Childhood Cancer Survivor Study Siblings Research Articles

Impact of risk-based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the Childhood Cancer Survivor Study.

Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described. Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings. Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1]). Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.

Cardiovascular Risk Factor Disparities in Adult Survivors of Childhood Cancer Compared With the General Population.

It is unknown whether a history of childhood cancer modifies the established disparities in cardiovascular risk factors (CVRFs) observed in the general population. We sought to determine if disparities in CVRFs by race/ethnicity are similar among childhood cancer survivors compared with the general population. The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort with a longitudinal follow-up of 24,084 5-year survivors diagnosed between 1970 and 1999. Multivariable piecewise exponential regression estimated incidence rate ratios (IRRs) for hypertension, hyperlipidemia, diabetes, obesity, and≥2 CVRFs by race/ethnicity. The CCSS sibling cohort and the National Health and Nutrition Examination Survey cohort were used to compare the sociodemographic-adjusted IRRs for same-race/same-ethnicity disparities. Non-Hispanic Black (NHB) (n=1,092) and Hispanic (n=1,405) survivors compared with non-Hispanic White (NHW) (n=13,960) survivors reported a higher cumulative incidence of diabetes (8.4%, 9.7%, and 5.1%, respectively); obesity (47.2%, 48.9%, and 30.2%, respectively); multiple CVRFs (17.7%, 16.6%, and 12.3%, respectively); and, for NHB survivors, hypertension (19.5%, 13.6%, and 14.3%, respectively) by 40 years of age (P< 0.001). Controlling for sociodemographic and treatment factors compared with NHW survivors, IRRs for NHB were increased for hypertension (IRR: 1.4; 95% CI: 1.1-1.8), obesity (IRR: 1.7; 95% CI: 1.4-2.1), and multiple CVRFs (IRR: 1.6; 95% CI: 1.2-2.1). IRRs for Hispanic survivors were increased for diabetes (IRR: 1.8; 95% CI: 1.2-2.6) and obesity (IRR: 1.4; 95% CI: 1.2-1.7). The pattern of IRRs for CVRF differences was similar among CCSS sibling and National Health and Nutrition Examination Survey cohorts. The higher burden of CVRFs among NHB and Hispanic survivors compared with NHW survivors was similar to the general population. The promotion of cardiovascular health equity is critical in this high-risk population.

Accelerated cognitive decline in adult survivors of pediatric central nervous system (CNS) tumors: A report from the Childhood Cancer Survivor Study (CCSS).

10049 Background: Survivors of pediatric CNS tumors may be at elevated risk for accelerated cognitive decline as they age through adulthood relative to the general population, which may be an early risk factor for dementia. Methods: Longitudinal analysis of 512 CNS tumor survivors (52.3% female, mean [SD] 30.6 [7.1] years at T1) and 232 siblings (57.8% female, mean [SD] 34.2 [8.4] years at T1) from the CCSS was conducted using the Neurocognitive Questionnaire (NCQ) to assess task efficiency, emotional regulation, organization and memory at two timepoints separated by a mean of 11.6 [0.7] years. Impairment in each NCQ domain was defined as a score ≥ 90th percentile of the CCSS sibling distribution at each survey, with decline defined as moving from unimpaired at T1 to impaired at T2. Treatment exposures were abstracted from medical records. Chronic health conditions were self-reported at T1 and graded according to CTCAE v4.3. Relative risk of decline for group, treatment and chronic condition predictors was estimated using generalized linear models with robust variance estimates. Mediation analysis examined direct effects of treatments and mediating effects of chronic conditions. All models were adjusted for age, sex, and race. Results: At T1, survivors demonstrated higher frequency of impaired memory (24.5% vs. 6.5%, p &lt; 0.001), emotional regulation (14.3 % vs. 5.6%, p &lt; 0.001), task efficiency (43.3% vs. 13.8%, p &lt; 0.001) and organization (17.7% vs. 10.8%, p = 0.015) than siblings. Among those unimpaired at T1, more survivors vs. siblings declined in memory (34.7% vs. 7.8; RR 4.2, 95% CI 2.6-6.9), emotional regulation (15.5% vs. 5.0%; RR 2.8, 95% CI 1.5-5.3), task efficiency (22.7% vs. 7.0%; RR 2.9, 95% CI 1.7-5.2), and organization (14.5% vs. 2.9%; RR 4.9, 95% CI 2.1-11.0) by T2. Decline in survivor memory was associated with exposure to craniospinal irradiation (RR 1.9, 95% CI 1.3-2.8) and focal irradiation (RR 1.6, 95% CI 1.1-2.3) compared with no radiation, and exposure to Ara-C (RR 1.7, 95% CI 1.0-2.8) and cyclophosphamide (RR 1.7, 95% CI 1.01-2.8). Independent of therapy, serious/disabling or life-threatening cardiopulmonary conditions at T1 predicted future decline in memory (RR 1.5, 95% CI 1.02-2.2) and organization (RR 2.0, 95% CI 1.1-3.6), with the presence of 2 or more cardiopulmonary conditions associated with even higher risk (memory RR 2.6, 95% CI 2.0-3.1; organization RR 3.4, 95% CI 1.1-10.5). Chronic conditions did not mediate associations between treatment exposures and cognitive decline. Conclusions: CNS tumor survivors are at elevated risk for impairment and accelerated cognitive decline compared to siblings. Cranial radiation, Ara-C, cyclophosphamide, and cardiopulmonary morbidity are risk factors for decline. Survivors with these exposures/conditions may benefit from interventions to prevent additional future cognitive decline.

