Childhood Cancer Survivor Study Cohort Research Articles

The cumulative burden of self-reported, clinically relevant outcomes in long-term childhood cancer survivors and implications for survivorship care: A DCCSS LATER study.

The aim of this study is to evaluate how cumulative burden of clinically relevant, self-reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. The authors invited 5925 5-year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete aquestionnaire on health outcomes. Health outcomes were validated by self-reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30-year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30-year MCC, and compared the ranking to levels of care according to existing risk stratifications. At median 18.5years after 5-year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30-year MCC=0.79; 95% confidence interval [CI], 0.74-0.85 vs. 30-year MCC=0.29; 95% CI, 0.25-0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30-year MCC often did not correspond with levels of care in existing risk stratifications. CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity.

Primary Care Utilization and Cardiovascular Screening in Adult Survivors of Childhood Cancer

Cardiovascular disease is the leading noncancer cause of premature death among survivors of childhood cancer. Adult survivors of childhood cancer are largely managed by primary care practitioners (PCPs), and health care utilization patterns related to cardiovascular screening are not well described. To examine screening and health care utilization among survivors of childhood cancer at high risk for cardiovascular complications. This multicenter cross-sectional study included participants enrolled in a randomized clinical trial from 2017 to 2021. Abstracted documentation of participants' cancer history, cardiotoxic treatment exposures, and survivorship care plans were obtained from participants' PCPs spanning 2 years preceding trial enrollment. Participants were members of the Childhood Cancer Survivor Study cohort at elevated risk for ischemic heart disease or heart failure, enrolled in a randomized trial focused on improving cardiovascular risk factor control. Data were analyzed from November 2022 to July 2023. Outcomes of interest were numbers of PCP and specialist visits, cardiovascular risk factors (hypertension, dyslipidemia, and diabetes), risk factor screening, and cardiac testing. Multivariable logistic regression assessed characteristics associated with up-to-date cardiac testing at enrollment. Of 347 enrolled participants, 293 (84.4%) had evaluable medical records (median [range] age, 39.9 [21.5-65.0] years; 149 [50.9%] male) and were included in analyses. At baseline, 238 participants (81.2%) had a documented PCP encounter; 241 participants (82.3%) had undergone blood pressure screening, 179 participants (61.1%) had undergone lipid testing, and 193 participants (65.9%) had undergone diabetes screening. A total of 63 participants (21.5%) had echocardiography completed or planned. Only 198 participants (67.6%) had records referencing a cancer history. PCP documentation of prior cardiotoxic exposures was low compared with known exposures, including radiation therapy (103 participants [35.2%] vs 203 participants [69.3%]; P < .001) and anthracycline chemotherapy (27 participants [9.2%] vs 222 participants [75.8%]; P = .008). Few records referenced a need for cancer-related late effects surveillance (95 records [32.4%]). Independent factors associated with cardiac screening included documentation of increased cardiovascular disease risk (odds ratio [OR], 11.94; 95% CI, 3.37-42.31), a late-effects surveillance plan (OR, 3.92; 95% CI, 1.69-9.11), and existing cardiovascular risk factors (OR per each additional factor, 2.09; 95% CI, 1.32-3.31). This cross-sectional study of adult survivors of childhood cancer at increased risk of cardiovascular disease found low adherence to recommended cardiac testing and documentation of risk for these individuals. Improving accuracy of reporting of survivors' exposures and risks within the medical record may improve screening.

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort

Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. Canadian Institutes of Health Research, US National Cancer Institute.

Increased Cardiac Risk After a Second Malignant Neoplasm Among Childhood Cancer Survivors: A FCCSS Study

