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

Version 3.0 – October 2008www.survivorshipguidelines.org

Copyright 2008 © Children’s Oncology GroupAll rights reserved worldwide

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 3.0 – October 2008www.survivorshipguidelines.org

Copyright 2008 © Children’s Oncology GroupAll rights reserved worldwide

COG Long-Term Follow-Up Guidelines
Content Outline
Long-Term Follow-Up Guidelines• Abstract• Disclaimer• Contributors- Panel of Experts- Task Force Membership- Health Link Authors and Reviewers- Guideline Development Task Force and Reviewers• Introductory Material- Introduction- Explanation of Scoring- Instructions for Use- New to Version 3.0• Long-Term Follow-Up Guidelines

Appendix I: Materials for Clinical Application of LTFU Guidelines• Patient-Specific Guideline Identification Tool
• Radiation Reference Guide• Health Link Index by Guideline Section Number• 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)• Reference Materials- Abbreviations- Chemotherapy Agents
Appendix II: Health Links (Patient Education Materials)

Suggested Citations for COG Long-Term Follow-Up Guidelines
Guidelines
Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers, Version 3.0. Arcadia, CA: Children's Oncology Group;
October 2008; Available on-line: www.survivorshipguidelines.org.

Guidelines Methodology:
Landier W, Bhatia S, Eshelman DA, Forte KJ, Sweeney T, Hester AL, Darling J, Armstrong FD, Blatt J, Constine LS, Freeman CR, Friedman DL, Green DM, Marina N, Meadows AT,
Neglia JP, Oeffinger KC, Robison LL, Ruccione KS, Sklar CA, Hudson MM. Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group
long-term follow-up guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 2004; 22(24):4979-90.

Health Links Background and Application:
Eshelman D, Landier W, Sweeney T, Hester AL, Forte K, Darling J & Hudson MM. Facilitating care for childhood cancer survivors: integrating Children's Oncology Group long-term
follow-up guidelines and health links in clinical practice. J Pediatr Oncol Nurs 2004; 21(5): 271-280.

Content Outline

Abstract – Version 3.0
The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors ofChildhood, Adolescent, and Young Adult Cancers
Release date: October 2008
Status:Updated from Version 2.0 incorporating modifications based on recommendations from the Children’s Oncology Group’s LongTerm Follow-Up Guideline Core Committee and its eighteen associated multidisciplinary Task Forces.ersion 3.0 - 7/08

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, a radiation reference guide, and a tool to assist in identifying guideline applicability for
individual patients based on therapeutic exposures. The information provided in these guidelines is important for primary
healthcare providers in the fields of pediatrics, oncology, internal medicine, family practice, and gynecology, as well as
subspecialists in many fields. Implementation of these guidelines is intended to increase awareness of potential late effects andto standardize and enhance follow-up care provided to survivors of pediatric malignancies throughout their lifespan.

Source:Version 3.0 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 and are maintained and updated by the Children’s Oncology
Group’s Long-Term Follow-up Guidelines Core Committee and its associated Task Forces.
For Informational Purposes Only: The information and contents of each document or series of documents made available by the Children’s Oncology Group relating to late effects of cancer
treatment and care or containing the title "Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers" or the title "Health Link", whether available in print
or electronic format (including any digital format, e-mail transmission, or download from the website), shall be known hereinafter as "Informational Content". All Informational Content is for
informational purposes only. The Informational Content is not intended to substitute for medical advice, medical care, diagnosis or treatment obtained from a physician or healthcare provider.
To cancer 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
related to or arising out of use, review or access of the Informational Content.
Proprietary Rights: The Informational Content is subject to protection under the copyright law and other intellectual property law in the United States and worldwide. The Children's Oncology
Group retains excusive copyright and other right, title, and interest to the Informational Content and claims all intellectual property rights available under law. You hereby agree to help the Children’s
Oncology Group secure all copyright and intellectual property rights for the benefit of the Children’s Oncology Group by taking additional action at a later time, action which could include signing
consents and legal documents and limiting dissemination or reproduction of Informational Content.

Disclaimer

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 3.0 – October 2008

Contributors

Copyright 2008 © Children’s Oncology GroupAll rights reserved worldwide

Long-Term Follow-Up Guidelines
Panel of Experts
The following members of the Children’s Oncology Group Long-Term Follow-Up (LTFU) Guidelines Core Committee participated in comprehensive
review and scoring of Version 3.0 of the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, andYoung Adult Cancers:
Melissa M. Hudson, MD
Co-Chair – COG LTFU Guidelines Core Committee
Member, Department of Hematology-Oncology
Director, Cancer Survivorship Division
Co-Leader, Cancer Prevention & Control Program
St. Jude Children’s Research Hospital
Memphis, TN
Wendy Landier, RN, MSN, CPNP, CPON®
Co-Chair – COG LTFU Guidelines Core Committee
Clinical Director, Center for Cancer Survivorship
City of Hope National Medical Center
Duarte, CALouis S. Constine, MD, F.A.S.T.R.O.
Co-Chair – COG LTFU Guidelines Core Committee
Professor of Radiation Oncology and Pediatrics
Vice Chair, Department of Radiation Oncology
James P. Wilmot Cancer Center
University of Rochester Medical Center
Rochester, NY
Smita Bhatia, MD, MPH
Co-Chair – COG LTFU Guidelines Core Committee
Professor and Chair, Department of Population Sciences
City of Hope National Medical Center
Associate Director, Population Research
City of Hope Comprehensive Cancer Center
Duarte, CA

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
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
Debra L. Friedman MD, MS
Associate Professor of Pediatrics
Ingram Distinguished Chair in Pediatric Oncology
Leader, Cancer Control and Prevention Program
Vanderbilt Ingram Cancer Center
Nashville, TN
Daniel M. Green, MD
Member, Departments of Hematology-Oncology
and Epidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TN

Panel of Experts
Page 1Long-Term Follow-Up Guidelines
Panel of Experts (cont)
Nina Kadan-Lottick, MD, MSPH
Associate Research Scientist
Department of Pediatrics
Yale University School of Medicine
New Haven, CT
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

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

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

Panel of Experts
Page 2

COG Long Term Follow-Up Guidelines
Task Force Membership 2006 - 2008
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, MD

City of Hope National Medical Center

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*

Cincnnati Children’s Hospital Medical 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

Satkiran S. Grewal, MD*

Baystate Medical Center

Pediatric oncology

Cathy Hodge, Patient Advocate

Children’s Oncology Group

Patient advocacy

Wendy Landier, RN, MSN, CPNPCity 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

Renee F. Reymond, MD

Ochsner Clinic

Primary care

Patricia Shearer, MD, MS*

University of Florida

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

Task Force Members

Institution

Expertise

Cancer Screening

Louis S. Constine, MD
Debra Friedman, MD, MS
Melissa M. Hudson, MD
Marilyn Leitch, MD
Martin Mahoney, MD, PhD, FAAFP
Kathleen 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
Vanderbilt Children’s Hospital
St. Jude Children’s Research Hospital
University of Texas Southwestern Medical Center
Roswell Park Cancer InstituteChildrens Hospital Los Angeles
Emory University
St. Jude Children’s Research Hospital
Memorial Sloan-Kettering Cancer Center
American Cancer SocietyChildrens Hospital Los Angeles

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

Cardiovascular

M. Jacob Adams, MD, MPH
Ming Hui Chen, MD, MMSc
David Hodgson, MD
Karen Kinahan, MS, RN
Neyssa Marina, MD*
Kathleen Meeske, PhD, RN
David Rosenthal,MD*
Sadhna Shankar, MD*
Julia Steinberger, MD, MS*Co-Chair

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

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

Task Force Membership
Page 2

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

Task Force Members
Nathalie Alos, MD
Eric Chow, MD, MPH
Laurie Cohen, MD
Kimberley Dilley, MD, MPH
Eileen Duffey-Lind, RN, MS, PNP
Wendy Hobbie, MSN, RN, CRNP
Kala Kamdar, MD
Caroline Laverdiere, MD*
Lillian R. Meacham, MD
Daniel Mulrooney, MD*
Jill Simmons, MD
Charles Sklar, MD
Stacey Urbach, MD

Institution

Expertise

Ste-Justine Hospital
Seattle Children’s HospitalDana-Farber Cancer InstituteChildren’s Memorial HospitalDana-Farber Cancer Institute
The Children’s Hospital of Philadelphia
Texas Children’s Cancer Center
Ste-Justine HospitalChildren’s Healthcare of Atlanta
University of Minnesota Cancer Center
Vanderbilt Children’s Hospital
Memorial Sloan-Kettering Cancer Center
Hospital for Sick Children

Pediatric endocrinology
Pediatric oncology
Pediatric endocrinology
Primary care
Pediatric oncology nursing
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology
Pediatric endocrinology
Pediatric oncology
Pediatric endocrinology
Pediatric endocrinology
Pediatric endocrinology

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
St. Jude Children’s Research HospitalChildren’s Memorial Medical Center at Chicago
The Children’s Hospital of Philadelphia
Dana-Farber Cancer Institute
C. S. Mott Children’s HospitalChildren’s Oncology Group
University of Tennessee
St. Jude Children’s Research Hospital
Inova Fairfax Hospital

Pediatric oncology
Pediatric oncology
Pediatric oncology
Radiation oncology
Urology
Pediatric oncology
Pediatric oncology
Pediatric oncology nursing
Pediatric oncology
Pediatric oncology nursing
Patient advocacy
Nursing
Pediatric oncology
Pediatric Oncology*Co-Chair

Fertility/Reproduction

Sharon Abish, MD
Jacqueline Casillas, MD
Mishel L. Davis, CRA
James Douglas, MD
Fernando A. Ferrer, MD
Daniel Green, MD
Nobuko Hijiya, MD
Wendy Hobbie, MSN, RN, CRNP
Lisa Kenney, MD
Marcia Leonard, RN, CPNP*Louis Leone, Patient Advocate
Wendy Likes, DNSc, ARNP-BC
Monika Metzger, MD*
Marcie Weil, MD*Co-Chair

Task Force Membership
Page 3

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

Hematopoietic Cell
Transplant

Immune/Spleen

Task Force Members
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
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
Scott Baker, MD
Katharina Elliott, MD
Jill Ginsberg, MD
Seira Kurian, MD, MS, MPH
Karen Mandel, MD, FRCPC, FAAP
Anna Meadows, MD
Joanna Perkins, MD, MS*
Karla Wilson, RN, MSN, FNP-C*ChairInstitution

Expertise

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

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

University of Minnesota Cancer Center
Kalamazoo Center for Medical Studies
The Children’s Hospital of Philadelphia
City of Hope National Medical Center
Children’s Hospital of Eastern Ontario
The Children’s Hospital of Philadelphia
Children’s Hospitals and Clinics of Minnesota
City of Hope National Medical Center

Pediatric oncology
Pediatric oncology
Pediatric oncology
Primary care
Pediatric oncology
Pediatric oncology
Pediatric oncology
Pediatric oncology nursing

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
Sue Kaste, DO*
Missy Layfield, Patient Advocate
Rex Marco, MD
Man Wai Ng, DDS, MPH
Arnold Paulino, MD
Susan F. Shaw, RN, MS, PNP
Pamela Smith, MSN, RN, FNP-C
Sheri Spunt, MD
Lynn Tanner, MS, PT*Chair

UCLA School of Medicine
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 SyracuseWest Virginia University HSC - Charleston
St. Jude Children’s Research HospitalChildren’s Hospitals and Clinics of Minnesota

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

Neurocognitive/Behavioral

F. Daniel 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 Center
Vanderbilt Children’s Hospital
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 Kent, 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*ChairCincinnati Children’s Hospital Medical Center
Hospital for Sick Children
Yale University School of Medicine
St. Jude Children’s Research Hospital
Emory University
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

Cindy CochranNatia Esiashvili, MD
Sue Kaste, DO
Missy Layfield, Patient Advocate
Leonard A. Mattano, Jr., MD*
Lillian R. Meacham, MD*
Kirsten Ness, PT, PhD
Susan Shannon, RN, MSN, CPNP, CPON
Karen Wasilewski, MD*Co-Chair

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

Pediatric oncology nursing
Radiation oncology
Diagnostic imaging
Patient advocacy
Pediatric oncology
Pediatric endocrinology
Physical therapy
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 Center
Vanderbilt Children’s Hospital
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
St. Jude Children’s Research Hospital
LeBonheur Children’s Medical Center
Virginia Commonwealth University
Methodist Hospital Houston
Pediatric Urology Associates Phoenix
University of Florida
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 System
Richmond, 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

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

Sunita Patel, PhD
Department of Pediatric Hematology/Oncology
City of Hope Comprehensive Cancer Center
Duarte, CA

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:
F. 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
Guideline Development Task Force – Initial Versions
The Children’s Oncology Group Nursing Discipline and Late Effects Committee developed the initial versions (1.0, 1.1, and 1.2) of the Children’s
Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers collaboratively through 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 National Medical 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
Reviewers - Initial Versions
The following individuals participated in the review process during development of the initial versions (1.0, 1.1, and 1.2) of the Children’s Oncology
Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers:
Arlina Ahluwalia, MD
Department of General Internal Medicine
Stanford University
Palo Alto, CA

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

Marcia Leonard, RN, CPNP
Department of Pediatric Hematology/Oncology
C.S. Mott Children’s Hospital
Ann Arbor, MI

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

Wendy Hobbie, MSN, RN, PNP
Division of Oncology
Children’s Hospital of Philadelphia
Philadelphia, PA

Mary Leonard, MD, MSCE
Division of Nephrology
Children’s Hospital of Philadelphia
Philadelphia, PA

Anna T. Meadows, MD
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

Louis A. Leone, Esq.
COG Patient Advocacy Committee
Walnut Creek, CA

Grace Powers Monaco, MDChildhood Cancer Ombudsman Program
Heathsville, VA

Neyssa Marina, MD
Pediatric Hematology Oncology
Stanford University Medical Center
Stanford,CA

Raymond Mulhern, PhD
Division of Behavioral Medicine
St. Jude Children's Research Hospital
Memphis, TN

Leonard Mattano, MD
Pediatric Hematology/Oncology
Kalamazoo Center for Medical Studies
Michigan State University
Kalamazoo, MIJohn R. Mussman
COG Patient Advocacy Committee
Chicago, IL

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

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

Michael Neel, MD
Division of Orthopedics
St. Jude Children's Research Hospital
Memphis, TN
Joseph P. Neglia, MD, MPH
Department of Pediatrics
Division of Hematology, Oncology,
Blood and Marrow Transplantation
University of Minnesota School of Medicine
Minneapolis, MN

Reviewers
Page 2

Long-Term Follow-Up Guidelines
Reviewers (cont)
Mary Nelson, RN, MS, CPNP, CPON®
Childrens Center for Cancer and Blood Diseases
Childrens Hospital Los Angeles
Los Angeles, CA

Kathy Ruble, RN, MSN, CPNP, AOCN®
Pediatric Oncology
Johns Hopkins Hospital
Baltimore, MD

Deborah Waber, PhD
Department of Psychiatry
Boston Children's Hospital
Boston, MA

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

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

Susan L. Weiner, PhD
The Children’s Cause, Inc.
Silver Spring, MD

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

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

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

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

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

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

Leslie L. Robison, PhD
Department of Epidemiology and Cancer Control
St. Jude Children’s Research Hospital
Memphis, TNDavid Rosenthal, MD
Department of Pediatrics/Cardiology
Lucile Packard Children’s Hospital at Stanford
Palo Alto, 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

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

Reviewers
Page 3

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 3.0 – October 2008

Introductory Material

Copyright 2008 © Children’s Oncology GroupAll rights reserved worldwide

Introduction – Version 3.0
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 32 (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, a radiation reference guide, and a tool to assist in identifying guideline applicability for
individual patients based on therapeutic exposures.

Goal:

Implementation of these guidelines is intended to increase quality of life and decrease complication-related healthcare
costs for pediatric cancer survivors by providing standardized and enhanced follow-up care throughout the lifespan that(a) promotes healthy lifestyles, (b) provides for ongoing monitoring of health status, (c) facilitates early identification oflate effects, and (d) provides timely intervention for late effects.
Introduction
Page 1

Introduction – Version 3.0 (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 3.0 (cont)
Developer:

The COG-LTFU Guidelines were developed as a collaborative effort of the Children’s Oncology Group Nursing Disciplineand Late Effects Committee and are maintained and updated by the Children’s Oncology Group’s Long-Term Follow-Up
Guidelines Core Commitee and its associated Task Forces. All Children’s Oncology Group members have complied with
the COG conflict of interest policy, which requires disclosure of any potential financial or 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 2008) 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 3.0 (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 3.0 (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 are charged with the responsibility for monitoring the
medical literature in regard to specific system-related clinical topics relevant to the guidelines (e.g., cardiovascular,
neurocognitive, fertility/reproductive), providing periodic reports to the Late Effects Committee, and recommending
revisions to the guidelines and their associated health education materials and references (including the addition oftherapeutic exposures) as new information becomes available. Task force members are assigned according to theirrespective areas of expertise and clinical interest and membership is updated every 2 years. A list of these task forces
and their membership is included in the "Contributors" section of this document. The revisions incorporated into theprevious (Version 2.0 – March 2006) and current (Version 3.0 – October 2008) release of these guidelines reflect thecontributions 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 COG Long-Term Follow-Up
Guideline Core Committee on a bi-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 the guidelines, 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 3.0 (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 3.0 (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 Long-Term Follow-Up Guideline Core Committee, and proposals to study
feasibility of guideline use in limited institutions are currently underway. Issues to be addressed include description of
anticipated barriers to application of the recommendations in the guidelines and development of review criteria formeasuring changes in care when the guidelines are implemented. Additional concerns surround the lack of current
evidence establishing the efficacy of screening for late complications in pediatric cancer survivors. While mostclinicians believe that ongoing surveillance for these late complications is important in order to allow for early detection
and intervention for complications that may arise, development of studies addressing the efficacy of this approach isimperative in order to determine which screening modalities are optimal for asymptomatic survivors.
In addition, the clinical utility of this lengthy document has also been a top concern of the COG Long-Term Follow-Up
Guideline Core Committee. While recognizing that the length and depth of these guidelines is important in order toprovide 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 their clinical application. Therefore, the COG Long-Term Follow-Up Guideline Core Committee iscurrently 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 clinicianfocused format for ease of patient-specific application 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 atwww.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 3.0
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.

Therapeutic Agent

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

Potential Late Effects

Most common late treatment complications associated with specified therapeutic intervention.

Risk Factors

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

Instructions for Use
Page 1

Instructions for Use – Version 3.0 (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).

Instructions for Use
Page 2

Instructions for Use – Version 3.0 (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.

Patient-Specific
Guideline IdentificationTool

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 Patient-Specific
Guideline Identification Tool is imperative in order to determine each potential late effect associated witheach therapeutic agent within this document (see Appendix I).

USING THE COG LTFU GUIDELINES TO DEVELOP INDIVIDUALIZED SCREENING RECOMMENDATIONS:In order to accurately derive individualized screening recommendations for a specific childhood cancer survivor using the Children’s Oncology
Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, the following procedure should be
followed. (Note: For ease of use, a Patient-Specific Guideline Identification Tool has been developed to streamline the following process and isincluded in Appendix I).
Instructions for Use
Page 3

Instructions for Use – Version 3.0 (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 (Sections 6-37), see
the "Chemotherapy" portion of the Patient-Specific Guideline Identification Tool in Appendix I. For list of generic and brand names ofchemotherapy 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 radiation, include age at first dose). For list of radiation fields
addressed by these guidelines (Sections 38-91), see "Radiation" portion of the Patient-Specific Guideline Identification Tool in Appendix
I. For clarification of anatomical areas included in common radiation fields, see the Radiation Reference Guide in Appendix I. For
clarification regarding radiation dose calculations for determining screening recommendations for individual patients, see Determining
Applicability of Radiation Sections for Specific Patients Based on Exposure on Page 48 of these guidelines and in the Radiation
Reference Guide in Appendix I.
• Whether or not the survivor underwent a hematopoietic cell transplant (HCT), and if so, whether or not the survivor has a history ofchronic graft-versus-host disease (cGVHD).
• Names of all relevant surgical procedures. For list of surgical procedures addressed by these guidelines (Sections 107-132), see"Surgery" portion of the Patient-Specific Guideline Identification Tool in Appendix I.
• Names of all other therapeutic modalities. For list of other therapeutic modalities addressed by these guidelines (Sections 133-36), see"Other Therapeutic Modalities" portion of the Patient-Specific Guideline Identification Tool in Appendix I.
Instructions for Use
Page 4

Instructions for Use – Version 3.0 (cont)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• For survivors who received chemotherapy, include relevant sections:- If survivor received any chemotherapy, include Section 6.
- Review "Chemotherapy" portion of the Patient-Specific Guideline Identification Tool in Appendix I and include Sections 7-37 asapplicable 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 – 41. Exception: If the survivor’s only radiation exposure was TBI,
do NOT include sections 40 or 41.
- Review "Radiation" portion of the Patient-Specific Guideline Identification Tool in Appendix I and include Sections 42-91 as
applicable based on survivor’s radiation exposures (Note: Some sections are gender-specific and some are relevant only forpatients who received the minimum specified dose of radiation to the indicated field or anatomic area).
• For survivors who underwent hematopoietic cell transplant (HCT), include Sections 92-97. If the survivor has a history of chronic GVHD
(cGVHD), also include sections 98-106 (Note: Section 103 is applicable only to survivors with currently active cGVHD; Section 105 is
applicable only to females).
• For survivors who underwent surgery, review "Surgery" portion of the Patient-Specific Guideline Identification Tool in Appendix I 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 the Patient-Specific Guideline
Identification Tool in Appendix I 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.
4. Identify Health Links appropriate for individual survivors by guideline section number using the Health Link Index inAppendix I. Individual Health Link files are available in Appendix II.

