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Abbreviation: 0R, objective response.

Abbreviation: 0R, objective response.

Reported response rates of combination schedules are not very much better, except perhaps for infusional 5-FU-leucovorin-cisplatin combinations, with reported response rates of 19 (29) to 30% (30), however at the expense of increased toxicity. This increase in toxicity was clearly demonstrated in a randomized trial of European Organisation for Research and Treatment of Cancer (EORTC) with high-dose infusional 5-FU in one arm (n = 27 patients) and high-dose infusional 5-FU and leucovorin and cisplatin in the other arm (n = 26 patients). Overall response rate was 7% in the arm with 5-FU alone and 19% in the combined arm. However, there was one toxic death is this arm confirming that cisplatin in combination with 5-FU and leucovorin has a higher activity than 5-FU alone but is more toxic (31). A phase II trial of combined 5-FU, leucovorin, and oxaliplatin in 16 patients with advanced biliary tract adeno-carcinomas showed a disease control rate of 56% and a median overall survival of 9.5 months (32,33). However, capecitabine-based combinations with cisplatin or oxaliplatin have given rather encouraging results with 21% and 23% response rates, respectively (33,34).

Extrapolating results obtained in pancreatic carcinoma, gemcitabine has been evaluated in different phase II trials, with a favorable toxicity profile, response rates of 8% to 60%, and overall survival times from 6.3 to 16.0 months (23). Possible options currently being investigated to further improve these results include modifications of the dose regimen (in particular, fixed dose rate infusion) as well as combinations with other potentially synergistic anticancer drugs (23). The combination of gemcitabine and irinotecan has given encouraging results in a very small phase II trial in 14 patients, with two objective responses (14%) (35). The combination of gemcitabine plus capecitabine has given interesting response rates of 24% in 16 patients with gallbladder carcinoma and 36% in 19 with cholangiocarcinoma (36). After these promising initial results, the same combination of gemcitabine plus cisplatin has recently given a somewhat disappointing response rate of 21% in a phase II trial of 42 patients, but an encouraging median overall survival exceeding nine months (34,37).

These results have been confirmed in a recent British randomized study: patients were randomized to receive either gemcitabine as a monotherapy or gemcitabine plus cisplatin. Eighty-six patients were included with metastatic or locally advanced diseases (38). Around 25% of the patients had gallbladder carcinoma in each arm. Severe lethargy was more frequently observed in the group of patients receiving gemcitabine plus cisplatin (29% vs. 9%). Seventy-six percent of tumor growth control was observed when combination therapy was given versus 58% with gemcitabine alone (evidence level 1b). Time to progression was also increased to eight months versus four months. An objective response rate of 27.5% has been previously observed with the same combination in a single-arm phase II trial including 40 assessable patients (I gallbladder carcinoma, 39 cholangiocarcinomas) (39).

However, the need for hyperhydration to prevent cisplatin nephrotoxicity and subsequent impairment of quality-of-life limits the use of this combination. At variance from cisplatin, oxaliplatin abrogates the need for such hyperhydration, has a more favorable safety profile, and can be administered to patients with hepatic dysfunction. In combination with gemcitabine, oxaliplatin has given very encouraging results in a phase II trial of 33 patients, with a response rate of 35%, and a remarkably long overall survival of 14.3 months (evidence level 2b) (40). An European multicentric evaluation of the same regimen has given less encouraging results with 12% of response in 70 patients (41).

Hepatic arterial chemotherapy is theoretically an attractive approach in patients with biliary tract neoplasms, as the biliary tree depends predominantly on the hepatic artery for its blood supply. However, high response rates (up to 44%) reported in the few short studies available are counterbalanced by short median survival times and durations of response, and because of the patterns of relapse, this approach is unlikely to replace systemic chemotherapy entirely (1).

Regarding results of recent phase II trials, it seems that gallbladder carcinomas and chol-angiocarcinomas have different sensitivities to various drugs of chemotherapy. (Figs 1-3) Combination therapy with gemcitabine and capecitabine was more active in cholangiocarcino-mas than in gallbladder tumors: 19 months of overall survival versus 6.6 months (42). The same was observed with combination of gemcitabine and oxaliplatin which gave 6.2 months of overall survival in 25 patients with gallbladder carcinoma, versus 11.2 months in 35 patients with other cholangiocarcinomas (41). On the other hand, combination chemotherapy with

FIGURE 1 Gallbladder tumor with major heterogeneous thickening of the wall of gallbladder {white arrow).

capecitabine and oxaliplatin has given opposite results with 27% of objective response and 12.8 months of overall survival in 27 patients with gallbladder carcinoma, versus 0% of objective response and 5.8 months of overall survival in 18 patients with intrahepatic cholangiocarci-noma. Efficacy in extrahepatic cholangiocarcinoma was similar to that observed in gallbladder tumors. An innovative approach using percutaneous transhepatic biliary drainage tube coated with carboplatin has been evaluated. Five patients have been treated with these tubes for four months. Overall efficacy rate was 60%, but no confirmatory data have been published (43).

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