Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors.

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.

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.

Neurologic morbidity and functional independence in adult survivors of childhood cancer.

OBJECTIVE: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies. METHODS: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. RESULTS: Among CNS-treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non-independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non-independent (5.7%). In contrast to 50% of non-CNS-treated survivors and 60% of siblings, a fourth fully independent class of CNS-treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70-3.68), seizure (OR = 9.70, 95% CI: 7.37-12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16-3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40-3.88) were associated with non-independence among CNS-treated survivors. Non-independence was associated with emotional distress symptoms. INTERPRETATION: CNS-treated survivors do not attain full independence comparable to non-CNS-treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment-related neurological sequalae.

The Pediatric Proton and Photon Therapy Comparison Cohort: Study Design for a Multicenter Retrospective Cohort to Investigate Subsequent Cancers After Pediatric Radiation Therapy.

Purpose: The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need. Methods and Materials: We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks. Results: For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s). Conclusions: Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy.

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

Background: It is unknown whether a history of childhood cancer modifies the established disparities in cardiovascular risk factors (CVRFs) observed in the general population. Objectives: We sought to determine if disparities in CVRFs by race/ethnicity are similar among childhood cancer survivors compared with the general population. Methods: 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. Results: 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. Conclusions: 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.

Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Despite survival improvements, there is a paucity of data on neurocognitive outcomes in neuroblastoma survivors. This study addresses this literature gap. METHODS: Neurocognitive impairments in survivors were compared to sibling controls from the Childhood Cancer Survivor Study (CCSS) using the CCSS Neurocognitive Questionnaire. Impaired emotional regulation, organization, task efficiency, and memory defined as scores ≥90th percentile of sibling norms. Modified Poisson regression models evaluated associations with treatment exposures, era of diagnosis, and chronic conditions. Analyses were stratified by age at diagnosis (≤1 and >1 year) as proxy for lower versus higher risk disease. RESULTS: Survivors (N = 837; median [range] age, 25 [17-58] years, age diagnosed, 1 [0-21] years) were compared to sibling controls (N = 728; age, 32 [16-43] years). Survivors had higher risk of impaired task efficiency (≤1 year relative risk [RR], 1.48; 95% confidence interval [CI], 1.08-2.03; >1 year RR, 1.58; 95% CI, 1.22-2.06) and emotional regulation (≤1 year RR, 1.51; 95% CI, 1.07-2.12; >1 year RR, 1.44; 95% CI, 1.06-1.95). Impaired task efficiency associated with platinum exposure (≤1 year RR, 1.74; 95% CI, 1.01-2.97), hearing loss (≤1 year RR, 1.95; 95% CI, 1.26-3.00; >1 year RR, 1.56; 95% CI, 1.09-2.24), cardiovascular (≤1 year RR, 1.83; 95% CI, 1.15-2.89; >1 year RR, 1.74; 95% CI, 1.12-2.69), neurologic (≤1 year RR, 2.00; 95% CI, 1.32-3.03; >1 year RR, 2.29; 95% CI, 1.64-3.21), and respiratory (>1 year RR, 2.35; 95% CI, 1.60-3.45) conditions. Survivors ≤1 year; female sex (RR, 1.54; 95% CI, 1.02-2.33), cardiovascular (RR, 1.71; 95% CI, 1.08-2.70) and respiratory (RR, 1.99; 95% CI, 1.14-3.49) conditions associated impaired emotional regulation. Survivors were less likely to be employed full-time (p < .0001), graduate college (p = .035), and live independently (p < .0001). CONCLUSIONS: Neuroblastoma survivors report neurocognitive impairment impacting adult milestones. Identified health conditions and treatment exposures can be targeted to improve outcomes. PLAIN LANGUAGE SUMMARY: Survival rates continue to improve in patients with neuroblastoma. There is a lack of information regarding neurocognitive outcomes in neuroblastoma survivors; most studies examined survivors of leukemia or brain tumors. In this study, 837 adult survivors of childhood neuroblastoma were compared to siblings from the Childhood Cancer Survivorship Study. Survivors had a 50% higher risk of impairment with attention/processing speed (task efficiency) and emotional reactivity/frustration tolerance (emotional regulation). Survivors were less likely to reach adult milestones such as living independently. Survivors with chronic health conditions are at a higher risk of impairment. Early identification and aggressive management of chronic conditions may help mitigate the level of impairment.