Long term morbidity and mortality among survivors of infant neuroblastoma: A report from the Childhood Cancer Survivor Study (CCSS).

10051 Background: Infants with neuroblastoma typically have low-risk disease with excellent survival. Therapy has been de-intensified over time to minimize late effects, however the impact on survivors’ risk of late mortality, subsequent malignant neoplasms (SMN), and chronic health conditions (CHC) is unclear. Methods: We evaluated late mortality, SMNs and CHCs (graded according to CTCAE v4.03), overall and by diagnosis era, among 990 5-year neuroblastoma survivors diagnosed at &lt; 1 year of age between 1970-1999. Cumulative mortality, standardized mortality ratios (SMR), and standardized incidence ratios (SIR) of SMNs were estimated using the National Death Index and SEER rates, respectively. Cox proportional hazards estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC, compared to 5,051 CCSS siblings. Results: Among survivors (48% female; median attained age: 24 years, range 6-46), there was increased treatment with surgery alone across the 1970s, 1980s and 1990s (21.5%, 35.3%, 41.1%, respectively), but decreased treatment with combination surgery + radiation (22.5%, 5.3%, 0.3%, respectively) and surgery + radiation + chemotherapy (28.7%, 14.7%, 9.3%, respectively). The 20-year cumulative mortality was 2.3% (95% CI, 1.4-3.8), primarily due to SMNs (SMRSMN= 10.0, 95% CI, 4.5-22.3). The 20-year cumulative incidence of SMN was 1.2% (95% CI, 0.3-3.2), 2.5% (95% CI, 1.3-4.4), and zero for those diagnosed in the 1970s, 1980s, and 1990s, respectively. SIR was highest for renal SMNs (SIR 12.5, 95% CI, 1.7-89.4). Compared to siblings, survivors were at increased risk for grade 1-5 CHC (HR 2.1, 95% CI, 1.9-2.3) with similar HR across eras (HR1970s= 1.9, 95% CI, 1.6-2.2; HR1980s= 2.2, 95% CI, 1.9-2.6; HR1990s= 2.0, 95% CI, 1.7-2.4). The HR of severe, disabling, life-threatening and fatal CHC (grades 3-5) decreased in more recent eras (HR1970s= 4.7, 95% CI, 3.4-6.6; HR1980s= 4.4, 95% CI, 3.2-6.2; HR1990s= 2.9, 95% CI, 2.0-4.3). Conclusions: Survivors of infant neuroblastoma remain at increased risk for late mortality, SMN, and CHCs many years after diagnosis. However, the risk of grade 3-5 CHCs has declined in more recent eras, likely reflecting de-intensification of therapy.

