VOLUME 33 䡠 NUMBER 5 䡠 FEBRUARY 10 2015

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Individual Prediction of Heart Failure Among Childhood

Cancer Survivors
Eric J. Chow, Yan Chen, Leontien C. Kremer, Norman E. Breslow, Melissa M. Hudson, Gregory T. Armstrong,
William L. Border, Elizabeth A.M. Feijen, Daniel M. Green, Lillian R. Meacham, Kathleen A. Meeske,
Daniel A. Mulrooney, Kirsten K. Ness, Kevin C. Oeffinger, Charles A. Sklar, Marilyn Stovall,
Helena J. van der Pal, Rita E. Weathers, Leslie L. Robison, and Yutaka Yasui
See accompanying editorial on page 379
Author affiliations appear at the end of
this article. A B S T R A C T

Published online ahead of print at Purpose

www.jco.org on October 6, 2014. To create clinically useful models that incorporate readily available demographic and cancer treatment
Processed as a Rapid Communication characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer.
manuscript.

Supported by Grants No. U24 Patients and Methods

CA55727, K07 CA151775, R01 Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease
CA054498, and P30 CA21765 from the 5 years after cancer diagnosis (n ⫽ 13,060) were observed through age 40 years for the
National Institutes of Health and No. development of heart failure (ie, requiring medications or heart transplantation or leading to death).
257505 from PanCareSurFup EU and by Siblings (n ⫽ 4,023) established the baseline population risk. An additional 3,421 survivors from
the American Lebanese Syrian Associ-
Emma Children’s Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and
ated Charities, Leukemia and
Lymphoma Society, and Tom Voûte
the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models.
Fund.
Results
Presented in part at the 12th Interna- Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at
tional Conference on Long-Term cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74
Complications of Treatment of Children
and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68
and Adolescents for Cancer, Williams-
burg, VA, June 8-9, 2012.
to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups,
corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%),
The content of this research is
solely the responsibility of the authors
2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings
and does not necessarily represent the had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%).
official views of the National Institutes
of Health. No funder was involved
Conclusion
with the review or approval of
Using information available to clinicians soon after completion of childhood cancer therapy,
the manuscript. individual risk for subsequent heart failure can be predicted with reasonable accuracy and
discrimination. These validated models provide a framework on which to base future screening
Authors’ disclosures of potential
conflicts of interest are found in the
strategies and interventions.
article online at www.jco.org. Author
contributions are found at the end of J Clin Oncol 33:394-402. © 2014 by American Society of Clinical Oncology
this article.

Corresponding author: Eric J. Chow, though CHF risk predictors exist for the general
MD, MPH, Fred Hutchinson Cancer INTRODUCTION
older adult population14-16 and have been recently
Research Center, PO Box 19024,
M4-C308, Seattle, WA 98109; e-mail: There are now more than 400,000 childhood cancer reported for patients with breast cancer,17 given the
[email protected]. survivors in the United States,1 and cardiovascular increased incidence of CHF among adolescent and
© 2014 by American Society of Clinical disease is increasingly recognized as one of the lead- young adult survivors, this high-risk population
Oncology ing contributors to late morbidity and mortality in may benefit from customized and validated risk pre-
0732-183X/15/3305w-394w/$20.00 this population.2-8 Survivors are at significant risk of diction models starting at a time point soon after
DOI: 10.1200/JCO.2014.56.1373 cardiomyopathy leading to eventual congestive therapy completion, which, to our knowledge, cur-
heart failure (CHF) compared with siblings and the rently do not exist.
general population, with risk ratios ranging from 5 Our goal was to use the large Childhood Cancer
to 15.3,6,9-12 Important risk factors for CHF include Survivor Study (CCSS) cohort to create clinically
attained age, doses of chest radiotherapy and anthra- useful models that incorporate demographic and
cyclines, presence of conventional cardiovascular cancer treatment information available at the end of
risk factors such as hypertension, and, in some stud- therapy to predict subsequent CHF risk with reason-
ies, age at initial cancer diagnosis and sex.13 Al- able discrimination among 5-year survivors and to

394 © 2014 by American Society of Clinical Oncology

 Heart Failure Prediction in Childhood Cancer Survivors

then validate the resulting risk scores among external cohorts. Impor- mitoxantrone, 4.0.10 Sensitivity analyses considered the effect of alternative doxo-
tantly, many of the cancer treatments used in these cohorts remain in rubicin toxicity equivalence formulas: daunorubicin, 0.83; and idarubicin, 5.0.22,23
common use today.18,19 The development of a robust CHF prediction Radiotherapy records were centrally reviewed, and exposures to the neck,
chest, and abdomen were categorized as yes versus no (yes if at least part of region
modelforthispopulationmayhelpcliniciansrefinesurveillancestrategies
was in direct treatment field); field-specific maximum total doses were calculated
to better identify and counsel patients at higher risk of future events. for the chest and abdomen separately.24 Chest fields included any abdominal
treatment that included the lower part of the chest (ie, above diaphragm), as well as
treatmentsdirectedatthethorax(eg,shoulders,ribs,and/orsupraclavicularareas),
PATIENTS AND METHODS even if the central chest was not a target. In defining dose-specific exposures for
each region, radiation scatter from adjacent fields also was noted, but these expo-
sures were categorized as ⬍ 5 Gy. Heart-specific absorbed doses were estimated by
Primary Study Population
applying water phantom measurements to a three-dimensional mathematic
CCSS methodology and participant accrual have been reported previ-
phantom allowing simulation of a patient of any age or size.24
ously.20,21 The cohort consists of children (diagnosed before age 21 years)
treated for the most common types of childhood cancer at 26 institutions in Outcome Definitions
the United States and Canada between 1970 and 1986 who survived at least CCSS participants completed a baseline questionnaire covering demo-
5-years after diagnosis. For our study, the analytic cohort excluded those who graphic characteristics, health care use, health conditions, and health-related
did not provide consent for medical record abstraction (n ⫽ 1,110) and those behaviors and were then prospectively observed using periodic questionnaires
who experienced a major cardiovascular event (CHF, myocardial infarct, or (available on CCSS Web site25). Proxy responses from family members were
stroke) within 5 years of their initial cancer diagnosis (n ⫽ 188, including 42 used for 5-year survivors who had subsequently died, were age ⬍ 18 years, or
who experienced CHF), leaving 13,060 members of the original cohort (91%) were unable to complete the questionnaires. The cohort also was linked with
available for analysis. A random sample of siblings served as a comparison the National Death Index to ascertain CHF-related deaths (International Clas-
population (n ⫽ 4,023). The protocol was approved by the human subjects sification of Diseases, ninth revision [ICD-9], codes 425 to 428 and V42.1 or
committee at each institution. Participants provided informed consent. ICD-10 codes I42 to I52). Using previously described methodology to define
CHF,3,11 baseline and subsequent questionnaire items related to cardiomyopathy,
Cancer Therapy Exposures CHF, and heart transplantation, including information on medications, were
Chemotherapy, surgery, and radiotherapy information was abstracted from classified and graded using the Common Terminology Criteria for Adverse Events
medical records. Anthracycline exposures included doxorubicin, daunorubicin, (CTCAE; version 4.03).26 Only those outcomes graded as severe (grade 3; self-
idarubicin, epirubicin, and mitoxantrone (an anthraquinone). In the primary reported cardiomyopathy or CHF, plus medications), life threatening (grade 4;
analysis, anthracycline doses were based on the following doxorubicin hemato- requiring heart transplantation), or fatal (grade 5) were included. If insufficient
logic toxicity equivalence: daunorubicin, 1.0; idarubicin, 3.0; epirubicin, 0.67; and information existed to distinguish between grades, the lower grade was applied.

