Oral metronomic therapy in head and neck cancer
Authors: Vinod Sharma, Akash Kumar
Journal: The Lancet Global Health (2020)

In the open-label, non-inferiority trial by Vijay Patil and colleagues,1Patil V Noronha V Dhumal SB et al.Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial.Lancet Glob Health. 2020; 8: e1213-e1222Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar metronomic therapy was found to be non-inferior and possibly superior (pre-specified) to platinum monotherapy. Three main benefits were seen with metronomic therapy: non-inferiority of overall survival, less toxicity, and better quality of life. However, all three benefits appear less than modest on critical analysis. First, a group of patients were included who relapsed or recurred within 3–6 months of platinum-based therapy. No standard definition of platinum resistance in head and neck cancer exists; however, retrospective data suggest that a similar definition is clinically useful. The expected survival of platinum-refractory patients is less than 6 months. In a large retrospective analysis in Japan among patients with platinum-refractory head and neck cancer (<6 months of platinum),2Tahara M Doi I Murata T Mishina S Takai S Kaneko H Re-challenge of platinum-based chemotherapy for platinum-refractory patients with recurrent or metastatic head and neck cancer: claims data analysis in Japan.J Health Econ Outcomes Res. 2020; 7: 43-51Crossref PubMed Google Scholar re-challenge with platinum yielded poor outcomes. In real-world settings, platinum re-challenge was less often used (36% vs 64% non-platinum-based chemotherapy).2Tahara M Doi I Murata T Mishina S Takai S Kaneko H Re-challenge of platinum-based chemotherapy for platinum-refractory patients with recurrent or metastatic head and neck cancer: claims data analysis in Japan.J Health Econ Outcomes Res. 2020; 7: 43-51Crossref PubMed Google Scholar The median number of cycles received was one, with 90% of patients receiving no more than three cycles.2Tahara M Doi I Murata T Mishina S Takai S Kaneko H Re-challenge of platinum-based chemotherapy for platinum-refractory patients with recurrent or metastatic head and neck cancer: claims data analysis in Japan.J Health Econ Outcomes Res. 2020; 7: 43-51Crossref PubMed Google Scholar In single-arm studies, non-platinum-based chemotherapy showed a median overall survival of 6–8·5 months.3Grau JJ Caballero M Verger E Monzó M Blanch JL Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients.Acta Otolaryngol. 2008; 129: 1-6Crossref Google Scholar, 4Cho BC Keum KC Shin SJ et al.Weekly docetaxel in patients with platinum-refractory metastatic or recurrent squamous cell carcinoma of the head and neck.Cancer Chemother Pharmacol. 2009; 65: 27-32Crossref PubMed Scopus (22) Google Scholar Nearly 30% of patients in each arm had platinum-refractory disease in the study by Patil and colleagues;1Patil V Noronha V Dhumal SB et al.Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial.Lancet Glob Health. 2020; 8: e1213-e1222Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar the enrolment of this group of patients might have contributed to the poor performance of cisplatin compared with metronomic therapy. Second, the rate of grade 3 or worse adverse events between the metronomic chemotherapy group and the cisplatin group was 19% vs 30%, respectively.1Patil V Noronha V Dhumal SB et al.Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial.Lancet Glob Health. 2020; 8: e1213-e1222Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar The major reason for this difference was due to an increased rate of hyponatraemia in the cisplatin arm. Such laboratory test abnormalities are often asymptomatic and require minor interventions in real-world settings. The clinical relevance of the given benefit is unknown. There was no significant difference between the groups for other adverse events, with a similar incidence of all-grade events. Third, the authors suggest a quality of life benefit of metronomic therapy, but the number of patients who underwent assessment was very small.1Patil V Noronha V Dhumal SB et al.Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial.Lancet Glob Health. 2020; 8: e1213-e1222Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar On assessment of quality of life at the second month, only 56 (13%) of 422 patients had their quality of life assessed. It would be inappropriate to conclude an improved quality of life given the proportion of patients assessed. In conclusion, we would suggest caution in concluding non-inferiority given the inclusion of patients with platinum-refractory disease (who relapsed within 3–6 months), interpreting the limited clinical relevance of asymptomatic differences between the two study arms, and assessing the quality of life data. We declare no competing interests. Oral metronomic therapy in head and neck cancer – Authors' replyWe thank Raja Pramanik and colleagues and Vinod Sharma and Akash Kumar for their interest and appreciation of our study.1 Their comments are useful, but partly misplaced. In our study, 29·6% of patients progressed between 3 and 6 months after platinum-based therapy, not 48–54% of patients, as suggested. Different trials using platinum-based therapy have used variable definitions for platinum resistance and have included patients progressing on treatment within 3–6 months.2,3 Full-Text PDF Open AccessLow-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trialOral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible. Full-Text PDF Open AccessOral metronomic therapy in head and neck cancerWe congratulate Vijay Patil and colleagues (September, 2020)1 for providing level 1 evidence of the upfront use of oral metronomic chemotherapy for head and neck squamous cell carcinoma, which is a huge burden in low-income and middle-income countries (LMICs), where affording immuno-oncology drugs and EGFR-targeted agents is out of the question. This study is extremely relevant during the current pandemic, allowing oral therapy at home. Although the study appears practice-changing, certain issues should be put into perspective. Full-Text PDF Open Access