FDG-PET-based Selective De-escalation of Chemoradiation in Human Papillomavirus-related Oropharyngeal Squamous Cell Carcinoma: a Multi-center Phase II Trial

Abstract Purpose: We conducted a phase II multicenter clinical trial to test the hypothesis that FDG-PET based chemoradiation (CRT) dose de-escalation would provide non-inferior loco-regional control compared to historical controls among patients with early-stage p16+ oropharyngeal cancer. We also hypothesized that HPVctDNA changes during treatment predict loco-regional recurrence (LRR). Patients and Methods: Patients with Stage I/II p16+ oropharyngeal squamous cell carcinoma were planned to receive radiation 70Gy in 35 fractions with concurrent weekly carboplatin and paclitaxel. All patients underwent FDG-PET at baseline and at RT fraction 10. Patients with ≥50% decrease from baseline to mid-treatment metabolic tumor volume (MTV)2.5 had treatment deescalated to 54Gy in 27 fractions. The primary endpoint was LRR. Plasma HPVctDNA was evaluated weekly and in surveillance. Results: Of 84 evaluable patients, 43% met de-escalation criteria. With a median follow-up of 37.8 months, 24-month LRR for the entire cohort was 7.8% (90% CI: 2.6% - 12.6%), which was less than the 25% rate specified for assessing non-inferiority, thereby meeting the primary endpoint. At 1 month post RT, the mean of multiple quality of life measures between the two groups were improved in the 54Gy cohort, exceeding the minimal clinically important difference (MCID) threshold. During CRT, week 1 percentage increase in ctDNA relative to baseline was significantly associated with worse LRC (HR=1.052 per 10 percentage points increase in ctDNA, 95% CI: 1.007-1.099; p=0.023) and LRPFS (HR=1.038, 95% CI: 1.002-1.076; p=0.035). Conclusion: FDG-PET-based RT dose personalization resulted in promising LRR outcomes in early stage oropharynx cancer with improved short- term PROs. Furthermore, HPVctDNA changes early in treatment may predict LRC.