The Childhood Cancer Survivor Study: A National Cancer Institute-Supported Resource for Outcome and Intervention Research

Article (PDF Available)inJournal of Clinical Oncology 27(14):2308-18 · May 2009with109 Reads
DOI: 10.1200/JCO.2009.22.3339 · Source: PubMed
Abstract
Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.

Figures

The Childhood Cancer Survivor Study: A National Cancer
Institute–Supported Resource for Outcome and
Intervention Research
Leslie L. Robison, Gregory T. Armstrong, John D. Boice, Eric J. Chow, Stella M. Davies, Sarah S. Donaldson,
Daniel M. Green, Sue Hammond, Anna T. Meadows, Ann C. Mertens, John J. Mulvihill, Paul C. Nathan,
Joseph P. Neglia, Roger J. Packer, Preetha Rajaraman, Charles A. Sklar, Marilyn Stovall, Louise C. Strong,
Yutaka Yasui, and Lonnie K. Zeltzer
From the Departments of Epidemiology
and Cancer Control, St Jude Children’s
Research Hospital, Memphis, TN; Interna-
tional Epidemiology Institute; Division of
Cancer Epidemiology and Genetics,
National Cancer Institute, Rockville, MD;
Department of Pediatrics, University of
Washington, Seattle, WA; Department of
Pediatrics, Cincinnati Children’s Hospital
Medical Center, Cincinnati; Department of
Pathology, OH State University School
of Medicine, Columbus, OH; Department
of Radiation Oncology, Stanford University
Medical Center, Stanford; Department of
Pediatrics, University of California at Los
Angeles, Los Angeles, CA; Department of
Pediatrics, Children’s Hospital of Philadel-
phia, Philadelphia, PA; Department of Pedi-
atrics, Emory University, Atlanta, GA;
Department of Pediatrics, University of
Oklahoma Health Sciences Center, Okla-
homa City, OK; Department of Pediatrics,
University of Minnesota, Minneapolis, MN;
Department of Neurology, Children’s
National Medical Center, Washington, DC;
Department of Pediatrics, Memorial Sloan-
Kettering Cancer Center, New York, NY;
Departments of Radiation Physics and
Cancer Genetics, The University of Texas
M. D. Anderson Cancer Center, Houston,
TX; Division of Haematology/Oncology,
Hospital for Sick Children, Toronto, Ontario;
and Department of Public Health Sciences,
University of Alberta School of Public
Health, Edmonton, Alberta, Canada.
Submitted December 12, 2008; accepted
February 23, 2009; published online ahead
of print at www.jco.org on April 13, 2009.
Written on behalf of the Steering Commit-
tee of the Childhood Cancer Survivor
Study.
Supported by Grant No. U24 CA 55727
(L.L.R.) from the National Cancer Institute,
Bethesda, MD, with additional support
provided to St Jude Children’s Research
Hospital by the American Lebanese Syrian
Associated Charities.
Authors’ disclosures of potential conflicts
of interest and author contributions are
found at the end of this article.
Clinical Trials repository link available on
JCO.org
Corresponding author: Leslie L. Robison,
PhD, Department of Epidemiology and
Cancer Control, St Jude Children’s
Research Hospital, 262 Danny Thomas
Place, Mail Stop 735, Memphis, TN 38105-
2794; e-mail: les.robison@stjude.org.
© 2009 by American Society of Clinical
Oncology
0732-183X/09/2714-2308/$20.00
DOI: 10.1200/JCO.2009.22.3339
ABSTRACT
Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival
rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the
1970s with the broader introduction of multimodality approaches, often including combination
chemotherapy with or without radiation therapy. With this increase in rates of survivorship has
come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with
risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National
Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research
initiative designed to establish a large and extensively characterized cohort of more than 14,000
5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This
ongoing study, which reflects the single most comprehensive body of information ever assembled
on childhood and adolescent cancer survivors, provides a dynamic framework and resource to
investigate current and future questions about childhood cancer survivors.
J Clin Oncol 27:2308-2318. © 2009 by American Society of Clinical Oncology
INTRODUCTION
It is well recognized that survival rates for many of
the childhood and adolescent cancers have improved
at a remarkable pace over the last four decades. With
this success came the need and responsibility to con-
sider the long-term morbidity and mortality associ-
ated with treatments responsible for the increases in
survival. Early efforts to describe the late effects of
treatment in this population included single-
institution and limited consortia studies, as well as
occasional cooperative clinical trials group investi-
gations of late sequelae. However, by the mid-1980s,
it became increasingly clear that there were serious
limitations inherent in these approaches, such as
small study sizes, incomplete population character-
izations, and limited length of follow-up. To over-
come these limitations, the Childhood Cancer
Survivor Study (CCSS) was proposed and, in 1994,
funded by the National Cancer Institute (NCI). The
key components of the rationale for initiating the
CCSS are summarized in the following sections.
Improved Survival
Today, cure is the likely outcome for most chil-
dren diagnosed with cancer. Improvements in ther-
apy have increased the 5-year relative survival rate
from less than 30% in 1960 to 79% in 2004.
1,2
Long-
term survival rates vary substantially according to
initial diagnosis, demographic characteristics (eg,
age, sex, race), and presenting clinical characteristics
(eg, extent of disease, location, morphology, bio-
logic features). Thus, more recent clinical trials are
often designed with the general philosophy of inten-
sifying therapy among poor prognosis patients to
further increase survival, while reducing/modifying
therapy in patients with a good prognosis to de-
crease the potential for acute and long-term toxici-
ties without compromising survival.