Instructions for Use
Page 5

Instructions for Use – Version 3.0 (cont)Note: The above procedure is applicable to generation of follow-up guidelines from the current version of this document; however, the COG
Long-Term Follow-Up Guidelines Core Committee recognizes that as new evidence becomes available and these guidelines are updated,additional details regarding the childhood cancer survivor’s therapeutic exposures may be required in order to generate comprehensive
recommendations. Therefore, we strongly advise that a comprehensive treatment summary be prepared 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 these guidelines.
The COG Long-Term Follow-Up Guidelines Core Committee 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, COG is currently partnering with the Baylor Schoolof 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 atwww.survivorshipguidelines.org. In the meantime, use of the Patient-Specific Guideline Identification Tool and Health Links Index by Guideline
Section Number (see Appendix I) should serve to reduce the time required for patient-specific application of these guidelines.
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:
Co-Chairs, COG Long-Term Follow-Up Guidelines Core Committee:
Melissa M. Hudson, MD
St. Jude Children’s Research Hospital
Memphis, Tennessee(901) 595-3445
Melissa.Hudson@stjude.org

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

Wendy Landier, RN, MSN, CPNPCity of Hope National Medical Center
Duarte, California(626) 471-7320
wlandier@coh.org

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

Instructions for Use
Page 6

New to Version 3.0 of the COG Long-Term Follow-Up Guidelines
All guideline sections have been reviewed by the Long-Term Follow-Up Guidelines Task Forces and modifications have been made per theirrecommendations and with the approval of the Expert Panel. The most significant modifications are detailed below.
• Breast MRI is now recommended as an adjunct to annual mammography in females who received chest radiation placing them at increased
risk for breast cancer (see Section 68).
• Clarification has been added to indicate the potential need to screen for breast and colorectal cancers in patients who received TBI alone(see Sections 68 and 78).
• Anthracycline isotoxic dose equivalent formulas have been updated (see Section 28).
• Detailed instructions have been added for determining applicability of radiation sections with minimum dose specifications for individual
patients (see Page 48 of Guidelines and Radiation Reference Guide in Appendix I).
• The definition of metabolic syndrome has been clarified and serum insulin is no longer recommended as a screening measure in those atrisk for overweight/obesity and metabolic syndrome (see Sections 48 and 49).
• The recommendation for obtaining fasting blood glucose and lipid profiles in patients at risk for overweight/obesity, metabolic syndrome, andcoronary artery disease has changed from a frequency of every 2-5 years, to every 2 years for patients at risk (see Sections 48, 49, and 71).
• Screening for pulmonary complications is now recommended for patients who received radiation to the axillary and mini-mantle fields (seeSection 70).
• Screening for cardiac complications is no longer recommended for patients who received radiation to axillary and mini-mantle fields (seeSection 71).
• New endocarditis prophylaxis recommendations from the American Heart Association are addressed in Section 71.
• Clarification has been added regarding the definition of “complete audiological evaluation” (see Sections 14 and 58).
• Routine screening for precocious puberty with FSH, LH, and testosterone/estradiol levels is no longer routinely recommended and is now
offered for further consideration in patients with an abnormal history or physical exam (see Section 51).
• Routine screening for hypogonadism following unilateral orchiectomy is no longer recommended and is now offered for further considerationin those with an abnormal history or physical exam, and endocrinology referral at age 11 is recommended for boys who have undergone
bilateral orchiectomy (see Section 125).
• The reference to new post-transplantation follow-up guidelines from the Center for International Blood and Marrow Transplant Research(CIBMTR) and the American Society for Blood and Marrow Transplant (ASBMT) is provided (see Section 92).
• The risk for post-transplantion functional asplenia has been clarified as applicable to patients with currently active chronic graft-vshost disease (see Section 103).
New to Version 3.0
Page 1

New to Version 3.0 of the COG Long-Term Follow-Up Guidelines (cont)• Terminology regarding complications related to reduced bone mineral density has been revised (see Sections 22, 31, and 97).
• Screening for Vitamin B12 deficiency has been added for patients who have undergone ileal enterocystoplasty (see Section 109).
• An Info Link discussing the role of post-splenectomy prophylactic antibiotic therapy and monitoring of pneumococcal titers post-vaccinationin splenectomized patients has been added (see Section 131).
• Information regarding the role of the human papillomavirus (HPV) vaccine in prevention of cervical cancer has been added (see Section 138)
• Radiation fields and guideline section numbers have been clarified according to anatomic area (see pages 48-49 of guidelines).
• Sections have been divided into “Male” and “Female” throughout the guidelines as appropriate to content.
• Updated references have been added and outdated reference removed throughout the guidelines.
In addition, the following modifications have been made to Version 3.0 of these guidelines:• A new “Radiation Reference Guide” has been added to provide radiation field definitions, detailed diagrams of radiation sections by anatomic
region, and instructions for determining applicability of guideline sections that have minimum dose specifications (see Appendix 1).
• The “Patient-Specific Guideline Identification Tool” has been updated to incorporate all guideline changes and serves as a useful tool for
determining applicable guideline sections for individual patients based on therapeutic exposures.
• Health Links have been updated to reflect changes in guideline Version 3.0.
• Health Links are now available in Spanish for five commonly used topics (Introduction to Long-Term Follow-Up, Diet and Physical Activity,
Finding Healthcare, Emotional Issues, and Reducing the Risk of Second Cancers).
• TBI sections have been removed and their content incorporated into the relevant radiation sections of the guidelines.
• The Index has been replaced by the Patient-Specific Guideline Identification Tool (see Appendix I).
Special Appreciation To:
Anne Arewasikporn, BA, CRA- City of Hope, Duarte, CA- Typesetting - Guidelines and Health Links
Shweta Bhatia- Westridge School, Pasadena, CA- Illustrations - Radiation Reference Guide

New to Version 3.0
Page 2

Long-Term Follow-Up Guidelines
for Survivors of Childhood, Adolescent,and Young Adult Cancers
Version 3.0 – October 2008

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

Copyright 2008 © 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
Hearing loss
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
YearlyHealth 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

COG LTFU Guidelines – Page 1

Version 3.0 – October 2008

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 1 REFERENCES
Psychosocial Disorders
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.
Barrera M et al. Educational and social late effects of childhood cancer and related clinical, personal and familial characteristics. Cancer. 2005;104:1751-60.
Boman 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.
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.
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.
Frobisher C et al. Long term population based marriage rates among adult survivors of childhood cancer in Britain. Int J Cancer. 2007;121:84-855.
Gurney JG et al. Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors. Pediatrics. 2007;120(5):e1229-36.
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.
Stam H et al. The course of life of survivors of childhood cancer. Psycho-oncology. 2005;14:227-38.
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.
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.
Santacroce SJ. Parental uncertainty and posttraumatic stress in serious childhood illness. J Nurs Scholarsh. 2003;35(1):45-51.
Schrag NM et al. Stress-related mental disorders in childhood cancer survivors. Pediatr Blood Cancer. 2008; 50:98-103.
Schultz KA et al. Behavioral and social outcomes in adolescent survivors of childhood cancer. J Clin Oncol. 2007;20;25(24):3649-56.
Stuber ML, 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.

COG LTFU Guidelines – Page 2

Version 3.0 – October 2008

(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
Carswell K et al. Smoking and binge drinking among Canadian survivors of childhood and adolescent cancers. Pediatric Blood & Cancer. 2008;51(2):280-7.
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.
Lown EA et al. Alcohol consumption patterns and risk factors among childhood cancer survivors compared to siblings and general population peers. Addiction. 2008;103(7):1139-48.
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
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.
NIH Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of Chronic Pain and Insomnia. Integration of behavioral and relaxation approaches into the treatment ofchronic pain and insomnia. JAMA. Jul 24-31 1996;276(4):313-318.
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.
Jacobsen PB. Assessment of fatigue in cancer patients. J Natl Cancer Inst Monogr. 2004(32):93-97.
Knobel H, Havard Loge J, Brit Lund M, Forfang K, Nome O, Kaasa S. Late medical complications and fatigue in Hodgkin's disease survivors. J Clin Oncol. Jul 1 2001;19(13):3226-3233.
Lawrence DP, Kupelnick B, Miller K, Devine D, Lau J. Evidence report on the occurrence, assessment, and treatment of fatigue in cancer patients. J Natl Cancer Inst Monogr. 2004(32):40-50.
Mulrooney DA et al. Fatigue and sleep disturbance in adult survivors of childhood cancer. Sleep. 2008; 31(2) 271-281.

COG LTFU Guidelines – Page 3

Version 3.0 – October 2008

(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
Unemployment

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
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.
Oeffinger KC, Mertens AC, Hudson MM, et al. Health care of young adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Fam Med. Jan-Feb 2004;2(1):61-70.
Park ER et al. Health insurance coverage in survivors of childhood cancer: the Childhood Cancer Survivor Study. J. Clin Oncol. 2005;20;23(36):9187-97.

COG LTFU Guidelines – Page 4

Version 3.0 – October 2008

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.

COG LTFU Guidelines – Page 5

Version 3.0 – October 2008

(cont)BLOOD/SERUM PRODUCTS
Sec#
4

Therapeutic
Agent(s)Potential
Late Effects

Chronic Hepatitis C
Diagnosed prior to 1993:
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 initiated and donors with selfHepatitis C PCR (to establish chronic
reported high-risk behaviors
infection)
were deferred)
Once in patients with positive Hepatitis
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.
Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) and HCV-related disease. MMWR Recomm Rep. 1998 Oct 16;47(RR-19):1-39.
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.

COG LTFU Guidelines – Page 6

Version 3.0 – October 2008

(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 testingOnce 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
HIV/infectious diseases specialist consultation for patients withchronic 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.

COG LTFU Guidelines – Page 7

Version 3.0 – October 2008

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
YearlySCREENING
Dental exam and cleaning
Every 6 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.

COG LTFU Guidelines – Page 8

Version 3.0 – October 2008

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
Ifosfamide ≥ 60 gm/m2
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
YearlyPHYSICAL
Tanner staging
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 in hypogonadal patients. Refer toendocrinology/urology for delayed puberty, persistently
abnormal hormone levels or hormonal replacement for
hypogonadal patients. Reproductive endocrinology/urology
referral for infertility evaluation and consultation regarding
assisted reproductive technologies.
SYSTEM = Reproductive (male)
SCORE =
Alkylating Agents: 1
Heavy Metals: 2A
Non-Classical Alkylators: 2A

SECTION 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.
Greenfield DM, Walters SJ, Coleman RE, et al. Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab. Sep
2007;92(9):3476-3482.
Howell SJ, Shalet SM. Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr. 2005(34):12-17.
Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer.
Feb 1 2001;91(3):613-621.
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.
Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatr Blood Cancer. Feb 2008;50(2):347-351.

COG LTFU Guidelines – Page 9

Version 3.0 – October 2008

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
YearlyHealth 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 staging
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 in hypogonadal patients. Refer toendocrinology/gynecology for delayed puberty, persistently
abnormal hormone levels or hormonal replacement for
hypogonadal patients. Reproductive endocrinology referral for
infertility evaluation and consultation regarding assisted
reproductive technologies.
SYSTEM = Reproductive (female)
SCORE =
Alkylating Agents: 1
Heavy Metals: 2A
Non-Classical Alkylators: 2A

SECTION 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.
Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. May 2006;91(5):1723-1728.
Muller J. Disturbance of pubertal development after cancer treatment. Best Pract Res Clin Endocrinol Metab. Mar 2002;16(1):91-103.
Sklar CA, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst. Jul 5 2006;98(13):890-896.
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.

COG LTFU Guidelines – Page 10

Version 3.0 – October 2008

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 to
agent

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 indicated.

CounselingCounsel 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.

COG LTFU Guidelines – Page 11

Version 3.0 – October 2008

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
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
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 pulmonologist.
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.

COG LTFU Guidelines – Page 12

Version 3.0 – October 2008

ALKYLATING AGENTS (cont)CHEMOTHERAPY
Sec
#
10

Therapeutic
Agent(s)ALKYLATING AGENTS
Busulfan

Potential
Late Effects
Cataracts

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Treatment Factors
Combined with corticosteroids

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

HISTORY
Visual changes (decreased acuity,
halos, diplopia)
YearlyPHYSICAL
Eye exam (visual acuity, funduscopic
exam for lens opacity)
YearlyHealth Counseling
Further Considerations
Health Links
Cataracts
Considerations for Further Testing and Intervention
Ophthalmology consultation if problem identified. Refer patientswith visual deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) to facilitate acquisition of educational resources.

SYSTEM = Ocular
SCORE = 2B

SECTION 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.

COG LTFU Guidelines – Page 13

Version 3.0 – October 2008

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
YearlySCREENING
Urinalysis
YearlyHealth 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.
Lima MV, Ferreira FV, Macedo FY, de Castro Brito GA, Ribeiro RA. Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis. Cancer Chemother Pharmacol. Apr
2007;59(5):643-650.
Stillwell TJ, Benson RC, Jr. Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer. Feb 1 1988;61(3):451-457.
Stillwell TJ, Benson RC, Jr., Burgert EO, Jr. Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma. J Clin Oncol. Jan 1988;6(1):76-82.

COG LTFU Guidelines – Page 14

Version 3.0 – October 2008

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
YearlySCREENING
Urinalysis
YearlyHealth 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 = 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.

COG LTFU Guidelines – Page 15

Version 3.0 – October 2008

ALKYLATING AGENTS (cont)CHEMOTHERAPY
Sec
#
13

Therapeutic
Agent(s)ALKYLATING AGENTS
Ifosfamide

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

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

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. Repeat as clinically indicated.

PHYSICAL
Blood pressure
YearlyHealth 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 withhypertension, proteinuria, or progressive renal insufficiency

SYSTEM = Urinary
SCORE = 1

Urinalysis
YearlyMedical 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.
Stohr W, Paulides M, Bielack S, et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer. Apr 2007;48(4):447-452.

COG LTFU Guidelines – Page 16

Version 3.0 – October 2008

HEAVY METALSCHEMOTHERAPY
Sec#

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
VertigoYearlyPHYSICAL
Otoscopic exam
YearlySCREENING
Complete audiological evaluation
Baseline at entry into long-term followup. If hearing loss is detected, test atleast yearly, or as recommended byaudiologist. If clinical suspicion ofhearing loss at any time, test as
clinically indicated. If audiogram isinconclusive 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 amplification in patients with
progressive hearing loss. Speech and language therapy forchildren with hearing loss. Otolaryngology consultation inpatients with chronic infection, cerumen impaction, or otheranatomical problems exacerbating or contributing to hearing
loss. Refer patients with auditory deficits to school liaison incommunity or cancer center (psychologist, social worker,
school counselor) to facilitate provision of educational
resources. Consider specific needs and/or preferential
classroom seating, FM amplification system, and othereducational assistance as indicated.

SYSTEM = Auditory
SCORE = 1

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

COG LTFU Guidelines – Page 17

Version 3.0 – October 2008

HEAVY METALS (cont)CHEMOTHERAPY
Sec#

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.
Gilmer Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin
Oncol. 2005 Dec 1;23(34):8588-8596.
Gurney JG, Tersak JM, Ness KK, Landier W, Matthay KK, Schmidt ML. Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group.
Pediatrics. Nov 2007;120(5):e1229-1236.
Knight KR, Kraemer DF, Winter C, Neuwelt EA. Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic
emissions. J Clin Oncol. Apr 1 2007;25(10):1190-1195.
Kushner BH, Budnick A, Kramer K et al. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006 Jul 15;107(2):417-22.
Laverdiere C, Cheung N-K V, Kushner BH et al. Long-term complications in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer. 2005. Sept;45(3):324-332.
Parsons SK, Neault MW, Lehmann LE, et al. Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant.
Oct 1998;22(7):669-674.
Punnett A, Bliss B, Dupuis LL, Abdolell M, Doyle J, Sung L. Ototoxicity following pediatric hematopoietic stem cell transplantation: a prospective cohort study. Pediatr Blood Cancer. Jun 2004;42(7):598-603.
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.

COG LTFU Guidelines – Page 18

Version 3.0 – October 2008

HEAVY METALS (cont)CHEMOTHERAPY
Sec
#
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.

COG LTFU Guidelines – Page 19

Version 3.0 – October 2008

HEAVY METALS (cont)CHEMOTHERAPY
Sec
#
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
YearlySCREENING
BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term
follow-up. Repeat as clinicallyindicated.

Urinalysis
YearlyHealth 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 withhypertension, 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.
Stohr W, Paulides M, Bielack S, et al. Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system. Pediatr Blood Cancer. Feb 2007;48(2):140-147.
von der Weid NX, Erni BM, Mamie C, Wagner HP, Bianchetti MG. Cisplatin therapy in childhood: renal follow up 3 years or more after treatment. Swiss Pediatric Oncology Group. Nephrol Dial Transplant.
Jun 1999;14(6):1441-1444.

COG LTFU Guidelines – Page 20

Version 3.0 – October 2008

HEAVY METALS (cont)CHEMOTHERAPY
Sec
#
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 withdyslipidemia.

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

COG LTFU Guidelines – Page 21

Version 3.0 – October 2008

ANTIMETABOLITESCHEMOTHERAPY
Sec#

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
YearlySCREENING
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 ofprocessing speed, computer-based attention, visual motor
integration, memory, comprehension of verbal instructions,verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orcancer center (psychologist, social worker, school counselor) 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 = 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.

COG LTFU Guidelines – Page 22

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec#

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
YearlyPHYSICAL
Neurologic exam
YearlyHealth 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:- White matter: MRI with diffusion-tensor imaging (DTI)- Microvascular injury: Gadolinium-enhanced MRI withdiffusion-weighted imaging (DWI)- Calcifications: CT
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.

COG LTFU Guidelines – Page 23

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec#

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

COG LTFU Guidelines – Page 24

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec
#
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 maintenancetherapy requires longer followup to determine long-termsequelae. 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
YearlySCREENING
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.
De Bruyne R, Portmann B, Samyn M, et al. Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol. Feb 2006;44(2):407-410.
Einhorn M, Davidsohn I. Hepatotoxicity of Mercaptopurine. JAMA. Jun 1 1964;188:802-806.
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.
Ravikumara M, Hill FG, Wilson DC, et al. 6-Thioguanine-related chronic hepatotoxicity and variceal haemorrhage in children treated for acute lymphoblastic leukaemia--a dual-centre experience. J Pediatr
Gastroenterol Nutr. May 2006;42(5):535-538.

COG LTFU Guidelines – Page 25

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec
#
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
Reduced Bone Mineral Density(BMD)
Defined as Z-score > 2.0 SD
below the mean in survivors < 20years old or T-score >1.0 SD
below the mean in survivors ≥ 20
years old
Info Link: The World HealthOrganization definition of
osteoporosis in adults is based oncomparison of a measured bonemineral density (BMD) of young
adults at peak bone age anddefined as a T-score. A T-score is
the number of standard deviations
the BMD measurement is above or
below the mean.
Note: Current
definitions of osteopenia (T-scores
between 1.0 and 2.5 SD below themean) and osteoporosis (T-scores> 2.5 SD below the mean) weredeveloped primarily in the context
of postmenopausal women. In thispopulation, T-scores have a wellvalidated correlation with fracturerisk that increases with age. The
fracture risk associated with Tscores in younger populations,
including cancer survivors withtreatment-related hypogonadism,
has not been established. T-scores
are not appropriate to assess
skeletal health in pediatric patients
who have not achieved peak adultbone mass. Instead, pediatric BMD
reference data sets calculate Zscores based on age and gender. A
Z-score is the number of standard
deviations the measurement isabove or below the AGE-MATCHED
MEAN BMD. Again, the fracturerisk in pediatric patients with lowbone density for chronologic age
based on Z-scores has not been
established. There are no defined
standards for referral or treatmentof low BMD in children.

COG LTFU Guidelines – Page 26

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

HighestRisk Factors

Periodic
Evaluation

Host Factors
Older age at time of treatment

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

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

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
Ensure recommended daily allowance of Vitamin D intake (200
IU/day) and adequate dietary calcium (see table in the “BoneHealth” Health Link for age-appropriate recommendations).
Supplements may be necessary if there are dietary restrictions.
Advocate for regular weight-bearing exercises such as runningand jumping. Use caution regarding calcium supplementationin 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 patients withosteoporosis or history of multiple fractures for pharmacologic
interventions (e.g., bisphosphonates, calcitonin, selective
estrogen receptor modulators).

SYSTEM = Musculoskeletal
SCORE = 2B

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 22 REFERENCES
Greer FR, Krebs NF. Optimizing bone health and calcium intakes of infants, children, and adolescents. Pediatrics. Feb 2006;117(2):578-585.
Grigg AP, Shuttleworth P, Reynolds J, et al. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. Oct 2006;91(10):3835-3843.
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.
International Society for Clinical Densitometry. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom. Spring 2004;7(1):17-26.
Kaste SC. Bone-mineral density deficits from childhood cancer and its therapy. A review of at-risk patient cohorts and available imaging methods. Pediatr Radiol. May 2004;34(5):373-378; quiz 443-374.
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.
Kelly J, Damron T, Grant W, et al. Cross-sectional study of bone mineral density in adult survivors of solid pediatric cancers. J Pediatr Hematol Oncol. May 2005;27(5):248-253
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.
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.
Sala A, Barr RD. Osteopenia and cancer in children and adolescents: the fragility of success. Cancer. Apr 1 2007;109(7):1420-1431.
van der Sluis IM, van den Heuvel-Eibrink MM, 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.

COG LTFU Guidelines – Page 27

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec
#
23

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
YearlySCREENING
BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, P04
Baseline at entry into long-term followup. Repeat as clinically indicated.

Health Counseling
Further Considerations
Health Links
Kidney HealthSee also: Single Kidney Health
Considerations for Further Testing and Intervention
Nephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency.

SYSTEM = Urinary
SCORE = 2A

Urinalysis
YearlySECTION 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.
Gronroos MH, Jahnukainen T, Mottonen M, Perkkio M, Irjala K, Salmi TT. Long-term follow-up of renal function after high-dose methotrexate treatment in children. Pediatr Blood Cancer. Oct 2008;51(4):535-539.
Kreusser W, Herrmann R, Tschope W, Ritz E. Nephrological complications of cancer therapy. Contrib Nephrol. 1982;33:223-238.
Yetgin S, Olgar S, Aras T, et al. Evaluation of kidney damage in patients with acute lymphoblastic leukemia in long-term follow-up: value of renal scan. Am J Hematol. Oct 2004;77(2):132-139.

COG LTFU Guidelines – Page 28

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec
#
24

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
YearlySCREENING
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.

COG LTFU Guidelines – Page 29

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec
#
25

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
YearlySCREENING
Referral for formal
neuropsychological evaluation
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 patientswith neurocognitive deficits to school liaison in community orcancer 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 25 REFERENCES
Buizer AI, de Sonneville LMJ, van den Heuvel-Eibrink MM, et al. Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. J Intern Neuropsych Soc 11: 554-565, 2005.
Buizer AI, de Sonneville LM, van den Heuvel-Eibrink MM, Veerman AJ. Chemotherapy and attentional dysfunction in survivors of childhood acute lymphoblastic leukemia: effect of treatment intensity. Pediatr Blood Cancer.
Sep 2005;45(3):281-290.
Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol. Jan-Feb 2005;30(1):65-78.
Campbell LK, Scaduto M, Sharp W, et al. A meta-analysis of the neurocognitive sequelae of treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer. Jul 2007;49(1):65-73.
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.
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.
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.

COG LTFU Guidelines – Page 30

Version 3.0 – October 2008

ANTIMETABOLITES (cont)CHEMOTHERAPY
Sec
#
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
YearlyHealth 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:- White matter: MRI with diffusion-tensor imaging (DTI)- Microvascular injury: Gadolinium-enhanced MRI withdiffusion-weighted imaging (DWI)- Calcifications: CT
Neurology consultation and follow-up as clinically indicated.

PHYSICAL
Neurological exam
YearlySYSTEM = 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.

COG LTFU Guidelines – Page 31

Version 3.0 – October 2008

ANTHRACYCLINE ANTIBIOTICSCHEMOTHERAPY
Sec#

Therapeutic
Agent(s)27

ANTHRACYCLINE ANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone*

Potential
Late Effects
Acute myeloid leukemia*Info link (Mitoxantrone):
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.

