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PDF file - 56K, Diagnosis and treatment-related characteristics of the cancer survivor population (participants) and non-participants.

PURPOSE To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy. METHODS Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures. RESULTS HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition ( P trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8). CONCLUSION This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.

BACKGROUND: Retrospective multicenter research using echocardiograms obtained for routine clinical care can be hampered by issues of individual center quality, thus limiting the application of post-hoc research analytics. We sought to evaluate imaging and patient characteristics associated with poorer quality of archived echocardiograms from a cohort of childhood cancer survivors. METHODS: A single blinded reviewer at a central core lab graded quality of clinical echocardiograms from 5 contributing centers focusing on images to derive 2D and M-mode fractional shortening (FS), biplane Simpson ejection fraction (EF), myocardial performance index (MPI), tissue Doppler imaging (TDI) derived velocities and global longitudinal strain (GLS). RESULTS: Of 535 studies analyzed in 102 subjects from 2004 to 2017, all measures of cardiac function could be assessed in only 7%. While FS by 2D or M-mode, MPI and septal E/E’ could be measured in >80% studies, mitral E/E’ was less consistent (69%), but better than EF (52%) and GLS (10%). At least one quality issue was identified in 66% studies, with technical issues (ex. lung artifact, poor endocardial definition) being the most common (33%). Lack of 2- and 3-chamber views was associated with the performing center. Patients < 5 years had a higher chance of apex cut-off in 4-chamber views compared to 16–35 year old (RR 1.99 (1.07–3.72), p = 0.03). Overall, for any quality issue, earlier era of echo and center were the only significant risk factors. CONCLUSION: Assessment of cardiac function using pooled multicenter archived echocardiograms was significantly limited. Efforts to standardize clinical echocardiographic protocols to include apical 2- and 3-chamber views and TDI will improve the ability to quantitate LV function.

Objectives: The purpose of this study was to assess the timing of changes in serial echocardiographic parameters in pediatric cancer survivors and to evaluate their associations with cardiomyopathy development. Background: Pediatric cancer survivors undergo serial echocardiograms to screen for cardiotoxicity. It is not clear whether small longitudinal changes in functional or structural parameters over time have clinical significance. Methods: This is a multicenter, retrospective, case-control study of ≥1-year survivors following the end of cancer therapy. Cardiomyopathy cases (fractional shortening [FS] ≤28% or ejection fraction [EF] ≤50% on ≥2 occasions) were matched to control subjects (FS ≥30%, EF ≥55%, not on cardiac medications) by cumulative anthracycline and chest radiation dose, follow-up duration, and age at diagnosis. Digitally archived clinical surveillance echocardiograms were quantified in a central core laboratory, blinded to patient characteristics. Using mixed models with interaction terms between time and case status, we estimated the least square mean differences of 2-dimensional, M-mode, pulsed wave Doppler, and tissue Doppler imaging–derived parameters over time between cases and control subjects. Results: We identified 50 matched case-control pairs from 5 centers. Analysis of 412 echocardiograms (cases, n = 181; control subjects, n = 231) determined that indices of left ventricular systolic function (FS, biplane EF), diastolic function (mitral E/A ratio), and left ventricular size (end-diastolic dimension z-scores) were significantly different between cases and control subjects, even 4 years prior to the development of cardiomyopathy. Conclusions: Longitudinal changes in cardiac functional parameters can occur relatively early in pediatric cancer survivors and are associated with the development of cardiomyopathy.

10056 Background: Treatment exposure-based risk-stratification oflong-term cancer survivors is needed to allocate tailored health care in survivorship clinics. Investigators from the United Kingdom (UK) developed a treatment exposure-based algorithm that stratifies survivors into low, medium, and high risk groups. Because this algorithm has not been validated, we sought to use the large, diverse population of the Childhood Cancer Survivor Study (CCSS) to validate risk for poor outcomes. Methods: Five-year survivors of childhood cancer (diagnosed between 1970-1999 at < 21 years of age) were categorized into low, medium, and high risk groups based on treatment exposures and diagnoses (Table). Primary endpoints included cumulative health-related (i.e., non-recurrence, non-external) late mortality and cumulative incidence of grade 3-5 chronic conditions (CTCAEv4.03) conditional on reaching age 20 without the outcome. Siblings were a comparison group for chronic conditions. Cox proportional hazards models among survivors estimated hazard ratios (HRs) and 95% confidence intervals (CI) adjusted for sex and race. Results: A total of 21,504 survivors were analyzed with a median follow-up of 22 years. Application of the risk stratification algorithm resulted in 3,152 low risk, 6,443 medium risk, and 11,909 high risk survivors. Among those who survived to age 20 without any grade 3-5 conditions, the risk of developing one by age 35 was 12.2% (95% CI 1.0-14.7%), 14.2% (12.8-15.7%) and 25.4% (24.2-26.6%) for low, medium, and high-risk patients, respectively, and 6.9% (6.1-7.9%) for siblings. HRs of grade 3-5 conditions for medium (HR 1.8, 95% CI 1.6-2.1) and high (HR 3.9, 95% CI 3.5-4.4) risk relative to low risk survivors, respectively, were elevated. Cumulative health-related mortality was similarly associated with risk categories; conditional on being alive at age 20, survivors within low, medium, and high risk groups had cumulative incidences of 2.3% (95% CI 1.7-3.1%), 3.3% (2.8-3.9%) and 6.1% (5.6-6.6%), respectively, by age 35. Conclusions: Risk categorizations based on treatment exposures were effective at providing generalized risk stratification within the CCSS with respect to risk of grade 3-5 conditions and health related mortality, particularly for identifying high risk survivors. These risk groups may be useful to physicians in determining follow-up intervals and guiding management and long-term surveillance of these survivors. [Table: see text]

