Risk of increased mortality in underweight survivors: A brief report from the Childhood Cancer Survivor Study.

BACKGROUND: Approximately 1 in 10 adult survivors of childhood cancer is underweight. Although the consequences of being overweight or obese have been well described, outcomes among childhood cancer survivors who are underweight are unknown. OBJECTIVE: To determine whether underweight status increases the risk of mortality. PROCEDURE: Cohort study: Marginal models with generalized estimating equations to evaluate the associations between body mass index (BMI), serious or life-threatening chronic conditions, and death in the setting of long-term follow-up questionnaires and National Death Index search. PARTICIPANTS: Childhood cancer five-year survivors diagnosed during 1970-1986 in the Childhood Cancer Survivor Study Exposure: Underweight status, defined as body mass index (BMI) < 18.5 kg/m2 compared with ideal body weight. Based on available literature on body weight and mortality from the general population, ideal body weight was defined as BMI 22.0-24.9 kg/m2. MAIN OUTCOMES: Overall mortality and cancer-specific mortality. RESULTS: Of 9454 survivors (median age 35 years old (range, 17-58), an average of 17.5 years from diagnosis), 627 (6.6%) participants were underweight at baseline or follow-up questionnaire. Of 184 deaths, 29 were among underweight survivors. Underweight status was more common among females (9.1% vs. 4.5%, p < .01) and participants with younger age at diagnosis (8.2% for < 5 years vs. 6.1% for ≥5 years, p < .01), lower household income (8.9% for < $20,000 vs. 6.0% for ≥ $20,000, p < .01), or a history of serious chronic condition (p = .05). After adjustment for these factors, in addition to prior smoking and a history of radiation therapy, the risk of all-cause mortality within two years of BMI report was increased (OR 2.85; 95% CI: 1.63-4.97; p < .01) for underweight survivors, compared with ideal-weight survivors. CONCLUSIONS: Childhood cancer survivors who are underweight are at increased risk for late mortality that appears unrelated to smoking status, recognized chronic disease, or subsequent malignancy. Whether targeted nutritional interventions would ameliorate this risk is unknown.

Primary hypothyroidism in childhood cancer survivors: Prevalence, risk factors, and long-term consequences.

BACKGROUND: Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes. METHODS: This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored. RESULTS: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01-1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05-2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14-2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12-2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07-2.12). CONCLUSIONS: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further.

General cancer screening practices among adult survivors of retinoblastoma: Results from the Retinoblastoma Survivor Study.

We assessed breast, cervical, and colorectal cancer screening practices in adult retinoblastoma (Rb) survivors and non-Rb controls. We found that most Rb survivors adhered to general population cancer screening recommendations. Rates did not differ among Rb survivors and non-Rb controls, or among survivors by laterality, even though bilateral survivors reported higher levels of concern about future health and cancer risk. Older age, being overweight/obese, and lack of recent contact with medical personnel were independently associated with decreased utilization of Pap smear among female Rb survivors. Future studies are warranted to determine whether these associations might provide an opportunity for intervention.

Training in Long-Term Follow-Up: Fellowship in Childhood Cancer Survivorship.

Childhood cancer survivors are a growing population with high morbidity and many healthcare needs. As time from treatment lengthens, these patients are more and more likely to be followed in community primary care. Yet, studies suggest that primary care providers are unprepared (although not unwilling) to care for childhood cancer survivors. The 1-year fellowship in childhood cancer survivorship presented herein represents an educational intervention designed to prepare clinical leaders in survivorship. Ultimately, this effort may help address current gaps in care for childhood cancer survivors.

Predicting acute ovarian failure in female survivors of childhood cancer: a cohort study in the Childhood Cancer Survivor Study (CCSS) and the St Jude Lifetime Cohort (SJLIFE).