BackgroundChildhood cancer survivors (CCS) are at an elevated risk of developing both a second malignant neoplasm (SMN) and cardiac disease. ObjectivesThis study sought to assess the excess of occurrence of cardiac disease after a SMN among CCS. MethodsAnalyses included 7,670 CCS from the French Childhood Cancer Survivors Study cohort diagnosed between 1945 and 2000. To account for the time dependence of the occurrence of a SMN, we employed a landmark approach, considering an additive regression model for the cumulative incidence of cardiac disease. We estimated the effect of a SMN on the instantaneous risk of cardiac disease using a proportional cause-specific hazard model, considering a SMN as a time-dependent exposure. In both models, we adjusted for demographic and treatment information and considered death as a competing event. ResultsIn 7,670 CCS over a median follow-up of 30 years (IQR: 22-38 years), there were 378 cases of cardiac disease identified, of which 49 patients experienced a SMN. Patients who survived 25 years after their childhood cancer diagnosis and had a SMN in that time frame had a significantly increased cumulative incidence of cardiac disease, which was 3.8% (95% CI: 0.5% to 7.1%) higher compared with those without a SMN during this period. No SMN-induced excess of cardiac disease was observed at subsequent landmark times. SMNs were associated with a 2-fold increase (cause-specific HR: 2.0; 95% CI: 1.4-2.8) of cardiac disease. ConclusionsThe occurrence of a SMN among CCS is associated with an increased risk of cardiac disease occurrence and risk at younger ages.

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study

Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001). Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden. American Lebanese Syrian Associated Charities and US National Institutes of Health.

Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report.

Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases. SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models. A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P < .01), anthracyclines (20% v 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% v 1%; HR, 12.20; P < .001), or platinums (46% v 7%; HR, 8.58; P < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors. A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.

Risk factors for obesity in adulthood among survivors of childhood cancer

AbstractObjectiveThe aim of this study was to identify risk factors for obesity in childhood cancer survivors (CCSs).MethodsThe study included 3199 patients of the French Childhood Cancer Survivor Study cohort, with 303 patients with obesity who had returned the self‐questionnaire. Analyses were adjusted for social deprivation index and sex.ResultsCCSs were less likely to have obesity (9.5%; 95% CI: 8.5%–10.5%) than expected from the general French population rates (12.5%; p = 0.0001). Nevertheless, brain tumor survivors were significantly more likely to develop obesity than the general French population (p = 0.0001). Compared with patients who did not receive radiotherapy to the pituitary gland, those who received a dose &gt;5 Gy had an increased risk of obesity: relative risk 1.9 (95% CI: 1.2–3.1), 2.5 (95% CI: 1.7–3.7), and 2.6 (95% CI: 1.6–4.3), respectively, for participants with 6 to 20 Gy, 20 to 40 Gy, and ≥40 Gy of radiation. Etoposide administration significantly increased the risk of obesity (relative risk 1.7; 95% CI: 1.1–2.6). High social deprivation index was also a risk factor, just like BMI at diagnosis.ConclusionsLong‐term follow‐up of CCSs should include weight follow‐up during adulthood.

Primary care utilization and cardiovascular screening in adult-aged survivors of childhood cancer: A report from the childhood cancer survivor study (CCSS).

e22020 Background: Among the half million survivors of childhood cancer in the US, cardiovascular disease (CVD) is the leading non-cancer cause of premature death. Adult survivors of childhood cancer are largely managed by community-based primary care providers (PCPs), and healthcare utilization patterns related to CVD screening and survivorship care are not well-described. Methods: Within the CCSS cohort, we conducted a randomized intervention trial (NCT03104543) focused on improving CVD risk factor control among survivors at increased risk for CVD due to prior chest radiotherapy and/or anthracycline chemotherapy. Using medical records from participants’ PCPs over the 2 years preceding trial enrollment, we ascertained the numbers of PCP and specialist visits, CVD conditions (i.e., hypertension, dyslipidemia, diabetes) and screening (i.e., blood pressure, lipid, diabetes testing, and cardiac testing [ECG, echocardiogram, or other imaging completed or planned]). We also abstracted acknowledgement of participants’ cancer history, cardiotoxic treatment exposures, or a survivorship care plan (SCP). Multivariable logistic regression assessed characteristics associated with having cardiac testing, retaining covariates associated with p &lt; 0.10 in univariate testing. Results: Of 347 enrolled participants, 293 (84%) had evaluable data (median age 40y, range 22–65; 49% female; 87% non-Hispanic White; mean 31y since childhood cancer). In the prior 2y, 81% of participants had a documented PCP office visit (median 3 visits [IQR 2–5]), 22% had a subspecialty visit (4% saw cardiology), and 16% had no visits. The prevalence of blood pressure, lipid, and diabetes screening was 82%, 57%, and 63%, respectively; 29% had cardiac testing done or planned, including 22% with echocardiography. Only 68% of participants had records referencing a history of cancer. PCP documentation of prior cardiotoxic exposures was low compared with known exposures: radiotherapy (35% vs 69%; p &lt; 0.001), anthracycline chemotherapy (9% vs 76%; p = 0.017); only 12% had any documentation noting an increased risk for CVD. Few participants’ records referenced a need for cancer-related late effects surveillance (38%), and even fewer referenced an SCP (5%). In multivariable analysis, independent predictors of cardiac testing included documentation of increased CVD risk (Odds Ratio [OR] 11.61, 95% CI 3.31–40.67), presence of a late effects surveillance plan (OR 3.71, 95% CI 1.62–8.48), and existing CVD conditions (modeled as 0, 1, or 2+ conditions; OR 2.21, 95% CI 1.41–3.47, for each additional level). Conclusions: Adult survivors of childhood cancer at increased risk of CVD had low rates of cardiac testing and documentation of risk in PCP medical records. Increasing participant and PCP awareness of CVD risks and late effects surveillance recommendations may improve screening.

Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort.

Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions. We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions. Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system. Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible. US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.

Abstract 34: Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania

Abstract Purpose: Global advancement in pediatric cancer treatment has significantly increased survival rates for children with cancer. Childhood cancer survivors (CCS) now represent a growing population at risk of potentially debilitating late effects of their treatment. This study evaluates the potential risk for long-term complications related to cancer therapy among childhood cancer survivors who completed treatment in Tanzania at Bugando Medical Centre (BMC), and compares the relative risk assessment of childhood cancer survivors at BMC as compared to the published British Childhood Cancer Survivor Study (BCCSS) cohort. Methods: Files of all patients age &amp;lt;18 yo with an oncologic diagnosis who received and completed their treatment at BMC from 2016 to 2020 were retrospectively reviewed. Extracted data included patient demographics, primary disease diagnosis and site, treatment received, and cumulative treatment doses. BCCSS risk assessment was assigned and predicted long-term follow-up surveillance needs were extrapolated from published Children’s Oncology Group Long-Term Follow-Up Guidelines. Results: 190 patients were initially identified, with 17 excluded due to missing treatment information. Among the remaining 173 patients, the mean age was 7yo, 47% were female (n=82), and the most common diagnoses were Wilms tumour (30%, n=52) and Burkitt’s Lymphoma (26%, n=45). 98% received chemotherapy (n=170), 42% (n=73) underwent tumour resection, and 8% (n=18) received radiation. Distribution of BCCSS late effect risk assessment included 6% low risk (n=10), 80% moderate risk (n=139) and 14% (n=24) high risk. This was a higher rate of moderate/severe risk (94%) compared to the published UK BCCSS cohort (84%). Based on treatment received, the late effects with highest potential risk were cardiomyopathy (57% of patients, n=98), bladder and urinary tract toxicity (50%, n=87), and ototoxicity (22%, n=38). Conclusion: Childhood cancer survivors at BMC have a higher risk of late effects as compared to published survivor cohorts in high-income countries. There is a need to develop and improve long-term follow-up care for survivors by enhancing patient and provider education to promote early detection of late effects. Based on risk assessment, survivorship programs in Tanzania should at a minimum include the capacity to perform echocardiograms, urinalysis, renal ultrasound, audiological evaluation, fundoscopic and neurological exams, and renal function test. Citation Format: Goodluck Nchasi, Gaudence Ajuaye, David Noyd, Hannah Spiegl, Erica Sanga, Heronima Joas, Kristin Schroeder. Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 34.

Medicaid enrollment changes among U.S. adult survivors of childhood cancer following medicaid expansion: A report from the Childhood Cancer Survivor Study (CCSS).

