Gallbladder and Biliary Tract Carcinoma: A Comprehensive Update, Part 2

Palliative Chemotherapy

Patients with cholangiocarcinoma or gallbladder carcinoma typically present late in the course of their disease and often are not candidates for curative surgical resection. In cases where surgical intervention is not warranted, palliative chemotherapy has been used to diminish symptoms and possibly to extend survival.

Only one large randomized trial has addressed the role of palliative chemotherapy in advanced biliary tract cancer. Glimelius et al randomized patients with pancreatic cancer and biliary tract cancer to a regimen of 5-FU/leucovorin with or without etoposide(Drug information on etoposide), or best supportive care, and evaluated these strategies for disease response and quality-of-life indicators. Of 90 enrolled patients, 37 had advanced biliary tract carcinoma. Marked although short-term improvements in survival (6.5 vs 2.5 mo) and quality of life (measured with the European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30 instrument) were noted in the treatment group, establishing a role for palliative treatment in unresectable disease.[31,32]

Several phase I and II trials, as well as numerous case and series reports, have assessed the efficacy and toxicity profiles of various chemotherapy regimens in the palliative treatment of biliary tract tumors. A variety of single-agent and multiagent chemotherapy regimens have yielded modest results in palliating patients with advanced carcinomas. Response rates have ranged from 0% to 47%. No consensus has been reached regarding standard of care.

Many drugs including 5-FU/leucovorin, cisplatin(Drug information on cisplatin), oxaliplatin(Drug information on oxaliplatin) (Eloxatin), carboplatin(Drug information on carboplatin) (Paraplatin), mitomycin(Drug information on mitomycin) C (Mutamycin), doxorubicin, interferon-alfa 2b (Intron A), gemcitabine (Gemzar), epirubicin(Drug information on epirubicin) (Ellence), capecitabine(Drug information on capecitabine) (Xeloda), irinotecan(Drug information on irinotecan) (Camptosar), and docetaxel(Drug information on docetaxel) (Taxotere) continue to be evaluated alone and in combination for the treatment of advanced biliary cancer. While the results of these phase II trials do not permit conclusive recommendations for a particular regimen, they do indicate that progression of advanced carcinoma of the biliary tract can in many cases be temporarily controlled. Partial responses consistently ranging from 10% to 30% and disease stabilization rates from 10% to 50%, as well as improving median time to progression and median overall survival time, indicate that investigation of palliative treatment warrants continued attention.

This section summarizes recent phase I and II trials in the management of biliary tract tumors. Small sample sizes in each trial and the small number of trials preclude the development of statistically significant findings in cross-study analyses. Furthermore, studies seldom examine identical dosing and delivery schedules, making cross-study comparison difficult. However, analyzing the results of these trials can provide guidance in the clinical management of patients and suggest new avenues for investigation.

5-FU/Leucovorin

Either in combination or as a single agent, 5-FU has been used in the management of biliary carcinomas for almost 30 years. Single-agent studies have met with variable success. From 1974 to 1994, four small studies (enrolling between 7 and 30 patients) investigated the efficacy of singleagent 5-FU. Response rates ranged from 0% to 24% in a total of 78 patients.[31]

TABLE 3
Trial of Fluorouracil(Drug information on fluorouracil)/Leucovorin Treatments

Table 3 summarizes the results of the Glimelius et al randomized trial and three additional 5-FU/leucovorin trials.[32-35] Response rates in these trials appear better than those reported for 5-FU alone.[32] The toxicity of 5-FU/leucovorin regimens is tolerable and easily managed. Grade 3/4 toxicities have included mucositis, diarrhea, hematologic toxicity, asthenia, and abdominal pain.

5-FU Combination Regimens

TABLE 4
Fluorouracil Combination Regimens

Given the poor responses with 5-FU/leucovorin alone, investigators have evaluated 5-FU-based combinations in a number of phase I and II clinical trials. These trials are summarized in Table 4.[36-47] Outcomes have been mixed, with partial response rates ranging between 0% and 64% and disease stabilization rates from 0% to 50%. Complete responses have been rare. Reported median time to progression ranges from 3 to 10 months, while reported median survival ranges from 5 to 32 months.

5-FU and Mitomycin—Single-agent mitomycin has been used in several trials, with response rates ranging from 0% to 47%.[31] The FAM regimen (5-FU, doxorubicin(Drug information on doxorubicin) [Adriamycin], mitomycin) demonstrated a disease control rate (complete and partial responses plus disease stabilization) of 81%.[36] Unfortunately, other mitomycin-based trials have shown unacceptable toxicity. A trial of mitomycin, 10 mg/m² every 8 weeks, together with weekly 5-FU at 2,600 mg/m² plus leucovorin at 150 mg/m² was stopped after treatment-related deaths exceeded 10% in the first 25 patients.[48] Given the potential toxicity of mitomycin and the availability of other agents, further investigation of mitomycin regimens is probably not warranted.

