The HYPCON 3 Trial: A phase II/III randomized study evaluating hypo-fractionated accelerated versus conventional fractionated adjuvant radiation therapy in head and neck malignancies.

TPS244

Background: Postoperative radiotherapy (PORT) for intermediate-risk head and neck squamous cell carcinoma (HNSCC) conventionally requires 6 weeks (60 Gy/30 fractions). In high-volume settings, prolonged schedules contribute to treatment delays, non-compliance, and resource strain. Hypofractionation is established in several solid tumors, and emerging data from the HYPNO trial and HYPORT study suggest that moderate hypofractionation is oncologically sound and well tolerated. HYPCON III evaluates whether PORT duration can be safely reduced by 50% without compromising loco-regional control (LRC). Methods: HYPCON III is a prospective, randomized, phase II/III non-inferiority trial enrolling 369 patients with resected pT1–4 squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx with intermediate-risk features (positive nodes without ENE, PNI, LVSI, or close margins). Patients are randomized 1:2 to: Arm A: 60 Gy in 30 fractions over 6 weeks (n=133) Arm B: 45 Gy in 15 fractions over 3 weeks (n=246) All patients receive swallowing-sparing IMRT/VMAT with daily IGRT and structured organ-at-risk constraints. Stratification factors include primary site, T stage, and unilateral versus bilateral neck irradiation. The primary endpoint is 24-month LRC. Secondary endpoints include disease-free survival, overall survival, acute and late toxicity (RTOG, LENT-SOMA), swallowing outcomes (MDADI), and quality of life (EORTC QLQ-C30, HN35). Statistical Design: Assuming a 2-year LRC of 70% in the standard arm, the study is powered at 90% (α=0.05) to test non-inferiority within a 5% margin, incorporating 10% attrition. Impact: If non-inferiority is demonstrated, HYPCON III will support a 3-week PORT regimen as a new standard for intermediate-risk HNSCC—doubling radiotherapy capacity, reducing patient burden, and maintaining oncologic and functional outcomes. This strategy has immediate scalability for resource-constrained and high-volume centers globally.