10050 Background: Childhood cancer survivors are at risk for shortened lifespan. Projections of life expectancy (LE) by diagnosis can provide benchmarks for assessing improvements over time. Methods: We developed a simulation model to project risk for common, life-threatening chronic health conditions (CHCs; heart failure, myocardial infarction, valvular disease, stroke, secondary breast cancer, colorectal cancer, glial tumors, sarcomas) and excess mortality among 5-year survivors, based on patient characteristics (sex, age at diagnosis, diagnosis) and treatment exposures (chemotherapy, radiation dose). Risk was estimated using statistical models and Childhood Cancer Survivor Study data. Age-related CHC risks (SEER, NHLBI) and competing mortality (CDC Wonder) were based on national databases. We used model calibration to identify parameter sets that generated outcomes consistent with observed data. Model outcomes included conditional LE and 10-year survival probability at age 40. For comparisons to the general population, we simulated age-, sex-, and diagnosis year-matched individuals who faced only competing mortality rates. Results: Among a cohort representative of the CCSS (mean diagnosis age, 7.4 yrs), compared to the general population, the gap in LE among survivors diagnosed in the 1970s vs. 1990s decreased from 17 yrs (25%) to 11 yrs (17%). Changes in LE among survivors diagnosed in the 1990s vs. 1970s varied by diagnosis, with leukemia, lymphoma, and CNS tumor survivors estimated to live an additional 8 to 11 yrs (Table). In contrast, considerably smaller gains were estimated for sarcoma and renal tumor survivors (1–3 yrs) and a loss for neuroblastoma (-3 yrs). Among survivors who reached age 40, the probability of surviving an additional 10 years increased from 89% to 92% between 1970s vs. 1990s, with the greatest gains for lymphoma and CNS tumors. Conclusions: Although temporal changes in pediatric oncology are projected to result in LE gains among survivors, considerable variation is projected across diagnoses. These findings highlight the uneven success of improving treatments for all cancers. [Table: see text]

Objective Positive psychological outcomes among adolescent and young adult survivors of childhood cancer may influence long-term health status. We examined posttraumatic growth (PTG) and Life satisfaction (LS) in adolescence, and their impact on future emotional and physical health status in young adulthood. Methods Survivors (n = 2802) from the Childhood Cancer Survivor Study were longitudinally analyzed across social, emotional, and physical factors during adolescence (12-17 years old), and PTG (PTG-Inventory) and LS (Cantril-Ladder-of-Life) during young adulthood (19-24 years old). The impact of PTG and LS on survivors' future long-term mental health, physical health, and social skills was also examined (23-28 years old) using Structural Equation Modeling. Results Survivors reported high levels of LS (M = 7.43, range 1 to 10) and a positive impact from their cancer experience (M = 48.78, range 0 to 105). Adolescent predictors of higher PTG included older age at diagnosis (p = 0.001), experiencing more severe chronic health conditions (p = 0.01), cancer recurrence/relapse (p = 0.01), and being diagnosed with a non-CNS cancer (p = 0.001). Higher perceived general health (p = 0.01), higher social skills (p = 0.001), and diagnosis with a non-CNS cancer (p = 0.02) were associated with higher LS. Higher PTG during young adulthood predicted poorer perceived health (p = 0.04) and worse emotional health (p = 0.001) in later adulthood. Higher LS predicted better emotional health (p = 0.001) and better perceived health (p = 0.001). Conclusions While LS was found to help survivors have better perceived long-term emotional and physical health outcomes, survivors with higher PTG fond both positive and negative impacts from cancer. Future therapeutic trials to improve LS should be considered.

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 2017. © 2017 American Cancer Society.

Summary 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.

Importance Anthracyclines are part of many effective pediatric cancer treatment protocols. Most pediatric oncology treatment groups assume that the hematologic toxicity of anthracycline agents is equivalent to their cardiotoxicity; for example, Children’s Oncology Group substitution rules consider daunorubicin and epirubicin isoequivalent to doxorubicin, whereas mitoxantrone and idarubicin are considered 4 to 5 times as toxic as doxorubicin. Objective To determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or the anthraquinone mitoxantrone. Design, Setting, and Participants This multicenter cohort study of childhood cancer survivors who survived 5 or more years analyzed data pooled from 20 367 participants in the Childhood Cancer Survivor Study treated from 1970 to 1999, 5741 participants in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001, and 2315 participants in the St Jude Lifetime study treated from 1962 to 2005. Exposures Cumulative doses of each agent (the anthracyclines doxorubicin, daunorubicin, epirubicin, and idarubicin; and the anthraquinone mitoxantrone) along with chest radiotherapy exposure were abstracted from medical records. Main Outcomes and Measures Cardiomyopathy (severe, life-threatening, or fatal) by 40 years of age. Agent-specific Cox proportional hazards models evaluated cardiomyopathy risk, adjusting for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to an anthraquinone. An agent-specific cardiomyopathy equivalence ratio (relative to doxorubicin) was estimated for each dose category as a ratio of the hazard ratios, and then a weighted mean determined the overall agent-specific equivalence ratio across all dose categories. Results Of 28 423 survivors (46.4% female; median age at cancer diagnosis 6.1 years [range, 0.0-22.7 years]), 9330 patients received doxorubicin, 4433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone. After a median follow-up of 20.0 years (range, 5.0-40.0 years) following receipt of a cancer diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Outcomes were too rare to generate idarubicin-specific estimates. Ratios based on a continuous linear dose-response relationship were similar for daunorubicin (0.5 [95% CI, 0.4-0.7]) and epirubicin (0.8 [95% CI, 0.3-1.4]). The relationship between mitoxantrone and doxorubicin appeared better characterized by a linear exponential model. Conclusions and Relevance In a large data set assembled to examine long-term cardiomyopathy risk in childhood cancer survivors, daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin, whereas epirubicin was approximately isoequivalent. By contrast, the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk.