5-FU and Platinum—Cisplatin has minimal activity as a single agent against biliary tract carcinomas.[31] The combination of 5-FU and cisplatin has been assessed in several trials with variable success. An overall response rate of 24% was attained in a 25-patient trial evaluating 5-FU, 1,000 mg/m² intravenous infusion daily for 5 days, plus a 1-hour infusion of cisplatin, 100 mg/m² on day 2.[37] The PIAF regimen (cisplatin, interferon alfa-2b(Drug information on interferon alfa-2b), doxorubicin, 5-FU) produced response rates of 35% and 9.5% in 19 gallbladder carcinoma patients and 22 cholangiocarcinoma patients, respectively. Although the median survival of 14 months was encouraging, the significant toxicity profile of PIAF, which included grade 3/4 neutropenia (41%), nausea and vomiting (34%), thrombocytopenia (20%), and anemia (15%), precludes future use.[38] In addition, it is impossible to discern the contribution, if any, of interferon in this regimen.

Gemcitabine as a Single Agent

TABLE 5
Trials of Gemcitabine(Drug information on gemcitabine) as a Single Agent

Gemcitabine is a deoxycytidine analog related to cytarabine(Drug information on cytarabine) with demonstrated success in the palliative treatment of patients with advanced pancreatic cancer.[49] Hence, clinical investigators were eager to develop this agent in the treatment of biliary tract neoplasms. A number of small clinical trials summarized in Table 5 have examined the palliative effects of gemcitabine on biliary tract carcinomas.[42,50-57]

In general, gemcitabine therapy has produced moderate disease-control rates, time to progression, and median survival. These trials have shown objective response rates up to 60%, with disease-control rates ranging from 50% to 93%.[42,57,58] Clinical benefit with relief of tumor-related symptoms and weight gain has also been attained in more than 60% of evaluable patients.[51,52]

A unique schedule consisting of larger gemcitabine doses (2,200 mg/m² as a 30-minute infusion every 2 weeks for 6 months) was administered to 30 patients with biliary tract tumors. The partial response and disease stabilization rates were 22% and 44%, respectively. Median time to progression and median overall survival were 5.6 and 11.5 months.[57] The tolerance was excellent, with minimal myelosupression despite the increase in dosage. These results with gemcitabine are comparable to, or better than, those achieved with 5-FU/leucovorin. Single-agent gemcitabine treatments are remarkably well tolerated and result in encouraging progression-free and overall survivals. Grade 3/4 hematologic toxicity is rarely observed, with thrombocytopenia the most common event, affecting 0% to 18% of patients.

Gemcitabine in Combination Regimens

TABLE 6
Trials of Gemcitabine in Combination Regimens

Table 6 summarizes the dosing schedules and outcomes of 12 phase II trials of gemcitabine-based combinations.[55,59-73] Gemcitabine has been combined with 5-FU, docetaxel, irinotecan, cisplatin, and capecitabine. The efficacy of combination treatments has varied, but some of these phase II trials have shown encouraging activity as compared with single-agent gemcitabine. Several of these trials have been associated with improved survival outcomes of 11 months. However, in order for these regimens to be acceptable in clinical practice, they need to demonstrate tolerable toxicity profiles and reproducible survival benefits.

Gemcitabine and Cisplatin—Gemcitabine/cisplatin regimens have been well tolerated with few grade 4 toxicities. Response rates have ranged from 47.6% to 57% and disease stabilization rates from 28% to 41%.[60-62] The efficacy of this combination needs to be further assessed in larger randomized trials.

Gemcitabine and Capecitabine—Single-agent capecitabine at a dosage of 2,000 mg/m²/d has been evaluated in a study of 26 patients with biliary and gallbladder cancers.[74] A 50% response rate and 1-year overall survival rate of 70% was attained. These encouraging outcomes prompted studies of capecitabine-based combination regimens. In one such trial, gemcitabine at 1,000 mg/m² on days 1 and 8 and capecitabine at 650 mg/m² po bid on days 1 to 14 was administered every 21 days.[63] Of 15 patients assessable for response, 33% attained a partial response and 33% had stable disease. The regimen was well tolerated, with less than 5% of patients developing grade 3/4 toxicity.

Gemcitabine and Irinotecan—The combination of gemcitabine at 1,000 mg/m² and irinotecan at 100 mg/m² on days 1 and 8 every 21 days has been evaluated in a small trial including 13 patients.[64] Objective responses were observed in 18.2% of patients, with stable disease in 54.5%. Grade 3/4 toxicities were rare and tolerable. The regimen appears to be feasible in the treatment of biliary cancers, but it is not clear whether irinotecan adds appreciably to treatment with gemcitabine alone.[64]

Gemcitabine and 5-FU—Two trials have examined the efficacy of gemcitabine/ 5-FU combinations for the treatment of biliary tract tumors. Gemcitabine at 1,000 mg/m² followed by 5-FU at 500 mg/m² once a week for 3 weeks on a 4-week cycle has been evaluated in nine patients; three experienced a partial response.[59] Gemcitabine at 1,000 mg/m² in combination with 5-FU/leucovorin has been evaluated in 42 patients.[65] Patients were treated on days 1, 8, and 15 of 4-week cycles, and partial responses were attained in 9.5% of patients. Median time to progression and median overall survival were 3.8 and 6.8 months, respectively. The combination was well tolerated, with few grade 3/4 toxicities. Based on these data, however, the combination of 5-FU and gemcitabine appears to have little benefit.

