HYPORT: A Phase I Study of Hypofractionated Post-Operative Radiation Therapy for Head and Neck Squamous Cell Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Shortening the overall radiotherapy (RT) treatment time decreases the burden and costs of treatment while minimizing the effects of accelerated repopulation in head and neck squamous cell carcinoma (HNSCC). However, data on hypofractionated RT in HNSCC are limited with no published prospective studies in the post-operative setting. This phase I study was conducted to assess the toxicity and tolerability of moderately hypofractionated post-operative RT and to select the dose/fractionation for the phase II study. <h3>Materials/Methods</h3> 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 dose escalation phase I study from 2020-2021. Biologically effective dose (BED) approximately equivalent to 60 Gy in 30 fractions (for alpha/beta ratio of 3 and 10 accounting for repopulation) were chosen with level 0 consisting of 46.5 Gy in 15 fractions (3.1 Gy/fraction) delivered 5 days a week and level 1 consisting of 44.4 Gy in 12 fractions (3.7 Gy/fraction) delivered 4 days a week. The primary endpoint was maximum tolerated dose/fraction (MTD) of moderately hypofractionated RT. The MTD was defined as highest dose at which ≤ 1 of 6 patients experience a dose limiting toxicity (DLT), defined as persistent grade 3 mucositis at 3 months post-treatment or any grade 4 toxicity. <h3>Results</h3> A total of 12 patients were enrolled with 6 each on level 0 and level 1. Primary site included oral cavity, oropharynx, and larynx in 6, 5 (all p16+), and 1 patient, respectively. No patient experienced a DLT or grade 4-5 toxicity. Acute grade 3 toxicity occurred in 2 patients on level 0 (weight loss/anorexia, neck abscess) and 3 patients on level 1 (oral mucositis, all resolved by 3 months post-treatment). Overall, toxicity appeared more favorable on level 0 vs level 1 (Table). With a median follow-up of 8.7 months from end of RT (interquartile range 5.4-12.2), one patient had a regional recurrence in the undissected, unirradiated contralateral neck from a well-lateralized tonsil primary and one patient had an in-field local recurrence of oral tongue primary, both on level 1. The MTD was determined to be 44.4 Gy in 12 fractions, but given the favorable tolerability with equivalent BED, 46.5 Gy in 15 fractions was chosen as the recommended phase II dose/fractionation. <h3>Conclusion</h3> Moderately hypofractionated RT delivered over 3 weeks is well-tolerated in patients with HNSCC following surgical resection. A randomized phase II trial of 46.5 Gy in 15 fractions vs 60 Gy in 30 fractions is ongoing. Table. Cumulative grade 2+ acute toxicity