Long-Term Results of a Phase 2 Clinical Trial of Radiation Volume and Dose Deintensification Following Transoral Robotic Surgery and Neck Dissection for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma

PURPOSE: We conducted a phase 2 clinical trial reducing both dose and volume of adjuvant radiation in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We also examined whether postoperative circulating tumor DNA (ctDNA) was prognostic for outcomes. METHODS AND MATERIALS: Eligible patients had pT0 to pT3 pN0 to pN1 HPV-associated OPSCC (American Joint Committee on Cancer 8th edition) treated with primary transoral robotic surgery and neck dissection. Adjuvant radiation therapy (RT) was delivered in 25 fractions over 5 weeks. We reduced RT volumes in 2 ways: the primary oropharyngeal resection bed was omitted in select patients (pT1-T2 tumors with negative margins and no lymphovascular invasion or perineural invasion), and the contralateral neck targets were reduced to mirror the pathologically involved ipsilateral nodal levels. We also reduced RT doses: 50 Gy was given to primary resection beds requiring treatment and to ipsilateral neck levels with pathologically positive nodes; 45 Gy was delivered to other at-risk ipsilateral nodal regions and the contralateral neck. Concurrent chemotherapy was prescribed for positive margins and extranodal extension, although optionally omitted when extranodal extension was ≤1 mm. Baseline HPV ctDNA was collected after surgery and measured at 3 subsequent timepoints. RESULTS: We enrolled 150 patients between October 2018 and June 2022. One patient withdrew, leaving 149 patients treated per protocol. At a median follow-up of 48 months (IQR, 38-59 months), no patients developed local recurrence while 2 experienced regional recurrences. The estimated 5-year locoregional control (LRC) rate was 98.0% (95% CI, 95.3%-100%). Both regional recurrences were successfully salvaged. Ten patients (6.7%) developed distant metastases, and 3 (2.0%) died of disease. At 24 months post-RT, the median MD Anderson Symptom Inventory for head and neck cancer scores were dysphagia-2, xerostomia-2, and interference with work-0. For 79 patients with available blood samples, detectable postoperative HPV ctDNA was associated with subsequent metastatic disease but not LRC. CONCLUSIONS: Now with mature follow-up, our adjuvant RT strategy with reduced doses and volumes maintained high LRC with favorable toxicity in selected patients with HPV-associated OPSCC.