Table 1. Characteristics of Study Cohorts

Validation Data Sets
Training Data Set
Variable CCSS (n ⫽ 13,060) EKZ/AMC (n ⫽ 1,362) NWTS (n ⫽ 6,760)ⴱ† SJLIFE (n ⫽ 1,695)ⴱ
Population 26 North American Single Dutch center; North American clinical Single US center;
centers; diagnosed diagnosed age ⬍ 18 trials group; kidney diagnosed at any age
age ⬍ 21 years years between 1966 tumors only; (if pediatric histology)
between 1970 and and 1997; survived ⱖ diagnosed age ⬍ 16 between 1962 and
1986; survived ⱖ 5 5 years years between 1969 2001; alive and age ⱖ
years and 2002; survived ⱖ 18 years at cohort
5 years entry; survived ⬎ 10
years
Exposure information Chemotherapy doses, RT Chemotherapy doses, RT Chemotherapy doses, RT Chemotherapy doses, RT
fields and doses, fields and doses, fields and doses, no fields and doses, no
select organ-specific select organ-specific organ-specific organ-specific
dosimetry (based on dosimetry (maximum dosimetry; chest RT dosimetry; chest RT
average dose) and EQD2 doses); included any whole- fields defined similarly
chest RT fields defined abdomen or left-flank as CCSS
similarly as CCSS RT exposure
Outcome definition Self-report and death Medical and death Medical and death Medical and death
records; limited to records; prospective records; self-report records; prospective
CTCAE grades 3 to 5 clinical assessment; accepted if patient clinical assessment;
occurring ⬎ 5 years limited to CTCAE also reported receiving limited to CTCAE
from cancer diagnosis: grades 3 to 5 appropriate grades 3 to 5
cardiomyopathy or occurring ⬎ 5 years medications; limited to occurring ⬎ 10 years
CHF requiring from cancer diagnosis CTCAE grades 3 to 5 from cancer diagnosis
medication or cardiac (n ⫽ 26) occurring ⬎ 5 years (n ⫽ 19)
transplantation or from cancer diagnosis
leading to death (n ⫽ 48)
(n ⫽ 285)

Abbreviations: CCSS, Childhood Cancer Survivor Study; CHF, congestive heart failure; CTCAE, Common Terminology Criteria for Adverse Events; EKZ/AMC, Emma
Children’s Hospital and Academic Medical Center; EQD2, equivalent dose in 2-Gy fractions; NWTS, National Wilms Tumor Study; RT, radiotherapy; SJLIFE, St Jude
Lifetime Cohort.
ⴱ
CCSS participants who also were part of NWTS and/or SJLIFE were excluded from NWTS and SJLIFE for this analysis.
†Because NWTS did not have pre-existing chemotherapy dose information available, a nested case-cohort design was used for this analysis, which included all 48
patient cases of heart failure and 316 randomly selected members of overall cohort (as of December 31, 2012).

www.jco.org © 2014 by American Society of Clinical Oncology 395

 Chow et al

Outcomes were limited to those occurring by age 40 years, given the limited radiotherapy. For chemotherapy, only cumulative anthracycline doses were
number of events beyond that age because of the relative youth of the cohort. categorized (none, ⬍ 100, 100 to 249, and ⱖ 250 mg/m2), and for radiother-
Information on obesity, hypertension, dyslipidemia, and diabetes from the base- apy, only cumulative chest and heart doses were categorized (none, ⬍ 5, 5 to
line questionnaire was defined as previously described.11,27 14, 15 to 34, and ⱖ 35 Gy). Three prediction models were created for different
clinical scenarios: one, a simple model where cancer therapy–related exposures
Statistical Analysis were categorized as yes or no only; two, a standard model where clinical dose
Exposures selected a priori to be examined in our prediction models information was known; and three, a standard with heart dose model that used
included sex, age at diagnosis (5-year increments), anthracyclines, alkylating average radiation dose to the heart in lieu of chest field dose because contemporary
agents, platinum agents, vinca alkaloids, and neck, chest, and abdominal radiotherapy plans often provide heart-specific dosimetry. Secondary analyses

Table 2. Demographic and Clinical Characteristics of ⱖ 5-Year Childhood Cancer Survivor Cohorts

Validation Data Sets

Training Data Set EKZ/AMC

CCSS (n ⫽ 13,060) (n ⫽ 1,362) NWTS (n ⫽ 364) SJLIFE (n ⫽ 1,695)

Characteristic No. % No. % No. % No. %

Female sex 6,134 47.0 617 45.3 201 55.2 819 48.3
Age at diagnosis, years
⬍5 5,251 40.2 596 43.8 270 74.2 553 32.6
5-9 2,891 22.1 378 27.8 81 22.3 410 24.2
10-14 2,622 20.1 308 22.6 10 2.7 436 25.7
ⱖ 15 2,296 17.6 80 5.9 3 0.8 296 17.5
Cancer diagnosis
Acute lymphoblastic leukemia 3,987 30.5 302 22.2 — — 482 28.4
Other leukemia 452 3.5 30 2.2 — — 71 4.2
Hodgkin lymphoma 1,756 13.4 104 7.6 — — 203 12.0
Other lymphoma 965 7.4 167 12.3 — — 111 6.6
Brain tumor 1,687 12.9 124 9.1 — — 214 12.6
Neuroblastoma 871 6.7 85 6.2 — — 56 3.3
Kidney tumor 1,130 8.7 186 13.7 364 100.0 97 5.7
Soft tissue sarcoma 1,134 8.7 131 9.6 — — 135 7.9
Bone tumor 1,078 8.2 126 9.3 — — 97 5.7
Other neoplasm — — 107 7.9 — — 229 13.5
Anthracycline use
Yes 4,876 37.3 565 41.5 185 50.8 1,003 59.2
No 7,513 57.5 797 58.5 179 49.2 692 40.8
Unknown 671 5.1 0 0.0 0 0.0 0 0.0
Anthracycline dose, mg/m2
None 7,506 57.5 799 58.7 179 49.2 692 40.8
⬍ 100 422 3.2 32 2.3 23 6.3 218 12.9
100-249 1,354 10.4 263 19.3 95 26.1 549 32.4
ⱖ 250 2,584 19.8 259 19.0 61 16.8 231 13.6
Unknown 1,194 9.1 9 0.7 6 1.6 5 0.3
Chest RT
Yes 3,382 25.9 217 15.9 158 43.4 500 29.5
No 8,783 67.3 1,092 80.2 206 56.6 1,195 70.5
Unknown 895 6.9 53 3.9 0 0.0 0 0.0
Chest RT dose, Gy
None 7,577 58.0 825 60.6 164 45.1 1,195 70.5
⬍5 1,225 9.4 267 19.6 42 11.5 3 0.2
5-14 444 3.4 25 1.8 89 24.5 98 5.8
15-34 1,410 10.8 107 7.9 44 12.1 263 15.5
ⱖ 35 1,477 11.3 75 5.5 21 5.8 134 7.9
Unknown 927 7.1 63 4.6 4 1.1 2 0.1
Heart RT dose, Gy
None 8,104 62.1 1,096 80.5
⬍5 830 6.4 1 0.1
5-14 853 6.5 34 2.5
15-34 1,389 10.6 160 11.7
ⱖ 35 930 7.1 61 4.5
Unknown 954 7.3 10 0.7

