Treatment Intensification in Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: What Are the Options and for Whom?

AbstractCurrent treatment guidelines for patients with locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC) recommend multimodal treatment, including concurrent chemoradiotherapy (CCRT) or surgery followed by radiotherapy (RT), with/without chemotherapy (CT). Induction chemotherapy followed by (chemo)-RT has also level I evidence for larynx preservation procedures in patients with advanced laryngeal or hypopharyngeal cancer. The CT part of the CCRT consists of platinum-based chemotherapy, most often single agent cisplatin. Although for a long time high-dose cisplatin (100 mg/m2) three-times every three weeks during RT has been the standard of care, recent prospective randomized studies have indicated that weekly low-dose cisplatin (40 mg/m2) is a good alternative with less toxicity. For patients not eligible or not tolerating cisplatin there are other alternatives (such as carboplatin with or without 5-fluorouracil, taxanes or cetuximab). However, none of these have shown superior results over the use of cisplatin in randomized trials. Late toxicity is a major downside of CCRT, and this is most worrying for those with the highest chance of cure, i.e. low-risk human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). De-escalation approaches have priority in these patients, but this needs to be done with the utmost caution. In the remaining patient populations (high-risk HPV-positive OPSCC, HPV-negative OPSCC and non-OPSCC patients) there is room for improvement in both locoregional control and in distant control. Recent strategies of potential interest above and beyond CCRT are adding (1) more cytotoxic chemotherapy, (2) targeted therapy, (3) hypoxic sensitizers, (4) immunotherapy and (5) hyperthermia. Many of those options are being investigated in prospective randomized trials and will hopefully lead to further improvement in outcome for these less favorable HNSCC patient categories.