Recognition of Risks Associated
With Health-Related and
Psychosocial Outcomes
To varying degrees, it has been shown that
long-term survivors are at risk of developing a spec-
trum of adverse outcomes including early death,
second neoplasms, organ dysfunction (eg, cardiac,
pulmonary, gonadal), impaired growth and devel-
opment, decreased fertility, impaired cognitive
function, difficulties obtaining employment and in-
surance, and overall reduction in quality of life.
3
JOURNAL OF CLINICAL ONCOLOGY
REVIEW ARTICLE
VOLUME 27 NUMBER 14 MAY 10 2009
2308 © 2009 by American Society of Clinical Oncology
Because of the young age of childhood cancer survivors and thus the
potential longevity of survivorship, the delayed consequences of ther-
apy will likely have a substantial impact on their lives, their families,
and society at large.
Limitations of Single-Institution Studies, Consortia,
and Cooperative Groups
Single-institution investigations provided many of the initial
observations on selected sequelae occurring at relatively high fre-
quencies or associated with severe morbidity. However, many of
these single-institution and limited consortia investigations are
restricted by a small sample size and incomplete patient follow-up
and are often derived from patient populations that are treated on
a single uniform protocol. Thus, precise quantification of a com-
plete range of possible adverse outcomes is often impossible. Some
studies of long-term survivors have been carried out within estab-
lished cooperative clinical trials groups but with varied success.
The pediatric cooperative groups have a primary objective of con-
ducting therapeutic clinical trials, and although questions of
health-related outcomes are of interest, the resources do not always
exist to provide the necessary support to successfully conduct such
nontherapeutic studies.
Table 1. Childhood Cancer Survivor Study Consortium Institutions and Responsible Investigators
Institution Investigators
St. Jude Children’s Research Hospital, Memphis, TN Leslie L. Robison, PhD
†, Melissa M. Hudson, MD†‡, Greg T. Armstrong, MD, MSCE†,
Daniel M. Green, MD†, Kevin R. Krull, PhD†
Children’s Healthcare of Atlanta/Emory University,
Atlanta, GA Lillian Meacham, MD‡, Ann C. Mertens, PhD†
Children’s Hospitals and Clinics of Minnesota, Minneapolis/
St. Paul, MN Joanna Perkins, MD, MS‡
Children’s Hospital and Medical Center, Seattle, WA Douglas Hawkins, MD‡, Eric Chow, MD, MPH†
Children’s Hospital, Denver, CO Brian Greffe, MD‡
Children’s Hospital, Los Angeles, CA Kathy Ruccione, RN, MPH‡
Children’s Hospital, Oklahoma City, OK John Mulvihill, MD†
Children’s Hospital of Orange County, Orange, CA Leonard Sender, MD
Children’s Hospital of Philadelphia, Philadelphia, PA Jill Ginsberg, MD‡, Anna T. Meadows, MD†
Children’s Hospital of Pittsburgh, Pittsburgh, PA Jean Tersak, MD‡
Children’s National Medical Center, Washington, DC Gregory Reaman, MD‡, Roger Packer, MD†
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH Stella Davies, MD, PhD†
City of Hope Medical Center, Duarte, CA Smita Bhatia, MD†‡
Cook Children’s Medical Center, Ft. Worth, TX Paul Bowman, MD, MPH‡
Dana-Farber Cancer Institute/Children’s Hospital, Boston, MA Lisa Diller, MD†‡
Fred Hutchinson Cancer Research Center, Seattle, WA Wendy Leisenring, ScD†‡
Hospital for Sick Children, Toronto, Ontario, Canada Mark Greenberg, MBChB‡, Paul C. Nathan, MD†‡
International Epidemiology Institute, Rockville, MD John Boice, ScD†
Mayo Clinic, Rochester, MN Vilmarie Rodriguez, MD‡
Memorial Sloan-Kettering Cancer Center, New York, NY Charles A. Sklar, MD†‡, Kevin C. Oeffinger, MD†
Miller Children’s Hospital, Long Beach, CA Jerry Finklestein, MD‡
National Cancer Institute, Bethesda, MD Roy Wu, PhD†, Nita Seibel, MD†, Preetha Rajaraman, PhD†, Peter Inskip, PhD†
Nationwide Children’s Hospital, Columbus, OH Amanda Termuhlen, MD‡, Sue Hammond, MD†
Northwestern University, Chicago, IL Kimberley Dilley, MD, MPH‡
Riley Hospital for Children, Indianapolis, IN Terry A. Vik, MD‡
Roswell Park Cancer Institute, Buffalo, NY Martin Brecher, MD‡
St. Louis Children’s Hospital, St. Louis, MO Robert Hayashi, MD‡
Stanford University School of Medicine, Stanford, CA Neyssa Marina, MD‡, Sarah S. Donaldson, MD†
Texas Children’s Hospital, Houston, TX Zoann Dreyer, MD‡
University of Alabama, Birmingham, AL Kimberly Whelan, MD, MSPH‡
University of Alberta, Edmonton, Alberta, Canada Yutaka Yasui, PhD†‡
University of California, Los Angeles, Los Angeles, CA Jacqueline Casillas, MD, MSHS‡, Lonnie Zeltzer, MD†
University of California, San Francisco, San Francisco, CA Robert Goldsby, MD‡
University of Chicago, Chicago, IL Tara Henderson, MD, MPH‡
University of Michigan, Ann Arbor, MI Raymond Hutchinson, MD‡
University of Minnesota, Minneapolis, MN Joseph Neglia, MD, MPH†‡
University of Southern California, Los Angeles, CA Dennis Deapen, DrPH†‡
The University of Texas Southwestern Medical Center,
Dallas, TX
Daniel Bowers, MD‡
The University of Texas M. D. Anderson Cancer Center,
Houston, TX
Louise Strong, MD†‡, Marilyn Stovall, MPH, PhD†
Project Principal Investigator (supported by Grant No. U24 CA55727).
