Daniel A. Mulrooney

Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort

Objectives To assess the incidence of and risks for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities among adult survivors of childhood and adolescent cancers. Design Retrospective cohort study. Setting 26 institutions that participated in the Childhood Cancer Survivor Study. Participants 14 358 five year survivors of cancer diagnosed under the age of 21 with leukaemia, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer between 1970 and 1986. Comparison group included 3899 siblings of cancer survivors. Main outcome measures Participants or their parents (in participants aged less than 18 years) completed a questionnaire collecting information on demographic characteristics, height, weight, health habits, medical conditions, and surgical procedures occurring since diagnosis. The main outcome measures were the incidence of and risk factors for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities in survivors of cancer compared with siblings. Results Survivors of cancer were significantly more likely than siblings to report congestive heart failure (hazard ratio (HR) 5.9, 95% confidence interval 3.4 to 9.6; P<0.001), myocardial infarction (HR 5.0, 95% CI 2.3 to 10.4; P<0.001), pericardial disease (HR 6.3, 95% CI 3.3 to 11.9; P<0.001), or valvular abnormalities (HR 4.8, 95% CI 3.0 to 7.6; P<0.001). Exposure to 250 mg/m2 or more of anthracyclines increased the relative hazard of congestive heart failure, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. Cardiac radiation exposure of 1500 centigray or more increased the relative hazard of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by twofold to sixfold compared to non-irradiated survivors. The cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis. Conclusion Survivors of childhood and adolescent cancer are at substantial risk for cardiovascular disease. Healthcare professionals must be aware of these risks when caring for this growing population.

Clinical ascertainment of health outcomes among adults treated for childhood cancer.

IMPORTANCE Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions. OBJECTIVE To determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures in a large cohort of adult survivors of childhood cancer. DESIGN, SETTING, AND PARTICIPANTS Presence of health outcomes was ascertained using systematic exposure-based medical assessments among 1713 adult (median age, 32 [range, 18-60] years) survivors of childhood cancer (median time from diagnosis, 25 [range, 10-47] years) enrolled in the St Jude Lifetime Cohort Study since October 1, 2007, and undergoing follow-up through October 31, 2012. MAIN OUTCOMES AND MEASURES Age-specific cumulative prevalence of adverse outcomes by organ system. RESULTS Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary (abnormal pulmonary function, 65.2% [95% CI, 60.4%-69.8%]), auditory (hearing loss, 62.1% [95% CI, 55.8%-68.2%]), endocrine or reproductive (any endocrine condition, such as hypothalamic-pituitary axis disorders and male germ cell dysfunction, 62.0% [95% CI, 59.5%-64.6%]), cardiac (any cardiac condition, such as heart valve disorders, 56.4% [95% CI, 53.5%-59.2%]), and neurocognitive (neurocognitive impairment, 48.0% [95% CI, 44.9%-51.0%]) function, whereas abnormalities involving hepatic (liver dysfunction, 13.0% [95% CI, 10.8%-15.3%]), skeletal (osteoporosis, 9.6% [95% CI, 8.0%-11.5%]), renal (kidney dysfunction, 5.0% [95% CI, 4.0%-6.3%]), and hematopoietic (abnormal blood cell counts, 3.0% [95% CI, 2.1%-3.9%]) function were less common. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at age 50 years was 21.6% (95% CI, 19.3%-23.9%) for cardiomyopathy, 83.5% (95% CI, 80.2%-86.8%) for heart valve disorder, 81.3% (95% CI, 77.6%-85.0%) for pulmonary dysfunction, 76.8% (95% CI, 73.6%-80.0%) for pituitary dysfunction, 86.5% (95% CI, 82.3%-90.7%) for hearing loss, 31.9% (95% CI, 28.0%-35.8%) for primary ovarian failure, 31.1% (95% CI, 27.3%-34.9%) for Leydig cell failure, and 40.9% (95% CI, 32.0%-49.8%) for breast cancer. At age 45 years, the estimated cumulative prevalence of any chronic health condition was 95.5% (95% CI, 94.8%-98.6%) and 80.5% (95% CI, 73.0%-86.6%) for a serious/disabling or life-threatening chronic condition. CONCLUSIONS AND RELEVANCE Among adult survivors of childhood cancer, the prevalence of adverse health outcomes was high, and a systematic risk-based medical assessment identified a substantial number of previously undiagnosed problems that are more prevalent in an older population. These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer.

