Human Papillomavirus-positive oropharyngeal cancer is a rising tumor entity with unique characteristics and favorable prognosis. Because current multimodal therapies are associated with severe toxicity, different strategies for treatment de-intensification are being tested in clinical trials. In this context two phase 3 studies, which examined the potential of the monoclonal anti-EGFR antibody cetuximab to replace concomitant cisplatin-based chemotherapy, have concordantly reported inferiority of this de-intensification approach. In this opinion article we discuss these recent negative results in the light of previous clinical and preclinical research on the combination of EGFR-inhibition and irradiation. Collectively these data question the effectiveness of EGFR-inhibition in the curative treatment of both HPV-positive and HPV-negative head and neck cancer but provide guidance for future translational research.
