A multicenter, prospective, phase 2 trial on proton re‐irradiation for patients with previously treated head and neck cancer

BACKGROUND: Re-irradiation (re-RT) for recurrent head and neck cancer (HNC) can be potentially curative but is constrained by significant toxicity. Proton therapy may improve the therapeutic ratio. This multicenter phase 2 trial evaluated the safety and efficacy of proton re-RT in patients with HNC. METHODS: Patients received prior HNC radiotherapy at a dose of ≥40 gray (Gy). Salvage surgery and/or systemic therapy before re-RT were permitted. Considering clinical status, two pragmatic treatment approaches were used: fractionated re-RT (F-Re-RT; 60-70 Gy) or QUAD shot re-RT (QS-Re-RT; 14.8 Gy per cycle, up to four cycles; maximum total, 59.2 Gy). Primary end points were locoregional recurrence-free rates at 12 months for F-Re-RT and at 6 months for QS-Re-RT, and a fixed-time, binary proportion analyzed using 90% Clopper-Pearson confidence intervals (CIs) and prespecified success thresholds (lower bound, >55% and >10%, respectively). Secondary end points included overall survival (OS), progression-free survival, the cumulative incidence of distant metastasis and locoregional recurrence, clinician-reported toxicity, and patient-reported outcomes. RESULTS: From July 2017 to November 2022, 85 patients received either F-Re-RT (n = 57) or QS-Re-RT (n = 28), with a median follow-up of 38 months. The locoregional recurrence-free rates were 71% (90% CI, 59%-81%) at 12 months for F-Re-RT and 76% (90% CI, 58%-89%) at 6 months for QS-Re-RT, surpassing prespecified success thresholds. The highest late toxicity attributable to re-RT was grade 3 in 20% of patients, grade 4 in 11%, and grade 5 in 4%. The 5-year OS rate was 29%, and the 5-year progression-free survival rate was 23%. Patient-reported outcomes were stable at 1 year after F-Re-RT and after QS-Re-RT. CONCLUSIONS: Proton re-RT demonstrated encouraging locoregional control and survival in heavily pretreated patients, although late toxicities remain important concerns (ClinicalTrials.gov identifier: NCT03217188).