Secondary neoplasms in children with central nervous system (cns) tumors following radiotherapy in the modern era

Abstract PURPOSE: To assess reduction of secondary radiation-induced neoplasms over the past two decades, focusing on children with CNS tumors who received intensity modulated radiotherapy (IMRT) or proton therapy (PT). METHODS: A total of 1044 children received radiotherapy for a primary CNS tumor at 2 institutions between 1999 and 2020, including 99 treated with IMRT and 945 treated with PT. Median age was 8.7 years old. Median follow-up was 6.0 years and included 83 and 510 patients with >5 years follow-up in the IMRT and proton cohorts, respectively. Cumulative incidence method provided estimates of secondary neoplasms encompassing benign and malignant solid tumors as well as leukemia. Multiple variables were assessed using proportional hazard regression for competing risks. RESULTS: Ten-year overall survival was 87.4%. Patients treated with IMRT were significantly older, with a median age of 10.4 vs 8.4 years old (p <0.001), but were more likely to receive craniospinal irradiation (31.3% vs 14.2%, p <0.001) or alkylating chemotherapy (50.5% vs 29.7%, p <0.001). The 5- and 10-year cumulative incidence of second neoplasm was 0.7% and 2.3%, respectively. On multivariate analysis, age <5 (4.9% vs 0.7% at 10 years) and tumor predisposition syndrome (34.3% vs 1.5% at 10 years) were significantly associated with a second neoplasm (p < 0.01 for each). On both univariate and multivariate analyses, PT was not associated with a lower incidence of second neoplasm. Following IMRT, 1/2 second solid tumors occurred outside the target volume, compared to 2/11 after PT. CONCLUSION: Following modern radiotherapy, approximately 2% of children with a CNS tumor will develop a second neoplasm within 10 years of treatment. Compared to IMRT, PT was not associated with an overall reduction in second neoplasms. More events and follow-up beyond 10 years are needed to determine if proton therapy reduces the incidence of second solid tumors occurring specifically in the low dose region.