Abbreviations: CCSS, Childhood Cancer Survivor Study; EKZ/AMC, Emma Children’s Hospital and Academic Medical Center; NWTS, National Wilms Tumor Study;
RT, radiotherapy; SJLIFE, St Jude Lifetime Cohort.

396 © 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Heart Failure Prediction in Childhood Cancer Survivors

explored the influence of obesity, hypertension, dyslipidemia, and diabetes on the

performance of the standard model in a subset of survivors with available data. Table 3. CHF Risk Scores and Corresponding Model Discrimination and
Predictive Powerⴱ
Poisson regression models, adjusted for current age, estimated the rela-
tionships between selected exposures and CHF. Backward selection then de- Simple Standard Heart Dose
termined the most influential predictors, adjusted for sex and age at Characteristic Model† Model Model
diagnosis.28 Regression estimates that remained plus those associated with sex Sex
and age at diagnosis were then converted to integer risk scores for ease of Male 0 0 0
summing in subsequent risk models (relative risks ⬍ 1.3, 1.3 to 1.9, 2.0 to 2.9, Female 1 1 1
3.0 to 4.9, and ⱖ 5.0 corresponding to risk scores 0, 1, 2, 3, and 4, respec- Age at diagnosis, years
tively).29 Cox regression models estimated the discriminatory and predictive ⬍5 1 2 2
power of a model based on the area under the curve (AUC) at age 40 years and 5-9 0 1 1
the concordance (C) statistic (representing weighted average AUC from study 10-14 0 0 1
start through age 40 years), with values around 0.5 suggesting a model does no ⱖ 15 0 0 0
better than chance, and values approaching 1 equating to perfect discrimina- Anthracycline, mg/m2
tion and prediction.30,31 Values ⱖ 0.7 are considered reasonable, and values ⱖ None 0 0 0
0.8 are considered excellent. To minimize overfitting, the backward selection Any 3 — —
process and the C-statistics and AUCs reported were internally cross validated ⬍ 100 — 1 2
using random subsets of the CCSS cohort.32 100-249 — 3 3
Risk scores were then summed to create low-, moderate-, and high- ⱖ 250 — 4 4
risk groups for CHF based on the absolute (cumulative incidence at age 40 Chest or heart RT, Gy‡
years)33 and relative risks compared with siblings (Poisson regression)34 None 0 0 0
associated with individual risk scores. The risk groupings were designed Any 3 — —
such that each group ideally was significantly distinct from both siblings as ⬍5 — 0 0
well as the immediate lower group (P ⬍ .05) per our regression models. 5-14 — 2 1
Additional methodologic details, including software used, can be found in 15-34 — 2 3
the Appendix (online only). ⱖ 35 — 4 4
Cohort
External Validation CCSS (n ⫽ 285)§
We used several well-annotated childhood cancer populations with in- AUC 0.71 0.74 0.76
formation on both therapeutic exposures and CHF occurring ⱖ 5 years after C-statistic 0.72 0.76 0.77
cancer diagnosis for validation (Table 1): Emma Children’s Hospital and EKZ/AMC (n ⫽ 26)
Academic Medical Center (EKZ/AMC),7 the National Wilms Tumor Study AUC 0.74 0.81 0.74
(NWTS),35 and the St Jude Lifetime Cohort Study (SJLIFE; cohort and patient C-statistic 0.75 0.80 0.78
cases of CHF defined by minimum ⱖ 10-year survivorship).8 In contrast to NWTS (n ⫽ 48)
CCSS, in all three cohorts, CHF was ascertained via medical records if possible, AUC 0.76 0.72 —
supplemented by death records. Some EKZ/AMC and SJLIFE participants also C-statistic 0.79 0.82 —
had prospective clinical assessments. NWTS, similar to CCSS, accepted patient SJLIFE (n ⫽ 19)
or family self-report if corroborated by concurrent use of appropriate cardiac AUC 0.63㛳 0.68 —
medications. For each validation group, outcomes were restricted to CTCAE C-statistic 0.63㛳 0.68㛳 —
grade ⱖ 3 conditions. Abbreviations: AUC, area under the curve; C, concordance; CCSS, Child-
C-statistics and AUCs (through or at age 40 years) for CHF were esti- hood Cancer Survivor Study; CHF, congestive heart failure; EKZ/AMC,
mated for each validation cohort based on the CCSS risk scores. Each individ- Emma Children’s Hospital and Academic Medical Center; NWTS, National
ual in these cohorts was then categorized into the appropriate CCSS-based risk Wilms Tumor Study; RT, radiotherapy; SJLIFE, St Jude Lifetime Cohort.
ⴱ
Risk scores 0, 1, 2, 3, and 4 correspond to relative risks ⬍ 1.3, 1.3 to 1.9, 2.0
groupings, and the resulting cumulative incidence of CHF was plotted and to 2.9, 3.0 to 4.9, and ⱖ 5.0, respectively.
compared against those derived from the CCSS. †Anthracycline and RT exposures classified as yes versus no only.
‡Simple model: patients who received only radiation scatter from adjacent
fields classified as unexposed; standard model: scatter from adjacent fields
RESULTS classified as ⬍ 5 Gy; heart dose model: exposures based on heart-specific
dosimetry.
§Training data set, with estimates reflecting within CCSS cohort cross-validation.
㛳Estimate is significantly different (P ⬍ .05) from corresponding
Within the CCSS cohort, 37.3% of individuals received an anthra- CCSS estimate.
cycline (Table 2; Appendix Table A1, online only), whereas 25.9%
received chest radiotherapy, excluding scatter ⬍ 5 Gy. The median
age at last follow-up among CCSS participants was 32 years (range,
6 to 59 years), and the median duration of follow-up was 19 years
(range, 0 to 34 years). Among CCSS siblings (51.9% female), the Using this approach, alkylating agents, vinca alkaloids, platinum
median age at last follow-up was 34 years (range, 3 to 63 years). agents, and neck and abdominal radiotherapy did not meet criteria to
Compared with only 12 affected siblings (cumulative incidence, be included in any of the models. In secondary analyses, if survivors
0.3%; 95% CI, 0.1% to 0.5%), 285 CCSS participants had CHF who had received 250 to 299 mg/m2 of anthracyclines were analyzed as
(cumulative incidence, 2.8%; 95% CI, 2.4% to 3.2%) by age 40 a separate dose category, they had risk scores identical to those of
years: 258 individuals receiving medications, 10 with history of survivors who received ⱖ 300 mg/m2 (risk score 4), in contrast to
heart transplantation, and 17 deaths resulting from CHF. those who received ⬍ 250 mg/m2 (risk score 3).
Poisson regression using backward selection identified the most The resulting AUCs and C-statistics for CCSS-derived integer
influential CHF predictors for each model, from which corresponding risk scores at or through age 40 years ranged from 0.71 to 0.77, with the
scoring tables were created (Table 3; Appendix Table A2, online only). standard and heart dose models performing modestly better than the

www.jco.org © 2014 by American Society of Clinical Oncology 397

 Chow et al

Table 4. Classification of CHF Risk Groups Within CCSS Cohort Based on Summed Risk Scores

