Long term outcomes of phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early failure oral cancer

BACKGROUND: Triple metronomic chemotherapy is one of the options of treatment in platinum-refractory/early failure oral cancer. However, long term outcomes with this regimen are unknown. METHODS: Adult patients with platinum-refractory/early-failure oral cancer were enrolled in the study. Patients were administered triple metronomic chemotherapy ie erlotinib 150 mg once daily celecoxib 200 mg twice daily and methotrexate weekly (phase 1 in variable dose 15-6 mg/m(2) & 9 mg/m(2) in phase 2), all taken orally till progression of disease or development of intolerable adverse events. The primary objective was to estimate the long-term overall survival and factors impacting it. The Kaplan Meier method was used for time-to-event analysis. Cox proportional hazard model was used to identify factors impacting overall survival (OS) and progression-free survival (PFS). The factors included in the model were age, sex, Eastern Cooperative Oncology Group - performance status (ECOG PS), tobacco exposure and a subsite of primary and circulating endothelial cell levels at baseline. A p-value of 0.05 was considered significant. Clinical trials information: CTRI/2016/04/006834. RESULTS: A total of 91 patients were recruited (15 in phase 1 & 76 in phase 2), the median follow-up was 41 months and 84 events of death had occurred. The median OS was 6.7 months (95% CI 5.4–7.4). The 1-year, 2-years and 3-year OS’ were 14.1% (95% CI 7.8–22.2), 5.9% (95% CI 2.2–12.2) and 5.9% (95% CI 2.2–12.2) respectively. The only factor favorably impacting OS was the detection of circulating endothelial cells at baseline (HR = 0.46; 95% CI 0.28–0.75, P = 0.0020). The median PFS was 4.3 months (95% CI 4.1–5.1) and the 1-year PFS was 13.0% (95% CI 6.8–21.2). The factors with statistically significant impact on PFS were detection of circulating endothelial cells at baseline (HR = 0.48; 95% CI 0.30–0.78, P = 0.0020) and no tobacco exposure at baseline (HR = 0.51; 95% CI 0.27–0.94, P = 0.030). INTERPRETATION: The long-term outcomes with triple oral metronomic chemotherapy ie erlotinib, methotrexate and celecoxib are unsatisfactory. Detection of circulating endothelial cells at baseline is a biomarker predicting efficacy of this therapy. FUNDING: The study was funded by an intramural grant from Tata Memorial Center Research Administration Council (TRAC) and Terry Fox foundation.