BACKGROUND: Cancer treatment can cause gonadal impairment. Acute ovarian failure is defined as the permanent loss of ovarian function within 5 years of cancer diagnosis. We aimed to develop and validate risk prediction tools to provide accurate clinical guidance for paediatric patients with cancer. METHODS: In this cohort study, prediction models of acute ovarian failure risk were developed using eligible female US and Canadian participants in the Childhood Cancer Survivor Study (CCSS) cohort and validated in the St Jude Lifetime Cohort (SJLIFE) Study. 5-year survivors from the CCSS cohort were included if they were at least 18 years old at their most recent follow-up and had complete treatment exposure and adequate menstrual history (including age at menarche, current menstrual status, age at last menstruation, and menopausal aetiology) information available. Participants in the SJLIFE cohort were at least 10-year survivors. Participants were excluded from the prediction analysis if they had an ovarian hormone deficiency, had missing exposure information, or had indeterminate ovarian status. The outcome of acute ovarian failure was defined as permanent loss of ovarian function within 5 years of cancer diagnosis or no menarche after cancer treatment by the age of 18 years. Logistic regression, random forest, and support vector machines were used as candidate methods to develop the risk prediction models in the CCSS cohort. Prediction performance was evaluated internally (in the CCSS cohort) and externally (in the SJLIFE cohort) using the areas under the receiver operating characteristic curve (AUC) and the precision-recall curve (average precision [AP; average positive predictive value]). FINDINGS: Data from the CCSS cohort were collected for participants followed up between Nov 3, 1992, and Nov 25, 2016, and from the SJLIFE cohort for participants followed up between Oct 17, 2007, and April 16, 2012. Of 11 336 female CCSS participants, 5886 (51·9%) met all inclusion criteria for analysis. 1644 participants were identified from the SJLIFE cohort, of whom 875 (53·2%) were eligible for analysis. 353 (6·0%) of analysed CCSS participants and 50 (5·7%) of analysed SJLIFE participants had acute ovarian failure. The overall median follow-up for the CCSS cohort was 23·9 years (IQR 20·4-27·9), and for SJLIFE it was 23·9 years (19·0-30·0). The three candidate methods (logistic regression, random forest, and support vector machines) yielded similar results, and a prescribed dose model with abdominal and pelvic radiation doses and an ovarian dose model with ovarian radiation dosimetry using logistic regression were selected. Common predictors in both models were history of haematopoietic stem-cell transplantation, cumulative alkylating drug dose, and an interaction between age at cancer diagnosis and haematopoietic stem-cell transplant. External validation of the model in the SJLIFE cohort produced an estimated AUC of 0·94 (95% CI 0·90-0·98) and AP of 0·68 (95% CI 0·53-0·81) for the ovarian dose model, and AUC of 0·96 (0·94-0·97) and AP of 0·46 (0·34-0·61) for the prescribed dose model. Based on these models, an online risk calculator has been developed for clinical use. INTERPRETATION: Both acute ovarian failure risk prediction models performed well. The ovarian dose model is preferred if ovarian radiation dosimetry is available. The models, along with the online risk calculator, could help clinical discussions regarding the need for fertility preservation interventions in girls and young women newly diagnosed with cancer. FUNDING: Canadian Institutes of Health Research, Women and Children's Health Research Institute, National Cancer Institute, and American Lebanese Syrian Associated Charities.

Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

BACKGROUND: Treatment outcomes among survivors of cancer diagnosed during adolescence and early young adulthood have not been characterised independently of survivors of cancers diagnosed during childhood. We aimed to describe chronic health conditions and all-cause and cause-specific mortality among survivors of early-adolescent and young adult cancer. METHODS: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study with longitudinal follow-up of 5-year survivors diagnosed with cancer before the age of 21 years at 27 academic institutions in the USA and Canada between 1970 and 1999. We evaluated outcomes among survivors of early-adolescent and young adult cancer (aged 15-20 years at diagnosis) and survivors diagnosed at age younger than 15 years (matched on primary cancer diagnosis, including leukaemia, lymphoma, CNS tumours, neuroblastoma, Wilms tumour, soft-tissue sarcomas, and bone cancer) by comparing both groups to siblings of the same age. Mortality was ascertained with the National Death Index. Chronic health conditions were classified with the Common Terminology Criteria for Adverse Events. Standardised mortality ratios (SMRs) were estimated with age-specific, sex-specific, and calendar year-specific US rates. Cox proportional hazard models estimated hazard ratios (HRs) for chronic health conditions and 95% CIs. FINDINGS: Among 5804 early-adolescent and young adult survivors (median age 42 years, IQR 34-50) the SMR compared to the general population for all-cause mortality was 5·9 (95% CI 5·5-6·2) and among 5804 childhood cancer survivors (median age 34 years; 27-42), it was 6·2 (5·8-6·6). Early-adolescent and young adult survivors had lower SMRs for death from health-related causes (ie, conditions that exclude recurrence or progression of the primary cancer and external causes, but include the late effects of cancer therapy) than did childhood cancer survivors (SMR 4·8 [95% CI 4·4-5·1] vs 6·8 [6·2-7·4]), which was primarily evident more than 20 years after cancer diagnosis. Early-adolescent and young adult cancer survivors and childhood cancer survivors were both at greater risk of developing severe and disabling, life-threatening, or fatal (grade 3-5) health conditions than siblings of the same age (HR 4·2 [95% CI 3·7-4·8] for early adolescent and young adult cancer survivors and 5·6 [4·9-6·3] for childhood cancer survivors), and at increased risk of developing grade 3-5 cardiac (4·3 [3·5-5·4] and 5·6 [4·5-7·1]), endocrine (3·9 [2·9-5·1] and 6·4 [5·1-8·0]), and musculoskeletal conditions (6·5 [3·9-11·1] and 8·0 [4·6-14·0]) when compared with siblings of the same age, although all these risks were lower for early-adolescent and young adult survivors than for childhood cancer survivors. INTERPRETATION: Early-adolescent and young adult cancer survivors had higher risks of mortality and severe and life threatening chronic health conditions than the general population. However, early-adolescent and young adult cancer survivors had lower non-recurrent, health-related SMRs and relative risks of developing grade 3-5 chronic health conditions than childhood cancer survivors, by comparison with siblings of the same age, which were most notable more than 20 years after their original cancer. These results highlight the need for long-term screening of both childhood and early-adolescent and young adult cancer survivors. FUNDING: National Cancer Institute and American Lebanese-Syrian Associated Charities.

Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children's Oncology Group ALTE03N1 report.

BACKGROUND: Anthracycline-related cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Glutathione S-transferases (GSTs) are a class of phase II detoxification enzymes that facilitate the elimination of anthracyclines. As free-radical scavengers, GSTs could play a role in oxidative damage-induced cardiomyopathy. Associations between the GSTµ1 (GSTM1) null genotype and iron-overload-related cardiomyopathy have been reported in patients with thalassemia. METHODS: The authors sought to identify an association between the GSTM1 null genotype and anthracycline-related cardiomyopathy in childhood cancer survivors and to corroborate the association by examining GSTM1 gene expression in peripheral blood and human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from survivors with and without cardiomyopathy. GSTM1 gene deletion was examined by polymerase chain reaction in 75 survivors who had clinically validated cardiomyopathy (cases) and in 92 matched survivors without cardiomyopathy (controls). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, chest radiation, and anthracycline dose was used to assess the association between genotype and cardiomyopathy. Proprietary bead array technology and quantitative real-time polymerase chain reaction were used to measure GSTM1 expression levels in samples from 20 cases and 20 matched controls. hiPSC-CMs from childhood cancer survivors (3 with cardiomyopathy, 3 without cardiomyopathy) also were examined for GSTM1 gene expression levels. RESULTS: A significant association was observed between the risk of cardiomyopathy and the GSTM1 null genotype (odds ratio, 2.7; 95% CI, 1.3-5.9; P = .007). There was significant downregulation of GSTM1 expression in cases compared with controls (average relative expression, 0.67 ± 0.57 vs 1.33 ± 1.33, respectively; P = .049). hiPSC-CMs from patients who had cardiomyopathy revealed reduced GSTM1 expression (P = .007). CONCLUSIONS: The current findings could facilitate the identification of childhood cancer survivors who are at risk for anthracycline-related cardiomyopathy.

Late morbidity and mortality in adult survivors of childhood glioma with neurofibromatosis type 1: report from the Childhood Cancer Survivor Study.

PURPOSE: Neurofibromatosis type 1 (NF1) is associated with tumor predisposition and nonmalignant health conditions. Whether survivors of childhood cancer with NF1 are at increased risk for poor long-term health outcomes is unknown. METHODS: One hundred forty-seven 5+ year survivors of childhood glioma with NF1 from the Childhood Cancer Survivor Study were compared with 2629 non-NF1 glioma survivors and 5051 siblings for late mortality, chronic health conditions, and psychosocial, neurocognitive, and socioeconomic outcomes. RESULTS: Survivors with NF1 (age at diagnosis: 6.8 ± 4.8 years) had greater cumulative incidence of late mortality 30 years after diagnosis (46.3% [95% confidence interval: 23.9-62.2%]) compared with non-NF1 survivors (18.0% [16.1-20.0%]) and siblings (0.9% [0.6-1.2%]), largely due to subsequent neoplasms. Compared with survivors without NF1, those with NF1 had more severe/life-threatening chronic conditions at cohort entry (46.3% [38.1-54.4%] vs. 30.8% [29.1-32.6%]), but similar rates of new conditions during follow-up (rate ratio: 1.26 [0.90-1.77]). Survivors with NF1 were more likely to report psychosocial impairments, neurocognitive deficits, and socioeconomic difficulties compared with survivors without NF1. CONCLUSIONS: Late mortality among glioma survivors with NF1 is twice that of other survivors, due largely to subsequent malignancies. Screening, prevention, and early intervention for chronic health conditions and psychosocial and neurocognitive deficits may reduce long-term morbidity in this vulnerable population.