†Member of Childhood Cancer Survivor Study Steering Committee.
‡Institutional Principal Investigator.
Childhood Cancer Survivor Study
www.jco.org © 2009 by American Society of Clinical Oncology 2309
A Large and Increasing Proportion of Survivors Are
No Longer Being Observed Systematically
The long-term follow-up of children successfully treated for can-
cer is challenging, and deficiencies in follow-up may obscure the true
frequency and nature of the late effects of therapy. For example, in the
majority of survivors, long-term outcomes are not being reported
systematically by clinical trials groups.
4
This deficiency is underscored
by the fact that when the CCSS was first proposed, the status of 68% of
survivors diagnosed between 1970 and 1986 had not been updated
within the cooperative groups for more than 10 years. Moreover,
among survivors eligible for the CCSS cohort, 39% required extensive
tracing (beyond use of telephone directory assistance) because their
treating institution no longer had current contact information. To
address the potential biases associated with incomplete long-term
follow-up of patients, a well-organized and experienced resource like
the CCSS is required.
ORGANIZATIONAL STRUCTURE
With the recognition of the need for systematic surveillance of long-
term survivors of childhood cancer, efforts in 1990 were begun to form
a consortium of institutions and investigators to establish a mecha-
nism to facilitate survivorship research. After a series of organizational
and planning meetings, a group of 26 contributing clinical pediatric
centers from the United States and Canada was selected to form the
CCSS consortium. These centers were chosen based on criteria that
included the size of the patient population, investigator expertise and
interest in issues relating to childhood cancer survivorship, previous
history of successful multi-institutional collaborative research, and
geographic location. Over a 2-year period, the consortium investiga-
tors developed and agreed on the objectives of the project; eligibility
criteria for study participants; and study design, methods, and out-
comes. In addition, pilot studies were conducted to demonstrate the
feasibility of constructing a retrospective cohort and to generate pre-
liminary data regarding resources required to successfully complete an
undertaking of this scope. Subsequent submission and peer review of
a grant application resulted in funding by the National Institutes of
Health in 1994. Since the original establishment of the CCSS, the
project Coordinating Center has been relocated from the University of
Minnesota to St Jude Children’s Research Hospital, and with the
current expansion of the study cohort, four new contributing institu-
tions have been added recently (Table 1 and Fig 1).
Provided in Figure 2 is the organizational structure of the CCSS.
Both the population of childhood cancer survivors and most of the
scientific input are derived from the contributing/participating cen-
ters. Investigators interested in survivorship research, whether or not
they are from a contributing CCSS center, can participate in one or
more of nine working groups, which provide the primary focus for
development and conduct of research initiatives. The CCSS Steering
Committee represents the leadership body for the project and is com-
posed of the Principal Investigator, Project Director, Working Group
Coordinating center
Contributing clinical centers
Resource centers
New clinical centers (expansion cohort)
Fig 1. Childhood Cancer Survivor Study consortium centers.
SUPPORT FACILITIES
Coordinating center
Statistics and data center
Radiation physics center
Biopathology center
Molecular genetic bank
WORKING GROUPS
Second malignancies
Chronic disease
Reproductive
Cancer control
Genetics
Neurologic
Neuropsychologic
Chemotherapy,
radiation, and
surgery
Epidemiology and
biostatistics
STEERING
COMMITTEE
Principal investigator
Project director
Working group chairs
NCI collaborators
Facility directors
Advisory
Committee
Resource
Access and Utilization
Committee
Education
Committee
Publications
Committee
Survivor Population
CONTRIBUTING INSTITUTIONS
RESEARCH
COMMUNITY
Fig 2. Childhood Cancer Survivor Study
organizational structure. NCI, National
Cancer Institute.
Robison et al
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Chairs/Co-Chairs, NCI Collaborators, and Directors of the support
facilities (ie, Radiation Physics Center, Biopathology Center, Data and
Statistics Center, and Bio-repository Center). Recently, the Steering
Committee was expanded to invite several investigators who are early
in their academic careers to participate in leadership activities of CCSS
within a mentored environment. A number of committees have been
established and charged with oversight of activities related to educa-
tion of survivors, analysis and publication of results from CCSS, and
access and utilization of the CCSS resource. Lastly, an external advi-
sory committee, consisting of survivor advocates and experts in pedi-
atric oncology, epidemiology, biostatistics, and radiation oncology,
attend and participate in annual CCSS investigators’ meetings and
provide input into the current and future activities.
ESTABLISHMENT AND FOLLOW-UP OF THE CCSS COHORT
Details concerning the initial establishment of the cohort, includ-
ing characteristics of the survivor and sibling cohorts, have been
previously published.
5
Briefly, the CCSS cohort is restricted to
5-year survivors of the following diagnoses: leukemia, CNS can-
cers, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, Wilms
(kidney) tumor, neuroblastoma, soft tissue sarcoma, or bone tu-
mor. The original CCSS proposal did not restrict eligibility based
on type of malignancy, but funding restrictions limited inclusion
to only the most common diagnoses among cancer patients diag-
nosed before the age of 21 years. Eligibility for entry into the cohort
required that a patient be diagnosed between January 1, 1970 and
December 31, 1986 and have survived 5 years from his or her date
of diagnosis (regardless of disease or treatment status). The insti-
tutional review board at each participating center reviewed and
approved the CCSS protocol, and all study participants provided
informed consent. Of the 20,720 eligible survivors identified,
14.6% were deemed to be lost to follow-up after extensive tracing
efforts failed to locate them. Of those successfully contacted, 81.2%
completed a 24-page baseline questionnaire. The geographic dis-
tribution of participating survivors is provided in Figure 3. The
demographic-, disease-, and treatment-related characteristics of par-
ticipants, contacted nonparticipants, and those lost to follow-up
were compared to determine the potential for bias.