Background Although paediatric astrocytoma has an excellent 5-year survival rate, survivors remain at risk for morbidity and late mortality. This study aimed to estimate the risk of late mortality, chronic conditions, poor health status and social impairment in ageing paediatric astrocytoma survivors. Methods We longitudinally evaluated 1182 5-year astrocytoma survivors diagnosed between 1970 and 1986 and 4023 siblings enrolled in a retrospective cohort study. Kaplan–Meier estimates of late mortality and cumulative incidence of serious chronic conditions were estimated. Cox regression models provided hazard ratios (HRs) with 95% confidence intervals (CIs) for development of chronic conditions, and generalised linear models provided relative risks (RRs) of the poor health status and social outcomes. Results At 30 years from diagnosis, cumulative late mortality was 22.1% (CI 20.0–24.3%), primarily due to disease progression or recurrence. Compared with siblings, survivors were at increased risk of serious chronic conditions (HR 4.6, CI 3.8–5.5). Survivors reported higher rates of poor general health (RR 3.3, CI 2.8–3.8), poor mental health (RR 1.9, CI 1.7–2.1), functional impairment (RR 9.0, CI 7.7–10.5) and activity limitation (RR 3.6, CI 3.1–4.2) and lower rates of college graduation (RR 0.75, CI 0.69–0.82), marriage (RR 0.62, CI 0.58–0.66), employment (RR 0.75, CI 0.72–0.79) and household income ≥$40,000 (RR 0.68, CI 0.64–0.73). Even survivors without radiation exposure had elevated risk of chronic conditions, poor health status and social impairment compared with siblings. Conclusions Survivors of paediatric astrocytoma are at high risk for long-term complications of their disease and its treatment. They require lifelong monitoring for late effects.

10049 Background: Survivors of pediatric CNS tumors may be at elevated risk for accelerated cognitive decline as they age through adulthood relative to the general population, which may be an early risk factor for dementia. Methods: Longitudinal analysis of 512 CNS tumor survivors (52.3% female, mean [SD] 30.6 [7.1] years at T1) and 232 siblings (57.8% female, mean [SD] 34.2 [8.4] years at T1) from the CCSS was conducted using the Neurocognitive Questionnaire (NCQ) to assess task efficiency, emotional regulation, organization and memory at two timepoints separated by a mean of 11.6 [0.7] years. Impairment in each NCQ domain was defined as a score ≥ 90th percentile of the CCSS sibling distribution at each survey, with decline defined as moving from unimpaired at T1 to impaired at T2. Treatment exposures were abstracted from medical records. Chronic health conditions were self-reported at T1 and graded according to CTCAE v4.3. Relative risk of decline for group, treatment and chronic condition predictors was estimated using generalized linear models with robust variance estimates. Mediation analysis examined direct effects of treatments and mediating effects of chronic conditions. All models were adjusted for age, sex, and race. Results: At T1, survivors demonstrated higher frequency of impaired memory (24.5% vs. 6.5%, p < 0.001), emotional regulation (14.3 % vs. 5.6%, p < 0.001), task efficiency (43.3% vs. 13.8%, p < 0.001) and organization (17.7% vs. 10.8%, p = 0.015) than siblings. Among those unimpaired at T1, more survivors vs. siblings declined in memory (34.7% vs. 7.8; RR 4.2, 95% CI 2.6-6.9), emotional regulation (15.5% vs. 5.0%; RR 2.8, 95% CI 1.5-5.3), task efficiency (22.7% vs. 7.0%; RR 2.9, 95% CI 1.7-5.2), and organization (14.5% vs. 2.9%; RR 4.9, 95% CI 2.1-11.0) by T2. Decline in survivor memory was associated with exposure to craniospinal irradiation (RR 1.9, 95% CI 1.3-2.8) and focal irradiation (RR 1.6, 95% CI 1.1-2.3) compared with no radiation, and exposure to Ara-C (RR 1.7, 95% CI 1.0-2.8) and cyclophosphamide (RR 1.7, 95% CI 1.01-2.8). Independent of therapy, serious/disabling or life-threatening cardiopulmonary conditions at T1 predicted future decline in memory (RR 1.5, 95% CI 1.02-2.2) and organization (RR 2.0, 95% CI 1.1-3.6), with the presence of 2 or more cardiopulmonary conditions associated with even higher risk (memory RR 2.6, 95% CI 2.0-3.1; organization RR 3.4, 95% CI 1.1-10.5). Chronic conditions did not mediate associations between treatment exposures and cognitive decline. Conclusions: CNS tumor survivors are at elevated risk for impairment and accelerated cognitive decline compared to siblings. Cranial radiation, Ara-C, cyclophosphamide, and cardiopulmonary morbidity are risk factors for decline. Survivors with these exposures/conditions may benefit from interventions to prevent additional future cognitive decline.

10528 Background: Some treatment exposures for childhood cancer reduce ovarian reserve. Registry-based evaluation has not been conducted for assisted reproductive technology (ART) outcomes of female survivors. Methods: The Childhood Cancer Survivor Study, a retrospective cohort of five-year survivors and siblings, was linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS), which captures nationwide, CDC-required reporting of ART outcomes. We assessed live birth rate and relative risk (RR, 95% CI) as a function of treatment exposure, using generalized estimating equation to account for multiple ovarian stimulations per subject. Results: Among 9885 female survivors, 137 (1.4%; median age at diagnosis 10 years, range 0-20; 11 years of follow-up, 2-11) underwent 243 ART cycles (mean 1.8 cycles) and among 2419 siblings, 33 (1.4%) underwent 60 ART cycles (mean 1.8). Median age at autologous egg retrieval was 30 years (19-44) for survivors and 34 (24-43) for siblings. In the subset using autologous eggs (Table), 99 survivors underwent 155 ovarian stimulation cycles that resulted in 113 embryo transfers and 49 live births for a live birth rate of 32% per ovarian stimulation and 43% per transfer. Sibling live birth rate was 38% (p = 0.39 compared to survivors) per autologous ovarian stimulation and 53% (p = 0.33) per transfer. 38 survivors and 1 sibling underwent egg donor ovarian stimulation cycles. Two survivors used autologous eggs with gestational carriers and one cycle resulted in live birth. Cranial radiation therapy (RT) [RR 0.48 (0.27-0.87) p = 0.02] and pelvic RT [0.30 (0.14-0.66) p = 0.002], compared with no RT, resulted in lower RR of live birth in survivors. The likelihood of live birth after ART in survivors was not impacted by alkylator exposure [CED < 8000 mg/m2 vs. none: 1.14 (0.65-2.02); CED >8000 mg/m2 vs none: 1.07 (0.06-1.91)]. Conclusions: While live birth rates among survivors were lower compared with siblings, differences were not statistically significant. Pelvic and cranial RT were associated with a decreased likelihood of live birth, with no association with alkylator exposure identified. [Table: see text]

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.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.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; p0·0001) 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]; p0·0001), 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]; p0·0001), 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]; p0·0001). 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; pOur 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.National Cancer Institute and the American Lebanese-Syrian Associated Charities.