Emotional, behavioral, and physical health consequences of loneliness in young adult survivors of childhood cancer: Results from the Childhood Cancer Survivor Study.

BACKGROUND: Young adults in the general population are at risk of experiencing loneliness, which has been associated with physical and mental health morbidities. The prevalence and consequences of loneliness in young adult survivors of childhood cancer remain unknown. METHODS: A total of 9664 young adult survivors of childhood cancer (median age at diagnosis 10.5 years [interquartile range (IQR), 5-15], 27.1 years at baseline [IQR, 23-32]) and 2221 siblings enrolled in the Childhood Cancer Survivor Study completed a self-reported survey question assessing loneliness on the Brief Symptom Inventory-18 at baseline and follow-up (median follow-up, 6.6 years). Multivariable models evaluated the prevalence of loneliness at baseline only, follow-up only, and baseline + follow-up, and its associations with emotional distress, health behaviors, and chronic conditions at follow-up. RESULTS: Survivors were more likely than siblings to report loneliness at baseline + follow-up (prevalence ratio [PR] 2.2; 95% confidence interval [CI], 1.7-3.0) and at follow-up only (PR, 1.4; 95% CI, 1.1-1.7). Loneliness at baseline + follow-up was associated with elevated risk of anxiety (relative risk [RR], 9.8; 95% CI, 7.5-12.7), depression (RR, 17.9; 95% CI, 14.1-22.7), and current smoking (odds ratio [OR], 1.7; 95% CI, 1.3-2.3) at follow-up. Loneliness at follow-up only was associated with suicidal ideation (RR, 1.5; 95% CI, 1.1-2.1), heavy/risky alcohol consumption (RR, 1.3; 95% CI, 1.1-1.5), and new-onset grade 2-4 chronic conditions (RR, 1.3; 95% CI, 1.0-1.7). CONCLUSIONS: Young adult survivors of childhood cancer have elevated risk of experiencing loneliness, which is associated with future emotional distress, risky health behaviors, and new-onset chronic conditions.

Advancing Survivors Knowledge (ASK Study) of Skin Cancer Surveillance After Childhood Cancer: A Randomized Controlled Trial in the Childhood Cancer Survivor Study.

PURPOSE: To improve skin cancer screening among survivors of childhood cancer treated with radiotherapy where skin cancers make up 58% of all subsequent neoplasms. Less than 30% of survivors currently complete recommended skin cancer screening. PATIENTS AND METHODS: This randomized controlled comparative effectiveness trial evaluated patient and provider activation (PAE + MD) and patient and provider activation with teledermoscopy (PAE + MD + TD) compared with patient activation alone (PAE), which included print materials, text messaging, and a website on skin cancer risk factors and screening behaviors. Seven hundred twenty-eight participants from the Childhood Cancer Survivor Study (median age at baseline 44 years), age > 18 years, treated with radiotherapy as children, and without previous history of skin cancer were randomly assigned (1:1:1). Primary outcomes included receiving a physician skin examination at 12 months and conducting a skin self-examination at 18 months after intervention. RESULTS: Rates of physician skin examinations increased significantly from baseline to 12 months in all three intervention groups: PAE, 24%-39%, relative risk [RR], 1.65, 95% CI, 1.32 to 2.08; PAE + MD, 24% to 39%, RR, 1.56, 95% CI, 1.25 to 1.97; PAE + MD + TD, 24% to 46%, RR, 1.89, 95% CI, 1.51 to 2.37. The increase in rates did not differ between groups (P = .49). Similarly, rates of skin self-examinations increased significantly from baseline to 18 months in all three groups: PAE, 29% to 50%, RR, 1.75, 95% CI, 1.42 to 2.16; PAE + MD, 31% to 58%, RR, 1.85, 95% CI, 1.52 to 2.26; PAE + MD + TD, 29% to 58%, RR, 1.95, 95% CI, 1.59 to 2.40, but the increase in rates did not differ between groups (P = .43). CONCLUSION: Although skin cancer screening rates increased more than 1.5-fold in each of the intervention groups, there were no differences between groups. Any of these interventions, if implemented, could improve skin cancer prevention behaviors among childhood cancer survivors.

