Charles A. Sklar

Objective To formulate clinical practice guidelines for the endocrine treatment of hypothalamic–pituitary and growth disorders in survivors of childhood cancer. Participants An Endocrine Society–appointed guideline writing committee of six medical experts and a methodologist. Conclusions Due to remarkable improvements in childhood cancer treatment and supportive care during the past several decades, 5-year survival rates for childhood cancer currently are >80%. However, by virtue of their disease and its treatments, childhood cancer survivors are at increased risk for a wide range of serious health conditions, including disorders of the endocrine system. Recent data indicate that 40% to 50% of survivors will develop an endocrine disorder during their lifetime. Risk factors for endocrine complications include both host (e.g., age, sex) and treatment factors (e.g., radiation). Radiation exposure to key endocrine organs (e.g., hypothalamus, pituitary, thyroid, and gonads) places cancer survivors at the highest risk of developing an endocrine abnormality over time; these endocrinopathies can develop decades following cancer treatment, underscoring the importance of lifelong surveillance. The following guideline addresses the diagnosis and treatment of hypothalamic–pituitary and growth disorders commonly encountered in childhood cancer survivors.

Background: Thyroid cancers are rare in the pediatric age group, and unlike in adults, few data are available regarding the clinical implication of histologic subtypes in the pediatric population. The purpose of the current study was to determine the prognostic significance of histologic subtypes of differentiated thyroid cancer (DTC) in a large series of children and adolescents followed at a single institution. Methods: A retrospective review was conducted of all pediatric DTC patients who were treated and followed between 1988 and 2012. Sixty-two patients (median age at diagnosis 13.8 years, median age at follow-up 18 years, 77% female) were assessed. The most common subtypes included classic papillary thyroid carcinoma (PTC; 48%), diffuse sclerosing PTC (16%), and follicular variant PTC (15%); 37% were considered “high-risk” histologies based on adult criteria. Results: In a multivariate model, only extensive extrathyroidal extension (ETE), defined as the presence of two or more microscopic foci of tumor cells ≤1 mm in size each or any foci >1 mm in size invading beyond the thyroid capsule into perithyroid soft tissue or organs, was significantly associated with extent of disease at presentation. At last follow-up, 76% of subjects had no evidence of disease, 18% had persistent disease, and 5% had recurrent/progressive disease. Event-free survival was associated with extent of disease at presentation ( p = 0.01), extensive ETE at diagnosis ( p < 0.01), and male sex ( p = 0.01), but not histologic subtype ( p = 0.20). Conclusions: Pediatric DTC carries an excellent prognosis. Extensive ETE at diagnosis was found to be an independent predictor of extent of disease at presentation, as well as event-free survival. Unlike in the adult population, “high-risk” histologic subtypes did not independently predict extent of disease at presentation or event-free survival in this pediatric population with DTC.

Background: Data on 25‐hydroxyvitamin D (25‐OH D) status among survivors of childhood cancer are limited. Our aim was to determine the prevalence of and risk factors for 25‐OH D insufficiency in a large, diverse population of cancer survivors being followed in a childhood cancer survivor clinic.Procedure: Retrospective chart review in survivors seen for routine long‐term follow‐up, who underwent routine screening blood studies including 25‐OH D levels. Vitamin D insufficiency was defined as 25‐OH D P < 0.05). In multivariate analysis, a model including race and pubertal status provided a good fit for the data.Conclusions: The prevalence of 25‐OH D insufficiency in these cancer survivors was high but similar to what has been described in the general population. No cancer specific variables were associated with 25‐OH D insufficiency. Since cancer survivors are at a higher risk for subsequent malignancies, cardiovascular disease, and low bone mineral density, all of which may be affected by 25‐OH D levels, interventions to improve 25‐OH D status in this vulnerable population are needed. Pediatr Blood Cancer 2013; 60: 1237–1239.

