Reirradiation With Proton Therapy Using Hypofractionated Schedules: A Systematic Review of the Literature

Re-irradiation (re-RT) with hypofractionated proton therapy (PT) may be a treatment option in selected cases. Aim is to provide a critical overview of the state of the art. PRISMA-compliant systematic review was performed on 2nd October 2025. All tumor sites were considered, provided that re-RT was performed with dose/fraction>2Gy(RBE) in adults. Oncological and toxicity outcomes were retrieved. Twelve original research works were identified. The total number of patients treated with hypofractionated PT re-RT was 478. The majority of patients were treated for recurrent tumors of either the gastrointestinal (GI) region (n = 143) or the lung (n = 123). The majority of the published series refers to data derived from retrospective and monoinstitutional experiences. Most patients were treated for recurrent tumors of either the gastrointestinal (GI) region (n = 143) or the lung (n = 123). Median sample size was 32 (interquartile range: 26-46, range: 14-83). Moderate hypofractionation (< 5 Gy(RBE)/fraction) was the most frequent schedule. All included studies had a radical intent. Overall, 2 year overall survival ranged from 8.4% (head & neck) to 87.5% (liver). The rate of severe side effects remained relevant. Of note, clinical outcomes and toxicity profiles were highly heterogeneous among the different tumor sites. Therefore, in the setting of re-RT with PT, conclusive data on the efficacy and toxicity profile of hypofractionated schedules could not be provided yet. Re-RT remains a personalized approach in almost all settings of tumor recurrence. Evidence supporting the use of hypofractionated PT re-RT remains limited but encouraging. Identifying predictors of toxicity and treatment response is essential to guide future research and to establish this approach as a viable option for selected patients.