Hanne Verswyvel

Chapter 3 │ Page 68 1. INTRODUCTION Recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains a significant clinical challenge, burdened by limited treatment options and a poor prognosis[1, 2]. Patients in this disease stage face a median survival between 6 and 15 months, and often su er from a severely impacted quality-of-live due to severe comorbidities, functional impairments, and a declining performance status[2-4]. Given these limitations, symptom-directed (palliative) care plays a crucial role in disease management, yet strategies to improve currently established therapies for R/M HNSCC are clinically both urgent and necessary. R/M HSCC patients are extremely challenging to treat and a multimodal, systemic therapy approach is primarily required[2]. Only a small number of patients can be salvaged by surgical intervention or (re)irradiation, both of which associated with significant comorbidities[4, 5]. Therefore, conventional cytotoxic agents and immune checkpoint inhibitors (ICI) are the primary treatment options in R/M HNSCC, and the choice of therapy depends on factors such as prior treatments, PD-L1 expression, and overall patient condition[2, 6]. Adding to this complexity is the highly heterogeneous character of the disease, arising from various anatomical subsites of the head and neck region, each with distinct biological behaviors, molecular profiles, and treatment responses [7, 8]. The KEYNOTE-48 trial marked a shift in the first-line treatment, demonstrating that combined ICI with platinum-based chemotherapy e.g. cisplatin (cisdiamminedichloroplatinum (II), CDDP) improved overall survival compared to previous standard-of-care[6, 9]. However, despite these advancements, major limitations persist: ICI o ers a lasting response in a limited subset of patients but faces low overall response rates, while significant toxicity is a major concern in the systemic administration of platinum compounds in already weakened patients[2, 10-

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