9547 Background: The Alkylating Agent Dose (AAD) score has been widely employed previously for quantifying alkylating agent exposure in analyses of second malignant neoplasms, mortality and fertility of adult survivors of childhood cancer. However, the AAD is calculated based on the the drug dose distribution of each study in which it is utilized, making comparisons across studies difficult and limiting its usefulness for counseling. Methods: We normalized alkylating agent doses to a cyclophosphamide equivalent dose (CED) using published toxicity and/or treatment data and evaluated the CED in an analysis of risk of pregnancy of partners of 4,797 male participants in the Childhood Cancer Survivor Study who were 15 to 44 years of age when they completed the baseline questionnaire. Cox proportional hazard models with age as the time-scale were used to compare hazards of a pregnancy between same age subjects. Univariable and multivariable analyses were carried out, with final treatment variables included in the multivariable model that were significant at the 0.1 level or that markedly influenced (>10% change) the effect of another factor in the model (confounder). Demographic, socioeconomic and exposure variables were evaluated for inclusion in multivariable models. Results: The hazard radio (HR) for siring a pregnancy, adjusted for demographic and other treatment variables, decreased with increasing CED (Table). Comparison of results using the AAD versus the CED, demonstrated better model fit with CED. Conclusions: Increasing CED is correlated with decreasing HR for siring a pregnancy. CED was a better predictor of pregnancy than the AAD. Since CED is independent of the drug dose distribution of the cohort being evaluated and can be compared across studies this approach should be incorporated into analyses assessing long-term outcomes associated with alkylating agent exposure. CED (mg/m2) HR 95% confidence interval P value 0 1.00 > 0 to < 4,000 0.97 0.66, 1.43 0.8729 ≥ 4,000 to < 8,000 0.73 0.51, 1.05 0.0873 ≥ 8,000 to < 12,000 0.48 0.33, 0.70 0.0001 ≥ 12,000 to < 16,000 0.36 0.22, 0.59 <0.0001 ≥ 16,000 to < 20,000 0.49 0.29, 0.84 0.0089 ≥ 20,000 0.21 0.12, 0.38 <0.0001

9507 Background: Childhood cancer survivors have an increased risk of late-onset treatment-related cardiotoxicity. How traditional cardiovascular disease risk factors (CVRFs) modify this risk is unknown. Methods: Analyses included 14,358 >5 yr survivors of childhood cancer diagnosed 1970-86 (median age at last follow-up 31.9 yrs, range 5.6-58.9). Rates of obesity (BMI≥30), CVRFs requiring medical treatment (diabetes, hypertension, dyslipidemia) and cardiac outcomes (coronary artery disease, congestive heart failure, valvular abnormality, stroke and arrhythmia) were collected at baseline and subsequent follow-up questionnaires and compared to a sibling cohort (n=4,023). Associations between CVRFs and cardiac outcomes and the predictive ability of CVRFs for future cardiac events were assessed. Results: Survivors reported higher rates of diabetes (3.7% vs. 2.5%, OR= 1.7, 95% CI 1.4-2.1), hypertension (15.1% vs. 9.7%, OR= 2.1, 95% CI 1.9-2.4),dyslipidemia (8.2% vs. 5.7%, OR= 1.9, 95% CI 1.7-2.3), but not obesity (24.3% vs. 25.4%, OR= 1.0, 95% CI 0.9-1.1), and a higher rate of clustering of CVDRFs (any 3 of 4 CRFs, 2.5% vs. 1.9%, OR= 1.7, 95% CI 1.3-2.2) compared to siblings. Cumulative incidence (CI) at 45 years of age for coronary artery disease, congestive heart failure, valvular abnormality, stroke and arrhythmia was 4.2%, 6.7%, 6.2%, 2.5%, and 11.7%, respectively. The 45-yr CI for cardiac-related mortality was 1.6% (95% CI 1.2-1.9; standardized mortality ratio = 4.4, 95% CI 3.6-5.3). Presence of a CVRF cluster was associated with an increased risk of congestive heart failure (RR= 4.2, 95% CI 2.6-6.7) among survivors treated with anthracyclines (>250mg/m²) and of coronary artery disease (RR= 4.6, 95% CI 3.0-7.0) among those who received chest-directed radiotherapy. Presence of hypertension (RR=2.2, 95% CI 1.6-3.1) and obesity (RR=1.3, 95% CI 1.1-1.6) were predictive of future cardiac events. Conclusions:Among adult survivors of childhood cancer exposed to cardiotoxic therapy, presence of traditional cardiovascular disease risk factors further increase the risk for poor cardiovascular outcome.

