Systemic Treatment Sequencing and Prediction of First-line Therapy Outcomes in Recurrent or Metastatic Head and Neck Cancer
Authors: Szturz Petr , Vermorken Jan B. 
Published: March 2023

In the palliative management of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who are not candidates for a complete resection or full-dose radiotherapy, systemic treatment has seen important advances over the past several decades. In general, there are six major factors impacting on the decision-making process. Four of them belong to a class of continuous functions and include overall health status (from fitness to frailty), disease burden (from high to low), pace of the disease (from fast to slow), and expression of programmed-death ligand 1 (PD-L1, from high to low). In addition, there are two categorical variables including disease site (e.g., locoregional recurrence versus metastatic) and platinum-sensitivity or resistance depending on disease-free interval after previous platinum-based therapy with a usual cut-off of 6 months. Taking into account these six factors and local drug policies, healthcare professionals opt either for 1) chemotherapy with or without cetuximab or 2) immunotherapy with or without chemotherapy. In platinum-sensitive cases, level I evidence based on data from the EXTREME and Keynote-048 randomized trials supports the use of the following three regimens. Biochemotherapy combining platinum, 5-fluorouracil, and cetuximab (the so-called EXTREME regimen) is suitable for fit patients with low PD-L1 expression measured as combined positive score (CPS). Higher CPS is predictive for improved overall survival when replacing cetuximab with the immune checkpoint inhibitor pembrolizumab, an anti-PD-1 antibody (immunochemotherapy regimen). Further, Keynote-048 demonstrated activity of single-agent pembrolizumab in patients with high CPS values. The latter (third) treatment retained its efficacy in the elderly, suggesting possible advantage in less fit patients who otherwise receive best supportive care only or single-agent cytotoxic chemotherapy with dubious impact on survival. In selected patients, the TPEx regimen consisting of cisplatin, docetaxel, and cetuximab represents an alternative to EXTREME. Treatment choice can also be influenced by disease extension (site). Compared with disseminated cancer cases, presence of locoregional recurrence without distant metastases may have a negative predictive value for immune checkpoint inhibitors, while favouring biochemotherapy. If the tumour is deemed platinum-resistant, the only evidence-based systemic approach is monotherapy with either pembrolizumab or nivolumab, another anti-PD-1 antibody. Alternatively, being especially pertinent to resource-limited countries, a taxane with or without cetuximab can be prioritized. Obviously, the list of different treatment schedules is longer, but the level of supporting evidence is proportionally lower. One of modern approaches to multidisciplinary management of SCCHN patients is treatment sequencing. It should be understood as a deliberate process of treatment planning typically starting in the locally advanced setting and reaching beyond several treatment failures. This has been enabled by a growing portfolio of effective anticancer modalities complemented by progress in supportive care. Finally, all therapeutic interventions impact somehow on quality of life, either in a positive or negative way, and the choice of anticancer agents should therefore not be reduced to a simple estimate of survival benefit but should contain an adequate appraisal and understanding of individual patient’s situation comprising emotional and spiritual dimensions, cultural and financial aspects, and environmental, social, and educational contexts.