5,6
To provide a
comparison population, a cohort of siblings of survivors was con-
structed. A randomly selected subset of survivors was asked to
identify all their living siblings, from which the sibling closest in age
to the survivor was selected and asked to participate. Of the 4,782
eligible siblings, 80.4% participated. Information collected from
the sibling cohort is, with the exception of cancer-specific topics,
identical to that obtained on the survivor population.
Fig 3. Geographic distribution of survi-
vors participating in the Childhood Cancer
Survivor Study.
Childhood Cancer Survivor Study
www.jco.org
© 2009 by American Society of Clinical Oncology 2311
Follow-Up of the CCSS Cohort
As detailed in Figure 4, there were four follow-up surveys con-
ducted after the collection of the baseline data from the study cohort.
All study surveys are available on the CCSS Web site (www.stjude.org/
ccss). Although the specific content of follow-up surveys has varied,
each typically updates major health events in addition to collecting
information on focused topics (eg, health utilization, quality-of-life
measures, health behaviors, medical outcomes, mental health, psy-
chosocial outcomes, use of complementary and alternative therapies,
and so on). Beyond the biannual follow-up surveys, a variety of topic-
specific surveys were conducted within the cohort. The majority of
these ancillary studies were supported by investigator-initiated grants
addressing specific study populations to conduct more in-depth eval-
uations. Topics of ancillary studies included barriers to health care
utilization among survivors, psychosexual function among female
and male survivors, health behaviors and quality of life among adoles-
cent survivors, prevalence and risk factors for sleep disorders and
fatigue, physical function and quality of life among survivors of lower
extremity bone tumors, health information–seeking behaviors, and
breast cancer screening practices among female survivors.
Collection and Banking of Biologic Material
To further enhance the scope of research that can be conducted
within the CCSS, a biologic repository was established for banking of
genomic DNA obtained from buccal cell samples of survivors and
siblings, plus peripheral-blood samples from survivors with a second
or subsequent neoplasm. Lymphoblastoid cell lines were established
from the peripheral-blood samples. Those study participants who
provided a biologic sample have given informed consent for the col-
lection, storage, and future use of the material to investigate a spec-
trum of genetic issues including phase I and II enzymes, DNA repair
genes, and other metabolic pathways. Use of the material to investigate
genes known to be associated with disease-risk (eg, p53, BRCA, ATM,
and so on) require independent informed consent by study partici-
pants. The initial collection of buccal cell DNA used a mouthwash-
based approach. Currently, the active cohort members are being
contacted and asked to provide a saliva sample using an approach that
provides a higher quality and quantity of DNA. CCSS investigators at
the Biopathology Center have initiated collection and storage of pa-
thology specimens on second and subsequent malignancies. The in-
ventory of available biospecimens is available at the CCSS Web
site (www.stjude.org/ccss).
ACCESS AND UTILIZATION OF THE CCSS RESOURCE
With the successful establishment of the CCSS cohort, the potential of
this large multidisciplinary project has been realized through the qual-
ity and quantity of publications in the peer-reviewed literature, pre-
sentations at national and international meetings, and funding of
investigator-initiated peer-reviewed grants that use the CCSS re-
source. As an NCI-funded resource, CCSS has been contacted by
more than 100 new investigators (ie, those not previously associated
with CCSS) regarding information and/or opportunities involving the
cohort. More than a quarter of these new investigators are not from
contributing CCSS institutions and the majority of the new investiga-
tors contacting CCSS have become actively involved through devel-
opment of an analysis concept proposal, analysis of study data,
submission of a grant application involving CCSS, and/or presenta-
tion or publication of CCSS data.
CCSS Publications and Presentations at
Scientific Meetings
The CCSS has proven to be a highly used source for data analyses
and publications.
5-103
Since establishing the first complete analytic
data set containing baseline questionnaire information, completed
medical record abstraction, and validation of second malignancies,
investigators have conducted analyses on a wide range of outcomes
(Table 2). Because of the cohort study design, it has been possible to
address issues spanning many topics such as health care utilization,
health behaviors, health status, chronic health conditions, psychoso-
cial and quality-of-life factors, second malignancies, endocrine and
1994 1998 2000
2002 2004 2006 2008
Follow-up 2000
(No. 1) 02/01/00 to 12/10/02
Men’s health
survey
02/08 to present
Women’s health
survey
05/27/01 to 01/23/03
Healthcare
barriers survey
02/01/01 to 10/10/01
Sleep/Fatigue
survey
11/06/02 to 02/10/04
Bone tumor
survey
11/08/00 to 07/05/02
Teen survey
12/10/01 to 02/27/03
Mammography
survey
06/06/05 to 08/34/06
Health information
survey
11/05 to 08/06
09/08/98 to 01/10/06
Follow-up 2003
(No. 2) 11/06/02 to 04/25/05
Follow-up 2007
(No. 4) 07/13/07 to 2/01/09 (est.)
Baseline
survey
Buccal cell collection Expansion
Follow-up 2005
(No. 3) 04/09/05 to 11/15/06
Fig 4. Chronology of Childhood Cancer
Survivor Study surveys and specimen
collection.
Robison et al
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© 2009 by American Society of Clinical Oncology
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Table 2. Childhood Cancer Survivor Study Publications Through 2008
Topic Population Citation
Reference
No.