9542 Background: Female childhood cancer survivors (CCS) are less likely to report having been pregnant when compared with females within the CCSS sibling cohort (Sibs) as the result of direct damage to the ovaries produced by radiation therapy (XRT) and/or chemotherapy. High-dose hypothalamic/pituitary (HPT) XRT, which causes central or secondary hypogonadism, may result in infertility due to failure to stimulate ovulation. Recently, another possible central mechanism has been postulated, luteal phase deficiency, resulting from low-dose HPT XRT. Methods: We evaluated the occurrence of pregnancy in 3,666 female CCS who participated in the CCSS and 2,082 Sibs. The association between low- dose HPT XRT and fertility was studied by restricting analyses to those female CCS who received no/scatter (≤10 cGy) radiation to the ovaries and comparing their fertility rates with those of Sibs using Cox-proportional hazards models. Specific treatment effects were studied by further limiting analyses to only CCS. Results: These CCS who received no/scatter (≤ 10 cGy) ovarian radiation were more likely to report being pregnant (hazard ratio [HR]:1.5, 95% confidence interval [95%CI]: 1.3, 1.7) when adjusted for race/ethnicity, smoking, marital status, and education than Sibs. Multivariable models showed a significant decrease in the risk of reporting pregnancy with HPT XRT doses of ≥ 2,200 cGy when compared with those CCS receiving no HPT XRT when adjusted for race/ethnicity, smoking, marital status, education, age at diagnosis, and treatment with VP16 (Table) (137 had missing HPT radiation doses). Conclusions: The results of this study support the hypothesis that low-dose HPT XRT may be a contributing factor to infertility among female CCS. HPT radiation dose (cGy)Number of CCSS participantsHR ever pregnant95% CI ever pregnant01,9961.0> 0 to < 15003710.80.7-1.1≥ 1500 to < 22005990.90.7-1.1≥ 2200 to < 27003160.60.5-0.8≥ 27002470.70.5-0.9No significant financial relationships to disclose.

9514 Background: High proportions of children with Wilms Tumor (WT), cured by surgery, chemotherapy, ± irradiation (RT), risk late effects of therapy. Methods: Self-reported chronic medical conditions (CMCs), health status, and health care practices were analyzed in this retrospective cohort including 1,256 5-yr survivors of WT diagnosed 1970-1986 and a sibling comparison group (n=4023). The risk of specific CMCs was analyzed by treatment. Results: The cumulative incidence at 25 yrs of any CMC was 51% and severe/disabling CMC was 11%. Compared to the siblings, WT survivors were twice as likely to report a CMC (hazard ratio [HR]2.0, 95% confidence interval (CI), 1.8-2.4) and almost five- times more likely to have a severe/disabling CMC (HR4.7, 95%CI, 3.6-6.1). The HR of specific CMCs were: congestive heart failure (CHF) 23.6 (95% CI, 10.8- 51.5), renal failure 50.7 (95% CI, 14.5-177.4), and hypertension (HTN) 8.2 (95% CI, 6.4-10.5). RT to the heart increased the likelihood of reporting CHF without doxorubicin (HR6.6, 95% CI, 1.6-28.3), with ≤ 250 mg/m² (HR13.0, 95% CI, 1.9-89.7), and with > 250 mg/m² (HR18.3, 95% CI, 3.8-88.2). Doxorubicin without RT did not increase the likelihood of CHF. RT to the contralateral kidney did not increase the likelihood of reporting renal failure or HTN. The prevalence ratio (PR) of adverse health status was significantly different from the sibling group for general overall health (PR 1.7, p=0.001), functional impairment (PR 3.3, p<0.001) and activity limitations (PR 1.9, p<0.001), but not for mental health status (PR 1.2, p=0.09). WT survivors and the siblings showed no differences in self or professional screening for cancer. WT survivors <30 yrs old reported more general medical exams (PR 1.1, p<0.001). Female WT survivors <30 yrs were more likely to report having had a mammogram (PR 1.6, p=0.008). Of female WT survivors who received chest RT, only 13% <30 yrs and 57% ≥30 yrs reported having had a mammogram. Conclusions: Survivors of WT have an excess risk of chronic medical conditions and adverse health status. The health care practices of WT survivors were similar to their siblings, providing opportunity for intervention. No significant financial relationships to disclose.