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.

Patient-reported neurocognitive function in adult survivors of childhood and adolescent osteosarcoma and Ewing sarcoma.

PURPOSE: Little is known regarding long-term neurocognitive outcomes in osteosarcoma and Ewing sarcoma (EWS) survivors despite potential risk factors. We evaluated associations among treatment exposures, chronic health conditions, and patient-reported neurocognitive outcomes in adult survivors of childhood osteosarcoma and EWS. METHODS: Five-year survivors of osteosarcoma (N = 604; median age 37.0 years) and EWS (N = 356; median age 35.0 years) diagnosed at < 21 years from 1970 to 1999, and 697 siblings completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire and reported chronic health conditions, education, and employment. Prevalence of reported neurocognitive difficulties were compared between diagnostic groups and siblings. Modified Poisson regression identified factors associated with neurocognitive difficulties. RESULTS: Osteosarcoma and EWS survivors, vs. siblings, reported higher prevalences of difficulties with task efficiency (15.4% [P = 0.03] and 14.0% [P = 0.04] vs. 9.6%, respectively) and emotional regulation (18.0% [P < 0.0001] and 15.2% [P = 0.03] vs. 11.3%, respectively), adjusted for age, sex, and ethnicity/race. Osteosarcoma survivors reported greater memory difficulties vs. siblings (23.5% vs. 16.4% [P = 0.01]). Comorbid impairment (i.e., ≥ 2 neurocognitive domains) was more prevalent in osteosarcoma (20.0% [P < 0.001]) and EWS survivors (16.3% [P = 0.02]) vs. siblings (10.9%). Neurological conditions were associated with worse task efficiency (RR = 2.17; 95% CI = 1.21-3.88) and emotional regulation (RR = 1.88; 95% CI = 1.01-3.52), and respiratory conditions were associated with worse organization (RR = 2.60; 95% CI = 1.05-6.39) for EWS. Hearing impairment was associated with emotional regulation difficulties for osteosarcoma (RR = 1.98; 95% CI = 1.22-3.20). Patient report of cognitive difficulties was associated with employment but not educational attainment. CONCLUSIONS: Survivors of childhood osteosarcoma and EWS are at increased risk for reporting neurocognitive difficulties, which are associated with employment status and appear related to chronic health conditions that develop over time. IMPLICATIONS FOR CANCER SURVIVORS: Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes.

Development and Validation of Models to Predict Poor Health-Related Quality of Life Among Adult Survivors of Childhood Cancer.