10011 Background: Little is known about whether Medicaid expansion under the Affordable Care Act (ACA) affected insurance coverage among adult survivors of childhood cancer, a population at high-risk for poor health outcome. We addressed this gap by evaluating the association between ACA Medicaid expansion and Medicaid enrollment among participants in the Childhood Cancer Survivor Study (CCSS). Methods: The CCSS cohort of 5-year survivors of childhood cancer was linked to administrative Medicaid insurance data in 2010-2016. We identified 13,895 adult survivors (aged 18-64 years) diagnosed with cancer under age 21 and between 1970 and 1999. Outcomes included (1) percentage with any Medicaid enrollment by year; and (2) Medicaid-covered days (number of days when a survivor was enrolled in Medicaid) during each year. Multivariable difference-in-differences (DD) models were used to examine outcome changes pre vs. post ACA Medicaid expansion, in expansion- vs. non-expansion states, adjusting for age, sex, race/ethnicity, income, education, and chronic conditions. Multivariable models were conducted overall and then stratified by cancer type, race/ethnicity, income, and education. Results: Medicaid enrollment rates increased more in expansion states (17.6% pre-expansion to 24.1% post-expansion) than non-expansion states (16.4% to 16.9%), leading to a net increase in enrollment of 6.6 percentage points (ppt; 95% CI = 5.5-7.7) in the multivariable DD model. Multivariable DD model showed a net increase of 18.4 days (95% CI = 13.8-23.1) in Medicaid-covered days in expansion states relative to non-expansion states. The expansion-associated increase in Medicaid enrollment rates was greatest among survivors of leukemia (multivariable DD estimate: 8.9 ppt, 95% CI = 6.9-11.0) and non-Hodgkin lymphoma (8.0 ppt, 95% CI = 5.0-10.9). Greater increases in Medicaid enrollment were seen in non-Hispanic Black (13.5 ppt, 95% CI = 8.0-19.1) and Hispanic survivors (15.8 ppt, 95% CI = 10.6-21.0) than non-Hispanic White peers (5.1 ppt; 95% CI = 4.0-6.2); in survivors with &lt; $20K household income (11.7 ppt, 95% CI = 8.9-14.4) compared to those with ≥$60K household income (2.9 ppt, 95% CI = 1.6-4.2); and in survivors with high school or lower education (9.3 ppt, 95% CI = 6.9-11.8) compared to those with a college or higher degree (3.9 ppt, 95% CI = 2.6-5.3). Similar patterns were observed across survivor subgroups when examining Medicaid-covered days. Conclusions: We provide the first evidence on increased Medicaid enrollment and longer coverage duration among adult survivors of childhood cancer following Medicaid expansion, with greater increases seen among survivors of underrepresented racial/ethnic populations, those with low socioeconomic status, and high medical need survivors.

Accumulation of Chronic Disease Among Survivors of Childhood Cancer Predicts Early Mortality.

Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality. CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and members of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. CIRS-G metrics were analyzed using Cox proportional hazards regression to determine subsequent mortality risk. In total, 14,355 survivors with a median age of 24 (IQR, 18-30) years and 4,022 siblings with a median age of 26 (IQR, 19-33) years provided baseline data; 6,138 survivors and 1,801 siblings provided follow-up data. Cancer survivors had higher median baseline TS than siblings at baseline (5.75 v 3.44) and follow-up (7.76 v 4.79), all P < .01. The mean increase in TS from baseline to follow-up was significantly steeper in cancer survivors (2.89 males and 3.18 females) vs. siblings (1.79 males and 1.69 females) and NHANES population (2.0 males and 1.94 females), all P < .01. Every point increase in baseline TS increased hazard for death by 9% (95% CI, 8 to 10) among survivors. Application of a geriatric rating scale to characterize disease supports the hypothesis that morbidity accumulation is accelerated in young adult survivors of childhood cancer when compared with siblings and the general population.

Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort

5-year survival after childhood cancer does not fully describe life-years lost due to childhood cancer because there are a large number of deaths occurring beyond 5-years (late mortality) related to cancer and cancer treatment. Specific causes of health-related (non-recurrence, non-external) late mortality and risk reduction through modifiable lifestyle and cardiovascular risk factors are not well described. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk. In this multi-institutional, hospital-based, retrospective cohort study, late mortality (death ≥5 years from diagnosis) and specific causes of death were evaluated in 34 230 5-year survivors of childhood cancer diagnosed at an age younger than 21 years from 1970 to 1999 at 31 institutions in the USA and Canada; median follow-up from diagnosis was 29 years (range 5-48) in the Childhood Cancer Survivor Study. Demographic, self-reported modifiable lifestyle (ie, smoking, alcohol, physical activity, and BMI) and cardiovascular risk factors (ie, hypertension, diabetes, and dyslipidaemia) associated with health-related mortality (which excludes death from primary cancer and external causes and includes death from late effects of cancer therapy) were evaluated. 40-year cumulative all-cause mortality was 23·3% (95% CI 22·7-24·0), with 3061 (51·2%) of 5916 deaths from health-related causes. Survivors 40 years or more from diagnosis experienced 131 excess health-related deaths per 10 000 person-years (95% CI 111-163), including those due to the top three causes of health-related death in the general population: cancer (absolute excess risk per 10 000 person-years 54, 95% CI 41-68), heart disease (27, 18-38), and cerebrovascular disease (10, 5-17). Healthy lifestyle and absence of hypertension and diabetes were each associated with a 20-30% reduction in health-related mortality independent of other factors (all p values ≤0·002). Survivors of childhood cancer are at excess risk of late mortality even 40 years from diagnosis, due to many of the leading causes of death in the US population. Modifiable lifestyle and cardiovascular risk factors associated with reduced risk for late mortality should be part of future interventions. US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Frailty and sarcopenia within the earliest national Dutch childhood cancer survivor cohort (DCCSS-LATER): a cross-sectional study.

Childhood cancer survivors appear to be at increased risk of frailty and sarcopenia, but evidence on the occurrence of and high-risk groups for these aging phenotypes is scarce, especially in European survivors. The aim of this cross-sectional study was to assess the prevalence of and explore risk factors for pre-frailty, frailty, and sarcopenia in a national cohort of Dutch childhood cancer survivors diagnosed between 1963 and 2001. Eligible individuals (alive at the time of study, living in the Netherlands, age 18-45 years, and had not previously declined to participate in a late-effects study) from the Dutch Childhood Cancer Survivor Study (DCCSS-LATER) cohort were invited to take part in this cross-sectional study. We defined pre-frailty and frailty according to modified Fried criteria, and sarcopenia according to the European Working Group on Sarcopenia in Older People 2 definition. Associations between these conditions and demographic and treatment-related as well as endocrine and lifestyle-related factors were estimated with two separate multivariable logistic regression models in survivors with any frailty measurement or complete sarcopenia measurements. 3996 adult survivors of the DCCSS-LATER cohort were invited to participate in this cross-sectional study. 1993 non-participants were excluded due to lack of response or a decline to participate and 2003 (50·1%) childhood cancer survivors aged 18-45 years were included. 1114 (55·6%) participants had complete frailty measurements and 1472 (73·5%) participants had complete sarcopenia measurements. Mean age at participation was 33·1 years (SD 7·2). 1037 (51·8%) participants were male, 966 (48·2%) were female, and none were transgender. In survivors with complete frailty measurements or complete sarcopenia measurements, the percentage of pre-frailty was 20·3% (95% CI 18·0-22·7), frailty was 7·4% (6·0-9·0), and sarcopenia was 4·4% (3·5-5·6). In the models for pre-frailty, underweight (odds ratio [OR] 3·38 [95% CI 1·92-5·95]) and obesity (OR 1·67 [1·14-2·43]), cranial irradiation (OR 2·07 [1·47-2·93]), total body irradiation (OR 3·17 [1·77-5·70]), cisplatin dose of at least 600 mg/m2 (OR 3·75 [1·82-7·74]), growth hormone deficiency (OR 2·25 [1·23-4·09]), hyperthyroidism (OR 3·72 [1·63-8·47]), bone mineral density (Z score ≤-1 and >-2, OR 1·80 [95% CI 1·31-2·47]; Z score ≤-2, OR 3·37 [2·20-5·15]), and folic acid deficiency (OR 1·87 [1·31-2·68]) were considered significant. For frailty, associated factors included age at diagnosis between 10-18 years (OR 1·94 [95% CI 1·19-3·16]), underweight (OR 3·09 [1·42-6·69]), cranial irradiation (OR 2·65 [1·59-4·34]), total body irradiation (OR 3·28 [1·48-7·28]), cisplatin dose of at least 600 mg/m2 (OR 3·93 [1·45-10·67]), higher carboplatin doses (per g/m2; OR 1·15 [1·02-1·31]), cyclophosphamide equivalent dose of at least 20 g/m2 (OR 3·90 [1·65-9·24]), hyperthyroidism (OR 2·87 [1·06-7·76]), bone mineral density Z score ≤-2 (OR 2·85 [1·54-5·29]), and folic acid deficiency (OR 2·04 [1·20-3·46]). Male sex (OR 4·56 [95%CI 2·26-9·17]), lower BMI (continuous, OR 0·52 [0·45-0·60]), cranial irradiation (OR 3·87 [1·80-8·31]), total body irradiation (OR 4·52 [1·67-12·20]), hypogonadism (OR 3·96 [1·40-11·18]), growth hormone deficiency (OR 4·66 [1·44-15·15]), and vitamin B12 deficiency (OR 6·26 [2·17-1·81]) were significantly associated with sarcopenia. Our findings show that frailty and sarcopenia occur already at a mean age of 33 years in childhood cancer survivors. Early recognition and interventions for endocrine disorders and dietary deficiencies could be important in minimising the risk of pre-frailty, frailty, and sarcopenia in this population. Children Cancer-free Foundation, KiKaRoW, Dutch Cancer Society, ODAS Foundation.

