Metronomic adjuvant chemotherapy evaluation in locally advanced head and neck cancers post radical chemoradiation - a randomised trial

Background: Locally advanced head and neck cancers treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to maximum tolerated dose chemotherapy in the palliative setting. Limited evidence suggests that it may do so in an adjuvant setting. Hence this randomized study was conducted.Methods: Patients of head and neck (HN) cancer with primary in oropharynx, larynx or hypopharynx, with PS 0-2 post radical chemoradiation with documented complete response were randomized 1:1 to either observation or oral metronomic adjuvant chemotherapy (MAC) for 18 months. MAC consisted of weekly oral methotrexate (15 mg/m(2)) and celecoxib (200 mg PO BD). The primary endpoint was OS and the overall sample size was 1038. The study had 3 planned interim analyses for efficacy and futility. Trial registration- Clinical Trials Registry- India (CTRI): CTRI/2016/09/007315 [Registered on: 28/09/2016] Trial Registered Prospectively.Findings: 137 patients were recruited and an interim analysis was done. The 3 year PFS was 68.7% (95% CI 55.1-79.0) versus 60.8% (95% CI 47.9-71.4) in the observation and metronomic arm respectively (P value = 0.230). The hazard ratio was 1.42 (95% CI 0.80-2.51; P value = 0.231). The 3 year OS was 79.4% (95% CI 66.3-87.9) versus 62.4% (95% CI 49.5-72.8) in the observation and metronomic arm respectively (P value = 0.047). The hazard ratio was 1.83 (95% CI 1.0-3.36; P value = 0.051).Interpretation: In this phase 3 randomized study, oral metronomic combinations of weekly methotrexate and daily celecoxib failed to improve the PFS or OS. Hence observation post-complete response post radical chemoradiation remains the standard of care.