Importance: Risk prediction models are important to identify survivors of childhood cancer who are at risk of experiencing poor health-related quality of life (HRQOL) as they age. Objective: To develop and validate prediction models for a decline in HRQOL among adult survivors of childhood cancer. Designs, Setting, and Participants: This prognostic study included 4755 adults from the Childhood Cancer Survivor Study (CCSS) diagnosed between January 5, 1970, and December 31, 1986, who completed baseline (time 0 [November 3, 1992, to August 28, 2003]) and 2 follow-up (time 1 [February 12, 2002, to May 21, 2005] and time 2 [January 6, 2014, to November 30, 2016]) surveys. Data were analyzed from June 19, 2019, to February 2, 2022. Exposures: Sociodemographic, lifestyle, and emotional factors, and chronic health conditions (CHCs) were assessed at time 0 and time 1, and neurocognitive factors were assessed at time 1 to predict HRQOL at time 2 and a decline in HRQOL between time 1 and time 2. Impaired health states were defined as CHC grades 2 to 4 using the modified Common Terminology Criteria for Adverse Events, version 4.03, and mental and neurocognitive status as 1 SD or more below reference levels. Main Outcomes and Measures: Health-related quality of life was operationalized using the Medical Outcomes Study 36-Item Short Form Health Survey Physical (PCS) and Mental (MCS) Component Summary and classified by optimal (≥40) or suboptimal (<40) at each point (main outcome). A decline in HRQOL was defined as a change from optimal to suboptimal between time 1 and time 2. Multivariable logistic regression identified factors associated with HRQOL decline. The cohort was randomly split into training (80%) and test (20%) data sets for model development and validation; the area under the receiver operating characteristic curve was used to evaluate prediction performance. Results: A total of 4755 adults (mean [SD] age at time 0, 24.3 [7.6] years; 2623 [55.2%] women) were included in the analysis. Between time 1 and time 2, 285 of 3294 survivors (8.7%) had declining PCS and 278 of 3294 (8.4%) had declining MCS. Risk factors associated with PCS decline included female sex (odds ratio [OR], 1.67 [95% CI, 1.25-2.24]), family income less than $20 000 vs $80 000 or more (OR, 2.00 [95% CI, 1.21-3.30]), presence of CHCs (OR for neurological, 2.16 [95% CI, 1.51-3.10]; OR for endocrine, 2.25 [95% CI, 1.44-3.52]; OR for gastrointestinal tract, 1.89 [95% CI, 1.32-2.69]; OR for respiratory, 1.66 [95% CI, 1.06-2.59]; OR for cardiovascular, 1.53 [95% CI, 1.14-2.06]), and depression (OR, 1.79 [95% CI, 1.20-2.67]). Risk factors associated with MCS decline included unemployment vs full-time employment (OR, 1.68; [95% CI, 1.19-2.38]), current vs never cigarette smoking (OR, 2.03 [95% CI, 1.37-3.00]), depression (OR, 4.29 [95% CI, 2.44-7.55]), somatization (OR, 1.63 [95% CI, 1.05-2.53]), impaired task efficiency (OR, 1.90 [95% CI, 1.34-2.68]), and impaired organization (OR, 1.67 [95% CI, 1.12-2.48]). The areas under the receiver operating characteristic curve for the test models were 0.74 (95% CI, 0.67-0.81) for declining PCS and 0.68 (95% CI, 0.60-0.75) for declining MCS. Conclusions and Relevance: In this prognostic study of adult survivors of childhood cancer who experienced declining HRQOL, CHCs were associated with a decline in physical HRQOL, whereas current smoking and emotional and neurocognitive impairment were associated with a decline in mental HRQOL. These findings suggest that interventions targeting modifiable risk factors are needed to prevent poor HRQOL in this population.

Underdiagnosis and Undertreatment of Modifiable Cardiovascular Risk Factors Among Survivors of Childhood Cancer.

Background Determine the prevalence and predictors associated with underdiagnosis and undertreatment of modifiable cardiovascular disease (CVD) risk factors (hypertension, dyslipidemia, glucose intolerance/diabetes) among adult survivors of childhood cancer at high risk of premature CVD. Methods and Results This was a cross-sectional study of adult-aged survivors of childhood cancer treated with anthracyclines or chest radiotherapy, recruited across 9 US metropolitan regions. Survivors completed questionnaires and in-home clinical assessments. The comparator group was a matched sample from the National Health and Nutrition Examination Survey. Multivariable logistic regression estimated the risk (odds ratios) of CVD risk factor underdiagnosis and undertreatment among survivors compared with the National Health and Nutrition Examination Survey. Survivors (n=571; median age, 37.7 years and 28.5 years from cancer diagnosis) were more likely to have a preexisting CVD risk factor than the National Health and Nutrition Examination Survey (n=345; P<0.05 for all factors). While rates of CVD risk factor underdiagnosis were similar (27.1% survivors versus 26.1% National Health and Nutrition Examination Survey; P=0.73), survivors were more likely undertreated (21.0% versus 13.9%, P=0.007; odds ratio, 1.8, 95% CI, 1.2-2.7). Among survivors, the most underdiagnosed and undertreated risk factors were hypertension (18.9%) and dyslipidemia (16.3%), respectively. Men and survivors who were overweight/obese were more likely to be underdiagnosed and undertreated. Those with multiple adverse lifestyle factors were also more likely undertreated (odds ratio, 2.2, 95% CI, 1.1-4.5). Greater health-related self-efficacy was associated with reduced undertreatment (odds ratio, 0.5; 95% CI, 0.3-0.8). Conclusions Greater awareness of among primary care providers and cardiologists, combined with improving self-efficacy among survivors, may mitigate the risk of underdiagnosed and undertreated CVD risk factors among adult-aged survivors of childhood cancer. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03104543.

