Phase II Trial of Infusional 5 FLUOROURACIL, LEUCOVORIN, OXALIPLATIN AND IRINOTECAN (FOLFIRINOX) in First Line Treatment of Advanced Biliary Tract Cancers

Biliary tract carcinomas (BTCs) are invasive adenocarcinomas that arise from the epithelial cells of the biliary tree, which comprises intrahepatic and extrahepatic bile ducts, and the gallbladder. Even though BTCs are considered as rare tumors, they represent about 30% of the total primary liver cancers with an incidence rate close to that of hepatocellular carcinoma. Approximately 1200 new cases in the United Kingdom and 9000 in the United States are diagnosed annually. The Saudi Cancer Registry reported 911 case of gall bladder cancer, 318 intrahepatic cholangiocarcinoma and 574 extrahepatic cholangiocarcinoma between 1994 and 2009. Unfortunately, only a minority of patients diagnosed with these aggressive tumors present at an early resectable stage, and disease recurrence rates are high despite curative-intent surgery

The prognosis of patients with advanced biliary tract cancers is poor and median survival for those undergoing supportive care alone is short. Systemic chemotherapy is increasingly being applied in cases of advanced biliary tract cancers. A benefit for chemotherapy over best supportive care alone was suggested in a trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to fluorouracil (FU)-based systemic chemotherapy or best supportive care alone with median survival of 6 months for chemotherapy versus 2.5 months for best supportive care.

Different drugs has demonstrated activity in BTCs, including fluoropyrimidines, gemcitabine, cisplatin, and oxaliplatin. A pooled analysis from Eckel et al. that evaluated 104 trials with 2810 patients, has established gemcitabine combined with platinum compounds as the provisional standard of chemotherapy in advanced biliary tract cancer.

In a randomized phase two study of 51 patients, Kornek et al, established the efficacy of mitomycin in combination with gemcitabine or capecitabine in previously untreated patients with advanced biliary tract cancers. Mitomycin and capecitabine was associated with superior complete response rate (31% vs 20%), median progression free survival (5.3 months vs 4.2 months), and overall survival (9.25 months and 6.7 months). The EORTC 40955 trial randomized patients with BTCs to high dose 5FU vs combination of 5-FU, Leucovorin and cisplatin. The results showed that cisplatin and fluorouracil was more active than high-dose fluorouracil in terms of overall response rates (19% and 7.1%, respectively) and overall survival (8 months and 5 months, respectively), but progression free surviva; was similar in both treatment arms (3.3 months).

The randomized, controlled, phase three ABC-02 study, which enrolled 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary cancer, demonstrated that the combination of gemcitabine and cisplatin improved overall and progression free survival by 30% over gemcitabine alone. Median overall survival was 11.7 months vs 8.1 months (HR, 0.64; 95% confidence interval, 0.52-0.80; p˂.001), and progression free survival was 8 months (HR, 0.51; 95% confidence interval, 0.51-0.77; p˂.001), both in favor of the combination arm. Although the rate of neutropenia was higher in the group receiving gemcitabine and cisplatin, there was no significant difference in the rate of neutropenia-associated infections between the 2 arms. Okusaka et al also reported similar findings in a phase two randomized study of 84 patients with advanced biliary tract cancers. Based on these results, the combination of gemcitabine and cisplatin is considered to be the standard of care for first-line chemotherapy for patients with advanced or metastatic biliary tract cancers.