COG LTFU Guidelines – Page 32

Version 3.0 – October 2008

ANTHRACYCLINE ANTIBIOTICS (cont)CHEMOTHERAPY
Therapeutic
Agent(s)28

ANTHRACYCLINE ANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone*(Male)

Sec#

Potential
Late Effects
Cardiac toxicity
Cardiomyopathy
Arrhythmias
Subclinical left ventricular
dysfunction (systolic
dysfunction as assessedby ECHO or MUGA)*Info Link (Mitoxantrone):
Although Mitoxantrone
technically belongs to theanthracenedione class of antitumor antibiotics, it is related tothe anthracycline family and isincluded 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 (Dose Conversion):
infections) have been
Pediatric studies ofanecdotally reported toanthracycline cardiotoxicity
precipitate cardiac
typically describe risks based on decompensation. Prospective
combined cumulative doses ofstudies are needed to define
doxorubicin. There is a paucity
risk factors.
of literature to support isotoxic
dose conversion; however, thefollowing conversion factors
may be used for convenience inorder to gauge screening
frequency. Clinical judgment
should ultimately be used todetermine indicated screening
for individual patients. Use thefollowing formulas to convert todoxorubicin isotoxic equivalents
prior to calculating total
cumulative anthracycline dose.
Doxorubicin:
Multiply total dose x 1
Daunorubicin:
Multiply total dose x 0.833
Epirubicin:
Multiply total dose x 0.67
Idarubicin:
Multiply total dose x 5
Mitoxantrone:
Multiply total dose x 4

COG LTFU Guidelines – Page 33

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
Health Behaviors
Isometric exercise
Smoking
Drug use (e.g., cocaine, diet pills,
ephedra, mahuang)

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

Periodic
Evaluation
HISTORY
SOB
DOE
Orthopnea
Chest pain
Palpitations
If under 25 years:
Abdominal symptoms(nausea, vomiting)
YearlyInfo Link: Exertional intolerance isuncommon in patients younger than 25
years old. Abdominal symptoms(nausea, emesis) may be observed
more frequently than exertional
dyspnea or chest pain in younger
patients.
PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlyHealth 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. High repetition weight lifting involving
lighter weights is more likely to be safe. The number ofrepetitions should be limited to that which the survivor canperform with ease. Patients who choose to engage in strenuousor varsity team sports should discuss appropriate guidelines
and a plan for ongoing monitoring with a cardiologist.
Considerations for Further Testing and Intervention
Cardiology consultation in patients with subclinical abnormalities
on screening evaluations, left ventricular dysfunction,
dysrhythmia, or prolonged QTc interval. Consider excess risk ofisometric exercise program in any high risk patient (defined as
needing screening every 1 or 2 years).

SYSTEM = Cardiovascular
SCORE = 1

SCREENINGECHO or MUGA for evaluation ofsystolic function
Baseline at entry to long-term followup, then periodically, based on age attreatment, radiation dose, andcumulative anthracycline
dose - see table
EKG (include evaluation of QTc
interval)
Baseline at entry into long-term followup. Repeat as clinically indicated.

Version 3.0 – October 2008

ANTHRACYCLINE ANTIBIOTICS (cont)CHEMOTHERAPY
Therapeutic
Agent(s)28

ANTHRACYCLINE ANTIBIOTICS
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone*(Female)Sec#

Potential
Late Effects
Cardiac toxicity
Cardiomyopathy
Arrhythmias
Subclinical left ventricular
dysfunction (systolic
dysfunction as assessedby ECHO or MUGA)*Info Link (Mitoxantrone):
Although Mitoxantrone
technically belongs to theanthracenedione class of antitumor antibiotics, it is related tothe anthracyclinefamily and isincluded 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 (Dose Conversion):
infections) have been
Pediatric studies ofanecdotally reported toanthracycline cardiotoxicity
precipitate cardiac
typically describe risks based on decompensation. Prospective
combined cumulative doses ofstudies are needed to define
doxorubicin. There is a paucity
risk factors.
of literature to support isotoxic
dose conversion; however, thefollowing conversion factors
may be used for convenience inorder to gauge screening
frequency. Clinical judgment
should ultimately be used todetermine indicated screening
for individual patients. Use thefollowing formulas to convert todoxorubicin isotoxic equivalents
prior to calculating total
cumulative anthracycline dose.
Doxorubicin:
Multiply total dose x 1
Daunorubicin:
Multiply total dose x 0.833
Epirubicin:
Multiply total dose x 0.67
Idarubicin:
Multiply total dose x 5
Mitoxantrone:
Multiply total dose x 4

COG LTFU Guidelines – Page 34

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

Periodic
Evaluation

HISTORY
SOB
DOE
Orthopnea
Chest pain
Palpitations
If under 25 years:
Treatment Factors
Abdominal symptoms
Higher cumulative(nausea, vomiting)anthracycline doses:- ≥ 550 mg/m2 in patients 18 Yearlyyears or older at time oftreatment
Info Link: Exertional intolerance is- ≥ 300 mg/m2 in patients
uncommon in patients younger than 25
younger than 18 years at
years old. Abdominal symptoms
time of treatment(nausea, emesis) may be observed- Any dose in infant
more frequently than exertional
Chest radiation ≥ 30 Gy
dyspnea or chest pain in younger
Longer time elapsed sincepatients.
treatment
PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlyHost Factors
Female sex
Black/of African descent
Younger than age 5 years
at time of treatment

SCREENINGECHO or MUGA for evaluation ofsystolic function
Baseline at entry to long-term followup, then periodically, based on age attreatment, radiation dose, and cumulative anthracycline
dose - see table

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. High repetition weight lifting involving
lighter weights is more likely to be safe. The number ofrepetitions should be limited to that which the survivor canperform with ease. Patients who choose to engage in strenuousor varsity team sports should discuss appropriate guidelines
and a plan for ongoing monitoring with a cardiologist.
Considerations for Further Testing and Intervention
Cardiology consultation in patients with subclinical abnormalities
on screening evaluations, left ventricular dysfunction,
dysrhythmia, or prolonged QTc interval. Consider excess risk ofisometric exercise program in any high risk patient (defined as
needing screening every 1 or 2 years). Additional cardiology
evaluation in patients who received ≥ 300 mg/m2 or < 300
mg/m2 plus chest radiation who are pregnant or planning
pregnancy. Evaluation to include an echocardiogram before andperiodically during pregnancy (especially during third trimester)and monitoring during labor and delivery due to risk of cardiac
failure.

SYSTEM = Cardiovascular
SCORE = 1

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

Version 3.0 – October 2008

ANTHRACYCLINE ANTIBIOTICS (cont)CHEMOTHERAPY
Sec#

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*

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

1-4 years oldNoYes≥5 years oldNo

Anthracycline Dose†

Recommended Frequency

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 year

Any age with decrease in serial function

Every year

*Age at time of first cardiotoxic therapy (anthracycline or radiation [see fields below],whichever was given first)§See Section 71†Based on doxorubicin isotoxic equivalent dose [see conversion factors in Section 28 “Info Link (DoseConversion)”]

COG LTFU Guidelines – Page 35

Version 3.0 – October 2008

ANTHRACYCLINE ANTIBIOTICS (cont)CHEMOTHERAPY
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 28 REFERENCES
Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. Jun 15 2005;44(7):600-606.
Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. Sep 1
2007;25(25):3991-4008.
Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol. Apr 1 2001;19(7):1926-1934.
Hudson MM, Rai SN, Nunez C, et al. Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol. Aug 20 2007;25(24):3635-3643.
Kremer LC, van Dalen EC, Offringa M, Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review. Ann Oncol. Apr 2002;13(4):503-512.
Kremer LC, van der Pal HJ, Offringa M, van Dalen EC, Voute PA. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. Jun 2002;13(6):819829.
Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2005;23(12):2629-2636.
Shankar SM, Marina N, Hudson MM, et al. Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children's Oncology Group. Pediatrics. Feb
2008;121(2):e387-39.
Sorensen K, Levitt GA, Bull C, Dorup I, Sullivan ID. Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study. Cancer. Apr 15 2003;97(8):1991-1998.
van Dalen EC, Caron HN, Kremer LC. Prevention of anthracycline-induced cardiotoxicity in children: the evidence. Eur J Cancer. May 2007;43(7):1134-1140.
van Dalen EC, van der Pal HJ, Kok WE, Caron HN, Kremer LC. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer. Dec 2006;42(18):3191-3198.
van Dalen EC, van der Pal HJ, van den Bos C, Kok WE, Caron HN, Kremer LC. Clinical heart failure during pregnancy and delivery in a cohort of female childhood cancer survivors treated with anthracyclines. Eur J
Cancer. Oct 2006;42(15):2549-2553.

COG LTFU Guidelines – Page 36

Version 3.0 – October 2008

ANTI-TUMOR ANTIBIOTICSCHEMOTHERAPY
Sec
#
29

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
YearlyHealth 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
Notify healthcare providers of history of bleomycin therapy andrisk of worsening fibrosis with high oxygen exposure such as
during general anesthesia. Administration of highconcentrations of oxygen may result in chronic progressive
pulmonary fibrosis. Counsel regarding tobacco avoidance/
SCREENING
smoking cessation. Due to the potential pulmonary toxicity of
Chest x-ray
this therapy, patients who desire to SCUBA dive should be
PFTs (including DLCO and spirometry) advised to obtain medical clearance from a pulmonologist.
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
YearlySYSTEM = 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.

COG LTFU Guidelines – Page 37

Version 3.0 – October 2008

ANTI-TUMOR ANTIBIOTICS (cont)CHEMOTHERAPY
Sec
#
30

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.

COG LTFU Guidelines – Page 38

Version 3.0 – October 2008

CORTICOSTEROIDSCHEMOTHERAPY
Sec
#
31

Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

Potential
Late Effects

Risk
Factors

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

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

Info Link: The World HealthOrganization definition of
osteoporosis in adults is based oncomparison of a measured bonemineral density (BMD) of young
adults at peak bone age anddefined as a T-score. A T-score is
the number of standard deviations
the BMD measurement is above or
below the mean.

Treatment Factors
Corticosteroids
Cyclosporine
Tacrolimus
Cranial radiation
Craniospinal radiation
HCT/TBI

Note: Current definitions ofosteopenia (T-scores between 1.0
and 2.5 SD below the mean) andosteoporosis (T-scores > 2.5 SD
below the mean) were developed
primarily in the context of postmenopausal women. In thispopulation, T-scores have a wellvalidated correlation with fracturerisk that increases with age. The
fracture risk associated with
T-scores in younger populations,
including cancer survivors withtreatment-related hypogonadism,
has not been established. T-scores
are not appropriate to assess
skeletal health in pediatric patients
who have not achieved peak adultbone mass. Instead, pediatric BMD
reference data sets calculate
Z-scores based on age and gender.
A Z-score is the number ofstandard deviations themeasurement is above or below
the AGE-MATCHED MEAN BMD.
Again, the fracture risk in pediatricpatients with low bone density forchronologic age based on Z-scores
has not been established. There
are no defined standards forreferral or treatment of low BMD inchildren.

COG LTFU Guidelines – Page 39

Medical Conditions
Growth hormone deficiency
Hypogonadism/delayed puberty
Hyperthyroidism
Health Behaviors
Inadequate intake of calcium
and vitamin D
Lack of weight bearing exercise
Smoking
Alcohol use
Carbonated beverages

HighestRisk Factors
Host Factors
Older age at time of treatment

Periodic
Evaluation

SCREENING
Bone density evaluation (DEXA orquantitative CT)
Treatment Factors
Baseline at entry into long-term followGlucocorticoid 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.

Health Counseling
Further Considerations
Health Links
Bone HealthResources
National Osteoporosis Foundation Website: www.nof.org
Considerations for Further Testing and Intervention
Ensure recommended daily allowance of Vitamin D intake (200
IU/day) and adequate dietary calcium (see table in the “BoneHealth” Health Link for age-appropriate recommendations).
Supplements may be necessary if there are dietary restrictions.
Advocate for regular weight-bearing exercises such as runningand jumping. Use caution regarding calcium supplementationin 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 patients withosteoporosis or history of multiple fractures for pharmacologic
interventions (e.g., bisphosphonates, calcitonin, selective
estrogen receptor modulators).

SYSTEM = Musculoskeletal
SCORE = 2B

Version 3.0 – October 2008

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.
Greer FR, Krebs NF. Optimizing bone health and calcium intakes of infants, children, and adolescents. Pediatrics. Feb 2006;117(2):578-585.
Grigg AP, Shuttleworth P, Reynolds J, et al. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. Oct 2006;91(10):3835-3843.
International Society for Clinical Densitometry. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom. Spring 2004;7(1):17-26.
Kaste SC, 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.
Sala A, Barr RD. Osteopenia and cancer in children and adolescents: the fragility of success. Cancer. Apr 1 2007;109(7):1420-1431.
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.

COG LTFU Guidelines – Page 40

Version 3.0 – October 2008

CORTICOSTEROIDS (cont)CHEMOTHERAPY
Sec
#
32

Therapeutic
Agent(s)CORTICOSTEROIDS
Dexamethasone
Prednisone

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

PHYSICAL
Musculoskeletal exam
YearlyHealth 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
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.
Ha YC, Jung WH, Kim JR, Seong NH, Kim SY, Koo KH. Prediction of collapse in femoral head osteonecrosis: a modified Kerboul method with use of magnetic resonance images. J Bone Joint Surg Am. Nov 2006;88
Suppl 3:35-40.
Ito H, Matsuno T, Minami A. Relationship between bone marrow edema and development of symptoms in patients with osteonecrosis of the femoral head. AJR Am J Roentgenol. Jun 2006;186(6):1761-1770.
Kaneshiro Y, Oda Y, Iwakiri K, et al. Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis. Clin Pharmacol Ther. Oct 2006;80(4):396-402.
Karimova EJ, Rai SN, Howard SC, et al. Femoral head osteonecrosis in pediatric and young adult patients with leukemia or lymphoma. J Clin Oncol. Apr 20 2007;25(12):1525-1531.
Karimova EJ, Rai SN, Ingle D, et al. MRI of knee osteonecrosis in children with leukemia and lymphoma: Part 2, clinical and imaging patterns. AJR Am J Roentgenol. Feb 2006;186(2):477-482.
Mattano LA, Jr., Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol.
Sep 15 2000;18(18):3262-3272.
Niinimaki RA, Harila-Saari AH, Jartti AE, et al. High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2007;25(12):1498-1504.
Ojala AE, Paakko E, Lanning FP, Lanning M. Osteonecrosis during the treatment of childhood acute lymphoblastic leukemia: a prospective MRI study. Med Pediatr Oncol. Jan 1999;32(1):11-17.
Relling MV, Yang W, Das S, et al. Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. J Clin Oncol. Oct 1 2004;22(19):3930-3936.
Sedonja I, Jevtic V, Milcinski M. Bone scintigraphy as a prognostic indicator for bone collapse in the early phases of femoral head osteonecrosis. Ann Nucl Med. Jun 2007;21(3):167-173.

COG LTFU Guidelines – Page 41

Version 3.0 – October 2008

CORTICOSTEROIDS (cont)CHEMOTHERAPY
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 changes (decreased acuity,
halos, diplopia)
YearlyPHYSICAL
Eye exam (visual acuity, funduscopic
exam for lens opacity)
YearlyHealth Counseling
Further Considerations
Health Links
Cataracts
Considerations for Further Testing and Intervention
Ophthalmology consultation if problem identified. Refer patientswith visual deficits to school liaison in community or cancer
center (psychologist, social worker, school counselor) 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.

COG LTFU Guidelines – Page 42

Version 3.0 – October 2008

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.

COG LTFU Guidelines – Page 43

Version 3.0 – October 2008

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;
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.

COG LTFU Guidelines – Page 44

Version 3.0 – October 2008

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
HISTORY
Vasospasms of hands, feet, nose,
lips, cheeks, or earlobes related tostress or cold temperatures
YearlyPHYSICAL
Physical exam of affected area
As indicatedHealth Counseling
Further Considerations
Health Links
Raynaud's PhenomenonCounselingCounsel to wear appropriate protective clothing in cold
environments and not to use tobacco or illicit drugs(vasoconstrictors such as cocaine).
Considerations for Further Testing and Intervention
Consider vasodilating medications (calcium- channel blockers,alpha blockers) for patients with frequent, severe vasospastic
attacks unresponsive to behavioral management.

SYSTEM = 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.

COG LTFU Guidelines – Page 45

Version 3.0 – October 2008

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.

COG LTFU Guidelines – Page 46

Version 3.0 – October 2008

RADIATIONINSTRUCTIONSDETERMINING APPLICABILITY OF RADIATION SECTIONS FOR SPECIFIC PATIENTS BASED ON EXPOSURE
GENERAL CONSIDERATIONS:x

The radiation sections of the COG Long-Term Follow-Up Guidelines(Sections 38 – 91) are organized by anatomic region from the head
downward. For specifics regarding relevant exposures to each anatomic
region and radiation field, refer to the applicable pages of the “Radiation
Reference Guide” in Appendix I and to the Figures in this section.

x

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

RADIATION DOSE CALCULATIONS:
Some sections of the COG Long-Term Follow-Up Guidelines relevant toradiation exposure include dose specifications. These specifications indicate
the minimum dose of radiation that is believed (based on available evidence
and the recommendations of the expert panel) to place patients sufficiently atrisk of the referenced late effect to recommend screening. For guideline
sections that have a minimum specified dose, the following considerations
apply in determining the applicability of the section for a patient based on
his/her radiation exposure (see Appendix I – “Radiation Reference Guide” –for examples).
Sections with minimum dose specifications are applicable to a patient only if:
1. Patient received radiation to any field(s) relevant to the particular
guideline section at > the specified minimum dose†OR†
2. Patient received a combination of radiation to any relevant field(s) plus
relevant spinal radiation‡ and/or TBI, the sum of which is > the specified
minimum dose§†

Total dose to each field should include boost dose, if given. If patient
received radiation to more than one field relevant to a particular guideline
section during a single planned course of radiation treatment (excluding
spinal radiation and TBI), the field that received the largest radiation doseshould be used in making the determination as to the applicability of theindicated guideline section(s). Exception: If patient received radiation to thesame field at different times (e.g., at time of diagnosis AND at relapse), thesedoses should be added together when considering the applicability of theindicated guideline section.
‡
Use the largest dose of radiation delivered to the spinal field(s) specified in
the guideline section§

Whole lung radiation, if given, should be included in minimum dose
calculations for Sections 65, 66, 67, 68, 73, and 91.

COG LTFU Guidelines – Page 47

Radiation Fields by Anatomic Region

Version 3.0 – October 2008

INSTRUCTIONS (cont)

RADIATIONGUIDE TO RADIATION SECTION NUMBERS BY ANATOMIC REGIONNOTES:x

This diagram provides an overview of theorganization of the radiation sections of the COG
Long-Term Follow-Up Guidelines.

x

Radiation sections are arranged by anatomic region
beginning with the cranium and proceeding
downward.

x

Arrows traversing multiple anatomic areas indicate
body systems or organs (i.e., oral cavity, neck/thyroid,
heart, esophagus, and bowel) that may be affected byradiation to any of the indicated anatomic regions.

x

See page 48 of these guidelines for information
regarding minimum radiation dose specifications
included in some guideline sections.

x

Additional detailed information, including examples ofradiation dose calculations and diagrams of each
body region are provided in the “Radiation Reference
Guide” (Appendix I).

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

§

Screening may be
indicated for patients
who received TBI alone– see Info Link inindicated section(s)Radiation Section Numbers by Anatomic Region

COG LTFU Guidelines – Page 48

Version 3.0 – October 2008

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

Secondary benign ormalignant neoplasm
Occurring in or near radiation
field

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

Info Link: Patients 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• See “Radiation Reference Guide” in Appendix I for list of all radiation fields
applicable to this section.

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

Periodic
Evaluation
PHYSICAL
Inspection and palpation of skin andsoft tissues in irradiated field(s)YearlyHealth Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
Surgical and/or oncology consultation as clinically indicated.

SCREENING
Other evaluations based ontreatment volumes
See recommendations for specificfieldsSYSTEM = SMNSCORE = 1

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

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.

COG LTFU Guidelines – Page 49

Version 3.0 – October 2008

ALL FIELDS (INCLUDING TBI) (cont)

RADIATION
Sec#
39

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

Potential
Late Effects

Risk
Factors

Dysplastic nevi; Skin cancer
Basal cell carcinoma
Squamous cell carcinoma
Melanoma

Host Factors
Gorlin's syndrome (nevoid basal
cell carcinoma syndrome)
Health Behaviors
Sun exposure
Tanning booths• See “Radiation Reference Guide” in Appendix I for list of all radiation fields
applicable to this section.

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

Periodic
Evaluation
HISTORY
Skin lesions
Changing moles (asymmetry,
bleeding, increasing size,
indistinct borders)YearlyPHYSICAL
Dermatologic exam of irradiatedfieldsYearlyHealth 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

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

SECTION 39 REFERENCES
American Cancer Society, Cancer Prevention and Early Detection Facts and Figures: Atlanta, GA: American Cancer Society; 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.
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.

COG LTFU Guidelines – Page 50

Version 3.0 – October 2008

ALL FIELDS (EXCEPT TBI)RADIATION
Sec#
40

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

Potential
Late Effects
Dermatologic changes
Fibrosis
Telangiectasias
Permanent alopecia
Altered skin pigmentation

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

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

Periodic
Evaluation
PHYSICAL
Dermatologic exam of irradiatedfieldsYearlyHealth Counseling
Further Considerations
Health Links
Skin Health

SYSTEM = Dermatologic
SCORE = 1

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

SECTION 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.
Sanli H, Akay BN, Arat M, et al. Vitiligo after hematopoietic cell transplantation: six cases and review of the literature. Dermatology. 2008;216(4):349-354.
Severs GA, Griffin T, Werner-Wasik M. Cicatricial alopecia secondary to radiation therapy: case report and review of the literature. Cutis. Feb 2008;81(2):147-153.
Skert C, Patriarca F, Sperotto A, et al. Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica. Feb
2006;91(2):258-261.

COG LTFU Guidelines – Page 51

Version 3.0 – October 2008

ALL FIELDS (EXCEPT TBI) (cont)

RADIATION
Sec#
41

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

Potential
Late Effects
Bone malignancies

Risk
Factors
Host Factors
Adolescent at treatment
Cancer-predisposing mutation(e.g., p53, RB1, NF1)
Treatment Factors
Higher radiation dose
Combined with alkylating agentsHighestRisk Factors
Treatment Factors
Radiation dose ≥ 30 Gy
Orthovoltage radiation(commonly used before1970) due to delivery ofgreater dose to skin andbones

Periodic
Evaluation

Health Counseling
Further Considerations

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

PHYSICAL
Palpation of bones in irradiated field
YearlyConsiderations for Further Testing and Intervention
X-ray or other diagnostic imaging in patients with clinicalsymptoms. Oncology consultation as clinically indicated.

SYSTEM = SMN• See “Radiation Reference Guide” in Appendix I for list of all radiation fields
applicable to this section.

SCORE = 1

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

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.

COG LTFU Guidelines – Page 52

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
42

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

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

Risk
Factors
Host Factors
Younger age at treatment
Neurofibromatosis
Treatment Factors
Higher radiation dose
(Risk of subsequent CNS tumor
after cranial radiation increases
in a dose-response relationship)• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

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

Periodic
Evaluation
HISTORY
Headaches
Vomiting
Cognitive, motor or sensory deficits
Seizures and other neurologic
symptoms
YearlyPHYSICAL
Neurologic exam
YearlyHealth 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
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.
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.
Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. Nov 1
2006;98(21):1528-1537.
Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. Jun 1 2006;24(16):2570-2575.
Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. Jan 2000;18(2):348-357.
Walter AW, Hancock ML, Pui CH, et al. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital. J Clin Oncol. Dec 1998;16(12):3761-3767.
Witherspoon RP, Fisher LD, Schoch G, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med. Sep 21 1989;321(12):784-789.

