Beyond conventional chemotherapy, targeted therapy and immunotherapy in squamous cell cancer of the oral cavity

•Metronomic chemotherapy is an attractive approach for head and neck squamous cell cancer (HNSCC) in the palliative setting.•Results of weekly low dose methotrexate plus celecoxib seem promising in phase 2.•Metronomic chemotherapy seems beneficial as adjuvant or neoadjuvant in the curative setting.•Repurposed drugs have no clinical studies reported in patients with head and neck cancer. The focus of this review article is to throw light on non-conventional systemic chemotherapy that affects the tumour microenvironment and potentially has a favourable impact on the management of squamous cell cancer of the oral cavity. A metronomic combination of weekly methotrexate and celecoxib seems equally effective to single agent cisplatin in the palliative setting, but needs phase III testing. The same metronomic combination seems inferior to paclitaxel-cetuximab. Triple drug metronomic chemotherapy (methotrexate, celecoxib, and erlotinib) is still under development with promising data from pilot studies. Metronomic chemotherapy also seems beneficial in the curative setting but results of confirmatory studies are eagerly awaited. The low rate of adverse events and low cost make this regimen an attractive alternative. Both in vivo and in-vitro data suggests that numerous drugs like anthelmintics, DMARDs, antimalarials can be repurposed for Head and Neck Cancers. However, there is a dearth of clinical studies reported till date.