Oral metronomic therapy in head and neck cancer – Authors' reply
Authors: Vijay Patil, Vanita Noronha, Amit Joshi, Nandini Menon, Shripad Banavali, Kumar Prabhash
Journal: The Lancet Global Health (2020)

We thank Raja Pramanik and colleagues and Vinod Sharma and Akash Kumar for their interest and appreciation of our study.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 (13) Google Scholar 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.2Burtness B Goldwasser MA Flood W Mattar B Forastiere AA Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.J Clin Oncol. 2005; 23: 8646-8654Crossref PubMed Scopus (724) Google Scholar, 3Urba S van Herpen CML Sahoo TP et al.Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study.Cancer. 2012; 118: 4694-4705Crossref PubMed Scopus (32) Google Scholar We are not aware of any data from India justifying the authors' suggestion for use of combination chemotherapy by most medical oncologists. In many countries, such as Brazil, Canada, and Australia, monotherapy is frequently used as per the GLANCE H&N study.4Grünwald V Chirovsky D Cheung WY et al.Global treatment patterns and outcomes among patients with recurrent and/or metastatic head and neck squamous cell carcinoma: Results of the GLANCE H&N study.Oral Oncol. 2020; 102104526Crossref PubMed Scopus (14) Google Scholar There have been FDA-approved studies with single-agent cisplatin as the standard of care3Urba S van Herpen CML Sahoo TP et al.Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study.Cancer. 2012; 118: 4694-4705Crossref PubMed Scopus (32) Google Scholar and this is a treatment option provided by National Comprehensive Cancer Network guidelines. Our primary endpoint was overall survival, and, to our knowledge, no study has shown that combination chemotherapy improves overall survival compared with single-agent cisplatin, as suggested by Pramanik and colleagues and Sharma and Kumar. Our response rate was 9·6% (95% CI 6·24–14·4) in the cisplatin arm versus 13·1 (9·23–18·42) in the metronomic arm (p=0·284). Adverse events, particularly electrolyte abnormalities with three-weekly cisplatin, are important and we investigate and manage them appropriately as per guidelines, even in our routine practice. To our knowledge, the number of patients assessed for quality of life in most trials is similar to that in our trial, for two main reasons: patients whose disease progresses or who die cannot be evaluated for quality of life and missing data. This pattern is also seen in other pivotal studies, for example in the EXTREME study,5Mesía R Rivera F Kawecki A et al.Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck.Ann Oncol. 2010; 21: 1967-1973Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar global health status data were available for 203 (45·9%) of 442 patients at baseline, 143 (32·3%) at 3 months, and 65 (14·7%) at 6 months. Even so, the findings remain meaningful. Triple metronomic chemotherapy showed promising results in the initial study. We added erlotinib as a second-line treatment option post-progression on the metronomic combination. There is a fair amount of literature showing the activity of celecoxib alone and in combination with methotrexate and erlotinib.6Nair SV Joshi A Patil VM et al.A phase II randomized control trial of erlotinib in combination with celecoxib in patients with operable oral squamous cell carcinoma (OSCC): Erlo-Xib Study.J Clin Orthod. 2019; 376054Google Scholar, 7Patil VM Noronha V Joshi A et al.Phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early-failure oral cancer.J Clin Oncol. 2019; 37: 3032-3041Crossref PubMed Scopus (23) Google Scholar In conclusion, to our knowledge, this is the first large study beyond cetuximab or immunotherapy to show improvement in survival and quality of life in this group of patients compared with chemotherapy. VN reports grants from Dr Reddy's Laboratories, Amgen, and Sanofi, outside the submitted work. KP reports grants from Tata Memorial Center Research Administration Council, the Indian Cooperative Oncology Network, and Glenmark Pharmaceuticals, during the conduct of the study; grants from Dr Reddy's Laboratories, Fresenius Kabi India, Alkem Laboratories, Natco Pharma, BDR Pharmaceuticals India, and Roche Holding, outside the submitted work. All other authors declare no competing interests. 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 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 cancerIn the open-label, non-inferiority trial by Vijay Patil and colleagues,1 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. 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