KEY POINTS
- This PRISMA-compliant systematic review identified 12 non-overlapping clinical series encompassing 478 patients treated with proton re-irradiation using doses above 2 Gy(RBE) per fraction. Gastrointestinal tumors (n=143) and lung cancers (n=123) were the largest groups.
- Most evidence came from small retrospective, single-institution series, with a median study size of 32 patients. Moderate hypofractionation below 5 Gy(RBE) per fraction was the most common approach, although reported fraction sizes ranged widely.
- Clinical outcomes varied dramatically by disease site. Reported 2-year overall survival ranged from approximately 8% in recurrent head and neck cancer to 87.5% in liver cancer, making pooled efficacy estimates clinically meaningless.
- Serious toxicity remained possible despite the dosimetric advantages of protons. In recurrent head and neck cancer, one 30-patient series reported five severe toxicities and one fatal carotid hemorrhage; thoracic series also included fatal pulmonary hemorrhage after heavily cumulative treatment.
- Recurrent rectal cancer provided one of the more encouraging signals: in a 33-patient proton series, estimated 2-year overall survival was 86.5%, while severe toxicity occurred in 9%, including one grade 4 rectal perforation.
- Repeated proton treatment for hepatocellular carcinoma also showed potentially useful normal-tissue sparing. One series reported 87.8% 5-year local control, but severe toxicity occurred in 19%; outcomes appeared most favorable for peripheral tumors, Child-Pugh A liver function, and adequate preservation of non-irradiated liver.
- Evidence quality was the central limitation: 9/12 studies mixed conventional and hypofractionated schedules, several mixed treatment modalities, proton-specific outcomes were sometimes inseparable, toxicity reporting was inconsistent, and no formal meta-analysis or structured risk-of-bias assessment was possible.
CLINICAL TAKEAWAY
Protons are conceptually attractive for re-irradiation because reducing integral dose may create treatment opportunities that are difficult with photons. But hypofractionated proton re-RT is not yet a standardized strategy: patient selection, cumulative EQD2 assessment, critical-organ constraints, and comparison with modern photon plans remain essential on a case-by-case basis.