Behavioral, Social, and Emotional Symptom Comorbidities and Profiles in Adolescent Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

In the general population, psychological symptoms frequently co-occur; however, profiles of symptom comorbidities have not been examined among adolescent survivors of childhood cancer. Parents of 3,893 5-year survivors of childhood cancer who were treated between 1970 and 1999 and who were assessed in adolescence (age 12 to 17 years) completed the Behavior Problems Index. Age- and sex-standardized z scores were calculated for symptom domains by using the Childhood Cancer Survivor Study sibling cohort. Latent profile analysis identified profiles of comorbid symptoms, and multivariable multinomial logistic regression modeling examined associations between cancer treatment exposures and physical late effects and identified symptom profiles. Odds ratios (ORs) and 95% CIs for latent class membership were estimated and analyses were stratified by cranial radiation therapy (CRT; CRT or no CRT). Four symptoms profiles were identified: no significant symptoms (CRT, 63%; no CRT, 70%); elevated anxiety and/or depression, social withdrawal, and attention problems (internalizing; CRT, 31%; no CRT, 16%); elevated headstrong behavior and attention problems (externalizing; CRT, no observed; no CRT, 9%); and elevated internalizing and externalizing symptoms (global symptoms; CRT, 6%; no CRT, 5%). Treatment with ≥ 30 Gy CRT conferred greater risk of internalizing (OR, 1.7; 95% CI, 1.0 to 2.8) and global symptoms (OR, 3.2; 95% CI, 1.2 to 8.4). Among the no CRT group, corticosteroid treatment was associated with externalizing symptoms (OR, 1.9; 95% CI, 1.2 to 2.8) and ≥ 4.3 g/m(2) intravenous methotrexate exposure was associated with global symptoms (OR, 1.5; 95% CI, 0.9 to 2.4). Treatment late effects, including obesity, cancer-related pain, and sensory impairments, were significantly associated with increased risk of comorbid symptoms. Behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors of childhood cancer and are associated with treatment exposures and physical late effects. Assessment and consideration of symptom profiles are essential for directing appropriate mental health treatment for adolescent survivors.

Chronic medical conditions in adult survivors of retinoblastoma: Results of the Retinoblastoma Survivor Study.

Limited data are available regarding long-term morbidity in adult survivors of retinoblastoma (Rb). The Retinoblastoma Survivor Study is a retrospective cohort of adult survivors of Rb diagnosed between 1932 and 1994. Participants completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study surveys. Chronic conditions were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03). Multivariate Poisson regression was used to compare survivors of Rb with 2377 non-Rb controls, consisting of the Childhood Cancer Survivor Study sibling cohort and survivors with bilateral versus unilateral disease. Survivors of Rb (53.6% with bilateral disease) and non-Rb controls had a mean age of 43.3 years (standard deviation, 11 years) and 37.6 years (SD, 8.6 years), respectively, at the time of study enrollment. At a median follow-up of 42 years (range, 15-75 years), 86.6% of survivors of Rb had at least 1 condition and 71.1% had a severe/life-threatening (grade 3-4) condition. The adjusted relative risk (RR) of a chronic condition in survivors compared with non-Rb controls was 1.4 (95% confidence interval [95% CI], 1.3-1.4; P<.01); for a grade 3 to 4 condition, the RR was 7.6 (95% CI, 6.4-8.9; P<.01). Survivors were at an excess risk regardless of laterality. After stratifying by laterality and excluding ocular conditions and second malignant neoplasms (SMNs), only those with bilateral disease were found to be at an increased risk of any nonocular, non-SMN condition (RR, 1.2; 95% CI, 1.1-1.2) and for grade 3 to 4 nonocular, non-SMN conditions (RR, 1.7; 95% CI, 1.2-2.5). Survivors of Rb have an increased risk of chronic conditions compared with non-Rb controls. After excluding ocular conditions and SMNs, this excess risk was found to persist only for those with bilateral disease. Cancer 2016;122:773-781. © 2016 American Cancer Society.

Psychosocial Outcomes in Adult Survivors of Retinoblastoma.

