Multitudes of studies have been published recently stating the role of OMCT in HNSCC, but the studies with the category of level of evidence required to advocate OMCT as a recognized therapy are still scarce. On careful stratification of these studies, we found that OMCT has a lot to offer in palliative settings, recurrent, and metastatic HNSCC. There is some limited evidence of its role in adjuvant therapy as maintenance and in neoadjuvant setting. The summary of the studies in palliative and curative setting is depicted in Tables 1 and 2, respectively.

Palliative chemotherapy for head and neck cancers with metastatic, recurrent, or inoperable setting has evolved over time. It started with a small pilot study indicating a survival benefit of chemotherapy over patients treated with only supportive measures. Over next 3–4 decades, we have significantly improved survival rates by adding targeted therapy to conventional chemotherapy. The benefit of targeted therapy, that is cetuximab was seen in multiple trials and studies with selected cohort of patients who were non-responders to platinum-based chemotherapy. Since then, many studies indicated that cetuximab as a single agent seems to provide an appropriate option in these setting. These findings were further strengthened by EXTREME study with median overall survival (OS) of 11 months in patients receiving cetuximab, cisplatin, and 5-fluorouracil [12].

Palliative chemotherapy involves patients who presents with metastatic disease, who fails within 6 months of CT-RT or within 1 month of RT or patients presenting with platinum refractory disease. EXTREME trial and KEYNOTE-048 trials [13] have already set the landmarks and standards of care with targeted therapy for such patients, but access of such drug regimen to general population of Indian subcontinent is still a matter of debate keeping in view the logistic and financial issues. For the same reasons requirement for an alternative therapy, if not ideal are the need of hour where OMCT steps in for these subsets of patients.

A prospective randomized phase II study was done by VM Patil et al. in patients requiring palliative chemotherapy which compared oral MCT [daily celecoxib (200 mg twice daily) and weekly methotrexate (15 mg/m2)] and intravenous single agent cisplatin (IP) (75 mg/m2) given 3 weekly. A total of 110 patients were recruited out of which 57 were randomized to the OMCT arm and 53 to the IP arm. They reported that patients in the MCT arm had significantly longer progression-free survival as compared to the IP arm (p = 0.014). The overall survival (OS) was also noted to be increased significantly in the OMCT arm when compared to the IP arm. They concluded by stating that OMCT has significantly better outcomes in terms of progression-free survival (PFS) and OS as compared to single agent platinum in the palliative setting [5].

Patil et al. conducted an open-label, parallel group, non-inferiority, randomized, phase 3 trial on patients with recurrent, metastatic, inoperable head and neck carcinoma. A total of 422 patients were included in the study (213 in OMCT group and 209 in cisplatin group). Primary endpoint was overall survival measured from the date of randomization to the date of death or censored to the date of last follow-up. Secondary endpoints included progression-free survival, the number of patients who responded to the therapy, toxicity, and quality of life. At a median follow-up of 15·73 months, median overall survival was 7·5 months for the oral metronomic chemotherapy group compared with 6·1 months in the intravenous cisplatin group. Grade 3 or higher adverse side effects were noted in 19% of 196 patients in the oral metronomic chemotherapy group versus 30% of 202 patients in the intravenous cisplatin group. They concluded that OMCT can be a good alternative standard of care if current National Comprehensive Cancer Network (NCCN)-approved options for palliative therapy are not feasible [14].

Another study was published by Kalaichelvi et al. to evaluate the efficacy and toxicity profile of metronomic chemotherapy in patients with advanced or recurrent HNSCC. Efficacy was noted in terms of clinical benefit rate, pain control, changes in quality of life and median time to progression of disease. Their study suggested that 60% patients had stable disease, 10% had partial response, and 30% had progressive disease. They finally concluded that OMCTs with advanced/recurrent HNSCC was effective and well tolerated while providing good pain control and improves quality of life with least toxicity profile [9].