ObjectiveTo estimate the rates and predictors of recurrent stroke among survivors of pediatric cancer who have had a first stroke.MethodsThe Childhood Cancer Survivor Study is a retrospective cohort study with longitudinal follow-up that enrolled 14,358 survivors (

BACKGROUND Childhood cancer survivors treated with radiotherapy to a field including the colon or rectum have an elevated risk of developing radiation-induced colorectal cancer (CRC). The Children's Oncology Group recommends colonoscopy every 5 years beginning at age 35 years for at-risk survivors. METHODS Analyses included 702 five-year survivors (Childhood Cancer Survivor Study) aged ≥36 years who received ≥30 gray of abdominal, pelvic, or spinal radiotherapy. Multivariate generalized linear models were used to calculate relative risks (RR) with 95% confidence intervals (95% CI) for adherence to the Children's Oncology Group's CRC surveillance recommendations. RESULTS With a median age of 43 years (range, 36-58 years), 29.5% of the survivors (207 of 702 survivors) met surveillance recommendations. In multivariate analyses, age ≥50 years versus age 36 to 49 years (RR, 2.6; 95% CI, 2.0-3.4), reporting a routine cancer follow-up visit within 1 year before the study (RR, 1.5; 95% CI, 1.0-2.2), reporting ≥10 physician visits within the past year versus 0 to 9 visits (RR, 1.4; 95% CI, 1.1-1.7), and discussing future cancer risk with a physician at the time of the most recent follow-up visit (RR, 1.4; 95% CI, 1.1-1.7) were found to be associated with adherence to CRC surveillance recommendations. CONCLUSIONS Greater than 70% of survivors at an increased risk of CRC were not screened as recommended. Regular physician contact and discussion of screening were associated with a 60% increase in CRC surveillance. Educational interventions targeted at survivors and their primary care physicians are needed to heighten knowledge of CRC risk after radiotherapy and the importance of appropriate surveillance. Cancer 2015;121:1856–1863. © 2015 American Cancer Society.

Purpose Cumulative anthracycline dose is one of the strongest predictors of heart failure (HF) after cancer treatment. However, the differential risk for cardiotoxicity between daunorubicin and doxorubicin has not been rigorously evaluated among survivors of childhood cancer. These risks, which are based on hematologic toxicity, are currently assumed to be approximately equivalent. Patients and Methods Data from 15,815 survivors of childhood cancer who survived at least 5 years were used. Survivors were from the Emma Children's Hospital/Academic Medical Center (n = 1,349), the National Wilms Tumor Study (n = 364), the St Jude Lifetime Cohort Study (n = 1,695), and the Childhood Cancer Survivor Study (n = 12,407). The hazard ratio (HR) for clinical HF through age 40 years for doses of daunorubicin and doxorubicin (per 100-mg/m2 increments) was estimated by using Cox regression adjusted for sex, age at diagnosis, treatment with other anthracycline agents and chest radiation, and cohort membership. Results In total, 5,144 (32.5%) patients received doxorubicin as part of their cancer treatment, whereas 2,243 (14.7%) received daunorubicin. On the basis of 271 occurrences of HF during a median follow-up time after cohort entry of 17.3 years (range, 0.0 to 35.0 years), the cumulative incidence of HF at age 40 years was 3.2% (95% CI, 2.8% to 3.7%). The average ratio of HRs for daunorubicin to doxorubicin was 0.45 (95% CI, 0.23 to 0.73). A similar ratio was obtained by using a linear dose-response model, which yielded an HR of 0.49 (95% CI, 0.28 to 0.70). Conclusion Compared with doxorubicin, daunorubicin was less cardiotoxic among survivors of childhood cancer than most current guidelines suggest. This may have implications for follow-up guidelines. The feasibility of substitution of doxorubicin with daunorubicin in childhood cancer treatment protocols to reduce cardiotoxicity should be additionally investigated.

Purpose The first generation of childhood cancer survivors is now aging into their fourth and fifth decades of life, yet health risks across the aging spectrum are not well established. Methods Analyses included 14,359 5-year survivors from the Childhood Cancer Survivor Study, who were first diagnosed when they were younger than 21 years old and who received follow-up for a median of 24.5 years after diagnosis (range, 5.0 to 39.3 years) along with 4,301 of their siblings. Among the survivors, 5,604 were at least 35 years old (range, 35 to 62 years) at last follow-up. Severe, disabling, life-threatening, and fatal health conditions more than 5 years from diagnosis were classified using the Common Terminology Criteria for Adverse Events, grades 3 to 5 (National Cancer Institute). Results The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6%; 95% CI, 51.5 to 55.6; v 19.8%; 95% CI, 17.0 to 22.7) by age 50 years. When comparing survivors with siblings, hazard ratios (HR) were significantly increased within the age group of 5 to 19 years (HR, 6.8; 95% CI, 5.5 to 8.3), age group of 20 to 34 years (HR, 3.8; 95% CI, 3.2 to 4.5), and the ≥ 35 years group (HR, 5.0; 95% CI, 4.1 to 6.1), with the HR significantly higher among those ≥ 35 years versus those 20 to 34 years old (P = .03). Among survivors who reached age 35 years without a previous grade 3 or 4 condition, 25.9% experienced a subsequent grade 3 to 5 condition within 10 years, compared with 6.0% of siblings (P < .001). Conclusion Elevated risk for morbidity and mortality among survivors increases further beyond the fourth decade of life, which affects the future clinical demands of this population relative to ongoing surveillance and interventions.

Purpose To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS). Methods and Materials Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology, and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking, and alcohol consumption. Results During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR = 39.4; 95% CI = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking, or alcohol intake. Conclusion Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.