Whole-body magnetic resonance imaging as surveillance for subsequent malignancies in preadolescent, adolescent, and young adult survivors of germline retinoblastoma: An update.

BACKGROUND: Germline retinoblastoma (Rb) survivors are at lifelong risk for developing subsequent malignancies (SMNs). Optimal surveillance modalities are needed to detect SMN at an early stage in this high-risk cohort. We investigated the use of rapid whole-body magnetic resonance imaging (WB-MRI) as a noninvasive screening modality in this cohort. PROCEDURE: WB-MRI was performed in asymptomatic preadolescent, adolescent, or young adult survivors of germline Rb from February 1, 2008 to December 31, 2018 at a tertiary cancer center. We calculated sensitivity and specificity of WB-MRI and rate of false-positive findings requiring additional evaluation. RESULTS: Overall, 110 WB-MRI were performed in 47 germline Rb survivors (51% female; median age at initial WB-MRI: 15.5 years [range 8-25.3]). Patients received 1-10 annual WB-MRI examinations (median: two). Thirteen patients had an abnormal WB-MRI; three findings were deemed to be likely benign and were not evaluated further. Ten patients required dedicated imaging and three required biopsy; two patients were diagnosed with localized high-grade osteosarcoma, while the other eight had benign findings. One patient was diagnosed with secondary osteosarcoma 3 months after normal WB-MRI. In total, there were 96 true negatives, 11 false positives, two true positives, and one false negative. The sensitivity of WB-MRI in this cohort was 66.7% (95% confidence interval [CI], 14.2-96.0) and the specificity was 89.7% (95% CI, 83.6-93.7). CONCLUSIONS: Based on our 10-year experience, surveillance WB-MRI appears to have limited utility as a surveillance modality for SMN in germline Rb survivors. Alternate screening modalities should be investigated.

Impact of enucleation on adult retinoblastoma survivors' quality of life: A qualitative study of survivors' perspectives.

OBJECTIVES: Retinoblastoma is the most common primary intraocular tumor of childhood with >95% survival rates in the US. Traditional therapy for retinoblastoma often included enucleation (removal of the eye). While much is known about the visual, physical, and cognitive ramifications of enucleation, data are lacking about survivors' perception of how this treatment impacts overall quality of life. METHODS: Qualitative analysis of an open-ended response describing how much the removal of an eye had affected retinoblastoma survivors' lives and in what ways in free text, narrative form. RESULTS: Four hundred and four retinoblastoma survivors who had undergone enucleation (bilateral disease = 214; 52% female; mean age = 44, SD = 11) completed the survey. Survivors reported physical problems (n = 205, 50.7%), intrapersonal problems (n = 77, 19.1%), social and relational problems (n = 98, 24.3%), and affective problems (n = 34, 8.4%) at a mean of 42 years after diagnosis. Three key themes emerged from survivors' responses; specifically, they (1) continue to report physical and intrapersonal struggles with appearance and related self-consciousness due to appearance; (2) have multiple social and relational problems, with teasing and bullying being prominent problems; and (3) reported utilization of active coping strategies, including developing more acceptance and learning compensatory skills around activities of daily living. SIGNIFICANCE OF RESULTS: This study suggests that adult retinoblastoma survivors treated with enucleation continue to struggle with a unique set of psychosocial problems. Future interventions can be designed to teach survivors more active coping skills (e.g., for appearance-related issues, vision-related issues, and teasing/bullying) to optimize survivors' long-term quality of life.

