Most patients with recurrent or metastatic head and neck squamous cell cancers qualify for palliative treatment. The management of these patients includes supportive care only,
mono- or multiagent chemotherapy, and more recently targeted therapies. While platinum-based combinations are superior to single-agent therapies in terms of response rate, they are
more toxic and so far have not shown to lead to meaningful survival benefit. Attempts to improve on this by using other or additional cytotoxic drugs were unsuccessful in the last
30 years. It was therefore an urgent need to investigate the efficacy of novel anticancer therapies that specifically target the tumor cells in such patients. A recent randomized trial
showed that adding cetuximab, an EGFR-directed monoclonal antibody, to a standard platinum-based chemotherapy regimen led to an important survival benefit. Despite the still
dismal prognosis, the outcome of this latter trial has changed practice in this category of head and neck cancer patients. The next challenge will be to sort out how to incorporate the
numerous targeted agents that are currently studied into the existing treatment strategies, also in consideration of an optimization of their therapeutic index. Human papillomavirus
status with immunohistochemical p16 expression as its surrogate marker represents promising prognostic and possibly predictive biomarkers that need to be prospectively validated in
future randomized trials.