In Vivo Assessment of the Safety of Standard Fractionation Temporally Feathered Radiation Therapy (TFRT) for Head and Neck Squamous Cell Carcinoma: An R-IDEAL Stage 1/2a First-in- Humans/Feasibility Demonstration of New Technology Implementation

Introduction: Prior in silico simulations of studies of Temporally Feathered Radiation Therapy (TFRT) have demonstrated potential reduction in normal tissue toxicity. This R-IDEAL Stage 1/2A study seeks to demonstrate the first-in-human implementation of TFRT in treating patients with head and neck squamous cell carcinoma (HNSCC). Materials and Methods: Patients with HNSCC treated with definitive radiation therapy were eligible (70 Gy in 35 fractions) were eligible. The primary endpoint was feasibility of TFRT planning as defined by radiation start within 15 days of CT simulation. Secondary endpoints included estimates of acute grade 3-5 toxicity. Results: The study met its accrual goal of 5 patients. TFRT plans were generated in four of the five patients within 15 business days of CT simulation, therefore meeting the primary endpoint. One patient was not treated with TFRT at physician's discretion, though the TFRT plan had been generated within sufficient time from the CT simulation. For patients who received TFRT, the median time from CT simulation to radiation start was 10 business days (range 8-15). The average time required for radiation planning was 6 days. In all patients receiving TFRT, each subplan and every daily fraction was delivered in the correct sequence without error. The OARs feathered included: oral cavity, each submandibular gland, each parotid gland, supraglottis, and posterior pharyngeal wall (OAR pharynx). Prescription dose PTV coverage (>95%) was ensured in each TFRT subplan and the composite TFRT plan. One of five patients developed an acute grade 3 toxicity. Conclusions: This study demonstrates the first-in-human implementation of TFRT (R-IDEAL Stage 1), proving its feasibility in the modern clinical workflow. Additionally, assessments of acute toxicities and dosimetric comparisons to a standard radiotherapy plan were described (R-IDEAL Stage 2a).