HYPOCON: A Randomised Proof of Concept Clinical Trial of Biphasic Fractionation Schedules to Overcome Hypoxia in Locally Advanced Squamous Cell Carcinoma of the Head and Neck Treated with Curative Intent Primary Chemo-radiotherapy.

INTRODUCTION: Squamous cell carcinoma of the head and neck is the most common cancer in Sri Lanka, with around 4000 new cases annually. While radiotherapy is a key treatment, its efficacy is limited by tumour hypoxia, which reduces radiosensitivity and promotes aggressive tumour behaviour. Radiobiological modelling suggests that a biphasic fractionation regimen of conventional fractionation followed by hypofractionation could overcome hypoxia-related challenges and enhance treatment outcomes without increasing toxicity. METHODS AND ANALYSIS: The HYPOCON pilot trial is an investigator-initiated, multicentre, open-label, randomised trial designed to assess the feasibility of delivering a biphasic fractionation regimen in patients with squamous cell carcinoma of the head and neck. A total of 46 participants will be recruited across four centres and randomised 1:1 to either the control or experimental arm. The control arm will receive 55 Gy in 20 fractions over 4 weeks, while the experimental arm will follow a biphasic fractionation schedule: phase 1 involves 40 Gy in 20 fractions over 3 weeks and 3 days, followed by phase 2 with 15 Gy in 3 fractions delivered on consecutive days. All participants will also receive concurrent chemotherapy with intravenous cisplatin. Participants will be followed up monthly during the first year post-treatment and every two months in the second year. The primary objective is to assess the feasibility of delivering the experimental regimen. Secondary objectives include evaluating rates of grade 3 or higher acute and late toxicities, as well as response rates, disease-free survival, and overall survival. This trial aims to establish the groundwork for a larger definitive study to evaluate the efficacy of this novel biphasic fractionation approach. RESULTS: The trial is currently open and actively recruiting participants across the participating centres. Data collection regarding the primary feasibility endpoint, as well as secondary toxicity and survival endpoints, is ongoing. CONCLUSION: The HYPOCON pilot trial will establish the feasibility of a novel biphasic hypofractionated radiotherapy regimen with concurrent chemotherapy for head and neck squamous cell carcinoma. If successful, data from the study will help design a larger, definitive randomised controlled trial.