The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy.We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group.We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4-12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6-15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58-0·68; p0·0001; female survivors: 0·87, 0·81-0·94; p0·0001) or of having a livebirth (male survivors: 0·63, 0·58-0·69; p0·0001; female survivors: 0·82, 0·76-0·89; p0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51-0·71; p0·0001), ifosfamide (0·42, 0·23-0·79; p=0·0069), procarbazine (0·30, 0·20-0·46; p0·0001) and cisplatin (0·56, 0·39-0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m(2) increments: HR 0·82, 95% CI 0·79-0·86; p0·0001). However, in female survivors, only busulfan (450 mg/m(2) HR 0·22, 95% CI 0·06-0·79; p=0·020; ≥450 mg/m(2) 0·14, 0·03-0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m(2) (0·41, 0·17-0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74-0·98; p=0·023). Results for livebirth were similar to those for pregnancy.Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer.National Cancer Institute, National Institutes of Health, and the American Lebanese-Syrian Associated Charities.

In the United States, an estimated 14 000 children younger than 20 years are diagnosed annually with a first primary cancer (1). The decline in cancer mortality due to advances in cancer treatment over the past 30 years has resulted in a large and increasing population of long-term cancer survivors; currently, there are more than 352 000 pediatric cancer survivors in the United States (2). These individuals are at risk for many late effects of the therapy they received for their initial cancer, including subsequent primary malignancies. Previous research within the Childhood Cancer Survivor Study (CCSS) demonstrated an excess risk of subsequent primary neoplasms for childhood survivors of all primary diagnoses compared to the general population (3). In addition, as childhood cancer survivors progress through adulthood, this excess risk of subsequent neoplasms continues to increase with a cumulative incidence at 30 years of 7.9% (95% confidence interval [CI] = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer [NMSC]) and 9.1% (95% CI = 8.1% to 10.1%) for NMSC (3). Skin cancer is the most common malignancy in the United States, and basal cell carcinomas (BCCs) account for 75% of the 1 million NMSCs diagnosed annually (4,5). Although 95% of BCCs are cured with surgery, the cosmetic outcome is often unsatisfactory and sometimes disfiguring (6). The predominant risk factor for NMSC is sun exposure (7). Exposure to ionizing radiation is also an established risk factor for NMSC (8–10). For example, survivors of the atomic bombing of Hiroshima and Nagasaki (8,10) and patients treated for tinea capitis with radiation (9,11) were found to be at increased risk of developing NMSCs, of which 50% and 98%, respectively, were BCCs. In a study of stem cell transplant recipients, those who underwent a conditioning regimen that included total body irradiation had an absolute excess risk of 24 cases of BCC per 10 000 person-years compared with those who did not receive total body irradiation prior to transplant (12). A previous analysis of 213 CCSS participants who developed NMSC found that white race, a family history of skin cancer, longer follow-up, history of radiation therapy, and older age at initial cancer diagnosis were associated with an increased risk of BCC (13); however, the radiation dose–response relationship was not quantified. This study was designed to quantify the risks of BCC associated with therapeutic ionizing radiation doses within the CCSS. We also evaluated contributions of other factors, such as chemotherapy exposure, sun sensitivity, and sex, to the risk of BCC.

Background Few studies have examined risk factors for smoking among adolescent survivors of childhood cancer. The present study reports on the rate of smoking and identifies factors associated with smoking in a sample of adolescent survivors from the Childhood Cancer Survivor Study (CCSS). Procedure Participants included 307 adolescent survivors and 97 healthy siblings (ages 14–20) who completed a self-report survey of health, quality of life, and health behaviors. Results Smoking rates did not differ significantly between survivor and sibling groups (ever smokers: 28% vs. 33%, recent smokers: 10% vs. 9%, respectively). Ever smoking was significantly associated with peer smoking, smokers in the household, binging, suicidal behavior, and no history of CRT. There were significant interactions of peer smoking with gender and CRT for ever smoking and with binging for recent smoking. Recent smoking was more likely for survivors with other household smokers (RR = 2.24, CI = 1.21–4.16), past suicidality (RR = 1.89, CI = 1.00–3.56), and no CRT (RR = 2.40, CI = 1.12–5.17). Among survivors with few smoking friends, ever smoking was more likely for survivors with no CRT (RR = 4.47, CI = 1.43–13.9), and recent smoking was more likely among survivors who binged (RR = 3.37, CI = 1.17–9.71). Conclusions Despite the health risks associated with survivorship, nearly one in three adolescent survivors of childhood cancer has smoked. Exposure to other smokers, in particular, appears to increase the likelihood of smoking for some survivors. Providing smoking cessation programs targeted to family members, helping survivors choose non-smoking friends, and teaching ways to resist smoking influences from peers may be important pathways for smoking prevention with adolescent survivors. Pediatr Blood Cancer 2012; 58: 428–434. © 2011 Wiley Periodicals, Inc.

Background Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures. Procedure The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to 5 years post-diagnosis, and ≥5 years post-diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure. Results Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR = 2.3; 95% CI: 1.8–2.8), tinnitus (RR = 1.7; 95% CI: 1.4–2.1), hearing loss requiring an aid (RR = 4.4; 95% CI: 2.8–6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR = 5.2; 95% CI: 2.8–9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose-dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR = 2.1; 95% CI: 1.3–3.2), tinnitus (RR = 2.8; 95% CI: 1.9–4.2), and hearing loss requiring an aid (RR = 4.1; 95% CI: 2.5–6.7). Conclusions Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life. Pediatr Blood Cancer 2011;57:126–134. © 2011 Wiley-Liss, Inc.

