FDG-PET–Based Selective Deescalation of Chemoradiation in Human Papillomavirus–Related Oropharyngeal Squamous Cell Carcinoma: A Multicenter Phase II Trial

Abstract Purpose: We conducted a phase II multicenter clinical trial to test the hypothesis that 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)–based chemoradiation (CRT) dose deescalation would provide noninferior locoregional control compared with historical controls among patients with early-stage p16+ oropharyngeal cancer. We also hypothesized that human papillomavirus (HPV) circulating tumor DNA (ctDNA) changes during treatment predict locoregional recurrence (LRR). Patients and Methods: Patients with stage I/II p16+ oropharyngeal squamous cell carcinoma were planned to receive radiation 70 Gy in 35 fractions with concurrent weekly carboplatin and paclitaxel. All patients underwent FDG-PET at baseline and at radiation therapy (RT) fraction 10. Patients with ≥50% decrease from baseline to mid-treatment metabolic tumor volume had treatment deescalated to 54 Gy in 27 fractions. The primary endpoint was LRR. Plasma HPV ctDNA was evaluated weekly and in surveillance. Results: Of 84 evaluable patients, 43% met deescalation criteria. With a median follow-up of 37.8 months, 24-month LRR for the entire cohort was 7.8% [90% confidence interval (CI), 2.6%–12.6%], which was less than the 25% rate specified for assessing noninferiority, thereby meeting the primary endpoint. At 1 month after RT, the mean of multiple quality of life measures between the two groups was improved in the 54 Gy cohort, exceeding the minimal clinically important difference threshold. During CRT, week 1 percentage increase in ctDNA relative to baseline was significantly associated with worse loco-regional control (LRC; HR = 1.052 per 10 percentage point increase in ctDNA; 95% CI, 1.007–1.099; P = 0.023) and loco-regional progression-free survival (HR = 1.038; 95% CI, 1.002–1.076; P = 0.035). Conclusions: FDG-PET–based RT dose personalization resulted in promising LRR outcomes in early-stage oropharynx cancer with improved short-term patient-reported outcomes. Furthermore, HPV ctDNA changes early in treatment may predict LRC.