Gonadal dysfunction (ovarian)

7F

Acute myeloid leukemia

27

Acute myeloid leukemia/myelodysplasia

8

Cardiac toxicity

28

Idarubicin

Ototoxicity

14

Peripheral sensory neuropathy

15

Acute myeloid leukemia

27

Renal toxicity

16

Cardiac toxicity

28

Dyslipidemia

17

Mitoxantrone

Antimetabolites

Acute myeloid leukemia

27

Cardiac toxicity

28

Cytarabine (high dose IV)
Neurocognitive deficits

18

Anti-Tumor Antibiotics

Clinical leukoencephalopathy

19

Bleomycin

20

Dactinomycin

Pulmonary toxicity

Cytarabine (SQ, IT, IO, low dose IV)
No known late effects

No known late effects

M = Males only; F = Females only

29
30

Index
Page 2

Index (cont)
Therapeutic Exposure

SectionCorticosteroids

Therapeutic Exposure

Section

RADIATION

Dexamethasone
Osteopenia, osteoporosis

31

All Radiation Fields

Osteonecrosis (avascular necrosis)

32

Secondary benign or malignant neoplasm

38

Cataracts

33

Dysplastic nevi, skin cancer

39

Dermatologic changes (all radiation fields except TBI)

40

Bone malignancies (all radiation fields except TBI)

41

Prednisone
Osteopenia, osteoporosis

31

Osteonecrosis (avascular necrosis)

32

Cataracts

33

Total Body Irradiation (TBI)
Brain tumor

42

Enzymes

Neurocognitive deficits

43

Asparaginase

Metabolic syndrome

49

Growth hormone deficiency

50

No known late effects

34

Cataracts

56

Plant Alkaloids

Dental abnormalities

60

Vinblastine

Thyroid nodules

62
63

Peripheral sensory or motor neuropathy

35

Thyroid cancer

Vasospastic attacks (Raynaud’s phenomenon)

36

Hypothyroidism

64

Female: Breast tissue hypoplasia

69F
70

Vincristine
Peripheral sensory or motor neuropathy

35

Pulmonary toxicity

Vasospastic attacks (Raynaud’s phenomenon)

36

Renal toxicity

79

Female: Uterine vascular insufficiency

83F

Epipodophyllotoxins

Female: Gonadal dysfunction (ovarian)

84F

Etoposide (VP-16)

Male: Gonadal dysfunction (testicular) – germ cell failure

86M

Acute myeloid leukemia

37
Cranial Radiation

Teniposide (VM-26)
Acute myeloid leukemia

37

Brain tumor

42

Neurocognitive deficits

43

Clinical leukoencephalopathy

44

Craniofacial abnormalities

46

Chronic sinusitis

47

Overweight/obesity48

Metabolic syndrome

49

Growth hormone deficiency

50

M = Males only; F = Females only

Index
Page 3

Index (cont)
Therapeutic Exposure

Section

Cranial Radiation (continued)

Therapeutic Exposure

SectionOrbital/Eye Radiation (continued)

Precocious puberty

51

Cataracts

56

Cerebrovascular complications

45

Xerostomia/salivary gland dysfunction

59

Hyperprolactinemia

52

Dental abnormalities

60

Central hypothyroidism

53

Thyroid nodules

62

Gonadotropin deficiency

54

Thyroid cancer

63

Central adrenal insufficiency

55

Hypothyroidism

64

Orbital/Eye radiation dose >40 Gy:

Ear/Infratemporal Radiation

Cranial radiation dose >30 Gy:
Ocular toxicity

57

Brain tumor

42

Ototoxicity

58

Neurocognitive deficits

43

Craniofacial abnormalities

46

Cranial radiation dose >40 Gy:
Cerebrovascular complications

45

Chronic sinusitis

47

Hyperprolactinemia

52

Overweight/obesity

48

Central hypothyroidism

53

Metabolic syndrome

49

Gonadotropin deficiency

54

Growth hormone deficiency

50

Central adrenal insufficiency

55

Precocious puberty

51

Osteoradionecrosis

61

Ear/Infratemporal radiation dose >30 Gy:

Hyperthyroidism

65

Ototoxicity

Carotid artery disease66

Ear/Infratemporal radiation dose >40 Gy:

Orbital/Eye Radiation

58

Cerebrovascular complications

45

Hyperprolactinemia

52
53

Brain tumor

42

Central hypothyroidism

Craniofacial abnormalities

46

Gonadotropin deficiency

54

Chronic sinusitis

47

Central adrenal insufficiency

55

Overweight/obesity48

Metabolic syndrome

49

Nasopharyngeal Radiation

Growth hormone deficiency

50

Brain tumor

Precocious puberty

51

Craniofacial abnormalities

46

Cataracts

56

Chronic sinusitis

47

Overweight/obesity48

Metabolic syndrome

49

Orbital/Eye radiation dose >30 Gy:
Ocular toxicity

57

M = Males only; F = Females only

42

Index
Page 4

Index (cont)
Therapeutic Exposure

SectionNasopharyngeal Radiation (continued)

