Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial

Background Outcomes are poor for patients with recurrent or metastatic nasopharyngeal carcinoma and no well established first-line chemotherapy is available for the disease. We compared the efficacy and safety of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. Methods In this multicentre, randomised, open-label, phase 3 trial, patients with recurrent or metastatic nasopharyngeal carcinoma were recruited from 22 hospitals in China. Key inclusion criteria were Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and measurable lesions according to Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned in a 1: 1 ratio to receive either gemcitabine (1 g/m(2) intravenously on days 1 and 8) and cisplatin (80 mg/m(2) intravenously on day 1), or fluorouracil (4 g/m(2) in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m(2) on day 1 given intravenously) once every 3 weeks for a maximum of six cycles. The randomisation was done centrally via an interactive phone response system using block randomisation with a size of six. The primary endpoint was progression-free survival assessed by the independent image committee in the intention-to-treat population. Safety analyses were done in patients who received at least one cycle of study drug. This study is ongoing and is registered with ClinicalTrials. gov, number NCT01528618. Findings Between Feb 20, 2012, and Oct 30, 2015, 362 patients were randomly assigned to a group (181 to the gemcitabine [ plus cisplatin] group and 181 to the fluorouracil [plus cisplatin] group). Median follow-up time for progression-free survival was 19.4 months (IQR 12.1-35.6). The median progression-free survival was 7.0 months (4.4-10.9) in the gemcitabine group and 5.6 months (3.0-7.0) in the fl uorouracil group (hazard ratio [HR] 0.55 [ 95% CI 0.44-0.68]; p< 0.0001). A total of 180 patients in the gemcitabine group and 173 patients in the fl uorouracil group were included in the safety analysis. Significantly different treatment-related grade 3 or 4 adverse events between the gemcitabine and fl uorouracil groups were leucopenia (52 [29%] vs 15 [9%]; < 0.0001), neutropenia (41 [23%] vs 23 [13%]; p= 0.0251), thrombocytopenia (24 [13%] vs three [2%]; p= 0.0007), and mucosal inflammation (0 vs 25 [14%]; < 0.0001). Serious treatment-related adverse events occurred in seven (4%) patients in the gemcitabine group and ten (6%) in the fluorouracil group. Six (3%) patients in the gemcitabine group and 14 (8%) patients in the fluorouracil group discontinued treatment because of drug-related adverse events. No treatment-related deaths occurred in either group. Interpretation Gemcitabine plus cisplatin prolongs progression-free survival in patients with recurrent or metastatic nasopharyngeal carcinoma. The results establish gemcitabine plus cisplatin as the standard first-line treatment option for this population.