Stereotactic Boost and Short-Course Radiotherapy for p16-Associated Oropharynx Cancer (SHORT-OPC): First Planned Interim Safety Analysis from a Randomized Phase II Trial

Abstract

There is a need for safe treatment de-intensification in p16+ oropharynx cancer (OPC). The standard of care (SOC) radiotherapy (RT) regimen is cumbersome and associated with high toxicity. Stereotactic radiotherapy (SBRT) and multimodality image guidance is an opportunity to precisely target the gross tumor while safely reducing elective irradiation dose. We aim to assess the safety and efficacy of a short course RT for p16+ OPC, consisting of an SBRT boost to the gross tumor volume (GTV) followed by de-escalated elective irradiation. In this randomized phase II trial, patients with p16-positive, stage I-II OPSCC with primary tumor <30 cc (8th Ed AJCC) are planned with combined CT, MRI and FDG-PET, and randomized to 1) SBRT boost (14 Gy in 2 fractions) to the GTV followed with de-escalated RT (+/- Cisplatin) to a dose of 40 Gy in 20 fractions, or 2) SOC RT (+/- Cisplatin) to a dose of 70 Gy in 33 fractions to the GTV and 59.4-54Gy (or equivalent) to the intermediate-to-low dose elective region. Patients are stratified by stage (I vs. II) and use of chemotherapy. The primary endpoint of the trial is locoregional control at 2 years, powered for a sample size of 100 patients. A Bayesian adaptive design includes 2 planned safety interim analysis using grade ≥ 3 subacute toxicities >40% as a stopping criterion, and 1 planned futility analysis. Acute adverse events (AE) are defined as those occurring ≤ 60 days from RT, subacute AE between 60-180 days after RT, and late AE >180 days from RT. This is the first planned toxicity analysis. Twenty-one patients were randomly assigned and eligible (11 in SOC and 10 in experimental arm). Median age was 69 years (range 49-84); 29% and 71% had stage T1 and T2, while 10%, 85% and 1 patient had N0, N1 and N2 disease, respectively. RT alone and chemoradiation was administered in 67% and 33% of patients, respectively. At a median follow-up of 11 months (range 1.7-17.6), there was 1 local recurrence at the primary tumor site in the SOC arm (at 10 month) and no recurrence in the experimental arm. All enrolled patients remain alive at the time of analysis. There was a 54.5% rate of grade 3 acute AE in the SOC arm and 30.0% rate of grade 3 acute AE in the experimental arm. More specifically, 1, 5 (45%), 2 (18%), and 2 (18%) versus 0, 1, 1 and 1 patient developed acute grade 3 dysphagia, mucositis, pain and dermatitis in the SOC and experimental arm, respectively. There was no acute grade 4 or 5 toxicity. There was no grade ≥ 3 subacute toxicity or late toxicity in both arms. This primary safety analysis showed that SBRT boost followed by a short course of de-escalated elective irradiation in p16+ OPC has limited early toxicity and meets criteria for study continuation.