HYPORT: Phase 1 Study of 3-Week Hypofractionated Postoperative Radiation Therapy for Head and Neck Squamous Cell Carcinoma

Purpose: Shortening the overall radiation therapy (RT) treatment time has advantages in cost and treatment burden, but data on hypofractionated RT in head and neck squamous cell carcinoma are limited. This study assessed the safety of moderately hypofractionated RT in the postoperative setting. Methods and Materials: Patients with completely resected stage I-IVB squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx with intermediate risk factor(s) including T3/4 disease, positive lymph node(s), close margin(s), perineural invasion, and/or lymphovascular invasion were enrolled on a rolling 6-design phase 1 study. Levels 0 and 1 consisted of 46.5 Gy in 15 fractions delivered 5 days a week and 44.4 Gy in 12 fractions delivered 4 days a week, respectively. The primary endpoint was maximum tolerated dose/fractionation of moderately hypofractionated postoperative RT. Results: Twelve patients were enrolled with 6 each on levels 0 and 1. No patient experienced a dose-limiting toxicity or grade 4 to 5 toxicity. Acute grade 3 toxicity occurred in 2 patients on level 0 (weight loss, neck abscess) and 3 patients on level 1 (all oral mucositis). One patient on level 0 experienced late grade 3 toxicity (persistent neck abscess). With a median follow-up of 18.6 months, 2 patients on level 1 had a recurrence: a regional recurrence in the undissected, unirradiated contralateral neck from a well-lateralized tonsil primary and an in-field local recurrence of oral tongue primary. The maximum tolerated dose/fractionation was determined to be 44.4 Gy in 12 fractions, but owing to more favorable tolerability in the setting of equivalent biologically effective dose, 46.5 Gy in 15 fractions was deemed the recommended phase 2 dose/fractionation. Conclusions: Moderately hypofractionated RT delivered over 3 weeks is well tolerated in the short term in this phase 1 cohort of patients with head and neck squamous cell carcinoma following surgical resection. The follow-up phase 2 randomized trial will deliver 46.5 Gy in 15 fractions as the experimental arm.