Impact of exercise on psychological burden in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Childhood cancer survivors are at risk for adverse psychological outcomes. Whether exercise can attenuate this risk is unknown. METHODS: In total, 6199 participants in the Childhood Cancer Survivor Study (median age, 34.3 years [range, 22.0-54.0 years]; median age at diagnosis, 10.0 years [range, 0-21.0 years]) completed a questionnaire assessing vigorous exercise and medical/psychological conditions. Outcomes were evaluated a median of 7.8 years (range, 0.1-10.0 years) later and were defined as: symptom level above the 90th percentile of population norms for depression, anxiety, or somatization on the Brief Symptom Inventory-18; cancer-related pain; cognitive impairment using a validated self-report neurocognitive questionnaire; or poor health-related quality of life. Log-binomial regression estimated associations between exercise (metabolic equivalent [MET]-hours per week-1 ) and outcomes adjusting for cancer diagnosis, treatment, demographics, and baseline conditions. RESULTS: The prevalence of depression at follow-up was 11.4% (95% CI, 10.6%-12.3%), anxiety 7.4% (95% CI, 6.7%-8.2%) and somatization 13.9% (95% CI, 13.0%-14.9%). Vigorous exercise was associated with lower prevalence of depression and somatization. The adjusted prevalence ratio for depression was 0.87 (95% CI, 0.72-1.05) for 3 to 6 MET hours per week-1 , 0.76 (95% CI, 0.62-0.94) for 9 to 12 MET-hours per week-1 , and 0.74 (95% CI, 0.58-0.95) for 15 to 21 MET-hours per week-1 . Compared with 0 MET hours per week-1 , 15 to 21 MET-hours per week-1 were associated with an adjusted prevalence ratio of 0.79 (95% CI, 0.62-1.00) for somatization. Vigorous exercise also was associated with less impairment in the physical functioning, general health and vitality (Ptrend  < .001), emotional role limitations (Ptrend  = .02), and mental health (Ptrend  = .02) domains as well as higher cognitive function in the domains of task completion, organization, and working memory (P < .05 for all), but not in the domain of cancer pain. CONCLUSIONS: Vigorous exercise is associated with less psychological burden and cognitive impairment in childhood cancer survivors.

Growth hormone deficiency and neurocognitive function in adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: The impact of growth hormone deficiency (GHD) on neurocognitive function is poorly understood in survivors of childhood acute lymphoblastic leukemia (ALL). This study examined the contribution of GHD to functional outcomes while adjusting for cranial radiation therapy (CRT). METHODS: Adult survivors of ALL (N = 571; 49% female; mean age, 37.4 years; age range, 19.4-62.2 years) completed neurocognitive tests and self-reported neurocognitive symptoms, emotional distress, and quality of life. GHD was defined as a previous diagnosis of GHD or a plasma insulin-like growth factor1 level less than -2.0 standard deviations for sex and age at the time of neurocognitive testing. Hypothyroidism, hypogonadism, sex, age at diagnosis, CRT dose, and intrathecal and high-dose intravenous methotrexate were included as covariates in multivariable linear regression models. RESULTS: Of the 571 survivors, 298 (52%) had GHD, and those with GHD received higher doses of CRT (P = .002). Survivors who had GHD, irrespective of prior growth hormone treatment, demonstrated poorer vocabulary (z-score, -0.84 vs -0.61; P = .02), processing speed (z-score, -0.49 vs -0.30; P = .04), cognitive flexibility (z-score, -1.37 vs -0.94; P = .01), and verbal fluency (z-score, -0.74 vs -0.44; P = .001), and they self-reported more neurocognitive problems and poorer quality of life compared with survivors who did not have GHD. Multivariable and mediation models revealed that GHD was associated with small effects on quality of life (general health, P = .01; vitality, P = .01; mental health, P = .01); and CRT dose accounted for the lower neurocognitive outcomes. CONCLUSIONS: Adult survivors of childhood ALL who receive CRT are at risk for GHD, although poor neurocognitive outcomes are determined by CRT dose and not by the presence of GHD.

Assessment of pulmonary outcomes, exercise capacity, and longitudinal changes in lung function in pediatric survivors of high-risk neuroblastoma.

