Head and Neck Cancer Treatment with Concurrent Chemoradiotherapy: A Multi-Institutional Phase III Randomized Controlled Trial with Biomarker-Integrated Treatment Stratification

Abstract

Head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, larynx, and hypopharynx represents a biologically heterogeneous malignancy with approximately 890,000 new cases and 450,000 deaths reported globally per year, with incidence rising in HPV-driven oropharyngeal cancers in Western countries while tobacco-related disease predominates in South and Southeast Asia [1, 16]. Despite the established superiority of concurrent chemoradiotherapy (CCRT) over radiotherapy (RT) alone in locally advanced HNSCC (LA-HNSCC), optimal chemotherapy selection, radiation dose-fractionation, and validated predictive biomarkers remain contested. This multi-institutional Phase III randomized controlled trial (RCT) is the first prospective evaluation of a multi-analyte Composite Biomarker Index (CBI) for treatment stratification in LA-HNSCC. From January 2020 to December 2023, 425 patients with Stage III–IVB HNSCC were enrolled at six international tertiary centres and randomised 1:1:1 to: (A) standard CCRT (cisplatin 100 mg/m² q21d, 70 Gy/35 fractions); (B) radiotherapy alone (RT); or (C) TPF induction chemotherapy followed by CCRT. The CBI integrates HPV/p16 status, tumour mutational burden (TMB), and plasma circulating tumour DNA (ctDNA) kinetics into a prospectively validated scoring system. Primary endpoints were 3-year overall survival (OS) and locoregional control (LRC). Secondary endpoints included disease-free survival (DFS), acute and late toxicity (CTCAE v5.0), and quality of life (EORTC QLQ-C30/H&N35). At a median follow-up of 38.4 months, CCRT demonstrated superior 3-year OS versus RT alone (64.2% vs 47.8%; HR 0.71, 95% CI 0.61–0.82; p<0.001) with comparable OS to induction+CCRT (67.1%; HR 0.94, 95% CI 0.80–1.10; p=0.44). CBI-High patients treated with CCRT achieved 3-year OS of 78.3% versus 51.4% in CBI-Low patients (interaction p=0.003), establishing the CBI as a clinically actionable predictive biomarker. Grade 3–4 toxicities were highest in the induction+CCRT arm. IMRT was associated with significantly lower Grade 2–3 xerostomia compared to 3D-CRT (31.2% vs 52.4%; p<0.001). These results support a precision oncology framework for LA-HNSCC treatment allocation guided by the CBI.