Survival rates for individuals diagnosed with retinoblastoma (RB) exceed 95% in the United States; however, little is known about the long-term psychosocial outcomes of these survivors. Adult RB survivors, diagnosed from 1932 to 1994 and treated in New York, completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study (CCSS), by mail or telephone. Psychosocial outcomes included psychological distress, anxiety, depression, somatization, fear of cancer recurrence, satisfaction with facial appearance, post-traumatic growth, and post-traumatic stress symptoms; noncancer CCSS siblings served as a comparison group. A total of 470 RB survivors (53.6% with bilateral RB; 52.1% female) and 2,820 CCSS siblings were 43.3 (standard deviation [SD], 11) years and 33.2 (SD, 8.4) years old at the time of study, respectively. After adjusting for sociodemographic factors, RB survivors did not have significantly higher rates of depression, somatization, distress, or anxiety compared with CCSS siblings. Although RB survivors were more likely to report post-traumatic stress symptoms of avoidance and/or hyperarousal (both P < .01), only five (1.1%) of 470 met criteria for post-traumatic stress disorder. Among survivors, having a chronic medical condition did not increase the likelihood of psychological problems. Bilateral RB survivors were more likely than unilateral RB survivors to experience fears of cancer recurrence (P < .01) and worry about their children being diagnosed with RB (P < .01). However, bilateral RB survivors were no more likely to report depression, anxiety, or somatic complaints than unilateral survivors. Most RB survivors do not have poorer psychosocial functioning compared with a noncancer sample. In addition, bilateral and unilateral RB survivors seem similar with respect to their psychological symptoms.

Chronic medical conditions in adult survivors of retinoblastoma.

10019 Background: Increased risk of second malignant neoplasms (SMN) in retinoblastoma survivors (RBS) is well documented, but little is known about their long-term burden of chronic non-visual morbidity. Methods: RBS treated in NYC were asked to complete a comprehensive questionnaire, adapted from the Childhood Cancer Survivor Study (CCSS) surveys; frequencies of chronic conditions, excluding SMN, in 470 RBS and 2,377 CCSS siblings were calculated. A severity score, based on the NCI CTCAE v4 (ranging from grade 1 [mild] to grade 4 [disabling/life-threatening]) was assigned to each condition. Logistic regression was used to estimateodds ratios of chronic condition risk in RBS vs CCSS siblings, adjusted for age, sex, and race/ethnicity, reported as relative risks (RR) and 95% confidence intervals (CIs). Results: RBS and CCSS siblings were mean ages of 43 years (SD 11) and 38 years (SD 9), respectively, at the time of questionnaire completion. 53.6% of RBS had bilateral disease. After excluding SMN, 70.2% of RBS had at least one non-visual chronic condition while 14% had a grade 3-4 condition. The adjusted RR of a non-visual chronic condition in a survivor compared to siblings was 1.5 (95% CI, 1.2-1.8); for a grade 3-4 condition, the risk was 1.5 (95% CI, 1.1-2.1). The most common grade 3-4 non-visual conditions in RBS were hearing loss (3.6%; bilateral 5.6%, unilateral 1.3%, p=0.023) and thyroid nodules requiring partial or full thyroidectomy (3.4%; bilateral 5.6%, unilateral 0.9%, p=0.008). Rates of grade 3-4 thyroid nodules and hearing loss did not differ significantly when stratified by treatment received. Rates of all conditions in RBS are reported in the Table. Conclusions: RBS have a modestly increased risk of non-visual chronic conditions when compared to individuals of comparable age, sex and race/ethnicity. [Table: see text]

Estimated long-term outcomes in children newly diagnosed with standard risk acute lymphoblastic leukemia (ALL) based on similarly treated members of the childhood cancer survivor study (CCSS) cohort.

10032 Background: Therapy for ALL has evolved such that the risk for late effects in children treated in early eras is likely different from those that will occur in children treated today. In order to estimate future risks for late effects in newly diagnosed children with standard risk ALL, we examined the long-term outcomes in a cohort of patients enrolled in the CCSS who were treated in a manner analogous to contemporary ALL therapies. Methods: We assessed outcomes that occurred ≥5 years from diagnosis in survivors of ALL enrolled in the CCSS who were aged 1-9.9 years at diagnosis, treated with 0-120 mg/m2 of anthracyclines and 0-1000 mg/m2 of alkylating agents, and no radiotherapy. We compared their risks for death, second malignant neoplasms (SMN), chronic physical health conditions and decreased health status with the general population (death and SMN) and the CCSS sibling cohort (remaining outcomes). Results: 556 survivors were eligible. At last assessment, they were a median of 27.8 years old (range 9.1 to 45.7) and 23.4 years (range 5.0-38.0) from diagnosis. 29/556 (5.2%) died (standardized mortality ratio 3.6, 95% CI 2.4-5.2); 12 of these deaths were due to ALL recurrence. Compared to siblings, the rate ratio for ≥1 chronic condition was 1.4 (95% CI 1.3-1.6), and for a severe/life threatening chronic condition was 1.7 (95% CI 1.3-2.3). Four survivors (0.7%) developed a SMN (standardized incidence ratio 1.7, 95% CI 0.5-4.5), 114 were obese (odds ratio (OR) 1.2, 95% CI 1.0-1.5), and 2 (0.4%) reported a stroke. No survivors reported symptomatic congestive heart failure. The OR for reporting adverse general health was 1.2 (95% CI 0.8-1.8), poor mental health 1.3 (95% CI 1.0-1.8), decreased functional status 2.1 (95% CI 1.4-3.0), and activity limitations 1.4 (95% CI 1.1-1.8). Conclusions: Children treated for standard risk ALL on contemporary protocols are at increased risk for future chronic health conditions and decreased health status. Despite excellent survival after leukemia therapy, such survivors will likely benefit from life-long medical care focused on the long-term risks stemming from their therapy.