Peer-reviewed publications
Alcohol All diagnoses Lown et al. Addiction 103:1139-1148, 2008 7
Chronic health conditions All diagnoses Oeffinger et al. N Engl J Med 355:1572-1582, 2006 8
Complementary/alternative therapy All diagnoses Mertens et al. Pediatr Blood Cancer 50:90-97, 2008 9
Education/employment/marriage/insurance All diagnoses Rauck et al. Med Pediatr Oncol 33:60-63, 1999 10
All diagnoses Mitby et al. Cancer 97:1115-1126, 2003 11
Bone malignancies Nagarajan et al. Cancer 97:2554-2564, 2003 12
All diagnoses Park et al. J Clin Oncol 23:9187-9197, 2005 13
All diagnoses Pang et al. Pediatr Blood Cancer 50:104-110, 2008 14
Endocrine and cardiovascular CNS malignancies Gurney et al. Cancer 97:663-673, 2003 15
General survivorship All diagnoses Robison et al. Cancer 104:2557-2564, 2005 16
Minority survivors Castellino et al. J Clin Oncol 23:6499-6507, 2005 17
Rhabdomyosarcoma Punyko et al. Pediatr Blood Cancer 44:643-653, 2005 18
Acute myeloid leukemia Mulrooney et al. Cancer 112:2071-2079, 2008 19
Non-Hodgkin’s lymphoma Bluhm et al. Blood 111:4014-4021, 2008 20
Acute lymphoid leukemia Mody et al. Blood 111:5515-5523, 2008 21
Genetics/family history All diagnoses Boice et al. Health Phys 85:65-85, 2003 22
All diagnoses Friedman et al. Cancer Epidemiol Biomarkers Prev 14:1922-1927, 2005 23
All diagnoses Kadan-Lottick et al. Pediatr Blood Cancer 46:476-481, 2006 24
All diagnoses Blanco et al. Cancer 112:2789-2795, 2008 25
Gonadal function/pregnancy All diagnoses Green et al. Am J Obst Gynecol 187:1070-1080, 2002 26
All diagnoses Green et al. J Clin Oncol 21:716-721, 2003 27
All diagnoses Chemaitilly et al. J Clin Endocrinol Metab 91:1723-1728, 2006 28
All diagnoses Sklar et al. J Natl Cancer Inst 98:890-896, 2006 29
All diagnoses Signorello et al. J Natl Cancer Inst 98:1453-1461, 2006 30
Acute lymphoid leukemia Chow et al. Pediatr Blood Cancer 50:854-858, 2008 31
All diagnoses Green et al. J Clin Oncol (in press) 32
CNS malignancies Armstrong et al. Cancer (in press) 33
Growth hormone All diagnoses Sklar et al. J Clin Endocrinol Metab 87:3136-3141, 2002 34
All diagnoses Brownstein et al. J Clin Endocrinol Metab 89:4422-4427, 2004 35
All diagnoses Ergun-Longmire et al. J Clin Endocrinol Metab 91:3494-3498, 2006 36
Acute lymphoid leukemia Gurney et al. Cancer 107:1303-1312, 2006 37
Health status All diagnoses Hudson et al. JAMA 290:1583-1592, 2003 38
Health care utilization/screening All diagnoses Yeazel et al. Cancer 100:631-640, 2004 39
All diagnoses Oeffinger et al. Ann Family Med 2:61-70, 2004 40
All diagnoses Yeazel et al. J Public Health Dent 64:50-54, 2004 41
All diagnoses Nathan et al. J Clin Oncol 26:4401-4409, 2008 42
All diagnoses Cox et al. Arch Intern Med 169:454-462, 2009 43
All diagnoses Cox et al. Oncol Nurs Forum (in press) 44
All diagnoses Oeffinger et al. JAMA 301:404-414, 2009 45
Knowledge of cancer history All diagnoses Kadan-Lottick et al. JAMA 287:1832-1839, 2002 46
Mortality All diagnoses Mertens et al. J Clin Oncol 19:3163-3172, 2001 47
All diagnoses Mertens et al. J Natl Cancer Inst 100:1368-1379, 2008 48
Neurologic/neurosensory CNS malignancies Packer et al. J Clin Oncol 21:3255-3261, 2003 49
Osteonecrosis All diagnoses Kadan-Lottick et al. J Clin Oncol 26:3038-3045, 2008 50
Physical function/quality of life Bone malignancies Nagarajan et al. Br J Cancer 91:1858-1865, 2004 51
All diagnoses Ness et al. Ann Intern Med 143:639-647, 2005 52
Wilms tumor and
neuroblastoma
Nathan et al. Pediatr Blood Cancer 49:704-715, 2006 53
Acute lymphoid leukemia Ness et al. Pediatr Blood Cancer 49:975-981, 2006 54
Rhabdomyosarcoma Punyko et al. Psychooncology 16:26-37, 2007 55
Acute lymphoid leukemia Florin et al. Cancer Epidemiol Biomarkers Prev 16:1356-1363, 2007 56
All diagnoses Ness et al. Arch Phys Med Rehabil 89:128-136, 2008 57
All diagnoses Zeltzer et al. Cancer Epidemiol Biomarkers Prev 17:435-446, 2008 58
All diagnoses Cox et al. Cancer (in press) 59
All diagnoses Ness et al. Cancer Epub ahead of print on February 17, 2009 60
Bone malignancies Nagarajan et al. J Cancer Surviv 3:59-65, 2009 61
(continued on following page)
Childhood Cancer Survivor Study
www.jco.org © 2009 by American Society of Clinical Oncology 2313
reproductive outcomes, and late mortality. In addition, the cohort has
been the basis of a number of methodologic publications relating to
survivorship-based research. Beyond the diversity of topics addressed,
it is important to note the generally high impact of CCSS publications.
Presentation of CCSS results at national and international meetings
has also been a significant method of disseminating findings from the
project. More than 120 abstracts have been presented at scientific
conferences (full listing available at www.stjude.org/ccss).
