The Trolley Problem of Perioperative Immunotherapy in Head and Neck Cancer

Perioperative immunotherapy has emerged as a new therapeutic paradigm in the management of locally advanced head and neck cancer following the publication of the KEYNOTE-689 trial, which demonstrated improved event-free survival with the addition of neoadjuvant and adjuvant pembrolizumab to surgery and risk-adapted adjuvant therapy. While these results represent important progress for a field that has seen few meaningful advances in decades, implementation of this strategy within real-world health-care systems may introduce unintended consequences. In the Canadian context, where head and neck cancer care is highly regionalized, perioperative immunotherapy may significantly lengthen the diagnosis-to-treatment interval through additional consultations, biomarker testing, and systemic therapy administration prior to definitive surgery. Delays in treatment initiation are themselves associated with worse oncologic outcomes and may narrow the window for curative resection in some patients. Beyond progression to unresectability, perioperative delay may also lead to surgical escalation, requiring more extensive resections associated with major functional consequences for speech, swallowing, and quality of life. These outcomes are difficult to capture within traditional trial endpoints yet remain highly relevant to patients and clinicians. The survival benefit observed in KEYNOTE-689 appeared largely driven by a reduction in distant recurrence, raising an important clinical question regarding the acceptable degree of locoregional morbidity to prevent systemic relapse. The recently published NIVOPOSTOP trial offers a potentially more conservative strategy by introducing postoperative immunotherapy without delaying surgery. Ultimately, the challenge is not whether progress should occur, but how it should be implemented within systems already constrained by delays and limited resources. Additional real-world and phase IV evidence will be essential to identify which patients derive net benefit from perioperative immunotherapy and how this strategy can be integrated safely into clinical practice.