No. of RR
Risk No. of Patients Cumulative RR (v preceding
Risk Group Score Events at Riskⴱ Incidence† 95% CI (v siblings) 95% CI group)‡ 95% CI
Siblings — 12 4,023 0.3 0.1 to 0.5 1.0 Referent — —
Simple model
Low ⬍3 15 5,112 0.5 0.2 to 0.8 1.6 0.7 to 3.4 — —
Moderate 3-4 160 4,857 3.1 2.5 to 3.7 14.6 8.0 to 26.4 9.2 5.4 to 15.6
High ⱖ5 92 2,030 9.2 6.8 to 11.6 33.0 18.0 to 60.7 2.3 1.7 to 3.0
Standard model
Low ⬍3 18 5,199 0.5 0.2 to 0.8 1.8 0.9 to 3.8 — —
Moderate 3-5§ 122 4,233 2.4 1.8 to 3.0 12.1 6.6 to 22.0 6.6 4.0 to 10.8
High ⱖ6 108 2,059 11.7 8.8 to 14.5 41.5 22.7 to 75.9 3.4 2.6 to 4.5
Heart dose model
Low ⬍3 15 5,187 0.5 0.2 to 0.7 1.6 0.7 to 3.3 — —
Moderate 3-5§ 103 3,883 2.3 1.7 to 2.9 11.3 6.2 to 20.8 7.3 4.2 to 12.5
High 6-8 105 2,236 7.8 5.9 to 9.7 32.8 17.9 to 60.1 2.9 2.2 to 3.8
Very high ⱖ9 25 164 23.7 14.5 to 32.9 118.1 58.8 to 236.9 3.6 2.3 to 5.6

Abbreviations: CCSS, Childhood Cancer Survivor Study; CHF, congestive heart failure; RR, relative risk.
ⴱ
No. at risk varies by outcome and model because it excludes individuals with missing data.
†At age 40 years.
‡Comparisons are versus immediate preceding group (eg, moderate- v low-risk group, high- v moderate-risk group).
§Survivors with total risk score of 3 under standard (n ⫽ 1,129) and heart dose (n ⫽ 1,179) models without both anthracycline and chest or heart radiotherapy
exposures are classified as low risk; cumulative incidence of CHF at age 40 years among these individuals was 0.2%.

simple model (Table 3). In general, AUCs and C-statistics were com- Risk scores were then summed for each individual, and the cor-
parable, suggesting that estimates were stable at least through age 40 responding absolute and relative risks associated with each risk score
years. Prediction estimates associated with the original regression value were estimated using rates among siblings as the referent group.
coefficients were virtually identical to those associated with integer risk Summed risk scores that shared similar relative and absolute risks were
scores (within 0.01 for five of six estimates and 0.04 for other estimate). then grouped together to form low-, moderate-, and high-risk groups,
Similarly, application of an alternative anthracycline drug toxicity equiv- corresponding to 40-year cumulative incidence rates of ⬍ 2.0%, 2.0% to
alence formula22 resulted in 1.4% of CCSS participants (n ⫽ 181) being 4.9%, and ⱖ 5.0%, respectively (Table 4). For the heart dose model, a
reclassified into different (ie, lower) dose categories (Appendix Table A3, fourth, very high–risk group (ⱖ 15.0%) was also able to be defined. The
online only). However, the AUCs and C-statistics using this alternative low-risk groups had minimally increased cumulative incidences and rel-
formula were virtually identical. ative risks of CHF compared with siblings (P ⬎ .05). For all other com-
When conventional cardiovascular risk factors were first evaluated parisons, the relative risks among survivor risk groups were statistically
by CCSS (n ⫽ 10,521; on average, 15 years after cancer diagnosis; median distinctfromoneanother(P⬍.01).TheCCSSriskgroupingswereableto
age of 24 years at time of assessment), these conditions were still relatively segregate different groups within the EKZ/AMC and NWTS cohorts,
rare: obesity (12.1%), hypertension (2.8%), diabetes (0.7%), and dyslipi- although the SJLIFE moderate- and high-risk groups overlapped (Fig 1;
demia (0.2%). Among this subset of the CCSS cohort, obesity and hyper- Appendix Tables A5 and A6, online only). Compared with high-risk
tension were found to be independently influential (Appendix Table A4, CCSS survivors, a smaller proportion of high-risk SJLIFE survivors had
online only). However, the prior risk scores were otherwise minimally high anthracycline exposure (ⱖ 250 mg/m2; 33.8% v 67.6%, respectively;
changed, and overall AUC and C-statistic for CHF at or through age 40 P ⬍ .001), which may have contributed to the lower incidence of CHF
years increased only by 0.01. However, by shifting the prediction time seen in the high-risk group of that cohort.
point from 5 years after cancer diagnosis to this later time point, the
number of available patient cases of CHF decreased from 285 to 182. This
illustrates the value of having a prediction model that starts at an earlier DISCUSSION
time point, given the occurrence of a significant number of CHF events
within 5 to 15 years of diagnosis. Various national groups have published recommendations regarding
Application of CCSS-based risk scores to the external cohorts cardiomyopathy screening for childhood23,36,37 and adult cancer sur-
showed that when compared with the CCSS results, the AUCs and vivors38 based on available evidence and expert opinion. Using treat-
C-statistics were similar when applied to the EKZ/AMC and NWTS ment and outcome data from one of the largest cohorts of childhood
cohorts (P ⬎ .2 for all comparisons) but lower when applied to SJLIFE cancer survivors, we take this one step further by developing the
(P ⫽ .01 to .06; Table 3). When the CCSS cohort was restricted to CCSS-CHF risk score as an easy-to-use clinical tool that can accurately
match SJLIFE more similarly (ie, patients alive at baseline who had predict individual CHF risk through age 40 years (Appendix [online
survived ⬎ 10 years from cancer diagnosis and were age ⱖ 18 only] details how models can be applied to hypothetical patient; online
years), the resulting AUCs and C-statistics were essentially un- calculator can also be found at the CCSS website38a). The information
changed for CCSS. needed to determine the CCSS-CHF risk score is included in the elements

398 © 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Heart Failure Prediction in Childhood Cancer Survivors