BACKGROUND/OBJECTIVES: Survivors of high-risk neuroblastoma (NB) are exposed to multimodality therapies early in life and confront late therapy-related toxicities. This study assessed respiratory symptoms, exercise capacity, and longitudinal changes in pulmonary function tests (PFTs) among survivors. DESIGN/METHODS: Survivors of high-risk NB followed in the long-term follow-up clinic at Memorial Sloan Kettering Cancer Center were enrolled. Symptom and physical activity questionnaires were completed. Medical records were reviewed for treatments and comorbidities. Participants completed spirometry, plethysmography, diffusion capacity of the lung for carbon monoxide, 6-minute walk tests (6MWTs), and cardiopulmonary exercise testing. Questionnaires and PFTs were repeated at least one year after enrollment. RESULTS: Sixty-two survivors participated (median age at study: 10.92 years; median age at diagnosis: 2.75 years; median time since completion of therapy: 5.29 years). Thirty-two percent had chronic respiratory symptoms. Seventy-seven percent had PFT abnormalities, mostly mild to moderate severity. Thirty-three completed 6MWTs (median, 634.3 meters); eight completed cardiopulmonary exercise tests (mean VO2 max: 63% predicted); 23 completed a second PFT revealing declines over a median 2.97 years (mean percent predicted forced vital capacity: 79.9 to 70.0; mean forced expiratory volume in 1 second: 81.6 to 69.9). Risks for abnormalities included thoracic surgery, chest radiation therapy (RT), thoracic surgery plus chest RT, and hematopoietic stem cell transplant. CONCLUSIONS: In this cohort of survivors of high-risk NB, PFT abnormalities were common but mostly mild or moderate. Maximal exercise capacity may be affected by respiratory limitations and declines in lung function may occur over time. Continued pulmonary surveillance of this at-risk population is warranted.

Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort.

BACKGROUND: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment. METHODS: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk. FINDINGS: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI 32·0-34·3) in those diagnosed 1970-79 to 29·3% (28·4-30·2; p<0·0001) in 1980-89, and 27·5% (26·4-28·6; p=0·012 vs 1980-89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4·6% (95% CI 3·9-5·2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17·7% [95% CI 15·0-20·5] vs 26·4% [23·8-29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0-19·7] vs 23·8% [19·9-27·7]; p=0.0053), astrocytoma (30·5% [27·8-33·2] vs 47·3% [42·9-51·7]; p<0·0001), Wilms tumour (11·9% [9·5-14·3] vs 17·6% [14·3-20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5-33·1] vs 36·5% [31·5-41·4]; p=0·021), and osteosarcoma (65·6% [60·6-70·6] vs 87·5% [84·1-91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4-63·3] vs 42·9% [34·9-50·9]; p=0·00060), and neuroblastoma (25·0% [21·8-28·2] vs 18·0% [14·5-21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64-0·92; HR with treatment in the model=0·89, 95% CI 0·72-1·11; pmediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65-0·85; HR with treatment=0·91, 95% CI 0·73-1·12; pmediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5·9% [5·3-6·4] vs 2·8% [2·5-3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3-3·1] vs 1·9% [1·6-2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2-6·4] vs 3·3% [2·9-3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0-2·7] vs 1·5% [1·3-1·8]; p=0·00037), while hearing loss increased (3·0% [2·6-3·5] vs 5·7% [5·2-6·1]; p<0·0001). INTERPRETATION: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population. FUNDING: National Cancer Institute and the American Lebanese-Syrian Associated Charities.

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

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

Long-term sequelae in survivors of childhood leukemia with Down syndrome: A childhood cancer survivor study report.

BACKGROUND: Children with Down syndrome (DS) are at increased risk of developing acute leukemia and are more prone to acute toxicities. We studied the incidence and severity of chronic health conditions among survivors of childhood leukemia with DS compared with those without DS. METHODS: Chronic health conditions reported by questionnaire were compared between 154 pediatric leukemia survivors with DS and 581 without DS, matched by leukemia, age at diagnosis, race/ethnicity, sex, radiation location and chemotherapy exposure using Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Subjects were selected from 7139 5-year survivors of leukemia in the Childhood Cancer Survivor Study. RESULTS: Risk of at least 1 late onset chronic health condition (grade 1-5) was similar in the DS population compared with the non-DS group (HR, 1.1; 95% CI, 0.7-1.5). Serious chronic health conditions (grade 3-5) were more common in DS survivors (HR, 1.7; 95% CI, 1.1-2.6), as were ≥ 3 chronic health conditions (grades 1-5) (HR, 1.7; 95% CI, 1.2-2.4). The 25-year cumulative incidence of any condition (grades 1-5) was 83% for DS survivors and 69% for non-DS survivors. CONCLUSION: Leukemia survivors with DS have therapy-related chronic health conditions comparable to those of similarly treated survivors without DS, with a few notable exceptions: 1) an increased risk of cataracts, hearing loss, and thyroid dysfunction compared with survivors without DS (though these are known risks in the DS population), 2) decreased risk of second cancers, and 3) increased risk of severe or multiple conditions. Practitioners should be aware of these risks during and after therapy. Cancer 2018;124:617-25. © 2017 American Cancer Society.

