Nonsurgical premature menopause and reproductive implications in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Survivors of childhood cancer are at risk of nonsurgical premature menopause (NSPM). To the authors' knowledge, risk factors for NSPM and its impact on reproduction remain poorly defined. METHODS: The menopausal status of 2930 survivors diagnosed between 1970 and 1986 (median age, 6 years [range, birth-20 years]) who were aged > 18 years at the time of the current study (median age, 35 years [range, 18-58 years]) was compared with 1399 siblings. NSPM was defined as the cessation of menses ≥6 months in duration occurring 5 years after diagnosis and before age 40 that was not due to pregnancy, surgery, or medications. Among survivors, multivariable logistic regression identified risk factors for NSPM. Pregnancy and live birth rates were compared between survivors with and without NSPM. RESULTS: A total of 110 survivors developed NSPM (median age, 32 years [range, 16-40 years]), with a prevalence at age 40 years of 9.1% (95% confidence interval [95% CI], 4.9%-17.2%); the odds ratio (OR) was 10.5 (95% CI, 4.2-26.3) compared with siblings. Independent risk factors included exposure to a procarbazine dose ≥4000 mg/m2 (OR, 8.96 [95% CI, 5.02-16.00]), any dose of ovarian radiation (OvRT) (OvRT < 500 cGy: OR, 2.73 [95% CI, 1.33-5.61] and OvRT ≥ 500 cGy: OR, 8.02 [95% CI, 2.81-22.85]; referent RT, 0), and receipt of a stem cell transplantation (OR, 6.35; 95% CI, 1.19-33.93). Compared with survivors without NSPM, those who developed NSPM were less likely to ever be pregnant (rate ratio, 0.49; 95% CI, 0.27-0.80) or to have a live birth (rate ratio, 0.42; 95% CI, 0.19-0.79) between ages 31 and 40 years. CONCLUSIONS: Survivors of childhood cancer are at risk of NSPM associated with lower rates of live birth in their 30s. Those at risk should consider fertility preservation if they anticipate delaying childbearing. Cancer 2018;124:1044-52. © 2018 American Cancer Society.

Factors associated with physical activity among adolescent and young adult survivors of early childhood cancer: A report from the childhood cancer survivor study (CCSS).

OBJECTIVE: To evaluate concurrent and longitudinal associations between psychosocial functioning and physical activity in adolescent and young adult survivors of early childhood cancer. METHODS: Adolescent survivors of early childhood cancer (diagnosed before age four) participating in the Childhood Cancer Survivor Study completed the Coping Health and Illness Profile-Adolescent Edition (CHIP-AE; n = 303; mean age at survey: 17.6 years). A subset of these survivors (n = 248) completed a follow-up survey an average of 6.0 years later (range: 4-10). Logistic regression identified associations between psychosocial functioning in adolescence and physical activity levels in adolescence and young adulthood. RESULTS: Survivors reported low physical activity as adolescents (46.1% scored below CHIP-AE cut-point) and young adults (40.8% below Centers for Disease Control guidelines). Poor physical activity during adolescence was associated with female sex (OR = 2.06, 95% CI, 1.18-3.68), parents with less than a college education (OR = 1.91, 95% CI, 1.11-3.32), previous treatment with cranial radiation (OR = 3.35, 95% CI, 1.69-6.88), TV time (OR = 1.77, 95% CI, 1.00-3.14), and limitations of activity due to health or mobility restrictions (OR = 8.28, 95% CI, 2.87-30.34). Poor diet (OR = 1.84, 95% CI, 1.05-3.26) and low self-esteem (OR = 1.80, 95% CI, 0.99-3.31) during adolescence were associated with lower odds of meeting Centers for Disease Control physical activity guidelines in young adulthood. CONCLUSION: These findings provide targets for future interventional studies to improve physical activity in this high-risk population.

Erectile Dysfunction in Male Survivors of Childhood Cancer-A Report From the Childhood Cancer Survivor Study.

