Standard adjuvant chemoradiotherapy (60–66 Gy) following surgery for HPV-associated oropharyngeal squamous cell carcinoma has excellent oncological control but high treatment morbidity. We aimed to compare toxicity of a 30–36 Gy regimen of de-escalated adjuvant radiotherapy and standard of care treatment.

We did this phase 3, open-label, randomised controlled trial in two academic sites in the USA. Eligible participants were adults aged 18 years or older, with American Joint Committee on Cancer 7th edition pathological stage III–IV HPV-associated oropharyngeal squamous cell carcinoma and had more than 70% p16-immunoreactivity on immunohistochemistry evaluation of the surgical specimen. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less and at least one intermediate pathological risk factor. Patients were stratified by the presence of extranodal extension and smoking status (<10 packs per year vs ≥10 packs per year) Eligible patients were randomly assigned (2:1) using a minimisation method with a random element to receive de-escalated adjuvant radiotherapy (30–36 Gy in 1·5–1·8 Gy fractions twice per day over 2 weeks plus intravenous docetaxel 15 mg/m² on days 1 and 8 of treatment) or standard of care (60 Gy in 2 Gy fractions once daily over 6 weeks plus intravenous cisplatin 40 mg/m² once a week). The primary endpoint was cumulative, chronic grade 3 or higher toxicity rate 3–24 months after radiotherapy. Primary analysis was done in patients who received treatment and had no missing data. This trial is registered with ClinicalTrials.gov, NCT02908477, and is complete.

Between Oct 11, 2016, and Aug 20, 2020, 254 patients with newly diagnosed oropharyngeal squamous cell carcinoma were assessed for inclusion. Nine did not meet inclusion criteria and 17 declined to participate. 228 patients were enrolled, with 194 proceeding to protocol treatment and analysis (130 in the de-escalated adjuvant radiotherapy group and 64 in the standard of care group). Median patient age was 59·4 years (range 37·9–81·6). 173 (89%) of 194 patients were male and 21 (11%) were female. 183 (95%) of 194 patients were White, four (2%) were Hispanic, three (2%) were Asian, and one (1%) was Native American. Median follow-up was 37·3 months (IQR 27·6–49·2). Seven patients were excluded from analysis of the primary late toxicity endpoint (five patients in the de-escalated adjuvant radiotherapy group and two patients in the standard of care group). The cumulative chronic grade 3 or higher toxicity rate at 3–24 months was 3% (four of 125 patients) in the de-escalated adjuvant radiotherapy group and 11% (seven of 62 patients) in the standard of care group (p=0·042) with a cumulative chronic percutaneous endoscopic gastric (PEG) tube rate of 2% (two of 125 patients) in the de-escalated adjuvant radiotherapy group and 8% (five of 62 patients) in the standard of care group (p=0·039). The most common grade 3 or higher toxic effects in the de-escalated adjuvant radiotherapy group were dysphagia (two [2%] of 125 patients), oesophagitis (one patient [1%]) and hearing impairment (one patient [1%]). The most common grade 3 or higher toxic effects in the standard of care group were dysphagia (five [8%] of 61 patients), oesophagitis (one patient [2%]), fatigue (one patient [2%]), pain (one patient [2%]), and osteonecrosis of the jaw (one patient [2%]).

De-escalated adjuvant radiotherapy was a more tolerable treatment in terms of chronic toxicities, demonstrating less cumulative grade 3 or higher toxicity compared with standard of care. Further clinical trials exploring indications for the DART regimen are warranted.

The Department of Radiation Oncology, Mayo Clinic, Minnesota and Arizona, the Braillier Family Research Fund, and the Matteson Family Research Fund.