There is currently no standard regimen for the treatment of advanced biliary cancer. Most commonly, single-agent gemcitabine or 5FU is used, with occasional combinations (including gemcitabine plus platinums) being offered. In our trial, the combination of gemcitabine and capecitabine was well tolerated, with 7 confirmed responses and an additional 6 unconfirmed responses, giving an overall response probability of 25% and an overall survival of 7 months. Generally, the reported toxicities were hematologic and manageable.
There have been three other phase II studies reported using the combination of gemcitabine and capecitabine in patients with biliary tumors. All were single institution trials. Riechelmann and colleagues at Princess Margaret in Canada report on a total of 75 patients treated with gemcitabine and capecitabine for advanced biliary cancer, detailing a response rate of 29% and an overall survival of 12.7 months.17
A second study performed in South Korea with a total of 44 patients had a response rate of 32% and median overall survival of 14 months.18
In this trial, 23% of patients accrued had locally advanced disease and 16% of patients had cancer of the ampulla, both of which tend to have a better prognosis. A third trial from Roswell Park accrued a total of 12 patients over 2 years with a response rate of 16% (the lowest response rate reported of the three studies).19
In these studies, there did not appear to be any significant issues with toxicity.
In our study, the confirmed responses and overall survival appear to be lower than that which has been generally reported. The overall response rate is consistent with the larger of the 3 previously reports using this combination. Although our overall response rate was similar, this did not translate into a median overall survival of a year, as described in the other trials.
Our study was conducted through the cooperative group setting, which usually offers a patient selection more representative of the community than single institution trials. Cooperative group studies usually report efficacy results inferior to those seen in highly selected patients from single institution trials. Further, the patient characteristics in these trials differed, and the Korean trial potentially reported on a better prognostic group of patients, thereby resulting in a higher response rate and median overall survival. There may also be potential inherent differences in the Korean population, related to the unidentified genetic differences within these populations in terms of the natural course of the disease, response and tolerability to chemotherapy.
Other trials with gemcitabine-containing regimens have also been conducted, including combinations with docetaxel, oxaliplatin, cisplatin and carboplatin.20–22
Gemcitabine with oxaliplatin was reported by GERCOR, with the combination reporting a response rate of 33% and a median overall survival of 8.3 months.22
Other platinum containing regimens report 20 to 24% response rates and similar median overall survivals.20,21
The tolerability of these regimens vary. Most recently, Valle and colleagues reported a randomized phase II with 314 patients with advanced biliary cancer randomized to gemcitabine/cisplatin vs. gemcitabine alone. The median overall survival was greater with the combination of gemcitabine/cisplatin than the single agent, 11.7 vs. 8.2 months (p=0.002), as was progression free survival 8.5 vs. 6.5 months, (p=0.003). 23
Nevertheless the combination of gemcitabine and capecitabine is reasonable to consider in patients with metastatic or advanced biliary cancer. The study reached the primary objective with evaluation of confirmed response rates. The regimen was well tolerated with the most significant toxicities being hematologic, consistent with what has been reported with gemcitabine as a single agent. Furthermore, the gemcitabine was administered as a fixed dose rate infusion, which tends to cause more hematologic toxicity as well. Other more common grades 3 and 4 toxicities were related to liver function abnormalities, which may be a function of the patients underlying biliary disease. Fatigue was also more commonly reported. Given these clinical data, the combination of gemcitabine and capecitabine is a reasonable option in the treatment of patients with advanced biliary cancer.
Evaluation of the molecular correlates was limited due to the small number of samples and frequency of the polymorphisms. Although no clear associations or conclusions regarding outcome can be made, the longest overall survival was reported in the functional polymorphism TS 5′GC, which causes a lower transcriptional activity of TS, consistent with previous data with treatment with fluoropyrimidines. The data are limited but are interesting in that evaluation in larger clinical studies is warranted. The combination of gemcitabine and capecitabine is a reasonable approach to the treatment of patients with advanced biliary cancer, a disease that has limited treatment options. Further studies to evaluating chemotherapy should consider the role of novel targeted therapies in this disease process. Both EGFR1 and EGFR2 have been shown to be over-expressed, and combining chemotherapy with such agents may offer improved outcome. Other novel targets to consider in this disease include anti-angiogenic therapies. Clearly, there is a need for improved therapeutics in biliary cancer and this reported combination offers another option of a combination as a potential starting point upon which to build.