Chronic Health Conditions and Longitudinal Employment in Survivors of Childhood Cancer.

Importance: Employment is an important factor in quality of life and provides social and economic support. Longitudinal data on employment and associations with chronic health conditions for adult survivors of childhood cancer are lacking. Objective: To evaluate longitudinal trends in employment among survivors of childhood cancer. Design, Setting, and Participants: Retrospective cohort study of 5-year cancer survivors diagnosed at age 20 years or younger between 1970 and 1986 enrolled in the multi-institutional Childhood Cancer Survivor Study (CCSS). Sex-stratified employment status at baseline (2002 to 2004) and follow-up (2014 to 2016) was compared with general population rates from the Behavioral Risk Factor Surveillance System cohort. Data were analyzed from July 2021 to June 2022. Exposures: Cancer therapy and preexisting and newly developed chronic health conditions. Main Outcomes and Measures: Standardized prevalence ratios of employment (full-time or part-time, health-related unemployment, unemployed, not in labor force) among adult (aged ≥25 years) survivors between baseline and follow-up compared with the general population. Longitudinal assessment of negative employment transitions (full-time to part-time or unemployed at follow-up). Results: Female participants (3076 participants at baseline; 2852 at follow-up) were a median (range) age of 33 (25-53) years at baseline and 42 (27-65) years at follow-up; male participants (3196 participants at baseline; 2557 at follow-up) were 33 (25-54) and 43 (28-64) years, respectively. The prevalence of full-time or part-time employment at baseline and follow-up was 2215 of 3076 (71.3%) and 1933 of 2852 (64.8%) for female participants and 2753 of 3196 (85.3%) and 2079 of 2557 (77.3%) for male participants, respectively, with declining standardized prevalence ratios over time (female participant baseline, 1.01; 95% CI, 0.98-1.03; follow-up, 0.94; 95% CI, 0.90-0.98; P < .001; male participant baseline, 0.96; 95% CI, 0.94-0.97; follow-up, 0.92; 95% CI, 0.89-0.95; P = .02). While the prevalence of health-related unemployment increased (female participants, 11.6% to 17.2%; male participants, 8.1% to 17.1%), the standardized prevalence ratio remained higher than the general population and declined over time (female participant baseline, 3.78; 95% CI, 3.37-4.23; follow-up, 2.23; 95% CI, 1.97-2.51; P < .001; male participant baseline, 3.12; 95% CI, 2.71-3.60; follow-up, 2.61; 95% CI, 2.24-3.03; P = .002). Among survivors employed full-time at baseline (1488 female participants; 1933 male participants), 285 female participants (19.2%) and 248 male participants (12.8%) experienced a negative employment transition (median [range] follow-up, 11.5 [9.4-13.8] years). Higher numbers and grades of chronic health conditions were significantly associated with these transitions. Conclusions and Relevance: In this retrospective analysis of adult survivors of childhood cancer, significant declines in employment and increases in health-related unemployment among cancer survivors compared with the general population were identified. A substantial portion of survivors in the midcareer age range fell out of the workforce. Awareness among clinicians, caregivers, and employers may facilitate clinical counseling and occupational provisions for supportive work accommodations.

Impact of Risk-Based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the childhood cancer survivor study.

BACKGROUND: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences have not been well-described. METHODS: Late mortality, subsequent malignant neoplasms (SMN), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year 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 (SMR) and standardized incidence ratios (SIR) of SMNs were compared to matched population controls. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC compared to 1,029 CCSS siblings. RESULTS: 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, while 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 to 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]). CONCLUSION: 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 multi-morbidity, while survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.

Long-Term Morbidity and Mortality Among Survivors of Neuroblastoma Diagnosed During Infancy: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures. METHODS: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 siblings. RESULTS: Among 1,397 eligible survivors, the 25-year cumulative incidence of late mortality was 2.1% (95% CI, 1.3 to 3.9) with no difference by treatment era. Among 990 participants who completed a baseline survey, fewer survivors received radiation in more recent eras (51.2% 1970s, 20.4% 1980s, and 10.1% 1990s; P < .001). Risk of SMN was elevated only among individuals treated with radiation-containing regimens compared with surgery alone (HR[C ± S], 3.2 [95% CI, 0.9 to 11.6]; HR[R ± C ± S], 5.7 [95% CI, 1.2 to 28.1]). In adjusted models, there was a 50% reduction in risk of grade 3-5 CHCs in the 1990s versus 1970s (HR, 0.5 [95% CI, 0.3 to 0.9]; P = .01); individuals treated with radiation had a 3.6-fold risk for grade 3-5 CHCs (95% CI, 2.1 to 6.2) versus those treated with surgery alone. When compared with siblings, risk of grade 3-5 CHCs for survivors was lowest in the most recent era (HR[1970s], 4.7 [95% CI, 3.4 to 6.5]; HR[1980s], 4.6 [95% CI, 3.3 to 6.4]; HR[1990s], 2.5 [95% CI, 1.7 to 3.9]). CONCLUSION: Neuroblastoma survivors treated during infancy have a relatively low absolute burden of late mortality and SMN. Encouragingly, risk of CHCs has declined in more recent eras with reduced exposure to radiation therapy.

