Brain and Brainstem Necrosis after Re-Irradiation for Recurrent Childhood Central Nervous System (CNS) Tumors: A Report from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Task Force

Abstract

<h3>Purpose/Objective(s)</h3> Re-irradiation is increasingly used in children, adolescents and young adults (AYA) with recurrent CNS tumors. The PENTEC re-irradiation task force reports the results on the risk of symptomatic necrosis following cranial re-irradiation, and its dependence on cumulative dose. <h3>Materials/Methods</h3> A systematic literature search for peer-reviewed articles 1975 to 2021 identified 1183 studies on re-irradiation and 92 studies on re-irradiation for recurrent CNS tumors. Studies on predominantly adult populations and re-irradiation for secondary neoplasms were excluded (n=49). Data from the remaining 43 studies were captured. 17 studies (n=449), reporting brain and brainstem necrosis were used for analysis. While all studies mentioned techniques and range of doses used for re-irradiation, they lacked details on significant dose-volume metrics (e.g., percentage of re-irradiation treatment volume overlapping with primary radiotherapy, mean and maximum cumulative equivalent dose in 2Gy fractions, with alpha-beta ratio=2 (EQD2/2) to organs at risk) necessary for a dose-response modelling. We, therefore, estimated the incidence of necrosis with an exact 95% confidence interval (CI) and provided a qualitative description of the data. <h3>Results</h3> Treated cancers included ependymoma (n=279;7 studies), medulloblastoma (n=98; 6 studies), any CNS tumors (n=62: 3 studies) and supratentorial high-grade gliomas (n=10: 1 study). The median interval between initial and re-irradiation was 2.3 years (range 1.2-4.75). The median cumulative EQD2/2 prescription dose was 103.8 Gy (range 79.7-141.3). Among 449 children/AYA treated with re-irradiation, 22 (4.9%, 95% CI 3.1-7.3%) developed brain necrosis and 14 (3.1%, 95% CI 1.7-5.2%) brainstem necrosis. The median cumulative prescription EQD2/2 was 111.4 Gy (range 79.7-141.3) for development of any necrosis, 107.7 Gy (range 79.7-141.3) for brain necrosis and 112.1 Gy (range 100.2-117) for brainstem necrosis. In 6 studies (n=176) of conventionally fractionated (≤2 Gy per fractions) re-irradiation, 7 patients developed brain necrosis (3.9%) and 4 brainstem necrosis (1.7). In the 5 studies (n=160) of hypofractionated (4-24 Gy per fraction) re-irradiation, 9 patients developed brain necrosis (5.6%) and 10 brainstem necrosis (6.9%). Though there were more necroses in the hypofractionated group, it was not statistically significant (Fisher's exact test 2-tailed p value=0.4664). The remaining six studies (n=113) used a range of fraction size (1.8-24 Gy). No studies reported cumulative dosing for individual organs at risk. <h3>Conclusion</h3> Existing literature suggests that in children and AYA with recurrent brain tumors, re-irradiation results in less than 5-7% incidence of brain/brainstem necrosis with conventional prescription doses after a median follow-up of 2.3 years. A uniform approach for reporting dosimetric endpoints is recommended to derive a robust predictive model of late toxicities following re-irradiation.