Table 2. Childhood Cancer Survivor Study Publications Through 2008 (continued)
Topic Population Citation
Reference
No.
Psychological Hematopoietic
malignancies
Zebrack et al. Pediatrics 110:42-52, 2002 62
CNS malignancies Zebrack et al. J Clin Oncol 22:999-1006, 2004 63
Solid tumors Zebrack et al. Pediatr Blood Cancer 49:47-51, 2007 64
All diagnoses Schultz et al. J Clin Oncol 25:3649-3656, 2007 65
Pulmonary All diagnoses Mertens et al. Cancer 95:2431-2441, 2002 66
Second neoplasms All diagnoses Neglia et al. J Natl Cancer Inst 93:618-629, 2001 67
All diagnoses Kenney et al. Ann Intern Med 141:590-597, 2004 68
Hodgkin’s disease Mertens et al. Cancer 101:1463-1472, 2004 69
All diagnoses Sigurdson et al. Lancet 365:2014-2023, 2005 70
All diagnoses Perkins et al. J Clin Oncol 23:3733-3741, 2005 71
All diagnoses Bassal et al. J Clin Oncol 24:476-483, 2006 72
All diagnoses Ronckers et al. Radiat Res 166:618-628, 2006 73
All diagnoses Neglia et al. J Natl Cancer Inst 98:1528-1537, 2006 74
All diagnoses Henderson et al. J Natl Cancer Inst 99:300-308, 2077 75
Sleep/fatigue All diagnoses Mulrooney et al. Sleep 31:271-281, 2008 76
Smoking All diagnoses Emmons et al. J Clin Oncol 20:1608-1616, 2002 77
All diagnoses Emmons et al. J Clin Oncol 21:189-196, 2003 78
All diagnoses Butterfield et al. Psychooncology 13:619-629, 2004 79
All diagnoses Emmons et al. J Clin Oncol 20:6516-6523, 2005 80
All diagnoses Park et al. Prev Med 42:435-442, 2006 81
All diagnoses Emmons et al. J Clin Oncol 27:52-60, 2009 82
Stroke Hodgkin’s disease Bowers et al. J Clin Oncol 23:6508-6515, 2005 83
Leukemia and CNS
malignancies
Bowers et al. J Clin Oncol 24:5277-5285, 2006 84
Survivorship methodology All diagnoses Yasui et al. J Clin Epidemiol 52:292-298, 1999 85
All diagnoses Robison et al. Med Pediatr Oncol 38:229-239, 2002 5
All diagnoses Kadan-Lottick et al. Epidemiology 14:737-740, 2003 86
All diagnoses Yasui et al. Am J Epidemiol 158:1108-1113, 2003 87
All diagnoses Stovall et al. Int J Radiat Oncol Biol Phys 60:542-552, 2004 88
All diagnoses Mertens et al. J Clin Epidemiol 57:933-944, 2004 6
All diagnoses Recklitis et al. Psychol Assess 18:22-23, 2006 89
All diagnoses Dinu et al. Pediatr Blood Cancer 50:1026-1031, 2008 90
All diagnoses Krull et al. Cancer 113:2188-2197, 2008 91
All diagnoses Ness et al. Pediatr Blood Cancer 52:379-386, 2009 92
Thyroid function Hodgkin’s disease Sklar et al. J Clin Endocrinol Metab 85:3227-3232, 2000 93
Weight/height/body mass index Acute lymphoid leukemia Oeffinger et al. J Clin Oncol 21:1359-1365, 2003 94
CNS malignancies Gurney et al. J Clin Endocrinol Metab 88:4731-4739, 2003 95
Acute lymphoid leukemia Ross et al. J Clin Oncol 22:3558-3562, 2004 96
All diagnoses Meacham et al. Cancer 103:1730-1739, 2005 97
Acute lymphoid leukemia Chow et al. J Pediatr 150:370-375, 2007 98
Acute lymphoid leukemia Garmey et al. J Clin Oncol 26:4639-4645, 2008 99
Non–peer-reviewed publications
General survivorship All diagnoses Robison. Minn Med 88:45-49, 2005 100
Mortality All diagnoses Mertens. Pediatr Blood Cancer 48:723-726, 2007 101
Second neoplasms All diagnoses Davies. Pediatr Blood Cancer 48:727-730, 2007 102
All diagnoses Robison. Pediatr Radiol 39:S32-S37, 2009 (suppl 1) 103
Submitted manuscripts
Cardiac All diagnoses Mulrooney et al (submitted for publication)
Dental All diagnoses Kaste et al (submitted for publication)
Diabetes All diagnoses Meacham et al (submitted for publication)
Education/employment/marriage/insurance All diagnoses Janson et al (submitted for publication)
General survivorship Neuroblastoma Laverdiere et al (submitted for publication)
CNS malignancies Armstrong et al (submitted for publication)
Second neoplasms All diagnoses Inskip et al (submitted for publication)
Robison et al
2314 © 2009 by American Society of Clinical Oncology
J
OURNAL OF CLINICAL ONCOLOGY
Mechanism for Using the CCSS Resource
The CCSS is a resource for the scientific community at large. Any
investigator interested in using the CCSS resource, whether through
analysis and publication of existing data, through use of stored bio-
logic samples, or by investigator-initiated research grant proposals, is
encouraged to contact the CCSS Coordinating Center or a Working
Group Chair. A formal process has been established to evaluate pro-
posed research involving the CCSS resource (Fig 5). The two-stage
process consists of submission of an Application of Intent to conduct
research, which is reviewed by the CCSS Steering Committee, fol-
lowed by completion of an Analysis Concept Form that is reviewed by
the CCSS Publication Committee. Details of this process and exam-
ples of the Application of Intent and Analysis Concept Form are
available at the CCSS Web site (www.stjude.org/ccss). As a resource,
CCSS has been well used by investigators to secure funding for survi-
vorship research through investigator-initiated grant applications. To
date, 19 externally funded grants have been awarded that use the CCSS
resource as a component of the research plan. These grants, totaling
more than $14,000,000 in funding, demonstrate the utility of the
CCSS to facilitate high-quality, peer-reviewed research from sources
including the National Institutes of Health (n 9) and nongovern-
mental agencies/foundations (n 10).