COG LTFU Guidelines – Page 53

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
43

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
TBI

BRAIN/CRANIUM (cont)
Potential
Late Effects

Risk
Factors

HighestRisk Factors

Neurocognitive deficits
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- Methotrexate(IT, IO, high-dose IV)- Cytarabine (high-dose IV)
Info Link: Neurocognitive
Higher radiation dose
deficits in survivors ofLarger radiation field
leukemia and lymphoma are
Greater cortical volumes
more frequently related to
Cranial radiation in
information processing (e.g.,combination with TBI
learning disability).
Neurocognitive deficits in brain Longer elapsed time since therapy
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.

Periodic
Evaluation
HISTORY
Educational and/or vocational
progress
YearlySCREENING
Referral for formal neuropsychologicalevaluation
Baseline at entry into long-term followup, 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 ofprocessing speed, computer-based attention, visual motor
integration, memory, comprehension of verbal instructions,verbal fluency, executive function and planning. Refer patientswith neurocognitive deficits to school liaison in community orcancer center (psychologist, social worker, school counselor) 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

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

COG LTFU Guidelines – Page 54

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

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.
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.
Keene N, Hobbie W, Ruccione K, eds. Childhood Cancer Survivors: A Practical Guide to Your Future. Sebastopol, CA: O'Reilly; 2002.
Kupst MJ, Penati B, Debban B, et al. Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study. Bone Marrow Transplant.
Nov 2002;30(9):609-617.
Mabbott DJ, Spiegler BJ, Greenberg ML, Rutka JT, Hyder DJ, Bouffet E. Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol. Apr 1
2005;23(10):2256-2263.
Mulhern RK, Palmer SL, Reddick WE, et al. Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss. J Clin Oncol. Jan 15 2001;19(2):472-479.
Palmer SL, Gajjar A, Reddick WE, et al. Predicting intellectual outcome among children treated with 35-40 Gy craniospinal irradiation for medulloblastoma. Neuropsychology. Oct 2003;17(4):548-555.
Phipps S, Dunavant M, Srivastava DK, Bowman L, Mulhern RK. Cognitive and academic functioning in survivors of pediatric bone marrow transplantation. J Clin Oncol. Mar 2000;18(5):1004-1011.
Reimers TS, Ehrenfels S, Mortensen EL, et al. Cognitive deficits in long-term survivors of childhood brain tumors: Identification of predictive factors. Med Pediatr Oncol. Jan 2003;40(1):26-34.
Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study.
J Clin Oncol. Aug 1 2001;19(15):3470-3476.
Simms S, Kazak AE, Gannon T, Goldwein J, Bunin N. Neuropsychological outcome of children undergoing bone marrow transplantation. Bone Marrow Transplant. Jul 1998;22(2):181-184.
Waber DP, Tarbell NJ, Fairclough D, et al. Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol. Oct 1995;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.

COG LTFU Guidelines – Page 55

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
44

Therapeutic
Agent(s)Cranial
Ear/Infratemporal
TBI

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

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
YearlyHealth 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:-White matter: MRI with diffusion-tensor imaging (DTI)-Microvascular injury: Gadolinium-enhanced MRI withdiffusion-weighted imaging (DWI)-Calcifications: CT
Neurology consultation and follow-up as clinically indicated.

PHYSICAL
Neurologic exam
YearlySYSTEM = CNSSCORE = 1

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

emerge over time.

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.

COG LTFU Guidelines – Page 56

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
45

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

BRAIN/CRANIUM (cont)
Potential
Late Effects
Cerebrovascularcomplications
StrokeMoyamoyaOcclusive cerebral
vasculopathy

Info Link: Moyamoya*TBI included for dose
syndrome is the complete
calculation purposes only; this
occlusion of one or more of
the three major cerebral
section not applicable topatients who received TBI alone. vessels with the developmentof small, immature collateral
vessels, which reflect anattempt to revascularize theischemic portion of the brain.

Risk
Factors

HighestRisk Factors

Host Factors
Down syndrome

Host Factors
Parasellar tumor

Treatment Factors
Suprasellar radiation

Treatment Factors
Radiation dose ≥ 50 Gy

Medical Conditions
Sickle cell disease
Neurofibromatosis

Periodic
Evaluation
HISTORY
Hemiparesis
Hemiplegia
Weakness
Aphasia
YearlyHealth 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
YearlySYSTEM = CNSSCORE = 1

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 18 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 18 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 45 REFERENCES
Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. Nov 20
2006;24(33):5277-5282.
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.
Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology. Mar 20 2007;68(12):932-938.

COG LTFU Guidelines – Page 57

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
46

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

BRAIN/CRANIUM (cont)
Potential
Late Effects
Craniofacial abnormalities

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

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

HighestRisk Factors
Host Factors
Age < 5 years at 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
YearlyHealth Counseling
Further Considerations
Resources
FACES - The National Craniofacial Association(www.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
PHYSICAL
Craniofacial abnormalities
YearlySCORE = 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.

COG LTFU Guidelines – Page 58

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
47

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

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
YearlyMedical Conditions
Atopic history
Hypogammaglobulinemia

PHYSICAL
Nasal exam
SinusesYearlyHealth 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

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

SECTION 47 REFERENCES
Chang CC, Chen MK, Wen YS, Lee HS, Wu HK, Liu MT. Effects of radiotherapy for nasopharyngeal carcinoma on the paranasal sinuses: study based on computed tomography scanning. J Otolaryngol. 2000 Feb;
29(1):23-27.
Ellingwood KE, Million RR. Cancer of the nasal cavity and ethmoid/sphenoid sinuses. Cancer. Apr 1979;43(4):1517-1526.

COG LTFU Guidelines – Page 59

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
48

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

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
YearlySCREENING
Fasting blood glucose
Fasting lipid profile
Every 2 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 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

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

SECTION 48 REFERENCES
ADA and CDA guidelines, Diabetes Care 2004 www.diabetes.ca/cpg2003/download.aspnx
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.
Nathan PC, Jovcevska V, Ness KK, et al. The prevalence of overweight and obesity in pediatric survivors of cancer. J Pediatr. Oct 2006;149(4):518-525.
Neville KA, Cohn RJ, Steinbeck KS, Johnston K, Walker JL. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab.
Nov 2006;91(11):4401-4407.
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.
Razzouk BI, Rose SR, Hongeng S, et al. Obesity in survivors of childhood acute lymphoblastic leukemia and lymphoma. J Clin Oncol. Apr 1 2007;25(10):1183-1189.
Reilly JJ, Ventham JC, Newell J, Aitchison T, Wallace WH, Gibson BE. Risk factors for excess weight gain in children treated for acute lymphoblastic leukaemia. Int J Obes Relat Metab Disord.
Nov 2000;24(11):1537-1541.
Sklar CA, Mertens AC, Walter A, et al. Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukemia: role of cranial irradiation. Med Pediatr Oncol.
Aug 2000;35(2):91-95.
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.

COG LTFU Guidelines – Page 60

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
49

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

BRAIN/CRANIUM (cont)
Potential
Late Effects
Metabolic syndrome
Info Link: Definitions of themetabolic syndrome are
evolving, but generally include
a combination of central(abdominal) obesity with atleast 2 or more of thefollowing: hypertension,
atherogenic dyslipidemia(elevated triglycerides,
reduced HDL cholesterol), andabnormal glucose metabolism(fasting hyperglycemia,
hyperinsulinism, insulin
resistance, diabetes mellitus
type II). 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)
TBI
Medical Conditions
Growth hormone deficiency
Hypogonadism

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

Periodic
Evaluation
PHYSICAL
HeightWeightBMI
Blood pressure
YearlySCREENING
Fasting blood glucose
Fasting lipid profile
Every 2 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 waist:hip ratio screening (>0.5=higher risk). Consider
endocrine consult if insulin resistance/metabolic syndrome issuspected. Nutritional counseling. Cardiology consultation asclinically indicated.

SYSTEM = Endocrine/Metabolic
SCORE = 2A

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

COG LTFU Guidelines – Page 61

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 49 REFERENCES
ADA and CDA guidelines, Diabetes Care 2004 www.diabetes.ca/cpg2003/download.aspnx
Baker KS, Ness KK, Steinberger J, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood. Feb
15 2007;109(4):1765-1772.
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.
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.
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.
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.
Neville KA, Cohn RJ, Steinbeck KS, Johnston K, Walker JL. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab.
Nov 2006;91(11):4401-4407.
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.
Shalitin S, Phillip M, Stein J, Goshen Y, Carmi D, Yaniv I. Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow
Transplant. Jun 2006;37(12):1109-1117.
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.
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.
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.
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.

COG LTFU Guidelines – Page 62

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
50

Therapeutic
Agent(s)CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
Waldeyer’s Ring
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 6 months until growth iscompleted, then yearly.

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

PHYSICAL
Tanner staging
Every 6 months until sexually mature
HeightWeightBMI
Every 6 months until growth iscompleted, then yearly.

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

Health Counseling
Further Considerations

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 growth
hormone replacement therapy. Consider bone density testing inpatients who are growth hormone deficient.

SYSTEM = Endocrine/Metabolic
SCORE = 1

COG LTFU Guidelines – Page 63

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 50 REFERENCES
Bongers ME, Francken AB, Rouwe C, Kamps WA, Postma A. Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation. Pediatr Blood Cancer. Aug
2005;45(2):139-143.
Brownstein CM, Mertens AC, Mitby PA, et al. Factors that affect final height and change in height standard deviation scores in survivors of childhood cancer treated with growth hormone: a report from the childhood
cancer survivor study. J Clin Endocrinol Metab. Sep 2004;89(9):4422-4427.
Cohen A, Rovelli A, Bakker B, et al. Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT.
Blood. Jun 15 1999;93(12):4109-4115.
Costin G. Effects of low-dose cranial radiation on growth hormone secretory dynamics and hypothalamic-pituitary function. Am J Dis Child. Aug 1988;142(8):847-852.
Couto-Silva AC, Trivin C, Esperou H, et al. Final height and gonad function after total body irradiation during childhood. Bone Marrow Transplant. Sep 2006;38(6):427-432.
Didcock E, Davies HA, Didi M, Ogilvy Stuart AL, Wales JK, Shalet SM. Pubertal growth in young adult survivors of childhood leukemia. J Clin Oncol. Oct 1995;13(10):2503-2507.
Frisk P, Arvidson J, Gustafsson J, Lonnerholm G. Pubertal development and final height after autologous bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant.
Jan 2004;33(2):205-210.
Giorgiani G, Bozzola M, Locatelli F, et al. Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human
growth hormone. Blood. Jul 15 1995;86(2):825-831.
Gleeson HK, Darzy K, Shalet SM. Late endocrine, metabolic and skeletal sequelae following treatment of childhood cancer. Best Pract Res Clin Endocrinol Metab. Jun 2002;16(2):335-348.
Gurney JG, Ness KK, Sibley SD, et al. Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer. Sep 15 2006;107(6):1303-1312.
Huma Z, Boulad F, Black P, Heller G, Sklar C. Growth in children after bone marrow transplantation for acute leukemia. Blood. Jul 15 1995;86(2):819-824.
Leung W, Ahn H, Rose SR, et al. A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore). Jul 2007;86(4):215-224.
Merchant TE, 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.
Sanders JE. Growth and development after hematopoietic cell transplant in children. Bone Marrow Transplant. Jan 2008;41(2):223-227.
Sanders JE, Guthrie KA, Hoffmeister PA, Woolfrey AE, Carpenter PA, Appelbaum FR. Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood. Feb 1 2005;105(3):1348-1354.
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.
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.

COG LTFU Guidelines – Page 64

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Male)

51

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

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects
Precocious puberty

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

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
HeightWeightTanner staging
Testicular volume by Prader
orchidometry
Yearly until sexually mature• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health Counseling
Further Considerations
Health Links
Precocious Puberty
Resources
www.magicfoundation.org
Considerations for Further Testing and Intervention
Obtain FSH, LH, testosterone as clinically indicated in patientswith signs of accelerated pubertal progression and growth.
Obtain x-ray for bone age in rapidly growing children.
Endocrine consultation for accelerated puberty (puberty in boy< 9 years old).
SYSTEM = Endocrine/Metabolic
SCORE = 1

(Female)51

CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
Waldeyer’s Ring

Precocious puberty

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

PHYSICAL
HeightWeightTanner staging
Yearly until sexually mature

Health Links
Precocious Puberty
Resources
www.magicfoundation.org
Considerations for Further Testing and Intervention
Obtain FSH, LH, estradiol as clinically indicated in patients withsigns of accelerated pubertal progression and growth. Obtain
x-ray for bone age in rapidly growing children. Endocrine
consultation for accelerated puberty (puberty in girl < 8 yearsold). Consider pelvic ultrasound in females to evaluate forovarian tumor.

SYSTEM = Endocrine/Metabolic
SCORE = 1

COG LTFU Guidelines – Page 65

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 51 REFERENCES
Chow EJ, Friedman DL, Yasui Y, et al. Timing of menarche among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer. Apr 2008;50(4):854858.
Darzy KH, Shalet SM. Hypopituitarism as a consequence of brain tumours and radiotherapy. Pituitary. 2005;8(3-4):203-211.
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.

COG LTFU Guidelines – Page 66

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Male)

52

Therapeutic
Agent(s)≥ 40 Gy to:
CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
Waldeyer’s Ring
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects
Hyperprolactinemia

Risk
Factors

HighestRisk Factors

Treatment Factors
Treatment Factors
Higher radiation dose
Radiation dose ≥ 50 Gy
Surgery or tumor in hypothalamicarea• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 40 Gy

Periodic
Evaluation
HISTORY
Decreased libido
Galactorrhea
YearlySCREENING
Prolactin level
In patients with galactorrhea ordecreased libido• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.

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.

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

(Female)52≥ 40 Gy to:
CranialOrbital/Eye
Ear/Infratemporal
Nasopharyngeal
Waldeyer’s Ring
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

Hyperprolactinemia

Treatment Factors
Treatment Factors
Higher radiation dose
Radiation dose ≥ 50 Gy
Surgery or tumor in hypothalamicarea• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 40 Gy

SCORE = 1

HISTORY
Galactorrhea
Menstrual history
YearlySCREENING
Prolactin level
In patients with galactorrhea or
amenorrhea• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Health 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, amenorrhea, or galactorrhea.

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.

COG LTFU Guidelines – Page 67

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
53

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

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects

Risk
Factors

Central hypothyroidism

Treatment Factors
Higher radiation dose

Info Link: Central
hypothyroidism includes
thyroid-releasing andthyroid-stimulating hormone
deficiency*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 40 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

HighestRisk Factors

Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly; Consider more frequent
screening during periods of rapid
growth.

PHYSICAL
HeightWeightHair
Skin
Thyroid exam
Yearly; Consider more frequent
screening during periods of rapid
growth.

Health 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.

COG LTFU Guidelines – Page 68

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Male)

54

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

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects

Risk
Factors

Gonadotropin deficiency

Treatment Factors
Higher radiation dose

Info Link: Gonadotropin
deficiency includes LH andFSH deficiency.

*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 40 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.

HighestRisk Factors

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction
YearlyPHYSICAL
Tanner staging
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.

Health Counseling
Further Considerations
Health Links
Male Health Issues
See also: Hypopituitarism
Resources
American Society for Reproductive Medicine: www.asrm.org
Fertile Hope: www.fertilehope.org
Considerations for Further Testing and Intervention
Refer to endocrinologist for delayed puberty or persistently
abnormal hormone levels. Hormonal replacement therapy for
hypogonadal patients. Reproductive endocrinology referral for
infertility evaluation and consultation regarding assisted
reproductive technologies. Consider bone density testing inpatients who are gonadotropin deficient.

SYSTEM = Reproductive (male)
SCORE = 1

Semen analysis
As requested by patient and forevaluation of infertility.

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

COG LTFU Guidelines – Page 69

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Female)54

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

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects

Risk
Factors

Gonadotropin deficiency

Treatment Factors
Higher radiation dose

Info Link: Gonadotropin
deficiency includes LH andFSH deficiency.

*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

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

HighestRisk Factors

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Menstrual/pregnancy history
Sexual function (vaginal dryness,
libido)Medication use impacting sexualfunction
YearlyPHYSICAL
Tanner staging
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, or clinical signs
and symptoms of estrogen deficiency.

Health Counseling
Further Considerations
Health Links
Female Health Issues
See also: Hypopituitarism
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 in patients
who are gonadotropin deficient.

SYSTEM = Reproductive (female)
SCORE = 1

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

COG LTFU Guidelines – Page 70

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 54 REFERENCES
Chow EJ, Friedman DL, Yasui Y, et al. Timing of menarche among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer. Apr 2008;50(4):854858.
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.

COG LTFU Guidelines – Page 71

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
55

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

NEUROENDOCRINE AXIS (cont)
Potential
Late Effects
Central adrenal insufficiency

Risk
Factors
Treatment Factors
Higher radiation dose
Surgery or tumor in the
suprasellar region*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

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

HighestRisk Factors
Treatment Factors
Prior development of anotherhypothalamic-pituitaryendocrinopathy

Periodic
Evaluation
HISTORY
Failure to thrive
Anorexia
Dehydration
Hypoglycemia
Lethargy
Unexplained hypotension
YearlySCREENING
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

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 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.

COG LTFU Guidelines – Page 72

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
56

Therapeutic
Agent(s)CranialOrbital/Eye
TBI
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.

EYE
Potential
Late Effects
Cataracts

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)
YearlyHealth 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 or
PHYSICAL
cancer center (psychologist, social worker, school counselor) to
Eye exam (visual acuity, funduscopic facilitate acquisition of educational resources.
exam to evaluate for lens opacity)
YearlySYSTEM = Ocular• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

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.
Ferry C, Gemayel G, Rocha V, et al. Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies. Bone Marrow Transplant. Aug 2007;40(3):219-224.
Gurney JG, Ness KK, Rosenthal J, Forman SJ, Bhatia S, Baker KS. Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood: resultsfrom the Bone Marrow Transplant Survivor study. Cancer. Mar 15 2006;106(6):1402-1408.
Holmstrom G, Borgstrom B, Calissendorff B. Cataract in children after bone marrow transplantation: relation to conditioning regimen. Acta Ophthalmol Scand. Apr 2002;80(2):211-215.
Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. May 1 2003;101(9):3373-3385.
van Kempen-Harteveld ML, Belkacemi Y, Kal HB, Labopin M, Frassoni F. Dose-effect relationship for cataract induction after single-dose total body irradiation and bone marrow transplantation for acute leukemia.
Int J Radiat Oncol Biol Phys. Apr 1 2002;52(5):1367-1374.
van Kempen-Harteveld ML, Struikmans H, Kal HB, et al. Cataract after total body irradiation and bone marrow transplantation: degree of visual impairment. Int J Radiat Oncol Biol Phys. Apr 1 2002;52(5):1375-1380.
Zierhut D, Lohr F, Schraube P, et al. Cataract incidence after total-body irradiation. Int J Radiat Oncol Biol Phys. Jan 1 2000;46(1):131-135.

COG LTFU Guidelines – Page 73

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
57

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

Risk
Factors

HighestRisk Factors≥ 30 Gy to:
CranialOrbital/Eye
TBI*

Treatment Factors
Host Factors
Ocular toxicity
Higher radiation dose
Chronic GVHD
Orbital hypoplasia
Higher daily fraction dose
(xerophthalmia only)
Lacrimal duct atrophy
Radiomimetic chemotherapy
Xerophthalmia(e.g., doxorubicin, dactinomycin) Treatment Factors(keratoconjunctivitis sicca)[problems related to tearing]
Fraction dose ≥ 2 Gy
*TBI included for dose
Keratitis
Telangiectasias
calculation purposes only; thisRetinopathy
section not applicable topatients who received TBI alone. Optic chiasm neuropathy
Enophthalmos
Chronic painful eye
Maculopathy
Info Link: Radiation-related
ocular complications other than Papillopathy
Glaucoma
cataracts are generally
associated only with orbital/eye
radiation or higher dose cranial Info Link: Reduced visualacuity may be associated withradiation. However, patientscataracts, retinal damage, andwith a history of an oculartumor (e.g., retinoblastoma) are optic nerve damage.
at higher risk for late-onset• This section is only applicable to patients who:
ocular complications and should
1) Received radiation to any of the specified fields at ≥ 30 Gy
receive ongoing follow-up by anophthalmologist at leastORannually, and more frequently if2) Received a combination of radiation to any of the specified fields and TBI, theclinically indicated.
sum of which is ≥ 30 Gy

Periodic
Evaluation
HISTORY
Visual changes (decreased acuity,
halos, diplopia)
Dry eye
Persistent eye irritation
Excessive tearing
Light sensitivity
Poor night vision
Painful eye
YearlyPHYSICAL
Visual acuity
Funduscopic exam
YearlyHealth 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
YearlySCORE = 1

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 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.
Monroe AT, Bhandare N, Morris CG, Mendenhall WM. Preventing radiation retinopathy with hyperfractionation. Int J Radiat Oncol Biol Phys. Mar 1 2005;61(3):856-864.
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.

COG LTFU Guidelines – Page 74

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
58

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

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*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.
Sensorineural hearing loss
Tinnitus

Host Factors
Younger age at treatment
CNS tumor
CSF shunting
Treatment Factors
Higher radiation dose;
Conventional (non-conformal)
radiation• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 30 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

COG LTFU Guidelines – Page 75

Periodic
Evaluation
HISTORY
Hearing difficulties(with/without background noise)
Tinnitus
VertigoYearlyPHYSICAL
Otoscopic exam
YearlyTreatment Factors
Radiation administered prior toplatinum chemotherapy
Combined with other ototoxic
agents such as:- Cisplatin- Carboplatin in
myeloablative doses- Aminoglycosides

SCREENING
Complete audiological evaluation
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:
A “complete audiological evaluation”
includes pure tone air and bone
conduction, speech audiometry, andtympanometry for both ears.
Frequency-specific auditory brainstem
response (ABR) can be performed if theabove is inconclusive.

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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.
Hua C, Bass JK, Khan R et al. Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose. Int J Biol Phys. 2008 Nov 1; 72(3):892-899.
Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys. Mar 1 2002;52(3):599-605.
Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of
medulloblastoma in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys. Jan 15 2000;46(2):269-279.
Low et al. Sensorineural hearing loss after radiotherapy and chemo-radiotherapy: a single, blinded, randomized study. J Clin Oncol. 2006;24(12):1904-9.
Merchant et al. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer. 2008; 51:
110-117.
Merchant TE, Gould CJ, Xiong X, et al. Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol Biol Phys. Mar 15 2004;58(4):1194-1207.
Paulino AC, Simon JH, Zhen W, Wen BC. Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol 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.

