Pooled Analysis of Meningioma Risk Following Treatment for Childhood Cancer.

Importance: Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy. Objective: To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk. Design, Setting, and Participants: This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022. Exposures: Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses. Main Outcomes and Measures: The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy). Results: The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose. Conclusions and Relevance: These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.

Longitudinal follow-up of adult survivors of Ewing sarcoma: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Ewing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown. METHODS: This study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Among 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively. CONCLUSIONS: With extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551-60. © 2017 American Cancer Society.

Pediatric cancer survivorship research: experience of the Childhood Cancer Survivor Study.

The Childhood Cancer Survivor Study (CCSS) is a comprehensive multicenter study designed to quantify and better understand the effects of pediatric cancer and its treatment on later health, including behavioral and sociodemographic outcomes. The CCSS investigators have published more than 100 articles in the scientific literature related to the study. As with any large cohort study, high standards for methodologic approaches are imperative for valid and generalizable results. In this article we describe methodological issues of study design, exposure assessment, outcome validation, and statistical analysis. METHODS for handling missing data, intrafamily correlation, and competing risks analysis are addressed; each with particular relevance to pediatric cancer survivorship research. Our goal in this article is to provide a resource and reference for other researchers working in the area of long-term cancer survivorship.

Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

PURPOSE: We examined the rate of increase in the body mass index (BMI; kg/m(2)) after final height attainment in survivors of acute lymphoblastic leukemia (ALL) and a noncancer comparison group. METHODS: Childhood Cancer Survivor Study (CCSS) is a retrospectively ascertained cohort study that prospectively tracks the health status of adults who were diagnosed with childhood cancer between 1970 and 1986 and a comparison group of siblings. Changes in BMI from baseline enrollment to time of completion of follow-up (mean interval, 7.8 years) were calculated for 1,451 ALL survivors (mean age, 32.3 years at follow-up) and 2,167 siblings of childhood cancer survivors (mean age, 35.9 years). RESULTS: The mean BMI of the CCSS sibling comparison group increased with age (women, 0.25 units/yr, 95% CI, 0.22 to 0.28 units; men, 0.23 units/yr, 95% CI, 0.20 to 0.25 units). Compared with CCSS siblings, ALL survivors who were treated with cranial radiation therapy (CRT) had a significantly greater increase in BMI (women, 0.41 units/yr, 95% CI, 0.37 to 0.45 units; men, 0.29 units/yr; 95% CI, 0.26 to 0.32 units). The rate of BMI increase was not significantly increased for ALL survivors who were treated with chemotherapy alone. Younger age at CRT exposure significantly modified risk. CONCLUSION: CRT used in the treatment of childhood ALL is associated with a greater rate of increasing BMI, particularly among women treated with CRT during the first decade of life. Health care professionals should be aware of this risk and interventions to reduce or manage weight gain are essential in this high-risk population.