Impact of COVID-19 pandemic on a large cohort of adult survivors of childhood cancer.

Childhood cancersurvivors may be differentially impacted by coronavirus disease 2019 (COVID-19). From April to June of 2020, we examined psychosocial/health concerns in 4148 adult survivors and 571 siblings. Although more survivors reported concerns about getting sick (p = .002) and needing hospitalization (p = .003) in general, survivors and siblings were comparably concerned about being infected with and the consequences of COVID-19. Cranial radiation was associated with social isolation (relative risk [RR] = 1.3, CI = 1.1-1.7), and central nervous system (CNS) tumors were associated with unemployment due to COVID-19 (RR = 1.7, CI = 1.2-2.2). Some survivors appear more vulnerable and may require more support to meet health care and vocational needs during COVID-19, though siblings also perceive substantial risk.

Long-Term Neurocognitive and Psychosocial Outcomes After Acute Myeloid Leukemia: A Childhood Cancer Survivor Study Report.

BACKGROUND: Survivors of childhood acute myeloid leukemia (AML) are vulnerable to medical late effects of treatment; however, less is known about their psychosocial outcomes. This study evaluated neurocognitive and psychosocial outcomes in long-term AML survivors treated with bone marrow transplantation (BMT) or intensive chemotherapy (IC) without BMT. METHODS: AML survivors (N = 482; median age at diagnosis = 8 [range = 0-20] years; median age at evaluation = 30 [range = 18-49] years) treated with BMT (n = 183) or IC (n = 299) and sibling controls (N = 3190; median age at evaluation = 32 [range = 18-58] years) from the Childhood Cancer Survivor Study were compared on emotional distress (Brief Symptom Inventory-18), neurocognitive problems (Childhood Cancer Survivor Study Neurocognitive Questionnaire), health-related quality of life (SF-36), and social attainment. Outcomes were dichotomized (impaired vs nonimpaired) using established criteria, and relative risks (RRs) were estimated with multivariable Poisson regression, adjusted for age at evaluation and sex. RESULTS: AML survivors were more likely than siblings to report impairment in overall emotional (RR = 2.19, 95% confidence interval [CI] = 1.51 to 3.18), neurocognitive (RR = 2.03, 95% CI = 1.47 to 2.79), and physical quality of life (RR = 2.71, 95% CI = 1.61 to 4.56) outcomes. Survivors were at increased risk for lower education (RR = 1.15, 95% CI = 1.03 to 1.30), unemployment (RR = 1.41, 95% CI = 1.16 to 1.71), lower income (RR = 1.39, 95% CI = 1.17 to 1.65), and not being married or having a partner (RR = 1.33, 95% CI = 1.17 to 1.51). BMT-treated survivors did not differ statistically significantly from IC-treated on any outcome measure. CONCLUSIONS: AML survivors are at increased risk for psychosocial impairment compared with siblings; however, BMT does not confer additional risk for psychosocial late effects compared with treatment without BMT.

Neuropsychological and socioeconomic outcomes in adult survivors of pediatric low-grade glioma.