Therapeutic Exposure

Section

Cervical Spine Radiation (Spine – Cervical)

Growth hormone deficiency

50

Xerostomia/salivary gland dysfunction

59

Precocious puberty

51

Dental abnormalities

60

Xerostomia/salivary gland dysfunction

59

Thyroid nodules

62

Dental abnormalities

60

Thyroid cancer

63
64

Thyroid nodules

62

Hypothyroidism

Thyroid cancer

63

Cervical spine radiation dose >12 Gy:

Hypothyroidism

64

Nasopharyngeal radiation dose >30 Gy:
Ototoxicity

58

Nasopharyngeal radiation dose >40 Gy:
Cerebrovascular complications

Musculoskeletal growth problems

88

Cervical spine radiation dose >30 Gy:
Esophageal stricture

73

Cervical spine radiation dose >40 Gy:
45Osteoradionecrosis

61

Hyperprolactinemia

52

Hyperthyroidism

65

Central hypothyroidism

53

Carotid artery disease

66

Gonadotropin deficiency

54

Subclavian artery disease

67

Central adrenal insufficiency

55

Radiation-induced fracture

91

Osteoradionecrosis

61

Hyperthyroidism

65

Carotid artery disease66

Thoracic Spine Radiation (Spine -Thoracic)
Cardiac toxicity

71

Thoracic spine radiation dose >12 Gy:
Oropharyngeal Radiation
Xerostomia/salivary gland dysfunction

Musculoskeletal growth problems

88

59

Scoliosis

89

Thoracic spine radiation dose >30 Gy:

Dental abnormalities

60

Thyroid nodules

62

Esophageal stricture73

Thyroid cancer

63

Bowel obstruction

76

Hypothyroidism

64

Oropharyngeal radiation dose >40 Gy:

Chronic enterocolitis, fistula, strictures

77

Colorectal cancer

78
90

Osteoradionecrosis

61

KyphosisHyperthyroidism

65

Thoracic spine radiation dose >40 Gy:

Carotid artery disease

66

Radiation-induced fracture

M = Males only; F = Females only

91

Index
Page 5

Index (cont)
Therapeutic Exposure

SectionLumbar Spine Radiation (Spine – Lumbar)

Therapeutic Exposure

Section

Cervical (Neck) Radiation
Xerostomia/salivary gland dysfunction

Lumbar spine radiation dose >12 Gy:

59

Musculoskeletal growth problems

88

Dental abnormalities

60

Scoliosis

89

Thyroid nodules

62

Thyroid cancer

63

Female: Uterine vascular insufficiency

83F

Hypothyroidism

64

Female: Gonadal dysfunction (ovarian)

84F

Musculoskeletal growth problems

88

Lumbar spine radiation dose >25 Gy:

Lumbar spine radiation dose >30 Gy:

Cervical (neck) radiation dose >30 Gy:

Bowel obstruction

76

Esophageal stricture

Chronic enterocolitis, fistula, strictures

77

Cervical (neck) radiation dose >40 Gy:

Colorectal cancer

78

Osteoradionecrosis

Lumbar spine radiation dose >40 Gy:
Radiation-induced fracture

91

Sacral Spine Radiation (Spine – Sacral)

73
61

Hyperthyroidism

65

Carotid artery disease66

Subclavian artery disease

67

Radiation-induced fracture

91

Sacral spine radiation dose >12 Gy:
Musculoskeletal growth problems

88

Supraclavicular Radiation

Scoliosis

89

Xerostomia/salivary gland dysfunction

Sacral spine radiation dose >25 Gy:

59

Dental abnormalities

60

Female: Uterine vascular insufficiency

83F

Thyroid nodules

62

Female: Gonadal dysfunction (ovarian)

84F

Thyroid cancer

63

Hypothyroidism

64
88

Sacral spine radiation dose >30 Gy:
Bowel obstruction

76

Musculoskeletal growth problems

Chronic enterocolitis, fistula, strictures

77

Supraclavicular radiation dose >30 Gy:

Colorectal cancer

78

Esophageal stricture

Hemorrhagic cystitis

80

Supraclavicular radiation dose >40 Gy:

73

Urinary tract toxicity

81

Osteoradionecrosis

61

Bladder malignancy

82

Hyperthyroidism

65

Carotid artery disease66

Sacral spine radiation dose >40 Gy:
Radiation-induced fracture91

Subclavian artery disease

67

Radiation-induced fracture91

M = Males only; F = Females only

Index
Page 6

Index (cont)
Therapeutic Exposure

SectionMantle Radiation

Therapeutic Exposure

SectionMini-Mantle Radiation (continued)