Based on above proposed mechanism of actions and hypothesis multiple pilot studies and trials have been performed. The findings of these trials pointed toward multiple variables affecting the outcome of OMCT. One of the biggest factors being the time of failure, with better OS in patients with time to failure of > 6 months as compared to failure within 6 months. This subgroup of patients who fail within 6 months are basically patients with platinum refractory disease, who usually performs worse [15]. This data have been consistently duplicated in multiple studies including EXTREME trial where PFS was better in platinum-based chemotherapy arm, the possible reason being the fact that the study excluded the patients with platinum refractory disease that is patients who failed within 6 months [12].This was in contrast to the prospective study by Patil et al. where PFS was only 66 days in chemotherapy-based arm because their study included the patients with chemotherapy free interval of less than 6 months. As compared to chemotherapy arm, OMCT arm performed better in terms of median OS, PFS and adverse outcomes and was noted to be non-inferior to chemotherapy arm [5]. The possible explanation for these better results in platinum refractory cases lies with OMCT’s antiangiogenesis effects and actions on endothelial cells of the vasculature supplying the tumor. Since the endothelial cells of vasculature are basically genotypically stable cells hence it should not be affected by somatic mutations in the tumor which are responsible for platinum-resistance [6, 7, 15].

The other important factor that has been echoed in multiple studies is the role of sites and subsites in OS and PFS. It has been reiterated that advanced or recurrent oral cavity primaries perform worst in terms of OS and PFS as compared to pharyngeal and laryngeal primaries. The general notion is that salvage surgery always provides best outcome as compared to chemotherapy in oral cavity primaries, but only about 16% of such patients present with a stage that is amenable to surgery. Study by Vermorken et al. which stated that patients on cetuximab performed better in terms of OS in palliative settings had a mixed subsets of patients with oral cavity primaries constituting only about 21% in study arm and 19% in control arm [16], while majority of trials and studies included in our review which represents Indian subset of population is majorly comprised oral cavity primaries. So, when compared to other studies, OMCT drug regimen performance is quite satisfactory as compared to established regimen. This difference in response rate between oral cavity and other head and neck primaries (laryngeal and pharyngeal) also needs further evaluation in terms of HPV association and other factors.

Lastly, one important factor that tips the balance toward the OMCT is the quality of life (QOL) and associated adverse effects. It has been noted that the QOL in patients receiving OMCT in terms of functional scale like pain, difficulty in swallowing, dry mouth, mouth opening, sticky saliva, social eating, and social contact is significantly better from the baseline values at an interval between 3 and 6 months [17]. Also, the grade 3 or higher adverse events were less commonly noted in OMCT arm (19%) as compared to chemotherapy arm (30%). This difference is statistically significant, thus suggesting that OMCT as a good alternative to standard regimen in resource constrained situations (in terms of PFS, OS and adverse events [5, 14, 15].

Complete surgical resection with R0 margins has been proven to be the most appropriate treatment option in oral cancers, especially in advanced oral cavity cancers. But to study the role of chemotherapeutic agents in resectable oral cancers, multiple studies have paved the way to present the aforementioned conclusion. Landmark studies in this field include studies by Licitra et al. and Zhong et al. [18, 19], both studies gave almost similar results, i.e., there was no difference in the OS and disease specific survival.

The above studies clearly made a line regarding the use of chemotherapeutic agents in induction settings in resectable oral cancers. But this interest was revived due to delay in definitive surgical treatment delivery to the patients, especially in developing countries like India where oral cancer is a major health problem. The delay can range from few weeks to a month or more which can very well turn a resectable oral cancer to borderline resectable or unresectable cancer and metastatic stage.

Chemotherapy agents and regimen can theoretically offer a useful way/approach to prevent progression during this waiting period. Although there is no randomized study to test this approach until now, there is some evidence from a study by Pai et al. The study compared two arms, i.e., one with direct surgery followed by adjuvant therapy and other arm included patients who received metronomic chemotherapy preoperatively followed by surgery and adjuvant therapy with maintenance OMCT. Two-year disease-free survivals (DFS) in OMCT group and control group was 86.5 and 71.6%, respectively. Also, the patients who received at least 3 months of adjuvant OMCT had 2 years DFS of 94.6% 4. Though short-term outcome in multiple studies by number of authors are similarly promising, we need to wait for long term results [20,21,22,23].