BACKGROUND: Current estimates suggest that 75% of children diagnosed with a central nervous system (CNS) tumor will become 5-year survivors. However, survivors of childhood CNS tumors are at increased risk for long-term morbidity. METHODS: To determine long-term neuropsychological and socioeconomic status (SES) outcomes, adult survivors of pediatric low-grade gliomas (n = 181) in the Childhood Cancer Survivor Study and a sibling comparison group that was frequency-matched by age and sex (n = 105) completed a comprehensive battery of standardized neuropsychological tests and an SES assessment. Multivariable regression models compared treatment-specific groups for neuropsychological and SES outcomes and evaluated associations with tumor location, age at diagnosis, sex, and age at evaluation. RESULTS: In adjusted models, survivors treated with surgery and radiotherapy (surgery+RT; median age at diagnosis, 7 years; median age at assessment, 41 years) scored lower on estimated IQ than survivors treated with surgery only, who scored lower than siblings (surgery+RT, 93.9; surgery only, 101.2; siblings, 108.5; all P values <.0001). Survivors diagnosed at younger ages had low scores for all outcomes (P < .05) except for attention/processing speed. For SES outcomes, survivors treated with surgery+RT had lower occupation scores (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.1-5.9), lower income (OR, 2.6; 95% CI, 1.3-5.0), and less education (OR, 2.1; 95% CI, 1.1-4.0) than those treated with surgery only. CONCLUSIONS: Decades after treatment, survivors treated with radiotherapy and at younger ages had poorer neuropsychological and SES outcomes. Lifelong surveillance of survivors of pediatric low-grade gliomas may be warranted as life events, stages, and transitions (employment, family, and aging) present new challenges and risks.

Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation.

We examined the impact of total body irradiation (TBI) dose and fractionation on risk of subsequent malignant neoplasms (SMNs) in the era of reduced-intensity and nonmyeloablative conditioning regimens for hematopoietic cell transplantation (HCT). Among 4905 1-year survivors of allogeneic HCT for hematologic malignancies (N = 4500) or nonmalignant disorders (N = 405) who received transplants between 1969 and 2014, we identified 581 SMNs (excluding squamous and basal cell of skin) in 499 individuals. With a median length of follow-up of 12.5 years, the cumulative incidence of SMNs by 30 years after HCT was 22.0%. Compared with age-, sex-, and calendar year-matched Surveillance, Epidemiology, and End Results (SEER) population rates, the standardized incidence ratio (SIR) of SMNs was increased 2.8-fold. The highest SIRs were for SMNs of bones (SIR, 28.8), oral cavity (SIR, 13.8), skin (SIR, 7.3), central nervous system (SIR, 6.0), and endocrine organs (SIR, 4.9). The highest excess absolute risks (EARs) were seen with breast cancer (EAR, 2.2) and cancers of the oral cavity (EAR, 1.5) and skin (EAR, 1.5) per 1000 person-years. The highest incidence of SMNs was in survivors exposed to unfractionated (600-1000 cGy) or high-dose fractionated (1440-1750 cGy) TBI. For patients receiving low-dose TBI, the incidence was comparable to myeloablative chemotherapy alone, although still twofold higher than in the general population. These data demonstrate a strong effect of TBI dose, dose fractionation, and risk of SMNs after HCT. The cumulative incidence of SMNs increases with follow-up time; thus, HCT survivors require lifetime monitoring for early detection and effective therapy of SMNs.

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.

Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) are more insulin resistant and have higher levels of several cardiovascular risk factors even while still children. This study examines specific treatment exposures associated with cardiovascular risk factors and insulin resistance. METHODS: CCS of ages 9 to 18 years at study entry and in remission 5 years or more from diagnosis (n = 319) and 208 sibling controls were recruited into this cross-sectional study that included physiologic assessment of insulin resistance (hyperinsulinemic euglycemic clamp) and assessment of cardiovascular risk factors. Regression and recursive tree modeling were used to ascertain treatment combinations associated with insulin resistance and cardiovascular risk. RESULTS: Mean current age of CCS was 14.5 years and 54% were male (siblings 13.6 years, 54% male). Diagnoses included leukemia (35%), brain tumors (36%), solid tumors (33%), or lymphoma (6%). Among CCS, analysis of individual chemotherapy agents failed to find associations with cardiovascular risk factors or insulin resistance. Compared with siblings, insulin resistance was significantly higher in CCS who received platinum plus cranial radiotherapy (CRT, 92% brain tumors) and in those who received steroids but no platinum (majority leukemia). Insulin resistance did not differ between CCS who received surgery alone versus siblings. Within survivor comparisons failed to elucidate treatment combinations that increased insulin resistance compared with those who received surgery only. CONCLUSIONS: Exposure to platinum, CRT, or steroids is associated with insulin resistance and cardiovascular risk factors and should be taken into consideration in the development of screening recommendations for cardiovascular risk. IMPACT: Earlier identification of CCS who may benefit from targeted prevention efforts may reduce their future risk of cardiovascular disease.

Cardiovascular risk and insulin resistance in childhood cancer survivors.

