Salvage Proton Therapy Re-Irradiation in Recurrent Head and Neck Cancer: Outcomes and Adverse Events by Re-Irradiated Target Site

Background/Objectives: Photon re-irradiation in previously treated head and neck cancer (HNC) is constrained by cumulative normal-tissue toxicity. Pencil-beam scanning intensity-modulated proton therapy (PBS-IMPT) allows for a sharper dose conformation than conventional photon techniques, which may widen the therapeutic window in previously irradiated tissue. Methods: Sixty-five patients with recurrent or second primary HNC were enrolled in a prospective single-institution registry and re-irradiated with PBS-IMPT between January 2020 and December 2025. Forty-five were treated with radical intent (69.2%), and 20 were treated postoperatively (30.8%), with a median prescribed dose of 66 Gy (RBE) in 30 fractions. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Locoregional control (LRC), adverse events and the prognostic impact of anatomical extent were secondary endpoints. Results: The median follow-up was 9.3 months. The median OS was 17.2 months (95% CI 13.9–NR), with a 12-month rate of 67.1%. The median PFS was 10.1 months and the median LRC was 28.1 months. Central/skull-base involvement was associated with a non-significant trend toward worse OS (14.3 vs. 35.2 months; p = 0.062) and with significantly worse PFS (9.1 vs. 14.7 months; p = 0.037) than peripheral disease, but LRC did not differ between the groups (p = 0.240). Grade ≥ 3 oral mucositis occurred in 7.7%, with no grade 4–5 acute events. Within a median follow-up of 9.3 months, late osteoradionecrosis affected 6.2%, but late toxicity data remain preliminary given the short follow-up. Ninety-two percent of patients completed treatment. Conclusions: PBS-IMPT re-irradiation provided adequate survival with low acute toxicity. T3–T4 stage at re-irradiation was the only variable retaining significance for PFS on multivariable analysis (HR 4.32, 95% CI 1.24–15.13; p = 0.022). The poor survival observed for central/skull-base disease on Kaplan–Meier curves disappeared after T-stage adjustment, indicating the higher concentration of advanced disease in that compartment. Multicentre prospective data and longer follow-up are needed.