Public Access Data
To further facilitate access to the vast amount of data generated
through the CCSS, efforts are underway to establish an extensive
library of public access data tables. The initial series of tables are
currently available on the CCSS Web site (www.stjude.org/ccss) and
will be expanded on an ongoing basis. The aim of the public access
data is to allow researchers and health care/public health professionals
to determine the frequency of self-reported information among long-
term survivors of childhood cancer. These data can then be used for
publication/citation and planning of proposed research.
PRIORITIES AND FUTURE DIRECTION OF CCSS
With the passage of time, the aging CCSS cohort increasingly brings
new information about the long-term effects of treatment. Although
this addresses an important aspect of cancer survivorship (ie, impact
of aging among patients exposed during childhood), the treatment-
related characteristics of the cohort increasingly reflect a greater his-
torical perspective. To maintain the scientific impact of the CCSS
resource, efforts are underway to expand the existing cohort by adding
5-year survivors diagnosed and treated between January 1, 1987 and
December 31, 1999. Expansion of the CCSS cohort through recruit-
ment of individuals who achieve long-term survival after more con-
temporary treatment is important to improve our understanding
about evolving late complications associated with new agents and
modalities. This includes the potential of altered risk for morbidity or
mortality, including the impact of reduction of therapy designed to
minimize late effects. Participating CCSS centers have identified
26,093 eligible 5-years survivors, of whom 20,729 were selected for
recruitment. Selection criteria for recruitment were based on the goal
of enriching the expansion cohort for ethnic/racial minorities and
disease/treatment groups of particular interest. Recruitment efforts
are underway for expansion of the CCSS cohort.
Another priority for CCSS is a greater emphasis on translation of
findings into intervention strategies. A primary focus of CCSS has
been to quantify the magnitude of and risk factors for adverse health
and quality-of-life outcomes. Although many of these observations
have helped define clinical care recommendations and screening
guidelines, it is now essential that this information be applied to
cancer control efforts, including the development of novel primary
risk-adapted interventions for newly diagnosed patients, second-
ary risk-reducing interventions for long-term survivors at risk of
cancer-related morbidity, and risk-based screening guidelines for
long-term survivor health care. Each of these aspects of translating
CCSS data into intervention strategies will require the development
and conduct of clinical trials to test the feasibility and efficacy of the
intervention. The CCSS resource represents a strong venue for testing
of interventions targeted to long-term survivors.
Lastly, it is well recognized that the strengths of CCSS are many,
but reliance on self-reported outcomes imposes limitations on the
scope of potential research. CCSS investigators are currently exploring
the potential for creating a subcohort of survivors for clinically based
assessments. As depicted in Figure 3, there are geographic clusters of
survivors within the United States and Canada. Participants who
reside within defined geographic areas of selected CCSS centers are
Research
idea
Access CCSS web site (www.stjude.org/ccss) to
review questionnaires and data
Consult working group chairs and project director
AOI
Application of
intent
Study
concept
proposal
CCSS Steering
Committee review
Assigned to
working group for
development of
analysis concept
Consult biostatistics,
radiation physics,
pathology, and so forth
Publications Committee review:
Recommendation and priority
Prioritization by assigned
working group
Data/Statistics
queue
Fig 5. Process for requesting access to
the Childhood Cancer Survivor Study (CCSS)
resource for analysis and publication.
Childhood Cancer Survivor Study
www.jco.org
© 2009 by American Society of Clinical Oncology 2315
being characterized, with plans to conduct pilot studies to determine
the feasibility of performing clinically based investigations.
SUMMARY
Over the last 14 years, the CCSS has significantly expanded our under-
standing of clinical factors predisposing to cancer-related morbidity
and mortality. This accomplishment was made possible by making
available information on long-term outcomes in a large, geographi-
cally diverse population that is well characterized regarding demo-
graphics, treatment exposures, and outcomes.
The importance of the CCSS encompasses the well-being of
the cancer survivor, the practice of the pediatric oncologists and
primary care physicians who see long-term survivors, and the
research questions posed by multidisciplinary teams of investiga-
tors. Through the education efforts of the CCSS, participants re-
ceive semiannual newsletters summarizing findings of the study
and addressing topics of health promotion (available to all inter-
ested parties at www.stjude.org/ltfu). The health behaviors of long-
term survivors may, compared with the general population, have a
greater impact on the quality and length of their lives. For the
pediatric treatment team, including surgeons, radiation oncolo-
gists, and oncologists, knowledge of the late effects of therapy is
critical for choosing initial therapy for current and future patients,
as well as recommendations for appropriate follow-up and screen-
ing of survivors. For health care providers and planners, CCSS
offers the first opportunity to assess in detail the impact of long-
term cancer survivorship on the delivery of care as these cancer
survivors age. Finally, the cohort provides a critical framework and
resource for epidemiologists and biologists to investigate current
and future questions regarding consequences of therapy, genetic
association, disease processes and causation, and quality of life.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Manuscript writing: Leslie L. Robison, Gregory T. Armstrong,
John D. Boice, Eric J. Chow, Stella M. Davies, Sarah S. Donaldson,
Daniel M. Green, Sue Hammond, Anna T. Meadows, Ann C. Mertens,
John J. Mulvihill, Paul C. Nathan, Joseph P. Neglia, Roger J. Packer,
Preetha Rajaraman, Charles A. Sklar, Marilyn Stovall, Louise C. Strong,
Yutaka Yasui, Lonnie K. Zeltzer
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■■■
Acknowledgment
Additional members of the Childhood Cancer Survivor Study Steering Committee who contributed to the preparation of this manuscript
include Smita Bhatia, MD; Dennis Deapen, PhD; Lisa Diller, MD; Melissa M. Hudson, MD; Peter D. Inskip, PhD; Kevin R. Krull, PhD;
Wendy M. Leisenring, ScD; Kevin C. Oeffinger, MD; Nita L. Seibel, MD; and Roy Wu, MD.