OBJECTIVE: This study compared the prevalence of symptoms of posttraumatic stress disorder (PTSD), with functional impairment and/or clinical distress, among very long-term survivors of childhood cancer and a group of healthy siblings. METHODS: A total of 6542 childhood cancer survivors >18 years of age who received diagnoses between 1970 and 1986 and 368 siblings of cancer survivors completed a comprehensive demographic and health survey. RESULTS: A total of 589 survivors (9%) and 8 siblings (2%) reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD. Survivors had more than fourfold greater risk of PTSD, compared with siblings (odds ratio [OR]: 4.14 [95% confidence interval [CI]: 2.08–8.25]). With controlling for demographic and treatment variables, increased risk of PTSD was associated with educational level of high school or less (OR: 1.51 [95% CI: 1.16–1.98]), being unmarried (OR: 1.99 [95% CI: 1.58–2.50]), having annual income below $20000 (OR: 1.63 [95% CI: 1.21–2.20]), and being unemployed (OR: 2.01 [95% CI: 1.62–2.51]). Intensive treatment also was associated with increased risk of full PTSD (OR: 1.36 [95% CI: 1.06–1.74]). CONCLUSIONS: PTSD was reported significantly more often by survivors of childhood cancer than by sibling control subjects. Although most survivors apparently are faring well, a subset reported significant impairment that may warrant targeted intervention.

Introduction: Previous research has suggested that childhood cancer survivors initiate smoking at rates approaching those of healthy individuals, even though smoking presents unique risks to survivors. The present study explores whether the attentional and executive functioning (EF) deficits associated with cancer and treatment place survivors of childhood cancer at increased risk for smoking. Methods: Data from the Childhood Cancer Survivor Study were examined to identify concurrent and longitudinal correlates of tobacco use. We explored whether childhood attention problems and adulthood executive dysfunction were associated with smoking among adult survivors of childhood cancer. Results: Childhood attention problems emerged as a striking predictor of adult smoking nearly a decade later on average. Nearly half (40.4%) of survivors who experienced attention problems in childhood reported a history of smoking, a significantly higher rate of ever smoking, than reported by those without childhood attention problems (relative risk [RR] = 1.53, 95% CI = 1.31―1.79). Furthermore, they were nearly twice as likely to be current smokers in adulthood compared with those without childhood attention problems (RR = 1.71, 95% CI = 1.38―2.11). Similar associations were found between components of adult executive dysfunction and adult smoking. Discussion: Childhood cancer and treatment are associated with subsequent deficits in attention and EF. Early detection of these deficits will allow clinicians to identify patients who are at increased risk for smoking, an important step in promoting and maintaining health in this medically vulnerable population.

Objectives The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose–response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. Methods This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands, and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site–specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Results Linear dose–response relationships over a wide range of radiation dose (0-50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27-0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. Conclusions The results suggest that the effect of high-dose irradiation is consistent with a linear dose–response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment.

Background Over half of U.S. adults use vitamin or mineral supplements, and some are likely using supplements to treat chronic diseases or risk factors for disease. Information on the relationship between supplement use and medical conditions is useful to health professionals to understand the self-medication behavior of their patients, and important for researchers because medical conditions may be potential confounding factors in observational studies of supplement use and disease risk. Methods The cross-sectional data in this report are from 45,748 participants, aged 50 to 75 years, who completed a self-administered, mailed questionnaire on current dietary supplement use (multivitamins plus 16 individual vitamins or minerals), medical history (cancer, cardiovascular-related diseases, and other self-reported medical conditions), and demographic characteristics. Results Supplement use (mean number used at least once a week) was higher among respondents who were older, female, highly educated, Caucasian, and of normal body mass index (all p

LBA10500 Background: Modifications in childhood cancer treatments in recent decades have contributed to reductions in late mortality among 5-year survivors. We used the recently expanded CCSS cohort to investigate whether these changes have also reduced the incidence of chronic disease. Methods: We evaluated the incidence of severe, disabling/life-threatening, or fatal chronic health conditions (Common Terminology Criteria for Adverse Events, CTCAE grades 3-5) among 5-year survivors diagnosed prior to age 21 years from 1970 through 1999. We calculated the 15-year cumulative incidence of chronic health conditions by decade of cancer diagnosis and compared risk across decades using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 23,601 survivors, median age 28 years (range 5-63), 21 years from diagnosis (5-43), the 15-year cumulative incidence of grade 3-5 conditions decreased from 12.7% in survivors diagnosed in the 1970s to 10.1% and 8.8% in those diagnosed in the 1980s and 1990s (per 10 years, HR 0.84 [95% CI = 0.80-0.89]). The association with diagnosis decade was attenuated (HR 0.92 [0.85-1.00]) when detailed treatment data were included in the model, indicating that treatment reductions mediated risk. Adjusted for sex and attained age, significant reduction in risk over time was found among survivors of Wilms tumor (HR 0.57 [0.46-0.70]), Hodgkin lymphoma (HR 0.75 [0.65-0.85]), astrocytoma (HR 0.77 [0.64-0.92]), non-Hodgkin lymphoma (HR 0.79 [0.63-0.99]), and acute lymphoblastic leukemia (HR 0.86 [0.76-0.98]). Decreases were largely driven by a reduced incidence of endocrine conditions (1970s: 4.0% v. 1990s:1.6%; HR 0.66 [0.59-0.73]) and subsequent malignant neoplasms (1970s: 2.4% v. 1990s: 1.6%; HR 0.85 [0.76-0.96]). Significant reductions were also found for gastrointestinal (HR 0.80 [0.66-0.97]) and neurological conditions (HR 0.77 [0.65-0.91]), but not cardiac or pulmonary conditions. Conclusions: Changes in childhood cancer treatment protocols have not only extended lifespan for many survivors, but have also reduced the incidence of serious chronic morbidity in this population.

Background: We aimed to identify demographic and health-related predictors of declining physical activity levels over a four-year period among participants in the Childhood Cancer Survivor Study. Methods: Analyses included 7,287 ≥5-year childhood cancer survivors and 2,107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. In addition, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only. Results: The median age at last follow-up among survivors and siblings was 36 (range, 21–58) and 38 (range, 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included body mass index ≥30 kg/m2 [RR = 1.32; 95% confidence interval (CI), 1.19–1.46, P < 0.01], not completing high school (RR = 1.31; 95% CI, 1.08–1.60, P < 0.01), and female sex (RR = 1.33; 95% CI, 1.22–1.44, P < 0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (P = 0.034), but not with the presence of cardiac (P = 0.10), respiratory (P = 0.92), or neurologic conditions (P = 0.21). Conclusions: Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled, and/or referred for physical therapy. Impact: Clinicians should be aware of low activity levels among subpopulations of childhood cancer survivors, which may heighten their risk for chronic illness. Cancer Epidemiol Biomarkers Prev; 23(8); 1619–27. ©2014 AACR.