Risk of Renal or Urinary Related Hospitalization in Survivors of Childhood Cancer: Results from the French Childhood Cancer Survivor Study.

Hospitalization rates can be used as an indirect indicator of the burden and severity of adverse health outcomes in childhood cancer survivors (CCS). We aimed to determine the long-term risks of hospitalization related to renal and urinary diseases among 5-year CCS. The French Childhood Cancer Survivor Study cohort was linked with data from the French National Healthcare System database, which enabled the identification of hospitalizations related to renal or urinary diseases. Clinical and detailed treatment data were collected from medical records. Dose-volume histograms were estimated for all patients treated with radiotherapy. Standardized Hospitalization Ratios and absolute excess risks (AER) were calculated. Relative risks were estimated using Poisson regression. A total of 5,498 survivors were followed for 42,118 person-years (PY). Survivors experience 2.9 times more renal hospitalizations than expected in the general population, with an AER of 21.2/10,000 PY. Exposing more than 10% of the kidneys' volume to at least 20 Gray increases the risk of being hospitalized for renal causes by 2.2 (95% confidence interval, 1.3-3.6). Nephrectomized survivors treated with high doses of ifosfamide (>60 g/m²) have an extremely high risk of hospitalization for renal causes. Patients with comorbidities have about a 3-fold higher risk, and nephrectomized patients a 2-fold higher risk of being hospitalized for renal causes compared with other subjects. In the case of hospitalization for urinary causes, treatment by anthracycline administration was found to be associated with an almost 2-fold higher risk of hospitalization compared with the general population. These results support the need for careful monitoring of long-term renal diseases in survivors who have undergone nephrectomy, those treated with high doses of radiation (≥20 Gy) even to small volumes of the kidneys, and those with predisposing risk factors. This study provides new evidence with potential impact on surveillance guidelines related to dose-volume indicators associated with renal toxicity.

An algorithm for identifying chronic kidney disease in the French national health insurance claims database

BackgroundPublished algorithms for identifying chronic kidney disease in healthcare claims databases have poor performance except in patients with renal replacement therapy. We propose and describe an algorithm to identify all stage chronic kidney disease in a French healthcare claims databases and assessed its performance by using data from the Renal Epidemiology and Information Network registry and the French Childhood Cancer Survivor Study cohort. MethodsA group of experts met several times to define a list of items and combinations of items that could be related to chronic kidney disease. For the French Childhood Cancer Survivor Study cohort, information on confirmed chronic kidney disease cases extracted from medical records was considered the gold standard (KDIGO definition). Sensitivity, specificity, and positive and negative predictive value and kappa coefficients were estimated. The contribution of each component of the algorithm was assessed for 1 and 2 years before the start of renal replacement therapy for confirmed end-stage kidney disease in the Renal Epidemiology and Information Network registry. ResultsThe algorithm's sensitivity was 78%, specificity 97.4%, negative predictive value 98.4% and positive predictive value 68.7% in French Childhood Cancer Survivor Study cohort and the kappa coefficient was 0.79 for agreement with the gold standard. The algorithm 93.6% and 55.1% of confirmed incident end-stage kidney disease cases from the Renal Epidemiology and Information Network registry when considering 1 year and 2 years, respectively, before renal replacement therapy start. ConclusionsThe algorithm showed good performance among younger patients and those with end-stage kidney disease in the twol last years prior to renal replacement therapy. Future research will address the ability of the algorithm to detect early chronic kidney disease stages and to classify the severity of chronic kidney disease.