INTRODUCTION: With survival rates higher than 80%, the number of survivors from pediatric cancer continues to increase. Late effects resulting from cancer and cancer therapy are being characterized, but little information exists on sexual health for men who have survived childhood cancer. AIM: To assess erectile dysfunction (ED) in men who survived childhood and adolescent cancers and to identify potential risk factors for ED. METHODS: In total, 1,622 men and 271 eligible brothers in the Childhood Cancer Survivor Study cohort completed the Male Health Questionnaire, which provided information on sexual practices and sexual function. Combined with demographic, cancer, and treatment information from medical record abstraction, results of the Male Health Questionnaire were analyzed using multivariable modeling. The International Index of Erectile Function was used to identify ED in subjects. MAIN OUTCOME MEASURE: International Index of Erectile Function. RESULTS: Survivors (mean age = 37.4 years, SD = 7.3 years) reported significantly lower sexual activity in the year before the survey than the brothers (mean age = 38.8 years, SD = 8.5 years) without cancer. ED was reported by 12.3% (95% CI = 10.4-14.3) of survivors and 4.2% (95% CI = 2.0-7.9) of brothers. Survivors showed significantly higher relative risk (RR) for ED (RR = 2.63, 95% CI = 1.40-4.97). In addition to older age, survivors who were exposed to higher-dose (≥10 Gy) testicular radiation (RR = 3.55, 95% CI = 1.53-8.24), had surgery on the spinal cord or nerves (RR = 2.87, 95% CI = 1.36-6.05), prostate surgery (RR = 6.56, 95% CI = 3.84-11.20), or pelvic surgery (RR = 2.28, 95% CI = 1.04-4.98) were at higher risk for ED. CONCLUSION: Men who have survived childhood cancer have a greater than 2.6-fold increased risk for ED and certain cancer-specific treatments are associated with increased risk. Attention to sexual health, with its physical and emotional implications, and opportunities for early detection and intervention in these individuals could be important.

The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses. METHODS: We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS) outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike's Information Criterion (AIC). RESULTS: The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure. CONCLUSION: The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.

Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study.

BACKGROUND: The reproductive implications of mutagenic treatments given to children with cancer are not clear. By studying the risk of untoward pregnancy outcomes, we indirectly assessed the risk of transmission of germline damage to the offspring of survivors of childhood cancer who were given radiotherapy and chemotherapy. METHODS: We did a retrospective cohort analysis, within the Childhood Cancer Survivor Study (CCSS), of the risk of stillbirth and neonatal death among the offspring of men and women who had survived childhood cancer. Patients in CCSS were younger than 21 years at initial diagnosis of an eligible cancer, were treated at 25 US institutions and one Canadian institution, and had survived for at least 5 years after diagnosis. We quantified the chemotherapy given to patients, and the preconception radiation doses to the testes, ovaries, uterus, and pituitary gland, and related these to the risk of stillbirth or neonatal death using Poisson regression analysis. FINDINGS: Among 1148 men and 1657 women who had survived childhood cancer, there were 4946 pregnancies. Irradiation of the testes (16 [1%] of 1270; adjusted relative risk 0.8 [95% CI 0.4-1.6]; mean dose 0.53 Gy [SD 1.40]) and pituitary gland (17 [3%] of 510, 1.1 [0.5-2.4] for more than 20.00 Gy; mean dose 10.20 Gy [13.0] for women), and chemotherapy with alkylating drugs (26 [2%] of 1195 women, 0.9 [0.5-1.5]; ten [1%] of 732 men, 1.2 [0.5-2.5]) were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased risk of stillbirth and neonatal death at doses greater than 10.00 Gy (five [18%] of 28, 9.1 [3.4-24.6]). For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1.00-2.49 Gy significantly increased the risk of stillbirth or neonatal death (three [4%] of 69, 4.7 [1.2-19.0]). INTERPRETATION: Our findings do not support concern about heritable genetic changes affecting the risk of stillbirth and neonatal death in the offspring of men exposed to gonadal irradiation. However, uterine and ovarian irradiation had serious adverse effects on the offspring that were probably related to uterine damage. Careful management is warranted of pregnancies in women given high doses of pelvic irradiation before puberty. FUNDING: Westlakes Research Institute, National Cancer Institute, and Children's Cancer Research Fund.