COG LTFU Guidelines – Page 76

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)59

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Mini-Mantle
MantleExtended Mantle
TLI
STLI

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
YearlyMedical Conditions
Chronic GVHD

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

PHYSICAL
Oral exam
YearlySCREENING
Dental exam and cleaning
Every 6 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

COG LTFU Guidelines – Page 77

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION

ORAL CAVITY (cont)

Sec#

Therapeutic
Agent(s)Potential
Late Effects

60

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Mini-Mantle
MantleExtended Mantle
TLI
STLI
TBI

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
YearlySCREENING
Dental exam and cleaning
Every 6 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

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

SECTION 60 REFERENCES
Dahllof G, Bagesund M, Remberger M, Ringden O. Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol. Sep 1997;33(5):327-331.
Dahllof G, Bagesund M, Ringden O. Impact of conditioning regimens on salivary function, caries-associated microorganisms and dental caries in children after bone marrow transplantation. A 4-year
longitudinal study. Bone Marrow Transplant. Sep 1997;20(6):479-483.
Dahllof G, Jonsson A, Ulmner M, Huggare J. Orthodontic treatment in long-term survivors after pediatric bone marrow transplantation. Am J Orthod Dentofacial Orthop. Nov 2001;120(5):459-465.
Goho C. Chemoradiation therapy: effect on dental development. Pediatr Dent. Jan-Feb 1993;15(1):6-12.
Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol. Nov 1
2007;25(31):4873-4879.
Kaste SC, Hopkins KP, Bowman LC. Dental abnormalities in long-term survivors of head and neck rhabdomyosarcoma. Med Pediatr Oncol. Aug 1995;25(2):96-101.
Kaste SC, Hopkins KP, Jones D, Crom D, Greenwald CA, Santana VM. Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia. Jun 1997;11(6):792-796.
Maguire A, Welbury RR. Long-term effects of antineoplastic chemotherapy and radiotherapy on dental development. Dent Update. Jun 1996;23(5):188-194.
Raney RB, Asmar L, Vassilopoulou-Sellin R, et al. Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup
Rhabdomyosarcoma Studies (IRS)-II and - III. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol. Oct 1999;33(4):362-371.
Sonis AL, Tarbell N, Valachovic RW, Gelber R, Schwenn M, Sallan S. Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities.
Cancer. Dec 15 1990;66(12):2645-2652.

COG LTFU Guidelines – Page 78

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)61≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Mini-Mantle
MantleExtended Mantle
TLI
STLI
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

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

Periodic
Evaluation
HISTORY
Impaired or delayed healing
following dental work
Persistent jaw pain or swelling
TrismusAs clinically indicated

PHYSICAL
Impaired wound healing
Jaw swelling
TrismusAs clinically indicatedHealth 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

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 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.

COG LTFU Guidelines – Page 79

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)62

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
Mini-mantle
MantleExtended Mantle
TLI
STLI
TBI

NECK/THYROID
Potential
Late Effects
Thyroid nodules

Risk
Factors
Host Factors
Younger age at treatment
Female sex

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 25 Gy

Treatment Factors
Higher radiation dose
Thyroid gland directly inradiation field
TBI

Periodic
Evaluation
PHYSICAL
Thyroid exam
YearlyHealth 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 = SMN• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SCORE = 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.
Faraci M, Barra S, Cohen A, et al. Very late nonfatal consequences of fractionated TBI in children undergoing bone marrow transplant. Int J Radiat Oncol Biol Phys. Dec 1 2005;63(5):1568-1575.
Metzger ML, Howard SC, Hudson MM, et al. Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma. Pediatr Blood Cancer. Mar 2006;46(3):314-319.
Schneider AB, Shore-Freedman E, Weinstein RA. Radiation-induced thyroid and other head and neck tumors: occurrence of multiple tumors and analysis of risk factors. J Clin Endocrinol Metab.
Jul 1986;63(1):107-112.
Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study.
Lancet. Jun 28 2005;365(9476):2014-2023.
Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. Sep 2000;85(9):3227-3232.

COG LTFU Guidelines – Page 80

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)63

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
Mini-Mantle
MantleExtended Mantle
TLI
STLI
TBI

NECK/THYROID (cont)
Potential
Late Effects
Thyroid cancer

Risk
Factors

HighestRisk Factors

Host Factors
Younger age at treatment
Female sex
Treatment Factors≥ 5 years after irradiation
Thyroid gland directly inradiation field
TBI
Risk increased up to 30 Gy
with a downturn of risk after
30 Gy• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Periodic
Evaluation
PHYSICAL
Thyroid exam
YearlyHealth 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
Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. Jan 15 2001;19(2):464-471.
Cohen A, Rovelli A, Merlo DF, et al. Risk for secondary thyroid carcinoma after hematopoietic stem-cell transplantation: an EBMT Late Effects Working Party Study. J Clin Oncol. Jun 10 2007;25(17):2449-2454.
Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med. Mar 27 1997;336(13):897-904.
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.
Schneider AB, Fogelfeld L. Radiation-induced endocrine tumors. Cancer Treat Res. 1997;89:141-161.
Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study.
Lancet. Jun 28 2005;365(9476):2014-2023.
Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. Sep 2000;85(9):3227-3232.
Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. Jan 2000;18(2):348-357.

COG LTFU Guidelines – Page 81

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)64

CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
Mini-Mantle
MantleExtended Mantle
TLI
STLI
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• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 20 Gy

Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly; Consider more frequent
screening during periods of rapid
growth.

PHYSICAL
HeightWeightHair and 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.
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.
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.

COG LTFU Guidelines – Page 82

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)65≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
Mini-Mantle
MantleExtended Mantle
TLI
STLI
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

NECK/THYROID (cont)
Potential
Late Effects
Hyperthyroidism

Risk
Factors

HighestRisk Factors

Treatment Factors
Higher radiation dose

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.

Periodic
Evaluation
HISTORY
Heat intolerance
Tachycardia
Palpitations
Weight loss
Emotional lability
Muscular weakness
Hyperphagia
YearlyHealth 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• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.
SCREENING
TSHFree T4
YearlySECTION 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.

COG LTFU Guidelines – Page 83

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION

NECK/THYROID (cont)

Sec#

Therapeutic
Agent(s)Potential
Late Effects

66≥ 40 Gy to:
CranialNasopharyngeal
Oropharyngeal
Waldeyer’s Ring
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
Mini-Mantle
MantleExtended Mantle
TLI
STLI
TBI*

Carotid artery disease*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

Risk
Factors

HighestRisk Factors• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 40 Gy

Periodic
Evaluation
HISTORY
Memory impairment
YearlyPHYSICAL
Diminished carotid pulses
Carotid bruits
Abnormal neurologic exam
(compromise of blood flow to brain)
YearlyHealth 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

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 66 REFERENCES
Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin's Disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol. Sep 20 2005;23(27):6508-6515.
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.
Meeske KA, Nelson MD, Lavey RS, et al. Premature carotid artery disease in long-term survivors of childhood cancer treated with neck irradiation: a series of 5 cases. J Pediatr Hematol Oncol. Jul 2007;29(7):480484.
Qureshi AI, Alexandrov AV, Tegeler CH, Hobson RW, 2nd, Dennis Baker J, Hopkins LN. Guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary
practice guidelines committee of the American Society of Neuroimaging; cosponsored by the Society of Vascular and Interventional Neurology. J Neuroimaging. Jan 2007;17(1):19-47.
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.

COG LTFU Guidelines – Page 84

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)67≥ 40 Gy to:
Spine (cervical, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
Mini-Mantle
MantleExtended Mantle
TLI
STLI
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

NECK/THYROID (cont)
Potential
Late Effects

Risk
Factors

HighestRisk Factors

Subclavian artery disease• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.

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

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

SECTION 67 REFERENCES
Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin's Disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol. Sep 20 2005;23(27):6508-6515.
Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy.
JAMA. Dec 3 2003;290(21):2831-2837.

COG LTFU Guidelines – Page 85

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Female)68

Therapeutic
Agent(s)≥ 20 Gy to:
Chest (thorax)
Whole lungMediastinal
AxillaMini-Mantle
MantleExtended Mantle
TLI
STLI
TBI*

BREAST
Potential
Late Effects
Breast cancer

Risk
Factors
Host Factors
Family history of breast cancer
Treatment Factors
Higher radiation doseLonger time since radiation(≥ 5 years)
Decreased risk in women treatedwith alkylating agents

Info Link:*Important: The risk of breast
cancer in patients who received
TBI alone is of a lower
magnitude compared to those
who received ≥ 20 Gy ofradiation with potential impact
to the breast (e.g.,thorax, axilla);therefore, monitoring of patients
who received TBI without
additional radiation potentially
impacting the breast 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 6 months.

SCREENING
Mammogram
Yearly, beginning 8 years after radiation
or at age 25, whichever occurs last.
Breast MRI
Yearly as an adjunct to mammography
beginning 8 years after radiation or atage 25, whichever occurs last.
Info Link: Mammography is currently
limited in its ability to evaluate thepremenopausal breast. MRI is now
recommended as an adjunct tomammography in women treated withchest radiation for childhood cancer
similar to screening of otherpopulations at high risk for breast
cancer (e.g., premenopausal known orlikely carriers of gene mutation of
known penetrance). The upper age limit
at which both modalities should be
used for breast cancer surveillance has
not been established.

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

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 20 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 20 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

COG LTFU Guidelines – Page 86

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

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.
Friedman DL, Rovo A, Leisenring W, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party. Blood.
Jan 15 2008;111(2):939-944.
Guibout C, Adjadj E, Rubino C, et al. Malignant breast tumors after radiotherapy for a first cancer during childhood. J Clin Oncol. Jan 1 2005;23(1):197-204.
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.
Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. Mar-Apr 2007;57(2):75-89.
Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. Jul 23 2003;290(4):465-475.
van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst. Jul 2 2003;95(13):971-980.
Wolden SL, Hancock SL, Carlson RW, Goffinet DR, Jeffrey SS, Hoppe RT. Management of breast cancer after Hodgkin's disease. J Clin Oncol. Feb 2000;18(4):765-772.

COG LTFU Guidelines – Page 87

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Female)69

Therapeutic
Agent(s)Chest (thorax)
Whole lungMediastinal
AxillaMini-Mantle
MantleExtended Mantle
TLI
STLI
TBI

BREAST (cont)
Potential
Late Effects
Breast tissue hypoplasia

Risk
Factors

HighestRisk Factors

Host Factors
Prepubertal at time of breast
irradiation

Treatment Factors≥ 20 Gy to prepubertal breast
bud may ablate development

Periodic
Evaluation
PHYSICAL
Breast exam
YearlyHealth Counseling
Further Considerations
Considerations for Further Testing and Intervention
Surgical consultation for breast reconstruction after completionof growth.

Treatment Factors
Radiation dose ≥ 10 Gy to
prepubertal breast bud may
cause failure of development(hypoplasia)

SYSTEM = Reproductive (female)
SCORE = 1

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

SECTION 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.

COG LTFU Guidelines – Page 88

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
70

Therapeutic
Agent(s)Chest (thorax)
Whole lungMediastinal
AxillaMini-Mantle
MantleExtended Mantle
TLI
STLI
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
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
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 pulmonologist.
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• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

COG LTFU Guidelines – Page 89

SCORE = 1

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 70 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.
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.
Hoffmeister PA, Madtes DK, Storer BE, Sanders JE. Pulmonary function in long-term survivors of pediatric hematopoietic cell transplantation. Pediatr Blood Cancer. Oct 15 2006;47(5):594-606.
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.
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.
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, 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, Hesse B, et al. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. Arch Dis Child. May 1996;74(5):432-436.
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.
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.

COG LTFU Guidelines – Page 90

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Male)71

HEART

Therapeutic
Agent(s)Spine (thoracic, whole)
Chest (thorax)
Whole lungMediastinal
MantleExtended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI
TBI

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

RECOMMENDED FREQUENCY OF ECHOCARDIOGRAM
Age atTreatment*

Radiation Dose

< 5 years oldAny≥ 5 years old

Anthracycline
Dose†

Recommended
Frequency

None
Any

Every 2 years
Every year

<30 Gy‡≥30 Gy‡None
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 radiation
with potential impact to heart, whichever was given first)†Based on doxorubicin isotoxic equivalent dose [see conversion
factors in Section 28 “Info Link (Dose Conversion)”]‡If patient received radiation to more than one specified field, seedose calculation rules on page 48.

COG LTFU Guidelines – Page 91

Periodic
Evaluation

HISTORY
SOB
DOE
Orthopnea
Chest pain
Palpitations
Treatment Factors
Treatment Factors
Radiation dose ≥ 20 Gy to chest Anteriorly-weighted radiation ‘ If under 25 years: Abdominal
symptoms (nausea, vomiting)fieldsTBI
YearlyCombined with radiomimetic
Lack of subcarinal shielding
chemotherapy
Doses ≥ 30 Gy in patients who(e.g., doxorubicin, dactinomycin) have received anthracyclines Info Link: Exertional intolerance isuncommon in patients younger than 25
Combined with other cardiotoxic Doses ≥ 40 Gy in patients
years old. Abdominal symptoms
chemotherapy
who have not received(nausea, emesis) may be observed- Anthracyclines
anthracyclines
more frequently than exertional- Cyclophosphamide
Longer time since treatment
dyspnea or chest pain in younger
conditioning for HCT
patients.
- Amsacrine
Medical Conditions
Hypertension
Obesity
Dyslipidemia
Diabetes mellitus
Congenital heart disease
Febrile illness
Health Behaviors
Smoking
Isometric exercise
Drug use (e.g., cocaine,
diet pills, ephedra)• See “Patient-Specific Guideline Identification Tool” inAppendix I to determine specific screening guidelines
by section number for individual patients.

PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlySCREENING
Fasting glucose and lipid profile
Every 2 years; If abnormal, refer for
ongoing management.
EKG (include evaluation of QTc
interval)
Baseline at entry into long-term followup, repeat as clinically indicated.
ECHO
Baseline at entry into long-term followup, then periodically based on age attreatment, radiation dose, andcumulative anthracycline dose [seetable]

Health Counseling
Further Considerations
Health Links
Heart Health
Diet and Physical Activity
Dental 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 endocarditis prophylaxis if at highest risk. Note: The
AHA now limits their recommendation regarding endocarditis
prophylaxis only to patients whose cardiac conditions areassociated with the highest risk of adverse outcome, which
includes, but is not limited to the following four categories: (1)prosthetic heart valves, (2) previous history of infective
endocarditis, (3) certain patients with congenital heart disease,and (4) valvulopathy following cardiac transplantation. Survivors
diagnosed with heart valve disorders should discuss the need for
endocarditis prophylaxis with their cardiologist. See Wilson et al.
(2007) for specifics. Counsel regarding appropriate exercise.
Aerobic exercise is generally safe and should be encouraged formost patients. Intensive isometric activities (e.g., heavy weightlifting, wrestling) should generally be avoided. High repetition
weight lifting involving lighter weights is more likely to be safe.
The number of repetitions should be limited to that which thesurvivor can perform with ease. Patients who choose to engage
in strenuous or varsity team sports should discuss appropriate
guidelines and a plan for ongoing monitoring with a cardiologist.
Considerations for Further Testing and Intervention
Cardiology consultation for patients with subclinical abnormalities
on screening evaluations or with left ventricular dysfunction,
dysrhythmia or prolonged QTc interval. Consider cardiology
consultation (5 to 10 years after radiation) to evaluate risk forcoronary artery disease in patients who received ≥ 40 Gy chest
radiation alone or ≥ 30 Gy chest radiation plus anthracycline.
Consider excess risk of isometric exercise program in any highrisk patient defined as needing screening every 1 or 2 years.
SYSTEM = Cardiovascular
SCORE = 1

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Female)71

HEART (cont)

Therapeutic
Agent(s)Spine (thoracic, whole)
Chest (thorax)
Whole lungMediastinal
MantleExtended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI
TBI

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 oldAny≥ 5 years old

Anthracycline
Dose†

Recommended
Frequency

None
Any

Every 2 years
Every year

<30 Gy‡≥30 Gy‡None
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 radiation
with potential impact to heart, whichever was given first)†Based on doxorubicin isotoxic equivalent dose [see conversion
factors in Section 28 “Info Link (Dose Conversion)”]‡If patient received radiation to more than one specified field, seedose calculation rules on page 48.

COG LTFU Guidelines – Page 92

Periodic
Evaluation

HISTORY
SOB
DOE
Orthopnea
Chest pain
Palpitations
Treatment Factors
If under 25 years: Abdominal
Radiation dose ≥ 20 Gy to chest Treatment Factors
Anteriorly-weighted radiation ‘ symptoms (nausea, vomiting)
TBI
YearlyfieldsCombined with radiomimetic
chemotherapy
Lack of subcarinal shielding(e.g., doxorubicin, dactinomycin) Doses ≥ 30 Gy in patients who Info Link: Exertional intolerance ishave received anthracyclines uncommon in patients younger than 25
Combined with other cardiotoxic
years old. Abdominal symptoms
Doses ≥ 40 Gy in patientschemotherapy(nausea, emesis) may be observed- Anthracyclines
who have not received
more frequently than exertional- Cyclophosphamide
anthracyclines
dyspnea or chest pain in younger
Longer time since treatment
conditioning for HCT
patients.
- Amsacrine
Medical Conditions
Hypertension
Obesity
Dyslipidemia
Diabetes mellitus
Congenital heart disease
Febrile illness
Pregnancy
Premature ovarian failure(untreated)

PHYSICAL
Cardiac murmur
S3, S4
Increased P2 sound
Pericardial rub
Rales
WheezesJugular venous distension
Peripheral edema
YearlyHealth Behaviors
Smoking
Isometric exercise
Drug use (e.g., cocaine,
diet pills, ephedra)

SCREENING
Fasting glucose and lipid profile
Every 2 years; If abnormal, refer for
ongoing management.

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

EKG (include evaluation of QTc
interval)
Baseline at entry into long-term followup, repeat as clinically indicated.
ECHO
Baseline at entry into long-term followup, then periodically based on age attreatment, radiation dose, andcumulative anthracycline dose [seetable]

Health Counseling
Further Considerations
Health Links
Heart Health
Diet and Physical Activity
Dental 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
endocarditis prophylaxis if at highest risk. Note: The AHA now
limits their recommendation regarding endocarditis prophylaxis
only to patients whose cardiac conditions are associated with thehighest risk of adverse outcome, which includes, but is not limited
to the following four categories: (1) prosthetic heart valves,(2) previous history of infective endocarditis, (3) certain patientswith congenital heart disease, and (4) valvulopathy following
cardiac transplantation. Survivors diagnosed with heart valve
disorders should discuss the need for endocarditis prophylaxis
with their cardiologist. See Wilson et al. (2007) for specifics.
Counsel regarding appropriate exercise. Aerobic exercise isgenerally safe and should be encouraged for most patients.
Intensive isometric activities (e.g., heavy weight lifting, wrestling)should generally be avoided. High repetition weight lifting involving
lighter weights is more likely to be safe. The number ofrepetitions should be limited to that which the survivor canperform with ease. 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 for patients with subclinical abnormalities onscreening evaluations or with left ventricular dysfunction,
dysrhythmia or prolonged QTc interval. Additional cardiology
evaluation for patients who are pregnant or planning pregnancy
who: (1) received ≥ 30 Gy chest radiation, or (2) received chest
radiation in combination with cardiotoxic chemotherapy(anthracyclines or high-dose cyclophosphamide). Evaluation to
include echocardiogram before and periodically during pregnancy(especially during third trimester) and monitoring during labor anddelivery due to risk of cardiac failure. Consider cardiology
consultation (5 to 10 years after radiation) to evaluate risk forcoronary artery disease in patients who received ≥ 40 Gy chest
radiation alone or ≥ 30 Gy chest radiation plus anthracycline.
Consider excess risk of isometric exercise program in any highrisk patient defined as needing screening every 1 or 2 years.
SYSTEM = Cardiovascular
SCORE = 1

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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.
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.
Heidenreich PA, Schnittger I, Strauss HW, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease. J Clin Oncol. Jan 1 2007;25(1):43-49.
Hertenstein B, Stefanic M, Schmeiser T, et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol. May 1994;12(5):998-1004.
Hogarty AN, Leahey A, Zhao H, et al. Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr. Mar 2000;136(3):311-317.
Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA.
Dec 3 2003;290(21):2831-2837.
Jakacki RI, Goldwein JW, Larsen RL, Barber G, Silber JH. Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol. Jun 1993;11(6):1033-1038.
Lonnerholm G, Arvidson J, Andersson LG, Carlson K, Jonzon A, Sunnegardh J. Myocardial function after autologous bone marrow transplantation in children: a prospective long-term study. Acta 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.
Qureshi AI, Alexandrov AV, Tegeler CH, Hobson RW, 2nd, Dennis Baker J, Hopkins LN. Guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary
practice guidelines committee of the American Society of Neuroimaging; cosponsored by the Society of Vascular and Interventional Neurology. J Neuroimaging. Jan 2007;17(1):19-47.
Swerdlow AJ, Higgins CD, Smith P, et al. Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst. Feb 7 2007;99(3):206-214.
Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, andKawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes
Research Interdisciplinary Working Group. Circulation. Oct 9 2007;116(15):1736-1754.

COG LTFU Guidelines – Page 93

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)72≥ 40 Gy to:Left upper quadrant
Spleen (entire)
Paraaortic*
Left flank/hemiabdomen
Whole abdomen
Inverted Y*
TLI
STLI
TBI**

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
spleen*If spleen in field**TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

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

HighestRisk 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 ≥ 101ºF

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). Discuss with dental provider potential need for antibiotic
prophylaxis based on planned procedure.

SYSTEM = Immune
SCORE = 1

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

COG LTFU Guidelines – Page 94

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

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

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 72 REFERENCES
American Academy of Pediatric Dentistry, Guideline on Antibiotic Prophylaxis for Dental Patients at Risk for Infection. American Academy of Pediatric Dentistry Reference Manual. Vol 29, No. 7. Chicago: American
Academy of Pediatric Dentistry; 2007:pp. 202-204, available: http://www.aapd.org/media/policies.asp (accessed 2-24-08).
American Acadamy of Pediatrics. Section 1. Immunocompromised Children. Red Book 2006: Report of the Committee on Infectious Diseases (27th ed.). Elk Grove Village, IL: AAP.
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.
Mourtzoukou EG, Pappas G, Peppas G, Falagas ME. Vaccination of asplenic or hyposplenic adults. Br J Surg. Mar 2008;95(3):273-280.
Price VE, Dutta S, Blanchette VS, et al. The prevention and treatment of bacterial infections in children with asplenia or hyposplenia: practice considerations at the Hospital for Sick Children, Toronto. Pediatr Blood
Cancer. May 1 2006;46(5):597-603.
Smets F, Bourgois A, Vermylen C, et al. Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine. Vaccine. Jul 20
2007;25(29):5278-5282.
Spelman D, Buttery J, Daley A, et al. Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J. May 2008;38(5):349-356.

COG LTFU Guidelines – Page 95

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
73

Therapeutic
Agent(s)≥ 30 Gy to:
Spine (cervical, thoracic,
whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
Mini-Mantle
MantleExtended mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI alone.

GI/HEPATIC SYSTEM
Potential
Late Effects
Esophageal stricture

Risk
Factors
Treatment Factors
Higher radiation doseRadiomimetic chemotherapy(e.g., doxorubicin, actinomycin)

HighestRisk Factors
Treatment Factors
Radiation dose ≥ 40 Gy
Medical Conditions
Gut GVHD

Medical Conditions
Gastroesophageal reflux
History of Candida esophagitis

Periodic
Evaluation
HISTORY
Dysphagia
HeartburnYearlyHealth 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

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 73 REFERENCES
Lal DR, Foroutan HR, Su WT, Wolden SL, Boulad F, La Quaglia MP. The management of treatment-related esophageal complications in children and adolescents with cancer. J Pediatr Surg. Mar 2006;41(3):495-499.
Mahboubi S, Silber JH. Radiation-induced esophageal strictures in children with cancer. Eur Radiol. 1997;7(1):119-122.

