Perioperative immunotherapy in resectable HNSCC: biological rationale to practical multidisciplinary implementation

Perioperative immune checkpoint inhibition (ICI) has moved from investigational window studies to phase III supported strategies for resectable, locally advanced head and neck squamous cell carcinoma (HNSCC), with direct consequences for surgical timing, neck management, reconstruction and pathology workflows.

We performed a narrative review of phase III perioperative trials and key neoadjuvant studies in resectable HNSCC, focusing on outcomes and practical questions most relevant to surgeons and multidisciplinary teams (MDTs): pathway timing and attrition, operability, perioperative safety and feasibility of standardized response assessment.

Phase III evidence supports two complementary perioperative approaches: (i) neoadjuvant PD-1 priming followed by surgery and risk-adapted postoperative radiotherapy/chemoradiotherapy with continued PD-1 blockade, improving event-free survival compared with standard care; and (ii) postoperative nivolumab added to adjuvant chemoradiotherapy in patients with pathological high-risk features, improving disease-free survival. Across neoadjuvant programs, short preoperative ICI exposure was generally feasible without compromising resectability but requires protected timelines to avoid delays to curative treatment. Key surgical considerations include management of the tumor-draining lymph nodes, anticipation of immune-related adverse events affecting wound healing and rehabilitation, and coordination of treatment with systemic therapy. Pathologic response, preferably reported as percent residual viable tumor separately in the primary tumor bed and nodal compartments, is currently the most widely used endpoint and a prerequisite for response-adapted de-escalation or escalation studies.

Perioperative ICI turns curative-intent HNSCC care into a tightly timed program. Successful implementation will depend on standardized pathology and radiology workflows, MDT-owned scheduling and prospective registries to define optimal sequencing and salvage after perioperative PD-1 exposure.