Background: Radiation therapy has vascular sequelae including moyamoya (brain radiation), and accelerated cervical atherosclerosis (neck radiation). However, the impact of cranial radiation therapy (CRT) and modifiable stroke risk factors such as hypertension (HTN) on stroke risk in adulthood remains poorly understood. Objective: To assess long-term incidence rates and risk factors for stroke in survivors of childhood cancer followed by the Childhood Cancer Survivor Study (CCSS). Methods: CCSS is a multi-institutional longitudinal cohort study of 14,358 survivors of childhood cancer diagnosed between 1970 and 1986, and 4,023 randomly selected sibling controls. The age-adjusted incidence rates of self-reported late-occurring first-stroke (≥ 5 years after cancer diagnosis) were calculated for survivors compared to siblings. Multivariable Cox Proportional Hazards models were used to identify independent stroke predictors. Results: During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke of which 125 (42.8%) occurred in CNS tumor survivors who constituted only (13%) of the survivor population. The age-adjusted stroke rate per 100,000 person-years at age 23 was 77 (95% CI 62 - 96) for all pediatric cancer survivors and 292 (95% CI 208-409) for CNS tumor survivors compared to 9.3 (95% CI 4 - 23) for siblings. CRT increased stroke risk in a dose dependent manner and cumulative incidence continues to rise decades after diagnosis (see Figure ). Treatment with 30-49 Gy CRT had a relative stroke risk of 5.9 (95% CI 3.5-9.9) compared to 11.0 (95% CI 7.4-16.5) in the 50+ Gy CRT group. The cumulative incidence of stroke 20 years post diagnosis was 0.7% (95% CI 0.5 - 1.0) for no CRT, 2.9% (95% CI 1.4 - 4.4) for 30-49.9 Gy CRT, and 4.9% (95% CI 3.4-6.4) for ≥ 50 Gy CRT. HTN increased stroke risk by 4-fold. If diabetes was present together with HTN in CNS tumor survivors, the RR increased from 2.9 (95% C.I. 1.6-5.3) for HTN alone to 14.4 (95% CI 5.7 - 36.2). Conclusion: Survivors of pediatric cancer treated with CRT have an increased stroke risk that is dose dependent and increases with age. Modifiable risk factors such as HTN and diabetes further increased this risk and should be monitored and treated aggressively in these survivors to reduce the risk of late-occurring stroke.

Few studies have examined risk factors for smoking among adolescent survivors of childhood cancer. The present study reports on the rate of smoking and identifies factors associated with smoking in a sample of adolescent survivors from the Childhood Cancer Survivor Study (CCSS).Participants included 307 adolescent survivors and 97 healthy siblings (ages 14-20) who completed a self-report survey of health, quality of life, and health behaviors.Smoking rates did not differ significantly between survivor and sibling groups (ever smokers: 28% vs. 33%, recent smokers: 10% vs. 9%, respectively). Ever smoking was significantly associated with peer smoking, smokers in the household, binging, suicidal behavior, and no history of CRT. There were significant interactions of peer smoking with gender and CRT for ever smoking and with binging for recent smoking. Recent smoking was more likely for survivors with other household smokers (RR=2.24, CI=1.21-4.16), past suicidality (RR=1.89, CI=1.00-3.56), and no CRT (RR=2.40, CI=1.12-5.17). Among survivors with few smoking friends, ever smoking was more likely for survivors with no CRT (RR=4.47, CI=1.43-13.9), and recent smoking was more likely among survivors who binged (RR=3.37, CI=1.17-9.71).Despite the health risks associated with survivorship, nearly one in three adolescent survivors of childhood cancer has smoked. Exposure to other smokers, in particular, appears to increase the likelihood of smoking for some survivors. Providing smoking cessation programs targeted to family members, helping survivors choose non-smoking friends, and teaching ways to resist smoking influences from peers may be important pathways for smoking prevention with adolescent survivors.

Objective To examine the implications of use of differential thresholds for studying medical Posttraumatic Stress Disorder (PTSD). Methods Self-report data from 6,542 young adult survivors of childhood cancer and 374 of their siblings were used to create clearly differentially defined groups to compare prevalence, correlations and predictors of posttraumatic stress. Results Prevalence of posttraumatic stress in survivors compared to siblings differed by definition used, ranging from an odds ratio of 4.21 (95% CI 2.11–8.38) when posttraumatic stress was defined as meeting full symptoms plus functional impairment to 1.42 (95% CI 0.79–2.56) for partial symptoms with functional impairment. Re-experiencing symptoms did not substantially contribute to the ability to identify functional impairment and emotional distress. Although most of the variables associated with posttraumatic stress symptoms and impairment were consistent across definitions of PTSD, marital status and employment demonstrated nonproportional relationships. Conclusions Choice of the definition used in studying posttraumatic stress after serious illness alters not only epidemiological findings, but also associations with correlates and predictors. This is important in the current debate about the criteria for PTSD in the upcoming DSMV. Further study is needed to determine if these findings are applicable to people exposed to other types of traumatic events.

Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures.The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to 5 years post-diagnosis, and ≥ 5 years post-diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure.Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR = 2.3; 95% CI: 1.8-2.8), tinnitus (RR = 1.7; 95% CI: 1.4-2.1), hearing loss requiring an aid (RR = 4.4; 95% CI: 2.8-6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR = 5.2; 95% CI: 2.8-9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose-dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR = 2.1; 95% CI: 1.3-3.2), tinnitus (RR = 2.8; 95% CI: 1.9-4.2), and hearing loss requiring an aid (RR = 4.1; 95% CI: 2.5-6.7).Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life.