Radiation Dose and Volume to the Pancreas and Subsequent Risk of Diabetes Mellitus: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for diabetes mellitus, but the association between risk and radiation dose and volume is unclear. METHODS: Participants included 20 762 5-year survivors of childhood cancer (4568 exposed to abdRT) and 4853 siblings. For abdRT, we estimated maximum dose to abdomen; mean doses for whole pancreas, pancreatic head, body, tail; and percent pancreas volume receiving no less than 10, 20, and 30 Gy. Relative risks (RRs) were estimated with a Poisson model using generalized estimating equations, adjusted for attained age. All statistical tests were two-sided. RESULTS: Survivors exposed to abdRT (median age = 31.6 years, range = 10.2-58.3 years) were 2.92-fold more likely than siblings (95% confidence interval [CI] = 2.02 to 4.23) and 1.60-times more likely than survivors not exposed to abdRT (95%CI = 1.24 to 2.05) to develop diabetes. Among survivors treated with abdRT, greater attained age (RRper 10 years = 2.11, 95% CI = 1.70 to 2.62), higher body mass index (RRBMI 30+ = 5.00, 95% CI = 3.19 to 7.83 with referenceBMI 18.5-24.9), and increasing pancreatic tail dose were associated with increased diabetes risk in a multivariable model; an interaction was identified between younger age at cancer diagnosis and pancreatic tail dose with much higher diabetes risk associated with increasing pancreatic tail dose among those diagnosed at the youngest ages (P < .001). Radiation dose and volume to other regions of the pancreas were not statistically significantly associated with risk. CONCLUSIONS: Among survivors treated with abdRT, diabetes risk was associated with higher pancreatic tail dose, especially at younger ages. Targeted interventions are needed to improve cardiometabolic health among those at highest risk.

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

BACKGROUND: To determine the risk of thyroid dysfunction and subsequent thyroid cancer among childhood acute lymphoblastic leukemia (ALL) survivors. PROCEDURE: Rates of self-reported thyroid dysfunction and thyroid cancer were determined among 3,579 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of pediatric cancers diagnosed from 1970 to 1986, and compared with 3,846 siblings and population rates, respectively. RESULTS: The cumulative incidence of hypo- and hyperthyroidism among survivors 15 years following leukemia diagnosis was 1.6% (95% CI 1.1, 2.1) and 0.6% (95% CI 0.3, 1.1), respectively, both significantly increased compared with siblings. In multivariate analysis, survivors who received >or=20 Gy cranial radiotherapy plus any spinal radiotherapy had the highest risk of subsequent hypothyroidism (HR 8.3, 95% CI 3.3, 20.5) compared with those treated with chemotherapy alone. Craniospinal radiotherapy also was associated with an increased risk of subsequent hyperthyroidism (HR 6.1, 95% CI 1.1, 34.2) compared with chemotherapy alone, as well as an increased risk of subsequent thyroid cancers (SIR 30.3, 95% CI 14.5, 55.7) compared with population rates. In radiation dosimetry analysis, pituitary doses >or=20 Gy combined with thyroid doses >or=10 Gy were associated with hypothyroidism, whereas pituitary doses >or=20 Gy combined with thyroid doses >or=15 Gy were associated with hyperthyroidism. CONCLUSIONS: The risk of thyroid dysfunction and thyroid cancer was increased among childhood ALL survivors treated with craniospinal radiotherapy. In these individuals, long-term surveillance is warranted as no obvious plateau in risk was seen, even after 25 years of follow-up.

