Purpose: Pediatric central nervous system (CNS) tumors often recur despite multimodality therapy. Although re-irradiation (re- RT) has historically been limited by concerns for severe late toxicities, modern techniques have renewed interest in this approach. Proton therapy provides dosimetric advantages that may enable curative re-treatment with reduced normal tissue exposure. Methods: We retrospectively reviewed 54 pediatric patients who underwent proton re-RT for recurrent CNS tumors at our institution (2010–2024). Eligible patients had received prior CNS-directed RT at ≤ 20 years of age. Toxicities were graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 as acute ( < 3 months) or late ( ≥ 3 months). Cumulative dosimetry was assessed by registering RT1 and RT2 plans and converting doses to EQD2 ( α/ β = 2 Gy). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier methods. Results: Median age at re-RT was 11 years, with a median interval of 28.5 months between RT courses. The median prescribed re-RT dose was 54 Gy (range, 25–60), yielding a cumulative EQD2 of 102.6 Gy (range, 46.8–112.9). Median OS and PFS were 46.0 and 16.5 months, respectively. Among 16 ependymoma patients, all received full-dose proton re-RT (54–59.4 Gy), yielding a 1-year OS of 91.7% and PFS of 50.0%. Glioma patients had inferior outcomes (1-year OS 55.4%, PFS 41.6%) with a median re-RT EQD2 of 48.1 Gy. An RT interval of ≥ 12 months was associated with improved OS and PFS. Composite dosimetry in 21 patients showed a median cumulative brain D0.1cc of 109.0 Gy; only one patient developed Grade 3 radiation necrosis (RN). High-grade acute toxicity occurred in 13.0% of patients, all manageable with supportive care. Conclusion: Proton re-RT for pediatric CNS tumors is feasible and associated with encouraging survival and low rates of serious late toxicity.
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