Perceptions of risk of infertility among male survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: The objective of the current study was to characterize and identify factors associated with perceptions of risk of infertility among adult male survivors of childhood cancer. METHODS: A total of 1233 adult male survivors from the Childhood Cancer Survivor Study who were without a history of disease recurrence or subsequent malignancy reported their perceptions of their risk of infertility compared with men never diagnosed with cancer. Survivors were a median age of 37.8 years (range, 22.0-58.7 years) and were 28.4 years from their diagnosis (range, 21.4-39.2 years). Multivariable logistic regression evaluated factors associated with perceptions of risk. RESULTS: Overall, 35.9% of the survivors (443 of 1233 survivors) reported perceptions of their risk of infertility that were discordant with their actual risk based on previous cancer treatment exposures. Discordant perceptions were equally common among men exposed to gonadotoxic therapies (36.3%; 311 of 857 men) and those with no history of gonadotoxic exposure (35.1%; 132 of 376 men). Survivors who fathered children (odds ratio [OR], 4.14; 95% confidence interval [95% CI], 2.74-6.24), had no survivor-focused health care (OR, 3.07; 95% CI, 1.57-5.99), were nonwhite (OR, 2.28; 95% CI, 1.10-4.75), and were of lower income were more likely to report no increased risk of infertility after gonadotoxic treatment. Perceptions of increased risk of infertility among men with no history of gonadotoxic treatment were predicted by never having fathered a child (OR, 1.88; 95% CI, 1.17-3.03), recent participation in survivor-focused health care (OR, 2.11; 95% CI, 1.01-4.42), and higher educational achievement. CONCLUSIONS: Many male survivors of childhood cancer are unaware of how their cancer treatments could impact their reproductive health, underscoring the need for all patients to receive education regarding their risk of infertility throughout the continuum of cancer care. Cancer 2018;124:2447-55. © 2018 American Cancer Society.

Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study.

BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for both insulin-dependent and non-insulin-dependent diabetes. We sought to clarify the pathophysiology of diabetes after abdRT by performing dynamic studies of insulin and glucose and testing for type 1 diabetes-associated autoantibodies. PROCEDURE: Cross-sectional analysis of 2-year childhood cancer survivors treated with abdRT at age ≤21 years who underwent oral glucose tolerance testing and assessment of diabetes-related autoantibodies from December 2014 to September 2016. Prevalence of insulin/glucose derangements, indices of insulin sensitivity/secretion (homeostatic model assessment of insulin resistance [HOMA-IR], whole-body insulin sensitivity, insulinogenic index), autoantibody positivity, and treatment/demographic factors associated with adverse metabolic outcomes were assessed. RESULTS: Among 40 participants previously exposed to abdRT (57.5% male; median age at cancer diagnosis, 3.3 years [range, 0.5-20.1]; median age at study 14.3 years [range, 8.3-49.8]; none with obesity), 9 (22.5%) had glucose derangements (n = 4 with impaired fasting glucose [≥100 mg/dL]; n = 4 with impaired glucose tolerance [2-hour glucose 140-199 mg/dL]; n = 1 with previously unrecognized diabetes [2-hour glucose ≥200 mg/dL]). Three of the four individuals with impaired fasting glucose also had insulin resistance, as measured by HOMA-IR; an additional four subjects with normal glucose tolerance were insulin resistant. The subject with diabetes had normal HOMA-IR. No participant had absolute insulinopenia or >1 positive diabetes-related autoantibody. CONCLUSIONS: This study suggests that radiation-induced damage to the insulin-producing ß-cells is an unlikely explanation for the early derangements in glucose metabolism observed after abdRT. Research into alternative pathways leading to diabetes after abdRT is needed.

Impact of ovarian transposition before pelvic irradiation on ovarian function among long-term survivors of childhood Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study.

