Long-term outcomes of ¹⁸ F-fluoromisonidazole positron emission tomography (FMISO PET)–guided major radiation dose de-escalation in HPV-associated oropharyngeal cancer: The 30 ROC approach.

103 Background: We previously demonstrated favorable short-term outcomes in patients with human papillomavirus–associated oropharyngeal carcinoma (HPV+ OPC) treated with biologically selected major radiation dose de-escalation, guided by functional hypoxia imaging. We now report mature long-term outcomes from a substantially larger prospective cohort to evaluate the durability and long-term safety of this approach. Methods: We conducted a pre-specified integrated analysis of a series of three consecutive phase II trials, each trial representing a progressive refinement with the same therapeutic strategy, enrolling patients with T0–3/N1–2c HPV+ OPC from 10/1/2015 to 11/30/2023. 18 F-fluoromisonidazole positron emission tomography (FMISO PET) assessed intratumoral hypoxia to stratify treatment: patients without hypoxia received de-escalated chemoradiotherapy (CRT) to 30Gy, while those with intra-treatment hypoxia received standard CRT to 70Gy. The primary endpoint was 5-year overall survival (OS); secondary endpoints included local, regional, and distant failure, progression-free survival (PFS), treatment-related toxicities, and patient-reported outcomes (PROs). Time-to-event outcomes were analyzed using Kaplan-Meier method and cumulative incidence function. Results: A total of 430 patients were enrolled and received treatment. T, N stages were: T0/TX(51), T1(198), T2(173), T3(8); N1 (62), N2a (48), N2b (252), and N2c (68). 96 patients (22.3%) had >10 pack-years of smoking history. There were 323 patients (75%) who had no hypoxia on FMISO PET and received 30Gy while 107 patients (25%) had evidence of intra-treatment tumor hypoxia and received 70Gy. With a median follow-up of 4.05 years (range 1.27–10.03 years), the 5-year OS was 97% in both the 30Gy and 70Gy cohorts. All oncologic endpoints were equivalent in the 30Gy vs 70Gy cohorts: 5-year local failure (2.2% vs 1.9%, p=0.7), regional failure (6.2% vs 3.9%, p=0.4), and PFS (91% vs 89%, p=0.5). Notably, patients with intra-treatment hypoxia, who received 70Gy had higher distant failure rates versus those without intra-treatment hypoxia and received 30Gy (7.5% vs 1.3%, p=0.004). Detailed acute/late toxicities and PROs will be presented at the meeting. Conclusions: FMISO PET–guided biological and personalized major radiation dose de-escalation results in durable long-term outcomes, benefiting ~75% of the patients. These findings establish a precision-based paradigm for definitive CRT in HPV+ OPC, currently being validated in an on-going randomized phase III trial (NCT06563479, >1/3 randomized). Patients with intra-treatment hypoxia had a higher rate of distant metastasis where additional therapy can be considered in future trials. Clinical trial information: NCT03323463 , NCT05491512 .