Proton versus photon radiotherapy for patients with oropharyngeal cancer in the USA: a multicentre, randomised, open-label, non-inferiority phase 3 trial

Background Radiotherapy is an integral component of treatment for oropharyngeal cancer. Toxicity from the current state-of-the-art photon radiotherapy, intensity-modulated radiation therapy (IMRT), has prompted the search for alternative, less toxic therapies. One such alternative that might de-intensify treatment is proton therapy. In this trial, we aimed to directly compare IMRT with intensity-modulated proton therapy (IMPT), both concurrent with systemic therapy, hypothesising comparable disease control and survival and lower toxicity. Methods This randomised, multicentre, open-label, non-inferiority, phase 3 trial was conducted in 21 sites (cancer centres or universities) in the USA. Patients (aged ≥18 years) with stage III or stage IV oropharyngeal cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited and randomly assigned 1:1 to receive IMPT or IMRT. All patients were treated with radiotherapy to 70 Gy in 33 fractions to the primary tumour site and cervical lymphadenopathy. The type, schedule, and dose of induction or concurrent systemic therapy were chosen locally by each institution's multidisciplinary tumour board and were consistent with international guidelines. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population; safety outcomes were assessed in the per-protocol population (ie, patients who received the assigned therapy). A non-inferiority margin of 9 percentage points for progression-free survival at 3 years was used. This trial is registered with ClinicalTrials.gov ( NCT01893307 ) and is closed to further accrual after prespecified interim analysis. Findings From Oct 10, 2013, to May 1, 2022, 440 patients consented (median age 61 years [IQR 55–68], 399 [91%] male, 409 [93%] White); 221 were allocated to the IMPT group (with 160 [72%] receiving IMPT) and 219 to the IMRT group (136 [62%] receiving IMRT). At a median follow-up time of 3·2 years, progression-free survival rates for the IMPT group were 82·5% (95% CI 76·1–87·3) at 3 years and 81·3% (74·5–86·5) at 5 years; corresponding rates for the IMRT group were 83·0% (76·7–87·7) and 76·2% (68·0–82·6; hazard ratio [HR] 0·88 [95% CI 0·57–1·35]; p=0·005 for non-inferiority of IMPT). Overall survival rates after IMPT were 90·9% at 5 years versus 81·0% after IMRT (HR 0·58 [95% CI 0·34–0·99]; p=0·045). Treatment-related deaths occurred in nine patients; six in the IMRT group and three in the IMPT group. Deaths from disease progression occurred in 27 patients; 18 in the IMRT group and nine in the IMPT group. 5-year disease control rates for IMPT versus IMRT were similar between treatment groups (local recurrences 2·9% vs 5·6%, p=0·474; regional recurrences 3·4% vs 3·2%, p=0·860; and distant metastases 9·1% vs 8·9%, p=0·897). Severe lymphopenia was more common in the IMRT group (89% vs 76%), as were dysphagia (49% vs 31%), xerostomia (45% vs 33%), and gastrostomy tube dependence (40·2% vs 26·8%; p=0·018). Interpretation IMPT showed non-inferiority to IMRT for progression-free survival, improvement in overall survival, similar disease control, and reduced high-grade toxicity relative to IMRT. Treatment-related and post-progression deaths occurred more frequently with IMRT. IMPT is a new standard-of-care treatment option for patients with oropharyngeal cancer. Funding MD Anderson Cancer Center, Massachusetts General Hospital, National Institutes of Health, Hitachi America.