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.

High-Risk Populations Identified in Childhood Cancer Survivor Study Investigations: Implications for Risk-Based Surveillance

Childhood cancer survivors often experience complications related to cancer and its treatment that may adversely affect quality of life and increase the risk of premature death. The purpose of this manuscript is to review how data derived from Childhood Cancer Survivor Study (CCSS) investigations have facilitated identification of childhood cancer survivor populations at high risk for specific organ toxicity and secondary carcinogenesis and how this has informed clinical screening practices. Articles previously published that used the resource of the CCSS to identify risk factors for specific organ toxicity and subsequent cancers were reviewed and results summarized. CCSS investigations have characterized specific groups to be at highest risk of morbidity related to endocrine and reproductive dysfunction, pulmonary toxicity, cerebrovascular injury, neurologic and neurosensory sequelae, and subsequent neoplasms. Factors influencing risk for specific outcomes related to the individual survivor (eg, sex, race/ethnicity, age at diagnosis, attained age), sociodemographic status (eg, education, household income, health insurance) and cancer history (eg, diagnosis, treatment, time from diagnosis) have been consistently identified. These CCSS investigations that clarify risk for treatment complications related to specific treatment modalities, cumulative dose exposures, and sociodemographic factors identify profiles of survivors at high risk for cancer-related morbidity who deserve heightened surveillance to optimize outcomes after treatment for childhood cancer.

Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study

PURPOSE Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality. METHODS Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fishers exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death. RESULTS The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2). CONCLUSION The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.

Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: A report from the Childhood Cancer Survivor Study

Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML).

Endocrine late effects of childhood cancer therapy: a report from the Children's Oncology Group.

Pediatric oncologists are curing increasing numbers of patients with childhood cancer, and most children diagnosed with a malignancy may now be expected to become long-term survivors. As the number of childhood cancer survivors grows, so too does the need for evidence-based surveillance of the long-term effects of cancer therapy. Long-term effects involving the endocrine system represent a frequent complication of therapy. The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers(COG LTFUG), most recently updated in 2006, provide a summary of the known endocrine late effects of surgery, radiation, chemotherapy, and stem cell transplant. This paper summarizes the scope and nature of the endocrine late effects of childhood cancer therapy based upon a review of the pertinent medical literature, and demonstrates how pediatric oncologists can use these guidelines in clinical practice.

The impact of limitations in physical, executive, and emotional function on health-related quality of life among adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

OBJECTIVE To examine associations between limitations in physical performance, executive function, and emotional health (activity domains) and either social role attainment or health-related quality of life (HRQOL) in adult survivors of childhood cancer. DESIGN Cross-sectional analysis. SETTING Cancer survivors living in the community; previously treated for childhood cancer at one of 26 institutions. PARTICIPANTS Subjects included 7147 (76.8%) of 9307 eligible adult members of the Childhood Cancer Survivor Study who completed a follow-up questionnaire between 2002 and 2004. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Demographic information was used to classify social roles and the Medical Outcomes Survey 36-Item Short-Form Health Survey to ascertain HRQOL. Questions from the National Health Interview Survey were used to represent physical performance; from the Brief Symptom Inventory to classify emotional health; and from the Behavioral Rating of Executive Function to describe executive function. Multivariate logistic regression was used to examine the association between limitations in activity domains, role attainment, and HRQOL. RESULTS In this cohort, 18.1% reported deficits in physical performance, 10.5% in emotional health, and 14.0% in executive function. In adjusted models, when compared with survivors who reported no limitations, those with physical performance, executive function, or emotional health deficits were less likely to be employed, married, or have incomes greater than

Individual Prediction of Heart Failure Among Childhood Cancer Survivors

20,000 a year. Limitations in executive function or emotional health were associated with no health insurance. Limitations in any activity domain were associated with poor HRQOL. Emotional health limitations had the most impact, with odds ratios from 3.18 (physical performance summary) to 25.81 (mental health). CONCLUSIONS The results of these analyses show the need for development and testing of interventions to remediate limitations in activity domains, because they negatively impact role attainment and HRQOL.