Xerostomia/salivary gland dysfunction

59

Dental abnormalities

60

Female: Breast cancer

Thyroid nodules

62

Mini-Mantle radiation dose >30 Gy:

Thyroid cancer

63

Esophageal stricture

Hypothyroidism

64

Mini-Mantle radiation dose >40 Gy:

Mini-Mantle radiation dose >20 Gy:
68F
73

Female: Breast tissue hypoplasia

69F

Osteoradionecrosis

61

Pulmonary toxicity

70

Hyperthyroidism

65

Cardiac toxicity

71

Carotid artery disease66

Musculoskeletal growth problems

88

Subclavian artery disease67

Scoliosis

89

Radiation-induced fracture

91

Kyphosis90
Mediastinal Radiation

Mantle radiation dose >20 Gy:
Female: Breast cancer

68F

Mantle radiation dose >30 Gy:
Esophageal stricture73

Mantle radiation dose >40 Gy:

Female: Breast tissue hypoplasia

69F

Pulmonary toxicity

70

Cardiac toxicity

71

Musculoskeletal growth problems

88

Osteoradionecrosis

61

Scoliosis

89

Hyperthyroidism

65

Kyphosis90

Carotid artery disease

66

Mediastinal radiation dose >20 Gy:

Subclavian artery disease67

Female: Breast cancer

Radiation-induced fracture

91

Mediastinal radiation dose >30 Gy:
Esophageal strictureMini-Mantle Radiation

68F
73

Mediastinal radiation dose >40 Gy:

Xerostomia/salivary gland dysfunction

59

Dental abnormalities

60

Radiation-induced fracture91

Thyroid nodules

62

Thyroid cancer

63

Female: Breast tissue hypoplasia

69F

Hypothyroidism

64

Pulmonary toxicity

70

Female: Breast tissue hypoplasia

69F

Cardiac toxicity

71

Musculoskeletal growth problems

88

Musculoskeletal growth problems

88

Scoliosis

89

Scoliosis

89

Kyphosis

90

Kyphosis90

Chest (Thorax) Radiation

M = Males only; F = Females only

Index
Page 7

Index (cont)
Therapeutic Exposure

Section

Therapeutic Exposure

Chest (Thorax) Radiation (continued)

Whole Abdominal Radiation (continued)

Chest (thorax) radiation dose >20 Gy:

Whole abdominal radiation dose >30 Gy:

Female: Breast cancer

68F

Chest (thorax) radiation dose >30 Gy:
Esophageal stricture

73

Chest (thorax) radiation dose >40 Gy:
Radiation-induced fracture

91

Axillary (Axilla) Radiation

Esophageal stricture

73

Hepatic fibrosis, cirrhosis

74

Cholelithiasis

75

Bowel obstruction

76

Chronic enterocolitis, fistula, strictures

77

Colorectal cancer

78

Hemorrhagic cystitis

80
81

Female: Breast tissue hypoplasia

69F

Urinary tract toxicity

Cardiac toxicity

71

Whole abdominal radiation dose >40 Gy:

Musculoskeletal growth problems

88

Axillary radiation dose >20 Gy:
Female: Breast cancer

Functional asplenia

72

Radiation-induced fracture

91

68F
All Upper Abdominal Fields*

Axillary radiation dose >40 Gy:
Radiation-induced fracture

Section91*Includes hepatic, hemiabdomen/flank, upper quadrant, renal bed,
spleen (partial, entire), splenic pedicle, inverted Y, paraaortic

Whole Lung Radiation

Cardiac toxicity

71

Female: Breast tissue hypoplasia

69F

Renal toxicity (note: does not apply to paraaortic field)

79
88

Pulmonary toxicity

70

Musculoskeletal growth problems

Musculoskeletal growth problems

88

Scoliosis

89

Scoliosis

89

Kyphosis

90

Kyphosis

90

Upper abdominal radiation dose >30 Gy:

Whole Abdominal Radiation
Cardiac toxicity

71

Esophageal stricture

73

Hepatic fibrosis, cirrhosis

74

Cholelithiasis

75

Renal toxicity

79

Bowel obstruction76

Bladder malignancy

82

Chronic enterocolitis, fistula, strictures

77
78

Female: Uterine vascular insufficiency

83F

Colorectal cancer

Female: Gonadal dysfunction (ovarian)

84F

Upper abdominal radiation dose >40 Gy:

Musculoskeletal growth problems

88

Radiation-induced fracture

Scoliosis

89>40 Gy to entire spleen, left upper quadrant or inverted Y field:

