Neoadjuvant Therapy for Mucosal Head and Neck Squamous Cell Carcinoma: A Review from the American Head and Neck Society

Importance: While neoadjuvant chemotherapy for head and neck squamous cell carcinoma dates to the earliest multidisciplinary approaches, the introduction of immune checkpoint inhibitors (ICIs) has renewed enthusiasm and research into its use. Although neoadjuvant therapy has remained mostly investigative through single-institutional clinical trials for mucosal head and neck squamous cell carcinoma, new data have emerged to support its use. Observations: A narrative review was conducted by the American Head and Neck Society to address current literature, evolving research, and gaps in knowledge surrounding neoadjuvant therapy. Neoadjuvant ICIs, most notably agents targeting anti-programmed cell death protein 1 (anti-PD-1), are a promising approach for bolstering antitumor immunity prior to ablating local structures. While neoadjuvant therapy may allow for an individualized approach, biomarkers to guide patient selection are limited. Potential benefits include de-escalation of subsequent treatment, but neoadjuvant therapy for curable disease also carries a small but real risk of progression and compromise of curative options. Measures of response include pathologic, clinical, and radiographic, but there are rapidly expanding capabilities in new diagnostics, such as circulating tumor DNA, with the emerging potential to provide objective quantification of disease burden. Further neoadjuvant strategies include response adaptive therapy, such as treatment selection/bioselection or modification of surgery, adjuvant therapy, or definitive treatment. Neoadjuvant ICI trials are summarized in this review. Optimized trial designs and additional research are needed to standardize surrogate outcomes and compare survival to standard treatment. Conclusions and Relevance: Neoadjuvant therapy can be an effective option for precision head and neck oncology bolstered by the advent of anti-PD-1 immunotherapy. However, tools for predicting and assessing treatment response remain limited. Further trials are evaluating adaptive strategies, combinations to increase efficacy, and comparisons to standard approaches.