Skin Cancer Early Detection Practices among Adult Survivors of Childhood Cancer Treated with Radiation.

Because rates of skin cancer are greater among adult survivors of childhood cancer who received radiation therapy than among the general population, the National Cancer Institute recommends skin self-examinations and annual physician examination. There has been no comprehensive assessment of survivors' adherence to the skin cancer screening guidelines associated with skin self-examination (SSE) and physician whole-body skin examination (PSE). We conducted a cross-sectional survey of radiation-treated, adult 5-year survivors of childhood cancer, diagnosed between 1970 and 1986, in the Childhood Cancer Survivor Study cohort. Multivariate multinomial logit regression investigated the association between demographic, cancer diagnosis, patient activation, cancer treatment characteristics, and skin cancer screening practice. Among 728 survivors, 13.1% reported performing SSE in the prior 2 months plus receiving PSE in the prior 12 months, and 16.4% and 11.0% reported performing only an SSE or a PSE, respectively; 59.5% of survivors reported having had neither. Participants at the highest patient activation score were most likely to report SSE plus PSE compared with neither (adjusted relative risk ratio = 4.16, 95% confidence interval = 1.34-12.85). Most adult survivors of childhood cancer who had radiation therapy do not practice strategies that promote early detection of skin cancer. Interventions designed to activate survivors to increase their participation in screening are needed.

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use: A Report From the Childhood Cancer Survivor Study.

Importance: Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. Objectives: To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. Design, Setting, and Participants: In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. Exposures: Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. Main Outcomes and Measures: Odds ratios (ORs) for subsequent breast cancer by ER status. Results: A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. Conclusions and Relevance: This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

Fatigue and sleep disturbance in adult survivors of childhood cancer: a report from the childhood cancer survivor study (CCSS).

STUDY OBJECTIVE: To examine the prevalence of and risk factors for fatigue and sleep disturbance among adult survivors of childhood cancer. DESIGN: Retrospective cohort of childhood cancer survivors. SETTING: Twenty-six academic institutions treating childhood cancer. PARTICIPANTS: Two thousand six hundred forty-five survivors of childhood acute lymphocytic leukemia, central nervous system tumors, Hodgkin lymphoma, soft-tissue sarcomas, or bone tumors diagnosed before age 21, surviving at least 5 years from diagnosis, and a 500-sibling comparison group. MEASUREMENTS: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale. RESULTS: Significant differences were found between survivors and siblings on the Functional Assessment of Chronic Illness Therapy-Fatigue (40.8 vs 42.0, P < 0.02), Pittsburgh Sleep Quality Index (6.1 vs 5.5, P < 0.004), and Epworth Sleepiness Scale (6.2 vs 5.4, P < 0.001). Nineteen percent of survivors were in the most fatigued range, 16.7% reported disrupted sleep, and 14% increased daytime sleepiness. Survivors with a history of radiation therapy were more likely to be fatigued (odds ratio 1.7, 95% confidence interval 1.3-2.3), yet without significantly different mean scores. Female sex, congestive heart failure, pulmonary fibrosis, depression, and being unmarried significantly predicted more fatigue, whereas obesity and an infant in the house predicted more daytime sleepiness. Similar sociodemographic predictors were also identified among the siblings. CONCLUSION: Because of the large sample size, we detected more objectively reported fatigue, sleep disturbance, and daytime sleepiness among adult survivors of childhood cancer. However, the clinical significance of these differences is questionable. Predictors of fatigue and poor sleep were similar in both survivors and the siblings.

