ArticlesGemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial
Introduction
Cancers of the biliary tract are a heterogeneous group of rare tumours that include intrahepatic and extrahepatic cholangiocarcinomas, gallbladder carcinomas, and ampullary carcinomas.1 Most patients are diagnosed with advanced-stage disease, making them ineligible for complete surgical resection, which is the only potentially curative modality available. Furthermore, recurrence is common even after complete resection, and is usually only amenable to palliative chemotherapy.
Very few randomised trials of chemotherapy have been done in patients with advanced biliary-tract cancer.2 In a pooled analysis of 104 trials (including only two randomised phase 2 trials and one phase 3 trial) in 2810 patients with advanced biliary-tract cancer, the combination of gemcitabine and platinum compounds was more effective than gemcitabine alone.2 The UK ABC-02 phase 3 trial3 confirmed the superiority of gemcitabine plus cisplatin over gemcitabine alone. Several single-group studies4, 5, 6 and one randomised trial7 showed that the combination of gemcitabine and oxaliplatin has antitumour activity with a favourable toxic-effect profile in advanced biliary-tract cancer, and is more efficacious than best supportive care and fluorouracil plus folinic acid.7 However, patients with advanced biliary-tract cancer still have a poor outlook, with median overall survival of less than 1 year.2, 3, 7
The EGFR signalling pathway regulates biliary epithelial cell growth and proliferation, and EGFR is overexpressed in 67–100% of biliary cancers, making it a rational target for treatment.8, 9, 10, 11, 12 One phase 2 trial in 30 patients with advanced biliary-tract cancer showed encouraging results when cetuximab, a chimeric monoclonal antibody directed against EGFR, was added to gemcitabine and oxaliplatin.13
We designed the BINGO trial to assess the efficacy and tolerability of gemcitabine and oxaliplatin plus cetuximab or gemcitabine and oxaliplatin alone as first-line treatment for patients with advanced biliary-tract cancer.
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Study design and participants
In this open-label, non-comparative, randomised phase 2 study, we recruited patients with biliary-tract cancer from university hospitals and cancer centres across France and Germany. Trial inclusion criteria were: age 18–75 years; histologically or cytologically confirmed adenocarcinoma of the biliary tract, including intrahepatic and extrahepatic bile ducts, gallbladder, and ampulla of Vater; and locally advanced (non-resectable) or metastatic disease. Because proper tumour staging (ie,
Results
From Oct 10, 2007, to Dec 18, 2009, 150 patients with advanced biliary-tract cancer were enrolled in the study across 11 centres in France and seven centres in Germany, with 76 patients randomly assigned to receive gemcitabine and oxaliplatin plus cetuximab and 74 assigned to gemcitabine and oxaliplatin alone (figure 1). Six (8%) patients in the chemotherapy plus cetuximab group and 11 (15%) patients in the chemotherapy alone group were not assessable for disease response for the whole duration
Discussion
Our data suggest that any potential antitumour activity of cetuximab does not translate into a survival advantage when combined with gemcitabine and oxaliplatin in patients with advanced biliary-tract cancer compared with chemotherapy alone. Neither tumour KRAS or BRAF mutations, nor EGFR overexpression (identified in nearly a quarter of patients), seemed to help to select patients able to respond to therapy.
Although gemcitabine and platinum-based chemotherapy has been established as the
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