Gemcitabine and Docetaxel—On the basis of the activity and safety profile of gemcitabine plus docetaxel in non-small-cell lung cancer, a phase II study of this combination administered weekly was conducted in 43 patients with unresectable biliary tract cancers.[66] A 9% partial response rate, 53% disease stabilization, and median overall survival of 11 months were attained with this welltolerated combination. The regimen is undergoing further investigation in a randomized multicenter study.

Gemcitabine, 5-FU/Leucovorin, Irinotecan, and Cisplatin—The novel combination known as G-FLIP (gemcitabine, 5-FU bolus plus infusion, leucovorin, irinotecan, and cisplatin [Platinol]) makes use of clinical evidence of known sequence-dependent synergy among these four drugs, while avoiding known sequence-dependent toxicity.[75] A phase I study included five patients with gallbladder cancer; three achieved a partial response.[67] The regimen was welltolerated, with largely hematologic toxicities consisting of anemia (9%), thrombocytopenia (9%), neutropenia (19%), and neutropenic fever (14%). These results require further evaluation in a phase II study in gallbladder cancer patients.

Other Gemcitabine-Based Combinatons—Some multidrug combinations, especially those with cisplatin and gemcitabine, show improved activity compared with single-agent gemcitabine. Most combinations have been well-tolerated and have produced improved response rates, but survival outcomes from randomized multicenter trials are lacking. Thus, while activity and survival outcomes are encouraging, definite confirmatory randomized trials are warranted before they can be recommended outside of a clinical trial.

New Anticancer Agents

TABLE 7
New Anticancer Agents Being Studied in Advanced Biliary and Gallbladder Cancers

Table 7 shows the results of clinical trials with several new anticancer agents being studied in advanced biliary and gallbladder cancers.[74,76-78] Dowlati et al reported an 11.1% partial response and 33.3% disease stabilization in 27 patients treated with the antitumor antibiotic rebeccamycin analog.[76] Rebeccamycin analog has both topoisomerase I and II activity and DNA intercalating properties. The 6-month survival rate in this study was 76%, with a median survival of 10 months. Grade 3/4 toxicity consisted of neutropenia (52%), thrombocytopenia and anemia (28%), and neutropenic fever (11.1%).[76]

An ongoing study by Philip et al involves 30 patients with advanced biliary carcinoma being treated with the epidermal growth factor receptor inhibitor erlotinib (Tarceva). To date, only toxicity data are available and only 4% grade 3/4 toxicity with nausea/ vomiting has been noted. Efficacy data are pending.[77]

Ueno et al recently reported preliminary data on the use of S-1 in 19 patients with advanced biliary and gallbladder cancers.[78] S-1 is a new oral anticancer agent that contains tegafur(Drug information on tegafur) (a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine (dihydropyrimidine dehydrogenase inhibitor), and potassium oxonate (orotate phosphoribosyl transferase inhibitor). A total of 21% of patients treated with 40 mg/m² bid for 28 consecutive days in 6-week cycles experienced a partial response and 47.4% had disease stabilization, with few grade 3/4 toxicities. Median overall survival was over 8 months. S-1 seems to be welltolerated and active in this disease and will be examined in a larger phase II trial.

Conclusions

Complete surgical resection is the only hope for cure in both gallbladder and cholangiocarcinomas. While a simple cholecystectomy is usually curative for T1 gallbladder tumors, radical cholecystectomy is required for T2 and more invasive lesions. Radical resection should be considered for stage I-III gallbladder carcinomas. Complete tumor resection for cholangiocarcinoma, including partial hepatectomy for hilar carcinomas, is necessary to achieve long-term survival.

Adjuvant radiotherapy with or without concurrent 5-FU and mitomycin may improve survival, especially in gallbladder tumors resected with microscopic residual disease. Large randomized prospective studies on the use of adjuvant therapy are lacking, and any recommendations are based on small studies and metaanalyses. Liver transplantation can provide long-term survivals for cholangiocarcinomas less than 1 cm in diameter but cannot be recommended routinely for all biliary tract tumors due to the high rate of recurrence and postoperative mortality.

Although advances in imaging techniques have improved preoperative diagnosis, most patients are diagnosed late and are not candidates for curative resection. Palliation in these patients includes relief of biliary obstruction with endoscopic or percutaneous stent placement as well as palliative chemotherapy, which improves both survival and quality of life. Gemcitabine probably offers the most favorable single-agent profile with respect to disease response and toxicity. Trials of gemcitabine/cisplatin combinations offer encouraging results and a tolerable toxicity profile. Other combinations including gemcitabine plus capecitabine or docetaxel seem promising but await confirmatory data from larger trials. Until conclusive disease-specific phase III data become available, single-agent therapy with gemcitabine is a reasonable standard of care for palliation of biliary tract tumors.

Financial Disclosure: Dr. Kozuch receives grant support from Pfizer (irinotecan) and Sanofi-Synthelabo.