Background: To determine the prevalence of and risk factors for primary hypothyroidism following treatment with a radiolabeled monoclonal antibody (¹³¹I‐3F8) in children with neuroblastoma.Procedure: In the current study, we assessed thyroid function in 51 neuroblastoma patients who survived for ≥3 months after treatment with ¹³¹I‐3F8 (a murine IgG3 monoclonal antibody that reacts with the ganglioside GD2) at 4 mCi/kg/day × 5 days (total 20 mCi/kg). Prior therapy in all subjects included dose‐intensive chemotherapy; 13 subjects also received external beam radiation to the neck. Oral iodide and liothyronine sodium (T3) were administered for protection of the thyroid gland.Results: Thirty‐two of 51 subjects (63%) developed hormonal evidence of primary hypothyroidism. The median time to hypothyroidism after treatment with ¹³¹I‐3F8 was 6.4 months. The probability of developing hypothyroidism was 56% at 2 years following treatment with ¹³¹I‐3F8. There was evidence for an association between thyroidal uptake of ¹³¹I and development of hypothyroidism (hazard ratio 1.83, 95% confidence interval 0.91–3.30; P = 0.09).Conclusions: We conclude that hormonal evidence of primary hypothyroidism developed in a majority of subjects treated with ¹³¹I‐3F8, despite pretreatment with oral iodide plus liothyronine sodium. Alternative strategies for thyroid gland protection are needed. Pediatr Blood Cancer 2010;55:76–80.

Background: Childhood cancer survivors are at higher risk of morbidity and mortality from cardiovascular disease compared with the general population. Methods: Eight thousand five hundred ninety-nine survivors (52% male) and 2,936 siblings (46% male) from the Childhood Cancer Survivor Study, a retrospectively ascertained, prospectively followed study of persons who survived 5 years after childhood cancer diagnosed from 1970 to 1986, were evaluated for body mass index of ≥30 kg/m² based on self-reported heights and weights and self-reported use of medications for hypertension, dyslipidemia, and impaired glucose metabolism. The presence of three or more of the above constituted Cardiovascular Risk Factor Cluster (CVRFC), a surrogate for Metabolic Syndrome. Results: Survivors were more likely than siblings to take medications for hypertension [odds ratio (OR), 1.9; 95% confidence interval (95% CI), 1.6-2.2], dyslipidemia (OR, 1.6; 95% CI, 1.3-2.0) or diabetes (OR, 1.7; 95% CI, 1.2-2.3). Among these young adults (mean age of 32 years for survivors and 33 years for siblings), survivors were not more likely than siblings to be obese or have CVRFC. In a multivariable logistic regression analysis, factors associated with having CVRFC included older age at interview [≥40 versus Conclusions: Among adult survivors of pediatric cancer, older attained age, exposure to total body irradiation or abdominal plus chest radiation, and a sedentary life-style are associated with CVRFC. Cancer Epidemiol Biomarkers Prev; 19(1); 170–81