Kyphosis90

Functional asplenia

M = Males only; F = Females only

91
72

Index
Page 8

Index (cont)
Therapeutic Exposure

Section

Therapeutic Exposure

SectionAll Pelvic Fields*

Hematopoietic Cell Transplant (HCT)*Includes pelvic, vaginal, prostate, bladder, iliac, inguinal,

Acute myeloid leukemia/myelodysplasia

femoral and inverted Y; hemiabdominal included only if field

Solid tumors

93

extended below iliac crest

Lymphoma

94

92

Bladder malignancy

82

Hepatic toxicity

95

Female: Uterine vascular insufficiency

83F

Osteonecrosis (avascular necrosis)

96

Osteopenia, osteoporosis

97

84F

HCT with chronic GVHD (cGVHD):(note: does not apply to iliac/inguinal fields)
Female: Gonadal dysfunction (ovarian)
Female: Vaginal fibrosis/stenosis

85F

Dermatologic toxicity

98

Male: Gonadal dysfunction (testicular) – germ cell failure

86M

Xerophthalmia (keratoconjunctivitis sicca)

99

Musculoskeletal growth problems

88

Xerostomia, salivary gland dysfunction, dental caries,

Scoliosis

89

Pelvic radiation dose >20 Gy:
Male: Gonadal dysfunction (testicular) – Leydig cell dysfunction

87M

Pelvic radiation dose >30 Gy:

periodontal disease, oral cancer

100

Pulmonary toxicity

101

Immunologic complications

102

Functional asplenia (patients with active cGVHD only)103

Bowel obstruction

76

Esophageal stricture

104

Chronic enterocolitis, fistula, strictures

77

Female: Vaginal fibrosis/stenosis

105F

Joint contractures

106

Colorectal cancer

78

Hemorrhagic cystitis

80

Urinary tract toxicity

81

Pelvic radiation dose >40 Gy:
Radiation-induced fracture

Surgery
Amputation

91

Amputation-related complications

107

Central venous catheter
Testicular Radiation
Male: Gonadal dysfunction (testicular) – germ cell failure

Thrombosis, vascular insufficiency, infection of retained cuff
86M

Testicular radiation dose >20 Gy:
Male: Gonadal dysfunction (testicular) – Leydig cell dysfunction

or line tract

108

Cystectomy
87M

Cystectomy-related complications

109

Enucleation
Extremity Radiation
Musculoskeletal growth problems

Impaired cosmesis, poor prosthetic fit, orbital hypoplasia
88

Female: Pelvic floor dysfunction, urinary incontinence,

Extremity radiation dose >40 Gy:
Radiation-induced fracture

110

Hysterectomy

91

sexual dysfunction

M = Males only; F = Females only

111F

Index
Page 9Index (cont)
Therapeutic Exposure

SectionSurgery (continued)

Pulmonary lobectomy, metastasectomy, wedge resection
112

Limb sparing procedure
Complications related to limb sparing procedure

SectionSurgery (continued)

Laparotomy
Adhesions, bowel obstruction

Therapeutic Exposure

Pulmonary dysfunction

130

Splenectomy
113

Nephrectomy

Asplenia

131

Thyroidectomy

Renal toxicity

114

Male: Hydrocele

114

Hypothyroidism

132

Other Therapeutic Modalities

Neurosurgery – brain
Neurocognitive deficits

115

Radioiodine therapy (I-131 thyroid ablation)

Motor and/or sensory deficits

116

Lacrimal duct atrophy

133

Seizures117

Hypothyroidism

134

Hydrocephalus; shunt malfunction

118

Systemic MIBG (in therapeutic doses)

119

Bioimmunotherapy

Neurogenic bowel; fecal incontinence

120

Insufficient information currently available regarding late effects

Male: Sexual dysfunction

121M

Female: Sexual dysfunction

121F

Hypothyroidism

Neurosurgery – spinal cord
Neurogenic bladder; urinary incontinence

Oophoropexy
Female: Oophoropexy-related complications

122F

137F

Female: Cervical

138F
139
140F

Lung

141

124F

Oral

142

Male: Prostate

143M

125M

Pelvic surgery
Urinary incontinence; urinary tract obstruction

Female: Breast

Female: Endometrial

Orchiectomy
Male: Hypogonadism, infertility

Cancer Screening Guidelines

123F

Oophorectomy (bilateral)
Female: Hypogonadism, infertility

136

Colorectal

Oophorectomy (unilateral)
Female: Premature menopause

135

Skin

144

Male: Testicular

145M

126

Fecal incontinence

127

General Health Screening

Male: Sexual dysfunction

128M

General Health Screening

Female: Sexual dysfunction

128F

Male: Hydrocele

129M

M = Males only; F = Females only

146

Index
Page 10