OBJECTIVE: Increased cardiovascular (CV) risk has been reported in adults who are childhood cancer survivors (CCS). We sought to determine the emergence of CV risk factors in CCS while still children. STUDY DESIGN: CCS in remission ≥5 years from cancer diagnosis (n=319, age=14.5 years) and their siblings (control subjects, n=208, age=13.6 years) participated in this cross-sectional study of CV risk, which included physiologic assessment of insulin sensitivity/resistance (hyperinsulinemic euglycemic clamp). Adjusted comparisons between CCS major diagnoses (leukemia [n=110], central nervous system tumors [n=82], solid tumors [n=127]) and control subjects were performed with linear regression for CV risk factors and insulin sensitivity. RESULTS: Despite no significant differences in weight and body mass index, CCS had greater adiposity (waist [73.1 versus 71.1 cm, P=.02]; percent fat [28.1 versus 25.9%, P=.007]), lower lean body mass (38.4 versus 39.9 kg, P=.01) than control subjects. After adjustment for adiposity, CCS had higher total cholesterol level (154.7 versus 148.3 mg/dL, P=.004), low-density lipoprotein cholesterol level (89.4 versus 83.7 mg/dL, P=.002), and triglyceride level (91.8 versus 84 mg/dL, P=.03) and were less insulin sensitive (insulin stimulated glucose uptake, measure of insulin resistance, adjusted for lean body mass 12.1 versus 13.4 mg/kg/min, P=.002) than control subjects. CONCLUSIONS: CCS have greater CV risk than healthy children. Because CV risk factors track from childhood to adulthood, early development of altered body composition and decreased insulin sensitivity in CCS may contribute significantly to their risk of early CV morbidity and mortality.

Long-term survivors of childhood Ewing sarcoma: report from the childhood cancer survivor study.

BACKGROUND: The survival of Ewing sarcoma (ES) patients has improved since the 1970s but is associated with considerable future health risks. METHODS: The study population consisted of long-term (> or =5-year) survivors of childhood ES diagnosed before age 21 from 1970 to 1986. Cause-specific mortality was evaluated in eligible survivors (n = 568), and subsequent malignant neoplasms, chronic health conditions, infertility, and health status were evaluated in the subset participating in the Childhood Cancer Survivor Study (n = 403). Outcomes were compared with the US population and sibling control subjects (n = 3899). Logistic, Poisson, or Cox proportional hazards models, with adjustments for sex, age, race/ethnicity, and potential intrafamily correlation, were used. Statistical tests were two-sided. RESULTS: Cumulative mortality of ES survivors was 25.0% (95% confidence interval [CI] = 21.1 to 28.9) 25 years after diagnosis. The all-cause standardized mortality ratio was 13.3 (95% CI = 11.2 to 15.8) overall, 23.1 (95% CI = 17.6 to 29.7) for women, and 10.0 (95% CI = 7.9 to 12.5) for men. The nonrecurrence-progression non-external cause standardized mortality ratio (subsequent non-ES malignant neoplasms and cardiac and pulmonary causes potentially attributable to ES treatment) was 8.7 (95% CI = 6.2 to 12.0). Twenty-five years after ES diagnosis, cumulative incidence of subsequent malignant neoplasms, excluding nonmelanoma skin cancers, was 9.0% (95% CI = 5.8 to 12.2). Compared with siblings, survivors had an increased risk of severe, life-threatening, or disabling chronic health conditions (relative risk = 6.0, 95% CI = 4.1 to 9.0). Survivors had lower fertility rates (women: P = .005; men: P < .001) and higher rates of moderate to extreme adverse health status (P < .001). CONCLUSION: Long-term survivors of childhood ES exhibit excess mortality and morbidity.

Knowledge of hepatitis C virus screening in long-term pediatric cancer survivors: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Pediatric cancer survivors who were treated before routine hepatitis C virus (HCV) screening of blood donors in 1992 have an elevated risk of transfusion-acquired HCV. METHODS: To assess long-term pediatric cancer survivors' knowledge of HCV testing and blood transfusion history, a questionnaire was administered to 9242 participants in the Childhood Cancer Survivor Study who are at risk for transfusion-acquired HCV after cancer therapy from 1970 to 1986. RESULTS: More than 70% of survivors reported either no prior HCV testing (41%) or uncertainty about testing (31%), with only 29% reporting prior testing. One half recalled having a treatment-related blood transfusion; those who recalled a transfusion were more likely to report HCV testing (39%) than those who did not (18%) or were unsure (20%). In multivariate models, survivors who reported no prior HCV testing were more likely to be older (odds ratio [OR] per 5-year increase, 1.1; 95% confidence interval [CI], 1.0-1.1) and to report no care at a cancer center within the past 2 years (OR, 1.2; 95% CI, 1.0-1.4), no cancer treatment summary (OR, 1.3; 95% CI, 1.2-1.5), and no transfusions (OR, 2.6; 95% CI, 2.3-3.0) or uncertainty about transfusions (OR, 2.2; 95% CI, 1.9-2.6), and less likely to be racial/ethnic minorities (OR, 0.9; 95% CI, 0.8-1.0) or survivors of acute myeloid leukemia (OR, 0.7; 95% CI, 0.5-1.0). CONCLUSIONS: Many pediatric cancer survivors at risk for transfusion-acquired HCV are unaware of their transfusion history and prior testing for HCV and would benefit from programs to increase HCV knowledge and screening.

Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The current study was performed to describe frequencies and risk factors of altered oral health and odontogenesis in childhood cancer survivors. METHODS: In total, 9308 survivors who were diagnosed between 1970 and 1986 and 2951 siblings from the Childhood Cancer Survivor Study completed a survey that contained oral-dental health information. The authors analyzed treatment impact, socioeconomic data, and patient demographics on dental outcomes using univariate and multivariate logistic regression models to estimate odds ratios (ORs). RESULTS: In multivariate analysis, survivors were more likely to report microdontia (OR, 3.0; 95% confidence interval [95% CI], 2.4-3.8), hypodontia (OR, 1.7; 95% CI, 1.4-2.0), root abnormalities (OR, 3.0; 95% CI, 2.2-4.0), abnormal enamel (OR, 2.4; 95% CI, 2.0-2.9), teeth loss>or=6 (OR, 2.6; 95% CI, 1.9-3.6), severe gingivitis (OR, 1.2; 95% CI, 1.0-1.5), and xerostomia (OR, 9.7; 95% CI, 4.8-19.7). Controlling for chemotherapy and socioeconomic factors, radiation exposure of >or=20 Gray to dentition was associated significantly with an increased risk of >or=1 dental abnormality. Dose-dependent alkylating agent therapy significantly increased the risk of >or=1 anatomic/developmental dental abnormalities in survivors who were diagnosed at age<5 years (OR, 1.7, 2.7, and 3.3 for alkylating agent scores of 1, 2, and 3, respectively). CONCLUSIONS: Radiation and chemotherapy were independent risk factors for adverse oral-dental sequelae among childhood cancer survivors. The authors concluded that patients who received receiving alkylating agents at age<5 years should be closely monitored.

Predictors of marriage and divorce in adult survivors of childhood cancers: a report from the Childhood Cancer Survivor Study.

BACKGROUND/OBJECTIVE: Adult survivors of childhood cancer can have altered social functioning. We sought to identify factors that predict marriage and divorce outcomes in this growing population. METHODS: This was a retrospective cohort study of 8,928 > or = 5-year adult survivors of childhood malignancy and 2,879 random sibling controls participating in the Childhood Cancer Survivor Study. Marital status, current health, psychological status, and neurocognitive functioning were determined from surveys and validated instruments. RESULTS: Survivors were more likely to be never-married than siblings [relative risk (RR), 1.21; 95% confidence interval (95% CI), 1.15-1.26] and the U.S. population (RR, 1.25; 95% CI, 1.21-1.29), after adjusting for age, gender, and race. Patients with central nervous system tumors were at greatest risk of not marrying (RR, 1.50; 95% CI, 1.41-1.59). Married survivors divorced at frequencies similar to controls. In multivariable regression analysis, nonmarriage was most associated with cranial radiation (RR, 1.15; 95% CI, 1.02-1.31 for > 2,400 centigray). In analysis of neurobehavioral functioning, nonmarriage was associated with worse task efficiency (RR, 1.27; 95% CI, 1.20-1.35), but not with emotional distress, or problems with emotional regulation, memory, or organization. Physical conditions predictive of nonmarriage included short stature (RR, 1.27; 95% CI, 1.20-1.34) and poor physical function (RR, 1.08; 95% CI, 1.00-1.18). Structural equation modeling suggested that cranial radiation influenced marriage status through short stature, cognitive problems, and poor physical function. CONCLUSIONS: Childhood cancer survivors married at lower frequencies compared with peers. Patients with central nervous system tumors, cranial radiation, impaired processing efficiency, and short stature were more likely to never marry. Divorce patterns in survivors were similar to peers.