Contemporary Opportunities in Nonsurgical Management of Locoregionally Advanced Head and Neck Squamous Cell Carcinoma

AbstractThe majority of head and neck squamous cell carcinoma (HNSCC) is now classified into two major types: HPV-mediated [HPV(+)] and HPV-negative [HPV(−)]. Within this paradigm, the 8th edition TNM staging system effected modification about what is considered “locally-advanced” HNSCC. Two phase-III trials (RTOG 1016 and De-ESCALATE HPV) disappointingly showed that cetuximab is not as effective in HPV(+) oropharyngeal cancer (OPC) compared to cisplatin with radiotherapy. The recent NRG HN002 de-escalation trial demonstrated the presence of outcome heterogeneity within “low-risk” HPV(+) OPC, some of which continue to benefit from cisplatin combined with reduced-dose radiotherapy. Moreover, distant metastasis (DM) has consolidated its position as the leading cause of death in HPV(+) OPC and strategies to mitigate it are necessary. Unanswered questions and ongoing-emerging concepts exist in both HPV(+) and HPV– diseases. These include understanding the importance of risk under the rubric of extranodal extension (ENE), including degrees of pathological ENE (pENE), and emerging knowledge about radiologic ENE (rENE). Strategies addressing modification of biological phenomena have become paramount and includes hypoxia modification (such as smoking cessation). In addition, contemporary evidence suggests that immunotherapy improves survival in recurrent/metastatic settings, and it is now also being explored in primary disease presentations in combination with (chemo-)radiotherapy. Induction chemotherapy achieves DM reduction in nasopharyngeal cancer but has only been explored minimally in HPV(+) OPC. Evidence that loco-regional management can be de-intensified following a favorable response to induction treatment would provide an attractive option for HPV(+) OPSCC patients while also addressing risk of developing distant disease.