# 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

## TL;DR

A new radiotherapy approach called HYDRA reduces doses to healthy organs while targeting tumors effectively in head and neck cancer patients.

## Contribution

HYDRA introduces a hypofractionated, dose-redistributed radiotherapy schedule that reduces toxicity and treatment burden in head and neck cancer.

## Key findings

- HYDRA photon therapy showed toxicity within acceptable limits, allowing inclusion of laryngeal carcinoma patients.
- Intra-patient comparisons revealed reduced doses to organs at risk with HYDRA, while delivering a focal boost to the tumor.
- Acute toxicity was manageable and transient, with no long-term need for tube feeding or opioids.

## Abstract

•HYDRA investigates hypofractionated (20 fractions), dose-redistributed (focal boost, lower elective dose) proton or photon therapy for HNSCC.•The planned interim analysis of HYDRA photon therapy showed toxicity within predefined limits, enabling inclusion of laryngeal carcinoma.•Acute toxicity of HYDRA is manageable and transient, with no tube feeding or opioid use beyond three months after treatment.•Intra-patient dosimetric comparison shows reduced dose to organs at risk with HYDRA, mean focal boost to GTV centers was 59.6 Gy.

HYDRA investigates hypofractionated (20 fractions), dose-redistributed (focal boost, lower elective dose) proton or photon therapy for HNSCC.

The planned interim analysis of HYDRA photon therapy showed toxicity within predefined limits, enabling inclusion of laryngeal carcinoma.

Acute toxicity of HYDRA is manageable and transient, with no tube feeding or opioid use beyond three months after treatment.

Intra-patient dosimetric comparison shows reduced dose to organs at risk with HYDRA, mean focal boost to GTV centers was 59.6 Gy.

(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).

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.

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).

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.