Eric J. Chow

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

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.

Chronic Disease in the Childhood Cancer Survivor Study Cohort: A Review of Published Findings

A primary objective of the Childhood Cancer Survivor Study (CCSS) is to characterize the major chronic health conditions faced by childhood cancer survivors, and to determine the risk factors for those conditions. In order to characterize these conditions, at entry into the study, participants completed questionnaires that documented self-reported chronic illnesses, symptoms, and medications. Over time, follow-up questionnaires (administered approximately every 2 to 3 years) have allowed analysis of changes in symptoms and disease burden. To date, analyses have been completed which describe the profile of chronic disease in the cohort at first entry into the study and for specific subgroups, defined by primary cancer, by specific exposures, and by demographic factors.1,2 Generally, these analyses estimate risk of chronic disease by calculating a risk estimate for self-reported symptoms or conditions. Relative risks for chronic disease or specific conditions are calculated comparing the survivor cohort with the sibling cohort or population norms. In addition, relative risk for an outcome in a subgroup with a specific treatment exposure or demographic characteristic is calculated relative to a comparison group without that specific factor of interest. Cumulative incidence of specific chronic illnesses is estimated in many of the reports, and analyses of chronic illnesses in each of the survivor groups by primary diagnosis are completed (acute lymphoblastic leukemia [ALL],3 acute myeloid leukemia [AML],4 and rhadbdomyosarcoma5) or in progress (neuroblastoma, bone sarcoma, renal tumors, lymphomas, and brain tumors). This review presents the completed analyses of overall chronic illness in the original cohort and then describes findings by organ system. Specific chronic diseases reported here will include: endocrinologic disorders (including thyroid disease, disorders of growth, weight, and pubertal regulation), osteonecrosis, cardiac disease, pulmonary conditions, and neurosensory/neurologic adverse outcomes. Adverse outcomes in some domains which might be considered chronic illnesses—secondary cancers, emotional and psychological disorders, pain—are not covered herein, but are reviewed separately in other articles within this issue of Journal of Clinical Oncology. For some outcomes, only subsets of the cohort have been analyzed, often because a hypothesis regarding a specific exposure or disease (eg, weight regulation in leukemia survivors or stroke after neck radiation therapy [RT]) has been explored. Analyses in progress, and not included in this report, include risk of renal and urinary disorders, gastrointestinal diseases, and more in depth cohort-wide characterizations of cardiovascular disease. Additional studies to characterize further longitudinal changes in risk as the cohort ages are planned.

Modifiable risk factors and major cardiac events among adult survivors of childhood cancer.

PURPOSE To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer. PATIENTS AND METHODS Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models. RESULTS Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all P(trend) < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7). CONCLUSION Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.

Cardiovascular Risk Factors in Adult Survivors of Pediatric Cancer—A Report from the Childhood Cancer Survivor Study

Background: Childhood cancer survivors are at higher risk of morbidity and mortality from cardiovascular disease compared with the general population. Methods: Eight thousand five hundred ninety-nine survivors (52% male) and 2,936 siblings (46% male) from the Childhood Cancer Survivor Study, a retrospectively ascertained, prospectively followed study of persons who survived 5 years after childhood cancer diagnosed from 1970 to 1986, were evaluated for body mass index of ≥30 kg/m2 based on self-reported heights and weights and self-reported use of medications for hypertension, dyslipidemia, and impaired glucose metabolism. The presence of three or more of the above constituted Cardiovascular Risk Factor Cluster (CVRFC), a surrogate for Metabolic Syndrome. Results: Survivors were more likely than siblings to take medications for hypertension [odds ratio (OR), 1.9; 95% confidence interval (95% CI), 1.6-2.2], dyslipidemia (OR, 1.6; 95% CI, 1.3-2.0) or diabetes (OR, 1.7; 95% CI, 1.2-2.3). Among these young adults (mean age of 32 years for survivors and 33 years for siblings), survivors were not more likely than siblings to be obese or have CVRFC. In a multivariable logistic regression analysis, factors associated with having CVRFC included older age at interview [≥40 versus <30 years of age (OR, 8.2; 95% CI, 3.5-19.9)], exposure to total body irradiation (OR, 5.5; 95% CI, 1.5-15.8) or radiation to the chest and abdomen (OR, 2.3; 95% CI, 1.2-2.4), and physical inactivity (OR, 1.7; 95% CI, 1.1-2.6). Conclusions: Among adult survivors of pediatric cancer, older attained age, exposure to total body irradiation or abdominal plus chest radiation, and a sedentary life-style are associated with CVRFC. Cancer Epidemiol Biomarkers Prev; 19(1); 170–81

Parental age and risk of childhood cancer: a pooled analysis.