Timing of menarche among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The objective of this study was to determine risk factors associated with abnormal timing of menarche among survivors of childhood acute lymphoblastic leukemia (ALL). PROCEDURE: Self-reported age of menarche was determined among 949 female ALL survivors participating in the Childhood Cancer Survivor Study (CCSS), a cohort of 5-year survivors of common pediatric cancers diagnosed from 1970 to 1986, and compared with 1,128 siblings. RESULTS: The majority of survivors (92%) and siblings (97%) reported menarche between the ages of 10 and 16. Survivors treated with chemotherapy alone, including those exposed to alkylating agents, experienced menarche at a similar rate to siblings. However, compared to chemotherapy alone, cranial radiotherapy was associated with early menarche (age < 10; OR 6.2, 95% CI 2.1, 18.5) while craniospinal radiotherapy was associated with both early (OR 8.6, 95% CI 1.9, 38.6) and late (age > 16; OR 4.8, 95% CI 1.4, 16.7) menarche. There were no differences in effect between <20 and >/=20 Gy radiotherapy doses. In multivariable analysis, younger age at diagnosis was an independent risk factor for early menarche. CONCLUSIONS: Few female childhood ALL survivors experienced menarche outside of the normal range. Alkylating agent exposure was not associated with abnormal timing. However, those exposed to cranial and craniospinal radiotherapy, especially at a young age, should be monitored closely for abnormal timing of menarche.

Employment status among adult survivors in the Childhood Cancer Survivor Study.

BACKGROUND: With increased cure, childhood cancer survivors are reaching adulthood and seeking employment. Host, disease and treatment risk factors may contribute to inability to attain or maintain employment. PROCEDURE: The prevalence and risk factors for unemployment were evaluated using self-reported employment history in 10,399 childhood cancer survivors and 3,083 siblings >/= age 18 in the Childhood Cancer Survivor Study (CCSS). RESULTS: Among survivors, 5.6% reported unemployment, compared with 1.2% of siblings (odds ratio [OR] 3.7; 95% confidence interval [CI] 2.6, 5.1). Increased risks were observed within all cancer diagnoses. In multivariate analysis, diagnosis of central nervous system (CNS) tumor (OR 1.5; 95% CI 1.1, 2.1), bone cancer (OR 1.5; 95% CI 1.0, 2.1), treatment with >/=30 Gy cranial radiotherapy (OR 4.0; 95% CI 2.9, 5.5), female gender (OR 1.4; 95% CI 1.2, 1.7) and age < 4 years at diagnosis (OR 1.4; 95% CI 1.1, 1.8) increased risk. Diagnosis of CNS or bone tumor or cranial radiotherapy >/=30 Gy remained significant after adjusting for treatment, medical late effects, age and gender. Risk of unemployment decreased with attained age (OR((year)) 0.89; 95% CI 0.87, 0.91). CONCLUSIONS: Compared to siblings, adult childhood cancer survivors are at increased risk for unemployment with highest risk defined by diagnosis, treatment and demographic factors.

Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

OBJECTIVE: To determine risk factors associated with reduced adult height in survivors of childhood acute lymphoblastic leukemia (ALL). STUDY DESIGN: This was a cross-sectional study. Attained adult height was determined among 2434 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of common pediatric cancers diagnosed from 1970 to 1986, and compared with 3009 siblings. RESULTS: All survivor treatment exposure groups (chemotherapy alone, chemotherapy with cranial or craniospinal radiotherapy) had decreased adult height and an increased risk of adult short stature (height standard deviation score < -2) compared with siblings (P < .001). Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (OR, 3.4; 95% CI, 1.9, 6.0). Among survivors, significant risk factors for short stature included diagnosis of ALL before puberty, higher-dose cranial radiotherapy (> or = 20 Gy versus < 20 Gy), any radiotherapy to the spine, and female sex. CONCLUSIONS: Survivors of childhood ALL are at increased risk of adult short stature, including those treated with chemotherapy alone. Risk is highest for those treated with cranial and craniospinal radiotherapy at a young age.

Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts. Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.