BACKGROUND: We reviewed the effect of ovarian transposition (OT) on ovarian function among long-term survivors of childhood Hodgkin lymphoma (HL) treated with pelvic radiotherapy. PROCEDURE: Female participants (age 18+ years) with HL in the St. Jude Lifetime Cohort Study (SJLIFE) were clinically evaluated for premature ovarian insufficiency (POI) 10 or more years after pelvic radiotherapy. Reproductive history including age at menopause and pregnancy/live births was available on all patients. RESULTS: Of 127 eligible females with HL, 90 (80%) participated in SJLIFE, including 49 who underwent OT before pelvic radiotherapy. Median age at STLIFE evaluation was 38 years (range 25-60). In a multiple regression adjusted for age at diagnosis, pelvic radiotherapy doses > 1,500 cGy (hazard ratio [HR] = 25.2, 95% confidence interval [CI] = 3.1-207.3; P = 0.0027) and cumulative cyclophosphamide equivalent doses of alkylating agents > 12,000 mg/m2 (HR = 11.2, 95% CI = 3.4-36.8; P < 0.0001) were significantly associated with POI. There was no significant association between OT and occurrence of POI (HR = 0.6, 95% CI = 0.2-1.9; P = 0.41). CONCLUSIONS: OT did not appear to modify risk of POI in this historic cohort of long-term survivors of HL treated with gonadotoxic therapy. Modern fertility preservation modalities, such as mature oocyte cryopreservation, should be offered to at-risk patients whenever feasible.

Cardiovascular Risk Factors in Survivors of Childhood Hematopoietic Cell Transplantation Treated with Total Body Irradiation: A Longitudinal Analysis.

Hematopoietic cell transplantation (HCT) survivors treated with total body irradiation (TBI) are known to be at increased risk for the development of cardiovascular risk factors (CVRFs). We sought to characterize the incidence of CVRFs in a TBI-exposed survivor cohort and to describe prognostic indicators of their development through a retrospective analysis of CVRFs in 1-year survivors of leukemia or lymphoma treated with TBI at Memorial Sloan Kettering between April 1987 and May 2011. Eligible participants were age ≤21 years at the time of TBI and were not receiving glucocorticoid therapy at the time of entry to long-term follow-up. Survivors were assessed for obesity (body mass index ≥95th percentile for age ≤ 20 years and ≥30 kg/m2 for age >20 years), elevated blood pressure, dyslipidemia (elevated triglycerides [TG], low high-density lipoprotein [HDL]), and glucose intolerance (fasting glucose ≥100 mg/dL); those with ≥3 risk factors were deemed to have a CVRF cluster, a surrogate for metabolic syndrome. Cox regression models were used to estimate hazard ratios (HRs) for factors associated with each CVRF. To compare the prevalence of CVRFs in HCT survivors and the general population, survivors were compared with age-, sex-, and race-matched controls from the National Health and Nutrition Examination Survey. A total of 123 survivors were evaluated (62.6% males). The median age at TBI was 11.8 years (range, 1.6 to 21.9 years). The median duration of follow-up was 8.0 years (range, 1.01 to 24.6 years), and the median age at last follow-up was 20.1 years (range, 4.0 to 41.3 years). The 5-year cumulative incidence was 14.7% for elevated blood pressure, 10.5% for elevated glucose, 26.8% for low HDL, 39.2% for hypertriglyceridemia, and 16.0% for obesity, and corresponding 10-year cumulative incidences of 28.8%, 33.1%, 52.0%, 65.0%, and 18.6%. The median cumulative incidence of a CVRF cluster rose from 10.6% (range, 5.6% to 17.5%) at 5 years to 28.4% (range, 18.8% to 38.7%) at 10 years. In multivariate analysis, growth hormone (GH) deficiency (hazard ratio [HR], 8.6; 95% confidence interval [CI], 2.1 to 34.4; P = .002), history of cranial radiation (HR, 4.0; 95% CI, 1.7 to 9.6; P = .002), and grade II-IV acute graft-versus-host disease GVHD (HR, 4.2; 95% CI, 1.5 to 12.2; P = .008) were associated with the risk of developing a CVRF cluster. Compared with a random sample of matched population controls, HCT survivors had an increased prevalence of hypertriglyceridemia and low HDL, but not of glucose intolerance, elevated blood pressure, or CVRF cluster. Given the young age of this HCT survivor cohort, these data highlight the importance of routine screening for CVRF starting in childhood in individuals exposed to TBI.