Obesity is rapidly becoming a health problem of epidemic proportions, bringing with it a host of health concerns. This study investigates the association of long-term (10-year) use of 14 nutritional supplements, marketed as weight-control aids, with weight change over the past 10 years among individuals age 53 to 57 years.Data are from the VITamins And Lifestyle (VITAL) cohort study of western Washington. Participants (n = 15,655) completed questionnaires about 10-year supplement use, diet, health habits, height, and present and former weights. The following supplements that are sometimes marketed for weight control or loss were examined: multivitamins; vitamins B6 and B12; chromium; coenzyme Q10, dehydroepiandrosterone, essential fatty acids (EFAs), fiber, garlic (Allium sativum), ginkgo (Ginkgo biloba), ginseng (Panax spp.), melatonin, soy, and St. John's wort (Hypericum perforatum). Linear regression was used to model 10-year change in weight from age 45 to ages 53-57, stratified by sex and body mass index (BMI, kg/m2) (normal, overweight, or obese) at age 45 years. Models were controlled for race/ethnicity, education, energy intake, physical activity, weight at age 45 years, and smoking.Among overweight or obese men and women, long-term use of multivitamins, vitamins B6 and B12, and chromium were significantly associated with lower levels of weight gain. For example, with chromium, weight gain in the past 10 years for obese men was 11.7 lb for no use, 6.1 lb for150 microg/day (10-year average), and a weight loss of 3.1 lb foror = 150 microg/day (p for trend,0.05). Among obese women, weight gain was 14.1 lb, 7.9 lb, and 3.2 lb for the three groups respectively (p for trend,0.01).These data suggest that long-term users of certain supplements experienced less weight gain than individuals who did not use the supplements. Further study is necessary before recommendations regarding these supplements can be made.

Purpose Both blood and toenail selenium are used to assess selenium exposure in epidemiologic studies. Little is known about the relationship of these biomarkers with each other or about whether there are differences in the relationships of these biomarkers with diet, supplement use, or participant characteristics. Methods Data are from 220 participants in a large cohort study of supplement use and cancer risk. Measures of selenium exposure included supplement use (current and 10-year) from a self-administered questionnaire, an inventory of currently used supplements (multivitamins and single supplements), dietary intake from a food frequency questionnaire (FFQ), and selenium concentration in toenails and plasma. Results Plasma and toenail selenium concentrations were significantly correlated (r=.56 [95% confidence interval: .46, .64]). Supplemental selenium was the strongest predictor of both selenium biomarkers, and these associations were slightly stronger when based on the supplement inventory and 10-year self-reported use compared to current self-reported use. Correlations of current and 10-year questionnaire dose and inventory dose with toenail selenium were .26, .36, and .33; for plasma selenium, these were .27, .36, and .36. Neither dietary selenium nor any participant characteristics, except smoking, was related to either biomarker. Current smokers had lower toenail, but not plasma, selenium levels compared to nonsmokers (.89 versus 1.03μg/g, p = .03); however, the difference was not significant after control for supplement use (p = .09). Conclusions Both toenail and plasma selenium levels similarly reflect selenium intake exposure. There do not appear to be independent associations of toenail or plasma selenium with FFQ-derived selenium intakes, health-related behaviors, or demographic characteristics.

By broadening the definition of a dietary supplement, the 1994 Dietary Supplements Health and Education Act opened the market to many herbals, botanicals, and other food ingredients that would have otherwise needed safety testing before being sold. Information regarding patterns and correlates of herbal and specialty supplement use can help nutritionists understand which compounds are most commonly used, who are likely to use these supplements, and whether the choice of herbal supplements appears motivated by specific health concerns.Data are from 61,587 participants, aged 50 to 76 years, who completed a self-administered mailed questionnaire in 2000-2002 on current dietary supplement use (20 herbal/specialty supplements, multivitamins, and 17 individual vitamins or minerals), demographic and lifestyle characteristics, and medical history.When compared with no supplement use, herbal/specialty supplement use was significantly higher among respondents who were older, female, educated, had a normal body mass index, were nonsmokers, engaged in exercise, and ate a diet lower in fat and higher in fruits and vegetables (all P.001). Similar trends were observed when herbal/specialty supplement users were compared with vitamin/mineral users. For specific supplements and medical conditions, the strongest associations were cranberry pills and multiple bladder infections (odds ratio [OR], 4.66; 95% confidence interval [CI], 4.03-5.38), acidophilus pills and lactose intolerance (OR, 3.37; 95% CI, 2.96-3.84), and saw palmetto and enlarged prostate (OR, 3.33; 95% CI, 3.00-3.72).Odds of supplement use are high for certain demographic and lifestyle characteristics. Additionally, persons with specific medical conditions are using supplements promoted to reduce risk for their particular conditions.

In the United States, dietary supplements contribute a large proportion of micronutrient intakes. Therefore, it is important to collect accurate information on supplement use for studies of micronutrients and disease risk. This report describes the test-retest reliability and validity of a detailed, self-administered mailed questionnaire on vitamin and mineral supplement use. Participants (n = 220) completed the questionnaire at baseline and 3 months later. During an in-person interview, participants provided spot urine and blood samples, and interviewers transcribed nutrient information from their supplement bottle labels. The questionnaire had very good test-retest reliability for mean supplement intake over the past 10 years, with intraclass correlations ranging from 0.69 for beta-carotene to 0.87 for vitamin E. Pearson's correlation coefficients comparing current supplemental intakes from the questionnaire and interviews/label transcriptions were high, ranging from 0.58 for beta-carotene to 0.82 for chromium; however, for some nutrients, median intakes from the questionnaire were slightly lower than from the interviews. Beta-carotene, vitamin C, and vitamin E (alpha-tocopherol) showed clear linear trends of increasing blood concentrations with higher self-reported supplemental intakes (Pearson's correlation coefficients adjusted for potential confounding factors and diet = 0.31, 0.29, and 0.69, respectively; all p < 0.0001). Creatinine-adjusted spot urinary calcium values were not associated with supplemental calcium intakes (Pearson's r = -0.07). This self-administered questionnaire demonstrated high reproducibility and validity for collecting detailed information on supplement use.