Simple Model Standard Model Standard + Heart Dose Model

A B C
Cumulative Incidence (%)

Cumulative Incidence (%)

Cumulative Incidence (%)

25 High risk
25 High risk
25 Very high risk
Medium risk Medium risk High risk
20 Low risk 20 Low risk 20 Medium risk
Low risk
15 15 15

10 10 10

5 5 5

0 0 0
25 30 35 40 25 30 35 40 25 30 35 40
Age (years) Age (years) Age (years)
D E F Very high risk
Cumulative Incidence (%)

Cumulative Incidence (%)

Cumulative Incidence (%)

25 High risk
25 High risk
25 High risk
Medium risk Medium risk Medium risk
20 Low risk 20 Low risk 20 Low risk

15 15 15

10 10 10

5 5 5

0 0 0
25 30 35 40 25 30 35 40 25 30 35 40
Age (years) Age (years) Age (years)
G H
Cumulative Incidence (%)

Cumulative Incidence (%)

25 25
High risk High risk
Medium risk Medium risk
20 Low risk
20 Low risk

15 15

10 10

5 5

0 0
25 30 35 40 25 30 35 40
Age (years) Age (years)
I J
Cumulative Incidence (%)

Cumulative Incidence (%)

25 25
High risk High risk
Medium risk Medium risk
20 Low risk 20 Low risk

15 15

10 10

5 5

0 0
25 30 35 40 25 30 35 40
Age (years) Age (years)

Fig 1. Cumulative incidence of congestive heart failure by risk group for each study cohort: (A) to (C) Childhood Cancer Survivor Study (training data set), (D)
to (F) Emma Children’s Hospital (validation set), (G) to (H) National Wilms Tumor Study (validation set), and (I) to (J) St Jude Lifetime Cohort (SJLIFE; validation
set). Curves start when all eligible cohort members have entered follow-up (age 26 years, except SJLIFE, which started at age 36 years); as such, initial values
shown may be ⬎ 0%.

www.jco.org © 2014 by American Society of Clinical Oncology 399

 Chow et al

of basic cancer survivorship care plans recommended by the Institute of CCSS patient was recorded as exposed), but even today, dexrazoxane
Medicine.39 Although knowledge of more detailed cancer treatment in- remains in limited pediatric use, with unclear long-term efficacy.13,50
formation such as radiotherapy and anthracycline doses was associated In applying these models, users should be aware that our models are
with improved prediction, simple models based on the presence or ab- specific to the risk of CHF (ie, CTCAE grade ⱖ 3) beginning 5 years after
sence of a given exposure performed well and permitted segregation of initial cancer diagnosis. Characteristics associated with earlier-onset CHF
survivors into distinct risk groups. Although the CCSS patient cases were may possibly differ. Furthermore, the cumulative incidence of subclinical
primarily defined by self-report and were not clinically ascertained and cardiomyopathy is likely greater than our estimates. The EKZ/AMC co-
thus subject to potentially greater misclassification, we showed that these hort reported a 27% prevalence of subclinical left ventricular dysfunction
prediction models were robust when applied to several large external (defined as shortening fraction ⬍ 30%) among patients with echocardio-
validation cohorts. Importantly, these external cohorts relied on medical graphic data at an attained age of 23 years (n ⫽ 525).7 The overall preva-
records and prospective clinical assessment of outcomes, supporting the lence of cardiomyopathy (defined as ejection fraction ⬍ 50% by
validity of the CCSS results.3,10,11,27 echocardiogram) among SJLIFE participants was 6.2%, with 61% having
The CCSS-CHF risk score is designed for patients who have recently CHF (ie, grade ⱖ 3 cardiomyopathy).8 Nevertheless, the predictors we
completed therapy (5 years after diagnosis; median age of 12 years in our tested are also associated with subclinical cardiomyopathy, and our re-
cohort) when conventional cardiovascular risk factors such as hyperten- striction to a clinical phenotype avoided issues related to variable defini-
sion, dyslipidemia, and diabetes are still typically rare. Although our anal- tions of subclinical cardiomyopathy used by different studies. Given the
ysis among an older subset of survivors (on average, 15 years after poor long-term prognosis associated with CHF, application of our pre-
diagnosis) found that some of these conditions can be independent pre- diction models will still help more clearly identify individual survivors
dictors, their contributions were modest because of their relatively low who may benefit from earlier detection and intervention.13
prevalence at the time point assessed. However, most of these conditions, Although there remains a paucity of evidence regarding the optimal
alongwithCHFandotherseriouscardiovascularevents,havebeenshown screening strategy and the most appropriate intervention should abnor-
to increase sharply as survivors enter middle age, rising beyond age 40 malities be detected,2,38,45 the CCSS-CHF prediction models provide a
yearswithoutanyobviousplateau.5,6,8,11,12,27 Similartomodelsnowbeing robust framework for personalized risk assessment. These models may
developed for survivors of adult cancers, future models conditioned on help refine cardiomyopathy surveillance by reducing screening among
more extended survival examining the influence of these conditions in low-risk survivors while identifying higher-risk individuals who may ben-
conjunction with cancer treatment exposures among older childhood efit from closer follow-up. Furthermore, they can serve as a platform to
cancer survivors will be important.17,40 test interventions designed to reduce CHF-related morbidity.
Other refinements in prediction may occur with the inclusion of
genetic characteristics pending validation.41-44 Although the main-
stays of contemporary pediatric cancer therapy remain similar to the AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
exposures assessed in this study,18,19 if newer agents such as trastu- OF INTEREST
zumab, sorafenib, and sunitinib associated with ventricular dysfunc-
tion are increasingly used in pediatrics, future models will need to Disclosures provided by the authors are available with this article at
assess their influence.17,38 www.jco.org.
The use of continuous dose (v categorical) information may also
improve prediction, although such changes may reduce the ease of
clinical application, requiring greater bioinformatics support. In our AUTHOR CONTRIBUTIONS
choice of anthracycline dose categories, we chose, based on the CCSS
data, a cutoff of 250 mg/m2 to denote the highest exposure category36 Conception and design: Eric J. Chow, Yan Chen, Charles A. Sklar,
Yutaka Yasui
rather than the 300-mg/m2 cutoff currently recommended by some
Financial support: Eric J. Chow, Leontien C. Kremer, Norman E.
groups.23,37 However, the 250-mg/m2 threshold, as well as the 35-Gy Breslow, Melissa M. Hudson, Leslie L. Robison
chest radiotherapy threshold, we adopted is in concordance with those Administrative support: Eric J. Chow, Leontien C. Kremer, Norman E.
proposed by an international guideline harmonization group after a Breslow, Melissa M. Hudson, Gregory T. Armstrong, Marilyn Stovall,
systematic review of the current literature.45 Leslie L. Robison, Yutaka Yasui
What remains unclear is the most appropriate method to convert Provision of study materials or patients: Leontien C. Kremer, Norman
different anthracycline derivatives to a doxorubicin equivalent dose, E. Breslow, Melissa M. Hudson, Daniel M. Green, Marilyn Stovall,
Helena J. van der Pal, Rita E. Weathers, Leslie L. Robison
with many formulas based on hematologic toxicity, which may differ
Collection and assembly of data: Eric J. Chow, Leontien C. Kremer,
from cardiotoxicity.22,46 Our analyses with two commonly used for- Norman E. Breslow, Melissa M. Hudson, Gregory T. Armstrong, Daniel M.
mulas revealed similar results. We chose the formula that was less Green, Lillian R. Meacham, Daniel A. Mulrooney, Kirsten K. Ness, Marilyn
likely to classify individuals as lower risk, with the assumption that any Stovall, Helena J. van der Pal, Rita E. Weathers, Leslie L. Robison
benefits from overscreening would outweigh the risks for this partic- Data analysis and interpretation: Eric J. Chow, Yan Chen, Leontien C.
ular outcome.47 Although these formulas do not account for alterna- Kremer, Gregory T. Armstrong, William L. Border, Elizabeth A.M.
tive anthracycline formulations (eg, liposomal) and dosing strategies Feijen, Daniel M. Green, Lillian R. Meacham, Kathleen A. Meeske,
Daniel A. Mulrooney, Kirsten K. Ness, Kevin C. Oeffinger, Charles A.
that may be associated with reduced cardiotoxicity (all information Sklar, Marilyn Stovall, Helena J. van der Pal, Rita E. Weathers, Leslie L.
that we lacked), the efficacy data for these interventions are limited Robison, Yutaka Yasui
and mixed in pediatrics.13,48,49 The CCSS treatment era also largely Manuscript writing: All authors
predates the introduction of dexrazoxane as a cardioprotectant (no Final approval of manuscript: All authors

