Review of gemcitabine in biliary tract carcinoma.

Cancers of the biliary tract are rare, and remain a major challenge to surgical, medical, and radiation oncologists. Unfortunately, the large majority of these tumors are not resectable at the time of initial diagnosis, and patients with advanced disease face a dismal prognosis. The efficacy of conventional palliative systemic chemotherapy (eg, with 5-fluorouracil, mitomycin-C, and cisplatin) seems negligible, and there is presently no agreement on the best chemotherapeutic regimen. Gemcitabine is among several different new anticancer drugs under investigation in the treatment of advanced biliary tract cancer. Apart from its favorable toxicity profile, this novel nucleoside analog has shown activity in many solid tumors, including pancreatic adenocarcinoma. In view of the histogenetic affinity between the pancreas and the biliary tract, and several case reports describing the efficacy of gemcitabine in advanced gallbladder or cholangiocellular carcinoma, a number of phase II investigations have been undertaken. In the majority of these trials a conventional gemcitabine dose regimen of 1,000 to 1,200 mg/m(2) given over 30 minutes on 3 consecutive weeks followed by a week of rest has been used. In a total of seven studies involving 167 assessable patients, objective response rates up to 60% (36% in the largest trial composed of 39 evaluable patients), abrogation of progressive disease (complete response + partial response + stable disease) in 50% to 93%, and overall survival times ranging from 6.3 to 16 months, have been reported. The consensus is that the tolerance of treatment was remarkable with only exceptional patients (< or = 5%) experiencing grade 4 hematologic toxicities. Nonhematologic side effects were infrequent and almost exclusively mild to moderate. In three of the trials, a formal clinical benefit analysis was included, suggesting that a considerable proportion of symptomatic patients will experience relief of tumor-related symptoms and/or weight gain. Possible options currently being investigated to further improve the therapeutic results of gemcitabine monotherapy include modifications of the dose regimen as well as combinations with other potentially synergistic anticancer drugs. In the latter approach, preliminary data have been reported for gemcitabine plus cisplatin, oxaliplatin, docetaxel, mitomycin-C, and continuous-infusion 5-fluorouracil/leucovorin. Objective response rates as high as 53% (for gemcitabine/cisplatin), and median survival times > or = 11 months with only a slight increase in frequency and severity of side effects have been reported. In conclusion, while the best available chemotherapeutic treatment for advanced biliary tract cancer remains to be determined, accumulating data from recent phase II trials suggest that single-agent gemcitabine represents an active and very well-tolerated treatment option. It may also be safely combined with other drugs, though further improvements in response activity and survival warrant confirmation in future randomized studies. Copyright 2002, Elsevier Science (USA). All rights reserved.