COG LTFU Guidelines – Page 96

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
74

Therapeutic
Agent(s)≥ 30 Gy to:
Extended mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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

Risk
Factors
Treatment Factors
Higher radiation dose
Medical Conditions
Chronic hepatitis
History of VOD

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

Health Behaviors
Alcohol use• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 30 Gy

Periodic
Evaluation
PHYSICAL
Jaundice
Spider angiomas
Palmar erythema
Xanthomata
Hepatomegaly
Splenomegaly
YearlySCREENING
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

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 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.

COG LTFU Guidelines – Page 97

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
75

Therapeutic
Agent(s)≥ 30 Gy to:
Extended mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI
TBI*
*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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 as clinically indicated

PHYSICALRUQ or epigastric tenderness
Positive Murphy's signYearly and as clinically indicatedHealth 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

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 30 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

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

COG LTFU Guidelines – Page 98

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
76

Therapeutic
Agent(s)≥ 30 Gy to:
Spine (thoracic, lumbar,
sacral, whole)
Extended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
Femoral
TLI
STLI
TBI*

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
Distention
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.

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 30 Gy

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

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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.

COG LTFU Guidelines – Page 99

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
77

Therapeutic
Agent(s)≥ 30 Gy to:
Spine (thoracic, lumbar,
sacral, whole)
Extended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
Femoral
TLI
STLI
TBI*

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• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 30 Gy

Periodic
Evaluation
HISTORY
NauseaVomiting
Abdominal pain
Diarrhea
YearlyHealth 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

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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.

COG LTFU Guidelines – Page 100

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)78≥ 30 Gy to:
Spine (thoracic, lumbar, sacral,whole)
Extended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
Femoral
TLI
STLI
TBI*
Info Link:*Important: Reports of colorectal
cancer in cohorts of long-term
survivors suggest that radiation
likely increases risk; however, therisk related to TBI alone has notbeen established. Therefore,monitoring of patients who
received TBI without additionalradiation potentially impacting thecolon/rectum should bedetermined on an individual basis.
(See Info Link in next column)

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 highrisk 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

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 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.
Hodgson DC, Koh ES, Tran TH, et al. Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin lymphoma. Cancer. Dec 1 2007;110(11):2576-2586.
Metayer C, Lynch CF, Clarke EA, et al. Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol. Jun 2000;18(12):2435-2443.
Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol. Feb 2000;18(3):498-509.
Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. Sep 21 2005;97(18):1354-1365.

COG LTFU Guidelines – Page 101

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
79

Therapeutic
Agent(s)Extended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI
TBI

URINARY TRACT
Potential
Late Effects
Renal toxicity
Renal insufficiency
Hypertension• See “Patient-Specific Guideline Identification Tool” inAppendix I to determine specific screening guidelines
by section number for individual patients.

Risk
Factors
Host Factors
Bilateral Wilms tumor
MononephricTreatment Factors
Radiomimetic chemotherapy(e.g., doxorubicin, dactinomycin)
Radiation dose ≥ 10 Gy
TBI combined with radiation to
the kidney
Combined with 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
YearlySCREENING
BUN, Creatinine, Na, K, Cl, CO2, Ca,
Mg, PO4
Baseline at entry into long-term followup, repeat as clinically indicated.
Urinalysis
YearlyHealth Counseling
Further Considerations
Health Links
Kidney HealthSee also: Single Kidney Health
Considerations for Further Testing and Intervention
Nephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency

SYSTEM = Urinary
SCORE = 1

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.
Delgado J, Cooper N, Thomson K, et al. The importance of age, fludarabine, and total body irradiation in the incidence and severity of chronic renal failure after allogeneic hematopoietic cell transplantation. Biol
Blood Marrow Transplant. Jan 2006;12(1):75-83.
Fels LM, Bokemeyer C, van Rhee J, Schmoll HJ, Stolte H. Evaluation of late nephrotoxicity in long-term survivors of Hodgkin's disease. Oncology. Jan-Feb 1996;53(1):73-78.
Frisk P, Bratteby LE, Carlson K, Lonnerholm G. Renal function after autologous bone marrow transplantation in children: a long-term prospective study. Bone Marrow Transplant. Jan 2002;29(2):129-136.
Gronroos MH, Bolme P, Winiarski J, Berg UB. Long-term renal function following bone marrow transplantation. Bone Marrow Transplant. Jun 2007;39(11):717-723.
Lawton CA, Cohen EP, Murray KJ, et al. Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant.
Dec 1997;20(12):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.
Ritchey ML, Green DM, Thomas PR, et al. Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol. Feb 1996;26(2):75-80.
Tarbell NJ, Guinan EC, Niemeyer C, Mauch P, Sallan SE, Weinstein HJ. Late onset of renal dysfunction in survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys. Jul 1988;15(1):99-104.

COG LTFU Guidelines – Page 102

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
80

Therapeutic
Agent(s)≥ 30 Gy to:
Spine (sacral, whole)
Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
TLI
TBI***Only if field extended below
iliac crest**TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 30 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlySCREENING
Urinalysis
YearlyHealth 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.

COG LTFU Guidelines – Page 103

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
81

Therapeutic
Agent(s)≥ 30 Gy to:
Spine (sacral, whole)
Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
TLI
TBI***Only if field extended below
iliac crest**TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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

Risk
Factors

HighestRisk Factors

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

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlyHealth Counseling
Further Considerations
Health Links
Bladder Health
Considerations for Further Testing and Intervention
Urologic consultation for patients with incontinence ordysfunctional voiding.

SYSTEM = Urinary• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 30 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 30 Gy

SCREENING
Urinalysis
YearlySCORE = 1

• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

SECTION 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.
Soler R, Macedo A, Jr., Bruschini H, et al. Does the less aggressive multimodal approach of treating bladder-prostate rhabdomyosarcoma preserve bladder function? J Urol. Dec 2005;174(6):2343-2346.
Yeung CK, Ward HC, Ransley PG, Duffy PG, Pritchard J. Bladder and kidney function after cure of pelvic rhabdomyosarcoma in childhood. Br J Cancer. Nov 1994;70(5):1000-1003.

COG LTFU Guidelines – Page 104

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
82

Therapeutic
Agent(s)Spine (sacral, whole)
Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
TLI*Only if field extended below
iliac crest

URINARY TRACT (cont)
Potential
Late Effects
Bladder malignancy

Risk
Factors

HighestRisk Factors

Treatment Factors
Radiation to pelvis
Combined with:- Cyclophosphamide- Ifosfamide
Health Behaviors
Alcohol use
Smoking• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Periodic
Evaluation
HISTORY
Hematuria
Urinary urgency/frequency
Urinary incontinence/retention
Dysuria
Nocturia
Abnormal urinary stream
YearlySCREENING
Urinalysis
YearlyHealth 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.
Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. Sep 21 2005;97(18):1354-1365.

COG LTFU Guidelines – Page 105

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATIONFEMALE REPRODUCTIVE SYSTEM

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

83

Spine (lumbar, sacral, whole)
Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicVaginalBladder
TLI
TBI

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(Female)Sec#*Only if field extended below
iliac crest

Treatment Factors
Higher radiation dose to pelvis

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

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

Periodic
Evaluation
HISTORY
PregnancyChildbirth history
Yearly and as clinically indicatedHealth 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 = Reproductive (female)
SCORE = 2B

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

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.
Critchley HO, Wallace WH. Impact of cancer treatment on uterine function. J Natl Cancer Inst Monogr. 2005(34):64-68.
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.
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.
Signorello LB, Cohen SS, Bosetti C, et al. Female survivors of childhood cancer: preterm birth and low birth weight among their children. J Natl Cancer Inst. Oct 18 2006;98(20):1453-1461.
Waring AB, Wallace WH. Subfertility following treatment for childhood cancer. Hosp Med. Aug 2000;61(8):550-557.

COG LTFU Guidelines – Page 106

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Therapeutic
Agent(s)84

Spine (lumbar, sacral, whole)
Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicVaginalBladder
Iliac
TLI
TBI

(Female)Sec#

FEMALE REPRODUCTIVE SYSTEM (cont)
Potential
Late Effects
Gonadal dysfunction(ovarian)
Delayed/arrested pubertyPremature menopause
Infertility

Risk
Factors
Host Factors
Older age at irradiation
Treatment Factors
Prepubertal female:
Radiation dose ≥10 Gy
Pubertal female:
Radiation dose ≥ 5 Gy
Combined with alkylating agent
chemotherapy
Longer time since treatment*Only if field extended below
iliac crest• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

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

SYSTEM = Reproductive (female)
SCORE = 1

COG LTFU Guidelines – Page 107

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)FEMALE REPRODUCTIVE SYSTEM (cont)
Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

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.
Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. May 2006;91(5):1723-1728.
Couto-Silva AC, Trivin C, Thibaud E, Esperou H, Michon J, Brauner R. Factors affecting gonadal function after bone marrow transplantation during childhood. Bone Marrow Transplant. Jul 2001;28(1):67-75.
Grigg AP, McLachlan R, Zaja J, Szer J. Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant. Nov 2000;26(10):1089-1095.
Hamre MR, Robison LL, Nesbit ME, et al. Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.
J Clin Oncol. Nov 1987;5(11):1759-1765.
Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am. Dec 1998;27(4):927-943.
Livesey EA, Brook CG. Gonadal dysfunction after treatment of intracranial tumours. Arch Dis Child. May 1988;63(5):495-500.
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.
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. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. Jul 1999;33(1):2-8.
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, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst. Jul 5 2006;98(13):890-896.
Stillman RJ, Schinfeld JS, Schiff I, et al. Ovarian failure in long-term survivors of childhood malignancy. Am J Obstet Gynecol. Jan 1981;139(1):62-66.
Thibaud E, Rodriguez-Macias K, Trivin C, Esperou H, Michon J, Brauner R. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant. Feb 1998;21(3):287-290.
Waring AB, Wallace WH. Subfertility following treatment for childhood cancer. Hosp Med. Aug 2000;61(8):550-557.

COG LTFU Guidelines – Page 108

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Female)85

Therapeutic
Agent(s)Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicVaginalBladder
Iliac
TLI

FEMALE REPRODUCTIVE SYSTEM (cont)
Potential
Late Effects
Vaginal fibrosis/stenosis*Only if field extended below
iliac crest

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

SYSTEM = Reproductive (female)
SCORE = 2A

Medical Conditions
Chronic GVHD

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

SECTION 85 REFERENCES
Brand AH, Bull CA, Cakir B. Vaginal stenosis in patients treated with radiotherapy for carcinoma of the cervix. Int J Gynecol Cancer. Jan-Feb 2006;16(1):288-293.
Flamant F, Gerbaulet A, Nihoul-Fekete C, Valteau-Couanet D, Chassagne D, Lemerle J. Long-term sequelae of conservative treatment by surgery, brachytherapy, and chemotherapy for vulval and vaginal
rhabdomyosarcoma in children. J Clin Oncol. Nov 1990;8(11):1847-1853.
Gaillard P, Krasin MJ, Laningham FH, et al. Hematometrocolpos in an adolescent female treated for pelvic Ewing sarcoma. Pediatr Blood Cancer. Jan 2008;50(1):157-160.
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.

COG LTFU Guidelines – Page 109

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Male)

86

Therapeutic
Agent(s)Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicProstate
Bladder
Iliac
Inguinal
FemoralTesticular
TLI
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.

Medical Conditions
Chronic GVHD

*Only if field extended below
iliac crest

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.

• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.
SYSTEM = Reproductive (male)
SCORE = 1

COG LTFU Guidelines – Page 110

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)MALE REPRODUCTIVE SYSTEM (cont)
Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 86 REFERENCES
Anserini P, Chiodi S, Spinelli S, et al. Semen analysis following allogeneic bone marrow transplantation. Additional data for evidence-based counselling. Bone Marrow Transplant. Oct 2002;30(7):447-451.
Bordallo MA, Guimaraes MM, Pessoa CH, et al. Decreased serum inhibin B/FSH ratio as a marker of Sertoli cell function in male survivors after chemotherapy in childhood and adolescence.
J Pediatr Endocrinol Metab. Jun 2004;17(6):879-887.
Couto-Silva AC, Trivin C, Thibaud E, Esperou H, Michon J, Brauner R. Factors affecting gonadal function after bone marrow transplantation during childhood. Bone Marrow Transplant. Jul 2001;28(1):67-75.
Goldman S, Johnson FL. Effects of chemotherapy and irradiation on the gonads. Endocrinol Metab Clin North Am. Sep 1993;22(3):617-629.
Grigg AP, McLachlan R, Zaja J, Szer J. Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant. Nov 2000;26(10):1089-1095.
Howell SJ, Shalet SM. Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr. 2005(34):12-17.
Jacob A, Barker H, Goodman A, Holmes J. Recovery of spermatogenesis following bone marrow transplantation. Bone Marrow Transplant. Aug 1998;22(3):277-279.
Kinsella TJ. Effects of radiation therapy and chemotherapy on testicular function. Prog Clin Biol Res. 1989;302:157-171; discussion 172-157.
Rovo A, Tichelli A, Passweg JR, et al. Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently
absence of chronic GvHD. Blood. Aug 1 2006;108(3):1100-1105.
Rowley MJ, Leach DR, Warner GA, Heller CG. Effect of graded doses of ionizing radiation on the human testis. Radiat Res. Sep 1974;59(3):665-678.
Sanders JE. Endocrine problems in children after bone marrow transplant for hematologic malignancies. The Long-term Follow-up Team. Bone Marrow Transplant. 1991;8 Suppl 1:2-4.
Sarafoglou K, Boulad F, Gillio A, Sklar C. Gonadal function after bone marrow transplantation for acute leukemia during childhood. J Pediatr. Feb 1997;130(2):210-216.
Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. Jul 1999;33(1):2-8.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.
Sklar CA, Robison LL, Nesbit ME, et al. Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer Study Group.
J Clin Oncol. Dec 1990;8(12):1981-1987.
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.

COG LTFU Guidelines – Page 111

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#(Male)

87

Therapeutic
Agent(s)≥ 20 Gy to:
Flank/Hemiabdomen(right, left)*
Whole abdomen
Inverted Y
PelvicProstate
Bladder
Iliac
Inguinal
FemoralTesticular
TLI
TBI**
*Only if field extended below
iliac crest**TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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
agentsCombined withcyclophosphamide
conditioning for HCT• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 20 Gy
OR2) Received a combination of radiation to any of the specified fields and TBI, thesum of which is ≥ 20 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

Periodic
Evaluation
HISTORY
Pubertal (onset, tempo)
Sexual function (erections, nocturnal
emissions, libido)
Medication use impacting sexualfunction
YearlyPHYSICAL
Tanner staging
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 or clinical signs and symptomsof testosterone deficiency.

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
Bone density evaluation in hypogonadal patients. Refer toendocrinology/urology for delayed puberty, persistently
abnormal hormone levels or hormonal replacement for
hypogonadal patients.

SYSTEM = Reproductive (male)
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.
Greenfield DM, Walters SJ, Coleman RE, et al. Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab. Sep
2007;92(9):3476-3482.
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.

COG LTFU Guidelines – Page 112

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
88

Therapeutic
Agent(s)Spine (cervical, thoracic,
lumbar, sacral, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
AxillaMini-Mantle
MantleExtended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
FemoralExtremity (upper, lower)
TLI
STLI
TBI

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
Host Factors
Younger age at treatment

HighestRisk Factors
Host Factors
Prepubertal at treatment

Treatment Factors
Treatment Factors
Higher cumulative radiation dose Orthovoltage radiation
Larger radiation treatment field(commonly used before
Higher radiation dose per fraction 1970) due to delivery ofgreater dose to skin andbones
Epiphysis in treatment field
Dose ≥ 20 Gy

Periodic
Evaluation
PHYSICAL
HeightWeightYearlySitting 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

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

COG LTFU Guidelines – Page 113

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#

Therapeutic
Agent(s)MUSCULOSKELETAL SYSTEM (cont)
Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 88 REFERENCES
Chow EJ, Friedman DL, Yasui Y, et al. Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr. Apr 2007;150(4):370-375, 375
e371.
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.

COG LTFU Guidelines – Page 114

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
89

Therapeutic
Agent(s)Spine (thoracic, whole)
Chest (thorax)
Whole lungMediastinal
MantleExtended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI

MUSCULOSKELETAL SYSTEM (cont)
Potential
Late Effects
Scoliosis

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

SECTION 89 REFERENCES
de Jonge T, Slullitel H, Dubousset J, Miladi L, Wicart P, Illes T. Late-onset spinal deformities in children treated by laminectomy and radiation therapy for malignant tumours. Eur Spine J. Oct 2005;14(8):765-771.
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.

COG LTFU Guidelines – Page 115

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
90

Therapeutic
Agent(s)Spine (thoracic, whole)
Chest (thorax)
Whole lungMediastinal
MantleExtended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
TLI
STLI

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

SCORE = 1

SECTION 90 REFERENCES
de Jonge T, Slullitel H, Dubousset J, Miladi L, Wicart P, Illes T. Late-onset spinal deformities in children treated by laminectomy and radiation therapy for malignant tumours. Eur Spine J. Oct 2005;14(8):765-771.
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.

COG LTFU Guidelines – Page 116

Version 3.0 – October 2008

POTENTIAL IMPACT TO

RADIATION
Sec#
91

Therapeutic
Agent(s)≥ 40 Gy to:
Spine (cervical, thoracic,
lumbar, sacral, whole)
Cervical (neck)
Supraclavicular
Chest (thorax)
Whole lungMediastinal
AxillaMini-Mantle
MantleExtended Mantle
Hepatic
Renal
Upper quadrant (right, left)Spleen (partial, entire)
Paraaortic
Flank/Hemiabdomen(right, left)
Whole abdomen
Inverted Y
PelvicVaginalProstate
Bladder
Iliac
Inguinal
FemoralExtremity (upper, lower)
TLI
STLI
TBI*

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 indicatedHealth 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

• This section is only applicable to patients who:
1) Received radiation to any of the specified fields at ≥ 40 Gy
OR2) Received a combination of radiation to any of the specified fields plus relevant
spinal radiation and/or TBI, the sum of which is ≥ 40 Gy• See dose calculation rules on page 48 for patients who received: (a) radiation tomore than one of the specified fields, or (b) more than one planned course oftreatment to the same field.
• See “Patient-Specific Guideline Identification Tool” in Appendix I to determine
specific screening guidelines by section number for individual patients.

*TBI included for dose
calculation purposes only; thissection not applicable topatients who received TBI
alone.

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.

COG LTFU Guidelines – Page 117

Version 3.0 – October 2008

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. See also Rizzo et al.
(2006) for HCT follow-up
recommendations from theEuropean Group for Blood andMarrow Transplantation, Center
for International Blood andMarrow Transplant Research,and the American Society for
Blood and Marrow
Transplantation(EBMT/CIBMTR/ASBMT).

COG LTFU Guidelines – Page 118

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

Version 3.0 – October 2008

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.
Kalaycio M, Rybicki L, Pohlman B, et al. Risk factors before autologous stem-cell transplantation for lymphoma predict for secondary myelodysplasia and acute myelogenous leukemia. J Clin Oncol. Aug 1
2006;24(22):3604-3610.
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.
Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood andMarrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant. Feb
2006;37(3):249-261.

COG LTFU Guidelines – Page 119

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Therapeutic
Agent(s)93

Hematopoietic Cell Transplant(HCT)(Male)

Sec#

Potential
Late Effects
Solid tumors

Risk
Factors
Host Factors
Younger age at transplant
Fanconi's anemia

HighestRisk Factors
Treatment Factors
TBI(cont)
Periodic
Evaluation
PHYSICAL
Evaluation for benign or malignant
neoplasms
YearlyTreatment Factors
Radiation therapy

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Counseling
Avoid excessive sun exposure and tanning booths.
Considerations for Further Testing and Intervention
Oncology consultation as clinically indicated.

Medical Conditions
Hepatitis C infection
Chronic GVHDSYSTEM = SMNSCORE = 1

(Female)93

Hematopoietic Cell Transplant(HCT)

Solid tumors

Host Factors
Younger age at transplant
Fanconi's anemia
Treatment Factors
Radiation therapy
Medical Conditions
Hepatitis C infection
Chronic GVHD
Human papilloma virus infection

Treatment Factors
TBI

PHYSICAL
Evaluation for benign or malignant
neoplasms
YearlyHealth Links
Reducing the Risk of Second Cancers
Counseling
Avoid excessive sun exposure and tanning booths.
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

COG LTFU Guidelines – Page 120

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors(cont)
Periodic
Evaluation

Health Counseling
Further Considerations

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.
Cohen A, Rovelli A, Merlo DF, et al. Risk for secondary thyroid carcinoma after hematopoietic stem-cell transplantation: an EBMT Late Effects Working Party Study. J Clin Oncol. Jun 10 2007;25(17):2449-2454.
Curtis RE, Metayer C, Rizzo JD, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood. May 15
2005;105(10):3802-3811.
Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med. Mar 27 1997;336(13):897-904.
Gallagher G, Forrest DL. Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer. Jan 1 2007;109(1):84-92.
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.
Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. Mar 1 2006;24(7):1119-1126.
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.

COG LTFU Guidelines – Page 121

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

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
YearlyHealth 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.

COG LTFU Guidelines – Page 122

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

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.

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.

COG LTFU Guidelines – Page 123

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec
#
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
YearlyMedical Conditions
Chronic GVHDPHYSICAL
Musculoskeletal exam
YearlyHealth 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
Faraci M, Calevo MG, Lanino E, et al. Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica. Aug 2006;91(8):1096-1099.
Fink JC, Leisenring WM, Sullivan KM, Sherrard DJ, Weiss NS. Avascular necrosis following bone marrow transplantation: a case-control study. Bone. Jan 1998;22(1):67-71.
Kaste SC, Shidler TJ, Tong X, et al. Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant. Feb 2004;33(4):435-441.
Leung W, Ahn H, Rose SR, et al. A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore). Jul 2007;86(4):215-224.
Mattano LA, Jr., Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol.
Sep 15 2000;18(18):3262-3272.
Schulte CM, Beelen DW. Low pretransplant bone-mineral density and rapid bone loss do not increase risk for avascular osteonecrosis after allogeneic hematopoietic stem cell transplantation. Transplantation. Jun 27
2005;79(12):1748-1755.
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.

COG LTFU Guidelines – Page 124

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec
#
97

Therapeutic
Agent(s)Hematopoietic Cell
Transplant (HCT)

Potential
Late Effects

Risk
Factors

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

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

Info Link: The World HealthOrganization definition of
osteoporosis in adults is based oncomparison of a measured bonemineral density (BMD) of young
adults at peak bone age anddefined as a T-score. A T-score is
the number of standard deviations
the BMD measurement is above or
below the mean.

Treatment Factors
Corticosteroids
Cyclosporine
Tacrolimus
Cranial radiation
Craniospinal radiation
HCT/TBI

Note: Current definitions ofosteopenia (T-scores between 1.0
and 2.5 SD below the mean) andosteoporosis (T-scores > 2.5 SD
below the mean) were developed
primarily in the context of postmenopausal women. In thispopulation, T-scores have a wellvalidated correlation with fracturerisk that increases with age. The
fracture risk associated with
T-scores in younger populations,
including cancer survivors withtreatment-related hypogonadism,
has not been established. T-scores
are not appropriate to assess
skeletal health in pediatric patients
who have not achieved peak adultbone mass. Instead, pediatric BMD
reference data sets calculate
Z-scores based on age and gender.
A Z-score is the number ofstandard deviations themeasurement is above or below
the AGE-MATCHED MEAN BMD.
Again, the fracture risk in pediatricpatients with low bone density forchronologic age based on Z-scores
has not been established. There
are no defined standards forreferral or treatment of low BMD inchildren.