400 © 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Heart Failure Prediction in Childhood Cancer Survivors

childhood cancer survivor care through outcomes 37. Sieswerda E, Postma A, van Dalen EC, et al:
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www.jco.org © 2014 by American Society of Clinical Oncology 401

 Chow et al

Affiliations
Eric J. Chow and Norman E. Breslow, Fred Hutchinson Cancer Research Center, Seattle Children’s Hospital, University of Washington,
Seattle, WA; Yan Chen and Yutaka Yasui, University of Alberta, Edmonton, Alberta, Canada; Leontien C. Kremer, Elizabeth A.M. Feijen, and
Helena J. van der Pal, Emma Children’s Hospital and Academic Medical Center, Amsterdam, the Netherlands; Melissa M. Hudson, Gregory
T. Armstrong, Daniel M. Green, Daniel A. Mulrooney, Kirsten K. Ness, and Leslie L. Robison, St Jude Children’s Research Hospital; Daniel A.
Mulrooney, University of Tennessee, Memphis, TN; William L. Border and Lillian R. Meacham, Children’s Healthcare of Atlanta, Emory
University, Atlanta, GA; Kathleen A. Meeske, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA; Kevin C.
Oeffinger and Charles A. Sklar, Memorial Sloan-Kettering Cancer Center, New York, NY; and Marilyn Stovall and Rita E. Weathers,
University of Texas MD Anderson Cancer Center, Houston, TX.
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 Heart Failure Prediction in Childhood Cancer Survivors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Individual Prediction of Heart Failure Among Childhood Cancer Survivors

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Eric J. Chow Kathleen A. Meeske
No relationship to disclose No relationship to disclose
Yan Chen Daniel A. Mulrooney
No relationship to disclose No relationship to disclose
Leontien C. Kremer Kirsten K. Ness
No relationship to disclose No relationship to disclose
Norman E. Breslow Kevin C. Oeffinger
No relationship to disclose No relationship to disclose
Melissa M. Hudson Charles A. Sklar
No relationship to disclose No relationship to disclose
Gregory T. Armstrong Marilyn Stovall
No relationship to disclose No relationship to disclose
William L. Border Helena J. van der Pal
No relationship to disclose No relationship to disclose
Elizabeth A.M. Feijen Rita E. Weathers
No relationship to disclose No relationship to disclose
Daniel M. Green Leslie L. Robison
No relationship to disclose No relationship to disclose
Lillian R. Meacham Yutaka Yasui
No relationship to disclose No relationship to disclose

www.jco.org © 2014 by American Society of Clinical Oncology

 Chow et al

Appendix

Application of Prediction Models

An 8-year-old girl who was diagnosed with acute lymphoblastic leukemia at age 3 years is seen for follow-up. As part of her cancer
therapy, she received no radiotherapy but received doxorubicin 75 mg/m2 and daunorubicin 100 mg/m2, for a total cumulative
anthracycline dose of 175 mg/m2. As noted in the primary text, some doxorubicin equivalence formulas adjust daunorubicin by a factor
of 0.83, which would result in a total anthracycline dose of 158 mg/m2 (75 ⫹ 83 mg/m2). Conversion formulas for other anthracyclines are
presented in the primary text. Her heart failure risk factors based on the standard model (Table 3) would include female sex (1 point),
diagnosis at age ⬍ 5 years (2 points), anthracycline 100 to 249 mg/m2 (3 points), totaling 6 points and putting her into the high-risk group,
with a predicted cumulative incidence of clinical cardiomyopathy or heart failure of approximately 12% by age 40 years (relative risk,
approximately 40 v siblings; relative risk, approximately 3 v medium risk group; Table 4). Prediction is similar if the heart dose model is
used, although a more refined categorization is available with a separate very high–risk group. If cumulative anthracycline dose
information was not available, using the simple model, she would have a total of 5 points (female sex, 1 point; diagnosis at age ⬍ 5 years,
1 point; any anthracyclines, 3 points; Table 3) and still be classified as high risk (cumulative incidence of approximately 9% by age 40 years;
relative risk, approximately 30 v siblings; Table 4). Because the performance of the standard model at least through age 40 years is superior
to that of the simple model (Table 3), we recommend using the richer model (ie, standard or heart dose model) when possible. For
convenience, an online calculator is available (The Childhood Cancer Survivor Study: CHF risk calculator. ccss.stjude.org/chfcalc).