Pregnancy outcome of partners of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

PURPOSE: This study was undertaken to determine the effect, if any, on pregnancy loss, live births, and birthweight of treatment for cancer diagnosed during childhood or adolescence. PATIENTS AND METHODS: We reviewed pregnancy outcome among sexually active male Childhood Cancer Survivor Study (CCSS) participants who responded to a questionnaire before February 3, 2000. 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 radiotherapy. RESULTS: There were 4,106 sexually active males; 1,227 reported they sired 2,323 pregnancies (69% live births, 1% stillbirths, 13% miscarriages, 13% abortions, 5% unknown or in gestation). The male-to-female ratio of the offspring of the partners of the male survivors was significantly different from that of the offspring of the partners of the male siblings of the survivors (1.0:1.03 v 1.24:1.0) (P =.016). The proportion of pregnancies of the partners of male survivors that ended with a liveborn infant was significantly lower than for the partners of the male siblings of the survivors who were the control group for comparison (relative risk = 0.77, P =.007). There were no significant differences in pregnancy outcome by treatment. CONCLUSION: This large study did not identify adverse pregnancy outcomes for the partners of male survivors treated with most chemotherapeutic agents. The reversal of the sex ratio and the association observed for procarbazine warrant further investigation.

Risk of Subsequent Neoplasms During the Fifth and Sixth Decades of Life in the Childhood Cancer Survivor Study Cohort.

PURPOSE: Survivors of childhood cancer have an increased risk for subsequent neoplasms (SNs), but the incidence beyond the age of 40 years and associations with therapeutic exposures have not been well described. PATIENTS AND METHODS: Among 14,364 survivors of childhood cancer diagnosed between 1970 and 1986, 3,171 had an attained age of 40 years or older at the time of last contact. Cumulative incidence of SNs, standardized incidence ratios (SIRs), excess absolute risk of subsequent malignant neoplasms (SMNs), and relative risks (RRs) for SMNs and nonmelanoma skin cancers were calculated. RESULTS: In total, 679 SNs were diagnosed in patients age 40 years or older. These included 196 SMNs, 419 nonmelanoma skin cancers, 21 nonmalignant meningiomas, and 43 other benign neoplasms. At age 55 years, the cumulative incidence of new SNs and SMNs occurring after age 40 years was 34.6% (95% CI, 28.7 to 40.6) and 16.3% (95% CI, 11.7 to 20.9), respectively. Survivors were twice as likely as the general population to receive a diagnosis of SMN after age 40 years (SIR, 2.2; 95% CI, 1.9 to 2.5). Among SMNs, risk was increased for breast cancer (SIR, 5.5; 95% CI, 4.5 to 6.7), renal cancer (SIR, 3.9; 95% CI, 2.0 to 7.5), soft tissue sarcoma (SIR, 2.6; 95% CI, 1.5 to 4.4), and thyroid cancer (SIR, 1.9; 95% CI, 1.0 to 3.5). Female sex (RR, 1.9; 95% CI, 1.3 to 2.6; P < .001) and therapeutic radiation exposure (RR, 2.2; 95% CI, 1.4 to 3.3; P < .001) were associated with an increased for risk for SMN in multivariable analysis. CONCLUSION: Even after age 40 years, survivors of childhood cancer remain at increased risk for treatment-related SNs. These data suggest the need for life-long monitoring and should inform anticipatory guidance provided to survivors of childhood cancer.

Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study.

PURPOSE: Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses. METHODS: Within the Childhood Cancer Survivor Study, we performed a retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female childhood cancer survivors. We quantified chemotherapy with alkylating agents and radiotherapy doses to the testes and ovaries and related these exposures to risk of congenital anomalies using logistic regression. RESULTS: One hundred twenty-nine children had at least one anomaly (prevalence = 2.7%). For children whose mothers were exposed to radiation or alkylating agents versus neither, the prevalence of anomalies was 3.0% versus 3.5% (P = .51); corresponding figures were 1.9% versus 1.7% (P = .79) for the children of male survivors. Neither ovarian radiation dose (mean, 1.19 Gy; odds ratio [OR] = 0.59; 95% CI, 0.20 to 1.75 for 2.50+ Gy) nor testicular radiation dose (mean, 0.48 Gy; OR = 1.01; 95% CI, 0.36 to 2.83 for 0.50+ Gy) was related to risk of congenital anomalies. Treatment with alkylating agents also was not significantly associated with anomalies in the children of male or female survivors. CONCLUSION: Our findings offer strong evidence that the children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. This information is important for counseling cancer survivors planning to have children.

Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study.

These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.

Promoting physical activity in childhood cancer survivors: results from the Childhood Cancer Survivor Study.

BACKGROUND: Although physical activity may modify the late effects of childhood cancer treatment, from 20% to 52% of adult survivors are sedentary. The authors of this report sought to identify modifiable factors that influence survivors' participation in physical activity. METHODS: Structural equation modeling of data were derived from the Childhood Cancer Survivors Study of adult survivors (current mean age, 30.98 years; mean years since diagnosis, 23.74; mean age at diagnosis, 9.25 years) who were diagnosed between 1970 and 1986. RESULTS: Approximately 40% of the variance in male survivors' recent participation versus nonparticipation in physical activity was explained directly and/or indirectly by self-reported health fears (P = .01), perceived primary-care physician (PCP) expertise (P = .01), baseline exercise frequency (P < or = .001), education level (P = .01), self-reported stamina (P = .01), cancer-related pain (P < or = .001), fatigue (P < or = .001), age at diagnosis (P = .01), cancer-related anxiety (P < or = .001), motivation (P = .01), affect (P = .01), and discussion of subsequent cancer risk with the PCP (P < or = .001) (N = 256; chi-square test statistic = 53.38; degrees of freedom [df] = 51; P = .38, Comparative Fit Index [CFI] = 1.000; Tucker Lewis Index [TLI] = 1.000; root mean square of approximation [RMSEA] = 0.014; weighted root mean square residual [WRMR] = 0.76). Thirty-one percent of the variance in women' recent physical activity participation was explained directly and/or indirectly by self-reported stamina (P < or = .001), fatigue (P = .01), baseline exercise frequency (P = .01), cancer-related pain (P < or = .001), cancer-related anxiety (P = .01), recency of visits with PCP (<0.001), quality of interaction with the PCP (P = .01), and motivation (P < or = .001; N = 366; chi-square test statistic = 67.52; df = 55; P = .12; CFI = 0.98; TLI = 0.98; RMSEA = 0.025; WRMR = 0.76). CONCLUSIONS: Gender-tailored intervention strategies in which providers specifically target motivation, fear, and affect may support physical activity in childhood cancer survivors.

Abnormal timing of menarche in survivors of central nervous system tumors: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Children who receive high-dose radiotherapy to the hypothalamic-pituitary (H-P) axis may be at risk for both early and late puberty. To the authors' knowledge, data regarding the risk of altered timing of menarche after higher dose radiotherapy (RT), as used in the treatment of central nervous system (CNS) tumors, are limited. METHODS: The authors evaluated 235 female survivors of CNS tumors, diagnosed between 1970 and 1986, and >1000 sibling controls who were participants in the Childhood Cancer Survivor Study, and provided self-reported data concerning age at menarche. RESULTS: Survivors of CNS tumors were more likely to have onset of menarche before age 10 years compared with their siblings (11.9% vs 1.0%) (odds ratio [OR], 14.1; 95% confidence interval [95% CI], 7.0-30.9). Of the 138 survivors who received RT to the H-P axis, 20 (14.5%) had onset of menarche before age 10 years, compared with 4.3% of those who did not receive RT (OR, 3.8; 95% CI, 1.2-16.5). Age 50 gray OR, 9.0; 95% CI, 2.3-59.5) and spinal RT conferred an increased risk of late menarche, as did older age (>10 years) at the time of diagnosis (OR, 3.0; 95% CI, 1.3-7.0). CONCLUSIONS: Survivors of CNS tumors are at a significantly increased risk of both early and late menarche associated with RT exposure and age at treatment.