COG LTFU Guidelines – Page 125

Medical Conditions
Growth hormone deficiency
Hypogonadism/delayed puberty
Hyperthyroidism
Health Behaviors
Inadequate intake of calcium
and vitamin D
Lack of weight bearing exercise
Smoking
Alcohol use
Carbonated beverages(cont)

HighestRisk Factors

Periodic
Evaluation

Host Factors
Older age at time of treatment

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

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

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
Ensure recommended daily allowance of Vitamin D intake (200
IU/day) and adequate dietary calcium (see table in the “BoneHealth” Health Link for age-appropriate recommendations).
Supplements may be necessary if there are dietary restrictions.
Advocate for regular weight-bearing exercises such as runningand jumping. Use caution regarding calcium supplementationin 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 patients withosteoporosis or history of multiple fractures for pharmacologic
interventions (e.g., bisphosphonates, calcitonin, selective
estrogen receptor modulators).

SYSTEM = Musculoskeletal
SCORE = 2B

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

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.
Greer FR, Krebs NF. Optimizing bone health and calcium intakes of infants, children, and adolescents. Pediatrics. Feb 2006;117(2):578-585.
Grigg AP, Shuttleworth P, Reynolds J, et al. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. Oct 2006;91(10):3835-3843.
International Society for Clinical Densitometry. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom. Spring 2004;7(1):17-26.
Kaste SC, Shidler TJ, Tong X, et al. Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant. Feb 2004;33(4):435-441.
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.
Sala A, Barr RD. Osteopenia and cancer in children and adolescents: the fragility of success. Cancer. Apr 1 2007;109(7):1420-1431.
Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci. Aug 1 2001;6:G17-22.

COG LTFU Guidelines – Page 126

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)98

HCT with any history of
Chronic GVHD

Potential
Late Effects
Dermatologic toxicity
Permanent alopecia
Nail dysplasia
Vitiligo
Scleroderma
Squamous cell carcinoma of
the skin

Risk
Factors

HighestRisk Factors

WITH CHRONIC GVHD
Periodic
Evaluation
PHYSICAL
Hair (alopecia)
Nails (hypoplasia)
Skin (vitiligo, scleroderma)YearlyHealth Counseling
Further Considerations
Health Links
Skin Health

SYSTEM = Dermatologic
SCORE = 1

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

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.
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.
Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. Mar 1 2006;24(7):1119-1126.
Sanli H, Akay BN, Arat M, et al. Vitiligo after hematopoietic cell transplantation: six cases and review of the literature. Dermatology. 2008;216(4):349-354.
Skert C, Patriarca F, Sperotto A, et al. Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica. Feb
2006;91(2):258-261.

COG LTFU Guidelines – Page 127

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)99

HCT with any history of
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)
YearlyPHYSICAL
Eye exam
YearlyHealth 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.

COG LTFU Guidelines – Page 128

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)100 HCT with any history of
Chronic GVHD

Potential
Late Effects
Xerostomia
Salivary gland dysfunction
Dental caries
Periodontal disease
Oral cancer (squamous cell
carcinoma)
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
Use of azathioprine for cGVHD
Radiomimetic chemotherapy
management(e.g., doxorubicin, dactinomycin)
Medical Conditions
High grade of cGVHD

Periodic
Evaluation
HISTORY
Xerostomia
YearlyPHYSICAL
Oral exam
YearlySCREENING
Dental exam and cleaning
Every 6 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
Curtis RE, Metayer C, Rizzo JD, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood. May 15
2005;105(10):3802-3811.
Dahllof G, Bagesund M, Remberger M, Ringden O. Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol. Sep 1997;33(5):327- 331.
Dahllof G, Bagesund M, Ringden O. Impact of conditioning regimens on salivary function, caries-associated microorganisms and dental caries in children after bone marrow transplantation.
A 4-year longitudinal study. Bone Marrow Transplant. Sep 1997;20(6):479-483.
Dahllof G, Jonsson A, Ulmner M, Huggare J. Orthodontic treatment in long-term survivors after pediatric bone marrow transplantation. Am J Orthod Dentofacial Orthop. Nov 2001;120(5):459-465.
Demarosi F, Lodi G, Carrassi A, Soligo D, Sardella A. Oral malignancies following HSCT: graft versus host disease and other risk factors. Oral Oncol. Oct 2005;41(9):865-877.
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.
Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. Mar 1 2006;24(7):1119-1126.
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.
Treister NS, Woo SB, O'Holleran EW, Lehmann LE, Parsons SK, Guinan EC. Oral chronic graft-versus-host disease in pediatric patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. Sep
2005;11(9):721-731.

COG LTFU Guidelines – Page 129

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)Potential
Late Effects

101 HCT with any history of
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
YearlyPHYSICAL
Pulmonary exam
YearlySCREENING
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 pulmonologist.
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

COG LTFU Guidelines – Page 130

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

WITH CHRONIC GVHD (cont)
Periodic
Evaluation

Health Counseling
Further Considerations

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.
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
Uderzo C, Pillon M, Corti P, et al. Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic
hematopoietic stem cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties. Bone Marrow Transplant. Jun 2007;39(11):667-675.
Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following
allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. Jul 2007;13(7):749-759.

COG LTFU Guidelines – Page 131

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)102 HCT with any history of
Chronic GVHD

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

Risk
Factors

HighestRisk Factors

WITH CHRONIC GVHD (cont)
Periodic
Evaluation

HISTORY
Chronic conjunctivitis
Chronic sinusitis
Chronic bronchitis
Medical Conditions
Prolonged immunosuppression Recurrent or unusual infections
Sepsisrelated to cGVHD and its
Yearlytreatment
Host Factors
Active cGVHD

PHYSICAL
Eye exam
Nasal exam
Pulmonary exam
YearlyHealth 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 infections. Immunologic abnormalities
may persist for up to 20 years post transplant.

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.
Clave E, Rocha V, Talvensaari K, et al. Prognostic value of pretransplantation host thymic function in HLA-identical sibling hematopoietic stem cell transplantation. Blood. Mar 15 2005;105(6):2608-2613.
Clinical Affairs Committee of the American Academy of Pediatric Dentistry. Guideline on Dental Management of Pediatric Patients Receiving Chemotherapy, Hematopoietic Cell Transplantation, and/or Radiation.
Revised 2008.
Engelhard D, Cordonnier C, Shaw PJ, et al. Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey. Br J Haematol.
May 2002;117(2):444-450.
Maury S, Mary JY, Rabian C, et al. Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients. Br J Haematol. Dec 2001;115(3):630-641.
Nordoy T, Kolstad A, Endresen P, et al. Persistent changes in the immune system 4-10 years after ABMT. Bone Marrow Transplant. Oct 1999;24(8):873-878.
Perez-Simon JA, Encinas C, Silva F, et al. Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the National Institutes Health scale plus the type of
onset can predict survival rates and the duration of immunosuppressive therapy. Biol Blood Marrow Transplant. Oct 2008;14(10):1163-1171.
Robin M, Porcher R, De Castro Araujo R, et al. Risk factors for late infections after allogeneic hematopoietic stem cell transplantation from a matched related donor. Biol Blood Marrow Transplant. Nov
2007;13(11):1304-1312.
Storek J, Dawson MA, Storer B, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood. Jun 1 2001;97(11):3380-3389.
Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol.
Feb 1997;54(2):131-138.

COG LTFU Guidelines – Page 132

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)103 HCT with currently active
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 as indicated forpatients with active chronic GVHDSCREENING
Blood culture
When febrile T ≥ 101ºF as indicated forpatients with active chronic GVHD

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: American
Academy of Pediatric Dentistry, Guideline on Antibiotic
Prophylaxis for Dental Patients at Risk for Infection). In patientswith T ≥ 101°F (38.3° C) or other signs of serious illness,
administer a long-acting, broad-spectrum parenteral antibiotic(e.g., ceftriaxone), and continue close medical monitoring while
awaiting blood culture results. Hospitalization and broadeningof antimicrobial coverage (e.g., addition of vancomycin) may benecessary under certain circumstances, such as the presenceof marked leukocytosis, neutropenia, or significant change frombaseline CBC; toxic clinical appearance; fever ≥ 104°F;
meningitis, pneumonia, or other serious focus of infection;
signs of septic shock; or previous history of serious infection.
Immunize with Pneumococcal, Meningococcal, and HIB
vaccines. Pneumovax booster in patients ≥10 years old at ≥ 5years after previous dose (AAP-CIDP Recommendations, 2003).
SYSTEM = Immune
SCORE = 1

SECTION 103 REFERENCES
American Academy of Pediatric Dentistry, Guideline on Antibiotic Prophylaxis for Dental Patients at Risk for Infection. American Academy of Pediatric Dentistry Reference Manual. Vol 29, No. 7. Chicago: American
Academy of Pediatric Dentistry; 2007:pp. 202-204, available: http://www.aapd.org/media/policies.asp (accessed 2-24-08).
American Acadamy of Pediatrics. Section 1. Immunocompromised Children. Red Book 2006: Report of the Committee on Infectious Diseases (27th ed.). Elk Grove Village, IL: AAP.
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.
Mourtzoukou EG, Pappas G, Peppas G, Falagas ME. Vaccination of asplenic or hyposplenic adults. Br J Surg. Mar 2008;95(3):273-280.
Picardi M, Selleri C, Rotoli B. Spleen sizing by ultrasound scan and risk of pneumococcal infection in patients with chronic GVHD: preliminary observations. Bone Marrow Transplant. Jul 1999;24(2):173-177. -138.
Price VE, Dutta S, Blanchette VS, et al. The prevention and treatment of bacterial infections in children with asplenia or hyposplenia: practice considerations at the Hospital for Sick Children, Toronto. Pediatr Blood
Cancer. May 1 2006;46(5):597-603.
Smets F, Bourgois A, Vermylen C, et al. Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine. Vaccine. Jul 20
2007;25(29):5278-5282.
Spelman D, Buttery J, Daley A, et al. Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J. May 2008;38(5):349-356.

COG LTFU Guidelines – Page 133

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)104 HCT with any history of
Chronic GVHD

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

Risk
Factors
Treatment Factors
Radiation involving theesophagus
Radiomimetic chemotherapy(e.g., doxorubicin, dactinomycin)

WITH CHRONIC GVHD (cont)HighestRisk Factors
Treatment Factors
Radiation dose ≥ 40 Gy
Medical Conditions
Gut GVHD

Periodic
Evaluation
HISTORY
Dysphagia
HeartburnYearlyHealth Counseling
Further Considerations
Health Links
Gastrointestinal Health
Considerations for Further Testing and Intervention
Surgery and/or gastroenterology consultation for symptomaticpatients.

Medical Conditions
Gastroesophageal reflux
History of Candida esophagitis
SYSTEM = GI/Hepatic
SCORE = 1

SECTION 104 REFERENCES
Lal DR, Foroutan HR, Su WT, Wolden SL, Boulad F, La Quaglia MP. The management of treatment-related esophageal complications in children and adolescents with cancer. J Pediatr Surg. Mar 2006;41(3):495-499.
Memoli D, Spitzer TR, Cottler-Fox M, Cahill R, Benjamin S, Deeg HJ. Acute esophageal stricture after bone marrow transplantation. Bone Marrow Transplant. Sep 1988;3(5):513-516.
Stemmelin GR, Pest P, Peters RA, Ceresetto JM, Shanley CM, Bullorsky EO. Severe esophageal stricture after autologous bone marrow transplant. Bone Marrow Transplant. Jun 1995;15(6):1001-1002.
Williams M. Gastrointestinal manifestations of graft-versus-host disease: diagnosis and management. AACN Clin Issues. Nov 1999;10(4):500-506.

COG LTFU Guidelines – Page 134

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)(Female)105 HCT with any history of
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
YearlyHealth Counseling
Further Considerations
Considerations for Further Testing and Intervention
Gynecologic consultation for management. Psychologicalconsultation in patients with emotional difficulties.

SYSTEM = Reproductive (female)
SCORE = 1

SECTION 105 REFERENCES
Costantini S, Di Capua E, Bosi S, Chiodi S, Spinelli S. The management of severe vaginal obstruction from genital chronic graft-versus-host disease: diagnosis, surgical technique and follow-up. Minerva Ginecol. Feb
2006;58(1):11-16.
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.
Stratton P, Turner ML, Childs R, et al. Vulvovaginal chronic graft-versus-host disease with allogeneic hematopoietic stem cell transplantation. Obstet Gynecol. Nov 2007;110(5):1041-1049.
Tauchmanova L, Selleri C, Di Carlo C, et al. Estrogen-progestogen induced hematocolpometra following allogeneic stem cell transplant. Gynecol Oncol. Apr 2004;93(1):112-115.
Zantomio D, Grigg AP. Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management. Bone Marrow Transplant. 2006 Oct;38(8):567-72.

COG LTFU Guidelines – Page 135

Version 3.0 – October 2008

HEMATOPOIETIC CELL TRANSPLANT
Sec#

Therapeutic
Agent(s)106 HCT with any history of
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
YearlyHealth 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.
Carpenter PA. Late effects of chronic graft-versus-host disease. Best Pract Res Clin Haematol. Jun 2008;21(2):309-331.
Flowers ME, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up
of a randomized trial. Blood. Jul 15 2002;100(2):415-419.

COG LTFU Guidelines – Page 136

Version 3.0 – October 2008

AMPUTATIONSURGERY
Sec#

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
YearlyPHYSICAL
Residual limb integrity
YearlySCREENING
Prosthetic evaluation
Every 6 months until skeletally mature,then yearly.

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.

COG LTFU Guidelines – Page 137

Version 3.0 – October 2008

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.

COG LTFU Guidelines – Page 138

Version 3.0 – October 2008

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 (patients with ileal
entercystoplasty only)
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
YearlyVitamin B12 level
Yearly starting 5 years after cystectomy(patients with ileal enterocystoplasty
only)

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.
Metcalfe PD, Casale AJ, Kaefer MA, et al. Spontaneous bladder perforations: a report of 500 augmentations in children and analysis of risk. J Urol. Apr 2006;175(4):1466-1470; discussion 1470-1461.
Raney B, Jr., Heyn R, Hays DM, et al. Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup Rhabdomyosarcoma Study
Committee. Cancer. Apr 1 1993;71(7):2387-2394.
Rosenbaum DH, Cain MP, Kaefer M, et al. Ileal enterocystoplasty and B12 deficiency in pediatric patients. J Urol. Apr 2008;179(4):1544-1547; discussion 1547-1548.
Sim HG, Lau WK, Cheng CW. A twelve-year review of radical cystectomies in Singapore General Hospital. Ann Acad Med Singapore. Sep 2002;31(5):645-650.

COG LTFU Guidelines – Page 139

Version 3.0 – October 2008

ENUCLEATIONSURGERY
Sec#

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
YearlyHealth 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.

COG LTFU Guidelines – Page 140

Version 3.0 – October 2008

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
YearlyHealth 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 = Reproductive (female)
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.
Benedetti-Panici P, Zullo MA, Plotti F, Manci N, Muzii L, Angioli R. Long-term bladder function in patients with locally advanced cervical carcinoma treated with neoadjuvant chemotherapy and type 3-4 radical
hysterectomy. Cancer. May 15 2004;100(10):2110-2117.
Brown JS, Sawaya G, Thom DH, Grady D. Hysterectomy and urinary incontinence: a systematic review. Lancet. Aug 12 2000;356(9229):535-539.
Butler-Manuel SA, Summerville K, Ford A, et al. Self-assessment of morbidity following radical hysterectomy for cervical cancer. J Obstet Gynaecol. Mar 1999;19(2):180-183.
Dragisic KG, Milad MP. Sexual functioning and patient expectations of sexual functioning after hysterectomy. Am J Obstet Gynecol. May 2004;190(5):1416-1418.
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.
Jensen PT, Groenvold M, Klee MC, Thranov I, Petersen MA, Machin D. Early-stage cervical carcinoma, radical hysterectomy, and sexual function. A longitudinal study. Cancer. Jan 1 2004;100(1):97-106.

COG LTFU Guidelines – Page 141

Version 3.0 – October 2008

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
Distention
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.

COG LTFU Guidelines – Page 142

Version 3.0 – October 2008

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
Skeletally immature
Treatment Factors
Tibial endoprosthesis
Use of biologic material (allograft
or autograft) for reconstruction

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 indicatedMedical Conditions
Endoprosthetic infection
Obesity

SCREENING
Radiograph of affected limb
YearlyHealth Behaviors
High level of physical activity(associated with higher riskloosening)
Low level of physical activity(associated with higher risk ofcontractures or functional
limitations)

Evaluation by orthopedic surgeon
Every 6 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 if applicable.
Considerations for Further Testing and Intervention
Antibiotics may be indicated prior to dental or invasive
procedures depending on length of time since surgery, current
immune status, history of previous infections, and other factors(see J Am Dent Assoc., 2003,134: 895-899). Physical therapy
consultation as needed per changes in functional status (suchas post-lengthening, revisions, life changes such as
pregnancy), and for non-pharmacological pain management.
Consider psychological consultation as needed to assist withemotional difficulties related to body image, marriage,
pregnancy, parenting, employment, insurance and depression.
Vocational counseling/training to identify vocations that will not
produce/exacerbate functional limitations.

SYSTEM = Musculoskeletal
SCORE = 1

SECTION 113 REFERENCES
American Dental Association and American Academy of Orthopedic Surgeons. Antibiotic prophylaxis for dental patients with total joint replacements. J Am Dent Assoc. Jul 2003;134(7):895-899.
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.

COG LTFU Guidelines – Page 143

Version 3.0 – October 2008

NEPHRECTOMY

SURGERY
Sec#

Therapeutic
Agent(s)(Male)

114 Nephrectomy

Potential
Late Effects
Renal toxicity
Proteinuria
Hyperfiltration
Renal insufficiency
Hydrocele

Info Link:
Surgery-induced renal atrophy(vanishing kidney) is a rarecomplication reported insurvivors who have undergone
retroperitoneal tumor
resections. Once thisdiagnosis is established,annual screening should
include evaluations
recommended for children
treated with nephrectomy.

(Female)114 Nephrectomy

Renal toxicity
Proteinuria
Hyperfiltration
Renal insufficiency

Info Link:
Surgery-induced renal atrophy(vanishing kidney) is a rarecomplication reported insurvivors who have undergone
retroperitoneal tumor
resections. Once thisdiagnosis is established,annual screening should
include evaluations
recommended for children
treated with nephrectomy.

COG LTFU Guidelines – Page 144

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Host Factors
Denys-Drash syndrome
WAGR syndrome
Hypospadias
Cryptorchidism
Bilateral Wilms tumor

PHYSICAL
Blood pressure
Testicular exam to evaluate forhydrocele
YearlyTreatment Factors
Combined with other nephrotoxic
therapy, such as:- Cisplatin- Carboplatin- Ifosfamide- Aminoglycosides- Amphotericin- Immunosuppressants- Methotrexate- Radiation impacting thekidneys

SCREENING
BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term followup. Repeat as clinically indicated.

Host Factors
Denys-Drash syndrome
WAGR syndrome
Bilateral Wilms tumor

PHYSICAL
Blood pressure
YearlyTreatment Factors
Combined with other nephrotoxic
therapy, such as:- Cisplatin- Carboplatin- Ifosfamide- Aminoglycosides- Amphotericin- Immunosuppressants- Methotrexate- Radiation impacting thekidneys

SCREENING
BUN
Creatinine
Na, K, Cl, CO2
Ca, Mg, PO4
Baseline at entry into long-term followup. Repeat as clinically indicated.

Urinalysis
YearlyUrinalysis
YearlyHealth Counseling
Further Considerations
Health Links
Single Kidney HealthSee also: Kidney HealthCounseling
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.
Considerations for Further Testing and Intervention
Nephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency.

SYSTEM = Urinary
SCORE = 1

Health Links
Single Kidney HealthSee also: Kidney HealthCounseling
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.
Considerations for Further Testing and Intervention
Nephrology consultation for patients with hypertension,
proteinuria, or progressive renal insufficiency.

SYSTEM = Urinary
SCORE = 1

Version 3.0 – October 2008

NEPHRECTOMY (cont)

SURGERY
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

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.
Breslow NE, Collins AJ, Ritchey ML, Grigoriev YA, Peterson SM, Green DM. End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data
System. J Urol. Nov 2005;174(5):1972-1975.
Cozzi F, Schiavetti A, Morini F, et al. Renal function adaptation in children with unilateral renal tumors treated with nephron sparing surgery or nephrectomy. J Urol. Oct 2005;174(4 Pt 1):1404-1408.
Finklestein JZ, Norkool P, Green DM, Breslow N, D'Angio GJ. Diastolic hypertension in Wilms' tumor survivors: a late effect of treatment? A report from the National Wilms' Tumor Study Group.
Am J Clin Oncol. Jun 1993;16(3):201-205.
Ginsberg JP, Hobbie WL, Ogle SK, Canning DA, Meadows AT. Prevalence of and risk factors for hydrocele in survivors of Wilms tumor. Pediatr Blood Cancer. Apr 2004;42(4):361-363.
Mitus A, Tefft M, Fellers FX. Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics. Dec 1969;44(6):912-921.
Paulino AC, Wen BC, Brown CK, et al. Late effects in children treated with radiation therapy for Wilms' tumor. Int J Radiat Oncol Biol Phys. Mar 15 2000;46(5):1239-1246.
Ritchey ML, Green DM, Thomas PR, et al. Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol. Feb 1996;26(2):75-80.
Sharp DS, Ross JH, Kay R. Attitudes of pediatric urologists regarding sports participation by children with a solitary kidney. J Urol. Oct 2002;168(4 Pt 2):1811-1814; discussion 1815.
Srinivas M, Agarwala S, Padhy AK, et al. Somatic growth and renal function after unilateral nephrectomy for Wilms' tumor. Pediatr Surg Int. Dec 1998;14(3):185-188.

COG LTFU Guidelines – Page 145

Version 3.0 – October 2008

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
YearlySCREENING
Referral for formal
neuropsychological evaluation
Baseline at entry into long-term followup. Periodically as clinically indicatedfor patients with evidence of impaired
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 patientswith neurocognitive deficits to school liaison in community orcancer 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 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.

COG LTFU Guidelines – Page 146

Version 3.0 – October 2008

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

COG LTFU Guidelines – Page 147

Version 3.0 – October 2008

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 6 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.

COG LTFU Guidelines – Page 148

Version 3.0 – October 2008

NEUROSURGERY - BRAIN (cont)

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 shunttubing in peritoneum.

Counseling
Education patient/family regarding potential symptoms of shunt
malfunction.

Evaluation by neurosurgeon
Yearly for patients with shunts.

Considerations for Further Testing and Intervention
Per the American Academy of Pediatric Dentistry endocarditis
prophylaxis guidelines, antibiotics are not indicated prior todental work for patients with V-P shunts (indicated for V-A and
V-V shunts only).