Genome-Wide Association Study of Pregnancy in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study.

Gonadotoxic treatment-related infertility has a significant impact on quality of life in childhood cancer survivors. Genome-wide association analyses to delineate the risk of infertility in childhood cancer survivors have not been previously reported. Leveraging genotype data from a large survivor cohort, the Childhood Cancer Survivor Study (CCSS), we investigated the role of SNPs on future pregnancy or siring a pregnancy in survivors without pelvic, testicular, or brain radiation who had ever been married. We calculated sex-stratified hazard ratios, using Cox proportional hazards modeling, adjusting for birth cohort (before 1965 vs. 1965 or later) and doses of relevant chemotherapies; replication was attempted in the independent St. Jude Lifetime Cohort study (SJLIFE). In the CCSS cohort, nine SNPs were found to be suggestive (P &lt; 10-7) or statistically significantly (P &lt; 5 × 10-8) associated with pregnancy, however, none of the SNPs were replicated in SJLIFE. Cohorts differed based on the overall pregnancy rate, frequency of sterilizing procedures, and birth cohort. We were not able to replicate our findings of SNPs associated with pregnancy in childhood cancer survivors. Future attempts at replication should be considered in cohorts treated in a comparable era. In addition, understanding the role of genetics in fertility in childhood cancer survivors may be better approached using more advanced sequencing techniques.

The Psychological Consequences of the COVID-19 Pandemic in Adults Treated for Childhood Cancer.

Background: Compared with the general population, childhood cancer survivors (CCS) could be at greater risk of psychological distress following the emergence of the COVID-19 pandemic. Purpose: This cross-sectional study assessed the psychological consequences of COVID-19 on the mental health of CCS. Design and participants: In December 2020, we interviewed through an online self-report questionnaire, 580 5-year CCS participating in the French Childhood Cancer Survivor Study (FCCSS) cohort. Methods: We first compared the mental health score of CCS with that observed in the French general population of the same age and gender. Subsequently, we studied predictors of the mental health score of CCS. Results: External comparisons revealed that the mental health score of CCS was similar to that of the general population. Among CCS, almost 42% stated that their psychological state had been worse during the lockdown. Predictors of poorer mental health included, among others, female gender, reporting a change in the occupational situation, having a relative who had been hospitalized or had died following COVID-19, and a greater perceived infection risk. Interpretation and Implications: Given the pre-existing vulnerability of some CCS to mental distress, the additional psychological consequences of COVID-19 in vulnerable survivors should receive attention from health care providers.

Health care expenditures among long-term survivors of pediatric solid tumors: Results from the French Childhood Cancer Survivor Study (FCCSS) and the French network of cancer registries (FRANCIM)

Childhood cancer survivors (CCS) may require lifelong medical care due to late effects of cancer treatments. Little is known about of their healthcare utilization and expenditures at long-term especially in publicly funded health care system. We aim to estimate and describe the health care expenditures among long-term CCS in France. A total of 5319 five-year solid CCS diagnosed before the age of 21 between 1945 and 2000 in France were identified in the French Childhood Cancer Survivors Study cohort (FCCSS) and the French cancer registry. Information about health care expenditure was taken from the French national health data system between 2011 and 2016, and was described according to survivors' characteristics. Generalized linear models were used to determine associations between health care expenditures and survivors' characteristics. Mean annual amount of healthcare expenditures was € 4,255. Expenditures on hospitalizations and pharmacy represents 60% of total expenditures. Mean annual of healthcare expenditures were higher at increasing age, among women survivors (€ 4,795 vs € 3,814 in men) and in central nervous system (CNS) tumor survivors (€ 7,116 vs € 3,366 in lymphoma and € 3,363 in other solid tumor survivors). Childhood cancer survivorship is associated with a substantial economic burden in France. We found that female gender and CNS primary cancer were associated with increased healthcare expenditures.

What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report.

What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report.