Physical activity among adult survivors of childhood lower-extremity sarcoma

Adult survivors of childhood lower-extremity sarcoma are largely physically inactive, a behavior which potentially compounds their health burden. Altering this behavior requires understanding those factors that contribute to their physical inactivity. Therefore, this investigation sought to identify factors associated with inactivity in this subpopulation of cancer survivors. Demographic, personal, treatment, and physical activity information from adult survivors of childhood lower-extremity sarcomas was obtained from the Childhood Cancer Survivor Study (CCSS) cohort. Generalized linear models were used to identify variables that best identified those individuals who were physically inactive. Only 41% of survivors met Center for Disease Control (CDC) activity guidelines. Survivors were 1.20 (95% confidence intervals (CI) 1.11-1.30) more likely compared to CCSS sibling cohort and 1.12 (95% CI 1.10-1.15) times more likely than the general population to fail to meet CDC guidelines. Significant predictors of physical inactivity included female sex, hemipelvectomy surgery, and platinum and vinca alkaloid chemotherapy. The primary findings of this study are that survivors of childhood onset lower-extremity sarcoma are (1) highly likely to be physically inactive and (2) less likely than their siblings or the general population to regularly exercise. This study has identified treatment-related risk factors associated with inactivity that will help health and wellness practitioners develop successful exercise interventions to help these survivors achieve recommended levels of physical activity for health. These results suggest that physical activity interventions for adult survivors of childhood lower-extremity sarcomas should be sex specific and responsive to unique physical late effects experienced by these survivors.

Unemployment Among Adult Survivors of Childhood Cancer

Adult childhood cancer survivors report high levels of unemployment, although it is unknown whether this is because of health or employability limitations. We examined 2 employment outcomes from 2003 in the Childhood Cancer Survivor Study (CCSS): (1) health-related unemployment and (2) unemployed but seeking work. We compared survivors with a nearest-age CCSS sibling cohort and examined demographic and treatment-related risk groups for each outcome. We studied 6339 survivors and 1967 siblings ≥25 years of age excluding those unemployed by choice. Multivariable generalized linear models evaluated whether survivors were more likely to be unemployed than siblings and whether certain survivors were at a higher risk for unemployment. Survivors (10.4%) reported health-related unemployment more often than siblings (1.8%; Relative Risk [RR], 6.07; 95% Confidence Interval [CI], 4.32-8.53). Survivors (5.7%) were more likely to report being unemployed but seeking work than siblings (2.7%; RR, 1.90; 95% CI, 1.43-2.54). Health-related unemployment was more common in female survivors than males (Odds Ratio [OR], 1.73; 95% CI, 1.43-2.08). Cranial radiotherapy doses ≥25 Gy were associated with higher odds of unemployment (health-related: OR, 3.47; 95% CI, 2.54-4.74; seeking work: OR, 1.77; 95% CI, 1.15-2.71). Unemployed survivors reported higher levels of poor physical functioning than employed survivors, and had lower education and income and were more likely to be publicly insured than unemployed siblings. Childhood cancer survivors have higher levels of unemployment because of health or being between jobs. High-risk survivors may need vocational assistance.

Twenty years of follow-up of survivors of childhood osteosarcoma: a report from the Childhood Cancer Survivor Study.

