Low-cost oral metronomic versus intravenous chemotherapy in recurrent, inoperable and metastatic head and neck cancer: Phase III Metro-CIS study.

Abstract

6506 Background: The NCCN preferred regimens for palliation in head and neck cancer, either EXTREME or KEYNOTE-048 are the only two regimens which have improved outcomes over chemotherapy, but they have limited applicability (1-3%) in low and middle-income countries due to the cost. Oral metronomic chemotherapy (OMC) has shown better outcomes than intravenous cisplatin; these results were obtained with a low incidence of adverse events and the cost of 1/100th of NCCN-preferred regimens in a Phase II study. Methods: This was a randomized Phase III non-inferiority open-label study. Adult patients with relapsed-recurrent or metastatic upfront palliatively treated squamous cell carcinoma of head and neck and ECOG PS 0-1 were eligible. Patients were randomized 1:1 between OMC (oral methotrexate 15 mg/m2 weekly with celecoxib 200 mg once daily or intravenous cisplatin (IVC) 75 mg/m2, 3-weekly for 6 cycles. CTCAE version 4.0 was used for adverse event recording. Response assessment (RECIST version 1.1) was performed every 2 months. EORTC QLQ-C 30 and EORTC QLQ -H&N 35 questionnaires were self-administered at baseline and 2-monthly thereafter. The primary endpoint was overall survival (OS) and was measured from the date of randomization to death. Assuming a 6-month OS in IVC arm of 40%, the non-inferiority margin of 13%, type 1 error of 5% (2-sided), type 2 error of 20% and lost-to-follow up rate of 20%, a total sample size of 422 subjects was required. Kaplan Meier method was used for the estimation of OS and progression-free survival (PFS). To determine non-inferiority the upper limit of 95% CI of difference between 6 months OS of the 2 arms had to be below 13%. Results: In the intention to treat analysis, the 6-months OS was 50.89% (95% CI, 43.3-57.97) and 62.26% (95% CI, 54.72-68.9) in the IVC and OMC arm respectively. The difference in 6-months OS between the 2 arms was - 11.37% (95% CI, -20.77 to -0.97). The median OS was 6.1 (95% CI, 5.33-6.93) versus 7.5 (95% CI, 6.5-8.8) months in IVC arm and OMC arm respectively ( P= .026). The unadjusted hazard ratio for death was 0.773 (95% CI, 0.615-0.97, P= .026). The median PFS was 1.67 (95% CI, 1.47-2.03) versus 3.23 (95% CI, 2.57-4.13) months in IVC and OMC arms respectively ( P< 0.001). Any grade 3 or above adverse events were seen in 61 (30.2%) versus 37 (18.9%) patients in IVC and OMC arm respectively ( P= .01). Conclusions: OMC improves outcomes in palliatively treated head and neck cancer and is a new standard of care in this setting, in addition to the EXTREME and KEYNOTE-048 regimen. Clinical trial information: CTRI/2015/11/006388 .