Toana Kawashima

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.

Fertility of female survivors of childhood cancer: A report from the childhood cancer survivor study

PURPOSE This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility. PATIENTS AND METHODS We reviewed the fertility of female participants in the Childhood Cancer Survivor Study (CCSS), which consisted of 5-year survivors, and a cohort of randomly selected siblings who responded to a questionnaire. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy. RESULTS There were 5,149 female CCSS participants, and there were 1,441 female siblings of CCSS participants who were age 15 to 44 years. The relative risk (RR) for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose > or = 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5 to 10 Gy; 95% CI, 0.37 to 0.85; RR, 0.18 for > 10 Gy; 95% CI, 0.13 to 0.26). Those with a summed alkylating agent dose (AAD) score of three or four or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant. CONCLUSION This large study demonstrated that fertility is decreased among female CCSS participants. The risk factors identified may be utilized for pretreatment counseling of patients and their parents.

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.

Fertility of Male Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

PURPOSE This study was undertaken to determine the effect of treatment for childhood cancer on male fertility. PATIENTS AND METHODS We reviewed the fertility of male Childhood Cancer Survivor Study survivor and sibling cohorts who completed a questionnaire. We abstracted the chemotherapeutic agents administered, the cumulative dose of drug administered for selected drugs, and the doses and volumes of all radiation therapy from medical records. Risk factors for siring a pregnancy were evaluated using Cox proportional hazards models. RESULTS The 6,224 survivors age 15 to 44 years who were not surgically sterile were less likely to sire a pregnancy than siblings (hazard ratio [HR], 0.56; 95% CI, -0.49 to 0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy of more than 7.5 Gy to the testes (HR, 0.12; 95% CI, -0.02 to 0.64), higher cumulative alkylating agent dose (AAD) score or treatment with cyclophosphamide (third tertile HR, 0.42; 95% CI, -0.31 to 0.57) or procarbazine (second tertile HR, 0.48; 95% CI, -0.26 to 0.87; third tertile HR, 0.17; 95% CI, -0.07 to 0.41). Compared with siblings, the HR for ever siring a pregnancy for survivors who had an AAD score = 0, a hypothalamic/pituitary radiation dose = 0 Gy, and a testes radiation dose = 0 Gy was 0.91 (95% CI, 0.73 to 1.14; P = .41). CONCLUSION This large study identified risk factors for decreased fertility that may be used for counseling male cancer patients.

Aging and Risk of Severe, Disabling, Life-Threatening, and Fatal Events in the Childhood Cancer Survivor Study

PURPOSE The first generation of childhood cancer survivors is now aging into their fourth and fifth decades of life, yet health risks across the aging spectrum are not well established. METHODS Analyses included 14,359 5-year survivors from the Childhood Cancer Survivor Study, who were first diagnosed when they were younger than 21 years old and who received follow-up for a median of 24.5 years after diagnosis (range, 5.0 to 39.3 years) along with 4,301 of their siblings. Among the survivors, 5,604 were at least 35 years old (range, 35 to 62 years) at last follow-up. Severe, disabling, life-threatening, and fatal health conditions more than 5 years from diagnosis were classified using the Common Terminology Criteria for Adverse Events, grades 3 to 5 (National Cancer Institute). RESULTS The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6%; 95% CI, 51.5 to 55.6; v 19.8%; 95% CI, 17.0 to 22.7) by age 50 years. When comparing survivors with siblings, hazard ratios (HR) were significantly increased within the age group of 5 to 19 years (HR, 6.8; 95% CI, 5.5 to 8.3), age group of 20 to 34 years (HR, 3.8; 95% CI, 3.2 to 4.5), and the ≥ 35 years group (HR, 5.0; 95% CI, 4.1 to 6.1), with the HR significantly higher among those ≥ 35 years versus those 20 to 34 years old (P = .03). Among survivors who reached age 35 years without a previous grade 3 or 4 condition, 25.9% experienced a subsequent grade 3 to 5 condition within 10 years, compared with 6.0% of siblings (P < .001). CONCLUSION Elevated risk for morbidity and mortality among survivors increases further beyond the fourth decade of life, which affects the future clinical demands of this population relative to ongoing surveillance and interventions.

Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H: quinone oxidoreductase 1 gene NQ01 in patients who developed anthracycline-related congestive heart failure after childhood cancer

Exposure to anthracyclines as part of cancer therapy has been associated with the development of congestive heart failure (CHF). The potential role of genetic risk factors in anthracycline‐related CHF remains to be defined. Thus, in this study, the authors examined whether common polymorphisms in candidate genes involved in the pharmacodynamics of anthracyclines (in particular, the nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and the carbonyl reductase 3 gene CBR3) had an impact on the risk of anthracycline‐related CHF.

Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study

Long-term survival is now an expected outcome after hematopoietic cell transplantation (HCT). However, the burden of morbidity long-term after HCT remains unknown. We examined the magnitude of risk of chronic health conditions reported by 1022 HCT survivors and their siblings (n = 309). A severity score (grades 1 [mild] through 4 [life-threatening]) was assigned to each health condition using the Common Terminology Criteria for Adverse Events, Version 3. Sixty-six percent of the HCT survivors reported at least one chronic condition; 18% reported severe/life-threatening conditions; comparable values in siblings were 39% and 8%, respectively (P < .001). The cumulative incidence of a chronic health condition among HCT survivors was 59% (95% confidence interval [CI], 56%-62%) at 10 years after HCT; for severe/life-threatening conditions or death from chronic health conditions, the 10-year cumulative incidence approached 35% (95% CI, 32%-39%). HCT survivors were twice as likely as siblings to develop a chronic condition (95% CI, 1.6-2.1), and 3.5 times to develop severe/life-threatening conditions (95% CI, 2.3-5.4). HCT survivors with chronic graft-versus-host disease were 4.7 times as likely to develop severe/life-threatening conditions (95% CI, 3.0-7.2). The burden of long-term morbidity borne by HCT survivors is substantial, and long-term follow-up of patients who received transplantation is recommended.

Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS)

HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N = 145), whereas conventionally treated survivors (N = 7207) and siblings (N = 4020) were drawn from CCSS. Self-reported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported ≥ 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/life-threatening (relative risk [RR] = 8.1, P < .01) and 2 or more (RR = 5.7, P < .01) conditions, as well as functional impairment (RR = 7.7, P < .01) and activity limitation (RR = 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/life-threatening conditions: RR = 3.9, P < .01; multiple conditions: RR = 2.6, P < .01; functional impairment: RR = 3.5, P < .01; activity limitation: RR = 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population.

Pain in long-term adult survivors of childhood cancers and their siblings: A report from the Childhood Cancer Survivor Study

Summary Adult survivors of childhood cancer experience increased risk for reporting a pain condition and for using prescription analgesics compared to a sibling control group. ABSTRACT Little is known about pain among long‐term adult survivors of childhood cancers. The study investigated pain prevalence in this population compared with sibling controls and examined pain‐related risk factors. Three self‐reported pain outcomes including pain conditions, prescription analgesics used, and pain attributed to cancer and treatment were assessed among 10,397 cancer survivors and 3034 sibling controls from the Childhood Cancer Survivor Study. Pain conditions (pain/abnormal sensation, migraines, and other headaches) were reported by 12.3%, 15.5%, and 20.5% of survivors, respectively; 16.7% of survivors reported use of prescription analgesics, and 21% attributed pain to cancer and treatment. Risks of reporting pain conditions and using prescription analgesics were higher among survivors than siblings, adjusting for sociodemographic factors. Younger age at diagnosis and a history of non‐Hodgkin lymphoma, Wilms tumor, or neuroblastoma (compared to leukemia) were associated with greater risk of reporting pain conditions. A history of bone cancer or soft tissue sarcoma (compared to leukemia) was associated with greater risks of using prescription analgesics and cancer‐related pain attribution. Non‐brain‐directed scatter irradiation was associated with elevated risk for migraines and cancer‐related pain attribution. Female gender and lower educational attainment were associated with increased reports of all 3 pain outcomes; minority status, unemployment, and being single were associated with greater risks for reporting pain conditions. These findings contribute to the understanding of pain and associated risk factors among adult survivors of childhood cancer and suggest areas of focus for pain intervention.