Statistical Approach
Model selection. The following variables were selected a priori for testing in our models: sex, age at diagnosis (5-year
increments), and exposure to anthracyclines, alkylating agents, platinum agents, vinca alkaloids, and neck, chest, and
abdominal radiotherapy (yes v no). For the standard and heart dose models, exposure doses were substituted for anthracy-
clines (none, ⬍ 100, 100 to 249, and ⱖ 250 mg/m2) and chest or heart radiotherapy (none, ⬍ 5, 5 to 14, 15 to 34, and ⱖ 35
Gy). Individuals with missing data relevant to each model were excluded. Using Poisson regression adjusted for current age
as a cubic spline, models were built to examine the relationships between these independent variables and outcome (ie,
congestive heart failure [CHF]). Current age was handled by splitting the records at each age (as integer) during follow-up.
Backward selection was then used to determine the most influential treatment predictors accounting for sex and age at
diagnosis.28 The least significant variable with P ⱖ .05 (as determined by likelihood ratio test) was dropped, and the reduced
model was refitted using the same rule until all remaining exposure variables were statistically significant (P ⬍ .05). To
minimize the possibility of overfitting, we performed 10-fold internal cross validation of the variable selection process.32
Exploratory analyses examining potential interaction between therapeutic exposures and sex or age at diagnosis did not reveal
any consistent relationships.
Risk score creation. Regression estimates that remained after backward selection plus those associated with sex and diagnosis age were
then converted to integer risk scores for ease of summing in subsequent risk models (relative risks ⬍ 1.3, 1.3 to 1.9, 2.0 to 2.9, 3.0 to 4.9,
and ⱖ 5.0 corresponding to risk scores 0, 1, 2, 3, and 4, respectively) based on previously published methods (Sorror ML et al: Bone
Marrow Transplant 46:464-466, 2011).29 Notably, prediction estimates associated with the original regression coefficients were virtually
identical to those associated with integer risk scores (within 0.01 for five of six estimates; 0.04 for other estimate).
Risk score discriminatory and predictive power. Cox regression models based on an age time scale estimated the discriminatory and
predictive power of our model.30 Specifically, we examined the area under the curve (AUC) at age 40 years and the concordance (C)
statistic through age 40 years.31 The AUC(t) is the probability that a classifier will rank a randomly chosen positive higher than a randomly
chosen negative on a given time t. The C(t)-statistic represents the weighted average of the AUC from study start time to time t. Similar to
the initial model selection process, the reported AUCs and C-statistics also reflected 10-fold internal cross validation based on random
subsets of the Childhood Cancer Survivor Study (CCSS) cohort.32
Risk group creation. Although other general population predictors are often based on the sum of individual risk scores (McGill HC
Jr et al: Circulation 117:1216-1227, 2008),14-16 given the relatively smaller number of patient cases we had available, estimates associated
with individual risk scores were not always precise. Therefore, we collapsed risk scores into several risk groups predictive of low, moderate,
and high risk of CHF.29 To determine the most appropriate groupings, the sums of individual risk scores were examined based on their
absolute risks (cumulative incidence at age 40 years, treating death resulting from other causes as competing risk event33) and relative risks
compared with siblings (Poisson regression, incorporating generalized estimating equation modification to account for potential
within-family correlation34). The resulting low-, moderate-, and high-risk groups corresponded in general to cumulative incidence rates
of ⬍ 2.0%, 2.0% to 4.9%, and ⱖ 5.0% at age 40 years, respectively. For the heart dose model, a fourth, very high–risk group was also able
to be defined, with cumulative incidence ⱖ 20%. The risk groupings were designed such that each group ideally would be significantly
distinct from both siblings as well as the immediate lower group (P ⬍ .05) per our Poisson regression models. However, for our CHF
models, the lowest-risk group ended up not being statistically distinct (P ⬎ .05) from siblings.
External validation. C-statistics and AUCs (through or at age 40 years) for CHF were estimated for each of the validation cohorts
based on the CCSS risk scores. Each individual in these cohorts was then categorized into the appropriate CCSS-based risk grouping, and

© 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Heart Failure Prediction in Childhood Cancer Survivors

the resulting cumulative incidence of CHF was plotted and compared against those derived from the CCSS cohort. Notably, exposure data
for the National Wilms Tumor Study (NWTS) were based on a nested case-cohort design (48 patient cases of CHF; 316 randomly selected
members of overall cohort [n ⫽ 6,760]), in which Barlow’s (Barlow WE: Biometrics 50:1064-1072, 1994) weighting method was applied
for all estimates (Prentice RL: Biometrics 42:301-310, 1986). This study design was chosen because the NWTS did not have pre-existing
chemotherapy dose information, and study resources did not allow for an exhaustive review of the entire cohort. We then assessed the
difference of the AUCs and C-statistics of each model between the external cohorts and the CCSS using 1,000 bootstrap iterations (Good
PI: New York, NY, Springer, 2005).
Software. R software (version 3.0; http://www.r-project.org/), specifically the function risksetROC (version 1.0), was used to
calculate the AUCs and C-statistics. SAS software (version 9.3; SAS Institute, Cary, NC) was used for the Poisson regression analyses. The
codes used are available from the authors on request.

Table A1. Distribution of Anthracycline Derivatives With Known Doses in Each Cohort
EKZ/AMC
CCSS (n ⫽ 13,060) (n ⫽ 1,362) NWTS (n ⫽ 364) SJLIFE (n ⫽ 1,695)

Anthracycline or Anthraquinone No. %ⴱ No. %ⴱ No. %ⴱ No. %ⴱ

None 7,506 57.5 798 58.6 179 49.2 692 40.8
Doxorubicin 3,416 26.2 392 28.8 179 49.2 572 33.7
Daunorubicin 1,425 10.9 138 10.1 0 450 26.5
Idarubicin 1 0.0 3 0.2 0 14 0.8
Epirubicin 0† 132 9.7 0 3 0.2
Mitoxantrone 0† 25 1.8 0 18 1.1
Unknown dose information 1,194 9.1 9 0.7 6 1.6 5 0.3

Abbreviations: CCSS, Childhood Cancer Survivor Study; EKZ/AMC, Emma Children’s Hospital and Academic Medical Center; NWTS, National Wilms Tumor Study;
SJLIFE, St Jude Lifetime Cohort.
ⴱ
Total percentages may exceed 100% because some patients may have received ⬎ one type of anthracycline.
†Epirubicin and mitoxantrone were administered to four and 11 individuals, respectively, but doses were unknown.

Table A2. Multivariable Poisson Regression Results for Each CHF Model in CCSS Cohortⴱ
Simple Model Standard Model Heart Dose Model

Covariate RR 95% CI RR 95% CI RR 95% CI

Sex
Male 1.0 Referent 1.0 Referent 1.0 Referent
Female 1.6 1.3 to 2.1 1.7 1.3 to 2.2 1.7 1.3 to 2.1
Age at diagnosis, years
⬍5 1.5 1.0 to 2.3 2.2 1.4 to 3.4 2.6 1.6 to 4.1
5-9 1.2 0.8 to 1.9 1.6 1.0 to 2.4 1.9 1.2 to 2.9
10-14 1.2 0.9 to 1.6 1.2 0.9 to 1.7 1.4 1.0 to 2.0
ⱖ 15 1.0 Referent 1.0 Referent 1.0 Referent
Anthracycline, mg/m2
Any v none 4.9 3.8 to 6.4 — — — —
None — — 1.0 Referent 1.0 Referent
⬍ 100 — — 1.9 0.7 to 5.1 2.1 0.8 to 5.9
100-249 — — 3.3 2.1 to 5.2 3.7 2.3 to 5.9
ⱖ 250 — — 8.6 6.4 to 11.5 10.5 7.7 to 14.4
Chest RT, Gy†
Any v none 3.2 2.5 to 4.1 — —
None — — 1.0 Referent 1.0 Referent
⬍5 — — 1.0 0.6 to 1.7 0.9 0.5 to 1.6
5-14 — — 2.1 1.1 to 3.8 1.6 1.0 to 2.7
15-34 — — 2.3 1.6 to 3.4 3.1 2.2 to 4.5
ⱖ 35 — — 6.5 4.6 to 9.0 10.5 7.2 to 15.4

Abbreviations: CHF, congestive heart failure; RR, relative risk; RT, radiotherapy.
ⴱ
The following covariates were tested but not selected for inclusion in final analytic model: alkylating agents, platinum agents, vinca alkaloids, neck and/or abdominal
RT (without any direct chest involvement).
†Corresponding heart RT dose used for heart dose model.

