HYpofractionated, dose-redistributed RAdiotherapy (HYDRA) versus conventional radiotherapy for head and neck cancer: planned interim analysis and dosimetric comparison from the phase I HYDRA trial

Purpose: (Chemo)radiotherapy for squamous cell carcinoma of the oropharynx, hypopharynx, and larynx results in significant treatment burden and may cause radiation-induced lymphopenia (RIL), which is associated with worse survival. We aim to reduce treatment burden and RIL using HYpofractionation and Dose-redistribution in patients treated with proton or photon RAdiotherapy (HYDRA, NCT05364411). Methods: Patients receiving curative (chemo)radiotherapy for cT1-4 N0-3bM0 oropharyngeal and hypopharyngeal carcinomas are eligible. Referral for proton therapy is determined by model-based selection (MBS) according to Dutch protocols, resulting in a HYDRA-proton and HYDRA-photon cohort. HYDRA in 20 fractions constitutes 40 Gy to the elective volume, 55 Gy to gross tumour volume (GTV) + 5 mm and 59 Gy to GTV − 3 mm. Safety interim analyses are conducted in each cohort when ten patients complete 6 months follow-up. The interim results determine trial continuation and expansion to inclusion of laryngeal carcinomas according to predefined dose limiting toxicities (DLT). Per included HYDRA-patient, we perform an intra-patient plan comparison of the HYDRA plan versus the conventional treatment plan that was used for MBS. Results: The HYDRA-photon interim analysis (reached in March 2024, n = 10) showed one DLT (osteoradionecrosis), with no other late grade ≥ 3 toxicity after a median follow-up of 10.6 months. Among all enrolled HYDRA-patients (photons: n = 14; protons: n = 5), intra-patient plan comparison showed that HYDRA delivered a focal boost of Dmean 59.6 Gy (range 59.0–60.1 Gy) to the GTV, while on average, organs at risk received a reduced dose (HYDRA-photons: 0.4–4.5 Gy EQD2; HYDRA-protons: 2.1–5.0 GyE EQD2). Conclusions: The predefined interim analysis of HYDRA-photons showed one DLT. Per protocol, inclusion of laryngeal carcinomas in the photon cohort is now possible. The 20 fraction HYDRA schedule delivers a focal boost to the tumour with reduced dose to all organs at risk.