Multimodality detection of early relapse in radically treated high-risk HPV-negative head and neck squamous cell carcinoma: study protocol for a prospective multicentre UK cohort study (HERD).

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally, with over 12 000 new cases annually in the UK. Despite aggressive radical treatment, approximately 50% of patients with locally advanced (stage III/IV), human papilloma virus (HPV)-negative disease relapse within 2 years, often in the first year. Although current post-treatment follow-up schedules are recommended by clinical guidelines, imaging surveillance is led by symptoms after the initial 3 months and reliable biomarkers for early relapse are lacking. Consequently, recurrences are frequently detected too late for surgical salvage, though timely surgery can improve survival by up to 73% in selected cases. Head and Neck Early Relapse Detection Study represents a large-scale, prospective effort to integrate imaging, genomic, immunologic and microbiome datasets for relapse risk stratification and post-treatment surveillance in this high-risk patient group. METHODS AND ANALYSIS: Design: Prospective, observational cohort study. SETTING: Secondary and tertiary NHS hospitals in the UK. PARTICIPANTS: Recruiting up to 200 patients with stage III/IV (high-risk) HPV-negative HNSCC. Participants are enrolled into discovery (n=100) and validation (n=100) cohorts. Patients with HPV-positive tumours, metastatic disease or other contraindications defined in the protocol will be excluded. INTERVENTIONS: Observational study with no experimental intervention. Participants are followed for 2 years with longitudinal collection of blood, saliva, urine, stool, fresh and archival tumour tissue and advanced MRI where possible in addition to their standard of clinical care. PRIMARY OUTCOMES: Development and independent validation of a multimodal recurrence risk prediction model. SECONDARY OUTCOMES: Identifying patient populations for primary treatment stratification, establishment of a longitudinal biorepository and identifying biological mechanisms of recurrence. Multimodal data will be integrated using machine learning and Bayesian modelling. ETHICS AND DISSEMINATION: Ethical approval was granted by the Bromley Research Ethics Committee (21/PR/1581). Findings will be disseminated through peer-reviewed publications, conference presentations and scientific meetings. TRIAL REGISTRATION NUMBER: NCT05097625.