Health-related and cancer risk concerns among siblings of childhood cancer survivors: a report from the Childhood Cancer Survivor Study (CCSS).

OBJECTIVE: To characterize the prevalence and predictors of concerns regarding future health and cancer risk among siblings of childhood cancer survivors. METHODS: This study reports longitudinal data (baseline and follow-up) from 3969 adult siblings (median age = 29 [range 18-56] years) of long-term survivors of childhood cancer (median time since diagnosis 19.6 [9.6-33.8] years). Self-reported future health and cancer risk concerns (concerned vs not concerned) were assessed. Demographics and health data reported by both the siblings and their matched cancer survivors were examined as risk factors for health concerns using multivariable logistic regression. RESULTS: Percentage of siblings reporting future health and cancer risk concerns, respectively, decreased across decade of survivors' diagnosis: 1970s (73.3%; 63.9%), 1980s (67.2%; 62.6%), and 1990s (45.7%; 52.3%). Risk factors associated with future health concerns included sibling chronic health conditions (grade 2 Odds Ratio [OR]=1.57, 95% CI: 1.12-2.20; grades 3-4 OR=1.86, 95% CI: 1.18-2.94; compared to less than grade 2). Risk factors associated with future cancer concerns included sibling chronic health conditions (grade 2 OR=1.43, 95% CI: 1.05-1.94; grades 3-4 OR=1.64, 95% CI: 1.09-2.47; compared to less than grade 2). CONCLUSIONS: Sibling concerns regarding future health and cancer have diminished in recent decades. There are subgroups of siblings that are at-risk for future health and cancer risk concerns. IMPLICATIONS FOR CANCER SURVIVORS: Routine screening of concerns in at-risk siblings of survivors of childhood cancer may benefit the siblings of cancer survivors. These individuals may benefit from early interventions during diagnosis and treatment of their siblings.

Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer.

BACKGROUND: Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction. METHODS: A polygenic risk score (PRS) was calculated from 12 independent SNPs associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS. RESULTS: Among 2,370 SJLIFE survivors with a median follow-up of 28.8 [interquartile range (IQR) = 21.9-36.1] years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC [relative rate (RR) = 1.57; 95% confidence interval (CI) = 1.24-1.98; P < 0.001]. Similar associations were replicated in 6,416 CCSS survivors, among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR = 22.6-34.6) years (RR = 1.52; 95% CI = 1.25-1.83; P < 0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE (P = 0.004, AUC = 83.2% vs. 82.1%, at age 40), which was further validated in CCSS (P = 0.010, AUC = 72.9% vs. 70.6%). CONCLUSIONS: Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest. IMPACT: PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care.

