Assessment methods of pathological complete response in neoadjuvant head and neck cancer clinical trials: a scoping review.

Head and neck cancer (HNC) trials have demonstrated pathological complete response (pCR) in patients receiving neoadjuvant treatment prior to surgery; however, systematic reviews have reported marked variation in pCR rates. This scoping review was designed to determine the definition, criteria, and assessment methodologies for pCR in interventional neoadjuvant HNC clinical trials. The review was conducted in accordance with the JBI Manual for Evidence Synthesis and the protocol prospectively registered. Medical databases, trial registries, and grey literature were systematically searched, and eligibility criteria applied. Study characteristics and pCR assessment methodologies were extracted and described. A total of 4,931 sources were identified, and screening identified 114 trials. Only 22 studies had publicly accessible protocols for assessment. Trials were initiated between 1989 and 2025, and the majority were phase II investigating chemotherapy + immunotherapy regimens (51%). pCR was most frequently classified as a secondary endpoint (55%), and reported pCR rates ranged from 0% to 100%. There was heterogeneity and incomplete documentation in both specimen preparation and pCR assessment. Where specified, most included assessment at both primary tumour and lymph nodes (50 of 69; 72%), and quantitative assessment calculating percentage residual viable tumour was common. While no formal guidelines for pCR assessment in HNC were identified, one trial outlined an immune-related pathological response criteria for oral squamous cell carcinoma, and another included a detailed 'pathological response assessment' proforma. Citation of methodologies used in other cancers, for example, lung and breast cancer, was a recurring theme. Based on these findings, we propose pragmatic definitions, assessment considerations, and a structured reporting proforma to support increased transparency and reproducibility in pCR reporting. While these proposed elements are not consensus based, they provide a foundation for harmonisation efforts and highlight priorities for development of international consensus guidelines to enable meaningful comparison of interventions and determine the validity of pCR as a surrogate endpoint in HNC.