Background: Few risk factors for childhood cancer are well-established. We investigated whether advancing parental age increases childhood cancer risk. Methods: We assessed the relationship between parental age and childhood cancer in a case-control study using pooled population-based data. Our pooling was based on linked cancer and birth registry records from New York, Washington, Minnesota, Texas, and California. Subjects included 17,672 cancer cases diagnosed at ages 0–14 years during 1980–2004 and 57,966 controls born during 1970–2004. Individuals with Down syndrome were excluded. Odds ratios and 95% confidence intervals were calculated by logistic regression for the association between parental age and childhood cancer after adjustment for sex, birth weight, gestational age, birth order, plurality, maternal race, birth year, and state. Results: Positive linear trends per 5-year maternal age increase were observed for childhood cancers overall (odds ratio = 1.08 [95% confidence interval = 1.06–1.10]) and 7 of the 10 most frequent diagnostic groups: leukemia (1.08 [1.05–1.11]), lymphoma (1.06 [1.01–1.12]), central nervous system tumors (1.07 [1.03–1.10]), neuroblastoma (1.09 [1.04–1.15]), Wilms’ tumor (1.16 [1.09–1.22]), bone tumors (1.10 [1.00–1.20]), and soft tissue sarcomas (1.10 [1.04–1.17]). No maternal age effect was noted for retinoblastoma, germ cell tumors, or hepatoblastoma. Paternal age was not independently associated with most childhood cancers after adjustment for maternal age. Conclusions: Our results suggest that older maternal age increases risk for most common childhood cancers. Investigation into possible mechanisms for this association is warranted.

Obesity and hypertension among children after treatment for acute lymphoblastic leukemia

The purpose was to determine the prevalence and treatment‐related risk factors for obesity and hypertension among childhood acute lymphoblastic leukemia (ALL) survivors treated with contemporary therapy.

Cancer risk among children with very low birth weights.

OBJECTIVE: The risk of hepatoblastoma is strongly increased among children with very low birth weight (<1500 g). Because data on very low birth weight and other childhood cancers are sparse, we examined the risk of malignancy with very low birth weight in a large data set. METHODS: We combined case-control data sets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which included 17672 children diagnosed as having cancer at 0 to 14 years of age and 57966 randomly selected control subjects. Unconditional logistic regression analysis was used to examine the association of cancer with very low birth weight and moderately low birth weight (1500–1999 g and 2000–2499 g, respectively), compared with moderate/high birth weight (≥2500 g), with adjustment for gender, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth. RESULTS: Most childhood cancers were not associated with low birth weights. However, retinoblastomas and gliomas other than astrocytomas and ependymomas were possibly associated with very low birth weight. The risk of other gliomas was also increased among children weighing 1500 to 1999 g at birth. CONCLUSIONS: These data suggested no association between most cancers and very low birth weight, with the exception of the known association of hepatoblastoma and possibly moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.

Individual Prediction of Heart Failure Among Childhood Cancer Survivors

PURPOSE To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer. PATIENTS AND METHODS Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Childrens Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models. RESULTS Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 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%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%). CONCLUSION Using information available to clinicians soon after completion of childhood cancer therapy, 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 strategies and interventions.

Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis.

OBJECTIVE To compare birth outcomes among female survivors of childhood and adolescent cancer who subsequently bear children, relative to those of women without a history of cancer. DESIGN Retrospective cohort study. SETTING Four US regions. PARTICIPANTS Cancer registries identified girls younger than 20 years who were diagnosed as having cancer from 1973 through 2000. Linked birth records identified the first live births after diagnosis (n = 1898). Comparison subjects were selected from birth records (n = 14 278). Survivors of genital tract carcinomas underwent separate analysis. MAIN EXPOSURE Cancer diagnosis at younger than 20 years. MAIN OUTCOME MEASURES Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, and delivery method, and maternal diabetes, anemia, and preeclampsia. RESULTS Infants born to childhood cancer survivors were more likely to be preterm (relative risk [RR], 1.54; 95% confidence interval [CI], 1.30-1.83) and to weigh less than 2500 g (1.31; 1.10-1.57). For the offspring of genital tract carcinoma survivors, RRs were 1.33 (95% CI, 1.13-1.56) and 1.29 (1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR, 4.92; 95% CI, 1.60-15.13), and anemia was more common among brain tumor survivors (3.05; 1.16-7.98) and childhood cancer survivors whose initial treatment was chemotherapy only (2.45; 1.16-5.17). CONCLUSIONS Infants born to female survivors of childhood and adolescent cancer were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest that close monitoring is warranted. Increased diabetes and anemia among subgroups have not been reported, suggesting areas for study.

Risk of thyroid dysfunction and subsequent thyroid cancer among survivors of acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

To determine the risk of thyroid dysfunction and subsequent thyroid cancer among childhood acute lymphoblastic leukemia (ALL) survivors.