SYSTEM = CNSSCORE = 1

SECTION 118 REFERENCES
American Academy of Pediatric Dentistry, Guideline on Antibiotic Prophylaxis for Dental Patients at Risk for Infection. American Academy of Pediatric Dentistry Reference Manual. Vol 29, No. 7. Chicago: American
Academy of Pediatric Dentistry; 2007:pp. 202-204, available: http://www.aapd.org/media/policies.asp (accessed 2-24-08).
Dias MS, Albright AL. Management of hydrocephalus complicating childhood posterior fossa tumors. Pediatr Neurosci. 1989;15(6):283-289; discussion 290.

COG LTFU Guidelines – Page 149

Version 3.0 – October 2008

NEUROSURGERY - SPINAL CORD

SURGERY
Sec#

Therapeutic
Agent(s)119 Neurosurgery - Spinal cord

Potential
Late Effects
Neurogenic bladder
Urinary incontinence

Risk
Factors
Host Factors
Tumor adjacent to orcompressing spinal cord or
cauda equina
Treatment Factors
Radiation dose ≥ 45 Gy tolumbar and/or sacral spine
and/or cauda equina

HighestRisk Factors
Host Factors
Injury above the level of thesacrumTreatment 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
YearlyHealth 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.
McGirt MJ, Chaichana KL, Atiba A, Attenello F, Yao KC, Jallo GI. Resection of intramedullary spinal cord tumors in children: assessment of long-term motor and sensory deficits. J Neurosurg Pediatrics. Jan
2008;1(1):63-67.
Moore SW, Kaschula ROC, Albertyn R, Rode H, Millar AJW, Karabus C. The outcome of solid tumors occurrring during the neonatal period. Pediatr Surg Int. 1996;10(5-6):366-370.
Poretti A, Zehnder D, Boltshauser E, Grotzer MA. Long-term complications and quality of life in children with intraspinal tumors. Pediatr Blood Cancer. Apr 2008;50(4):844-848.

COG LTFU Guidelines – Page 150

Version 3.0 – October 2008

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
YearlyPHYSICAL
Rectal exam
As clinically indicatedHealth 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.

COG LTFU Guidelines – Page 151

Version 3.0 – October 2008

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
YearlyTreatment 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
YearlySYSTEM = 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.

COG LTFU Guidelines – Page 152

Version 3.0 – October 2008

OOPHOROPEXYSURGERY
Sec#

Therapeutic
Agent(s)(Female)122 Oophoropexy
Info Link:
If shielding from radiation wasincomplete: See also Section 84

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
YearlyHealth Counseling
Further Considerations
Considerations for Further Testing and Intervention
Gynecologic consultation for patients with positive history
and/or physical findings.

SYSTEM = Reproductive (female)
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.

COG LTFU Guidelines – Page 153

Version 3.0 – October 2008

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
YearlyPHYSICAL
Tanner staging
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 = Reproductive (female)
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.

COG LTFU Guidelines – Page 154

Version 3.0 – October 2008

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 in hypogonadal patients. Reproductive
endocrinology referral regarding assisted reproductive
technologies.

SYSTEM = Reproductive (female)
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.

COG LTFU Guidelines – Page 155

Version 3.0 – October 2008

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
YearlyPHYSICAL
Tanner staging
Testicular volume by Prader
orchdiometry
Yearly until sexually mature

SCREENING
Semen analysis
As requested by patient and forevaluation of infertility.

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
Consider surgical placement of testicular prosthesis. For
patients with unilateral orchiectomy: Obtain FSH, LH andtestosterone as clinically indicated for signs and symptoms of
testosterone deficiency (e.g. those with delayed puberty,
persistently abnormal hormone levels). For patients withbilateral orchiectomy: Refer boys with post-surgicalhypogonadism after bilateral orchiectomy to endocrinology atage 11 for initiation of hormonal replacement therapy to initiate
puberty.

SYSTEM = Reproductive (male)
SCORE = 1

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.
Huddart RA, Norman A, Moynihan C, et al. Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer. Jul 25 2005;93(2):200-207.
Jacobsen KD, Fossa SD, Bjoro TP, Aass N, Heilo A, Stenwig AE. Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Eur Urol. Sep 2002;42(3):229-238; discussion 237-228.
Lee PA, Coughlin MT. The single testis: paternity after presentation as unilateral cryptorchidism. J Urol. Oct 2002;168(4 Pt 2):1680-1682; discussion 1682-1683.

COG LTFU Guidelines – Page 156

Version 3.0 – October 2008

PELVIC SURGERY

SURGERY
Sec#

Therapeutic
Agent(s)126 Pelvic surgery
Cystectomy
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
YearlyHealth 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
Derikx JP, De Backer A, van de Schoot L, et al. Long-term functional sequelae of sacrococcygeal teratoma: a national study in The Netherlands. J Pediatr Surg. Jun 2007;42(6):1122-1126.
Hale GA, Marina NM, Jones-Wallace D, et al. Late effects of treatment for germ cell tumors during childhood and adolescence. J Pediatr Hematol Oncol. Mar-Apr 1999;21(2):115-122.
Heyn R, Raney RB, Jr., Hays DM, et al. Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol. Apr 1992;10(4):614-623.
Koyle MA, Hatch DA, Furness PD, 3rd, Lovell MA, Odom LF, Kurzrock EA. Long-term urological complications in survivors younger than 15 months of advanced stage abdominal neuroblastoma. J Urol.
Oct 2001;166(4):1455-1458.
Ozkan KU, Bauer SB, Khoshbin S, Borer JG. Neurogenic bladder dysfunction after sacrococcygeal teratoma resection. J Urol. Jan 2006;175(1):292-296; discussion 296.
Raney B, Anderson J, Jenney M, et al. Late effects in 164 patients with rhabdomyosarcoma of the bladder/prostate region: a report from the international workshop. J Urol. Nov 2006;176(5):2190-2194; discussion
2194-2195.

COG LTFU Guidelines – Page 157

Version 3.0 – October 2008

PELVIC SURGERY (cont)

SURGERY
Sec#

Therapeutic
Agent(s)127 Pelvic surgery
Cystectomy

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
YearlyCounselingCounsel 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 indicatedConsiderations 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.

COG LTFU Guidelines – Page 158

Version 3.0 – October 2008

PELVIC SURGERY (cont)

SURGERY
Sec#(Male)

128

Therapeutic
Agent(s)Pelvic surgery
Cystectomy

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)
YearlyMedical 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 = Reproductive (male)
SCORE = 2A

Pelvic surgery
Cystectomy

Sexual dysfunction (Female)(Female)128

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
YearlySYSTEM = Reproductive (female)
SCORE = 2A

(Female)(Male)SECTION 128 REFERENCES
Brydoy M, Fossa SD, Klepp O, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst. Nov 2 2005;97(21):1580-1588.
Fossa SD. Long-term sequelae after cancer therapy--survivorship after treatment for testicular cancer. Acta Oncol. 2004;43(2):134-141.
Hale GA, Marina NM, Jones-Wallace D, et al. Late effects of treatment for germ cell tumors during childhood and adolescence. J Pediatr Hematol Oncol. Mar-Apr 1999;21(2):115-122.
Hartmann JT, Albrecht C, Schmoll HJ, Kuczyk MA, Kollmannsberger C, Bokemeyer C. Long-term effects on sexual function and fertility after treatment of testicular cancer. Br J Cancer. May 1999;80(5-6):801-807.
Jacobsen KD, Ous S, Waehre H, et al. Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection. Br J Cancer. Apr 1999;80(1-2):249-255.
Zippe C, Nandipati K, Agarwal A, Raina R. Sexual dysfunction after pelvic surgery. Int J Impot Res. 2006 Jan-Feb;18(1):1-18. Review.
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.

COG LTFU Guidelines – Page 159

Version 3.0 – October 2008

PELVIC SURGERY (cont)

SURGERY
Sec#

Therapeutic
Agent(s)Hydrocele(Male)

129 Pelvic surgery
Cystectomy

Potential
Late Effects

Risk
Factors
Treatment Factors
Retroperitoneal node dissection

HighestRisk Factors

Periodic
Evaluation
PHYSICAL
Testicular exam to evaluate forhydrocele
YearlyHealth 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.

COG LTFU Guidelines – Page 160

Version 3.0 – October 2008

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
YearlyPHYSICAL
Pulmonary exam
YearlyHealth 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 pulmonologist.
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.

COG LTFU Guidelines – Page 161

Version 3.0 – October 2008

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 clinicalappearance; fever ≥ 104°F; meningitis, pneumonia, or otherserious focus of infection; signs of septic shock; or previous
history of serious infection. Immunize with Pneumococcal,
Meningococcal, and HIB vaccines. Pneumovax booster inpatients ≥10 years old at ≥ 5 years after previous dose
(AAP-CIDP Recommendations, 2003). Discuss with dental
provider potential need for antibiotic prophylaxis based onplanned procedure.

Counseling
Medical alert bracelet/card noting asplenia. Counsel to avoid
malaria and tick bites if living in or visiting endemic areas.

Info Link:
Prophylactic antibiotic therapy may be indicated in a subset ofpatients. Consider prophylactic PCN for at least 2-3 years
post-splenectomy and until at least 5 years of age for young
children; some make a strong argument for 5 years postsplenectomy in adults and until age 18 in children. UK
investigators recommend lifelong use. Monitor antibody titers
to PPV23 annually for first 2-3 years after initial vaccine;
re-immunize if sub-protective levels, as opposed to just one
booster at 5 years. Check antibody titers to PPV23 after
booster at least once at 5 year mark to verify protective titer.

SYSTEM = Immune
SCORE = 1

COG LTFU Guidelines – Page 162

Version 3.0 – October 2008

SPLENECTOMY (cont)

SURGERY
Sec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 131 REFERENCES
American Academy of Pediatric Dentistry, Guideline on Antibiotic Prophylaxis for Dental Patients at Risk for Infection. American Academy of Pediatric Dentistry Reference Manual. Vol 29, No. 7. Chicago: American
Academy of Pediatric Dentistry; 2007:pp. 202-204, available: http://www.aapd.org/media/policies.asp (accessed 2-24-08).
American Acadamy of Pediatrics. Section 1. Immunocompromised Children. Red Book 2006: Report of the Committee on Infectious Diseases (27th ed.). Elk Grove Village, IL: AAP.
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.
Mourtzoukou EG, Pappas G, Peppas G, Falagas ME. Vaccination of asplenic or hyposplenic adults. Br J Surg. Mar 2008;95(3):273-280.
Newland A, Provan D, Myint S. Preventing severe infection after splenectomy. BMJ. Aug 20 2005;331(7514):417-418.
Omlin AG, Muhlemann K, Fey MF, Pabst T. Pneumococcal vaccination in splenectomised cancer patients. Eur J Cancer. Aug 2005;41(12):1731-1734.
Price VE, Dutta S, Blanchette VS, et al. The prevention and treatment of bacterial infections in children with asplenia or hyposplenia: practice considerations at the Hospital for Sick Children, Toronto. Pediatr Blood
Cancer. May 1 2006;46(5):597-603.
Smets F, Bourgois A, Vermylen C, et al. Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine. Vaccine. Jul 20
2007;25(29):5278-5282.
Spelman D, Buttery J, Daley A, et al. Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Intern Med J. May 2008;38(5):349-356.
Taylor MD, Genuit T, Napolitano LM. Overwhelming postsplenectomy sepsis and trauma: time to consider revaccination? J Trauma. Dec 2005;59(6):1482-1485.

COG LTFU Guidelines – Page 163

Version 3.0 – October 2008

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 ofhypoparathyroidism (e.g.,parasthesias, muscle cramping,altered mental status,
hyperreflexia, tetany,
hypocalcemia, andhyperphosphatemia).

Risk
Factors

HighestRisk Factors

Periodic
Evaluation
HISTORY
Fatigue
Weight gain
Cold intolerance
Constipation
Dry skinBrittle hair
Depressed moodYearly; 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 and skin
Thyroid exam
Yearly; Consider more frequent
screening during periods of rapid
growth.

SYSTEM = Endocrine/Metabolic
SCORE = 1

SCREENING
TSHFree T4
Yearly; Consider more frequent
screening during periods of rapid
growth.

SECTION 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.

COG LTFU Guidelines – Page 164

Version 3.0 – October 2008

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
YearlyHealth 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.

COG LTFU Guidelines – Page 165

Version 3.0 – October 2008

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 moodYearly; Consider more frequent
screening during periods of rapid
growth.

PHYSICAL
HeightWeightHair and 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.

COG LTFU Guidelines – Page 166

Version 3.0 – October 2008

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 moodYearly; Consider more frequent
screening during periods of rapid
growth.

PHYSICAL
HeightWeightHair and 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.

COG LTFU Guidelines – Page 167

Version 3.0 – October 2008

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.

COG LTFU Guidelines – Page 168

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

Organ

(Female)137 Breast

At Risk
Population

HighestRisk Factors

Over age 40
Family history of breast cancer
in first degree relative
Early onset of menstruation
Late onset of menopause(age 55 or older)
Older than 30 at birth 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:- Chest (thorax)- Whole lung
- Mediastinal- Axilla- Mini-Mantle- Mantle- Extended Mantle- TLI- STLI- TBI*
BRACA1, BRACA2, ATM mutation

Info Link:*Important: The risk of breast
cancer in patients who received
TBI alone is of a lower
magnitude compared to those
who received ≥ 20 Gy ofradiation with potential impact tothe breast (e.g.,thorax, axilla);therefore, monitoring of patients
who received TBI without
additional radiation potentially
impacting the breast should bedetermined on an individual
basis.

BREAST CANCER
Periodic
Evaluation

PATIENTS AT STANDARD RISK (ACS Recommendation)
PHYSICAL
Clinical breast exam
Every 3 years between ages 20-39, then yearly beginning at age 40
SCREENING
Mammogram
Yearly, beginning at age 40
PATIENTS AT HIGHEST RISK

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.

PHYSICAL
Breast self exam
Monthly, beginning at puberty
Clinical breast exam
Yearly, beginning at puberty until age 25, then every 6 months
SCREENING
Mammogram
Yearly, beginning 8 years after radiation or at age 25, whichever occurs
last.
Breast MRI
Yearly, as an adjunct to mammography beginning 8 years after radiation
or at age 25, whichever occurs last.
Info Link:
The risk of breast cancer in patients who received TBI alone is of a lower
magnitude compared to those who received ≥ 20 Gy of radiation withpotential impact to the breast (e.g., thorax, axilla); therefore, monitoringof patients who received TBI should be determined on an individual
basis.
Mammography is currently limited in its ability to evaluate thepremenopausal breast. MRI is now recommended as an adjunct tomammography in women treated with chest radiation for childhood
cancer similar to screening of other populations at high risk for breast
cancer (e.g., premenopausal known or likely carriers of gene mutation of
known penetrance). The upper age limit at which both modalities should
be used for breast cancer surveillance has not been established.

COG LTFU Guidelines – Page 169

Version 3.0 – October 2008

CANCER SCREENING GUIDELINESSec#

Therapeutic
Agent(s)Potential
Late Effects

Risk
Factors

HighestRisk Factors

BREAST CANCER (cont)
Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 137 REFERENCES
Breast Cancer Screening and Diagnosis Guidelines. National Comprehensive Cancer Network Clinical Practice Guidelines v.1.2008. April 15, 2008. Available at: www.nccn.org. Accessed October 24, 2008.
Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA.
Mar 26 1997;277(12):997-1003.
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.
Friedman DL, Rovo A, Leisenring W, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party. Blood.
Jan 15 2008;111(2):939-944.
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.
Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. Mar-Apr 2007;57(2):75-89.
Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. CA Cancer J Clin. May-Jun 2008;58(3):161-179.
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.
Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. Jul 23 2003;290(4):465-475.
Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA.
Sep 15 2004;292(11):1317-1325.

COG LTFU Guidelines – Page 170

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
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
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.

Health Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
CounselingCounsel regarding risk/benefits of HPV vaccination.
Info Link:
Human papillomavirus virus (HPV) is the leading cause of
cervical cancer in women. HPV vaccination protects against
70% of cervical cancers and reduces the incidence of genital
warts. The Centers for Disease Control Advisory Committee on
Immunization Practices (CDC/ACIP) and American Cancer
Society (ACS) both recommend routine HPV immunization ofgirls when they are 11-12 years old. Females as young as 9
years can the receive HPV vaccination at the discretion of theirhealth care provider. HPV vaccination is also recommended forfemales 13 years of age up to 18 (ACS) or 26 (CDC/ACIP) years
to catch up missed vaccines or to complete the series. For
optimal protection, the vaccine should be administered before
the onset of sexual activity. Females who are sexually active
may still benefit from vaccination through protection against
strains to which they have not been exposed. HPV vaccination
does not change recommendations for cervical cancer PAP
screening since the vaccine does not protect against all
cancer-causing types of HPV. See Markowitz LE et al. (2007)
and Saslow D et al. (2007), for further information.
Considerations for Further Testing and Intervention
Gynecology and/or oncology consultation as clinically indicated.

SECTION 138 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.
Cervical Screening. National Comprehensive Cancer Network Clinical Practice Guidelines v.1.2009. October 23, 2008. Available at: www.nccn.org. Accessed October 24, 2008.
Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Quadrivalent Human Papillomavirus
Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007 Mar 23;56(RR-2):1-24.
Saslow D, Castle PE, Cox JT, et al. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007;57:7-28.
Screening for Cervical Cancer. Jan 2003; File Inventory, Systematic Evidence Review #25. Available at: www.ahrq.gov/clinic/uspstf/uspscerv.htm. Accessed Oct 24, 2008.
Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. CA Cancer J Clin. May-Jun 2008;58(3):161-179.

COG LTFU Guidelines – Page 171

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

Organ

139 Colorectal

At Risk
Population
High fat/low fiber dietAge ≥ 50 years
Obesity

HighestRisk Factors
Radiation with potential impact tothe colon/rectum (see Section 78),
including ≥ 30 Gy to thefollowing fields:- Spine (thoracic, lumbar,
sacral, whole)- Extended Mantle- Hepatic- Renal- Upper quadrant (right, left)- Spleen (partial, entire)- Paraaortic- Flank/Hemiabdomen(right, left)- Whole abdomen- Inverted Y- Pelvic- Vaginal- Prostate- Bladder- Iliac- Inguinal- Femoral- TLI- STLI- TBI*
Personal history of ulcerative
colitis, gastrointestinal
malignancy, adenomatous
polyps or hepatoblastoma
Familial polyposis
Family history of colorectal cancer
or polyps in first degree relative
Info Link:*Important: Reports of colorectal
cancer in cohorts of long-term
survivors suggest that radiation
likely increases risk; however, therisk related to TBI alone has notbeen established. Therefore,monitoring of patients who
received TBI without additionalradiation potentially impacting thecolon/rectum should bedetermined on an individual basis.
(See Info Link in next column)

COG LTFU Guidelines – Page 172

COLORECTAL CANCER
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.
Option 2:
Double contrast barium enema
Every 5 years, beginning at age 50
Option 3:
Colonoscopy
Every 10 years, beginning at age 50

Health Counseling
Further Considerations
Health Links
Colorectal Cancer
Considerations for Further Testing and Intervention
Gastroenterology, surgery and/or oncology consultation asclinically indicated.

PATIENTS AT HIGHEST RISKSCREENING
Colonoscopy
Every 5 years (minimum); more frequently if indicated based on colonoscopy
results. Begin monitoring 10 years after radiation or at age 35, whicheveroccurs last. Monitor more frequently if clinically indicated. Per the ACS, begin
screening earlier for the following high-risk groups: HNPCC (at puberty), FAP(at age 21 years), IBD (8 years after diagnosis of IBD). Information from thefirst 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 of screening likely was
beneficial, and that a prudent course would be to initiate screening forcolorectal cancer for those at highest risk (abdominal, pelvic, and/or spinal
radiation ≥ 30 Gy) at age 35, or 10 years post radiation, whichever occurs
last. Surveillance should be done via colonoscopy as per recommendations
for populations at highest risk, with information from the first colonoscopy
informing the frequency of follow-up testing.
While the American Cancer Society recently added computed
tomographic colonography (CTC) (AKA “Virtual Colonoscopy”) as an
acceptable option for colorectal cancer screening of average-risk adults, theNational Comprehensive Cancer Network and United States Preventive
Services Task Force concluded that data was too premature to warrant its use
in screening. Colonoscopy remains the preferred screening modality forsurvivors at highest risk of colorectal cancer.

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

Organ

At Risk
Population

HighestRisk Factors

COLORECTAL CANCER (CONT)Periodic
Evaluation

Health Counseling
Further Considerations

SECTION 139 REFERENCES
Bhatia S, Yasui Y, Robison LL, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol. Dec 1
2003;21(23):4386-4394.
Colorectal Screening. National Comprehensive Cancer Network Clinical Practice Guidelines v.2.2008. June 17, 2008. Available at: www.nccn.org. Accessed October 24, 2008.
Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, Dash C, Giardiello FM, Glick S, Levin TR, Pickhardt P, Rex DK, Thorson A, Winawer SJ; for the American Cancer Society Colorectal Cancer
Advisory Group, the US Multi-Society Task Force, and the American College of Radiology Colon Cancer Committee. Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous
Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin, 2008 May-June;58(3):130-160.
Metayer C, Lynch CF, Clarke EA, et al. Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol. Jun 2000;18(12):2435-2443.
Provenzale D, Gray RN. Colorectal cancer screening and treatment: review of outcomes research. J Natl Cancer Inst Monogr. 2004(33):45-55.
Screening for Colorectal Cancer. Oct 2008; File Inventory, Recommendation Statement Publication No. 08-05124-EF-3. Available at: www.ahrq.gov/clinic/uspstf08/colocancer/colors.htm. Accessed Oct 24, 2008.
Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. CA Cancer J Clin. May-Jun 2008;58(3):161-179.
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.

COG LTFU Guidelines – Page 173

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
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, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. CA Cancer J Clin. May-Jun 2008;58(3):161-179.

COG LTFU Guidelines – Page 174

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

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 indicatedHealth Counseling
Further Considerations
Health Links
Reducing the Risk of Second Cancers
Considerations for Further Testing and Intervention
Imaging and surgery and/or oncology consultation as clinicallyindicated.

PHYSICAL
Pulmonary Exam
Yearly, and as clinically indicated

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.

COG LTFU Guidelines – Page 175

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

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
YearlyHealth 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.

COG LTFU Guidelines – Page 176

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

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. National Comprehensive Cancer Network Clinical Practice Guidelines v.2.2007. May 10, 2007. Available at: www.nccn.org. Accessed October 24, 2008.
Screening for Prostate Cancer. Aug 2008; File Inventory, Recommendation Statement Publication No. 08-05121-EF2. Available at: www.ahrq.gov/clinic/uspstf/uspsprca.htm. Accessed Oct 24, 2008.
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, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. CA Cancer J Clin. May-Jun 2008;58(3):161-179.

COG LTFU Guidelines – Page 177

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

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
YearlySECTION 144 REFERENCES
Screening for Skin Cancer. File Inventory, Systematic Evidence Review Number 2. Available at: www.ahrq.gov/clinic/serfiles.htm. Accessed Oct 24, 2008.
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.

COG LTFU Guidelines – Page 178

Version 3.0 – October 2008

CANCER SCREENING GUIDELINES
Sec
#

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. Apr 3, 2008. Available at: www.cancer.gov/cancertopics/screening. Accessed Oct 24, 2008.
Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. CA Cancer J Clin. May-Jun 2008;58(3):161-179.

COG LTFU Guidelines – Page 179

Version 3.0 – October 2008

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
YearlyHealth 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

COG LTFU Guidelines – Page 180

Version 3.0 – October 2008