Clinical Benefit and Safety of Reduced Elective Dose in Definitive Radiotherapy for Head and Neck Squamous Cell Carcinoma: The UPGRADE-RT Multicenter Randomized Controlled Trial

PURPOSE: Definitive radiotherapy (RT) for head and neck cancer (HNC) has significant long-term toxicity with elective neck irradiation (ENI) as a major contributor. In this multicenter randomized trial, the clinical benefit and safety of definitive RT with reduced versus standard elective dose were compared. METHODS: Newly diagnosed patients with cT2-4N0-2M0 HNC were accrued and treated in five Dutch centers (definitive accelerated RT, 68 Gy in 34 fractions in 5.5 weeks). Patients receiving concurrent chemotherapy were not eligible. Dose for ENI was randomly assigned (2:1; dose reduction, 43 Gy, versus control, 50 Gy). The primary outcome was normalcy of diet score at 1 year. The secondary outcome was recurrence in electively irradiated nodes at 2 years in the dose reduction group with the null hypothesis rejected if the upper-bound one-sided 95% CI exceeded 9%. RESULTS: Between 2016 and 2022, 300 patients were randomnly assigned, of whom 295 were evaluable and included in analysis (dose reduction, 196 and control, 99). The mean normalcy of diet score at 1 year was 91.6 (95% CI, 88.5 to 94.7) in the dose reduction group and 92.6 (95% CI, 88.2 to 97.1) in the control group (mean difference, -1.1 [95% CI, -6.5 to 4.4]). The 2-year recurrence rate in electively irradiated nodes in the dose reduction group was 4.9% (upper-bound one-sided 95% CI, 7.5%). In the control group, this was 4.3% (upper bound one-sided 95% CI, 7.7%). Exploratory analyses demonstrated less acute dysphagia grade ≥3 and better xerostomia-related quality of life in the dose reduction group. CONCLUSION: This is the second randomized controlled trial demonstrating that reduced elective dose is safe in definitive RT for HNC.