Osteosarcoma survivors have received significant chemotherapy and have undergone substantial surgeries. Their very long-term outcomes (20 year) are reported here. The authors assessed the long-term outcomes of 733 5-year survivors of childhood osteosarcoma diagnosed from 1970 to 1986 to provide a comprehensive evaluation of medical and psychosocial outcomes for survivors enrolled in the Childhood Cancer Survivor Study (CCSS). Outcomes evaluated included overall survival, second malignant neoplasms (SMNs), recurrent osteosarcoma, chronic health conditions, health status (general and mental health and functional limitations), and psychosocial factors. Outcomes of osteosarcoma survivors were compared with general-population statistics, other CCSS survivors, and CCSS siblings. Survivors had a mean follow-up of 21.6 years. The overall survival of children diagnosed with osteosarcoma who survived 5 years at 20 years from original diagnosis was 88.6% (95% confidence interval [CI], 86.6%-90.5%). The cumulative incidence of SMNs at 25 years was 5.4%, with a standardized incidence ratio of 4.79 (95% CI, 3.54-6.33; P<.01). Overall, 86.9% of osteosarcoma survivors experienced at least 1 chronic medical condition, and >50% experienced ≥2 conditions. Compared with survivors of other cancers, osteosarcoma survivors did not differ in their reported general health status (odds ratio [OR], 0.9; 95% CI, 0.7-1.2), but were more likely to report an adverse health status in at least 1 domain (OR, 1.9; 95% CI, 1.6-2.2), with activity limitations (29.1%) being the most common. Childhood osteosarcoma survivors in this cohort did relatively well, considering their extensive treatment, but are at risk of experiencing chronic medical conditions and adverse health status. Survivors warrant life-long follow-up.

Effect of hypothalamic/pituitary radiation exposure in low doses on fertility in female childhood cancer survivor study (CCSS) participants.

9542 Background: Female childhood cancer survivors (CCS) are less likely to report having been pregnant when compared with females within the CCSS sibling cohort (Sibs) as the result of direct damage to the ovaries produced by radiation therapy (XRT) and/or chemotherapy. High-dose hypothalamic/pituitary (HPT) XRT, which causes central or secondary hypogonadism, may result in infertility due to failure to stimulate ovulation. Recently, another possible central mechanism has been postulated, luteal phase deficiency, resulting from low-dose HPT XRT. Methods: We evaluated the occurrence of pregnancy in 3,666 female CCS who participated in the CCSS and 2,082 Sibs. The association between low- dose HPT XRT and fertility was studied by restricting analyses to those female CCS who received no/scatter (≤10 cGy) radiation to the ovaries and comparing their fertility rates with those of Sibs using Cox-proportional hazards models. Specific treatment effects were studied by further limiting analyses to only CCS. Results: These CCS who received no/scatter (≤ 10 cGy) ovarian radiation were more likely to report being pregnant (hazard ratio [HR]:1.5, 95% confidence interval [95%CI]: 1.3, 1.7) when adjusted for race/ethnicity, smoking, marital status, and education than Sibs. Multivariable models showed a significant decrease in the risk of reporting pregnancy with HPT XRT doses of ≥ 2,200 cGy when compared with those CCS receiving no HPT XRT when adjusted for race/ethnicity, smoking, marital status, education, age at diagnosis, and treatment with VP16 (Table) (137 had missing HPT radiation doses). Conclusions: The results of this study support the hypothesis that low-dose HPT XRT may be a contributing factor to infertility among female CCS. HPT radiation dose (cGy) Number of CCSS participants HR ever pregnant 95% CI ever pregnant 0 1,996 1.0 > 0 to < 1500 371 0.8 0.7-1.1 ≥ 1500 to < 2200 599 0.9 0.7-1.1 ≥ 2200 to < 2700 316 0.6 0.5-0.8 ≥ 2700 247 0.7 0.5-0.9 No significant financial relationships to disclose.

Breast Cancer Surveillance Practices Among Women Previously Treated With Chest Radiation for a Childhood Cancer