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 Chow et al

Table A3. Effect on Anthracycline Dose Categories Using Alternative Equivalence Formulas

CCSS (n ⫽ 13,060) EKZ/AMC (n ⫽ 1,362) SJLIFE (n ⫽ 1,695)

ⴱ ⴱ
Formula One Formula Two† Formula One Formula Two† Formula Oneⴱ Formula Two†
2
Anthracycline Dose (mg/m ) No. % No. % No. % No. % No. % No. %
None 7,506 57.5 7,506 57.5 799 58.7 799 58.7 692 40.8 692 40.8
⬍ 100 422 3.2 513 3.9 32 2.3 63 4.6 218 12.9 368 21.7
100-249 1,354 10.4 1,353 10.4 263 19.3 236 17.3 549 32.4 402 23.7
ⱖ 250 2,584 19.8 2,494 19.1 259 19.0 255 18.7 231 13.6 228 13.5
Unknown 1,194 9.1 1,194 9.1 9 0.7 9 0.7 5 0.3 5 0.3

Abbreviations: CCSS, Childhood Cancer Survivor Study; EKZ/AMC, Emma Children’s Hospital and Academic Medical Center; SJLIFE, St Jude Lifetime Cohort.
ⴱ
Formula One: doxorubicin 1 mg/m2 ⫽ daunorubicin, 1; idarubicin, 3; epirubicin, 0.67; mitoxantrone, 4.
†Formula Two: doxorubicin 1 mg/m2 ⫽ daunorubicin, 0.83; idarubicin, 5; epirubicin, 0.67; mitoxantrone, 4.

Table A4. Influence of Conventional Cardiovascular Risk Factors on CHF Prediction (n ⫽ 10,521)ⴱ†

Risk Factor Standard Model Risk Score‡

Original standard model
Sex
Male 0
Female 1
Age at diagnosis, years
⬍5 1 (2)
5-9 1
10-14 0
ⱖ 15 0
Anthracycline, mg/m2
None 0
⬍ 100 1
100-249 2 (3)
ⱖ 250 4
Chest RT, Gy
None 0 (0)
⬍5 1 (0)
5-14 3 (2)
15-34 3 (2)
ⱖ 35 4
Conventional risk factors§
Obesity 1
Diabetes 0
Dyslipidemia 0
Hypertension 2
Updated model
AUC 0.75㛳
C-index 0.77㛳

Abbreviations: AUC, area under the curve; C, concordance; CCSS, Childhood Cancer Survivor Study; CHF, congestive heart failure; RT, radiotherapy.
ⴱ
182 patient cases of CHF.
†Restricted to CCSS participants with available information from baseline questionnaire who were free of grade ⱖ 3 cardiomyopathy or CHF at time of
baseline questionnaire.
‡No. in parentheses indicates value derived from original analytic population without accounting for the four additional conventional risk factors.
§At time of baseline questionnaire, obesity defined by body-mass index ⱖ 30 kg/m2 based on self-reported height and weight; diabetes, dyslipidemia, and
hypertension defined as those who reported being diagnosed by a physician for the condition and who reported receiving specific medications prescribed for
treatment of the condition for ⬎ 1 month or for ⱖ 30 days in 1-year period during the previous 2 years.
㛳AUC and C-index values per original standard model based on 10,521 survivors with 182 patient cases of heart failure were 0.74 and 0.76, respectively.

© 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Heart Failure Prediction in Childhood Cancer Survivors

Table A5. Classification of CHF Risk Groups Within External Cohorts Based on CCSS-Derived Risk Scores

Risk Group Risk Score No. of Events No. at Riskⴱ Cumulative Incidence† P
EKZ/AMC simple model
Low ⬍3 1 646 0.2
Moderate 3-4 17 477 10.3 ⬍ .01
High ⱖ5 7 198 14.8 .41
EKZ/AMC standard model
Low ⬍3 1 651 0.2
Moderate 3-5‡ 14 468 9.0 ⬍ .01
High ⱖ6 11 228 21.4 .047
EKZ/AMC heart dose model
Low ⬍3 1 469 0.2
Moderate 3-5‡ 12 590 7.0 ⬍ .01
High 6-8 9 251 16.7 .16
Very high ⱖ9 4 30 35.3 .04
NWTS simple model
Low ⬍3 1 162 0.03
Moderate 3-4 5 40 1.0 ⬍ .01
High ⱖ5 42 163 8.5 .06
NWTS standard model
Low ⬍3 1 158 0.03
Moderate 3-5‡ 5 48 0.9 ⬍ .01
High ⱖ6 40 151 6.7 .01
SJLIFE simple model
Low ⬍3 1 512 0.8
Moderate 3-4 13 726 4.6 ⬍ .01
High ⱖ5 5 457 4.9 .19
SJLIFE standard model
Low ⬍3 1 603 0.7
Moderate 3-5‡ 12 740 5.3 ⬍ .01
High ⱖ6 6 352 4.2 .78

Abbreviations: CCSS, Childhood Cancer Survivor Study; CHF, congestive heart failure; EKZ/AMC, Emma Children’s Hospital and Academic Medical Center; NWTS,
National Wilms Tumor Study; SJLIFE, St Jude Lifetime Cohort.
ⴱ
No. at risk varies by outcome and model because it excludes individuals with missing data.
†At age 40 years, P value is for comparison with preceding risk group.
‡Survivors with total risk score of 3 with neither anthracycline nor chest or heart radiotherapy exposure are classified as low risk (EKZ/AMC, n ⫽ 137; NWTS, n ⫽ 66;
SJLIFE, n ⫽ 107); none of these patients developed subsequent CHF.

Table A6. Patients at Risk Over Timeⴱ

EKZ/AMC NWTS† SJLIFE

CCSS (No. of (No. of
Age (years) (No. of patients) patients) No. of Patients Total Survivors patients)
Baseline‡ 13,060 1,362 364 6,760 1,695
26 9,398 757 89 1,619 870
30 7,350 531 60 1,162 738
35 4,961 297 25 475 403
40 2,744 115 7 151 204

Abbreviations: CCSS, Childhood Cancer Survivor Study; EKZ/AMC, Emma Children’s Hospital and Academic Medical Center; NWTS, National Wilms Tumor Study;
SJLIFE, St Jude Lifetime Cohort.
ⴱ
Alive, without congestive heart failure, and not censored for other reasons.
†Case-cohort design with 364 patients used in actual analysis but based on 6,760 total survivors.
‡Five (CCSS, EKZ/AMC, NWTS) or 10 years after cancer diagnosis (SJLIFE); SJLIFE values at age 26 and 30 years exclude participants who had not yet
entered cohort.

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