Revisiting the concept of neoadjuvant and induction therapy in head and neck cancer with the advent of immunotherapy.

The treatment of locally advanced (LA) Head and Neck Squamous Cell Carcinoma (HNSCC) is based on surgery followed by (chemo)radiation or on curative (chemo)radiation, depending on site and stage. Despite optimal locoregional treatment, about 50% of patients recur, with a huge impact on prognosis and substantial morbidity. The advent of immunotherapy (IT) with immune checkpoint inhibitors (ICIs) changed the paradigm of systemic treatment for recurrent/metastatic (RM) disease, showing activity, efficacy, and safety in both platinum-resistant and platinum-naïve patients. Such data led clinicians to design clinical trials to investigate early administration of IT even in the neoadjuvant or window of opportunity setting. In this review, we examine the published and ongoing trials investigating IT in the neoadjuvant setting for LA HNSCC. We address the current challenges of this treatment modality: optimal patient selection for neoadjuvant IT; choosing the appropriate systemic approach to enhance response without compromising tolerability; determining the ideal study endpoint, with a focus on major pathological response as a potential surrogate for overall survival; evaluating treatment response through imaging, considering the discordance between radiological and pathological assessments; and the influence of neoadjuvant IT response on locoregional treatment de-escalation strategies.