Limited data are available on the breast cancer surveillance practices of adult women who were treated with chest radiation for pediatric malignancies. This study investigated breast cancer surveillance practices among a random sample of 625 women treated with chest radiation for a childhood cancer who were participants in the Childhood Cancer Survivor Study (CCSS), a North American cohort of long-term survivors diagnosed from 1970 to 1986. Comparison groups included female pediatric cancer survivors not treated with chest radiation and female CCSS siblings. A 114-item survey was administered by mail and telephone interview to the participants. The response rate was 87.9%. Among the cancer survivors who had chest radiation, only 36.5% (108/296) (95% confidence interval [CI], 31.0%–42.0%) of women aged 25 through 39 years reported a screening mammogram in the past 2 years, whereas 76.5% (195/255) (95% CI, 71.3%–81.7%) of those aged 40 through 50 years reported mammography during this same time period. Among the comparison groups, 40.5% (227/561) of survivors without chest radiation and 37.0% (230/622) of CCSS siblings reported a screening mammogram in the past 2 years. Of women with a history of chest radiation, 47.3% (95% CI, 41.6%–53.0%) of those aged 25 through 39 years had never had a mammogram and only 52.6% (95% CI, 46.4%–58.8%) of women older than 40 years had received 2 or more mammograms within 4 years. Among all groups, older women were more likely to have been screened in the prior 2 years or to have received regular screening. A physician recommendation for testing was the strongest predictor of mammography in women aged 25 through 39 years. Multivariate analysis showed that the likelihood of reporting a mammogram was especially strong among younger women who reported a physician recommendation for testing compared to those who did not (ages 25–39 years: prevalence ratio [PR], 3.0; 95% CI, 2.0–4.0; ages 40–50 years: PR, 1.3; 95% CI, 1.1–1.6). These findings suggest that most young women at risk of breast cancer following chest radiation for childhood cancer are not being appropriately screened.

Breast Cancer Surveillance Practices Among Women Previously Treated With Chest Radiation for a Childhood Cancer

Women treated with chest radiation for a pediatric malignancy have a significantly increased risk of breast cancer at a young age and are recommended to have an annual screening mammogram starting at age 25 years or 8 years after radiation, whichever occurs last. To characterize the breast cancer surveillance practices among female pediatric cancer survivors who were treated with chest radiation and identify correlates of screening. Between June 2005 and August 2006, a 114-item questionnaire was administered to a random sample of 625 women aged 25 through 50 years who had survived pediatric cancer, who had been treated with chest radiation, and who were participating in the Childhood Cancer Survivor Study (CCSS), a North American cohort of long-term survivors diagnosed from 1970-1986. Comparisons were made with similarly aged pediatric cancer survivors not treated with chest radiation (n = 639) and the CCSS siblings cohort (n = 712). Screening mammogram within the previous 2 years. Of 1976 cancer survivors and siblings who were contacted, 87.9% participated. Among the 551 women with a history of chest radiation, 55% reported a screening mammogram in the past 2 years (ages 25-39 years, 36.5%; 95% confidence interval [CI], 31.0%-42.0%; ages 40-50 years, 76.5%; 95% CI, 71.3%-81.7%). In comparison, 40.5% of survivors without chest radiation and 37.0% of CCSS siblings reported a screening mammogram in the same time interval. Notably, among women with a history of chest radiation, 47.3% (95% CI; 41.6%-53.0%) of those younger than 40 years had never had a mammogram and only 52.6% (95% CI; 46.4%-58.8%) of women aged 40 through 50 years were being regularly screened (2 mammograms within 4 years). Screening rates were higher among women who reported a physician recommendation than those who did not (ages 25-39 years, 76.0% vs 17.6%; ages 40-50 years, 87.3% vs 58.3%). In multivariate models, the association was particularly strong for younger women (ages 25-39 years, prevalence ratio [PR], 3.0; 95% CI, 2.0-4.0; ages 40-50 years, PR, 1.3; 95% CI, 1.1-1.6). In this cohort of women who had childhood cancer treated with chest radiation, 63.5% of those aged 25 through 39 years and 23.5% of those aged 40 through 50 years had not had mammography screening for breast cancer within the previous 2 years despite a guideline recommendation that survivors of childhood cancer who were treated with chest radiation should undergo annual screening mammography.