Robison et al
2318 © 2009 by American Society of Clinical Oncology
J
OURNAL OF CLINICAL ONCOLOGY
    • "In this section, we illustrate the AP t 0 metric with a data set from the Childhood Cancer Survivor Study (Robison et al. 2009). This cohort follows children who were initially treated for cancer at 26 US and Canada institutions between 1970 and 1986 and who survived at least 5 years after their cancer diagnosis. "
    [Show abstract] [Hide abstract] ABSTRACT: Prediction performance of a risk scoring system needs to be carefully assessed before its adoption in clinical practice. The choice of an appropriate performance metric is important. In risk prediction, the primary interest is to predict the risk of having an event by a pre-specified \textit{future} time $t_0$. Prospective accuracy measures such as positive predictive values have been recommended for evaluating the predictive performance. However, for commonly used continuous or ordinal risk score systems, these measures require a subjective cut-off threshold value that dichotomizes the risk scores. The need for a cut-off value has created barriers for practitioners and researchers. In this paper, we propose a threshold-free summary index of positive predictive values that accommodates time-dependent event status. For censored event times, we develop a non-parametric estimator for the proposed metric. We conduct a simulation study to examine the finite sample performance of our nonparametric estimator. Lastly, we illustrate this metric on a real data example, comparing two risk score systems for predicting heart failure in childhood cancer survivors.
    Article · Jun 2016 · Italian Journal of Pediatrics
    • "The CCSS is a retrospective cohort study of 5-year survivors of childhood cancer diagnosed between January 1, 1970 and December 31, 1986 and aggregated across 26 collaborating institutions in the United States and Canada. A description of the study design, methods, and sample utilized by the CCSS has been published previously.[25,26] Eligibility criteria for the CCSS include: (1) a diagnosis of leukemia, central nervous system malignancy, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney tumor, neuroblastoma, bone tumor, or soft tissue sarcoma prior to 21 years of age; and (2) survival to at least 5 years post-diagnosis.Figure 1 provides a flow diagram of sibling participants over three surveys showing an overall sibling participation rate of 59%. "
    [Show abstract] [Hide abstract] ABSTRACT: Having a brother or sister with childhood cancer may influence health behaviors during adulthood. The aim of this study was to compare tobacco use in siblings of survivors with peers and to identify factors associated with sibling tobacco use. A retrospective cohort study was conducted using adult siblings (N = 1,974) of 5+ year cancer survivors in the Childhood Cancer Survivor Study (CCSS) and participants (N = 24,105, weighted to match CCSS) in the 2007 National Health Interview Survey. Self-reported tobacco use, sociodemographic, and cancer-related risk factors were analyzed. Siblings were equally likely to have ever smoked compared to their peers (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.93-1.12). Siblings were less likely to be current smokers (OR 0.83, 95%CI 0.73-0.94), but more likely to be former smokers (OR 1.21, 95%CI 1.08-1.35). Siblings with low education were more likely to ever smoke (OR 1.51, 95%CI 1.15-2.00) and be current smokers (OR 1.67, 95%CI 1.24-2.26) compared to their peers. Among siblings, risk factors for current tobacco use included the following: low income <$20,000 (OR 1.66, 95%CI 1.09-2.54), low education (OR 6.68, 95%CI 4.07-10.97), psychological distress (OR 5.36, 95%CI 2.21-13.02), and heavy alcohol use (OR 3.68, 95%CI 2.50-5.41). Siblings of survivors take up smoking at similar rates to their peers, but are more likely to quit. Efforts are needed to address disparities by providing greater psychosocial support and education for the lowest socioeconomic status families facing childhood cancer. Pediatr Blood Cancer 2015; 9999:XX-XX © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2015
    • "Recent therapy progress has improved life expectancy in pediatric cancer patients, with a 5-year overall survival (OS) that increased from 39% in 1960 higher than 80% in 2004 [1]. Radiotherapy (RT) is a fundamental part of the multimodality treatment applied to achieve local (LC) and regional control in solid malignancies. "
    [Show abstract] [Hide abstract] ABSTRACT: Radiation therapy is a part of multidisciplinary management of several childhood cancers. Proton therapy is a new method of irradiation, which uses protons instead of photons. Proton radiation has been used safely and effectively for medulloblastoma, primitive neuro-ectodermal tumors, craniopharyngioma, ependymoma, germ cell intracranial tumors, low-grade glioma, retinoblastoma, rhabdomyosarcoma and other soft tissue sarcomas, Ewing¿s sarcoma and other bone sarcomas. Moreover, other possible applications are emerging, in particular for lymphoma and neuroblastoma. Although both photon and proton techniques allow similar target volume coverage, the main advantage of proton radiation therapy is to sparing of intermediate-to-low-dose to healthy tissues. This characteristic could translate into clinical reduction of side effects, including a lower risk for secondary cancers. The following review presents the state of the art of proton therapy in the treatment of pediatric malignancies.
    Full-text · Article · Sep 2014
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