Treatment challenges in developing nations for patients with locally advanced or metastatic head-and-neck cancer

Head-and-neck cancer is one of the most common cancers in low-and middle-income countries.[1] It leads to a significant burden in terms of cancer-related mortality and morbidity in these countries. As many patients with head-and-neck cancers belong to the lower socioeconomic class, social habits such as tobacco chewing and smoking are the prime cause of these neoplasms. Moreover, owing to a lack of awareness and financial constraints, these patients are commonly diagnosed at the locally advanced or metastatic stages, which results in reduced therapeutic options and dismal outcomes.[2,3] Currently, cetuximab-based regimens and single-agent immunotherapy with immune checkpoint inhibitors like nivolumab[4] and pembrolizumab are the treatment of choice for patients with advanced head-and-neck cancers. The response to these agents is largely dependent on the presence of molecular targets in the tumor microenvironment.[5] Numerous target molecules such as endothelial growth factor receptor (EGFR), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and HRAS have to be expressed in sufficient amounts in tumor cells to achieve responses to targeted therapies.[6] However, most patients in India cannot afford these treatments,[7–11] and biomarker identification tests are not routinely carried out in the real-world clinical scenario. Thus, the efforts made by Sarma et al. to develop novel therapeutic combinations for patients in developing nations can help identify effective alternatives to chemotherapy in patients with advanced head-and-neck cancers.[12] Sarma et al. evaluated the outcomes of the combination of paclitaxel and Mycidac-C as second-line therapy in patients with advanced/relapsed/refractory head-and-neck cancers. The authors have claimed that the outcomes achieved with this regimen were roughly similar to those achieved with pembrolizumab and nivolumab in clinical trials.[12] However, a comparison of the outcomes of a retrospective study in a small group of patients with those of large clinical trials in well-designed cohorts is of questionable value. Mycidac-C works by directing the immune response towards desmocollin-3 (DSC3) expressing neoplastic cells and enhancing the immune cell responses in the tumor microenvironment. DSC3 expression is commonly seen in the normal oral mucosa and is found to be decreased or absent in oral squamous cell carcinomas. In the study by Sarma et al.,[12] there was no mention of any attempt at identifying target molecules before the treatment. Additionally, the authors have also discussed encouraging results from the trials of Mycidac-C in non-small-cell lung cancer (NSCLC) to strengthen their hypothesis. In these NSCLC cases, the maximum benefit from the treatment was seen in the DSC3-expressing tumors.[13] Thus, directing the research effort towards correlating the expression of DSC3 and positive treatment outcomes could provide valuable insights regarding the differential clinical benefit of Mycidac-C in DSC3-expressing and non-expressing tumors. Additionally, the National Comprehensive Cancer Network recommends the use of paclitaxel in advanced head-and-neck cancers.[14] Paclitaxel has immunomodulatory effects which can enhance the response to immunotherapy.[15] The authors have suggested a randomized trial testing this combination for patients with relapsed/refractory head-and-neck cancers. We believe that the focus should be on proving the superiority of this regimen compared to chemotherapy alone, as this would provide a low-cost treatment option. Mycidac-C should also be evaluated as a single agent in patients with previously treated as well as treatment-naïve head-and-neck cancers. As is the case with other anti-cancer molecules, the probability of developing resistance to Mycidac-C cannot be disregarded. Thus, the long-term benefits of this agent have to be thoroughly studied by the researchers. When discussing economically feasible and effective regimens in cancer therapy, oral metronomic chemotherapy is an ideal candidate. Triple metronomic chemotherapy with erlotinib, methotrexate, and celecoxib has shown an outstanding response rate of 42% with improved patient outcomes in advanced head-and-neck cancers.[16] Comparing the Mycidac-C-based regimen with metronomic chemotherapy in patients with advanced head-and-neck cancers would be interesting. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.