Surveillance for Breast Cancer After Childhood Cancer

BREAST CANCER IS A RECOGNIZED COMPLICATION OF chest irradiation for childhood cancer, and surveillance for breast cancer with regular clinical examination and annual screening mammography starting at age 25 years or 8 years after radiation is recommended. However, uptake of screening mammograms in this high-risk group is suboptimal, as shown in the report by Oeffinger and colleagues in this issue of JAMA. The authors examined breast cancer surveillance practices in a survey of 625 female survivors of pediatric cancer who were between 25 and 50 years and participants in the longitudinal Childhood Cancer Survivor Study (CCSS). These survivors were at a significantly increased risk of breast cancer as a result of treatment they received in the form of moderateto high-dose ( 20 Gy) irradiation to the chest for treatment of a childhood cancer (chest RT group). The women in the chest RT group were compared with 639 similarly aged CCSS participants who did not receive chest irradiation and with 712 siblings in the CCSS siblings cohort. Oeffinger et al found that 55% of the women in the chest RT group reported having a screening mammogram within the previous 2 years. Rates of screening mammography varied by age at the time of the survey, with 23.3% of women aged 25 through 39 years and 53.6% of women aged 40 through 50 years reporting a screening mammogram in the previous year. Among women in the younger group, those who reported a physician recommendation for screening were 3 times as likely to have had screening in the previous 2 years when compared with those whose physician did not recommend that they have a mammogram. In light of a recognized increased risk of breast cancer following radiation to the chest, chest irradiation is now used less frequently for the curative treatment of some pediatric cancers, which include different types of childhood cancer including Hodgkin disease, Wilms tumor, neuroblastoma, and non-Hodgkin lymphoma; however, there are an estimated 20 000 to 25 000 adult survivors of pediatric cancer older than 25 years in the United States who are in this risk category. Current Childhood Oncology Group (COG) guidelines for breast cancer surveillance after pediatric cancer in the United States recommend yearly clinical breast examination from the age of puberty until age 25 years, and then every 6 months if the survivor was treated with irradiation of at least20 Gy to mantle, minimantle, mediastinal, chest (thoracic), or axillary fields. In addition, it is recommended that these survivors have annual mammography and an adjunct breast magnetic resonance imaging (MRI) starting at age 25 years or 8 years after radiation, whichever is last. The effectiveness of the standard mammogram in detecting preinvasive and invasive breast cancer is known to be relatively poor in young women due to the density of breast tissue in this age group, increasing the importance of MRI in the detection and diagnosis of breast cancer in younger women with dense breast tissue. The estimated dose of radiation from a standard 2-view screening mammogram is approximately 3.85 mGy per mammogram. Although it is accepted that the additional dose is small compared with the higher therapeutic dose already received, it is not known to what extent repeated exposure to small doses of breast irradiation in women already at an increased risk of breast cancer may result in a significantly increased risk of second primary breast cancer. This is an important question that needs to be addressed in future studies. The generally low uptake rate of screening mammogram in a high-risk population of pediatric cancer survivors has also been highlighted in a previous study of adult survivors. Some factors associated with the uptake of breast screening including age and race/ethnicity, physician recommendation, health beliefs, and personal understanding of breast cancer risk were explored by Oeffinger et al, but economic factors were not. Thus, whether the cost of annual breast cancer screening was a factor in this cohort is not known. In comparison, among a population of 461 Australian women at an increased risk of developing hereditary breast cancer, uptake of breast screening was 89% overall, although it decreased to 77% among those

Longitudinal Changes in Obesity and Body Mass Index Among Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study

We examined the rate of increase in the body mass index (BMI; kg/m(2)) after final height attainment in survivors of acute lymphoblastic leukemia (ALL) and a noncancer comparison group. Childhood Cancer Survivor Study (CCSS) is a retrospectively ascertained cohort study that prospectively tracks the health status of adults who were diagnosed with childhood cancer between 1970 and 1986 and a comparison group of siblings. Changes in BMI from baseline enrollment to time of completion of follow-up (mean interval, 7.8 years) were calculated for 1,451 ALL survivors (mean age, 32.3 years at follow-up) and 2,167 siblings of childhood cancer survivors (mean age, 35.9 years). The mean BMI of the CCSS sibling comparison group increased with age (women, 0.25 units/yr, 95% CI, 0.22 to 0.28 units; men, 0.23 units/yr, 95% CI, 0.20 to 0.25 units). Compared with CCSS siblings, ALL survivors who were treated with cranial radiation therapy (CRT) had a significantly greater increase in BMI (women, 0.41 units/yr, 95% CI, 0.37 to 0.45 units; men, 0.29 units/yr; 95% CI, 0.26 to 0.32 units). The rate of BMI increase was not significantly increased for ALL survivors who were treated with chemotherapy alone. Younger age at CRT exposure significantly modified risk. CRT used in the treatment of childhood ALL is associated with a greater rate of increasing BMI, particularly among women treated with CRT during the first decade of life. Health care professionals should be aware of this risk and interventions to reduce or manage weight gain are essential in this high-risk population.