Longitudinal Evaluation of Neuromuscular Dysfunction in Long-term Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: Children treated for cancer are at risk for neuromuscular dysfunction, but data are limited regarding prevalence, longitudinal patterns, and long-term impact. METHODS: Longitudinal surveys from 25,583 childhood cancer survivors ≥5 years from diagnosis and 5,044 siblings from the Childhood Cancer Survivor Study were used to estimate the prevalence and cumulative incidence of neuromuscular dysfunction. Multivariable models adjusted for age, sex, race, and ethnicity estimated prevalence ratios (PR) of neuromuscular dysfunction in survivors compared with siblings, and associations with treatments and late health/socioeconomic outcomes. RESULTS: Prevalence of neuromuscular dysfunction was 14.7% in survivors 5 years postdiagnosis versus 1.5% in siblings [PR, 9.9; 95% confidence interval (CI), 7.9-12.4], and highest in survivors of central nervous system (CNS) tumors (PR, 27.6; 95% CI, 22.1-34.6) and sarcomas (PR, 11.5; 95% CI, 9.1-14.5). Cumulative incidence rose to 24.3% in survivors 20 years postdiagnosis (95% CI, 23.8-24.8). Spinal radiotherapy and increasing cranial radiotherapy dose were associated with increased prevalence of neuromuscular dysfunction. Platinum exposure (vs. none) was associated with neuromuscular dysfunction (PR, 1.8; 95% CI, 1.5-2.1), even after excluding survivors with CNS tumors, cranial/spinal radiotherapy, or amputation. Neuromuscular dysfunction was associated with concurrent or later obesity (PR, 1.1; 95% CI, 1.1-1.2), anxiety (PR, 2.5; 95% CI, 2.2-2.9), depression (PR, 2.1; 95% CI, 1.9-2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90-0.94) and employment (PR, 0.8; 95% CI, 0.8-0.9). CONCLUSIONS: Neuromuscular dysfunction is prevalent in childhood cancer survivors, continues to increase posttherapy, and is associated with adverse health and socioeconomic outcomes. IMPACT: Interventions are needed to prevent and treat neuromuscular dysfunction, especially in survivors with platinum and radiation exposure.

Prevalence and predictors of cancer-related worry and associations with health behaviors in adult survivors of childhood cancer.

BACKGROUND: Cancer-related worry (CRW) is common among cancer survivors; however, little is known about factors associated with CRW or its impact on health behaviors in adult survivors of childhood cancer. METHODS: Survivors in the St. Jude Lifetime Cohort Study (n = 3211; 51% male; mean age, 31.2 years [SD, 8.4 years]; mean time after diagnosis, 22.8 years [SD, 8.3 years]) underwent medical evaluations and completed ratings of CRW, psychological symptoms, and health behaviors. Multivariable modified Poisson regression models examined associations between CRW and treatment exposures, chronic health conditions, psychological symptoms, and health behaviors. RESULTS: Sixty-four percent of survivors (95% confidence interval [CI], 62.6-65.9) reported worry about subsequent malignancy, 45% (95% CI, 43.5-46.9) reported worry about physical problems related to cancer, and 33% (95% CI, 31.2-34.4) reported worry about relapse. Multiple psychological symptoms, treatment exposures, and chronic conditions significantly increased the risk of CRW. Survivors reporting CRW were at increased risk for substance use, inadequate physical activity, and increased health care utilization after adjustments for chronic conditions. For example, with adjustments for chronic conditions, those who endorsed CRW were more likely to have ≥5 cancer-related physician visits, ≥5 physician visits related to cancer, and ≥5 calls to a physician's office in the previous 2 years in comparison with survivors who were not worried. CRW was also associated with an increased risk of current tobacco use, past marijuana use, and current marijuana use. CONCLUSIONS: A substantial proportion of adult survivors of childhood cancer reported CRW associated with increased health care utilization. CRW may serve as an intervention target to promote well-being and adaptive health behaviors.

Sex-Specific Associations Between Chemotherapy, Chronic Conditions, and Neurocognitive Impairment in Acute Lymphoblastic Leukemia Survivors: A Report From the Childhood Cancer Survivor Study.

BACKGROUND: The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only. METHODS: This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided. RESULTS: Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92). CONCLUSION: Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.

Psychological, educational, and social late effects in adolescent survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.

OBJECTIVE: To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor. METHODS: Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis. RESULTS: Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40). CONCLUSIONS: Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.

