Mid-treatment circulating tumor HPV DNA to guide early radiotherapy cessation in HPV-associated oropharyngeal cancer.

e18054 Background: Circulating tumor HPV DNA (ctHPVDNA) is an emerging biomarker in HPV-associated oropharyngeal squamous cell carcinoma (HPV+OPC) with established prognostic and surveillance value. However, limited data exist on its role in treatment adaptation during radiotherapy (RT). We evaluated whether mid-treatment ctHPVDNA clearance could identify patients who safely discontinue RT early due to severe toxicity without compromising oncologic outcomes. Methods: We conducted a single-institution retrospective cohort study of patients with HPV+OPC treated with definitive RT or chemoradiotherapy. Plasma ctHPVDNA testing was performed at week 4 of RT. Patients experiencing grade ≥3 acute toxicity who discontinued RT after approximately 60 Gy were compared with patients who completed standard 70 Gy based on ctHPVDNA status. One-year progression-free survival (PFS) was estimated using the Kaplan–Meier method and compared using log-rank testing. Results: Thirty-two patients with HPV+OPC were identified. Twenty-four (75%) experienced grade ≥3 acute toxicity, and 18 underwent mid-treatment ctHPVDNA testing. Ten patients achieved ctHPVDNA clearance at week 4 and discontinued RT at approximately 6 weeks (Group A), while eight patients remained ctHPVDNA-positive and completed 7 weeks of RT (Group B). Baseline characteristics, including age, stage, and smoking history, were similar between groups. At a median follow-up of 18 months, no locoregional or distant recurrences were observed in Group A. Group B experienced two disease recurrences, including one distant failure, and one disease-related death. One-year PFS was 100% in Group A versus 72% in Group B (p=0.08). Conclusions: Mid-treatment ctHPVDNA clearance was associated with excellent short-term disease control despite early cessation of RT due to toxicity. These findings suggest ctHPVDNA may serve as a clinically useful biomarker to guide adaptive radiotherapy de-escalation strategies in HPV+OPC. Prospective validation is warranted.