Wearable Respiratory Monitoring and Feedback for Chronic Pain in Adult Survivors of Childhood Cancer: A Feasibility Randomized Controlled Trial From the Childhood Cancer Survivor Study.

PURPOSE: Approximately 40% of childhood cancer survivors experience chronic pain, with many also reporting pain-related disability. Given associations established in the general population among respiration, anxiety, and pain, continuous tracking and feedback of respiration may help survivors manage pain. METHODS: A feasibility, nonblinded, randomized controlled trial (RCT) comparing wearable respiratory monitoring with a control group examined feasibility, acceptability, and preliminary efficacy among survivors of childhood cancer with chronic pain who were ≥ 18 years of age, able to speak and read English, lived in the United States, and had access to a smartphone and the Internet. The primary outcomes were pain interference, pain severity, anxiety, negative affect, and perceived stress. The intervention group (n = 32) received a wearable respiratory monitor, used the device, and completed an in-application breathing exercise daily for 30 days. The control group (n = 33) received psychoeducation after completion of the study. RESULTS: Almost all participants in the intervention group (n = 31 of 32) and control group (n = 32 of 33) completed the study. Of those who completed the intervention, 90.3% wore the device for ≥ 50% of the trial. Posttreatment improvement for negative affect (Cohen d = 0.59; 95% CI, 0.09 to 1.10) was significantly greater in the intervention group compared with the control group. A follow-up study (n = 24) examined acceptability and feasibility of a second-generation device among those who completed the RCT. Most survivors (81.0%) wore the device daily during the trial and 85.7% reported satisfaction with the device and the application. CONCLUSION: The results of this pilot study support the acceptability and feasibility of wearable respiratory monitoring among survivors of childhood cancer. Larger randomized trials are needed to assess efficacy and maintenance of this intervention for chronic pain.

Prescription Psychoactive Medication Use in Adolescent Survivors of Childhood Cancer and Association With Adult Functional Outcomes.

BACKGROUND: This study estimates the prevalence and identifies predictors of psychoactive medication use in adolescent survivors of childhood cancer (aged 12-18 years) and its associations with functional outcomes at young adulthood (aged 18-28 years). METHODS: This retrospective cohort study includes 5665 adolescent survivors of childhood cancer at no less than 5 years postdiagnosis (53.8% male, median age = 15 years, interquartile range [IQR] = 13-16 years) and 921 adolescent sibling controls. Parent-reported psychoactive medication use during adolescence was collected at baseline. After a median of 8 years, functional outcomes and social attainment were self-reported during adulthood (n = 3114, median age = 22 years, IQR = 20-24 years). Multivariable log-binomial models evaluated associations among risk factors, medication use, and adult outcomes. RESULTS: Higher prevalence of psychoactive medication use was reported in survivors compared with siblings (18.3% vs 6.6%; 2-sided P < .001), with trends for increasing antidepressant and stimulant use in recent treatment eras. After adjusting for cancer treatment and baseline cognitive problems, psychoactive medication use during adolescence was associated with impaired task efficiency (relative risk [RR] = 1.20, 95% confidence interval [CI] = 1.01 to 1.43) and memory (RR = 1.27, 95% CI = 1.05 to 1.52) during adulthood. Survivors who reported continued use of medications from adolescence to adulthood demonstrated poorer emotional regulation (RR = 1.68, 95% CI = 1.24 to 2.27) and organization (RR = 1.82, 95% CI = 1.28 to 2.59) compared with nonusers. Adolescent opioid use was associated with somatization symptoms (RR = 1.72, 95% CI = 1.09 to 2.73) during adulthood, after adjusting for cancer treatment and baseline behavioral problems. They were also more likely to not complete college (RR = 1.21, 95% CI = 1.04 to 1.41) or work full-time (RR = 1.60, 95% CI = 1.23 to 2.08) compared with nonusers. CONCLUSION: Use of psychoactive medication is more prevalent among adolescent survivors compared with siblings and does not normalize adult outcomes, as evidenced by poorer functional outcomes during young adulthood.